bims-mistre 2025-11-02 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–11–02
25 papers selected by
Ellen Siobhan Mitchell, MitoQ

Lac-Phe: a central metabolic regulator and biomarker.
Advances in Mitochondrial Dysfunction and Its Role in Cardiovascular Diseases.
GPR40 agonist ameliorates neurodegeneration by regulating mitochondria dysfunction and NLRP3 inflammasome in Alzheimer's disease animal models.
NMN supplementation as a strategy to improve oocyte quality: a systematic review and transcriptomic analysis.
Mitochondrial homeostasis: A key regulator in endometrial physiology and pathology.
Plant-based bioactives and oxidative stress in reproduction: anti-inflammatory and metabolic protection mechanisms.
Targeting Metabolic Dysregulation in Obesity and Metabolic Syndrome: The Emerging Role of N-Acetylcysteine.
Edaravone Mitigates Postovulatory Aging by Preserving Oocyte and Embryo Quality in Mice.
Integrated Multi-Omics Analysis and Cross-Model Validation Reveal Mitochondrial Signatures in Alzheimer's Disease.
L-Arginine Supplementation Improves Endurance Under Chronic Fatigue: Inducing In Vivo Paradigms with In Vitro Support.
Estrogen Degradation Metabolites: Some Effects on Heart Mitochondria.
PRDX5 Regulates Mitochondrial Function and Nuclear Spreading in Myogenesis and Acts With PRDX3 to Delay Muscle Aging.
Adipokines at the Metabolic-Brain Interface: Therapeutic Modulation by Antidiabetic Agents and Natural Compounds in Alzheimer's Disease.
Syringic acid, a promising natural compound for the prevention and management of metabolic syndrome: A systematic review.
Jiao-tai-wan and its component coptisine attenuate PCOS by regulating mitochondrial cholesterol import through suppression of SIRT1 ubiquitination.
Sophora tonkinensis enhances activation of cGAS-STING pathway and restrains HBV replication.
Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
Association between blood nicotinamide adenine dinucleotide levels and blood laboratory parameters at baseline and after nicotinamide mononucleotide supplementation in middle-aged healthy individuals: post hoc analysis of a randomized, double-blinded, placebo-controlled clinical trial.
V8, a lysosomotropic wogonin derivative, alleviates hepatic steatosis by modulating GDF15-dependent mitochondrial homeostasis.
The effects of trace element supplementation on glycolipid metabolism in PCOS: a systematic review and meta-analysis.
Association Between Depressive Symptoms and Insulin Resistance and the Impact of the Menopausal Transition.
The antioxidant, N-acetyl-L-cysteine, affects beta cell oxidative stress, insulin secretion, and intracellular signaling pathways in MIN6 cells.
Alleviating effect of ellagic acid on ovarian reserve function injury induced by zearalenone and its mechanism.
Estrogenic Effect of Probiotics on Anxiety and Depression: A Narrative Review.
Targeting Polycystic Ovary Syndrome (PCOS) Pathophysiology with Flavonoids: From Adipokine-Cytokine Crosstalk to Insulin Resistance and Reproductive Dysfunctions.

Med Rev (2021). 2025 Oct;5(5): 429-431

Lac-Phe: a central metabolic regulator and biomarker.

Taikang Yao, Guolin Alexander Wen, Zhenchao Wu, Ning Shen.

  N-lactoyl-phenylalanine (Lac-Phe), an exercise-induced metabolite that suppresses appetite, has quickly emerged as a key molecule in metabolic signaling networks. Lac-Phe, following its CNDP2-mediated synthesis, mediates key appetite- and weight-modulating effects of metformin, which acts primarily by mitochondrial inhibition in gut epithelial cells. Both Lac-Phe and related N-lactoyl-amino acids serve as potent biomarkers of mitochondrial dysfunction. Elevated levels of these metabolites are found in genetic mitochondrial diseases, offering potentially superior prognostic value compared to lactate in conditions alike. Despite uncertainties regarding its specific receptor(s) and signaling mechanisms, the expanding roles of Lac-Phe underscore its critical position at the intersection of exercise physiology, pharmacology, energy metabolism, and disease pathology, suggesting significant potential for future diagnostics and therapeutics in mitochondrial and metabolic disorders.

