Search Results (259)

Doxorubicin (Dox) is a potent anthracycline antitumor drug whose clinical utility is significantly restricted by its dose-dependent, cumulative cardiotoxicity, driven by increased oxidative stress, impaired antioxidant defenses, and apoptosis-mediated cardiomyocyte loss. Methylene blue (MB), a phenothiazine derivative with well-documented redox-modulating properties, is being explored as a viable cardioprotective agent due to its antioxidant and anti-apoptotic effects. This study evaluated the protective role of MB against Dox-induced cardiotoxicity in rats by examining its impact on oxidative stress markers (Kelch-like ECH-associated protein 1; KEAP1, nuclear factor erythroid 2-related factor 2; NRF2, Glutathione peroxidase 4; GPX-4, 8-hydroxy-2′-deoxyguanosine; 8-OHdG), neurohormonal indicators (noradrenaline), cardiac injury biomarkers (troponin I), and apoptotic mediators (p53, Caspase-3). Forty male albino rats were divided equally into four groups: control, Dox (15 mg/kg, i.p.), MB alone (4 mg/kg/day, p.o. for 7 days), and Dox plus MB. Dox administration significantly increased serum troponin I and noradrenaline levels, elevated cardiac KEAP1 and 8-OHdG, and reduced NFE2L2, NRF2, and GPX-4 expression. It also upregulated p53 and Caspase-3 and caused marked myocardial degeneration, necrosis, and inflammatory infiltration. MB co-treatment significantly reduced troponin I and noradrenaline levels, restored KEAP1/NFE2L2 (NRF2)/GPX-4 pathway balance, decreased oxidative DNA damage, and attenuated p53 and Caspase-3 activation, preserving myocardial architecture with minimal inflammatory changes. These findings demonstrate that MB confers potent cardioprotection against Dox-induced cardiac injury by enhancing antioxidant defenses, limiting oxidative DNA damage, suppressing apoptosis, and normalizing neurohormonal imbalance, suggesting its promise as an adjunctive strategy to mitigate anthracycline-associated cardiotoxicity. Full article

Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation participating in various diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular redox homeostasis and a key determinant of ferroptosis resistance. Nrf2 activates the expression of downstream antioxidant genes to protect cells from oxidative stress and ferroptosis. Consequently, precise regulation of Nrf2 expression is crucial. Recent studies have revealed that complex epigenetic mechanisms involving DNA methylation, histone modifications, and non-coding RNA networks regulate Nrf2 expression. DNA methylation usually suppresses while histone acetylation promotes Nrf2 expression. The influences of histone methylation on NFE2L2 are site- and methylation degree-dependent. m6A modification stabilizes NFE2L2 mRNA to promote Nrf2 expression and thereby inhibit ferroptosis. This article summarizes current understanding of the epigenetic mechanisms controlling Nrf2 expression and Nrf2-mediated ferroptosis pathways and their implications in disease models. The challenges associated with the epigenetic regulation of Nrf2 and future research directions are also discussed. A comprehensive understanding of this regulatory interplay could open new avenues for intervention in ferroptosis-related diseases by fine-tuning cellular redox balance through the epigenetic modulation of Nrf2. Full article

Coronavirus disease 2019 (COVID-19) causes cardiovascular complications, which contributes to the high mortality rate of the disease. Emerging evidence indicates that aberrant vascular smooth muscle cell (SMC) function is a key driver of vascular disease in COVID-19. While antivirals alleviate the symptoms of COVID-19, it is not known whether these drugs directly affect SMCs. Accordingly, the present study investigated the ability of three approved COVID-19 antiviral drugs to influence SMC function. Treatment of SMCs with remdesivir (RDV), but not molnupiravir or nirmatrelvir, inhibited cell proliferation, DNA synthesis, and migration without affecting cell viability. RDV also stimulated an increase in heme oxygenase-1 (HO-1) expression that was not observed with molnupiravir or nirmatrelvir. The induction of HO-1 by RDV was abolished by mutating the antioxidant responsive element of the promoter, overexpressing dominant-negative NF-E2-related factor-2 (Nrf2), or treating cells with an antioxidant. Finally, silencing HO-1 partly rescued the proliferative and migratory response of RDV-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the induction of HO-1 via the oxidant-sensitive Nrf2 signaling pathway contributes to the antiproliferative and antimigratory actions of RDV by generating carbon monoxide and bilirubin. These pleiotropic actions of RDV may prevent occlusive vascular disease in COVID-19. Full article

