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Saline–alkali stress is one of the important abiotic stresses, which affect plant growth and development. However, the understanding of miRNA pathways in different saline–alkali stress is still limited. In order to better understand the salt–alkali stress response mechanism of wheat, we analyzed miRNA transcription levels in two wheat varieties differing in saline–alkali tolerance (Qingmai 6, QM, tolerant; Meisheng 0308, MS, sensitive) under mixed saline–alkali stress (150 mmol·L¹ and 300 mmol·L¹) for 7 days. High-throughput sequencing identified 11,368 miRNAs (106 conserved, 11,262 non-conserved), among which four miRNAs (miR9653b, miR5384-3p, miR9777, and miR531) exhibited a consistent expression trend across both varieties and all stress concentrations. Additionally, a potential miRNA-mediated regulatory network (including miR408 and miR1135) was predicted to regulate reactive oxygen species (ROS) metabolism via cytochrome P450, plant hormone signal transduction, and MAPK pathways. Saline–alkali-tolerant and sensitive wheat cultivars exhibited distinct miRNA expression patterns under stress. QM maintained higher contents of non-enzymatic antioxidants (ascorbic acid, AsA; reduced glutathione, GSH) and activities of key antioxidant enzymes (ascorbate peroxidase, APX; glutathione reductase, GR), which contributed to balanced ROS homeostasis and enhanced saline–alkali tolerance. Full article

Neurodegenerative diseases, including Alzheimer’s disease, are marked by cholinergic dysfunction, oxidative stress, and reduced neurotrophic support, which drives the quest for multifunctional therapeutic agents. This pilot study presents four novel monoterpene–aminoadamantane conjugates (MACs 1–4) designed to combine the antioxidant and neuromodulatory characteristics of monoterpenes with the neuroprotective properties of aminoadamantane derivatives. Their physicochemical characteristics, blood–brain barrier permeability, and binding affinity to human acetylcholinesterase (AChE) were evaluated using molecular docking and in silico descriptor analysis. In vivo, the neuroprotective efficacy of the MACs was investigated in a scopolamine-induced dementia model in rats, employing behavioral tests. Biochemical assays conducted in the hippocampus and prefrontal cortex assessed AChE activity, antioxidant enzyme performance, lipid peroxidation levels, total glutathione content, and BDNF concentrations. The findings indicate that MAC1, MAC3, and MAC4 demonstrate favorable calculated blood–brain barrier permeability, strong predicted affinity for AChE, and significant in vivo alleviation of scopolamine-induced memory deficits, in conjunction with improvement of key markers of oxidative stress and cholinergic function. These results show that the structural hybridization of myrtenal with aminoadamantane frameworks produces promising multifunctional ligands that are relevant for Alzheimer’s-type neurodegeneration. Full article

Diabetes mellitus (DM) is recognized as a major contributor to impaired testicular function and compromised male fertility. In the present study, the protective effects of the natural flavonoid diosmin (Dios) against diabetes-induced testicular injury were investigated using a rat model of streptozotocin (STZ)-induced diabetes. Diabetes was induced in rats via a single intraperitoneal injection of STZ at a dose of 50 mg/kg body weight. Dios was administered at doses of 25 and 50 mg/kg body weight for eight weeks. Diabetic rats displayed marked testicular dysfunction, evidenced by reduced serum testosterone levels, deteriorated sperm parameters, and pronounced histopathological alterations in testicular tissues. Biochemical analysis revealed elevated levels of oxidative stress markers, including malondialdehyde and protein carbonyls, along with decreased levels of reduced glutathione and diminished activities of catalase and superoxide dismutase in the testicular tissues. Furthermore, diabetes exacerbated testicular inflammation, as indicated by increased immunoexpression of NF-κB p65 and levels of pro-inflammatory cytokines. Likewise, diabetes induced testicular apoptosis, demonstrated by increased Bax and caspase-3 levels and decreased Bcl-2 levels. Treatment of diabetic rats with Dios significantly attenuated sperm parameters and testicular architecture and mitigated oxidative stress, inflammatory responses, and apoptotic cell death. Additionally, Dios enhanced antioxidant defense mechanisms and restored the Sirt1/Nrf2/HO-1 signaling pathway in the testicular tissues of diabetic rats. These results suggest that Dios may serve as an adjuvant therapeutic agent for diabetes-associated testicular dysfunction. Full article

