Antioxidants doi: 10.3390/antiox15101333

Authors: Yusong Zhang Hongxia Long Li Qiao Huiling Zhang Dingyuan Chen Jingjing Chen Bo Wei Wei Li Haiyan Zhou

Oxidative stress is a major contributor to cardiomyoblast injury and cardiovascular disease progression. Huperzine A (HupA), a natural Lycopodium alkaloid, exhibits antioxidant and anti-inflammatory properties, but its cardioprotective mechanisms remain unclear. This study aimed to investigate the effects of HupA on oxidative stress-induced H9c2 cardiomyoblast injury and elucidate the underlying molecular mechanisms. Network pharmacology, molecular docking, molecular dynamics simulations, and cellular thermal shift assay (CETSA) were integrated to predict and investigate AKT1 involvement. An in vitro model of tert-butyl hydroperoxide (tBHP)-induced injury in H9c2 rat cardiomyoblasts was established. Oxidative stress status, mitochondrial function, and AKT-associated signaling were evaluated. The involvement of AKT signaling was examined using MK-2206. HupA significantly improved cell viability in a dose-dependent manner and markedly reduced lipid peroxidation and intracellular and mitochondrial ROS accumulation. In addition, HupA restored antioxidant defenses by increasing superoxide dismutase activity and glutathione levels. Mitochondrial dysfunction induced by tBHP was effectively alleviated, as evidenced by preserved mitochondrial membrane potential and reduced mitochondrial superoxide production. Furthermore, HupA enhanced AKT phosphorylation and MCL-1 expression while inhibiting extracellular HMGB1 release. Importantly, pharmacological inhibition of AKT largely abolished these protective effects, including antioxidant restoration, mitochondrial preservation, and anti-cell death activity. HupA protects H9c2 cardiomyoblasts against oxidative injury through AKT-associated survival signaling, thereby attenuating oxidative stress and preserving mitochondrial integrity. These findings suggest HupA as a promising therapeutic candidate in H9c2 cardiomyoblasts under oxidative stress conditions.

Antioxidants doi: 10.3390/antiox15101331

Authors: Ha-il Jung Myung-Sook Kim Eun-Jin Lee Tae-Gu Lee Theint Thandar Latt Jinwook Lee Chaw Su Lwin Bok-Rye Lee

Arsenic (As) contamination poses a serious threat to rice production and food safety. Although sulfur (S) nutrition is known to alleviate As toxicity through thiol-based detoxification, the mechanisms underlying the relationship between S-induced As accumulation and tolerance remain poorly understood. We investigated the effects of contrasting S levels (0, 1, and 4 mM) on As accumulation, translocation, oxidative stress responses, thiol metabolite pools, and mineral nutrient profiles in hydroponically grown rice seedlings exposed to 15 µM As for 15 days. S supplementation alleviated As-induced growth inhibition in a dose-dependent manner despite increasing total As accumulation in both roots and shoots, demonstrating that S-mediated tolerance is independent of reduced As accumulation. Elevated S supply reduced oxidative stress markers (O2•–, H2O2, and MDA), while markedly enlarged the pools of γ-glutamylcysteine (γ-EC), glutathione, and phytochelatins (PCs), particularly in roots. S supplementation also improved the uptake of major essential nutrients, including nitrogen and potassium in shoots, while selectively modulating micronutrient distributions under As stress. Correlation analysis showed that root As content was strongly and positively correlated with γ-EC and PC2–PC4, and principal component analysis separated the treatments along the S gradient in both roots and shoots. Collectively, these results suggest that S enhances As tolerance in rice seedlings through thiol-dependent detoxification, thereby decoupling As tolerance from As accumulation rather than by restricting As accumulation.

Antioxidants doi: 10.3390/antiox15101332

Authors: Hafiz Abdul Kareem Sana Saleem Muhammad Bilal Hafeez Naeem Ahmad Da-Chuan Yin

Soil salinity and drought can restrict oxygen availability in the root zone, adding hypoxic stress to the ionic, osmotic, and hydraulic constraints experienced by crops. Nanobubble (NB) water offers a chemical-free approach for delivering highly dispersed oxygen and sustaining dissolved oxygen during irrigation. This review connects the physicochemical behavior of NBs with plant responses to salinity- and drought-associated hypoxia. It examines restoration of aerobic respiration and ATP homeostasis, modulation of ethylene response factor group VII and hypoxia-responsive gene signaling, recovery of ion transport and aquaporin function, redox regulation, hormonal cross-talk, and rhizosphere microbiome responses. Evidence from rice, maize, wheat, cotton, and controlled-environment systems is evaluated alongside opportunities for nanoparticle co-delivery, nanofertilizers, seed priming, and sensor-guided irrigation. The review also outlines how transcriptomics, proteomics, metabolomics, epigenomics, ionomics, and phenomics can resolve NB-mediated mechanisms across the plant–soil continuum. Current evidence supports NB irrigation as a promising precision-aeration platform, but field-scale validation, standardized NB characterization, dose–response studies, energy and cost assessments, and long-term environmental safety analyses remain necessary before broad agricultural deployment.

Antioxidants doi: 10.3390/antiox15101330

Authors: Yanlu Yu Boyuan Liu Jing Wu Ji Wu Linguo Sheng Tao Xu Yuqi Wang Shuangchi Liu Roman A. Surmenev Kai Zheng Bin Xue

Partial hepatectomy (PH) causes bleeding and oxidative stress, which can slow early liver recovery. To address this, we made cerium-doped bioactive glass fibers (Ce-BGFs) using sol–gel electrospinning. We tested these fibers both in vitro and in a 70% PH mouse model. The fibers showed sustained ion release and lowered H2O2-induced ROS in hepatocytes. In vivo, Ce-BGFs lowered hepatic ROS fluorescence on postoperative day 1 compared to untreated PH controls (4.17 ± 1.20 vs. 34.52 ± 1.47). Serum AST levels decreased (66.42 ± 15.93 vs. 89.62 ± 16.66 U/L). Ce-BGFs also reduced blood loss (0.039 ± 0.016 vs. 0.102 ± 0.038 g) and bleeding times (13.67 ± 3.21 vs. 37.00 ± 1.73 s). By day 3, we observed more Ki67-positive cells, suggesting better early hepatocyte proliferation (3.92 ± 1.25% vs. 1.14 ± 0.29%). However, liver-to-body weight ratios were not significantly different at this stage. Proteomic profiling showed enrichment in pathways for oxidative stress, inflammation, and pentose phosphate metabolism. Ce-BGF treatment also led to time-dependent cytokine changes and helped preserve liver glycogen after PH. In addition, the PAS-positive area at postoperative day 1 was higher with Ce-BGF treatment than with untreated PH (10.27 ± 1.31% vs. 3.50 ± 1.03%), indicating greater hepatic glycogen preservation. These results show that Ce-BGFs provide local hemostasis and are associated with reduced oxidative stress, attenuated liver injury, enhanced early hepatocyte proliferation, and greater glycogen preservation after PH.

Antioxidants doi: 10.3390/antiox15101329

Authors: Jianming Xing Peng Ji Xintong Gu Shuoxi Guo Meilun Wang Xushuang Jia Jiaqi Chen Junjie Chang Xiaohan Cui Ye Jin Haicheng Gao Da Liu

Cryptotanshinone (CTS), a bioactive diterpenoid extracted from Salvia miltiorrhiza Bunge, has long been recognized as a traditional Chinese herbal compound. This study reveals that CTS exerts potent anti-hypertrophic effects against angiotensin II (Ang II)-induced cardiac hypertrophy by targeting Sirtuin 3 (SIRT3)-mediated epigenetic and mitochondrial pathways. In both in vitro and in vivo models, CTS ameliorated pathological hypertrophy, oxidative stress, inflammation, and apoptosis. Mechanistically, CTS upregulated SIRT3, reducing histone H3K9 acetylation (H3K9ac) and restoring mitochondrial dynamics by balancing fission (DRP1) and fusion (MFN2) proteins. Genetic ablation of SIRT3 exacerbated hypertrophy and mitochondrial dysfunction, while pharmacological inhibition with 3-TYP abolished CTS benefits. These findings elucidate CTS as a therapeutic candidate for cardiac hypertrophy by activating SIRT3, which is accompanied by reduced H3K9ac and restored DRP1/MFN2 balance, highlighting potential in cardiac hypertrophy treatment.

Antioxidants doi: 10.3390/antiox15101328

Authors: Kunhuan Yang Chaofeng Yu Danxue He Lei Tao Bo Yang Yuling Chen Jingmeng Chen Yalin Wu

Impaired clearance of all-trans-retinal (atRAL) during the visual cycle leads to retinal degeneration, which is closely associated with autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (dry AMD). Transient activation of activating transcription factor 4 (ATF4) generally supports cellular adaptation to stress, whereas excessive ATF4 expression or prolonged activation can become maladaptive and promote oxidative and metabolic disturbances. Here, we reported that activation of ATF4 promoted atRAL-induced photoreceptor damage through mitochondria-caspase/DNA damage-dependent apoptosis and gasdermin E (GSDME)-dependent pyroptosis and apoptosis, and identified ATF4 as an upstream transcriptional regulator of GSDME. Genetic ablation of Atf4 or pharmacological attenuation of ATF4 signaling with the integrated stress response inhibitor ISRIB visibly preserved the viability and morphology of atRAL-treated 661W cone photoreceptor cells. Both interventions lowered GSDME N-terminal fragment (GSDME-N) abundance, decreased intracellular and mitochondrial reactive oxygen species (ROS) production, and blunted damage to mitochondria and DNA. Notably, pharmacologically suppressing ATF4 expression in the neural retina effectively prevented retinal function loss and structural injury as well as photoreceptor apoptosis and pyroptosis in light-exposed Abca4−/−Rdh8−/− mice, which exhibit severe defects in atRAL clearance and recapitulate key features of STGD1 and dry AMD. Our findings demonstrate that ATF4 is a critical mediator of atRAL-induced retinal atrophy, suggesting that ATF4 inhibition represents a promising therapeutic strategy for STGD1 and dry AMD.

Antioxidants doi: 10.3390/antiox15101327

Authors: Kübra Öğüt Ana M. Troncoso María del Carmen García-Parrilla Gülmira Özek Okan Sezer Temel Özek

This study aimed to provide the first comprehensive seed-based phytochemical and biological investigation of Onosma onur-koyuncui Sezer, a species endemic to Türkiye, by characterizing its chemical composition and evaluating its in vitro antioxidant and enzyme inhibitory potential. A multi-technique approach combining SPME-GC-FID/MS, GC-FID/MS after silylation, ICP-OES, and UHPLC-HRMS/MS was applied to n-hexane and 70% aqueous methanol seed extracts, together with total phenolic and flavonoid determinations, complementary antioxidant assays, and α-amylase inhibition. p-Cymene (15.00%) was the major volatile, octadecatrienoic acid (27.77%) predominated in the fatty acid profile, and calcium (28.50 mg/gdw) was the most abundant mineral. UHPLC-HRMS/MS revealed chlorogenic acid (51.29 mg/gdw) and diosmetin (42.95 mg/gdw) as major constituents of the 70% aqueous methanol extract. This extract showed the highest phenolic and flavonoid contents and notable antioxidant activity, particularly in the DPPH assay (IC50 = 0.043 mg/mL), exceeding that of BHA (IC50 = 0.118 mg/mL), and exhibited α-amylase inhibition (IC50 = 0.40 mg/mL). These findings provide the first integrated characterization of O. onur-koyuncui seeds and highlight their phytochemical diversity and antioxidant potential.

Antioxidants doi: 10.3390/antiox15101326

Authors: Jianjun Guo Liang Yao Jiahao Liu Huanhuan Liu Qin Li Zishan Li Yinghao Li

Calcium oxalate (CaOx) nephrolithiasis is closely associated with crystal-induced oxidative injury, impaired antioxidant defenses, and enhanced crystal retention in renal tissues. Nephrolepis cordifolia is a medicinal fern traditionally used for urinary tract-related disorders and edema, but its antioxidant-related protective activity against CaOx nephrolithiasis has not been systematically investigated. In this study, ethanol and water extracts of Nephrolepis cordifolia tubers were evaluated using CaOx crystallization assays, HEK293T cell-based oxidative stress assays, and a glyoxylate-induced mouse model. The extracts inhibited CaOx crystal growth and aggregation and shifted SEM-observed crystal morphology from calcium oxalate monohydrate-like aggregates toward less adhesive calcium oxalate dihydrate-like forms. FTIR spectra further indicated extract-associated changes in the structural and hydration characteristics of the resulting CaOx crystals. In cells, the extracts showed good cytocompatibility and reduced intracellular reactive oxygen species. In vivo, both extracts reduced renal crystal deposition and histopathological injury, restored antioxidant defenses, decreased malondialdehyde accumulation, downregulated CD44 and osteopontin expression, and improved serum and urinary biochemical abnormalities. The water extract generally produced stronger protection than the ethanol extract. LC–MS profiling of both ethanol and water extracts annotated diverse constituents, including flavonoid-related compounds, glycosides, phenolic constituents, terpenoid-related molecules, and lipid-associated components. These findings indicate that Nephrolepis cordifolia extracts mitigate CaOx nephrolithiasis partly by restoring redox homeostasis and limiting oxidative injury-associated crystal retention.

Antioxidants doi: 10.3390/antiox15101325

Authors: Congyu Wu Yuan Kang Yu Liu Xin Huang Muqing Wang Min Cai Yuan Gao Yun Qi

The NLRP3 inflammasome is a cytosolic pattern-recognition complex that senses sterile and infectious insults and drives innate immune responses. Herein, we identify ponicidin (PON), a natural diterpenoid isolated from Rabdosia rubescens, as an inhibitor of NLRP3 inflammasome activation. In LPS-primed macrophages, PON suppressed IL-1β secretion by inhibiting caspase-1 activation and attenuated nigericin- or ATP-induced pyroptosis, as indicated by reduced LDH release and GSDMD cleavage. Meanwhile, AIM2 inflammasome-mediated IL-1β production was not affected by PON. Mechanistically, PON inhibited ASC oligomerization and speck formation, critical steps in NLRP3 inflammasome assembly. It could reduce mitochondria-derived danger signals related to NLRP3 activation, such as mtROS, mtDNA and ox-mtDNA, without affecting ion fluxes (e.g., K+, Ca2+, Cl−). Consistently, PON preserved the mitochondrial membrane potential and intracellular ATP levels, indicating comprehensive protection of mitochondrial function. In vivo, PON markedly reduced IL-1β levels in peritoneal lavage fluid of MSU-induced peritonitis mice and lowered serum IL-1β, TNF-α, and MCP-1 levels in endotoxemia mice. Collectively, PON alleviates mitochondrial dysfunction to prevent ASC oligomerization and NLRP3 inflammasome assembly, thereby reducing the cleavage of pro-IL-1β and GSDMD. Our findings suggest that PON may be a potential candidate for treating NLRP3 inflammasomopathies.

Antioxidants doi: 10.3390/antiox15101324

Authors: Huijin Jia Qiwei Liu Wanghong Zhang Guangyao Song Jingrong Feng Lanlan Yi Sumei Zhao Junhong Zhu

Oxidative stress constitutes a key restrictive factor that undermines growth performance, reproductive efficiency and meat quality throughout the entire production cycle of commercial pig herds. Vitamin A (VA), an essential fat-soluble nutrient for pigs, fulfills dual antioxidant regulatory functions: it directly scavenges free radicals, and indirectly mediates transcriptional regulation of antioxidant processes via retinoic acid receptor-associated signaling pathways. By integrating recent in vivo feeding trial data and in vitro molecular experimental evidence, this review demonstrates that the antioxidant effect of VA in pigs is characterized by significant stress dependence, dose responsiveness and physiological stage specificity. Under stress challenge conditions, VA can significantly upregulate the body’s antioxidant response, while its regulatory effect is relatively weak under non-stress basal physiological conditions. From the mechanistic perspective, all-trans retinoic acid (ATRA) bound to RAR/RXR receptors can exert synergistic effects with the Nrf2 antioxidant pathway when VA is supplied at physiological nutritional doses, whereas high pharmacological doses of ATRA may induce competitive inhibitory crosstalk. It should be noted that most existing direct promoter-binding evidence is derived from cell line models rather than in vivo porcine tissue samples. For weaned piglets, an optimal dietary VA level can alleviate oxidative damage and intestinal barrier impairment induced by weaning stress, but excessive VA supplementation will trigger lipotoxic oxidative disturbance. In growing-finishing pigs, appropriate VA supplementation can increase glutathione (GSH) content in skeletal muscle and improve the lipid oxidation stability and color stability of pork during post-mortem storage; however, supra-nutritional VA will compete with vitamin E for tissue deposition, which may in turn impair the storage quality of pork. For sows, most existing studies on the reproductive antioxidant effect of VA are derived from intramuscular injection trials, and data from practical dietary VA intervention studies are still insufficient. Existing evidence indicates that maternal VA can regulate the transfer of retinol to offspring via the placenta and colostrum-milk, but no consistent dose-response relationship has been confirmed to date. Meanwhile, relevant research in breeding boars remains extremely insufficient. In terms of nutrient interaction, VA shows antioxidant synergistic effects with vitamin E, vitamin C and selenium, while excessive intake of dietary vitamin D, copper or zinc will reduce the bioavailability of VA and weaken its antioxidant protective effect. Current research in this field is constrained by prominent inter-study heterogeneity, insufficient verification of in vivo molecular mechanisms in pigs, and the absence of antioxidant-targeted VA feeding standards adapted to diverse stress scenarios. The systematic summary of the above findings provides an important reference for the formulation of precision antioxidant nutritional strategies for commercial pig herds. To address the current knowledge gaps, future research should focus on constructing standardized porcine experimental stress models, applying multi-omics technical means to dissect tissue-specific VA antioxidant regulatory networks, clarifying the mechanism of maternal-offspring VA transfer under graded dietary VA intake, and optimizing compatible dosage forms and nutrient combinations adapted to on-farm application scenarios. The advancement of related research will help alleviate production losses caused by oxidative stress and promote the construction of healthy pig production systems.

Antioxidants doi: 10.3390/antiox15101323

Authors: Rongxia Guo Chenghui Jiang Xitong Yin Chun Niu Baoxia Chen Ziwen Yuan Hongjuan Wang Yanming Wei Yongli Hua

Background: Weaning stress induces intestinal oxidative imbalance, barrier dysfunction, and gut microbial disturbances in piglets. ShenQiGan Extract (CAG), a traditional herbal-derived additive, has shown potential antioxidant and intestinal protective properties; however, the underlying mechanisms remain unclear. This study investigated whether CAG protects weaned piglets against oxidative stress through modulation of the gut microbiota–bile acid (BA) axis and antioxidant signaling pathways. Methods: Eighty 28-day-old weaned piglets were assigned to control, 0.1%, 0.5%, or 1.0% CAG supplementation groups for 28 days. Serum antioxidant parameters, intestinal and hepatic histomorphology, bile acid profiles in feces and serum, gut microbiota composition, and intestinal expression of BA metabolism- and Nrf2/Keap1-related molecules were analyzed. Furthermore, HDCA, 7-ketoLCA, and CDCA, identified as differential bile acids associated with CAG supplementation, were evaluated in an H2O2-induced oxidative stress model using IPEC-J2 cells. Results: CAG supplementation improved systemic antioxidant status, intestinal morphology, mucus barrier integrity, and hepatic histological damage in weaned piglets. CAG reshaped the gut microbial community by increasing microbial richness and Lactobacillus abundance, which was associated with alterations in BA profiles, particularly increased HDCA, 7-ketoLCA, and CDCA levels. CAG also regulated intestinal BA metabolism-related molecules, including BA synthesis, transport, and signaling pathways, and activated Nrf2/Keap1 antioxidant signaling. In vitro, HDCA, 7-ketoLCA, and CDCA alleviated H2O2-induced oxidative stress and improved epithelial barrier function, with CDCA showing the most consistent regulatory effects with the in vivo response. Conclusions: CAG supplementation protects weaned piglets against oxidative stress and intestinal barrier impairment by remodeling the gut microbiota–BA axis, regulating BA metabolism, and activating Nrf2/Keap1 antioxidant signaling. Among the identified differential BAs, CDCA may represent an important mediator contributing to the intestinal protective effects of CAG.

Antioxidants doi: 10.3390/antiox15101322

Authors: Gazihan Harun Özsayın Özlem Yorulmaz-Özü Umay Merve Güven Serpil Demirci-Kayiran Yurdun Kuyucu Merve Nenni Gülçin Dağlıoğlu Olcay Kıroğlu Fatma Peyman Ertuğ Murat Türk Burçin Ün Eda Karabal-Kumcu Mehmet Ata Seçilmiş

Gentamicin is an aminoglycoside antibiotic and has therapeutic importance in the treatment of Gram-negative aerobic bacterial infections. However, its clinical use is limited by nephrotoxicity, in which oxidative stress plays an important role. In this study, we investigated the protective effects of Cyclotrichium niveum, an endemic plant with antioxidant properties, against gentamicin-induced nephrotoxicity in rats. Renal injury and protection were assessed using blood urea nitrogen (BUN) and serum creatinine as markers of renal function, malondialdehyde (MDA) as a marker of oxidative stress, and histopathological evaluation of renal cortical injury. We first characterized the chemical composition of C. niveum essential oil (EO) by GC-MS, identifying pulegone as its major constituent (79.6%). Next, we evaluated the in vitro antioxidant activity of EO and isolated pulegone using the DPPH assay. Their protective effects were then examined in vivo at two dose levels each (EO, 200 and 400 mg/kg/day; pulegone, 50 and 100 mg/kg/day, p.o.) in rats receiving gentamicin (100 mg/kg/day, i.m.) for 8 days. Both EO and pulegone exhibited DPPH radical-scavenging activity. Gentamicin induced pronounced renal injury, whereas co-administration of either EO or pulegone provided protection, with more pronounced effects at the higher doses. In particular, gentamicin increased BUN and creatinine 2.74- and 2.37-fold, respectively (p < 0.001 for both), and produced grade 4–5 cortical injury in all histologically evaluated animals. At the higher doses, EO and pulegone reduced BUN by 56% and 64%, respectively (p = 0.042 and p < 0.001), and MDA by 57% and 55%, respectively (p = 0.006 for both). Pulegone additionally reduced creatinine by 39% (p = 0.041). Both treatments significantly improved histopathological injury grade (p = 0.002 and p = 0.008 for EO and pulegone, respectively). Together, these findings demonstrate that C. niveum EO and pulegone attenuate gentamicin-induced renal injury across functional, oxidative, and structural measures, with the strongest protection observed at the higher doses. Their in vitro antioxidant activity and attenuation of lipid peroxidation in vivo support an antioxidant contribution to the nephroprotective response, while the activity of isolated pulegone identifies it as an important bioactive contributor to the protective effects of C. niveum EO.