The current study investigates the chemical profiling, antioxidant activities, and enzyme inhibitory and cytotoxic potential of the water and methanolic extracts of different parts (flower, leaf, and bulb) of Muscari armeniacum. Chemical profiling was performed using UHPLC-MS/MS. At the same time, different in vitro assays were employed to support the results for antioxidant potential, such as DPPH, ABTS, FRAP, CUPRAC, metal chelation, and PBD, along with the measurement of total phenolic and flavonoid contents. Enzyme inhibition was investigated for cholinesterase (AChE and BChE), α-amylase, α-glucosidase, and tyrosinase enzymes. Additionally, the relative expression of NRF2, HMOX1, and YGS was evaluated by qPCR. LC-MS/MS analysis indicated the presence of some significant compounds, including apigenin, muscaroside, hyacinthacine A, B, and C, and luteolin. According to the results, the highest TPC and TFC were obtained with both extracts of the leaves, followed by the water extract (flower) and methanolic extract of the bulb. In contrast, the methanolic extract from the bulb exhibited the highest antioxidant potential using DPPH, ABTS, CUPRAC, and FRAP, followed by the extracts of leaves. In contrast, the leaf extracts had the highest values for the PBD assay and maximum chelation ability compared to other tested extracts. According to the enzyme inhibition studies, the methanolic extract from the bulb appeared to be the most potent inhibitor for all the tested enzymes, with the highest values obtained for AChE (1.96 ± 0.05), BChE (2.19 ± 0.33), α-amylase (0.56 ± 0.02), α-glucosidase (2.32 ± 0.01), and tyrosinase (57.19 ± 0.87). Interestingly, the water extract from the bulb did not inhibit most of the tested enzymes. The relative expression of NRF2 based on qPCR analysis was considerably greater in the flower methanol extract compared to the other extracts (p < 0.05). The relative expression of HMOX1 was stable in all the extracts, whereas YGS expression remained stable in all the treatments and had no statistical differences. The current results indicate that the components of M. armeniacum (leaves, flowers, and bulb) may be a useful source of natural bioactive compounds that are effective against oxidative stress-related conditions, including hyperglycemia, skin disorders, and neurodegenerative diseases. Complementary in silico approaches, including molecular docking, dynamics simulations, and transcription factor (TF) network analysis for NFE2L2, supported the experimental findings and suggested possible multi-target interactions for the selected compounds. Full article

Wild edible mushrooms (WEMs) are a popular delicacy in Thailand, prized for their unique flavor, texture, and nutritional value. Despite their widespread consumption, there is limited scientific research on their chemical compositions, biological activities, and potential health benefits. To bridge this knowledge gap, a comprehensive study was conducted on sixteen WEM species from ten families—Polyporaceae, Pleurotaceae, Russulaceae, Marasmiaceae, Pluteaceae, Boletinellaceae, Diplocystaceae, Lyophyllaceae, Psathyrellaceae, and Auriculariaceae—commonly found in northern Thailand. The proximate composition varied significantly among the WEM species, particularly in crude protein (12–51% w/w), crude fiber (1–30% w/w), and glucans (4–25% w/w). Astraeus odoratus exhibited the highest phenolic content, while P. cf. portentosus demonstrated the most potent antioxidant activity. WEM extracts also displayed notable inhibitory effects on α-glucosidase (5.82–79.43%) and α-amylase (1.30–90.79%). All extracts induced antioxidant regulators of Nrf2 and NQO1, suggesting that WEMs can help protect cells from oxidative stress, environmental toxins, and xenobiotics from food. Importantly, all extracts maintained high cell viability (>80%), indicating their safety for consumption. Furthermore, the mushrooms demonstrated a strong ability to reduce hepatotoxicity in HepG2 cells induced by tert-butyl hydrogen peroxide, highlighting their potential in preventing liver damage. This study not only underscores the nutritional and health benefits of WEMs but also establishes a vital scientific foundation for future research on their health effects and in vivo applications. In turn, these findings could serve as a crucial resource for optimizing the use of WEMs in ethnic cuisines and strengthening claims regarding their functional food properties. Full article