Fucoxanthin, a marine carotenoid abundantly derived from brown algae, has been increasingly recognized for its broad-spectrum antitumor activities; however, its role in regulating ferroptosis remains insufficiently defined. Hypopharyngeal carcinoma is a highly aggressive head and neck malignancy with limited therapeutic options, highlighting the need for novel marine-derived anticancer agents. In this study, we investigated whether fucoxanthin induces ferroptosis in human hypopharyngeal carcinoma cells (Fadu) and elucidated the underlying molecular mechanisms. Transcriptome profiling combined with in vitro validation revealed that fucoxanthin markedly upregulated heme oxygenase−1 (HO−1), leading to increased intracellular Fe²⁺ levels, excessive reactive oxygen species (ROS) generation, and pronounced lipid peroxide accumulation. Fucoxanthin simultaneously reduced cysteine and glutathione (GSH) levels, disrupted mitochondrial membrane potential, and triggered ferroptotic cell death, which was significantly reversed by the ferroptosis inhibitor ferrostatin−1. Mechanistically, fucoxanthin activated the p53 pathway while suppressing SLC7A11 and GPX4, thereby impairing antioxidant defenses. Pharmacological inhibition of p53 with Pifithrin−α markedly attenuated fucoxanthin-induced cytotoxicity and ferroptosis. Together, these findings identify fucoxanthin as a promising marine-derived compound capable of inducing ferroptosis via modulation of the p53/SLC7A11/GPX4 axis, providing new insights into its potential application in hypopharyngeal carcinoma therapy. Full article

Cancer remains a leading global cause of death, with conventional treatments often limited by toxicity and recurrence. Recent advances in gene therapy and nanodrug delivery offer new avenues for precision oncology. Human telomerase reverse transcriptase (hTERT) and glutathione peroxidase 4 (GPX4) are overexpressed in many cancers and linked to apoptosis and ferroptosis, respectively. Here, we developed a manganese dioxide nanosheet (MnO₂-NS) probe co-loaded with antisense oligonucleotides targeting hTERT and GPX4 mRNA to synergistically down-regulate both genes and induce dual cell death pathways. The probe, assembled via adsorption of fluorescently labeled antisense strands, showed controllable release in the presence of glutathione (GSH). Cellular uptake and antisense release were confirmed in multiple cancer cell lines. The MnO₂-NS probe significantly suppressed cell proliferation, outperforming single-target or carrier-only controls. Molecular analyses confirmed reduced hTERT and GPX4 expression, along with GSH depletion, ROS accumulation, and elevated lipid peroxidation—collectively promoting enhanced cancer cell death. In summary, this MnO₂-NS-based co-delivery system enables synergistic gene silencing and GSH depletion, enhancing antitumor efficacy and providing a promising strategy for multifunctional nanotherapy. Full article

5-Aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) is one of the treatment modalities for oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC). However, the role of ferroptosis in ALA-PDT for OLK and OSCC remains unclear. Therefore, this study aimed to investigate whether ALA-PDT can induce ferroptosis in OLK and OSCC. We detected relative cellular dehydrogenase activity (CCK-8 assay), long-term proliferative viability, reactive oxygen species (ROS) generation, glutathione levels, and mitochondrial morphology after ALA-PDT. The expression of ferroptosis-related proteins was detected using Western blot. A tongue OSCC model was established in male BalB/c nude mice, and then ALA-PDT was performed. Immunohistochemical staining of Ki67, GPX4 and FTH1 was conducted to evaluate the effect of ALA-PDT. Subsequently, OLK and OSCC cells were pre-treated with ferrostatin-1 (Fer-1) before ALA-PDT. Relative cellular dehydrogenase activity, ROS generation, lipid peroxidation, Fe²⁺ levels, and ferroptosis-related protein expression were measured. Finally, OLK and OSCC cells were treated with a combination of ALA-PDT and erastin, and mitochondrial function was evaluated. In vitro study showed that ALA-PDT increased ROS generation and decreased GSH/GSSG ratio in OLK and OSCC cells. After ALA-PDT, mitochondrial morphology exhibited typical characteristics of ferroptosis. In vivo experiments showed that immunohistochemistry (IHC) scores of Ki67, GPX4 and FTH1 in the tissues decreased after ALA-PDT. Moreover, pre-treatment with Fer-1 could reverse ROS levels, lipid peroxidation and intracellular Fe²⁺ accumulation in OLK and OSCC cells after ALA-PDT. Additionally, Fer-1 pre-treatment reversed the changes in protein expression induced by ALA-PDT. The combination of ALA-PDT and erastin significantly reduced mitochondrial O₂•⁻ production and decreased mitochondrial membrane potential. Above all, ALA-PDT can induce ferroptosis in OLK and OSCC. The use of ferroptosis agonists may enhance the therapeutic efficacy of ALA-PDT for OLK and OSCC. Full article