Antioxidants doi: 10.3390/antiox15101321

Authors: Mert Yüksel Martina Schmidt

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and complex pathogenesis, involving amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation, driven by microglial shifts toward pro-inflammatory M1-like states, causing neuronal dysfunction and death, particularly by ferroptosis. Current diagnostic and therapeutic strategies remain limited, highlighting the need for novel molecular regulators. Circular RNAs (circRNAs) are covalently closed non-coding RNAs (ncRNAs), representing promising regulatory molecules and peripheral biomarkers. Evidence suggests that circRNAs regulate AD-related pathways, through microRNA (miRNA) sponging, including modulation of NF-κB/BACE1-dependent (nuclear-factor-kappa-B/beta-site APP-cleaving enzyme 1) amyloidogenic APP (amyloid precursor protein) processing and through disruption of NMDA (N-methyl-D-aspartate) receptor-dependent synaptic signaling, exemplified by circRIMS2-driven UBE2K (ubiquitin-conjugating enzyme E2K)-mediated GluN2B (glutamate ionotropic receptor NMDA type subunit-2B) degradation. Additionally, circRNAs represent promising non-invasive diagnostic biomarkers. Plasma hsa_circRNA_050263 showed high diagnostic accuracy for early-stage AD. CircRNAs may offer a therapeutic strategy for modulating cell-death pathways, particularly ferroptosis. Selectively targeting EPAC2 (exchange protein directly activated by cAMP2) may preserve EPAC2-associated neuroprotection, while limiting EPAC1-associated ferroptosis, although challenges such as blood–brain barrier delivery remain to be addressed. This review summarizes circRNA biogenesis, diagnostic potential, and roles in AD pathogenesis, and limitations and AD models, besides investigating the selective circRNA–EPAC axis.

Antioxidants doi: 10.3390/antiox15101320

Authors: Cheol-Yeong Yoo Rajasinghe Peli Gedara Sewwandi Kaushalya Amarasiri Sang-Woon Lee Jeong Min Lee Mi-Jin Yim Hyun-Soo Kim

Hairtail (Trichiurus lepturus) is a popular fish species in South Korea that generates substantial quantities of processing byproducts. This study investigated the potential functional properties of hairtail byproducts to enhance their utilization. Proximate composition analysis showed that crude protein was the most abundant component, accounting for approximately half of the total composition. Therefore, protein hydrolysates were prepared from hairtail byproducts using Protamex-assisted enzymatic hydrolysis. The yield of Protamex-assisted enzymatic hydrolysate (HBP) produced based on the raw material drying weight was 42.8%. Amino acid analysis revealed high levels of Aspartic acid and glutamic acid, which can provide instrumental help in muscle synthesis and growth, and free amino acids showed high L-leucine content. HBP also exhibited considerable antioxidant activity. In a dexamethasone-induced C2C12 cell atrophy model, HBP increased cell viability in a concentration-dependent manner, reaching 120.58% at 300 µg/mL. Cell proliferation also increased in a concentration-dependent manner, reaching 125.54% at the same concentration. Immunofluorescence analysis of myosin heavy chain (MyHC) and DAPI staining further indicated concentration-dependent enhancement of muscle cell differentiation. These findings suggest that hairtail byproducts may provide a sustainable source of functional protein hydrolysates with potential protective effects against muscle atrophy in a dexamethasone-induced C2C12 model.

Antioxidants doi: 10.3390/antiox15101319

Authors: Seohee Choi Chae-Young Kim Kayoung Ko Miri Jo Jinhye Kim Isaac Jinwon Yi Sang-Soep Nahm Kiyoung Kim Sun-Shin Yi

Oxidative stress contributes to neuronal injury in Parkinson’s disease (PD), and the cerebellum is increasingly recognized as an affected region. We previously reported that Fetuin-A (alpha-2-HS-glycoprotein) is reduced in cerebellar Purkinje cells in human PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and that silencing it reduces Purkinje cell survival without apoptosis. We asked whether this reduction is pharmacologically modifiable by saffron-derived antioxidant (SDA) and Passiflora incarnata L. extract (PIE). SDA and PIE were administered orally at 50 mg/kg/day for 5 weeks to MPTP-treated C57BL/6J mice, with resveratrol (RES) as a comparator. In 1-methyl-4-phenylpyridinium (MPP+)-challenged primary cerebellar neurons, SDA and PIE were tested at 25 µg/mL and RES at 200 µg/mL. MPTP lowered nigral tyrosine hydroxylase immunoreactivity, grip strength, rotarod performance, Purkinje cell density and cerebellar Fetuin-A and raised cleaved caspase-3, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and Fluoro-Jade C signals. SDA and PIE attenuated all these changes. In vitro, MPP+ raised 2′,7′-dichlorofluorescin diacetate (DCFDA) fluorescence and lowered Fetuin-A, and all three treatments reduced DCFDA fluorescence and restored Fetuin-A. Annexin V/propidium iodide (PI) profiling showed a substantial Annexin V−/PI+ necrotic component at 24 h, consistent with our earlier knockdown data. Cerebellar Fetuin-A emerges as a treatment-responsive correlate of Purkinje cell integrity.

Antioxidants doi: 10.3390/antiox15101318

Authors: John A. Taylor Rahul A. Parikh Qi Chen Benjamin L. Woolbright Ping Chen Junqiang Dai Mihaela Sardiu Joya He Jeanne Drisko

Purpose: Neoadjuvant cisplatin-based chemotherapy (NAC) is considered the standard of care (SOC) for patients with muscle-invasive bladder cancer (MIBC). However, approximately 50% of patients are cisplatin-ineligible (CI) and often proceed directly to surgery. We initiated a phase Ib/IIa trial to evaluate high-dose intravenous ascorbate (IVC) with gemcitabine/carboplatin (Gem/Carbo) as NAC for patients with CI-MIBC (NCT04046094). Patients and Methods: Patients with newly diagnosed CI-MIBC received a single cycle of Gem (1000 mg/m2 D1, 8)/Carbo (AUC 5 d 1) and IVC (25–125 g titrated to 350–400 mg/dL blood concentrations 2 × per week for 21 days) followed by definitive cystectomy. The primary outcome was pathological downstaging (<ypT2N0Mx) at cystectomy. Patient-reported quality of life (QOL) was assessed using the FACT-BI at enrollment, end of treatment, and 6 weeks after cystectomy. Results: Sixteen participants were enrolled, and 12 completed the protocol. The mean age was 76. Pathological downstaging was present in four patients (33%), with 3/4 patients having a pathologic complete response (pCR, ypT0N0Mx). The treatment was well tolerated. At a mean follow-up of 32.3 months (SD 18.9, range 6.6–63.8), four patients without response recurred and died of disease, and three with response had recurred, with one passing from disease. The QOL FACT-Bl did not change from baseline to the end of treatment to 6 weeks post-cystectomy. Conclusions: Neoadjuvant, single-cycle Gem/Carbo + IVC had significant activity in patients with CI-MIBC with a response rate (RR) comparable to historical outcomes of SOC therapy in this early-phase trial. Larger trials are warranted to confirm these findings and to identify biomarkers for response.

Antioxidants doi: 10.3390/antiox15101317

Authors: Xin Li Chuanbin Chen Lihua Li Minfeng Ding Wenyan Zhang Weifen Li Lanjiao Xu Qi Wang

Sanguinarine (SA), a bioactive benzophenanthridine alkaloid, has emerged as a potential alternative to antibiotic growth promoters; however, its effects on intestinal redox homeostasis and epithelial regeneration remain incompletely understood. This study investigated whether dietary SA could improve growth performance and intestinal health in yellow-feathered broilers and explored the potential involvement of gut microbiota-associated metabolite signaling pathways. Broilers were fed diets supplemented with different concentrations of SA (0.5 or 0.7 mg/kg feed), with an antibiotic-supplemented group serving as a comparator. High-dose SA (0.7 mg/kg feed) improved body weight and average daily gain while reducing the feed-to-gain ratio. SA also alleviated intestinal barrier dysfunction, as evidenced by reduced circulating diamine oxidase, D-lactate, and lipopolysaccharide levels, together with increased jejunal expression of tight-junction proteins and MUC2. In parallel, SA enhanced systemic and intestinal antioxidant capacity, as indicated by increased total antioxidant capacity and superoxide dismutase activity and decreased malondialdehyde accumulation. These changes were accompanied by increased immunoglobulin levels, reduced expression of pro-inflammatory mediators, and enhanced expression of anti-inflammatory cytokines. Cecal microbiota analysis demonstrated that SA markedly reshaped the microbial community, with enrichment of Faecalibacterium and depletion of several potentially unfavorable taxa. These microbial alterations, which were associated with improved antioxidant and immune indices, were accompanied by a selective increase in cecal butyrate levels. Consistently, SA enhanced intestinal GPR109A expression and upregulated genes associated with Wnt/β-catenin signaling. In LPS-challenged intestinal organoids, SA restored organoid growth and budding capacity, reduced apoptosis, increased Ki67-positive cell proliferation, and restored the expression of genes associated with Wnt/β-catenin signaling. Collectively, these findings indicate that dietary SA improves growth performance and intestinal homeostasis in broilers by attenuating oxidative stress and inflammation, strengthening epithelial barrier function, and supporting epithelial regeneration. The microbiota-associated butyrate/GPR109A/Wnt/β-catenin signaling pathway may contribute to these protective intestinal effects.

Antioxidants doi: 10.3390/antiox15101316

Authors: Ruolan Ding Li Tan Xitong Zuo Xiaonan Huang Qishen Liang Zhen Hu Yanqiao Li Weilong Shang Wanzhen Xiao Huagang Peng Ziqi Zhang Yuting Wang Zexian Xu Xiancai Rao Yi Yang

Antibiotic-resistant Staphylococcus aureus infections pose a formidable clinical challenge. Cold atmospheric plasma (CAP) has emerged as a promising disinfection technology; however, the underlying bacterial response mechanisms and potential resistance to CAP remain incompletely elucidated. Here, we validated the broad-spectrum and efficient bactericidal activity of CAP against both drug-sensitive and drug-resistant clinical isolates of S. aureus. Mechanistically, CAP primarily eliminated bacteria by inducing oxidative damage to proteins and lipids, thereby disrupting internal cellular structures. The addition of exogenous free radical scavengers significantly attenuated CAP-mediated oxidative killing. Transcriptomic analysis and RT-qPCR validation further revealed upregulation of redox-related genes in S. aureus following CAP exposure. Deletion of key antioxidant genes, particularly ahpC and mrgA, markedly enhanced bacterial susceptibility to CAP. Virtual screening and surface plasmon resonance analysis identified two small-molecular inhibitors, C4515 and A8226, which specifically target AhpC and MrgA, respectively, and potentiated CAP bactericidal efficacy. Collectively, this study delineates the molecular interactions between CAP and S. aureus, and underscores the potential of CAP-based strategies for combating drug-resistant bacterial infections.

Antioxidants doi: 10.3390/antiox15101315

Authors: Beata Krasińska Tomasz Urbanowicz Minseung Kang Siwon Baek Ayoub Kourima Priscilla Clarita Mariusz Kowalewski Giuseppe Maria Raffa Calogera Pisano Piotr Suwalski Ewelina Wojtasińska Łukasz Stryczyński Joanna Kujawska Lidia Gil Zbigniew Krasiński Joanna Rupa-Matysek Andrzej Tykarski

Background: ELAFIN (peptidase inhibitor 3, PI3) is an endogenous inhibitor of neutrophil elastase and proteinase 3, but its circulating profile in type 2 diabetes mellitus (T2DM) and cardiovascular disease remains poorly characterized. We investigated circulating ELAFIN in patients undergoing elective coronary angiography and explored its associations with metabolic, inflammatory, renal, cardiac, and angiographic phenotypes. Methods: Forty-three consecutive clinically stable patients undergoing elective coronary angiography, including nine with T2DM, were prospectively enrolled. Plasma ELAFIN was quantified by ELISA. Associations with clinical and laboratory variables were assessed using non-parametric comparisons, correlation analyses, and parsimonious multivariable regression. Discrimination analyses were considered exploratory. Results: Median ELAFIN was 5.03-fold higher in patients with T2DM than in those without T2DM (31.2 [28.3–36.2] vs. 6.2 [5.5–7.0] ng/mL; p < 0.001; Cliff’s δ = 0.85). The association remained pronounced after adjustment for age, sex, and renal function. ELAFIN was positively correlated with REG3A and creatinine, and inversely correlated with eGFR, whereas no significant associations were observed with angiographic coronary stenosis, LVEF, or NT-proBNP. Conclusions: Circulating ELAFIN was markedly elevated in T2DM and associated predominantly with renal and inflammatory characteristics rather than anatomical coronary disease or left ventricular dysfunction. Because oxidative stress and protease activity were not directly measured, their relationship with ELAFIN remains hypothesis-generating. These findings require validation in larger prospective cohorts.

Antioxidants doi: 10.3390/antiox15101314

Authors: Bingchen Guo Jing Wang Ran Zhao Shaowu Li Di Wang

Polysaccharides play crucial roles in medicine and nutrition, serving as dietary additives that help maintain fish health. This study systematically evaluated the effects of dietary supplementation with plant-derived Lycium barbarum polysaccharides (LBP) and Seaweed-derived polysaccharides (SPs) on growth, metabolism, and immune function in rainbow trout (Oncorhynchus mykiss). A total of 270 juvenile rainbow trout (15.50 ± 0.71 g) were randomly divided into three groups (control group, CG; 1.5 g/kg LBP; 1.5 g/kg SPs), with 90 fish in each group. The feeding trial lasted 56 days, with sampling at days 28 and 56. Compared with CG, SPs increased WGR by approximately 39.4%, decreased FCR by approximately 44.7%, and elevated muscle Ala, Glu, and Gly contents. SPs also improved intestinal microbiota balance and promoted the synthesis of amino acids and short-chain fatty acids (SCFAs). In addition, SPs significantly enhanced CAT and SOD activities and upregulated IL-10 expression by approximately 2.3-fold. Compared with the CG, LBP can reduce the total cholesterol content by 33.3%, inhibit lipid synthesis, and promote fatty acid oxidation. It also upregulates the expression of the PPARα gene by approximately 2.4-fold. In the Aeromonas salmonicida challenge test, survival rates of the SPs and LBP groups were 30% and 20% higher, respectively, than that of CG. These results indicate that SPs were more effective in promoting growth and enhancing immunity, whereas LBP showed superior performance in metabolic regulation. This study provides a basis for the targeted application of these two substances.

Antioxidants doi: 10.3390/antiox15101313

Authors: Vasile Valeriu Lupu Emil Anton Ileana Ioniuc Oana Raluca Temneanu Irina Tarnita Leonard Iosif Pertea Elena Cristina Mitrofan Magdalena Cuciureanu Alice Grudnicki Manuel Florin Rosu Sorana Caterina Anton Costica Mitrofan Silvia Fotea Alin Horatiu Nedelcu Ancuta Lupu

Pediatric obstructive sleep apnea syndrome (OSAS) is a common sleep-related breathing disorder increasingly recognized as a multisystem disease rather than an isolated disorder of the upper airway. Recurrent episodes of upper airway obstruction generate intermittent hypoxia, reoxygenation, and sleep fragmentation, promoting excessive production of reactive oxygen and nitrogen species and disruption of antioxidant defenses. This narrative review summarizes current evidence regarding the mechanisms, biomarkers, and clinical consequences of oxidative stress in pediatric OSAS. Intermittent hypoxia activates several redox-sensitive pathways, including NADPH oxidases, hypoxia-inducible factor-1α, nuclear factor-κB, mitochondrial dysfunction, and endoplasmic reticulum stress, thereby creating a bidirectional relationship between oxidative stress and systemic inflammation. Pediatric studies have demonstrated alterations in lipid peroxidation products, glutathione redox balance, urinary 8-hydroxy-2′-deoxyguanosine, isoprostanes, NOX2-related markers, and inflammatory mediators. These abnormalities are associated with endothelial dysfunction and cardiovascular, neurocognitive, metabolic, hepatic, renal, and immune consequences, and several may improve following effective treatment. Importantly, the magnitude of oxidative and end-organ injury does not consistently parallel the apnea-hypopnea index, suggesting that hypoxic burden, obesity, genetic susceptibility, antioxidant capacity, and disease duration influence individual biological vulnerability. Although several oxidative biomarkers show potential for disease characterization and treatment monitoring, methodological heterogeneity and the absence of standardized pediatric reference values currently limit their clinical application. Future integration of polysomnographic hypoxic-burden metrics with oxidative, inflammatory, metabolomic, and genomic biomarkers may improve risk stratification and facilitate more personalized management of pediatric OSAS.

Antioxidants doi: 10.3390/antiox15101312

Authors: Patryk Wiśniewski Monika Stępniewska Piotr Melion Zuzanna Poloczek Maksymilian Pawluczuk Dawid Chodziński Magdalena Sulewska Małgorzata Pietruska

Background: Oral leukoplakia (OL) is a common oral potentially malignant disorder in which oxidative imbalance and altered trace-element homeostasis may contribute to pathogenesis. This systematic review and meta-analysis evaluated serum/plasma zinc and copper concentrations in patients with OL versus healthy controls. Materials and Methods: Following PRISMA and Cochrane recommendations (PROSPERO: CDR420261427977), PubMed, Scopus, Web of Science, and Cochrane were searched for observational studies comparing circulating zinc and/or copper levels in OL and controls. Study quality was assessed using the Newcastle–Ottawa Scale and certainty of evidence using GRADE. Hedges’ g with 95% confidence intervals (CIs) was pooled. Results: Ten studies including 495 participants were analyzed. Zinc concentrations were significantly lower in OL (8 studies; 431 participants; g = −1.84, 95% CI: −3.25 to −0.43; p = 0.01; I2 = 96.85%), whereas copper concentrations were significantly higher (9 studies; 449 participants; g = 1.20, 95% CI: 0.70–1.70; p < 0.001; I2 = 81.90%). Sensitivity analyses confirmed the direction of both associations. Certainty of evidence was very low. Conclusions: Patients with OL showed lower circulating zinc and higher copper concentrations than healthy controls. Given the substantial heterogeneity and very low certainty of evidence, these findings should be interpreted as group-level differences only and do not establish a specific metabolic, pathogenic, causal, or diagnostic role of Zn or Cu in OL.

Antioxidants doi: 10.3390/antiox15101311

Authors: Adam B. Cohen Janmejay Hingu Abinav Udaiyar Nima Pourhabibi Zarandi Banafsheh Nikmehr Omar A. Abdelaal Nicos Prokopiou Samuel Pendergraft Anthony Atala Colin E. Bishop Stephen J. Walker Hooman Sadri-Ardekani

Oxidative stress driven by environmental and occupational exposure to heavy metals is increasingly recognized as a central, modifiable contributor to male infertility. Yet, the lack of physiologically relevant human models has limited mechanistic insight. We have previously described a three-dimensional Human Testis Tissue Equivalent (hTTE) that recapitulates the cellular composition and stem cell niche of the seminiferous tubule and is more resistant than two-dimensional (2D) culture to gonadotoxic chemotherapeutics. Here, we used the hTTE platform to compare heavy-metal cytotoxicity, cell-type–associated transcript responses, and exploratory microRNA (miRNA) profiles elicited by three prototypical pro-oxidant heavy metals: mercury (Hg2+), thallium (Tl+), and lead (Pb2+). Background and Aim: To determine whether the hTTE model exhibits greater resistance to heavy-metal cytotoxicity than matched 2D cultures and whether cell-type–associated responses differ following heavy-metal exposure within the established redox biology of these toxicants. Methods: Adult human testicular cells from three donors were expanded, characterized by RT-qPCR and flow cytometry, and assembled into hTTEs alongside matched 2D cultures. Cultures were exposed for 48 h to Hg2+, Tl+, or Pb2+ across graded concentrations; IC50 values were derived from ATP-based viability assays and used for selected downstream exposure concentrations. The relative abundances of cell-type–associated transcripts were profiled by digital PCR for ZBTB16 (spermatogonia), STAR (Leydig), SOX9 (Sertoli), and CD34 (peritubular cells), and global miRNA expression was quantified using the NanoString nCounter Human v3b miRNA panel (827 miRNAs). Exploratory Ingenuity Pathway Analysis of miRNA data was used to identify predicted mRNA associations with a testis/reproductive disease filter. Results: hTTEs exhibited significantly greater IC50 values than matched 2D cultures for all three metals (p < 0.05), demonstrating greater resistance to acute heavy-metal cytotoxicity in the hTTE culture system, consistent with enhanced antioxidant buffering in the 3D microenvironment. Metal-associated changes in cell-type marker transcripts were distinct: Hg2+ produced broad reductions in markers associated with all four populations; Pb2+ produced greater reductions in Sertoli and peritubular cell markers while relatively preserving spermatogonial and Leydig cell markers; and Tl+ reduced somatic support cell markers with relative enrichment of spermatogonial (~7-fold) and Leydig cell marker expression. Heavy-metal exposure was associated with exploratory miRNA changes previously linked to redox imbalance, BCL2-mediated apoptosis, MYC/CDKN1A-driven nucleolar stress, AHR/CYP1A1 activation, and EGFR/COX-2 signaling. Conclusions: These findings demonstrate greater resistance of the hTTE culture system to acute heavy-metal cytotoxicity and suggest metal-specific differences in testicular cell-type responses. Within the established redox biology of Hg2+, Tl+, and Pb2+, the observed patterns provide a framework for investigating oxidative stress mechanisms directly in a human-relevant testicular model. This system may provide a platform for future studies incorporating direct redox measurements and antioxidant rescue strategies.