Cisplatin (Cis) is a widely used chemotherapy drug, but its nephrotoxicity limits its clinical application. Acute kidney injury (AKI) is a common complication, restricting long-term use. This study investigates the mechanisms of cisplatin-induced AKI and explores potential therapeutic targets. C57BL/6J mice were intraperitoneally injected with 20 mg/kg cisplatin to establish an AKI model. Serum creatinine, urea nitrogen, and tubular injury biomarkers (NGAL, KIM-1) progressively increased, indicating kidney dysfunction. Mitochondrial ATP levels significantly decreased, along with reduced mitochondrial fission and fusion, suggesting mitochondrial dysfunction. Increased oxidases and reduced antioxidants indicated redox imbalance, and metabolic reprogramming was observed, with lipid deposition, impaired fatty acid oxidation (FAO), and enhanced glycolysis in proximal tubular epithelial cells (PTECs). Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcriptional regulator of redox homeostasis and mitochondrial function. We found NRF2 levels increased early in AKI, followed by a decrease in vivo and in vitro, suggesting activation in the stress response. Nfe2l2 knockout mice showed aggravated kidney injury, characterized by worsened kidney function and histopathological damage. Mechanistically, Nfe2l2 knockout resulted in redox imbalance, reduced ATP synthesis, mitochondrial dysfunction and metabolic dysregulation. Furthermore, we activated NRF2 using dimethyl fumarate (DMF), observing a reduction in kidney damage and lipid deposition in mice. In conclusion, activating NRF2-dependent antioxidant pathways plays a crucial role in protecting against cisplatin-induced AKI. NRF2 may serve as a potential target for developing therapeutic strategies to prevent cisplatin nephrotoxicity. Full article

Menopause is the natural period of aging in women induced by ovary deterioration, resulting in estrogen deficiency. We evaluated the antioxidative and anti-inflammatory properties of Cnidium officinale, Pueraria lobata Ohwi, and Leonurus japonicus (CPL) extracts on vascular endothelial dysfunction. After treatment, CPL extracts decreased serum lipid profiles, serum vasoactive substances, tail temperatures, and cardiovascular risk indices. In ovariectomized rats, vasodilation significantly increased, with an increase in endothelial nitric oxide synthase (eNOS) in the CPL200 and CPL500 groups compared with the OVX group (p < 0.05). The extracts also significantly reduced vascular cell adhesion protein 1 (VCAM-1) in the CPL50, CPL100, and CPL200 groups compared with the OVX group (p < 0.05, p < 0.01, and p < 0.001, respectively). Intercellular adhesion molecule 1 (ICAM-1) was also reduced in the CPL100 and CPL200 groups compared with the OVX group (p < 0.001 and p < 0.0001, respectively); this was achieved through the downregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inducible nitric oxide (iNOS), which resulted in the synthesis of nuclear factor erythroid 2-related factor 2 (NRF2) and eNOS in HUVECs. Our results show that CPL extracts could provide cardioprotective effects against vascular endothelium dysfunction by decreasing inflammation and upregulating vasodilation, ascertained by evaluating the antioxidant systems of ovariectomized rats. Further studies are needed to explore the long-term cardioprotective effects. Full article