Keywords:  Lac-Phe; appetite; metabolite; metformin; mitochondria

DOI:  https://doi.org/10.1515/mr-2025-0030
Cells. 2025 Oct 17. pii: 1621. [Epub ahead of print]14(20):

Advances in Mitochondrial Dysfunction and Its Role in Cardiovascular Diseases.

Yan Qiu, Shuo Chang, Ye Zeng, Xiaoqi Wang.

  Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide and is attributed to complex pathophysiological mechanisms that surpass the traditional risk factors. Emerging evidence indicates that mitochondrial dysfunction plays a central role in CVD progression, linking impaired bioenergetics, oxidative stress imbalance, and defective mitochondrial quality control to endothelial dysfunction, myocardial injury, and adverse cardiac remodeling. However, the mechanistic interplay between mitochondrial dysfunction and CVD pathogenesis remains unclear. This review provides a comprehensive synthesis of recent knowledge, focusing on the dysregulation of mitochondrial energy metabolism, alterations in mitochondrial membrane potential, and disruptions in mitochondrial dynamics, including the balance of fusion and fission, mitophagy, and biogenesis. Furthermore, we critically evaluated emerging mitochondria-targeted therapeutic strategies, including pharmacological agents, gene therapies, and regenerative approaches. By bridging fundamental mitochondrial biology with clinical cardiology, this review underscores the critical translational challenges and opportunities in developing mitochondria-focused interventions. A deeper understanding of the mitochondrial mechanisms in CVD pathophysiology will offer novel diagnostic biomarkers and precision-targeted therapeutics, thereby transforming CVD management.

Keywords:  cardiovascular disease; mitochondria dynamics; mitochondrial dysfunction; mitophagy; oxidative stress; targeted therapy

DOI:  https://doi.org/10.3390/cells14201621
Biomed Pharmacother. 2025 Oct 24. pii: S0753-3322(25)00872-8. [Epub ahead of print]192 118678

GPR40 agonist ameliorates neurodegeneration by regulating mitochondria dysfunction and NLRP3 inflammasome in Alzheimer's disease animal models.

Tae-Young Ha, Yeji Kim, Seung Min Lim, Yongjae Hong, Keun-A Chang.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction and chronic neuroinflammation. G-protein coupled receptor 40 (GPR40), primarily known for its role in metabolic regulation, has recently emerged as a modulator of neuronal activity and inflammatory signaling. In this study, we investigated the therapeutic potential of the selective GPR40 agonist TUG469 in both in vitro and in vivo models of AD. Treatment with amyloid-β oligomers (AβO) induced mitochondrial dysfunction in primary hippocampal neurons, as evidenced by disrupted mitochondrial morphology and membrane potential. TUG469 treatment restored mitochondrial integrity and membrane potential. Moreover, TUG469 significantly reduced AβO-induced reactive oxygen species (ROS) production. In the 5xFAD mouse model of AD, TUG469 administration improved cognitive performance and reduced Aβ plaque burden. Furthermore, TUG469 rescued impaired autophagy flux, as demonstrated by the regulation of LC3, p62, and LAMP1 expression, and attenuated neuroinflammatory responses by inhibiting NLRP3 inflammasome activation and modulating microglial reactivity. These findings indicate that GPR40 activation mitigates mitochondrial dysfunction and neuroinflammation, thereby alleviating AD-related pathology. Our results highlight the therapeutic potential of TUG469 as a multi-target modulator for AD.

Keywords:  5xFAD mice; Alzheimer’s disease; GPR40; Mitochondrial dysfunction; NLRP3 inflammasome; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1016/j.biopha.2025.118678
J Assist Reprod Genet. 2025 Oct 29.

NMN supplementation as a strategy to improve oocyte quality: a systematic review and transcriptomic analysis.

Hyunseo Noh, Sioban Sen Gupta, Srividya Seshadri, Xavier Viñals Gonzalez.