Antioxidants doi: 10.3390/antiox15101310

Authors: Chan Li Kexin Zhu Zhongzheng Niu Heather Ochs-Balcom Diana S. Aga Lisa Lenker Marina Feiler Changxing Ma Mindula K. Wijayahena Lina Mu

Research on per- and polyfluoroalkyl substances (PFAS) and biomarkers potentially related to oxidative stress in adolescents is limited. We investigated associations between serum PFAS and total bilirubin and albumin among 1474 participants aged 12–20 years using National Health and Nutrition Examination Survey 2011–2018 data. Six primary PFAS and two secondary measures, summed branched perfluorooctanesulfonic acid (Sm-PFOS) and total PFOS, were assessed. Survey-weighted linear regression with multiple imputation for missing covariates was used to assess associations and potential vitamin C effect modification. Bayesian kernel machine regression was used to evaluate PFAS mixture associations. After adjustment for multiple comparisons, perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorodecanoic acid (PFDeA) were positively associated with bilirubin, and seven PFAS measures were positively associated with albumin. Albumin associations for PFOA, perfluorononanoic acid (PFNA), and PFDeA were stronger among vitamin C-deficient participants (<11.4 µmol/L), with significant interactions. For example, the PFOA–albumin association was stronger among vitamin C-deficient than non-deficient participants (β = 2.276 vs. 0.544; interaction q = 0.013). Mixture associations were positive for both biomarkers and consistent with the primary analysis. These findings suggest PFAS are associated with bilirubin and albumin; vitamin C findings are exploratory and limited by the small deficient group.

Antioxidants doi: 10.3390/antiox15101309

Authors: Prayuth Kusolrat Jittraporn Prakaotan Thitipat Boonsit Pornnipa Chanpakdee Mattanawan Jiranuchaiwattana Worapol Aengwanich

Acute temperature elevation can challenge physiological regulation and cellular redox homeostasis in ectotherms, yet integrated physiological and redox responses remain poorly characterized in the Siamese crocodile (Crocodylus siamensis Schneider, 1801). This study aimed to evaluate physiological responses during acute warming and characterize biochemical responses in pooled blood cells. Six crocodiles were exposed to temperatures of 30–38 °C, while pooled blood cells were incubated at 30–40 °C. Body temperature increased from 31.35 ± 0.15 °C at 30 °C to 37.48 ± 0.20 °C at 38 °C (p < 0.0001), while pulse rate increased from 42.50 ± 5.82 bpm at 34 °C to 62.38 ± 6.33 bpm at 36 °C (p < 0.05); blood oxygen saturation remained unchanged. Within the pooled preparation, hydrogen peroxide increased and glutathione peroxidase activity decreased at higher temperatures (p < 0.05), accompanied by alterations in ferric iron, lipid hydroperoxide, and malondialdehyde. Mitochondrial activity, total antioxidant capacity, nitric oxide, and protein oxidation remained unchanged. Because the biochemical experiment comprised one pooled biological preparation, these results represent within-preparation responses rather than population-level effects. These findings provide an integrated characterization of whole-animal physiological responses and complementary changes in redox balance, iron status, and lipid peroxidation during acute warming in Siamese crocodiles.

Antioxidants doi: 10.3390/antiox15101308

Authors: Ahmet Akkoca Burcu Gültekin

Vincristine (Vin), a chemotherapeutic agent commonly used in clinical practice, frequently causes peripheral neuropathy (PN). The aim of this study was to compare the potential therapeutic effects of acetyl-L-carnitine (ALC) and the mitochondria-targeted antioxidant MitoQ, administered following the establishment of PN in rats. PN was induced in rats by administering Vin (0.1 mg/kg/day) for 5 consecutive days, followed by a 2-day break, and then for another 5 days (cumulative dose: 1 mg/kg). Animals were subsequently treated daily for 7 days with either 300 mg/kg/day of ALC or 2 mg/kg/day of MitoQ. At the end of the study, sciatic nerve function was assessed using ex vivo electrophysiological recordings, while morphological changes were examined via H&E, Klüver–Barrera, and MBP/MPZ immunohistochemical staining. Vin exposure caused significant impairments in sciatic nerve CAP amplitude, integral, and conduction velocity, and histopathologically led to myelin damage, axonal degeneration, and vacuolization. Both treatments administered after the injury significantly attenuated functional and structural impairments, restoring them toward baseline levels. Notably, MitoQ showed favorable numerical improvements across myelin sheath integrity, vacuolization scores, and CAP parameters. In conclusion, MitoQ demonstrates notable neuroprotective efficacy and promotes nerve structural recovery following Vin-induced PN.

Antioxidants doi: 10.3390/antiox15101307

Authors: Nina Kummer Sabina Gayibova Takhir Aripov Désirée Gül Mustafa Dolaz Burcu Önal Acet Leyla Polat Köse Mehmet Odabaşı Roland H. Stauber Ömür Acet

Breast cancer progression and therapeutic resistance are closely associated with disrupted redox homeostasis, in which oxidative stress drives tumor growth, metabolic adaptation, and treatment failure. Although antioxidants have traditionally been considered cytoprotective agents, their effects on tumor redox signaling are highly context-dependent, creating an antioxidant paradox that limits their therapeutic application. This review examines how dysregulated redox signaling shapes breast cancer biology and therapeutic response across ER+, HER2+, and triple-negative subtypes, with emphasis on the NRF2–KEAP1, p53, PI3K/AKT, MAPK, and HIF-1α pathways. These mechanisms provide a biological rationale for selectively modulating tumor redox states rather than broadly suppressing oxidative stress. Within this framework, redox-responsive nanocarriers and nanozymes offer opportunities for precise spatial and temporal redox modulation, enhanced tumor targeting, and controlled therapeutic activity while potentially minimizing effects on healthy tissues. Redox-directed nanotherapeutics may also influence the tumor immune microenvironment, angiogenesis, and metabolic rewiring. However, clinical translation remains constrained by dose- and context-dependent effects, intratumoral heterogeneity, limited biomarker validation, and inadequate predictive models. Personalized redox nanomedicine integrating subtype-specific redox profiling, smart nanotherapeutic platforms, and biomarker-guided patient stratification could establish redox modulation as a precision therapeutic axis and improve treatment outcomes in breast cancer.

Antioxidants doi: 10.3390/antiox15101306

Authors: Geunhyeok Yang Eo Jin Park

Simple tools for characterizing functional vulnerability after cholecystectomy are lacking, particularly among patients referred for outpatient rehabilitation. We examined whether a cumulative count of routine nutritional, inflammatory, and redox-related biomarker abnormalities at the first physical medicine and rehabilitation (PM&R) visit was associated with 12-week physical performance. This single-center retrospective cohort included 184 adults assessed 14–180 days after cholecystectomy. The exposure counted abnormalities in zinc, 25-hydroxyvitamin D, homocysteine, albumin, and neutrophil-to-lymphocyte ratio. The primary outcome was the 12-week Short Physical Performance Battery (SPPB) total score. After multivariable adjustment, each additional abnormality was associated with a 0.49-point lower 12-week SPPB score (β = −0.49, 95% confidence interval = −0.80 to −0.18; p = 0.002). Supportive analyses showed higher odds of low physical performance, lower odds of substantial SPPB improvement, lower grip strength, and a shorter 6-min walk distance. The additional explanatory value was modest (incremental R2 = 0.03). A higher routine biomarker abnormality burden may characterize postoperative vulnerability relevant to rehabilitation assessment, but the count is not a validated prediction or treatment selection tool and requires prospective validation.

Antioxidants doi: 10.3390/antiox15101305

Authors: Mohammad Ibtehaz Alam Fatima Farhana Tajiba Rahman Khan Farjana Sharmin Mst Hurunnaher Yu Katsuma Eiko Sakai Yoshinori Sumita

Osteoclasts are the primary bone-resorbing cells responsible for maintaining skeletal homeostasis through balanced bone remodeling. Accumulating evidence suggests that oxidative stress is an emerging regulator of osteoclast differentiation, metabolic reprogramming, and bone resorption, arising from excessive reactive oxygen species (ROS) and insufficient antioxidant defenses. Dysregulated redox signaling contributes to osteoporosis, rheumatoid arthritis, periodontitis, periapical lesions, and other osteolytic disorders. This review summarizes recent advances in the molecular mechanisms linking oxidative stress to osteoclast metabolism, focusing on ROS sources, mitochondrial dysfunction, redox-sensitive signaling pathways, endogenous antioxidant systems, and emerging antioxidant-based therapies. Oxidative stress regulates osteoclastogenesis through interconnected signaling networks, including NF-κB, MAPKs, PI3K/Akt, AMPK, mTOR, NFATc1, and Keap1/Nrf2. Under both physiological and pathological conditions, osteoclast function is regulated by mitochondrial dynamics, mitophagy, and epigenetic mechanisms. Although both synthetic and natural antioxidants have been shown to reduce pathological osteoclast activity in preclinical studies, limitations in bioavailability, target specificity, and long-term efficacy hinder clinical translation. Advances in multi-omics technologies, single-cell analyses, biomarker discovery, precision medicine, and targeted antioxidant delivery may facilitate the development of effective therapies for oxidative stress-related bone disorders.

Antioxidants doi: 10.3390/antiox15101304

Authors: Xiangbin Jia Yuzhao Wang Jiao Cao Lifei Pan Xiaoxuan Cui Hanxue Shan Yiqing Wang Xiao Cao Qin Zhou

Periodontitis is a prevalent chronic inflammatory disease characterized by gingival inflammation and progressive alveolar bone loss. The NLRP3 inflammasome functions as a molecular mediator that drives its pathogenesis. Bergapten (BeG), a natural furanocoumarin, exhibits anti-inflammatory properties and bone-protective effects. This study demonstrates that BeG alleviates experimental periodontitis in mice by inhibiting the NLRP3 inflammasome. Mechanistically, BeG does not affect NLRP3 priming, dispersed trans-Golgi network (dTGN) localization, or oligomerization; instead, it induces mitophagy by inhibiting the AKT–mTOR axis and consequently suppresses the mtROS-dependent NEK7–NLRP3 interaction. Notably, BeG also suppressed cytosolic release of oxidized mitochondrial DNA (ox-mtDNA), a known endogenous ligand for NLRP3. This effect was attributed to BeG-mediated inhibition of NLRP3 activation, likely via blockade of GSDMD-NT mitochondrial localization. These findings deepen our understanding of the anti-inflammatory mechanisms of BeG and position it as a promising candidate for periodontitis treatment.

Antioxidants doi: 10.3390/antiox15101303

Authors: Bo Shao Zhi-Guo Sheng Huan Li Shun-Li Jiang Gui-Zhi Han Chen-Jun Shao Ben-Zhan Zhu

Although ferroptosis is a programmed iron-dependent cell death, many lipophilic iron complexes fail to induce ferroptosis through iron overload. The underlying mechanisms remain unclear. Here we found that a typical lipophilic iron complex 8-hydroxyquinoline (8HQ)-Fe(III) (1: 1, 10 μM), can efficiently induce cellular iron overload, lipid peroxidation, and finally cytotoxicity. However, the resulting cell death mode was not typical ferroptosis: it was not inhibited by the classic ferroptosis inhibitors and exhibited mitochondrial swelling rather than shrinkage. Mechanistic studies revealed that 8HQ-Fe(III) triggered both endoplasmic reticulum (ER) peroxidation and mitochondrial damage. The ER-targeted antioxidant (stobadine) inhibited lipid peroxidation but did not suppress cell death. In contrast, mitochondrial protectants effectively blocked 8HQ-Fe-induced cell death by mitigating mitochondrial damage. This indicates that mitochondrial damage plays an overwhelmingly dominant role in driving cell death. Strikingly, pre-incubation with docosahexaenoic acid (DHA) can strongly enrich the ER membrane and increase its peroxidation. As expected, both stobadine and the well-known ferroptosis inhibitor (Fer-1) suppressed 8HQ-Fe(III)-induced cell death via inhibition of ER peroxidation, while mitochondrial protectants failed to prevent cell death. Mitochondrial shrinkage was also observed. Thus, making ER peroxidation the dominant driver of cell death by DHA pretreatment will switch the cell death modality from non-ferroptosis to classical ferroptosis. This study revealed that the balance between ER peroxidation and mitochondrial damage dictated the type of iron-dependent cell death, and established DHA-primed 8HQ-Fe(III) as a novel, tunable strategy for efficiently inducing ferroptosis by deliberately shifting subcellular peroxidation dominance.

Antioxidants doi: 10.3390/antiox15101302

Authors: Jiawei Wang Yongbo Hao Shaoyang Han Feifei Luo Ziyi Zheng Shuo Sun Xi Sun Yongkang Diao Jiahao Zhao Suqiao Chu Lijun Hou Boyang Shi Hui Chen Chong Li

Oxidative stress-induced impairment of chondrocyte differentiation and bone homeostasis is pivotal in tibial dyschondroplasia (TD). Sodium butyrate has been shown to modulate gut microbiota, improve redox homeostasis, and support skeletal metabolism; however, whether it exerts protection against TD specifically through oxidative stress modulation remains unclear. A total of 210 one-day-old male Arbor Acres broilers were randomly allocated to three treatment groups, with seven replicate pens per group and 10 birds per pen. The birds were housed in a windowless, climate-controlled indoor poultry house with floor pens and rice-husk bedding. In a thiram-induced broiler TD model, dietary sodium butyrate (500 mg/kg) reshaped the gut microbiota by increasing beneficial genera (Ligilactobacillus, Lactobacillus, Blautia, and Mediterraneibacter), decreasing Escherichia-Shigella abundance, and elevating ileal butyrate concentration. These shifts co-occurred with mitigated oxidative damage, including reduced ROS and MDA in both serum and ileal mucosa, partial elevations in SOD and GSH-Px activities, upregulated Nrf2 and HO-1 expression in both the ileal mucosa and tibial growth plate, and improved mitochondrial function in the ileal mucosa, as indicated by restored mitochondrial membrane potential, reduced superoxide anion levels, and increased respiratory chain complex I activity. Concomitantly, sodium butyrate improved growth performance and skeletal phenotypes, attenuating growth plate lesions and restoring tibial morphology and mineralization. It also favorably modulated bone metabolism by elevating the OPG/RANKL ratio and upregulating COL2A1 expression. Correlation analyses linked microbial alterations to antioxidant status and skeletal parameters. Collectively, these findings suggest that sodium butyrate alleviates thiram-induced TD in association with gut microbiota remodeling, which is correlated with enhanced redox homeostasis and bone metabolism, supporting a potential gut–bone axis mechanism.

Antioxidants doi: 10.3390/antiox15101301

Authors: Danyoung Kim JuDong Yeo

Lipid oxidation is an important factor affecting food quality and oxidative stability, but conventional oxidation indices provide limited information on individual oxidation products and changes in lipid species. This review focuses on liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based approaches for lipid oxidation analysis and their applications in food and selected biological systems. LC-MS/MS provides molecular-level information on individual oxidation products and oxidized lipid species; however, its analytical reliability can be affected by hydroperoxide instability, matrix effects, limited availability of authentic standards, and variability in data processing and lipid annotation. The analytical characteristics of hydroperoxides, aldehydes, alcohols, ketones, organic acids, hydrocarbons, and oxidized complex lipids are described together with the advantages and limitations of LC-MS/MS analysis. In addition, this review compares targeted analysis with untargeted and pseudotargeted lipidomics and discusses their applications to edible oils, meat, emulsions, and oleosomes. The use of lipidomics in selected biological systems and artificial intelligence (AI)-assisted lipid analysis is also discussed. Therefore, combining validated targeted analysis and lipidomics with conventional oxidation indices may provide a more reliable and comprehensive evaluation of lipid oxidation.

Antioxidants doi: 10.3390/antiox15101300

Authors: Shan Shen Mi Ae Lim Sicong Zheng Shuyu Piao Doh Hoon Kim Shengzhe Cui Young Il Kim Jae Won Chang Seung-Nam Jung Bon Seok Koo

Head and neck squamous cell carcinoma (HNSCC) remains one of the most prevalent and aggressive malignancies worldwide. Serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism, is essential for tumor cell proliferation and redox homeostasis. Whether SHMT2 regulates ferroptosis, an iron-dependent form of regulated cell death, in HNSCC remains unknown. Here, we demonstrate that SHMT2 suppression induces ferroptotic cell death in HNSCC cells, as evidenced by increased lipid peroxidation and elevated prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2) expression. Mechanistically, SHMT2 suppression decreased the intracellular GSH/GSSG ratio, while exogenous GSH partially restored cell viability and attenuated lipid peroxidation. Moreover, SHMT2 suppression reduced GPX4 protein levels, whereas SHMT2 overexpression increased GPX4 abundance. Conversely, GPX4 overexpression had little effect on SHMT2, placing SHMT2 upstream of GPX4. Functionally, GPX4 overexpression partially restored cell viability and reduced lipid peroxidation in SHMT2-knockdown cells, further supporting a functional role for GPX4 downstream of SHMT2. Both genetic and pharmacological inhibition of SHMT2 enhanced erastin-induced ferroptosis in vitro, while SHMT2 knockdown potentiated the antitumor activity of erastin in female BALB/c nude mouse xenografts. Collectively, our study identifies a novel SHMT2-regulated GSH–GPX4 axis that mediates ferroptosis in HNSCC and highlights SHMT2 suppression as a potential therapeutic strategy for head and neck cancer.

Antioxidants doi: 10.3390/antiox15101299

Authors: I-Ta Lee Yu-Chia Hsu Yung-Li Wang Sheng-Wei Feng Thi Thuy Tien Vo Tong-Hsien Chow

Sesamin is a furofuran lignan in sesame with reported antioxidant, anti-inflammatory, metabolic, and anticancer activities. However, its biological effects vary according to exposure, metabolism, cellular state, and stress-response capacity. This review examines sesamin as a context-dependent redox modulator, focusing on bioavailability, metabolite-dependent activity, organelle quality control, and regulated cell death. We integrate evidence on cytochrome P450-mediated metabolism, catechol formation, conjugation, tissue availability, mitochondrial redox regulation, mitophagy, autophagic flux, lysosomal function, innate immune signalling, and their intersections with apoptosis, ferroptosis, and pyroptosis. In non-malignant injury models, sesamin generally attenuates oxidative damage, preserves organelle function, and limits inflammatory or ferroptotic injury, whereas higher concentrations in selected malignant-cell models may increase oxidative stress, disrupt survival signalling, or enhance susceptibility to cell death. These divergent outcomes appear to depend on molecular species, dose, metabolic competence, baseline redox pressure, and organelle reserve. Translational limitations include sparse human pharmacokinetic and efficacy data, uncertain tissue exposure, frequent use of pharmacologically unverified micromolar concentrations, and limited metabolite-specific testing. Future studies should therefore combine exposure-matched experimental systems with quantitative redox measurements, organelle-flux assays, and pathway-specific validation to define the biological relevance of sesamin-mediated redox regulation and cell-fate control.

Antioxidants doi: 10.3390/antiox15101298

Authors: Mody Albalawi Sahar Khateeb

Radiation therapy is one of the most common treatments for cancer. However, side effects on normal tissues remain a major clinical concern. The ovary is highly radiosensitive, and ionizing radiation (IR) can impair ovarian function and fertility by inducing oxidative stress, mitochondrial dysfunction, and multiple forms of cell death, ultimately leading to follicular depletion. Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and has recently emerged as a potential contributor to IR-induced ovarian injury. IR can induce ferroptosis by disrupting iron homeostasis, impairing the System Xc−–GSH–GPX4 antioxidant defense pathway, and promoting lipid peroxidation. Recent preclinical studies have shown ferroptosis-related alterations in irradiated ovarian tissue and granulosa cells. In parallel, IR activates the well-established TAp63–PUMA/NOXA apoptotic pathway in oocytes, highlighting the involvement of multiple cell death mechanisms in ovarian injury. Nevertheless, targeting ferroptosis may help reduce granulosa cell injury and mitigate certain aspects of ovarian damage. This review evaluates current evidence for ferroptosis as one of the cell death mechanisms contributing to IR-induced ovarian injury, with particular emphasis on its molecular mechanisms, interactions with other cell death pathways, and emerging therapeutic strategies. Potential therapeutic strategies include the preservation of GPX4-dependent antioxidant defenses, inhibition of lipid peroxidation, regulation of iron homeostasis, and modulation of polyunsaturated fatty acid-related lipid metabolism. Nevertheless, direct evidence remains limited, and further research is needed to clarify the contribution of ferroptosis to IR-induced ovarian injury and evaluate whether targeting this pathway can mitigate ovarian damage without compromising tumor radiosensitivity.