Natural polysaccharides (NPs), as a class of bioactive macromolecules with multitarget synergistic regulatory potential, exhibit significant advantages in diabetes intervention. This review systematically summarizes the core hypoglycemic mechanisms of NPs, covering structure–activity relationships, integration of the gut microbiota–metabolism–immunity axis, and regulation of key signaling pathways. Studies demonstrate that the molecular weight, branch complexity, and chemical modifications of NPs mediate their hypoglycemic activity by influencing bioavailability and target specificity. NPs improve glucose metabolism through multiple pathways: activating insulin signaling, improving insulin resistance (IR), enhancing glycogen synthesis, inhibiting gluconeogenesis, and regulating gut microbiota homeostasis. Additionally, NPs protect pancreatic β-cell function via the nuclear factor E2-related factor 2 (Nrf2)/Antioxidant Response Element (ARE) antioxidant pathway and Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) anti-inflammatory pathway. Clinical application of NPs still requires overcoming challenges such as resolving complex structure–activity relationships and dynamically integrating cross-organ signaling. Future research should focus on integrating multi-omics technologies (e.g., metagenomics, metabolomics) and organoid models to decipher the cross-organ synergistic action networks of NPs, and promote their translation from basic research to clinical applications. Full article

Torreya grandis kernels, with their long cultivation history and significant economic value, have gained attention for their characteristic chemical components. This review systematically evaluates recent research on the chemical constituents and biological activities of T. grandis kernels. The key highlights include the following. (1) Chemical composition: This review details their unique fatty acid profile, particularly the high content of unsaturated fatty acids and rare polymethylene-interrupted polyunsaturated fatty acids such as sciadonic acid. It also examines polyphenolic compounds (flavonoids, phenolic acids, and biflavonoids like kayaflavone) and volatile components dominated by D-limonene. Other constituents, such as proteins, amino acids, vitamins, and minerals, are covered. Advanced analytical techniques (Gas Chromatography–Mass Spectrometry, GC-MS; Liquid Chromatography–Tandem Mass Spectrometry, LC-MS/MS) for component identification are discussed. (2) Biological activities: This review summarizes the major biological activities of T. grandis kernel extracts and key components. These include antioxidant effects (via the polyphenol-mediated NF-E2-related factor 2 (Nrf2) pathway), anti-inflammatory properties (via polymethylene-interrupted polyunsaturated fatty acids, PMI-PUFAs, inhibition of 5-LOX, and polyphenol regulation of NF-κB), and cardiovascular protection (potentially involving the AMPKα/SREBP-1c pathway). Research on gut microbiota regulation and enzyme inhibition is also outlined. (3) Research gaps and prospects: This review critically analyzes the limitations in the current research, including mechanism elucidation, component interactions, bioavailability, and safety assessment (especially the lack of human studies). Future research directions should focus on multiomics integration, structure–activity relationship analysis, standardization, and rigorous clinical evaluation. This review provides a theoretical reference for understanding the scientific value of T. grandis kernels and promoting their sustainable development. Full article

The skin is continuously exposed to environmental changes, rendering it vulnerable to damage from external stressors that contribute to premature skin aging. This study aims to explore skin longevity pathways stimulated by a rose extract (RE) derived from petals. Human keratinocytes treated with RE exhibited a significant increase in NRF2 (NF-E2-related factor 2; ≈2–4% of induction) and LAMP2A (Lysosome-Associated Membrane Protein 2A; ≈6–12% of induction) levels. The presence of RE significantly mitigated the increase in carbonylation levels (≈34–37% of protection) and the number of labeled P16^INK4A cells (≈60–72% of protection), associated with proliferation arrest, both induced by exposure to BAP (Benzo[a]pyrene) coupled with UV-A (Ultraviolet A) irradiation. The beneficial effects mediated by RE were inhibited by Compound C, a specific AMPK inhibitor (AMP-activated protein kinase). The involvement of the AMPK pathway in mediating the beneficial effects of RE has been confirmed by assessing its activation through the evaluation of its phosphorylation state which was significantly elevated in the presence of RE compared to the stress condition. In conclusion, the activation of the AMPK pathway enhances antioxidant defenses and promotes autophagy. This dual action, mediated by RE, helps protect skin cells from oxidative damage and senescence while maintaining proteostasis, skin integrity, and cellular proliferation under pollution-induced stress (BAP + UV-A). These findings highlight the potential in mitigating age-related skin changes through the modulation of longevity pathways. Full article