Objectives: Kadsura coccinea fruit is a traditional medicinal plant rich in dibenzocyclooctadiene lignans, with established hepatoprotective effects. Binankadsurin A (BKA), a dibenzocyclooctadiene lignan isolated from the K. coccinea fruits. This study aims to evaluate its hepatoprotective efficacy in an acetaminophen (APAP)-induced mouse liver injury model. Methods: The structure of BKA was elucidated by HR-ESI-MS, NMR, single-crystal X-ray diffraction and comparison of their data with those of the literature. Mice were randomly divided into five groups: Control, APAP (400 mg/kg, single intraperitoneal injection), APAP + bicyclol (50 mg/kg), APAP + low-dose BKA (50 mg/kg), and APAP + high-dose BKA (100 mg/kg). Untargeted metabolomics, immunohistochemistry, Western blot analysis, and molecular docking were performed. Results: BKA was determined as a dibenzocyclooctadiene lignan, and the single-crystal structure is reported for the first time. The untargeted metabolomics revealed that metabolites and pathways are closely associated with oxidative stress. In vivo studies showed that pretreatment with BKA can mitigate liver injury. BKA reduced serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and stored hepatic glutathione (GSH) levels. Immunohistochemical analysis results also showed that CYP2E1 expression in the mouse liver could be improved through BKA pretreatment. Furthermore, Western blot analysis presented that BKA could increase the protein expression of Nrf2, HO-1, and NQO-1. Additionally, molecular docking indicated that BKA directly blocks the binding site of Nrf2 with Keap1. Conclusions: BKA reduces APAP-induced acute liver damage by inhibiting oxidative stress by activating the Keap1/Nrf2/HO-1 signaling pathway, providing a theoretical basis for BKA as a potential therapeutic agent for APAP-induced liver injury. Full article

The critically endangered Asian giant softshell turtle (Pelochelys cantorii) is a national first-class protected aquatic animal in China, and artificial breeding is vital for its conservation. Given the pivotal role of substrate in captive rearing, this study aimed to investigate the effects of different substrate types on the growth, serum biochemistry, and behavior of juvenile P. cantorii. A total of 45 8-month-old juveniles [(121.11 ± 0.65) g] were randomly allocated to three groups (fine sand [FS], pea gravel [PG], and no substrate [NS]) for an 18-day rearing trial. Results indicated that the FS and PG groups exhibited significantly higher weight gain and specific growth rates than the NS group (p < 0.01). Serum malondialdehyde (MDA) levels were lower in the FS and PG groups than in the NS group (p < 0.05), with no significant difference between FS and PG. Notably, three individuals in the NS group exhibited symptoms of skin ulceration. No significant intergroup differences were observed in glucose (GLU), triglyceride (TG), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), or cortisol (CORT) levels (p > 0.05). Behaviorally, the FS group demonstrated the highest hidden rest frequency and duration (p < 0.01) and significantly lower active avoidance behavior compared to PG and NS (p < 0.01). In conclusion, substrate type significantly influences captive juvenile P. cantorii, with fine sand being optimal as it enhances growth, alleviates oxidative stress, and reduces maladaptive behaviors. Full article

Sarcopenic obesity, characterized by skeletal muscle loss concurrent with adipose tissue accumulation, has emerged as a global health threat. Exercise is established as an effective intervention; however, the molecular mechanisms underlying its protective effects remain incompletely defined. This study investigated whether exercise mitigates high-fat diet (HFD)-induced sarcopenic obesity, and whether the mechanism was related to the activation of the adenosine monophosphate-activated protein kinase (AMPK)/Acetyl-CoA carboxylase pathway (ACC) pathway and the inhibition of ferroptosis. Cell experiments demonstrated that palmitic acid induced ferroptosis in C2C12 mouse myoblasts. Animal experiments confirmed that HFD promoted skeletal muscle ferroptosis in C57BL/6 mice, evidenced by iron metabolism imbalance (solute carrier family 39 member14 upregulation, ferroportin downregulation), impaired antioxidant capacity (reduced glutathione, superoxide dismutase, glutathione peroxidase 4), and elevated lipid peroxidation (increased malondialdehyde). Meanwhile, both flat treadmill running and uphill treadmill running may reverse these changes by activating AMPK/ACC phosphorylation, reducing non-transferrin iron uptake, enhancing iron export and storage, and improving antioxidant status, jointly inhibiting ferroptosis and attenuating muscle mass loss and lipid deposition. These findings confirm that ferroptosis acts as one of the key pathogenic drivers in sarcopenic obesity and suggests that exercise may improve sarcopenic obesity by activating the AMPK/ACC pathway and inhibiting ferroptosis. This study provides novel mechanistic insights into exercise-mediated regulation of iron-lipid metabolism crosstalk and informs targeted interventions for sarcopenic obesity. Full article