   PURPOSE: Oocyte quality declines with age and metabolic stress, largely due to mitochondrial dysfunction and NAD⁺ depletion. Nicotinamide mononucleotide (NMN), a precursor of NAD⁺, has emerged as a potential intervention to restore cellular energy metabolism. This study systematically reviews preclinical evidence on NMN supplementation and integrates transcriptomic analysis of human oocytes to assess its relevance in human fertility.
METHODS: A systematic review was conducted following PRISMA guidelines across Medline, Embase, and Scopus (January 2015-October 2024). Seven high-quality original studies were included after screening and bias assessment. Data were synthesised through thematic analysis and pathway annotation. Additionally, single-oocyte RNA sequencing was performed on 46 human oocytes at germinal vesicle, metaphase I, and metaphase II stages to profile NAD⁺-related gene expression.
RESULTS: Across animal models, NMN supplementation has been shown to improve mitochondrial regulation, reduce oxidative stress, and modulate apoptotic and inflammatory pathways in response to metabolic, environmental, and ageing stress. Transcriptomic analysis identified 900 differentially expressed genes between germinal vesicle and metaphase II oocytes, with significant changes in mitochondrial and oxidative stress-related genes (i.e. SIRT3, DNM1L, SOD1), aligned with NMN's known mechanisms of action.
CONCLUSIONS: NMN supplementation shows improvements for oocyte function across diverse preclinical models. Human transcriptomic data further highlight mitochondrial and oxidative pathways as key regulatory points during oocyte maturation. Standardised protocols and clinical trials are needed to evaluate NMN's translational potential in the context of human reproduction.

Keywords:  Fertility; Mitochondrial function; Nicotinamide mononucleotide (NMN); Oocyte quality; Oxidative stress; Transcriptomics

DOI:  https://doi.org/10.1007/s10815-025-03720-1
Drug Discov Today. 2025 Oct 28. pii: S1359-6446(25)00232-6. [Epub ahead of print] 104519

Mitochondrial homeostasis: A key regulator in endometrial physiology and pathology.

Keke Zhang, Enfeng Zhang, Kun Wu, Wenxiu Cheng, Shaobin Wei.

  Endometrial cyclic remodeling and decidualization are critical physiological processes for female reproductive function and are profoundly influenced by mitochondrial homeostasis. Mitochondrial homeostasis is maintained through the mitochondrial quality control system, which precisely regulates mitochondrial energy metabolism via peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1 alpha (PGC-1α)-nuclear respiratory factor (NRF)1/2-mediated biogenesis, mitofusin (MFN)1/2-optic atrophy (OPA1)-dependent fusion, dynamin-related protein (DRP)1-regulated fission, and PTEN-induced putative kinase 1 (PINK1)-Parkin-executed mitophagy. Dysregulation of this system caused by infection, endocrine disruption, or iatrogenic injury can alter or reprogram endometrial energy metabolism, disrupt immune balance, and promote fibrosis and abnormal proliferation, leading to various endometrial diseases and impaired fertility. This review systematically summarizes recent research advances on mitochondrial homeostasis in endometrial physiology and pathology, and its emerging role as a therapeutic target, aiming to provide insights and references for therapeutic strategies against endometrial diseases.

Keywords:  endometrial pathology; endometrial physiology; mitochondrial homeostasis; therapeutic target

DOI:  https://doi.org/10.1016/j.drudis.2025.104519
Front Nutr. 2025 ;12 1650347

Plant-based bioactives and oxidative stress in reproduction: anti-inflammatory and metabolic protection mechanisms.

Xue Liu, Tongtong Zeng, Enfeng Zhang, Chengli Bin, Qun Liu, Kun Wu, Yiping Luo, Shaobin Wei.