As a moonlighting protein with multiple enzymatic activities, peroxiredoxin 6 (PRDX6) maintains redox homeostasis, regulates phospholipid metabolism, and mediates intra- and inter-cellular signaling transduction. Its expression and activity can be regulated by diverse stressors. However, the roles and relevant mechanisms of these regulators in various conditions have yet to be comprehensively reviewed. In this study, these stressors were systematically reviewed both in vivo and in vitro and classified into chemical, physical, and biological categories. We found that the regulatory effects of these stressors on PRDX6 expression were primarily mediated via key transcriptional factors (e.g., NRF2, HIF-1α, SP1, and NF-κB), micro-RNAs, and receptor- or kinase-dependent signaling pathways. Additionally, certain stressors, including reactive oxygen species, pH fluctuations, and post-translational modifications, induced the structure-based functional switches in the PRDX6 enzyme. We further reviewed the altered expression of PRDX6 under various disease conditions, with a particular focus on neuropsychiatric disorders and cancers, and proposed the concept of PRDX6-related disorders (PRD), which refers to a spectrum of diseases mediated by or associated with dysregulated PRDX6 expression. Finally, we found that an exogenous supplementation of PRDX6 protein provided preventive and therapeutic potentials for oxidative stress-related injuries in both in vivo and in vitro models. Taken together, this review underscores the critical role of PRDX6 as a cellular orchestrator in response to various stressors, highlighting its clinical potential for disease monitoring and the development of therapeutic strategies. Full article

(1) Background: Bovine mastitis is a lactational disease caused by infection and milk stagnation in the mammary glands. Danggui buxue decoction (DBD), a traditional remedy for blood tonification, anti-inflammation, and antioxidation, has not been used previously to treat mastitis. (2) Methods: In this study, an Escherichia coli mastitis model was established by infecting lactating Kunming mice with clinically isolated bovine mastitis-derived E. coli. Based on this, the effects of DBD on inflammation and oxidative stress in mastitis model mice were evaluated by conducting routine blood tests, H&E staining, qRT-PCR analysis, ELISA, and microcolorimetry. (3) Results: We found that DBD treatment reduced body weight loss, abnormal organ indices, abnormal blood cell counts, pathological damage to breast tissue, and the upregulation of the expression of inflammatory factor in mice caused by E. coli infection. We also found that DBD increased the expression of antioxidants and antioxidant genes and decreased the expression of oxidation products and oxidation-related genes in breast tissue. The therapeutic effect of DBD on inflammation and oxidative stress (OS) in mice occurred through the regulation of the TLR4/NF-κB and Nrf2/HO-1 signaling pathways. (4) Conclusions: DBD imparted its anti-inflammatory and antioxidant effects by inhibiting the TLR4/NF-κB signaling pathway and activating the antioxidant Nrf2/HO-1 signaling pathway Full article