Pre-sowing seed treatment (priming) is a strategic tool for programming future crop yield, aimed at improving early plant development and enhancing stress resilience. This study investigated the effects of priming wheat seeds with 100 µM ibuprofen on early ontogeny under optimal conditions and salt stress (100 mM NaCl). An evaluation of germination energy, growth parameters, phytohormone levels (abscisic acid, indolylacetic acid, and cytokinins) and the status of the antioxidant system in 7-day-old seedlings demonstrated that ibuprofen treatment stimulates wheat growth and tolerance, despite its absence of accumulation in plant tissues. Modulation of hormonal balance plays a key role in these protective effects: under optimal conditions, ibuprofen elevates abscisic acid and indolylacetic acid levels, while under salt stress, it prevents excessive abscisic acid accumulation and mitigates the stress-induced decline in indolylacetic acid and cytokinins. Furthermore, ibuprofen promotes a coordinated increase in glutathione, ascorbate, and H₂O₂ levels, concomitant with the activation of key enzymes (glutathione reductase and ascorbate peroxidase), thereby enhancing the plants’ antioxidant potential. Under saline conditions, ibuprofen pretreatment also reduces stress-induced dysregulation of this system. Therefore, ibuprofen acts as a hormetic preconditioning agent that improves seedling vigor and stress tolerance by fine-tuning hormonal signaling and redox metabolism. Full article

Eutrema salsugineum is a model species for studying stress resistance, particularly extreme salinity, and is often compared with Arabidopsis thaliana. Previous research has shown that basal salicylic acid (SA) levels are significantly lower in E. salsugineum than in A. thaliana. In this study, subtractive hybridization revealed that SA-related genes were extensively induced in Arabidopsis but not in Eutrema. Using exogenous SA and the biosynthesis inhibitor paclobutrazol (PBZ), we further demonstrated that the low endogenous SA level in Eutrema significantly upregulates dehydroascorbate reductase (DHAR) and glutathione reductase (GR) gene expression, doubling the pools of total ascorbic acid and total glutathione. While SA treatment decreased the ratios of reduced ascorbic acid (ASA) to dehydroascorbate (DHA) and reduced glutathione (GSH) to oxidized glutathione (GSSG), PBZ treatment increased them, correspondingly modulating DHAR and GR activities and gene expression. The resulting enhancement of these key non-enzymatic antioxidants is a critical mechanism underpinning the superior salt tolerance of Eutrema. Full article

This study evaluated the optimal dietary lipid level for Atlantic salmon (Salmo salar) reared in freshwater, aiming to provide foundational knowledge for the development of cost-effective and nutritionally balanced aquafeeds. Four experimental diets were formulated to contain comparable crude protein levels (47%) but graded lipid levels of 14% (L14), 16% (L16), 18% (L18), and 20% (L20), and were fed to salmon with an initial mean body weight of 241.5 ± 9.7 g during a 12-week feeding trial. Fish in the L16 group exhibited the highest weight gain (WG) and feed efficiency (FE), whereas those in the L14 group showed significantly reduced growth performance. Antioxidant analysis revealed that glutathione peroxidase (GPx) activity was lowest in the L14 group (p < 0.05), while plasma glucose concentration was minimized in the L16 group (p < 0.05). Transcriptomic profiling of liver tissue from the L14 and L16 groups identified 2117 differentially expressed genes (DEGs). Genes associated with lipid metabolism were more highly expressed in the L16 group, whereas immune- and inflammation-related genes were upregulated in the L14 group. These findings suggest that a dietary lipid level of approximately 16% is most favorable for promoting growth, metabolic stability, and overall health in freshwater-reared Atlantic salmon, thereby providing practical guidance for optimizing feed formulation and improving the economic efficiency of freshwater salmon aquaculture. Full article