Antioxidants doi: 10.3390/antiox15101297

Authors: Ufuk Ülker Bülent Bayraktar Mehmet Eray Alçığır Sibel Kızıl Fatih Aydin Gökşad Cemil Kotan Mustafa Yeni

Oxidative stress, immune dysregulation, and disturbed metabolic adaptation contribute to early sepsis pathophysiology. This exploratory study evaluated a commercial Annona muricata leaf extract in 40 male rats assigned to five groups (n = 8/group): healthy Control, laparotomy-only Sham, untreated cecal ligation and puncture (CLP), CLP plus a single 100 mg/kg extract dose, and CLP plus a single 200 mg/kg extract dose. Redox indices, circulating neuroendocrine and inflammatory biomarkers, bacterial translocation and peritoneal immune variables, 24 h functional measures, and multiorgan histopathology were assessed. All 40 animals reached the predefined 24 h endpoint. Relative to healthy Control and Sham animals, untreated CLP rats showed higher MDA, TOS, OSI, chemerin, asprosin, IL-1β, mesenteric lymph-node bacterial burden, peritoneal cfDNA, MPO activity, and anaerobic load, together with lower CAT, GPx, TAS, BDNF, circulating AMPK immunoreactivity, and phagocytic activity (all omnibus p < 0.001). The primary treatment comparison was with untreated CLP. Both extract doses shifted most continuous outcomes toward non-septic values, with the larger shift generally observed at 200 mg/kg; for example, MDA decreased from 6.92 ± 0.54 nmol/mL in untreated CLP rats to 4.15 ± 0.32 and 2.65 ± 0.21 nmol/mL at 100 and 200 mg/kg, respectively, while OSI decreased from 3.07 ± 0.28 to 1.21 ± 0.12 and 0.65 ± 0.06. Histological findings were heterogeneous and did not demonstrate uniform multiorgan protection. These data indicate short-term, dose-ordered associations between single-dose leaf-extract administration and biochemical, microbial, immune, and functional outcomes in this male-rat CLP model; they do not establish a molecular mechanism, direct antimicrobial activity, long-term survival benefit, safety, or clinical efficacy.

Antioxidants doi: 10.3390/antiox15101296

Authors: Yara Sheeni Prince Kumar Singh Shweta Maurya Sereen Sandouka Tawfeeq Shekh-Ahmad

We aimed to investigate the acute anticonvulsant and long-term antiepileptogenic effects of the synthetic triterpenoid CDDO-EA in complementary experimental models of epilepsy. CDDO-EA was evaluated in the pentylenetetrazol seizure model and a kainic acid-induced post-status epilepticus model. Acute seizure severity, latency to generalized seizures, oxidative stress and inflammatory markers, spontaneous recurrent seizures, and hippocampal neuronal survival were assessed. In the pentylenetetrazol model, CDDO-EA pretreatment reduced maximal seizure severity and prolonged the latency to stage V-VI seizures. These effects were associated with decreased inflammatory cytokine levels and malondialdehyde levels, alongside increased superoxide dismutase and catalase activities 24 h after pentylenetetrazol administration. In the post-status epilepticus model, two weeks of CDDO-EA treatment significantly delayed the onset of spontaneous recurrent seizures and produced sustained reductions in weekly seizure frequency and cumulative seizure burden. Histological analysis demonstrated greater neuronal preservation in the hippocampal CA1 and CA3 regions of CDDO-EA-treated animals compared with vehicle controls. CDDO-EA exerts both anticonvulsant and disease-modifying effects by attenuating seizure severity, restoring redox-inflammatory homeostasis, preserving hippocampal neurons, and suppressing epileptogenesis after status epilepticus, supporting its therapeutic potential as a novel strategy for epilepsy.

Antioxidants doi: 10.3390/antiox15101295

Authors: Benedetta Niccolini Martina Grandi Veronica Nobile Cecilia Pucci Francesco Boldrin Maria Elisabetta Clementi Patrizia Bottoni Alessia Riente Pietro Chiurazzi Giovanni Neri Maurizio Genuardi Alessandra Baracca Giuseppe Maulucci Elisabetta Tabolacci Valentina Giorgio

Fragile X syndrome (FXS) and related conditions associated with FMR1 gene alterations have increasingly been linked to mitochondrial dysfunction, although most available evidence derives from peripheral cell models. Whether these abnormalities also occur in disease-relevant neuronal populations remains largely unknown. Building on our previous observations in patient-derived fibroblasts, we investigated mitochondrial structure and function in neurons differentiated from induced pluripotent stem cells (iPSCs) generated from individuals with FXS and carriers of unmethylated full mutations, using matched healthy control lines. Mitochondrial integrity, bioenergetic properties, and network organization were evaluated to determine whether FMR1-associated mitochondrial defects are preserved in a neuronal context. Mitochondrial abnormalities previously identified in fibroblasts were recapitulated in iPSC-derived neurons. These findings demonstrate that impaired mitochondrial dynamics and function are conserved across different cell types, indicating that mitochondrial dysfunction represents a relevant cellular feature of FXS and related FMR1-associated conditions. Our results indicate that mitochondrial dysfunction is a shared feature of FMR1-related neuronal models, while the underlying patterns of mitochondrial remodeling are influenced by the specific FMR1-associated condition. These results support a role for mitochondrial alterations in FMR1-related neuronal dysfunction and provide a basis for the further investigation of the mechanisms linking mitochondrial homeostasis to the pathophysiology of FXS and related conditions.

Antioxidants doi: 10.3390/antiox15101294

Authors: Zhen He Decai Xiang Jing Fu Demeng Mu Xuemei Li Junyu Jiang Hongjiang Wei Baoyu Jia Guoquan Wu

Vitrification is an efficient approach to preserve porcine germinal vesicle (GV)-stage oocytes, yet cryo-induced damage remains a major limitation to subsequent embryonic development. Although previous studies have investigated transcriptomic and proteomic changes in oocytes and cumulus cells (CCs) following vitrification, the metabolic alterations underlying cryoinjury are poorly understood. In this study, metabolomic profiling of vitrified oocytes and CCs following in vitro maturation (IVM) was carried out identify key differential metabolites. Functional validation was further conducted by supplementing candidate metabolites during oocyte maturation. In vitrified oocytes, 19 metabolites were significantly upregulated, and 44 were significantly downregulated. Integrated metabolomic and transcriptomic profiling demonstrated that significantly altered metabolites and genes converged on biological pathways governing energy metabolism, glutathione metabolism, and glycerophospholipid metabolism. In CCs derived from vitrified oocytes, 70 metabolites exhibited marked upregulation, while 21 showed significantly downregulation. Integrated analysis profiling demonstrated that significantly altered metabolites and genes were converged on pathways such as glutathione metabolism and glycerophospholipid metabolism. Notably, oocytes and CCs shared 28 differentially expressed metabolites, among which cysteinyl-glycine (Cys-Gly) was significantly reduced in both oocytes and CCs following vitrification. Supplementing IVM with Cys-Gly improved vitrified oocyte quality, as evidenced by reduced oxidative stress, suppressed excessive apoptosis and aberrant autophagy, enhanced embryonic development, and increased cumulus expansion. Collectively, these findings provide a comprehensive metabolic profile of porcine GV oocytes and CCs after vitrification, offering new insights into the mechanisms of oocyte cryoinjury. Targeting key metabolic pathways or supplementing specific metabolites, such as Cys-Gly, may represent a promising strategy to improve the viability of vitrified porcine oocytes.

Antioxidants doi: 10.3390/antiox15101293

Authors: Yongmin Mason Park Byeoung-Kyu Choi Mingu Gordon Park Myeongju Kim Woojin Won Hee Jae Shin C. Justin Lee

Hydrogen peroxide (H2O2) contributes to oxidative stress in Alzheimer’s disease (AD), yet conventional antioxidants that directly scavenge H2O2 have shown limited therapeutic efficacy. Here, we investigated K34 (3,3″-dihydroxy-6′-desmethyl terphenyllin), a catechol-bearing para-terphenyl isolated from the marine fungus Penicillium janthinellum 168CLC-17.1, as an indirect H2O2-decomposing agent. Complementary cell-free assays showed that K34 promoted peroxidase-dependent H2O2 decomposition, including Hb-supported H2O2 decomposition, while molecular docking predicted a plausible binding pose near the Hbβ heme pocket. In amyloid-β42 (Aβ42)-stimulated primary astrocytes, K34 reduced intracellular H2O2. In APPswe/PSEN1dE9 (APP/PS1) mice subjected to focal GFAP-inducible diphtheria toxin receptor (fGiD), systemic K34 attenuated memory impairment, preserved NeuN-positive neurons, reduced GFAP immunoreactivity, and improved hippocampal spike probability. K34 also exhibited low passive blood–brain barrier (BBB) permeability and limited inhibition of five major cytochrome P450 (CYP) isoforms under the tested conditions. These findings extend Hb-supported H2O2 decomposition to a structurally distinct marine natural product and support further evaluation of K34 as an antioxidant scaffold for modulating oxidative stress-associated neurodegenerative phenotypes.

Antioxidants doi: 10.3390/antiox15101292

Authors: Tianjing Du Jiamin Zhao Xin Shao Minyue Zhao Wenhao Weng Ruibo Zhu Zhihui Feng Zhongbo Liu Kun Qi

Improper orthodontic treatment can disrupt alveolar bone remodeling, leading to excessive alveolar bone resorption and complications such as bone fenestration and dehiscence. Although ferroptosis has emerged as an important regulator of bone metabolism, its role in mechanical force-induced periodontal tissue remodeling during orthodontic tooth movement (OTM) remains incompletely understood. This study investigated whether ferroptosis regulates the osteogenic response of human periodontal ligament stem cells (hPDLSCs) under compressive force (CF), focusing on stearoyl-CoA desaturase 1 (SCD1). hPDLSCs were subjected to static CF, and RNA sequencing, RT–qPCR, Western blotting, and immunofluorescence were performed to analyze SREBP1 and SCD1 expression. Ferroptosis-related alterations were evaluated using biochemical and mitochondrial analyses. Ferrostatin-1 (Fer-1) rescue, SCD1 knockdown/overexpression, and a rat OTM model were used for functional validation. Prolonged CF downregulated SREBP1 and SCD1 expression, accompanied by ferroptosis-associated alterations and reduced RUNX2 and OPN expression. Fer-1 alleviated these changes, whereas SCD1 overexpression partially restored osteogenic markers and SCD1 knockdown further impaired osteogenic responses. In vivo, SREBP1 and SCD1 expression were reduced on the compression side. Collectively, these findings identify SCD1 as an important regulator linking CF-induced ferroptosis-associated alterations with impaired osteogenic differentiation of hPDLSCs, suggesting SCD1 as a potential target for orthodontic bone remodeling.

Antioxidants doi: 10.3390/antiox15101291

Authors: Songlin Luo Xudong Yang Shunqiang Wei Chushun Yi Fansheng Zeng Fali Zhang Wei Zhang Xiuli Chen Yongzhen Zhao Yinghui Wang Aiguo Huang

White Spot Syndrome Virus (WSSV) remains a major factor limiting the sustainable development of crustacean aquaculture, creating an urgent need to develop comprehensive antiviral strategies with multiple protective functions. Natural bioactive compounds with antiviral, immunomodulatory, and antioxidant activities hold great potential for application; however, their poor stability and low bioavailability limit their practical use. In this study, self-assembled nanosystem (CE SA) composed of epigallocatechin gallate (EGCG) and curcumin (Cur) was constructed based on noncovalent interactions, and its protective effects against WSSV-infected Procambarus clarkii were systematically evaluated. The results indicate that CE SA exhibits good stability, sustained-release properties, and biosafety. Compared with Cur, EGCG, and their physical mixture (CE), CE SA significantly improved the survival rate of infected shrimp and reduced viral copy numbers as well as the expression levels of key viral genes such as IE1, DNApol, and VP28. At the same time, CE SA significantly promoted the expression of relevant genes such as Dorsal, Relish, SOD, and CAT, increased SOD and CAT enzyme activities and hematopoietic cell viability, and effectively alleviated damage to the hepatopancreas and intestinal tissues. Furthermore, metabolomic analysis indicated that CE SA regulates key metabolic processes such as amino acid metabolism, inflammation-related metabolism, nucleotide metabolism, and redox homeostasis, further elucidating its potential mechanism for enhancing the host’s antiviral capacity. In summary, by enhancing the stability and utilization efficiency of natural bioactive components, CE SA achieves superior anti-WSSV efficacy compared to individual components. Its protective effects are closely related to the inhibition of viral replication, enhancement of the immune response, improvement of antioxidant defenses, and regulation of host metabolic homeostasis. This study provides a promising, self-assembling nanostructure strategy for the green prevention and control of viral diseases in aquatic animals.

Antioxidants doi: 10.3390/antiox15101290

Authors: Haowen Wang Sungkwon Park Jialin Zhang Wen Zhang Xuanying Xin Hangshu Xin Xiangzi Li

This study aimed to determine whether 20(S)-ginsenoside Rg3 (S-Rg3) and compound K (CK), two representative ginsenosides retained in red ginseng processing by-products, could restore redox homeostasis and alleviate lipopolysaccharide (LPS)-induced injury in bovine intestinal epithelial cells, and to clarify the associated autophagy–lysosome mechanisms. Ginsenoside constituents were characterized by LC-MS. Network pharmacology, machine learning-assisted target screening, molecular docking, and molecular dynamics simulations were integrated to predict compound–target interactions. For in vitro validation, bovine small intestinal epithelial cells were pretreated with 8 μM S-Rg3, 8 μM CK, or their combination for 24 h, followed by a 24 h challenge with 50 mg/L LPS. Computationally, S-Rg3 and CK showed favorable predicted binding with Keap1, TLR4, NKIRAS2 p65, and iNOS. Experimentally, S-Rg3, CK, and particularly their combined pretreatment significantly improved cell viability, reduced reactive oxygen species and nitric oxide accumulation, restored antioxidant enzyme activities and Nrf2/HO-1-associated antioxidant defense, suppressed inflammatory activation, and preserved tight junction protein expression compared with the LPS group. The treatments further alleviated LPS-induced autophagy–lysosome dysfunction, endoplasmic reticulum stress, mitochondrial injury, and apoptosis. Multi-omics integration linked these protective effects to inflammatory lipid mediator, arginine/nitric oxide, amino acid, and energy metabolism, together with redox-related signaling pathways. Collectively, S-Rg3 and CK protected bovine intestinal epithelial cells from LPS-induced injury primarily by restoring redox homeostasis and supporting autophagy–lysosome function. These findings provide mechanistic evidence supporting the valorization of red ginseng processing by-products as potential bioactive resources for improving intestinal epithelial resilience in animal production.

Antioxidants doi: 10.3390/antiox15101289

Authors: Mahmoud Soliman Cheng Du Xinyu Liu Liangwenyao Zhao Linli Cheng

Tanshinones from Salvia miltiorrhiza have been studied in biomedical systems, and a growing intestinal literature includes porcine epithelial-cell models and experimental colitis. This integrative narrative review summarizes intestinal findings separately from evidence in non-livestock models and from mechanistic extrapolation. Direct food-animal evidence for purified tanshinones as dietary additives remains limited; studies of whole-plant preparations and sodium tanshinone IIA sulfonate are not equivalent to feed trials of native tanshinones. Reported effects involve redox and inflammatory signaling, epithelial barrier-related measures, and intestinal injury models but do not establish species-specific efficacy, dose response, safety, or performance benefits. Microbiota–metabolite–immune relationships provide a rationale for future testing, not evidence that tanshinones improve livestock microbiota or production. Key translational gaps include dose escalation, pharmacokinetics, feed-processing stability, species-specific toxicology, residues, withdrawal periods, and interactions. The available evidence supports testable research questions rather than a validated feed-additive recommendation.

Antioxidants doi: 10.3390/antiox15101288

Authors: Max Denisson Maurício Viana Diego Domingues Pereira Sthefane Silva Santos Maria Laura Camilo Calderari Vinícius Eduardo Fernandes da da Silva Marvin Paulo Lins Luiz Henrique Agra Cavalcante-Silva

Research to date has predominantly focused on probiotic-induced microbiota modulation, anti-inflammatory effects, and generalized antioxidant activity. However, evidence regarding the role of probiotics in regulating the microbiota–mitochondria axis and its impact on immunoredox regulation remains fragmented and poorly characterized. This review discusses probiotics as immunoredox therapeutic modulators, rather than solely microbiota regulators, offering a conceptual framework with translational relevance. This manuscript explores how probiotics influence ROS/RNS production, Nrf2/NF-κB signaling, mitochondrial redox homeostasis, inflammatory immunometabolism, and antioxidant defenses in immune cells. Additionally, the review integrates emerging evidence linking these mechanisms to oxidative stress and autoimmunity. By focusing on mechanistic and translational aspects, this review aims to provide new insights into probiotic-based strategies targeting oxidative stress and immune dysfunction.

Antioxidants doi: 10.3390/antiox15101287

Authors: Gamze Camlik Ayça Altay Benetti Gokhan Ozokan Ulfet Erdogan Uzunoglu Meltem Macit Ebru Turkoz Acar Cetin Tas Ismail Tuncer Degim

Salicylic acid is widely used in dermatological and cosmetic formulations, yet the influence of its production route on solid-state structure and biological behaviour remains underexplored. This study compares a naturally derived salicylic acid (NSA), obtained from wintergreen oil through green chemistry, with a synthetic form (SSA) produced via the Kolbe–Schmitt reaction, integrating physicochemical characterization with antioxidant and immunomodulatory profiling. Crystal morphology, crystallinity (XRD, FTIR), melting point, solubility, dissolution and Franz-cell skin permeation were determined, alongside intrinsic radical scavenging (DPPH), intracellular reactive oxygen species (DCFH-DA), cytoprotection (MTT), CD9+ extracellular-vesicle (EV) release and cytokine transcription in RAW 264.7 macrophages. SSA formed uniform, needle-like crystals of higher crystallinity, comparable equilibrium solubility (2.239 vs. 2.115 mg/mL; not significant) and faster dissolution, whereas the less-ordered NSA showed a numerically higher steady-state flux (39.94 ± 16.43 µg cm−2 h−1) and a shorter lag time (2.47 ± 1.71 h). SSA was the stronger radical scavenger (DPPH 20.7% vs. 8.7%) and reduced intracellular ROS more effectively, while NSA afforded greater cytoprotection. Both forms were associated with a lower CD9+ EV concentration in the conditioned medium following LPS stimulation, with SSA consistently more active across radical scavenging, ROS and vesicle endpoints. These findings show that the synthesis route, through its effect on solid-state properties, influences the physical performance, while the biological behaviour is discussed separately from the anti-inflammatory behaviour of salicylic acid, informing the rational selection of natural versus synthetic material for topical applications.

Antioxidants doi: 10.3390/antiox15101286

Authors: Dordaneh Mirbabaei Ghafghazi Panagiota Klentrou Siu Kwan Sze Evangelia Litsa Tsiani

Tumor hypoxia is a defining feature of solid tumors, including lung cancer, and a major driver of aggressive disease progression, metastasis, and therapeutic resistance. Although hypoxia-induced signaling is well-characterized at the cellular level, emerging evidence highlights extracellular vesicles (EVs) as critical mediators through which hypoxic tumor cells remodel the tumor microenvironment. EVs transfer proteins, nucleic acids, and metabolites between cells, enabling complex intercellular communication. Their diverse cargo can act synergistically to promote cancer progression by modulating multiple signaling pathways in recipient cells. In lung cancer, hypoxia enhances EV biogenesis and promotes the loading of oncogenic cargo. Hypoxia-conditioned EVs subsequently drive key cancer hallmarks, including angiogenesis, epithelial–mesenchymal transition, metabolic reprogramming, immune suppression, and therapeutic resistance. Despite the diversity of EV cargo, these effects converge on major oncogenic pathways, including PI3K–Akt, STAT3, Wnt/β-catenin, and PD-1/PD-L1 signaling. Therefore, targeting hypoxia-driven EV signaling may suppress tumor progression and improve treatment efficacy. Clinically, the hypoxia–EV axis offers diagnostic and therapeutic opportunities. Circulating EVs containing hypoxia-associated tumor signatures may support non-invasive liquid biopsy approaches for early detection, prognosis, and treatment monitoring. Targeting EV biogenesis or transfer may also help overcome resistance to targeted therapy and immunotherapy.

Antioxidants doi: 10.3390/antiox15101284

Authors: Xingyao Pei Zibin Li Chun Chen Wenjuan Zhang Shang Wang Yuefei Sun Chongshan Dai Daowen Li

Zinc oxide nanoparticles (ZnO NPs) have been applied in biomedicine, food processing, and agricultural production. ZnO NPs can cause potential hepatotoxicity in animals and humans; however, the precise molecular mechanisms remain unclear and the effective treatment strategies are scarce. In this study, we investigated the protective effects of paeoniflorin (PF), a bioactive compound extracted from the roots of Paeoniaceae plants, on ZnO NPs-induced hepatotoxicity using a cell model. Our results showed that PF supplementation can dose-dependently attenuate ZnO NPs-induced decreases in cell viability and oxidative damage in HepG2 cells. Mechanistically, PF significantly reduced the activation of NLRP3 inflammasome, then reduced the expression of GSDMD-NT cleavage and the secretion of IL-1β and IL-18, and finally ameliorated ZnO NPs-induced pyroptosis. Furthermore, PF can directly interact with SIRT1, then deacetylate TFEB and promote autophagy-lysosome biogenesis. Overexpression of TFEB markedly attenuated ZnO NPs-induced pyroptosis. Consistently, the inhibition of SIRT1 or knockdown of TFEB both partly attenuated the protective effect of PF. Taken together, for the first time, our study demonstrated that PF can directly target SIRT1, then effectively attenuate ZnO NPs-induced pyroptosis via the activation the SIRT1/TFEB signaling pathway.

Antioxidants doi: 10.3390/antiox15101285

Authors: Gabriela Râpeanu Daniela Russo Marija Banožić Nicoleta Stănciuc

Due to its unique chemical structure, lycopene may induce multiple health benefits as a natural antioxidant. However, the biological properties of lycopene and, therefore, its wide applications in foods and feed, food supplements, pharmaceutics and cosmetics are limited due to its specific hydrophobic nature and low chemical stability. The specific biological and physicochemical characteristics are due to the presence of 11 conjugated double bonds, which highlights it among the >700 carotenoids discovered, being valued as the most efficient singlet oxygen quencher. However, due to its highly unsaturated hydrocarbon structure, lycopene is highly susceptible to chemical degradation when exposed to high temperatures, oxygen, and light, leading to color fading and the loss of bioactive properties. The stability, bioaccessibility and bioavailability of lycopene may be improved by using encapsulation, such as spray and freeze-drying, emulsions, liposomes, complex coacervation, electrospinning, etc. The main purpose of this study was to highlight the main characteristics of lycopene, the main sources, the principle and key factors of encapsulation, thus covering the most used and effective stabilization methods described in the literature. An important issue covered by this work is related to the bioaccessibility and bioavailability of different isomers of lycopene, with the main purpose of clarifying the mechanism of digestion.