Morinda citrifolia L. (M. citrifolia), commonly referred to as noni, a Polynesian medicinal plant with over 2000 years of traditional use, has garnered global interest for its rich repertoire of antioxidant phytochemicals, including flavonoids (kaempferol, rutin), iridoids (aucubin, asperulosidic acid, deacetylasperulosidic acid, asperuloside), polysaccharides (nonioside A), and coumarins (scopoletin). This comprehensive review synthesizes recent advances (2018–2023) on noni’s bioactive constituents, pharmacological properties, and molecular mechanisms, with a focus on its antioxidant potential. Systematic analyses reveal that noni-derived compounds exhibit potent free radical scavenging capacity (e.g., 2,2-Diphenyl-1-picrylhydrazyl/2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonicacid) (DPPH/ABTS) inhibition), upregulate endogenous antioxidant enzymes (Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPx)), and modulate key pathways such as Nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) and Nuclear Factor kappa-B (NF-κB). Notably, polysaccharides and iridoids demonstrate dual antioxidant and anti-inflammatory effects via gut microbiota regulation. This highlights the plant’s potential for innovation in the medical and pharmaceutical fields. However, it is also recognized that further research is needed to clarify its mechanisms of action and ensure its safety for widespread application. We emphasize the need for mechanistic studies to bridge traditional knowledge with modern applications, particularly in developing antioxidant-rich nutraceuticals and sustainable livestock feed additives. This review underscores noni’s role as a multi-target antioxidant agent and provides a roadmap for future research to optimize its health benefits. Full article

During the postpartum period, domestic ruminants suffer elevated endogenous cortisol levels, which are associated with an increased risk of uterine infections. Selenium is a trace mineral nutrient with beneficial impacts on animals. The study aimed to investigate whether selenium yeast (SeY) could attenuate Escherichia coli (E. coli)-induced endometrial injury in goats with high cortisol background. Goats were examined after oral SeY administration for 21 days and were treated with glacial acetic acid, E. coli, and hydrocortisone to establish an endometritis model with high cortisol background. The results showed that endometrial injury caused by E. coli was aggravated under high cortisol background. Supplementation with SeY alleviated endometrial inflammation and serum LDH content. The mRNA expression of pro-inflammatory cytokines and defensin beta 2 and the phosphorylation level of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-b (NF-κB) signaling pathways were decreased by SeY supplementation. Total antioxidant capacity and antioxidant enzymes activities were increased by SeY supplementation, but malondialdehyde and 4-hydroxynonenal content were decreased. Moreover, nuclear factor erythroid-2 related factor 2 (NRF2) in the nucleus, heme oxygenase-1, and NAD(P)H quinone dehydrogenase 1 were increased by SeY supplementation. So, supplementation with SeY alleviated E. coli-induced endometritis in goats by activating the NRF2 pathway and inhibiting the activation of the MAPK and NF-κB pathways under postpartum stress. Full article

Oxidative stress, endoplasmic reticulum (ER) stress, and alterations in autophagy activity have been described as prominent factors mediating many pathological processes in chronic kidney disease (CKD). The accumulation of misfolded proteins in the ER may stimulate the unfolded protein response (UPR). The interplay between autophagy and UPR in hemodialysis (HD) patients remains unclear. The aim of the present study was to explore the associations between serum oxidative stress markers, autophagy activity, and ER stress markers in the peripheral blood mononuclear cells (PBMCs) of patients on HD. Autophagy and ER stress-related protein expression levels in PBMCs were measured using western blotting. The redox state of human serum albumin was measured via high-performance liquid chromatography. Levels of the microtubule associated protein light chain 3 (LC3)-II, BECLIN1, and p62/SQSTM1 proteins were significantly increased in PBMCs of HD patients compared to healthy subjects. The PBMCs in HD patients also displayed augmented glucose-regulated protein 78 kDa (GRP78), phosphorylated eukaryotic translation initiation factor 2, subunit 1 alpha (p-eIF2α), and activating transcription factor 6 (ATF6) levels (p < 0.05). Additionally, nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) levels were elevated in the PBMCs of HD patients, compared to those of healthy subjects. Correlation analysis showed that the redox status of albumin was significantly correlated with the p62 protein level in PBMCs. Compared to healthy controls, we found elevated autophagosome formation in HD patients. Increased expression of ER stress markers was also observed in HD patients. Furthermore, increased p62 expression was positively correlated with the protein expression of NRF2, as well as a reduced form of serum albumin (human mercaptalbumin; HMA), in HD patients. Full article