  Oxidative stress plays a central role in reproductive disorders, with food bioactive compounds offering therapeutic potential through their antioxidant properties. This review examines antioxidant active ingredients from plant-based foods and their protective mechanisms in reproductive system oxidative stress management. Key phytochemicals including polyphenols (flavonoids, phenolic acids such as curcumin, resveratrol, and EGCG), carotenoids (lycopene, lutein), and organosulfur compounds demonstrate potent free radical scavenging capacity, regulate antioxidant enzyme activity, and inhibit lipid peroxidation through Nrf2 pathway activation and NF-κB inhibition. These natural food ingredients provide anti-inflammatory effects and metabolic benefits including improved insulin sensitivity and mitochondrial protection. Clinical evidence shows lycopene supplementation (4-8 mg/day) improves sperm motility and reduces DNA fragmentation in male infertility, resveratrol (150 mg/day) enhances ovarian reserve markers in female fertility, and curcumin reduces inflammatory markers (IL-8, TNF-α) in endometriosis while improving assisted reproductive outcomes. However, poor bioavailability limits therapeutic efficacy, with most compounds showing < 10% absorption. Advanced delivery technologies, including nanoencapsulation (5-30 fold enhancement), phospholipid complexation, and formulation with absorption enhancers (e.g., piperine), can substantially improve the bioavailability of these compounds for functional foods and dietary supplements. Emerging single-cell and multi-omics approaches provide powerful tools to unravel tissue-specific mechanisms, while future progress also depends on establishing uniform dosage standards and conducting rigorous safety assessments to address potential pro-oxidant effects and long-term interactions. Given that infertility affects 17.5% of adults globally, food-derived antioxidant interventions represent accessible strategies for managing reproductive disorders, supporting the development of nutraceuticals and novel foods for reproductive health protection.

Keywords:  anti-inflammation; antioxidant active ingredients; food bioactive compounds; functional foods; phytochemicals; reproductive health

DOI:  https://doi.org/10.3389/fnut.2025.1650347
Metabolites. 2025 Sep 26. pii: 645. [Epub ahead of print]15(10):

Targeting Metabolic Dysregulation in Obesity and Metabolic Syndrome: The Emerging Role of N-Acetylcysteine.

Dorota Magdalena Radomska-Leśniewska, Justyna Niderla-Bielińska, Marek Kujawa, Ewa Jankowska-Steifer.

  Obesity and metabolic syndrome (MetS), growing global health concerns, are closely linked to the development of insulin resistance, type 2 diabetes, steatotic liver disease, and cardiovascular diseases (CVDs). An increase in visceral adipose tissue, the main symptom of MetS, contributes to systemic metabolic dysfunction, resulting in disturbances in glucose and lipid metabolism, mitochondrial dysfunction, and redox imbalance, which creates a vicious cycle of inflammation and oxidative stress, accelerating comorbidities. N-acetylcysteine (NAC), a precursor to glutathione, with antioxidant and anti-inflammatory properties, is described as a potent metabolic modulator that restores metabolic homeostasis. NAC's ability to modulate oxidative stress and inflammation may be particularly valuable in preventing or mitigating cardiovascular complications of MetS. The aim of this narrative review is to summarize current evidence from cellular, animal, and human studies on NAC's impact on metabolic health. MetS affects nearly one-third of the global population; therefore, there is a pressing need for accessible therapeutic strategies. NAC appears to offer potential benefits as an adjunctive agent for individuals with metabolic disturbances, but further research is needed to confirm its efficacy and establish its role in clinical practice.

Keywords:  NAC; atherosclerosis; cardiovascular disease; dyslipidemia; insulin resistance; metabolic modulator; metaflammation; oxidative stress; type 2 diabetes; visceral fat

DOI:  https://doi.org/10.3390/metabo15100645
Antioxidants (Basel). 2025 Oct 09. pii: 1215. [Epub ahead of print]14(10):

Edaravone Mitigates Postovulatory Aging by Preserving Oocyte and Embryo Quality in Mice.

Kyeoung-Hwa Kim, Eun-Young Kim, Ah-Reum Lee, Mi-Kyoung Koong, Kyung-Ah Lee.

  Postovulatory aging (POA) significantly contributes to fertility decline, primarily through oxidative stress, which impairs oocyte quality, reduces embryonic developmental competence, and may adversely affect offspring health. Edaravone (EDA), a potent free radical scavenger, is known for its cytoprotective effects in various disease models. This study aimed to evaluate whether EDA can mitigate the detrimental effects of POA on mouse oocyte and embryo quality and confirm its reproductive safety. Supplementation with 10 nM EDA significantly reduced meiotic abnormalities, restored mitochondrial distribution, enhanced mitochondrial membrane potential and ATP production, and decreased intracellular reactive oxygen species (ROS) in aged oocytes. Although EDA did not markedly improve fertilization or blastocyst formation rates, it enhanced embryo quality, with morphokinetic parameters comparable to those of young oocytes. Moreover, F1 offspring derived from embryos produced by EDA-treated POA oocytes were healthy, and female progeny exhibited normal reproductive competence. These findings demonstrate that EDA safely improves oocyte quality by alleviating POA-induced oxidative damage, offering a potential antioxidant strategy to enhance assisted reproductive technology (ART) outcomes when applied to IVF clinics.