Antioxidants doi: 10.3390/antiox15101283

Authors: Natalia Kurhaluk Renata Kołodziejska Halina Tkaczenko

Glucagon-like peptide-1 (GLP-1) has emerged as a key regulator of metabolic, inflammatory and oxidative homeostasis, extending beyond its traditional function as an incretin hormone. This narrative review summarises the latest evidence from two decades of research into the role of GLP-1 in redox biology and metabolic regulation in tissues affected by obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. There is growing evidence that GLP-1 signalling modulates multiple oxidative pathways, including AMPK-dependent metabolic reprogramming, mitochondrial quality control, nitric oxide–cGMP signalling, the regulation of ferroptosis, and the suppression of inflammatory pathways such as the NLRP3 inflammasome. Through these mechanisms, GLP-1 contributes to maintaining cellular redox balance, mitochondrial resilience, and metabolic adaptation in conditions of chronic oxidative stress. The review also emphasises the complementary function of GLP-1 receptor agonists (GLP-1RAs) and natural bioactive compounds such as polyphenols, anthocyanins, terpenoids and omega-3 fatty acids. These compounds may reinforce antioxidant defences, reduce inflammatory signalling and support mitochondrial function. Particular attention is given to the role of the gut microbiota in determining GLP-1 responsiveness. Gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and bile acid derivatives, contribute to incretin secretion, intestinal barrier maintenance, and systemic redox regulation. This review integrates endocrinology, oxidative stress biology, microbiome science and nutritional biochemistry to provide a comprehensive framework describing GLP-1 as a multi-organ metabolic signal that coordinates endocrine, immune, mitochondrial and redox pathways. These insights will inform the development of future therapeutic strategies that combine GLP-1-based pharmacology with precision nutrition and microbiome-targeted approaches, with the aim of improving metabolic resilience and addressing the oxidative dysregulation associated with chronic metabolic diseases.

Antioxidants doi: 10.3390/antiox15101282

Authors: Radu Dumitru Moleriu Teodora Piroș Ruxandra-Cristina Marin Călin Muntean Lavinia Cristina Moleriu Adrian-Cosmin Ilie

Oxidative stress contributes substantially to skin aging, while antioxidant-based cosmetics and nutrition-oriented “skin-from-within” strategies are increasingly popular among young adults. However, no validated Romanian instrument integrates antioxidant-related knowledge, attitudes, nutrition/lifestyle behaviors, and cosmetic-use intentions. This study developed the 61-item Romanian Antioxidant Cosmetics and Nutrition Questionnaire (RO-ACNQ), including a 36-item psychometric core covering four hypothesized domains: Knowledge, Attitudes, Behavioral Intention, and Nutrition/Lifestyle. Initial psychometric evaluation used a unified dataset (N = 1013) comprising a reproducible synthetic multicenter benchmark (n = 957) and an observed pilot sample (n = 56). Exploratory factor analysis (KMO = 0.943) identified eight weak or structurally inconsistent items, yielding a refined 28-item, four-factor model with acceptable-to-good internal consistency (α = 0.70–0.89) and good fit in an internal, same-sample CFA evaluation (χ2/df = 1.43, CFI = 0.984, TLI = 0.982, RMSEA = 0.021, SRMR = 0.033). Discriminant validity was generally supported (HTMT ≤ 0.74), although convergent validity remained partial. Within the simulation-based benchmark, theoretically expected known-groups patterns, high synthetic test–retest stability (ICC ≥ 0.97), and a Knowledge → Attitudes → Intention pathway were reproduced. Importantly, the refined domains showed encouraging internal consistency in the observed participants (α = 0.78–0.89; total α = 0.91), while differences between observed and synthetic response distributions identified areas requiring further calibration. These findings support the RO-ACNQ as a promising candidate instrument and establish a refined 28-item structure for prospective multicenter validation in participant-derived data.

Antioxidants doi: 10.3390/antiox15101281

Authors: Melody Pan Eleonora Scarlata Fiona Hui Jianguo Xia Cristian O’Flaherty

Infertility affects one in six couples worldwide, with male infertility contributing to ~50% of cases. Rising obesity rates have been linked to impaired male fertility, potentially through alterations in the gut microbiota; however, underlying mechanisms remain poorly understood. We characterized gut microbiome composition and lipidomic profiles in stool, serum, and testis samples. We assessed sperm quality in C57BL6 male mice fed a 45% fat diet (high-fat diet, HFD) or a 10% fat diet (normal diet, ND). We analyzed the gut microbiota by 16S rRNA sequencing. We measured short-chain fatty acids by gas chromatography. We performed untargeted lipidomic profiling of stool, serum, and testis using UPLC-MS/MS. CASA and cytochemical and immunocytochemical analyses assessed sperm quality and oxidative stress markers. HFD-fed mice exhibited gut microbiota dysbiosis characterized by an increased Bacillota/Bacteroidota ratio, altered bacterial community composition, increased acetic acid, and reduced butyric acid. Lipidomic analyses revealed distinct stool, serum, and testis lipid profiles, including increased abundance of gut microbiota-associated lipids containing odd-chain fatty acyl groups in HFD-fed mice. These alterations were accompanied by reduced sperm motility, impaired acrosomal integrity and epididymal sperm maturation, and elevated oxidative and nitrosative stress. Collectively, these findings support a gut–testis–epididymis axis in which altered gut microbiota-derived lipids contribute to oxidative stress and reduced sperm quality.

Antioxidants doi: 10.3390/antiox15101280

Authors: Hae Sung Lee Jong-Shik Kim

Oxidative stress has been implicated in both cancer pathogenesis and treatment-related toxicity, and structured exercise has been proposed as a non-pharmacological strategy that may help modulate this redox imbalance in patients and survivors with cancer, although the consistency of this effect across the existing literature remains unclear. This scoping review, conducted in accordance with PRISMA-ScR guidance, searched four databases for exercise intervention studies reporting at least one oxidative stress or antioxidant biomarker in adult cancer patients or survivors, published between January 2000 and July 2026. Data were charted narratively rather than pooled, with attention to biomarker category, biological specimen, analytical method, sampling timing, and the completeness of exercise-prescription and treatment-context reporting. Twelve reports representing ten independent cohorts met the eligibility criteria. The evidence base consisted of randomized, non-randomized, and single-arm studies and was dominated by studies involving women with breast cancer. Because nine of the 12 reports enrolled women with breast cancer, the findings primarily characterize this population and may not be directly generalizable to other cancer types, male patients, or patients receiving different treatment regimens. Across the included reports, reductions in lipid peroxidation products and markers of protein or DNA oxidative damage were reported in some studies, whereas findings for enzymatic antioxidants and composite redox indices were directionally inconsistent. However, these descriptive patterns should be interpreted cautiously because the included studies varied substantially in design, specimen type, analytical platform, sampling timing relative to exercise and treatment, and reporting completeness. Overall, the heterogeneity in study design, treatment context, biomarker measurement, and sampling procedures precludes conclusions regarding the magnitude or direction of exercise-related redox effects in this population.

Antioxidants doi: 10.3390/antiox15101279

Authors: Katarzyna Męczarska Wiktoria Tarasiuk Dariusz Jedrejek Anna Bieniek Sabina Lachowicz-Wiśniewska Dorota Bonarska-Kujawa Sylwia Cyboran-Mikołajczyk

Elaeagnus multiflora Thunb. is a rich source of structurally diverse phytochemicals, yet the relationship between organ-specific composition, antioxidant activity, and protection of biological membranes remains insufficiently understood. In this study, XAD-16-purified phenolic-rich fractions obtained from leaves and fruits of the ‘Marianna’ cultivar were characterized using UHPLC–CAD–HR–QTOF–MS/MS and UHPLC–UV, and their antioxidant properties were evaluated using DPPH, CUPRAC, and ORAC assays as well as erythrocyte membranes and a lipid model of these membranes. Hereafter, these fractions are referred to as leaf and fruit extracts. The leaf extract was dominated by flavonol glycosides, with kaempferol derivatives as the major constituents, whereas the fruit extract contained higher contributions from gallic acid derivatives, flavan-3-ols, and hydrolysable tannins. The fruit extract showed stronger DPPH and CUPRAC activities than the leaf extract (IC50: 12.7 ± 0.7 vs. 63.5 ± 5.4 and 11.4 ± 2.0 vs. 33.1 ± 1.2 µg/mL, respectively), whereas the leaf extract exhibited greater ORAC activity (2.2 ± 0.3 vs. 6.0 ± 0.7 µg/mL). In AAPH-treated liposomes prepared from erythrocyte membrane lipids, the fruit extract showed stronger protection against lipid oxidation (IC50 = 3.8 ± 1.2 vs. 9.5 ± 1.1 µg/mL). Neither extract increased erythrocyte hemolysis relative to the control. Fluorescence measurements indicated more pronounced effects of the fruit extract on membrane-associated parameters, while the leaf extract produced no significant changes in DPH anisotropy or Laurdan generalized polarization. The results demonstrate that antioxidant efficacy depends on phytochemical composition and experimental context. Although the stronger DPPH and CUPRAC responses of the fruit fraction co-varied with its greater protection in AAPH-treated RBCL liposomes, this relationship was not reproduced across the remaining membrane models, and the superior ORAC response of the leaf fraction did not translate into greater membrane protection.

Antioxidants doi: 10.3390/antiox15101278

Authors: Ji-Won Kim Ye-Jee Lee Kyuho Kim Seung-Hyun Ko

Type 2 diabetes (T2D) develops when pancreatic beta cells progressively fail to compensate for insulin resistance in a host environment shaped by diet, adiposity, aging, medications, and genetics. Gut microbial dysbiosis and oxidative stress are often treated as parallel abnormalities; however, evidence increasingly supports a bidirectional microbiome–redox axis. Reduced butyrate production, altered bile-acid and amino-acid metabolism, intestinal barrier failure, and microbial products can promote mitochondrial dysfunction, NADPH oxidase activity, inflammation, and impaired insulin signaling. Conversely, hyperglycemia, lipotoxicity, inflammation, and reactive oxygen and nitrogen species remodel the intestinal habitat, favoring inflammation-adapted organisms and reinforcing dysbiosis. This review synthesizes evidence linking this circuit to insulin-responsive tissues, pancreatic islets, regulated cell death, and diabetic complications and critically examines dietary, microbiome-directed, antioxidant, glucose-lowering, and metabolic-surgical interventions. Human evidence is strongest for reproducible functional shifts, medication–microbiome interactions, and modest benefits of selected dietary and biotic interventions, whereas redox mediation and durable clinical efficacy remain heterogeneous. Future studies should integrate longitudinal metagenomics, metabolomics, validated redox biomarkers, strain-level and spatial sampling, and causal designs to identify patients with T2D most likely to benefit from microbiome–redox precision therapy.

Antioxidants doi: 10.3390/antiox15101277

Authors: Enric Rubio-Contreras Alonso Pérez-Toribio Patricia Álvaro Ana M. Cosialls Constanza Morén

Schizophrenia (SCZ) remains one of the most disabling psychiatric disorders, in large part because current antipsychotics (APs) inadequately address negative symptoms and cognitive deficits. Converging evidence implicates a set of interconnected mechanisms, NMDAR hypofunction, oxidative stress, and a possible low-grade neuroimmune activation, that converge on parvalbumin-positive GABAergic interneuron dysfunction, the likely substrate of these refractory symptom domains. N-Acetylcysteine (NAC) is an adjunctive candidate because it may act on several of these pathways: it replenishes glutathione (GSH), restores redox balance, and modulates glutamatergic transmission, while its immunomodulatory effects remain poorly characterized in SCZ. This comprehensive review synthesizes evidence from preclinical models and clinical trials, showing that NAC produces replicated but modest benefits for negative symptoms and cognitive function, with inconsistent effects on positive symptoms. Notably, null findings in clinical-high-risk and treatment-resistant populations, together with a single exploratory subgroup analysis in early psychosis in which a peripheral redox index (erythrocyte glutathione peroxidase activity) was associated with positive-symptom response, raise the hypothesis that NAC efficacy may depend on a pre-existing, measurable antioxidant deficit. Adequately powered, biomarker-enriched trials that stratify patients by redox status are therefore needed to determine whether NAC is an effective targeted therapy for a mechanistically defined SCZ subgroup. Such trials would resolve whether the modest effect sizes observed in unselected populations reflect true but limited efficacy or dilution by enrolment of redox-normal patients unlikely to benefit.

Antioxidants doi: 10.3390/antiox15101275

Authors: Jianfa Wu Ying Cui Huanang Chen Shaofeng Shuai Zhimin Zhou Sijing Su Yusen Hou Ce Tang Yi Zhang

Oxidative stress and inflammation are central barriers to oral mucosal ulcer repair, yet redox-oriented interventions for recurrent aphthous ulcer (RAU)-relevant injury remain insufficiently defined. Ellagic acid (EA) is a naturally occurring polyphenol with antioxidant and anti-inflammatory activities, but its role in oral mucosal repair and the associated signaling events require further characterization. Here, EA was selected from serum-exposed constituents of Yumai Kouyan Heji (YMKY) and evaluated using computational target prioritization, a rat model of acetic acid-induced oral ulcers, and H2O2-injured human oral keratinocytes. Network and molecular analyses identified STAT3 and EGFR as putative targets for further investigation. In vivo, EA accelerated ulcer closure, improved epithelial integrity and collagen organization, improved serum antioxidant indices, reduced serum MDA and inflammatory cytokine levels, and attenuated apoptosis. EA also reduced injury-associated phosphorylation of STAT3 and EGFR in ulcer tissues. In vitro, EA improved cell viability and migration-assay outcomes in H2O2-injured human oral keratinocytes, reduced DCF fluorescence and inflammatory responses, preserved mitochondrial membrane potential, reduced apoptosis, and regulated STAT3/EGFR phosphorylation together with Bax/Bcl-2 expression. These findings support the repair-promoting activity of EA in experimental oral mucosal injury, accompanied by improved redox-inflammatory indices and altered STAT3/EGFR signaling. The causal involvement of these pathways and the applicability of the findings to human RAU remain to be established.

Antioxidants doi: 10.3390/antiox15101276

Authors: Meixian Zhang Huan Chen Ting Liu Yunbo Wang Yining Cheng Yingquan Hao

Oxidative stress can impair calf health and performance, and oregano essential oil (OEO) has potential antioxidant activity. This study evaluated dietary OEO in a diquat-induced oxidative-stress model using 24 weaned male Holstein calves assigned to a 2 × 2 factorial design with OEO supplementation (0 or 8 g/day) and diquat challenge (saline or 8 mg/kg body weight). Growth performance, serum biochemical, antioxidant, oxidative-damage and inflammatory indices, hepatic Nrf2-related antioxidant gene expression, rumen microbiota, and rumen metabolomics were assessed. The results showed that growth responses were phase dependent: OEO increased overall average daily gain (ADG) and dry matter intake (DMI), whereas diquat reduced overall ADG; no OEO × diquat interaction was detected for overall growth outcomes. The OEO group had higher serum SOD, GSH-Px, and T-AOC levels and lower levels of selected oxidative-damage and inflammatory indices, although the responses varied by endpoint and time point. Hepatic RT-qPCR showed treatment-associated differences in Keap1, HMOX1, GCLC, GCLM, and SOD1 expression. Rumen 16S rRNA gene sequencing showed treatment-associated shifts in microbial community composition, whereas PICRUSt2 predicted differences in microbial functional potential, including amino-acid-metabolism-related functions. Untargeted metabolomics identified treatment-associated differences in rumen metabolite profiles and KEGG pathway-enrichment patterns. Correlation analysis indicated that OEO-associated characteristic metabolites were positively correlated with antioxidant markers and negatively correlated with oxidative-damage and pro-inflammatory indices. Overall, OEO supplementation was associated with improved antioxidant status and distinct rumen microbial-metabolic profiles in diquat-challenged calves, supporting its potential as a natural feed additive, while the involvement of specific molecular pathways requires further validation.

Antioxidants doi: 10.3390/antiox15101273

Authors: Babita Kumari Baniya Hye Jin Kim

The retinal pigment epithelium (RPE) plays a key role in age-related macular degeneration (AMD). With aging, bisretinoids such as A2E accumulate in RPE lysosomes, and this accumulation is markedly accelerated by ABCA4 loss of function, which impairs the clearance of retinaldehyde from photoreceptor disc membranes. A2E acts as a blue-light photosensitizer, generating reactive oxygen species that cause oxidative stress, lysosomal impairment, and mitochondrial dysfunction. This oxidative burden disrupts the balance between Nrf2-mediated antioxidant defense and NF-κB-driven inflammation. Astaxanthin, a marine-derived xanthophyll carotenoid, may regulate this balance by activating Nrf2/ARE-mediated cytoprotective responses and suppressing NF-κB-dependent inflammation. This review summarizes mechanistic, preclinical, and clinical evidence for astaxanthin’s protective effects on RPE cells, with emphasis on bisretinoid-induced retinal injury. Astaxanthin reduces oxidative stress, inhibits NF-κB activity, and enhances Nrf2-dependent antioxidant defenses in hydrogen peroxide-, light-, and ischemia-induced retinal damage; however, because these models do not directly reproduce A2E-mediated phototoxicity, A2E-specific protection remains an untested hypothesis. Standardized A2E-specific models are needed to determine whether these protective effects extend to A2E and its photoproducts. Clinical evidence is also limited and largely based on multi-carotenoid formulations, which prevents the isolation of the effects of astaxanthin.

Antioxidants doi: 10.3390/antiox15101271

Authors: Muhammad Zahoor Khan Mengmeng Li Abdul Qadeer Abd Ullah Junjie Liu Qingshan Ma Wenqiang Liu Changfa Wang

Mastitis, driven predominantly by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Streptococcus species, remains a leading cause of economic loss and antimicrobial use in dairy production. Growing evidence implicates ferroptosis—an iron-dependent, non-apoptotic cell death executed through uncontrolled membrane lipid peroxidation—as a central mechanism of mammary epithelial injury during intramammary infection. Synthesizing evidence from bovine, caprine and murine systems, this review shows that phylogenetically diverse mastitis pathogens converge on a shared three-pillar ferroptotic program: autophagic liberation of catalytic iron via ferritinophagy, mitophagy and chaperone-mediated degradation of glutathione peroxidase 4 (GPX4); lipid-metabolic remodeling that expands peroxidation-susceptible phospholipid substrates; and collapse of the system Xc−/glutathione (GSH)/GPX4 antioxidant axis under Nrf2 control. Viral, xenobiotic, nanomaterial and microbiota-driven insults all engage the same program. The endpoint is convergent, not pathogen-specific. Anti-ferroptotic interventions vary in mechanism, from phytochemicals and selenium nanomaterials to extracellular vesicles and engineered stem cells. Most act on the same few regulatory nodes, chiefly Nrf2, SIRT1, SLC7A11 and GPX4. Ferroptosis-associated genes are being tested as biomarkers for resistance breeding. We grade studies by how directly ferroptosis was shown, separating direct evidence from inference based on upstream omics alone. Questions remain about cell-type-specific roles, timing during natural infection, and whether models translate to the field.

Antioxidants doi: 10.3390/antiox15101274

Authors: Ducdat Le Dong Young Rhyu Mina Lee

Pyrus pyrifolia (Burm. f.) Nakai has long been utilized in traditional East Asian medicine to treat respiratory disorders, fever, cough, and inflammatory conditions. This study aimed to evaluate the antioxidative and anti-inflammatory effects of P. pyrifolia. UHPLC-MS/MS analysis revealed that P. pyrifolia contained 22 primary and other putative compounds belonging to diverse phytochemical groups—phenolics, flavonoids, fatty acids, terpenoids, alkaloids, and other compounds. Network pharmacology identified a subset of overlapping targets associated with inflammatory diseases, which were significantly enriched in immune- and inflammation-related biological processes. KEGG pathway analysis demonstrated that the Toll-like receptor was the principal pathway potentially regulated by overlapping targets. PPI network analysis revealed TNF to be the most influential hub target, which was verified by molecular docking analysis. Interestingly, the P. pyrifolia extract significantly inhibited LPS-induced TNF-α production by modulating IκBα phosphorylation and restoring IκBα expression in the NF-κB signaling pathway. Additionally, the P. pyrifolia extract also markedly reduced the phosphorylation of ERK, p38, and JNK, thereby affecting MAPK signaling pathways. Our findings provide mechanistic evidence supporting the traditional medicinal use of P. pyrifolia to establish a theoretical framework to develop phytopharmaceuticals for inflammatory diseases.

Antioxidants doi: 10.3390/antiox15101272

Authors: Ayanda Ngcobo Samukelisiwe C. Shabalala Nokulunga Hlengwa Ndivhuwo Muvhulawa Patrick Orlando Sonia Silvestri Luca Tiano Phiwayinkosi V. Dludla

Sulforaphane, a bioactive isothiocyanate abundant in cruciferous vegetables, has emerged as a potential multi-target therapeutic agent capable of mitigating these pathological processes. Here, using evidence from preclinical and clinical literature, we review the mechanistic and translational evidence linking sulforaphane with the preservation of skeletal muscle tissue in the context of sarcopenia associated with T2D. The reviewed evidence suggests sulforaphane modulates oxidative stress, inflammation, and mitochondrial dysfunction through activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and related signaling pathways. Preclinical rodent studies corroborate these findings, reporting improved muscle mass, contractility, metabolic homeostasis, and attenuation of inflammation via Nrf2/heme oxygenase (HO)-1, AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) pathways. Limited clinical evidence from two small studies in healthy adults suggest that short-term sulforaphane supplementation (30 mg/day) may reduce exercise-induced muscle damage and enhance antioxidant responses. The evidence collectively highlights sulforaphane as a promising candidate for preserving skeletal muscle integrity in T2D. However, more randomized controlled trials are required to define optimal dosing, long-term safety, and direct efficacy in patients with sarcopenia and diabetes. This review strengthens the translational value of sulforaphane while integrating mechanistic insights and therapeutic potential against T2D-associated sarcopenia.