To explore a safe and effective approach for producing strontium-enriched fish, in this study, we modified the feed for juvenile hybrid sturgeon (Acipenser baerii ♀ × Acipenser schrenckii ♂) and set three different levels of strontium chloride content in their diet (0 mg/kg (Sr0, control), 80 mg/kg (Sr80), and 160 mg/kg (Sr160)) for a period of 8 weeks, analyzing their growth performance, strontium enrichment, muscle nutrition, and hepatic physiological, biochemical, and transcriptomic characteristics. The results show that dietary strontium had no significant impact on sturgeon growth or survival rate (p > 0.05). The strontium content in tissues increased with dietary strontium levels, with the highest enrichment in bone plates (p < 0.05). However, muscle crude fat in the strontium-supplemented groups decreased significantly; the Sr160 group had higher glutamic acid, valine, docosahexaenoic acid methyl ester, lower myristic acid, palmitic acid, etc. (p < 0.05). In addition, strontium treatment alleviated hepatic lipid accumulation and mitochondrial swelling. Biochemical analyses revealed reduced plasma levels of Triglyceride (TG), Total Cholesterol (TC), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST), as well as decreased hepatic Malondialdehyde (MDA) content, while hepatic Glutathione (GSH) levels increased (p < 0.05). Transcriptomic data further showed that strontium downregulated the expression of fasn and tfrc and upregulated the expression of cpt1a, apoa1, cyp7a1, and slc3a2 (p < 0.05). In conclusion, dietary supplementation with 80–160 mg/kg strontium enables safe strontium enrichment in hybrid sturgeon, improves muscle nutritional quality, and protects liver function by regulating the genes related to lipid metabolism and antioxidant defense, providing a scientific basis for the development of strontium-enriched fish products. Full article

Short-term hypothermic storage at 4 °C represents a promising non-freezing alternative for transporting bovine embryos and synchronizing assisted reproductive procedures. However, chilling induces oxidative stress, mitochondrial dysfunction, and apoptosis, which markedly impair post-preservation embryonic viability. Glutathione (GSH), a key intracellular antioxidant, may mitigate these damaging effects, yet its protective mechanisms during bovine blastocyst hypothermic preservation remain unclear. Here, we investigated the impact of exogenous GSH supplementation on the survival, hatching ability, cellular integrity, mitochondrial function, and developmental potential of bovine blastocysts preserved at 4 °C for seven days. Optimization experiments revealed that 4 mM GSH provided the highest post-chilling survival and hatching rates. Using DCFH-DA, TUNEL, and γ-H2AX staining, we demonstrated that 4 °C preservation significantly increased intracellular reactive oxygen species (ROS), DNA fragmentation, and apoptosis. GSH supplementation markedly alleviated oxidative injury, reduced apoptotic cell ratio, and decreased DNA double-strand breaks. MitoTracker and JC-1 staining indicated severe chilling-induced mitochondrial suppression, including decreased mitochondrial activity and membrane potential (ΔΨm), which were largely restored by GSH. Gene expression analyses further revealed that chilling downregulated antioxidant genes (SOD2, GPX1, TFAM, NRF2), pluripotency markers (POU5F1, NANOG), and IFNT, while upregulating apoptotic genes (BAX, CASP3). GSH effectively reversed these alterations and normalized the BAX/BCL2 ratio. Moreover, SOX2/CDX2 immunostaining, total cell number, and ICM/TE ratio confirmed improved embryonic structural integrity and developmental competence. Collectively, our findings demonstrate that exogenous GSH protects bovine blastocysts from chilling injury by suppressing ROS accumulation, stabilizing mitochondrial function, reducing apoptosis, and restoring developmental potential. This study provides a mechanistic foundation for improving 4 °C embryo storage strategies in bovine reproductive biotechnology. Full article

Proteoglycans are macromolecules consisting of a core protein and one or more glycosaminoglycan side chains. Proteoglycans synthesized by vascular endothelial cells modulate various functions such as anticoagulant activity and vascular permeability. We previously reported that some heavy metals interfere with proteoglycan expression, and that organic–inorganic hybrid molecules, such as metal complexes and organometallic compounds, serve as useful tools to analyze proteoglycan synthesis mechanisms. However, the effects of metal compounds lacking electrophilicity on proteoglycan synthesis remain unclear. Au₂₅(SG)₁₈, a nanoscale gold cluster consisting of a metal core protected by gold–glutathione complexes, exhibits extremely low intramolecular polarity. In this study, we investigated the effect of Au₂₅(SG)₁₈ on proteoglycan synthesis in vascular endothelial cells. Au₂₅(SG)₁₈ accumulated significantly in vascular endothelial cells at low cell density and suppressed the expression of perlecan, a major heparan sulfate proteoglycan in cells, by inactivating ADP-ribosylation factor 6 (Arf6). Additionally, Au₂₅(SG)₁₈ reduced the expression of biglycan, a small dermatan sulfate proteoglycan, in vascular endothelial cells at low cell density; however, the underlying mechanisms remain unclear. Overall, our findings suggest that organic–inorganic hybrid molecules regulate the activity of Arf6-mediated protein transport to the extracellular space and that perlecan is regulated through this mechanism, highlighting the importance of Arf6-mediated extracellular transport for maintaining vascular homeostasis. Full article