Keywords:  Edaravone; antioxidant effect; oocyte quality; postovulatory aging; reproductive safety

DOI:  https://doi.org/10.3390/antiox14101215
CNS Neurosci Ther. 2025 Oct;31(10): e70634

Integrated Multi-Omics Analysis and Cross-Model Validation Reveal Mitochondrial Signatures in Alzheimer's Disease.

Xuan Xu, Sha-Sha Fan, Jiang Li, Hao Wu, Junwen He, Yang He, Xiang-Yu Meng, Yin Shen.

   AIMS: Alzheimer's disease (AD) is a devastating neurodegenerative disorder where mitochondrial dysfunction is increasingly recognized as pivotal, yet its comprehensive molecular underpinnings remain incompletely understood. This study aimed to systematically identify and validate mitochondria-related biomarkers associated with AD risk and brain resilience, thus elucidating the molecular mechanisms underpinning mitochondrial dysfunction in AD.
METHODS: We innovatively integrated a multi-omics approach, encompassing genomics, DNA methylation, RNA-sequencing, and miRNA profiles from the ROSMAP and ADNI cohorts (sample sizes ranging from 638 to 2090 per omic layer). Additionally, we applied 10 distinct machine learning methods to robustly identify and validate critical mitochondrial biomarkers relevant to AD progression. Subsequent validation was performed using a two-tiered approach: an in vivo AD mouse model to establish phenotypic relevance and an in vitro H2O2-induced oxidative stress model in HT22 cells to provide direct mechanistic validation.
RESULTS: Our computational analyses identified key biomarkers such as hsa-miR-129-5p and SLC6A12 as pivotal regulators and highlighted the importance of the tricarboxylic acid (TCA) cycle. Experimentally, our AD mouse model exhibited significant cognitive deficits and brain remodeling, linked to a specific transcriptomic signature. Our in vitro model functionally recapitulated mitochondrial dysfunction and oxidative stress. Crucially, a cross-model analysis revealed a core signature of seven genes (including APOE, CDKN1A, and CLOCK) consistently dysregulated in both the cognitively impaired mouse brain and in neuronal cells subjected to direct oxidative insult. This provides powerful functional evidence linking our computationally derived targets, such as mitochondrial-epistatic genes (CLOCK), to AD-relevant pathology.
CONCLUSION: These functionally validated findings provide deeper insights into the complex mitochondrial regulatory mechanisms involved in AD pathogenesis, offering robust biomarkers and novel potential avenues for developing targeted therapeutic strategies to address this challenging neurodegenerative disease.

Keywords:  Alzheimer's disease; biomarkers; machine learning; mitochondria; multiomics; polygenic risk scores

DOI:  https://doi.org/10.1111/cns.70634
Nutrients. 2025 Oct 15. pii: 3239. [Epub ahead of print]17(20):

L-Arginine Supplementation Improves Endurance Under Chronic Fatigue: Inducing In Vivo Paradigms with In Vitro Support.

Somin Lee, Woo Nam, Kyu Sup An, Eun-Ji Cho, Yong-Min Choi, Hyeon Yeol Ryu.