Antioxidants doi: 10.3390/antiox15101270

Authors: Qiming Duan Xiang Li Kunhong Xie Aibing Yu Yuheng Luo Ping Zheng Xiangbing Mao Hui Yan Jun He

Epigallocatechin-3-gallate (EGCG), a major catechin in green tea, possesses antioxidant and immunomodulatory properties. We hypothesized that dietary EGCG supplementation before oxidative challenge would attenuate Diquat-induced redox disturbance and help maintain intestinal epithelial integrity and immune-related homeostasis in weaned pigs. To test this hypothesis, 32 weaned piglets were assigned to a 2 × 2 factorial arrangements involving dietary EGCG supplementation (0 or 50 mg/kg) and saline or Diquat challenge (10 mg/kg body weight). Dietary EGCG increased serum superoxide dismutase activity and immunoglobulin A, G, and M concentrations and decreased serum IL-1β, whereas Diquat decreased superoxide dismutase activity and immunoglobulin concentrations and increased TNF-α (p < 0.05). A significant EGCG × Diquat interaction was detected for serum total antioxidant capacity (p = 0.020), which was increased by EGCG in Diquat-challenged pigs (Sidak-adjusted p = 0.001). Significant interactions were also observed for duodenal and jejunal ZO-1 immunoreactivity, jejunal sIgA immunoreactivity, and jejunal epithelial apoptosis (p < 0.05). Under Diquat challenge, EGCG increased ZO-1 and sIgA immunoreactivity and reduced TUNEL-positive staining (adjusted p < 0.05). Intestinal gene-expression responses were segment dependent: EGCG was associated with increased IL-10 and FOXP3 expression and with reduced expression of IL-17, IL-22, RORγT, STAT3, caspase-3, caspase-9, and BAX in several intestinal segments, particularly in Diquat-challenged pigs. Collectively, the observed findings indicate associations between dietary EGCG supplementation and systemic antioxidant and immune indices, epithelial barrier-related characteristics, immune-cell phenotypes, and mucosal transcriptional responses. Given the number of outcomes examined and the absence of a global multiplicity adjustment, these findings should be interpreted as exploratory and do not establish a specific protective mechanism.

Antioxidants doi: 10.3390/antiox15101269

Authors: Ziqi Wang Yifan Wang Guangyu Liu Jing Lv Hong Tang Zhongliang Jiang

Zinc oxide nanoparticles (ZnO NPs) are increasingly used as feed additives and antimicrobial alternatives in livestock production, but their potential reproductive toxicity remains insufficiently understood. Autophagy and apoptosis are central regulators of follicular atresia and granulosa cell fate, but whether ZnO NPs disrupt these processes in granulosa cells and how they interact mechanistically remain unclear. In this study, we tested whether ZnO NPs couple autophagy to apoptosis in mouse granulosa cells (GCs) through Notch3 signaling. Primary GCs were exposed to ZnO NPs and analyzed via viability assays, RT-qPCR, immunoblotting, and RNA-seq, with pharmacological perturbation of autophagy, apoptosis, and Notch signaling. ZnO NPs reduced viability and induced autophagic and apoptotic responses. The autophagy inhibitor 3-methyladenine (3-MA) partially attenuated ZnO NPs-induced autophagy-associated alterations, improved viability, and attenuated apoptosis. Conversely, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) reduced apoptosis and partially modulated autophagy-associated markers but did not fully reverse the ZnO NPs-induced autophagic response. Transcriptomics identified altered Notch signaling, and ZnO NPs reduced NOTCH3, the NOTCH3 intracellular domain, and HES1. 3-MA partially restored this axis, linking autophagy-associated alterations to Notch3 signaling suppression. Consistent with a protective role for Notch signaling, the γ-secretase inhibitor DAPT aggravated ZnO NPs-induced viability loss and apoptosis. Together, these pharmacological interventions support a model in which ZnO NPs-induced autophagic alterations contribute to apoptosis through suppression of Notch3 signaling, while apoptosis inhibition only partially modulates the autophagic response. This autophagy–Notch3–apoptosis regulatory network provides a framework for evaluating the ovarian toxicity of ZnO NPs.

Antioxidants doi: 10.3390/antiox15101268

Authors: Jiajia Yu Zhiyuan Liu Yanping Li Zhen Liu Cen Xiang Yuou Teng

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by lipid metabolism dysregulation, insulin resistance, inflammation, and potential progression to severe liver conditions. Xiaochaihutang (XCHT), a traditional Chinese medicine, has been explored for its therapeutic potential. This study aimed to systematically investigate the role and mechanisms of XCHT in the treatment of MASH. Network pharmacology and ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) were used to identify active components and pathways. In vitro models using free fatty acids (FFAs) and an in vivo methionine-choline-deficient (MCD) diet-induced MASH mouse model were employed to evaluate hepatoprotective effects, metabolic improvements, and gut microbiota modulation. XCHT reduced FFA-induced injury, decreased aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels, inhibited lipid accumulation (72% reduction in triglyceride, TG), and alleviated oxidative stress (67% decrease in oxygen species, ROS; 92% restoration of glutathione, GSH). It also modulated gut microbiota, increasing beneficial bacteria, and activated the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway (2.2-fold increase in phosphorylated AMPK, p-AMPK). Quercetin, kaempferol, β-sitosterol, and baicalin were predicted as key active components. XCHT ameliorates MASH through multi-target regulation of the AMPK pathway and gut–liver axis, supporting its potential as a complementary treatment for metabolic liver diseases.

Antioxidants doi: 10.3390/antiox15101267

Authors: Ziyi Zhang Xiaonan Zhang Chengchen Wang Yong Zhang Hai Bo

Mitochondrial-derived peptide MOTS-c is an exercise-responsive mitokine, yet its associations with exercise capacity and antioxidant markers remain unclear. This cross-sectional study examined serum MOTS-c across three stratified groups of 30 healthy young males aged 18 to 25 years: elite track and field athletes (n = 10), recreationally active individuals (n = 10), and sedentary controls (n = 10). Measurements included serum MOTS-c, SOD, post-exercise MDA, VO2max, forced vital capacity, vertical jump height, handgrip strength, back muscle endurance, and post-fatigue back muscle force. Serum MOTS-c increased progressively across groups (athletes: 507.51 ± 67.42 pg/mL; active: 440.32 ± 32.83 pg/mL; sedentary: 319.31 ± 99.07 pg/mL; p < 0.001; Hedges’ g = 2.13 for athlete vs. sedentary comparison). Serum MOTS-c was strongly correlated with absolute VO2max (r = 0.892), SOD (r = 0.847), post-exercise MDA (r = −0.910), back muscle endurance (r = 0.725), and post-fatigue back muscle force (r = 0.812) (all p < 0.001). In exploratory hierarchical regression, post-exercise MDA remained significantly associated with serum MOTS-c after adjustment for VO2max, whereas SOD was not independently associated. Handgrip strength showed no significant correlation with MOTS-c (r = 0.315, p = 0.090). These findings suggest that serum MOTS-c is associated with exercise capacity and circulating antioxidant markers in young males, although the cross-sectional design precludes causal inference.

Antioxidants doi: 10.3390/antiox15101266

Authors: László Kőrösi Okba Hatem Franco Röckel György Schneider Szilvia Papp

Polyphenols are plant secondary metabolites widely recognized for their antioxidant properties and potential health benefits. Grapevine leaves are a rich yet underexplored source of these bioactive compounds. In this study, caftaric acid, and predominant flavonol glycosides were characterized in leaves of seventeen grapevine genotypes by high-performance liquid chromatography, while total phenolic content (TPC) was determined using the Folin–Ciocalteu assay. In addition, the growth-promoting effect of a polyphenol-rich Vitis amurensis leaf extract on Lactiplantibacillus plantarum and its protective effect under H2O2-induced oxidative stress were evaluated. Both TPC and phenolic composition were strongly genotype-dependent, with TPC ranging from approximately 20 to 100 mg gallic acid equivalents (GAE) g−1 dry weight (DW). Quercetin and kaempferol glycosides were the predominant flavonols, and quercetin-3-O-glucuronide, one of the most abundant derivatives, varied nearly tenfold among genotypes (approximately 2100–20,000 mg kg−1 DW). The leaf extract of V. amurensis, the genotype with the highest TPC, significantly promoted the in vitro growth of L. plantarum in a dose-dependent manner, resulting in higher viable cell counts after 24 h. The extract also markedly enhanced bacterial survival under H2O2-induced oxidative stress. At 2 mM H2O2, no bacterial growth was detected in the absence of the extract, whereas extract-supplemented cultures maintained substantial growth and reached a viable cell count of 1.8 × 108 colony-forming units (CFU) mL−1 after 24 h. The phenolic patterns identified across the investigated genotypes provide a basis for selecting Vitis genotypes as sources of specific flavonol glycosides. Furthermore, our microbiological results provide preliminary evidence of the beneficial effects of V. amurensis leaf extract on L. plantarum and warrant further investigation of its potential functional applications.

Antioxidants doi: 10.3390/antiox15101265

Authors: Rabiea Ashowen Ahmoda Milena Milošević Tihomir Kovačević Sanja Savić Ivona Janković-Častvan Boban Anđelković Tamara Erceg Aleksandra A. Jovanović Aleksandar Marinković

The development of chitosan (CS)-based films incorporating antioxidant compounds offers a promising approach for the design of functional biobased materials. CS films containing propolis and Fumaria officinalis extract (FOE) were prepared with triglyceryl citrate (TGC) and modified with limonene, ethyl lactate (EL), or diethyl adipate (DEA); their physicochemical, release, and antioxidant properties were evaluated. EL- and DEA-containing films exhibited greater structural homogeneity than limonene-based; higher FOE concentrations increased surface heterogeneity and porosity. Dynamic mechanical analysis showed that the viscoelastic response depended on the additive, with CSEL retaining the highest moduli and CSL-FOE exhibiting the most pronounced softening after FOE/propolis incorporation (G′~105 Pa at 100–110 °C; G″~104 Pa at 120 °C). EL-based films retained the highest tensile resistance and the most balanced strength-deformability profile (stress at break: ~53.58 N/mm2; strain at break: ~14.05%); increasing FOE content reduced stress at break. Film wettability and water uptake were governed by additive and FOE concentration. The release study demonstrated sustained polyphenol delivery, with EL- and DEA-based systems showing approximately 50% release after 24 h. Antioxidant assays confirmed a time- and concentration-dependent increase in activity. The antioxidant response profiles differed among the films, with EL films showing an earlier increase in antioxidant activity, limonene films exhibiting a more gradual response, and DEA films displaying an intermediate response pattern.

Antioxidants doi: 10.3390/antiox15101264

Authors: Jing Liu Rui Jia Pengfei Wang Yuhao Liang Fen Feng Fei Wang Qiaoli Yang

Oxidative stress compromises intestinal barrier function and antioxidant defense in weaned piglets, causing substantial economic losses in the pig industry. Probiotic interventions to improve gut health are considered a highly promising solution; research indicates that certain Lactobacillus species can promote the proliferation of Lgr5+ stem cells and activate the AhR/STAT3 pathway by modulating microbiota metabolism, thereby enhancing intestinal barrier and antioxidant function. Although Limosilactobacillus mucosae (L. mucosae) has demonstrated antioxidant properties in rodent models, its involvement in modulating intestinal stem cell (ISC) fate in piglets, as well as the associated mechanisms, remains unclear. We hypothesized that L. mucosae could alleviate oxidative stress in weaned piglets by modulating intestinal microbiota and activating the aryl hydrocarbon receptor/signal transducer and activator of transcription 3 (AhR/STAT3) signaling-mediated intestinal epithelial renewal. We compared the gut microbiota composition between Hezuo pigs (a subgroup of the plateau-type Tibetan breed) and Landrace × Yorkshire (LY) pigs, and isolated L. mucosae LM410 from Hezuo pigs. The strain was evaluated for acid and bile tolerance, antioxidant activity, and inhibitory properties. Subsequently, a 14-day animal trial was conducted using Duroc × Landrace × Yorkshire (DLY) weaned piglets orally administered with 1 × 109 CFU/mL L. mucosae LM410. Intestinal morphology, barrier integrity, immune responses, antioxidant capacity and cecal microbiota composition and metabolic pathways were assessed. We found that Hezuo pigs harbored a higher abundance of L. mucosae in the gut compared with LY pigs. The isolate L. mucosae LM410 from Hezuo pigs, demonstrated strong acid and bile salt tolerance, as well as antioxidant and antimicrobial activities, and effectively improved intestinal morphology, barrier integrity, immune responses, and antioxidant capacity in DLY weaned piglets. Mechanistically, L. mucosae LM410 reshaped the cecal microbiota by enriching short-chain fatty acid (SCFA)-producing bacteria and upregulating the tyrosine metabolic pathway. Concomitantly, L. mucosae LM410 activated the AhR/STAT3 signaling axis, which likely promoted ISC proliferation and differentiation into goblet cells. These findings demonstrate for the first time that L. mucosae may enhance piglet antioxidant defense through coordinated cecal microbiome remodeling, upregulation of tyrosine metabolism and AhR/STAT3-driven epithelial renewal, providing a theoretical foundation for developing L. mucosae LM410 as a candidate probiotic to improve piglet health.

Antioxidants doi: 10.3390/antiox15101262

Authors: Yanfei Zhang Mengyuan Li Gezi Li Geng Ma Haiyan Zhang Lifang Wang Wei Feng Yingxin Xie Wanzhang Wang Dongyun Ma Chenyang Wang

WRKY (WRKY domain-containing) transcription factors represent one of the largest families of plant-specific transcription regulators and play pivotal roles in plant growth, development, nutrient acquisition, and responses to biotic and abiotic stresses. In this study, the coding sequence of TaWRKY65-3B was cloned from the hexaploid wheat cultivar Hanxuan 10. Domain analysis revealed that TaWRKY65-3B contains a conserved WRKY domain and a typical C2H2-type zinc finger motif. The gene spans 1478 bp and comprises two exons and one intron. Promoter analysis identified multiple cis-acting regulatory elements, including those responsive to abscisic acid, methyl jasmonate, drought, and low temperature. Quantitative real-time PCR (qRT-PCR) demonstrated that TaWRKY65-3B was significantly upregulated under polyethylene glycol (PEG)-simulated-drought stress in wheat. Overexpression of TaWRKY65-3B in rice resulted in marked growth inhibition, characterized by reduced plant height, shortened grains, and decreased grain width, perimeter, and surface area. These morphological changes led to a significant reduction in thousand-grain weight and overall grain yield. Mechanistically, TaWRKY65-3B activated the expression of OsCPS2, OsCPS4, and OsKS4, which encode key enzymes in the diterpenoid phytoalexin biosynthetic pathway. Subsequent oxidative modifications catalyzed by the cytochrome P450 monooxygenase OsCYP76M7 facilitated the accumulation of the defensive diterpenoid neoabietic acid. Integrated transcriptomic and metabolomic analyses revealed that constitutive TaWRKY65-3B overexpression reprograms simulated-drought-responsive metabolism in rice, with a diterpenoid metabolite annotated as neoabietic acid as a key correlative feature—though definitive structural confirmation requires authentic standards. These findings identify a WRKY-mediated regulatory module connecting diterpenoid phytoalexin metabolism to simulated-drought stress responses, although the precise molecular cascades governing the growth-defence trade-off between stress adaptation and yield warrant further investigation.

Antioxidants doi: 10.3390/antiox15101263

Authors: Yang Zhang Jaeyeon Lee Nan Nan Yu Mei-Hua Jin Ying-Hao Han Hyo-Jin Park Deog-Bon Koo Hu-Nan Sun Dong-Seok Lee

Peroxiredoxins (PRDXs) constitute a class of thiol-dependent oxidoreductive regulatory factors whose functions extend beyond peroxide detoxification to include the regulation of oxidoreductive signaling, organelle homeostasis, and cell fate determination. The emerging role of PRDX1–6 in fibrotic diseases—particularly PRDX1’s function as an oxidoreductive signaling modulator dependent on specific pathological contexts during renal injury and fibrosis—calls for further investigation. We propose a dual-regulatory model in which PRDX1 simultaneously governs both the mitochondrial reactive oxygen species (ROS)–JNK/Smad signaling pathway and the endoplasmic reticulum (ER) stress–protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP)-gasdermin E (GSDME) signaling pathway, thereby linking organelle oxidoreductive imbalance to epithelial cell injury, inflammatory cell death, and fibrotic remodeling. Notably, we hypothesize that the mitochondria-associated membranes (MAMs) serve as a critical spatial interface for the convergence of these signaling pathways. At the MAMs, PRDX1 may function as an “oxidoreductive gatekeeper,” buffering local peroxide signaling while coordinating the oxidoreductive balance, Ca2+ transport, and mitochondrial homeostasis between the ER and mitochondria. This theoretical framework provides a potential basis for elucidating the context-dependent role of PRDX1 in both acute and chronic renal injury, and identifies the PRDX1–MAMs oxidoreductive gating axis as a promising therapeutic target for renal fibrosis.

Antioxidants doi: 10.3390/antiox15101261

Authors: Tomasz Urbanowicz Mariusz Kowalewski Giuseppe Maria Raffa Beata Krasińska Calogera Pisano Vincenzo Nuzzi Mansur Rahnama Piotr Suwalski Zbigniew Krasiński Ewelina Grywalska

Heart transplantation remains the definitive treatment for selected patients with advanced heart failure, yet current donor heart assessment relies predominantly on clinical, functional, and biochemical variables that incompletely reflect the biological resilience of the graft. Increasing evidence indicates that oxidative stress represents a central mechanism linking donor characteristics, brain death, ischemia–reperfusion injury, endothelial dysfunction, mitochondrial impairment, inflammation, and regulated cell death. These interconnected processes collectively determine graft susceptibility to preservation injury and post-transplant dysfunction. This review introduces redox phenotyping as a novel conceptual framework for donor heart evaluation, integrating oxidative injury, antioxidant defenses, mitochondrial competence, endothelial integrity, metabolic adaptation, and redox-sensitive molecular signaling into a multidimensional assessment of graft biology. We summarize the mechanisms underlying donor heart oxidative remodeling throughout life, the molecular basis of ischemia–reperfusion injury, and emerging biomarkers, including metabolomics, lipidomics, extracellular vesicles, cell-free nucleic acids, and mitochondrial biomarkers. We further discuss how ex vivo machine perfusion enables real-time biological assessment and targeted therapeutic intervention, transforming organ preservation into a platform for dynamic redox characterization. Finally, we explore the integration of multi-omic profiling with artificial intelligence to enable individualized donor assessment and biological optimization.

Antioxidants doi: 10.3390/antiox15101260

Authors: Sandeep Kumar Gupta Jayantee Kalita Prakash C. Pandey Dhiraj Kumar Vivek Singh Roopali Mahajan

In intracerebral hemorrhage (ICH), an elevated oxidant level may lead to perihematoma edema (PHE) and adversely affect its outcome. We report circulating oxidative stress markers in ICH patients at different time points and their association with PHE on computerized tomographic (CT) scans. A total of 87 patients with CT confirmed ICH within 24 h of ictus were prospectively included, and a follow-up CT scan was performed on day 7. The location and volume of hematoma, hematoma edema complex (HEC), PHE, and intraventricular extension of hemorrhage were noted on both CT scans. Blood samples were collected on days 1, 7, and 15, and reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), and glutathione peroxidase (GPx) levels were measured using a microplate reader. These biomarkers were also measured in 57 age-matched healthy controls. The patients had elevated ROS (p < 0.001) and MDA (p < 0.001) levels, whereas CAT (p < 0.001) and GPx (p < 0.001) levels were reduced compared to the controls. The oxidants remained elevated on day 7 and decreased on day 15 but did not reach the control levels. Furthermore, the CAT and GPx showed recovery on day 7 and day 15 but did not achieve the control levels. ROS (r = 0.28, p = 0.02) and GPx (r = −0.29, p = 0.02) correlated with PHE, suggesting their role in the pathogenesis. The hematoma volume, HEC, and PHE at day 1 correlated with the day 15 CAT level and MDA with PHE. At one month, 15 (17.24%) patients died, 56 (64.36%) had poor recovery, and 16 (18.39%) had good recovery. The patients with higher antioxidant levels had better survival and good outcomes. Future studies may investigate the efficacy of antioxidant therapy in improving clinical outcomes and modulating oxidative stress biomarkers in ICH patients.

Antioxidants doi: 10.3390/antiox15101259

Authors: Magdalena Sulewska Patryk Wiśniewski Jagoda Tomaszuk Aleksandra Pietruska Anna Zalewska Emilia Szymańska Katarzyna Winnicka Mateusz Maciejczyk Małgorzata Żendzian-Piotrowska Małgorzata Pietruska

Background: Oxidative and nitrosative stress may contribute to the pathogenesis of oral lichen planus (OLP). This study compared the effects of photodynamic therapy (PDT) and topical corticosteroid therapy (CT) on selected salivary redox biomarkers. Materials and Methods: Thirty-nine patients with OLP were randomized to five weekly sessions of 5-aminolevulinic acid PDT (n = 20) or topical clobetasol applied for 14 days (n = 19). Salivary advanced oxidation protein products (AOPP), advanced glycation end products (AGE), 3-nitrotyrosine (NT), and peroxynitrite (PN) were measured before treatment, immediately after treatment, and after 6 and 12 months. Associations with lesion area and pain intensity were also assessed. Results: PDT significantly reduced AOPP concentrations, which remained below baseline throughout follow-up and were lower than after CT at all post-treatment assessments. AGE increased transiently after PDT but decreased thereafter and was lower than after CT at 12 months. NT was lower after PDT than after CT immediately after treatment. PN concentrations showed significant within-group changes over time in the CT group; however, baseline PN concentrations differed between the treatment groups, limiting direct interpretation of between-group differences. Biomarker concentrations showed no consistent associations with lesion area or pain intensity. Conclusions: PDT and CT were associated with different patterns of change in selected salivary redox biomarkers in OLP. PDT was particularly associated with a sustained reduction in AOPP concentrations, whereas the investigated biomarkers showed no consistent relationship with clinical disease severity.

Antioxidants doi: 10.3390/antiox15101256

Authors: George J. Dugbartey Liam McFarlane Talal Shamma Jifu Jiang Sally Major Aaron Haig Alp Sener

Background: Renal ischemia–reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). It is associated with reduced blood flow as encountered in vascular surgery, including aortic aneurysm repair and kidney transplantation. In this study, we investigated whether pre- and/or post-administration of sodium thiosulfate (STS), an FDA-approved hydrogen sulfide donor drug, attenuated IRI-induced AKI in rats. Methods: AKI was induced in male rats by clamping both renal arteries for 60 min. At 30 min before clamping, and 30 min after reperfusion, STS was administered at a weigh-based dose to achieve a circulating concentration of 150 μM, after which the rats were kept in metabolic cages for urine and blood collection on postoperative days (POD) 3, 5, and 7. Rats were sacrificed on POD3, POD5, and POD7, and kidneys were harvested for analysis. Sham-operated rats received no treatment. Results: AKI was evidenced by markedly higher acute tubular necrosis score, and renal protein and gene expression of damage markers (KIM-1 and NGAL), as well as markers of oxidative stress (MDA, GSH, and SOD), inflammation (MPO, IL-6), and apoptosis (TUNEL). While significant incremental improvement was observed in the expression of these markers in the pre-treatment only and post-treatment only groups over the POD3–7 observation period compared to untreated control group (p < 0.05), superior renal protection was observed in the pre + post-treatment group (p < 0.01). Functionally, serum creatinine levels were significantly higher over the POD3–7 observation period in the untreated group relative to pre-treatment and post-treatment groups (p < 0.05), and markedly lower in the pre + post-treatment group (p < 0.001), which positively correlated with urine output. Urine osmolality was statistically similar to sham-operated rats on POD5 and 7, while all other groups showed decreased urine osmolality on POD3 and 5 (p < 0.05). Mechanistically, the protective effect of STS correlated with upregulation of PGC1α and SIRT3 protein and gene expression and downregulation of NLRP3 protein and mRNA expression in the pre + post-treatment group compared to other groups (p < 0.05). Conclusions: The present study reports for the first time the protective effect of STS against IRI-induced AKI, and indicates PGC1α, SIRT3, and NLRP3 as molecular targets of STS.

Antioxidants doi: 10.3390/antiox15101258

Authors: Liyu Zhang Qi Tang Elsa Wilma Böhm Felix Mathias Wagner Adrian Gericke

Environmental pollution, a detrimental consequence of industrialization and globalization, is increasingly recognized as a potential risk factor for a wide range of human diseases, including retinal disorders. The retina is particularly vulnerable to environmental stressors, including particulate matter, nitrogen oxides, carbon monoxide, traffic-related noise, and extreme environmental conditions such as elevated temperatures. Epidemiological and experimental evidence suggests that these exposures may contribute to the development and progression of retinal diseases through mechanisms involving oxidative stress, chronic inflammation, immune dysregulation, and vascular dysfunction. These processes may ultimately contribute to retinal vasculopathies and degenerative disorders. Consequently, the pathophysiological mechanisms linking environmental exposures to retinal injury have received increasing attention in recent years. This review provides a disease-centered perspective on the relationship between environmental pollution and retinal diseases, integrating epidemiological evidence with experimental findings across specific retinal disorders. Among the environmental pollutants investigated to date, fine particulate matter (PM2.5) and nitrogen dioxide (NO2) have the most consistent epidemiological evidence for adverse effects on retinal health, particularly in relation to age-related macular degeneration (AMD). The review also discusses the methodological limitations and heterogeneity of the available evidence, as well as current knowledge gaps and future research perspectives.

Antioxidants doi: 10.3390/antiox15101257

Authors: Ruoyu Chai Zheng Liu Huihui Zhou Chengdong Liu Kangsen Mai Gen He Xuan Wang

This study investigated the effects of stocking density on growth, antioxidant responses, hepatic inflammatory signaling, and intestinal barrier function in cage-cultured large yellow croaker (Larimichthys crocea). Fish (~288 g) were reared for 8 weeks at low (5.73 kg/m3), medium (8.64 kg/m3), or high (11.55 kg/m3) initial stocking densities. High density reduced growth and survival and increased feed conversion ratio, serum cortisol, glucose, and malondialdehyde, while decreasing total antioxidant capacity and superoxide dismutase activity (p < 0.05). Hepatic Nrf2, SOD, CAT, and GPX expression decreased, whereas Keap1 expression increased at high density. High density also increased pro-inflammatory cytokine expression and NF-κB p65 phosphorylation, decreased anti-inflammatory factors and IκB abundance, shortened intestinal villi, reduced ZO-1, Occludin, and Claudin-1 abundance, and increased serum diamine oxidase, D-lactate, and endotoxin (p < 0.05). Medium-density fish showed generally comparable responses to low-density fish for most endpoints. These findings indicate that high stocking density induces physiological stress and oxidative imbalance associated with an impaired hepatic Nrf2-related antioxidant response, enhanced NF-κB inflammatory signaling, and impaired intestinal barrier integrity in large yellow croaker.

Antioxidants doi: 10.3390/antiox15101254

Authors: Shu-Xian Guo Zhi-Qiang Feng Run-Bo Li Fan Zhao Yan-Hua Li Wang Han Jian-Yong Han Zhi-Shen Mu Su-Ying Cao

Negative energy balance (NEB) in postpartum dairy cows elevates systemic non-esterified fatty acid (NEFA) levels, including palmitic acid (PA), which impair oocyte quality and contribute to reduced reproductive performance. Salidroside (SAL) has attracted attention for its prominent role in maintaining mitochondrial homeostasis. However, whether SAL can alleviate PA-induced oocyte damage remains unclear. Therefore, the present study was designed to investigate the protective effects of SAL against PA-induced oocyte damage and to explore the underlying mechanisms. We found that 0.2 mM PA triggered oxidative stress in oocytes, as evidenced by fluorescent staining results showing elevated ROS levels, reduced GSH content, and single-cell transcriptomic data revealing transcriptional suppression of HSPE1, ROMO1, and GSTM3. Meanwhile, PA treatment impaired mitochondrial function, reflected by decreased mitochondrial membrane potential and ATP levels, along with significant downregulation of mitochondrial function related genes, including NDUFA4, NDUFA6, ATP5PO, ATP5ME, COX5A, and UQCRH. These changes help explain why PA exposure reduces oocyte maturation rate and embryonic developmental potential. Notably, supplementation with 5 μM SAL effectively reversed the PA induced damage and restored oocyte developmental competence to control level to levels comparable to untreated controls. These findings suggest that SAL can restore oocyte developmental potential by mitigating the lipotoxic microenvironment induced by PA administration.

Antioxidants doi: 10.3390/antiox15101255

Authors: Shuaihu Chen Yulong Yin Jie Yin Xihong Zhou

The crosstalk between the gut microbiota and the host redox system is essential for maintaining intestinal homeostasis and systemic health. Disruption of this bidirectional interaction impairs redox balance, promotes oxidative stress, and contributes to the initiation and progression of a wide range of diseases, including inflammatory bowel disease, metabolic liver disease, neurodegenerative disorders, and chronic kidney disease. In this review, we comprehensively summarize the molecular mechanisms by which the gut microbiota regulates host redox homeostasis, focusing on microbial metabolites, immune signaling, and host antioxidant pathways. We also discuss emerging mechanisms underlying microbiota–host redox interactions, including extracellular vesicle (EV)-mediated interkingdom communication, microbiota-driven regulation of intestinal epithelial ferroptosis, and microbial metabolic reprogramming. Furthermore, we highlight how gut microbiota dysbiosis extends oxidative stress beyond the intestine through the gut–liver, gut–brain, and gut–kidney axes, thereby driving the development of multiple organ diseases. Finally, we summarize recent advances in microbiota-targeted therapies and engineered bacterial EVs as innovative strategies for restoring redox homeostasis, and discuss their potential for the precision prevention and treatment of oxidative stress-associated diseases as well as the development of next-generation microbiome-based therapeutics.

Antioxidants doi: 10.3390/antiox15101253

Authors: Tingting Feng Shengqin Liu Boxin Shi Liangliang Lv Xinyu Huang Ruining Li Hao Ai Zhanglun Sun Aifeng Zhou Yali Liu Rongfeng Cui Yuan Liu Xianzhong Huang

Rice, as a globally vital food crop, is frequently threatened by flooding, which adversely affects its growth and yield. The most immediate and prominent influence of waterlogging or submergence induced by flooding on rice is hypoxia (reduced oxygen availability) or anoxia (absence of oxygen) stress and the consequent energy deficiency. Rice has evolved specific acclimation strategies to counteract or alleviate flooding stress, including leaf gas film (LGF) formation, adventitious root (AR) emergence, aerenchyma formation, radial oxygen loss (ROL) barrier development, and the stunted or elongated growth of coleoptiles or internodes, all of which serve to secure oxygen supply and maintain energy homeostasis for sustaining survival. These adaptive traits and strategies are governed by the regulatory genes involved in the reprogramming of energy and carbohydrate metabolism, the accumulation and scavenging of reactive oxygen species (ROS), and the programmed cell death (PCD) process, as well as the phytohormone biosynthesis and signaling pathways. To facilitate a comprehensive understanding of the submergence response and tolerance and the intricate regulatory mechanisms in rice, this review integrates the impacts of flooding on the growth and development, the strategies employed to adapt to submergence, the physiological and biochemical characteristics, the phytohormonal signaling and crosstalk, and the molecular mechanistic framework of rice subjected to submergence stress. It also highlights the importance of key superior genes for flooding-tolerance, flooding-tolerant germplasms, and molecular breeding technologies in developing submergence-tolerant rice varieties. By aligning these advances, this review provides valuable insights into and guidance for improving resilience to submergence stress and enhancing crop production under constantly changing climate conditions.

Antioxidants doi: 10.3390/antiox15101252

Authors: Areti Kourti Paraskevi Karioti Foteini Chouliara Elisavet Georgiou Kali Makedou Ioannis Kalogiannidis

Background: Uterine smooth muscle tumors present a diverse clinical spectrum, ranging from ubiquitous benign leiomyomas to highly lethal uterine leiomyosarcomas (uLMSs). The preoperative differentiation of these entities, alongside the intermediate smooth muscle tumors of uncertain malignant potential (STUMP), remains an unresolved clinical challenge. Methods: This comprehensive review synthesizes the current literature on the pathogenesis of uterine smooth muscle tumors, focusing on the role of oxidative stress and its downstream molecular effectors. We evaluate the interplay between oxidative stress markers, epigenetic regulation via microRNAs (miRNAs), and circulating glycoproteins. Results: Increased oxidative stress is a hallmark associated with uLMS, characterized by altered antioxidant enzyme activity and elevated lipid peroxidation products such as malondialdehyde (MDA). This oxidative burden is associated with DNA damage and profound genomic instability, participating in the evolution of the malignant phenotype. Concurrently, the stressed tumor microenvironment exhibits significant epigenetic deregulation. Tumor-suppressive miRNAs (e.g., the miR-29 and miR-200 families) are downregulated, while oncogenic miRNAs (e.g., miR-21) are upregulated, promoting survival and proliferation pathways. Furthermore, galectin-1, a glycoprotein responsive to microenvironmental stress, is elevated in the serum of uLMS and STUMP patients, demonstrating high specificity in investigated cohorts, though limited sensitivity (47%), whereas mucin-1 (MUC1) shows no significant diagnostic utility. Conclusions: Oxidative stress is strongly associated with the genomic instability and molecular derangements observed in uterine sarcomas. Integrating oxidative stress indicators with specific miRNA signatures and galectin-1 levels could potentially yield robust, non-invasive diagnostic panels. However, prospective validation in large, independent cohorts is strictly required before these markers can be implemented to improve preoperative risk stratification and guide targeted therapeutic interventions.

Antioxidants doi: 10.3390/antiox15101251

Authors: Yong-Ha Jo Hannah Cho Dong-Sung Lee Jeong Hoon Cho

Dihydromyricetin (DHM), a dietary flavanonol known for its antioxidant and neuroprotective properties, has been connected to mitochondrial homeostasis, yet how it engages mitochondrial quality control during aging has not been resolved. This study examined DHM’s effects on lifespan, neuronal integrity, resistance to oxidative stress, mitochondrial status, and lipid handling in Caenorhabditis elegans. DHM (50–200 μM) extended mean lifespan by 9.1–15.0%, reduced age-related degeneration of ALM (anterior lateral microtubule) and PLM (posterior lateral microtubule) touch-receptor neurons, and preserved locomotor and anterior touch-response performance into later adulthood. Survival after juglone challenge improved with DHM treatment, and the compound showed robust 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging activity. DHM modestly lowered tetramethylrhodamine ethyl ester (TMRE) fluorescence. In a separate cohort assessed under a different exposure schedule, the mtDNA copy number did not differ significantly from that of the vehicle. DHM also increased GFP-negative/mCherry-positive mitochondrial puncta in ALM neurons, patterns consistent with a shifted mitochondrial energetic state and greater mitochondrial trafficking to acidic degradative compartments. The neuroprotective effect persisted in ucp-4(ok195) mutants but was not statistically detected in pink-1(tm1779); pdr-1(gk448) double mutants; since a formal cross-genotype interaction test was not performed, this pattern is treated as hypothesis-generating rather than definitive evidence of pathway dependency. DHM lowered intestinal lipid stores, suppressed fat-5, fat-6, and fat-7 expression, and modestly upregulated atfs-1. Neither the SOD-3 nor GST-4 canonical reporters showed significant induction, and DHM’s lifespan-extending effect was retained in daf-16(mu86) mutants, with an exploratory Cox model providing no evidence of a genotype × dose interaction. Together, these findings indicate that DHM is associated with healthspan-related phenotypes alongside a coordinated pattern of redox regulation, mitochondrial quality-control responses, and metabolic adjustment.

Antioxidants doi: 10.3390/antiox15101250

Authors: Baozhu Lu Vikas Vikas Weibing Yang Robert H. Hadfield Brian C. Wilson Timothy C. Zhu

Accurate quantification of singlet oxygen (1O2) production is central to photodynamic therapy (PDT) dosimetry, yet direct measurement remains challenging due to the weak and transient nature of 1O2 luminescence. To our knowledge, this study presents the first controlled exploratory cross-platform comparison of Multispectral Singlet Oxygen Luminescence Dosimetry (MSOLD) and Time-Resolved Singlet Oxygen Luminescence Detection (TSOLD) under matched irradiation conditions. MSOLD enables continuous monitoring during irradiation through spectral decomposition of near-infrared emission, whereas TSOLD uses pulsed excitation and time-correlated single-photon counting to provide lifetime-resolved 1O2 measurements. Across PpIX concentrations of 10–100 mg/kg, both methods detected irradiation-induced decreases in 1O2 luminescence, while TSOLD provided stable lifetime estimates of approximately 10 µs in the methanol-rich phantom. Across fluence rates of 1–5 W/cm2, both techniques showed progressively larger irradiation-induced reductions in 1O2 luminescence with increasing irradiance. Cumulative MSOLD-derived 1O2 signals showed an approximately linear relationship with Singlet Oxygen Explicit Dosimetry (SOED) calculations (R2 > 0.98) under the investigated conditions. Together, these results demonstrate consistent concentration- and fluence-rate-dependent trends between MSOLD and TSOLD and highlight their complementary measurement characteristics: MSOLD provides continuous spectral monitoring during irradiation, whereas TSOLD provides lifetime-resolved characterization of 1O2 and photosensitizer kinetics. These findings provide a basis for future replicated and biologically relevant studies of luminescence-based PDT dosimetry.

Antioxidants doi: 10.3390/antiox15101249

Authors: Husam Qanash Aisha M. H. Al-Rajhi Abdulrahman S. Bazaid Fahad Almarshadi Walid Alesefir Abdu Aldarhami Waleed Hakami Amro Duhduh Abeer Omar Ahmed

Natural products may address infection, oxidative stress and metabolic disorders. This study used gas chromatography-mass spectrometry (GC-MS), bioassays and molecular docking to characterize Delonix regia seed oil and evaluate its antimicrobial, antibiofilm, radical-scavenging and pancreatic lipase-inhibitory activities. The most abundant tentatively identified peaks in the GC-MS total ion chromatogram were β-sitosterol (26.35%), stigmasterol (14.57%), linoleic acid (10.39%), and oleic acid (5.82%). Minimum inhibitory concentrations (MICs) were 15.62 µg/mL for Listeria monocytogenes, Salmonella typhi, and Candida albicans, and 62.5 µg/mL for methicillin-resistant Staphylococcus aureus. The corresponding inhibition zones were 28 ± 0.7, 21 ± 0.3, 31 ± 0.1, and 15 ± 0.5 mm, respectively. At 75% of the minimum bactericidal/fungicidal concentration, the oil inhibited biofilm formation by 94.95% for both L. monocytogenes and C. albicans. DPPH and ABTS radical-scavenging IC50 values were 17.04 ± 0.25 and 13.17 ± 0.40 µg/mL, respectively, while the pancreatic lipase IC50 was 26.29 ± 0.08 µg/mL. Time-kill assays demonstrated ≥3 log10 CFU/mL reductions, with no recoverable colonies for any of the five tested pathogens within 3 h. Docking predicted stronger stigmasterol binding to L. monocytogenes Sortase A (−6.60 kcal/mol) than to C. albicans lanosterol 14α-demethylase (CYP51; −3.41 kcal/mol), involving hydrogen bonds with Met63 and Arg381, respectively, and hydrophobic contacts. These findings identify a phytosterol-enriched GC-MS-detectable fraction of Delonix regia seed oil with in vitro activities warranting further mechanistic and in vivo investigation.

Antioxidants doi: 10.3390/antiox15101248

Authors: Ziling Lin Yuning Lin Mingle Li Songye Zhan Qian Xu Feiyuan Yu

Polyamines are essential metabolites whose biological effects depend on the balance among putrescine, spermidine, and spermine. Spermine synthase (SMS) catalyzes the terminal step of mammalian spermine biosynthesis, simultaneously consuming spermidine and producing spermine. We use this reaction as the organizing framework of the review: SMS changes redox biology indirectly by redistributing spermidine and spermine and by altering the substrate available for oxidative catabolism. In Snyder–Robinson syndrome (SRS), severe SMS deficiency causes spermine depletion, spermidine accumulation, oxidative and organelle stress, and multisystem disease. In cancer, SMS-dependent remodeling can support or restrain tumor growth according to the resulting polyamine profile and downstream metabolic context. Intact spermine can scavenge reactive species and chelate Fe2+, whereas SMOX- and SSAT–PAOX-mediated oxidation generates H2O2 and reactive aldehydes; these opposing routes help explain divergent effects on lipid peroxidation and ferroptosis. This review focuses on evidence that directly connects SMS perturbation or altered spermidine/spermine balance with redox-relevant outcomes in SRS and cancer, distinguishes causal studies from metabolite-level associations, and defines the present limits of therapeutic translation. Together, these findings identify the SMS–polyamine axis as a regulator of the balance between antioxidant protection and oxidase-driven oxidative stress.

Antioxidants doi: 10.3390/antiox15101247

Authors: Panfeng Yao Junmei Cui Wenlin Li Ying Wang Jianguo Wei Zhenzhen Bi Chao Sun Zhen Liu Han Wang Zhanshu Song Yuhui Liu Jiangping Bai

Soil salinization restricts potato yield by inducing excessive reactive oxygen species (ROS) accumulation and oxidative damage. Exogenous silicon (Si) can alleviate salt-induced oxidative injury, yet the concentration-dependent mechanisms remain unclear in potato. Here, we conducted a tiered investigation combining phenotypic, physiological, and transcriptomic analyses. An in vitro gradient screening under 0.3% NaCl stress identified 1.0 mM Si as optimal. Compared with NaCl-alone treatment, 1.0 mM Si enhanced Catalase (CAT), Peroxidase (POD), and Superoxide Dismutase (SOD) activities by approximately 2.1-fold, 2.3-fold, and 1.3-fold, respectively. This Si supplementation also dramatically reduced ROS accumulation and membrane lipid peroxidation, as evidenced by 3,3′-diaminobenzidine (DAB) and nitroblue tetrazolium (NBT) staining and decreased Malondialdehyde (MDA) content. Subsequent pot experiments under 100 and 200 mM NaCl confirmed that 2.0 mM Si most effectively alleviated oxidative injury, accompanied by increased proline, higher relative water content, and reduced ROS and MDA. These data demonstrated that Si exerts dose-dependent protection by orchestrating both enzymatic (SOD, POD, CAT) and non-enzymatic (proline, glutathione) antioxidant systems. Transcriptome profiling coupled with Weighted Gene Co-expression Network Analysis (WGCNA) and RT-qPCR revealed eight candidate hub genes, with antioxidant defense-related StGSH1 (glutathione synthesis) and StPRX52 (peroxidase) as key components, alongside genes involved in protein homeostasis and osmotic adjustment. Collectively, our findings establish optimal Si regimes and demonstrate that Si mitigates salt injury primarily through enhancing antioxidative capacity and ROS detoxification, providing candidate genes for antioxidative breeding in potato.