   BACKGROUND: L-arginine is a conditionally essential amino acid that serves as a substrate for nitric oxide synthase and regulates energy metabolism. While its ergogenic effects have been proposed, the mechanisms underlying its anti-fatigue properties are not fully understood.
METHODS: Male ICR mice were orally administered L-arginine (300, 600, or 1200 mg/kg bw/day) for 28 days. Fatigue was chronically induced using twice-weekly forced swimming or treadmill running, and fatigue resistance was then assessed under these paradigms. Blood, skeletal muscle, and liver were analyzed for biomarkers including glucose, lactate, LDH, CPK, NEFA, ammonia, glycogen, nitric oxide, cortisol, and antioxidant enzymes. In parallel, C2C12 myoblasts were treated with L-arginine under proliferative and differentiated conditions to assess hexokinase (HK) activity, myogenin expression, and ROS generation.
RESULTS: In vivo, L-arginine decreased serum LDH, CPK, NEFA, ammonia, nitric oxide, and cortisol, while enhancing blood glucose and glycogen storage in both muscle and liver. Forced swimming reduced serum lactate, whereas treadmill exercise elevated intramuscular lactate, suggesting context-dependent lactate regulation. Importantly, L-arginine did not significantly improve forced-swimming immobility time, whereas treadmill time-to-exhaustion increased at the highest dose. Antioxidant responses were improved, as reflected by normalized hepatic catalase activity. In vitro, L-arginine increased HK activity, promoted myogenin expression, and reduced ROS levels, supporting improved glucose utilization, muscle differentiation, and oxidative stress resistance.
CONCLUSIONS: These findings demonstrate that L-arginine supplementation under chronic fatigue-inducing paradigms improves endurance and alleviates fatigue by enhancing energy metabolism, preserving glycogen, reducing muscle injury, and attenuating oxidative stress. L-arginine shows potential as a functional ingredient for promoting exercise performance and recovery.

Keywords:  C2C12 myoblasts; L-arginine; anti-fatigue; energy metabolism; oxidative stress

DOI:  https://doi.org/10.3390/nu17203239
J Xenobiot. 2025 Oct 18. pii: 170. [Epub ahead of print]15(5):

Estrogen Degradation Metabolites: Some Effects on Heart Mitochondria.

Cristina Uribe-Alvarez, Elizabeth Lira-Silva, Lilia Morales-García, Natalia Chiquete-Felix, Francisco Javier Roldán-Gómez, Jesús Vargas-Barrón, José J García-Trejo, Alejandro Silva-Palacios, Salvador Uribe-Carvajal, Natalia Pavón.

  Mitochondria play crucial roles in various cellular functions, including ATP production, apoptosis, and calcium homeostasis. Signaling pathways and hormones such as estrogens regulate the mitochondrial network through genetic, epigenetic, and metabolic processes. Estrogens increase the efficiency of mitochondrial oxidative phosphorylation by preventing uncoupling. Upon reaching menopause, when estrogen levels decrease, impaired mitochondrial function (uncoupled oxidative phosphorylation, lower ATP yields) is observed. Like all hormones in the body, estrogens undergo metabolic processing, resulting in estrogenic degradation metabolites (EDMs). These metabolites can form adducts with genomic and mitochondrial DNA and are of particular interest due to their potential role as carcinogens. Given that estradiol influences mitochondrial function, it is possible that EDMs may have an impact on heart mitochondria. To investigate this, we used isolated heart mitochondria from control and oophorectomized (mimicking menopausal stage) female Wistar rats of the same age. We found that mitochondria exposed to EDMs exhibited reduced coupling of oxidative phosphorylation and diminished ATP production, while increasing reactive oxygen species generation. Furthermore, these effects were significantly stronger in mitochondria from oophorectomized rats than in mitochondria from control (intact) rats. In addition, mitochondrial oxidative phosphorylation complex activities were differentially affected: complex I and ATPase activities decreased, while complex IV remained unaffected. We propose that exposure to EDMs promotes mitochondrial dysfunction in rats and that these effects are exacerbated by oophorectomy, a procedure commonly used to model the effects of menopause in women.

Keywords:  OXPHOS uncoupling; estrogen degradation metabolites; heart mitochondria; oophorectomy

DOI:  https://doi.org/10.3390/jox15050170
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70098

PRDX5 Regulates Mitochondrial Function and Nuclear Spreading in Myogenesis and Acts With PRDX3 to Delay Muscle Aging.

Joonho Suh, Je-Hyun Eom, Jongmin Baik, Wonn Shim, Max A Tischfield, Hyun Ae Woo, Yun-Sil Lee.