Antioxidants doi: 10.3390/antiox15101246

Authors: Lu Xiao Jin-Wen Tang Ya Mao Yuan-Shan Yu Xin Li Wen-Yong Lou

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global metabolic health burden, driving an urgent demand for safe, natural bioactive therapeutics derived from sustainable botanical sources. This study aimed to investigate the therapeutic efficacy and multi-target molecular mechanisms of litchi pericarp oligomeric polyphenols (LPPO) from Litchi chinensis Sonn. cv. Feizixiao against MASLD. A comprehensive multi-tiered pharmacological study design was conducted, integrating computational target prediction (network pharmacology and molecular docking) with in vitro cellular and in vivo animal disease models, combined with multi-omics profiling. Palmitate/oleate (FFA)-induced HepG2 cells and high-fat-diet (HFD)-fed C57BL/6J mice (JAX substrain) were treated with LPPO to evaluate hepatic steatosis, serum lipid profiles, oxidative stress parameters, and fecal lipid excretion. Integrated transcriptomics, metabolomics, network pharmacology, and molecular docking were conducted to pinpoint core bioactive constituents and validate key molecular targets and signaling pathways. LPPO markedly attenuated hepatic lipid accumulation, normalized serum lipid levels (TC, TG, and LDL-C), restored cellular redox balance (SOD and MDA), and promoted systemic lipid clearance via enhanced fecal excretion both in vitro and in vivo. Multi-omics integration identified quercetin as the principal bioactive metabolite driving LPPO-mediated metabolic reprogramming. Mechanistically, LPPO directly bound ALOX5 and downregulated ALOX12B to inhibit arachidonic acid-mediated inflammatory cascades, while suppressing NOS2/DUOX1 and upregulating MPV17L2 to alleviate oxidative/nitrosative stress. Additionally, quercetin downregulated the CD274 (PD-L1) checkpoint axis to reverse hepatic immunosuppression, alongside modulating GMPR, BCKDHA, and IDI1 to rebalance cellular energy allocation and lipid remodeling. LPPO exerts potent multi-target therapeutic effects against MASLD by alleviating lipotoxicity, oxidative stress, and inflammatory cascades. These findings elucidate the molecular basis of LPPO and highlight the potential of litchi pericarp waste as a high-value phytomedicinal resource.

Antioxidants doi: 10.3390/antiox15101245

Authors: Zhenhua Guo Lijun Cai Xirui Zhang Xuesong Zhou Yongsheng Cai Hu Cao Peng Li Junxiang Guo Wendong Ma Yanjiang Feng

Chilling damage at the booting stage represents a primary constraint limiting stable yields of japonica rice in cold-growing regions, yet the molecular mechanisms driving genotypic variation in chilling tolerance is still unclear. In this study, the cold-tolerant cultivar Kongyu 131 and the cold-sensitive cultivar Longjing 11 were used as contrasting materials and subjected to low-temperature treatment at the booting stage for 0 h (T1), 72 h (T3), and 120 h (T5). The results showed that low-temperature was the dominant factor driving the divergence in yield traits between the two varieties: after T5 treatment, the seed setting rate (SSR) and grain weight per plant (GW) of KY131 were 16.76% and 38.96% higher than those of LJ11, respectively. Physiologically, KY131 maintained higher SOD, POD, and CAT activities and proline content throughout the treatment, with significantly lower accumulation of O2− and H2O2. Metabolomic profiling detected 101 differentially accumulated metabolites (DAMs) between cultivars, which were enriched in of fructose and mannose metabolism, amino sugar and nucleotide sugar metabolism, glycolysis/gluconeogenesis pathways. Notably, D-fructose 6-phosphate (Com_764_neg) was identified as a core DAM (VIP ≥ 1, p < 0.05) that accumulated to a greater extent in KY131 than in LJ11 under cold stress. Transcriptome analysis identified 692 differentially expressed genes (DEGs) between varieties, and integrated co-expression network and WGCNA analyses pinpointed OsbZIP69 (Os08g0549600) as the candidate hub transcription factor with the highest connectivity, which showed the strongest co-expression association the hexokinase OsHXK7 (Os05g0187100). The candidate OsbZIP69-OsHXK7 association and the core genes identified in this study provided a theoretical basis and gene resources for molecular breeding of cold-tolerant japonica rice in cold regions.

Antioxidants doi: 10.3390/antiox15101244

Authors: Yahui Yan Chaoming Zhang Dan Rui Yongxia Tao Zuoshan Feng

Enzyme-assisted ultrasound extraction offers a synergistic dual-disruption strategy, yet its differential effects on the jujube metabolome and antioxidant capacity have not been systematically characterized. This study compared ultrasound-assisted extraction (UAE) alone (N), pectinase-assisted UAE (G), cellulase-assisted UAE (X), and composite enzyme-assisted UAE (GX) for metabolite recovery from Ziziphus jujuba Mill. cv. ‘Junzao’ fruits using untargeted metabolomics and multiple antioxidant assays. The GX group exhibited the highest total phenolic content (33.42 ± 0.73 mg GAE/g DW) and total flavonoid content (7.70 ± 0.18 mg RE/g DW), significantly exceeding those of the control (N). Untargeted metabolomic profiling annotated 839 metabolites classified into 16 chemical superclasses, with lipids and lipid-like molecules, amino acids and derivatives, and organic acids and derivatives being the most abundant categories. Multivariate analysis confirmed clear compositional separation between the enzyme-assisted groups and the control, with 107 differentially extracted metabolites (DEMs) identified across the three pairwise comparisons based on extraction efficiency differences. The GX group consistently showed the strongest antioxidant activity in 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and hydroxyl radical scavenging assays, and eight metabolites with significantly higher extraction yield showed significant positive correlations with multiple antioxidant indices in Spearman correlation analysis. These findings demonstrate that composite enzyme-assisted UAE achieved superior metabolite coverage and antioxidant potency through synergistic cell-wall deconstruction, providing a metabolomic framework for the green extraction of bioactive compounds from jujube fruits; however, further targeted validation is warranted.

Antioxidants doi: 10.3390/antiox15101242

Authors: Lele Fu Hai Xu Qing Wei Yungu Zheng Ling Cai Ming Yang

Tetrabromobisphenol A bis(allyl ether) (TBBPA-BAE) is an emerging aquatic contaminant, yet its developmental toxicity, particularly its stage-dependent skeletal effects, remains poorly understood. Zebrafish embryos and larvae were continuously exposed to nominal concentrations of 0.2, 2, 20, or 200 µg/L TBBPA-BAE (BAE0.2, BAE2, BAE20, and BAE200) through 14 days post-fertilization (dpf), with the lowest concentration approximating the upper end of reported environmental concentrations. Exposure transiently delayed hatching and altered heart rate and locomotion. At 5 dpf, H2O2 increased at all concentrations, whereas superoxide-scavenging capacity, catalase, and total superoxide dismutase showed distinct concentration-dependent responses, indicating disrupted redox homeostasis rather than uniform antioxidant activation. Selective craniofacial cartilage changes were also observed. At 14 dpf, craniofacial mineralization changed non-monotonically, increasing in BAE2 and BAE20 but decreasing in BAE200. Increased cranial TRAP staining together with osteoclast-related transcriptional changes indicated altered osteoclast-associated remodeling, while RANKL–RANK–OPG-related transcripts showed non-coordinated regulation. BAE20 produced the largest 5 dpf transcriptomic response, with changes involving redox response, extracellular matrix regulation, and osteoclast-related processes. Overall, TBBPA-BAE induced stage-dependent, non-monotonic developmental responses characterized by early redox disturbance and later osteoclast-associated skeletal alterations.

Antioxidants doi: 10.3390/antiox15101243

Authors: Maya A. K. Stelzer Abdul W. Khan Jeffrey Kroon Philippe Vangrieken Nordin M. J. Hanssen

Diabetes-related complications often continue to progress despite improved glycemic control, a phenomenon known as metabolic memory. Increasing evidence suggests that methylglyoxal (MGO), a highly reactive dicarbonyl generated during glycolysis, may be an important mediator of this process. Hyperglycemia-induced oxidative stress promotes MGO formation, where MGO further promotes mitochondrial dysfunction and reactive oxygen species production, establishing a self-reinforcing cycle of stress. In addition, MGO modifies proteins, impairing their structure and function and promoting persistent inflammatory signaling through advanced glycation end-products. More recently, nucleic acids have emerged as important targets of dicarbonyl stress, with MGO-induced DNA and RNA glycation contributing to genomic instability and altered cellular function. Furthermore, MGO-mediated histone glycation and epigenetic remodeling may provide a mechanistic link between hyperglycemia and long-lasting changes in gene expression. These mechanisms are particularly relevant in diabetic kidney disease, where MGO contributes to inflammation, fibrosis and renal injury. However, direct evidence that MGO-induced molecular alterations and their functional consequences persist after normalization of both glucose and MGO remains limited. This review discusses the role of MGO in metabolic memory, focusing on oxidative stress, protein glycation, nucleic acid damage and epigenetic remodeling, and highlights emerging therapeutic strategies targeting dicarbonyl stress to prevent the progression of diabetes-related complications.

Antioxidants doi: 10.3390/antiox15101241

Authors: Yousra Alsinani Hossein Shirvani Majid AL-Busafi Amr Mahmoud Abu El-Fadl Ibrahim

Exercise simultaneously challenges redox homeostasis, neuroendocrine regulation, metabolism, and immune function. The response is strongly dependent on exercise dose, recovery, nutritional status, and individual characteristics. This perspective updates the evidence on the relationship among exercise intensity, redox biology, and mucosal immunity, with particular emphasis on salivary secretory immunoglobulin A (sIgA) and antioxidant strategies. Current evidence supports a hormetic interpretation: exercise-derived reactive oxygen and nitrogen species (ROS/RNS) are not intrinsically harmful and participate in adaptive signaling, whereas excessive or poorly recovered exposure can contribute to oxidative damage, inflammation, impaired recovery, and transient changes in immune function. A 2024 randomized crossover study in 12 untrained young men found that the 75% VO2max condition produced a significantly lower percentage change in sIgA secretion rate compared with the 55% VO2max condition, while lower-intensity or shorter-duration trials did not. Importantly, this finding should be interpreted as a protocol-specific observation rather than evidence of a universal biological threshold. Salivary oxidative-stress evidence is also heterogeneous, and the quality of evidence remains low. Contemporary antioxidant guidance increasingly favors food-first approaches and selective supplementation for nutrient inadequacy or periods of unusually high training stress rather than routine high-dose antioxidant use. Evidence for specific interventions is mixed: astaxanthin, β-glucans, sesame, and polyphenol formulations show promising but still limited human evidence, while a 2024 trial in adults with obesity illustrates that melatonin, a pleiotropic redox-modulating molecule, can produce context-dependent effects. The most defensible personalized framework therefore combines training load, recovery, dietary adequacy, mucosal-immune monitoring, and—where clinically justified—redox phenotyping. Genetic and multi-omics approaches remain research tools rather than established clinical decision rules.

Antioxidants doi: 10.3390/antiox15101239

Authors: Yirui Chen Hongxin Gui Xingting Xue Mingyuan Liu Zixin Zhang Shibei Tang Kai Ma Mengyang Wang Rongrong Yang

Acute kidney injury (AKI) is characterized by tubular epithelial stress, inflammation, and metabolic dysfunction, yet the transcriptional programs associated with effective metabolic recovery remain poorly defined. Ergothioneine (EGT) has demonstrated renal and mitochondrial protective effects, but its potential involvement in conserved tubular injury programs is unclear. Here, we integrated human and mouse transcriptomic datasets to identify injury-associated programs that were conserved across proximal tubules and oppositely associated with EGT treatment. Pathway-level analyses revealed coordinated inflammatory and redox responses in human AKI, while the mouse intervention model showed broad reversal of disease-associated transcription following EGT treatment. Cross-species analysis of 9700 common orthologs identified seven pathways that consistently exhibited human injury-associated, mouse disease-associated, and EGT-opposed enrichment after removal of cytosolic ribosomal genes. These pathways converged on a mitochondrial bioenergetic–translation program involving oxidative phosphorylation, respiratory electron transport, complex I biogenesis, and mitochondrial translation, together with mTORC1 and MYC signaling. Within this conserved program, OXA1L, NDUFAB1, and TUFM repeatedly contributed to multiple pathway leading edges, highlighting them as potential candidates for functional investigation. Collectively, our findings identify a conserved mitochondrial transcriptional program associated with EGT in injured proximal tubules and provide a mechanistic framework for testing whether modulation of mitochondrial bioenergetics and translation contributes to the renal protective effects of EGT.

Antioxidants doi: 10.3390/antiox15101240

Authors: Sakurako Okada Yoshimi Shoji Masao Morita Mika Hayashi Wakana Shimizu Kei Ohkubo Hiromu Ito Ikuo Nakanishi Kiyoshi Fukuhara

Soy isoflavones exhibit diverse health-promoting effects, including antioxidant and anti-inflammatory activities. However, these biological effects have largely been attributed to the modulation of cellular signaling pathways, whereas the influence of intestinal microbial metabolism on their direct radical-scavenging properties remains poorly understood. In this study, synthetic routes were established for the major intestinal bacterial metabolites daidzein and genistein, equol (Eq), dehydroequol (DEq), 5-hydroxyequol (5-OH-Eq), and, for the first time, 5-hydroxydehydroequol (5-OH-DEq), and their direct radical-scavenging activities, reaction mechanisms, radical-scavenging capacities, and DNA protective effects were systematically evaluated. Introduction of a C-ring double bond markedly enhanced direct radical-scavenging activity, whereas the parent isoflavones and their reduced metabolites exhibited little or no activity. Among the compounds examined, 5-OH-DEq exhibited the highest antioxidant activity, scavenging radicals predominantly through hydrogen atom transfer, with a second-order rate constant of 1.44 × 103 M−1 s−1, exceeding that of Trolox and a radical-scavenging capacity of approximately three radical equivalents per molecule. Moreover, 5-OH-DEq protected plasmid DNA against radiation-induced oxidative damage. These findings demonstrate that intestinal microbial metabolism can function as a form of metabolic activation, converting dietary isoflavones into potent direct antioxidants. 5-OH-DEq was identified as a previously unexplored antioxidant metabolite and a promising lead scaffold for further development of next-generation phenolic antioxidants.

Antioxidants doi: 10.3390/antiox15101238

Authors: Nadrah S. Alamri Ahlam M. Alhusaini Wedad S. Sarawi Hala A. Attia Iman H. Hasan Alia O. Alshabanah Ragad A. Alharajeen Ahmed A. Altuwaijri Faris A. Almutairi Hanaa M. Altuwaijri Dalal A. Alkhelb Sahar S. Alotaibi Abdullah Y. Almubarak Yasser A. Alshawakir

Renal ischemia/reperfusion injury (RI/RI) is one of the major causes of acute kidney injury (AKI). Low molecular weight-dextran sulphate (LMW-DS) is a bioactive polysaccharide with anti-inflammatory and cytoprotective properties. This study investigated the nephroprotective potential of LMW-DS against the RI/RI. RI/RI rat model underwent surgery that involved a complete bilateral clamping of renal hila for 30 min, followed by unclamping for 30 min. LMW-DS (5 mg/kg, s.c.) was injected 5 min before unclamping. After 24 h, kidneys were collected for biochemical, histopathological, and immunohistochemical examinations. RI/RI dramatically induced renal deterioration, as reflected by marked elevation in the levels of renal oxidative stress, tumor necrosis factor-α, interleukin-6, and toll-like receptor-4, indicating lipid peroxidation and inflammatory response. Furthermore, RI/RI caused upregulation of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Additionally, morphological alterations and collagen deposition were also detected in kidney tissues. The immunohistochemical analysis revealed a strong positive immunoreaction for p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and caspase-3. Treatment with LMW-DS produced a pronounced amelioration in the altered parameters induced by RI/RI. In conclusion, LMW-DS exerts nephroprotective effects against RI/RI by restoring redox balance, suppressing inflammatory signaling, JNK/p38 MAPK, and caspase-3, highlighting its potential as a therapeutic strategy for renal I/R-induced AKI.

Antioxidants doi: 10.3390/antiox15101237

Authors: Gang Jiang Yu Zhang Qing Wang Jiayi Sang Wenrong Feng Yuanfeng Xu Jianlin Li Yongkai Tang

Fatty acid synthase (FASN) is the rate-limiting core enzyme for de novo fatty acid biosynthesis in aquatic animals, yet its regulatory role in teleost cellular antioxidant defense and redox balance remains poorly characterized. In this study, we identified and bioinformatically characterized the complete coding sequence (CDS) of Jian carp FASN, which encodes a 2514-amino acid polypeptide containing five conserved polyketide synthase (PKS) catalytic domains and 188 phosphorylation sites. qRT-PCR tissue profiling revealed ubiquitous FASN transcription across all tested tissues, with the highest abundance in liver tissue. To decipher the physiological functions of FASN, siRNA-mediated functional depletion was performed in isolated primary Jian carp hepatocytes. Suppression of endogenous FASN expression induced markers of oxidative damage, evidenced by significantly reduced activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) (p < 0.05), alongside elevated malondialdehyde (MDA) levels (p < 0.05). GC-MS detected global declines in cellular saturated, monounsaturated and polyunsaturated fatty acids, especially C14:0, C16:0 and C18:0. Transcriptionally, the 6-PGD was downregulated (p < 0.05), whereas the fatty acid oxidation gene PPARα was upregulated (p < 0.05). RNA-seq identified 13,546 differentially expressed genes, with enrichment analyses indicating transcriptional shifts associated with oxidative damage and NF-κB-related inflammatory signaling. A total of 23 hub genes related to lipid turnover and arachidonic acid metabolism were screened. Collectively, our results demonstrate that FASN acts as an essential upstream regulator of hepatic redox balance in Jian carp. FASN disrupts fatty acid pools and triggers metabolic–inflammatory reprogramming, offering new insights into lipid–antioxidant crosstalk in teleost hepatocytes.

Antioxidants doi: 10.3390/antiox15101236

Authors: Baotang Zhao Faqin Tao Shengfang Wang Jing He Shen Song

Polysaccharides (CDP-D2-N1) were extracted from Cistanche deserticola and used as an immunomodulatory substance to control inflammation and cytokines. This article chose LPS-induced inflammation model in RAW264.7 as the study subject and discloses the immune-inflammatory responses of CDP-D2-N1for lipopolysaccharide (LPS)-stimulated RAW264.7 cells. We investigated the screening of immunomodulatory activity of CDP-D2-N1 on LPS-induced RAW264.7 and the study of its pathway of action. CCK-8, qPCR and other tests were used to screen the CDP-D2-N1 with repairing effects on RAW264.7. The results show that CDP-D2-N1 pretreatment for 12 h at a concentration of 62.5–250 μg/mL improved the phagocytosis of RAW264.7, activated the expression of the TLR4 receptor, inhibited the expression of proinflammatory factors (TNF-α, IL-1, and IL-6) and the creation of iNOS, and modulated the NO of cell signaling molecules in RAW264.7 cells, thus improving the immunity of RAW264.7 cells and the activity of immune injury RAW264.7 cells. The combination of transcriptomics and p38 inhibitor analysis showed that CDP-D2-N1 could attenuate LPS-induced RAW264.7 cells’ immune injury by affecting the regulation of MAP3/6 expression in the TNF signaling pathway.

Antioxidants doi: 10.3390/antiox15101235

Authors: Hsuan-Chu Hsu Chia-Chao Wu Kuo-Cheng Lu

The novelty of this review lies in its falsifiable, time-resolved framework that integrates the parathyroid molecular clock with melatonin loss, compartment-specific redox failure, and bidirectional PTH–immune signalling rather than treating these mechanisms as parallel associations. Secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) is conventionally attributed to phosphate retention, calcitriol deficiency, hypocalcaemia, and fibroblast growth factor 23 (FGF23) resistance. We synthesise evidence linking mitochondrial reactive oxygen species (ROS), NADPH oxidase (NOX) activation and impaired nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) signalling to uraemic toxins, inflammation, hyperphosphataemia and dialysis-related oxidant stress. Sustained ROS engage NF-κB, MAPK and endoplasmic reticulum stress pathways that drive parathyroid dysfunction, RANKL-dependent osteoclastogenesis, endothelial dysfunction and vascular smooth-muscle-cell calcification. Inflammation is treated as bidirectional: immune activation amplifies ROS and mineral-tissue injury, while sustained PTH may reciprocally modify monocyte/macrophage, neutrophil and lymphocyte function—an immunological arm that remains hypothesis-generating given sparse, uraemia-confounded evidence in CKD–SHPT. We convert this synthesis into four testable predictions: CKD-stage-specific uncoupling of 24-h PTH and melatonin profiles; redox-dependent loss of chief-cell mineral sensing; cell-specific immune effects of PTH at patient-relevant concentrations; and differential responses to timed versus conventional SHPT therapy. Melatonin may oppose redox and inflammatory injury through receptor-dependent and mitochondrial actions. Because physiological ROS are essential signalling mediators, we emphasise redox balance rather than maximal antioxidant capacity, distinguish human, animal and cellular evidence, and flag supraphysiological PTH, phosphate and melatonin exposures. The proposed axis is a mechanistic research framework, not a basis for routine melatonin, antioxidant or immune-directed therapy pending dedicated CKD outcome trials.

Antioxidants doi: 10.3390/antiox15101234

Authors: Tina Oberacker Öztin Tüfek Tobias Leibold Adrian Salega Rebekka Schier Meng Dong Leonie Kraft Jörg Latus Severin Schricker Moritz Schanz

Peritoneal dialysis (PD) is an effective modality of renal replacement therapy that provides patients with a high degree of autonomy. However, its long-term use is limited by the detrimental effects of PD fluids on the structure and function of the peritoneal membrane, ultimately leading to a loss of dialysis efficacy. Disruption of redox homeostasis plays a central role in these pathological changes, highlighting the importance of endogenous defense mechanisms in maintaining membrane integrity. Nuclear factor erythroid 2–related factor 2 (NRF2) is a key transcription factor regulating cellular antioxidant and cytoprotective responses. However, its immunoreactivity and localization in the peritoneal tissue of PD patients and patients with encapsulating peritoneal sclerosis (EPS) have not been well characterized. Therefore, we analyzed peritoneal biopsies from healthy controls, pre-dialysis patients, PD patients, and EPS patients. Immunohistochemical analysis demonstrated significantly reduced NRF2 immunoreactivity in patients with EPS compared with all other study groups. In contrast, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) immunoreactivity was increased in PD and EPS patients. These results suggest that dysregulation of the NRF2–NFκB axis may be involved in peritoneal membrane injury, which warrants its further investigation as a potential target for preserving peritoneal membrane integrity during long-term PD.