   BACKGROUND: Skeletal muscle aging is associated with oxidative stress and mitochondrial dysfunction. Peroxiredoxins (PRDXs), particularly PRDX3 and PRDX5, are antioxidant enzymes that are uniquely localized to mitochondria. While PRDX3 has been reported to play a role in maintaining mitochondrial function in muscle, the specific function of PRDX5 in muscle remains unclear. This study investigated the role of PRDX5 in mitochondrial function, myonuclear distribution and muscle aging.
METHODS: Myoblasts were isolated from wild-type (WT), Prdx3-/-, Prdx5-/- and Prdx3-/-; Prdx5-/- mice crossed with mitochondria reporter (mt-GFP) mice. Nuclear and mitochondrial positioning were evaluated using confocal and super-resolution lattice structured illumination microscopy (SIM). Mitochondrial function was assessed by Seahorse oxygen consumption rates (OCR) assays. In vivo analyses included grip strength, treadmill performance and histological evaluation following venom-induced muscle injury.
RESULTS: During myogenesis, Prdx5-/- and Prdx3-/-; Prdx5-/- myotubes exhibited impairments in nuclear spreading, characterized by clustered nuclei, unlike the even distribution observed in WT and Prdx3-/- myotubes (44.4% and 44.9% vs. 17.1% and 21.9%, respectively; p < 0.001). Mitochondrial ATP production was significantly reduced in Prdx3-/-, Prdx5-/- and Prdx3-/-; Prdx5-/- myotubes (p < 0.05). The expression of Rhot1 and Trak1, key regulators of mitochondrial transport, was significantly decreased in Prdx5-/- and Prdx3-/-; Prdx5-/- myotubes (p < 0.01). Knockdown of Rhot1 or Trak1 in WT myotubes led to myonuclear clustering similar to that observed in Prdx5-deficient myotubes, supporting that PRDX5 facilitates mitochondrial transport and nuclear positioning, at least in part, through transcriptional regulation of genes including Rhot1 and Trak1. In vivo, 48-week-old Prdx5-/- mice exhibited mitochondrial dysfunction and myonuclear clustering in myofibers, with reduced treadmill performance (p < 0.05). Muscle regeneration was impaired in Prdx5-/- mice, with decreased expression of regeneration and mitochondrial transport markers and increased nuclear clustering in regenerating myofibers (p < 0.05). Prdx3-/-; Prdx5-/- double-knockout mice displayed accelerated muscle aging, including decreased muscle mass and strength, and elevated expression of E3 ligases Atrogin1 and MuRF1 as early as 10 weeks of age (p < 0.05). These mice also exhibited increased mitochondrial H2O2 production, which upregulated the expression of Atrogin1 and MuRF1 (p < 0.05).
CONCLUSIONS: Our findings reveal a previously unidentified role of PRDX5 in coordinating mitochondrial function and nuclear positioning during myogenesis and muscle regeneration. The combined deficiency of PRDX3 and PRDX5 accelerates muscle aging by exacerbating oxidative stress and mitochondrial dysfunction, suggesting that enhancing their activity may be a promising therapeutic strategy to prevent sarcopenia and age-related muscle degeneration.

Keywords:  PRDX3; PRDX5; mitochondrial dysfunction; muscle aging; myonuclear distribution

DOI:  https://doi.org/10.1002/jcsm.70098
Pharmaceuticals (Basel). 2025 Oct 11. pii: 1527. [Epub ahead of print]18(10):

Adipokines at the Metabolic-Brain Interface: Therapeutic Modulation by Antidiabetic Agents and Natural Compounds in Alzheimer's Disease.

Paulina Ormazabal, Marianela Bastías-Pérez, Nibaldo C Inestrosa, Pedro Cisternas.

  The parallel global increase in obesity and Alzheimer's disease (AD) underscores an urgent public health challenge, with converging evidence indicating that metabolic dysfunction strongly contributes to neurodegeneration. Obesity is now recognized not only as a systemic metabolic condition but also as a modifiable risk factor for AD, acting through mechanisms such as chronic low-grade inflammation, insulin resistance, and adipose tissue dysfunction. Among the molecular mediators at this interface, adipokines have emerged as pivotal regulators linking metabolic imbalance to cognitive decline. Adipokines are hormone-like proteins secreted by adipose tissue, including adiponectin, leptin, and resistin, that regulate metabolism, inflammation and can influence brain function. Resistin, frequently elevated in obesity, promotes neuroinflammation, disrupts insulin signaling, and accelerates β-amyloid (Aβ) deposition and tau pathology. Conversely, adiponectin enhances insulin sensitivity, suppresses oxidative stress, and supports mitochondrial and endothelial function, thereby exerting neuroprotective actions. The imbalance between resistin and adiponectin may shift the central nervous system toward a pro-inflammatory and metabolically compromised state that predisposes to neurodegeneration. Beyond their mechanistic relevance, adipokines hold translational promise as biomarkers for early risk stratification and therapeutic monitoring. Importantly, natural compounds, including polyphenols, alkaloids, and terpenoids, have shown the capacity to modulate adipokine signaling, restore metabolic homeostasis, and attenuate AD-related pathology in preclinical models. This positions adipokines not only as pathogenic mediators but also as therapeutic targets at the intersection of diabetes, obesity, and dementia. By integrating mechanistic, clinical, and pharmacological evidence, this review emphasizes adipokine signaling as a novel axis for intervention and highlights natural compound-based strategies as emerging therapeutic approaches in obesity-associated AD. Beyond nutraceuticals, antidiabetic agents also modulate adipokines and AD-relevant pathways. GLP-1 receptor agonists, metformin, and thiazolidinediones tend to increase adiponectin and reduce inflammatory tone, while SGLT2 and DPP-4 inhibitors exert systemic anti-inflammatory and hemodynamic benefits with emerging but still limited cognitive evidence. Together, these drug classes offer mechanistically grounded strategies to target the adipokine-inflammation-metabolism axis in obesity-associated AD.

Keywords:  Alzheimer’s disease; DPP-4 inhibitors; GLP-1 receptor agonists; SGLT2 inhibitors; adiponectin; adipose tissue dysfunction; insulin resistance; leptin; metabolic inflammation; metformin; pharmacological interventions; phytochemicals; resistin; thiazolidinediones

DOI:  https://doi.org/10.3390/ph18101527
Iran J Basic Med Sci. 2025 ;28(11): 1456-1476

Syringic acid, a promising natural compound for the prevention and management of metabolic syndrome: A systematic review.

Habibeh Mashayekhi-Sardoo, Fatemeh Sadeghzadeh, Maryam Rameshrad, Hossein Hosseinzadeh.

  In recent years, because of the changes in modern lifestyles, the incidence of metabolic syndrome (MetS) has been increasing. MetS is a cluster of conditions, including hypertension, insulin resistance, hyperlipidemia, and obesity, that occur together, increasing the risk of cardiovascular diseases (CVDs), stroke, and type 2 diabetes. Therefore, this review provided comprehensive information on the protective effects of syringic acid (SYR) on the main components of MetS using natural phenolic acid compounds such as SYR. An exhaustive search was conducted using keywords related to SYR and MetS in scientific databases like Scopus, Web of Science, PubMed, and Google Scholar from inception to August 2024. The review included all in vitro, in vivo, and clinical research. Preclinical studies showed that SYR has protective effects against MetS, including diabetes, CVDs, dyslipidemia, and obesity. SYR has shown antidiabetic effects in animal models, lowering blood glucose and improving insulin levels. It also mitigated cardiac injury biomarkers, decreased oxidative stress, and improved lipid profiles. In animal models, SYR could lower body weight and fat mass, lower leptin levels, enhance adiponectin circulation, and improve insulin resistance. Nonetheless, there was insufficient clinical research on SYR's influences on humans undergoing MetS. Further research, especially randomized controlled trials, is needed to examine its effectiveness, safety, optimal doses, and long-term effects.

Keywords:  Diabetes; Dyslipidemia; Hypertension; Metabolic syndrome; Obesity; Syringic acid

DOI:  https://doi.org/10.22038/ijbms.2025.85940.18568
Phytomedicine. 2025 Oct 21. pii: S0944-7113(25)01083-9. [Epub ahead of print]148 157446

Jiao-tai-wan and its component coptisine attenuate PCOS by regulating mitochondrial cholesterol import through suppression of SIRT1 ubiquitination.

Hongzhan Wang, Yang Gao, Ping Ma, Xinyue Jiang, Zhi Wang, Yueheng Tang, Hao Su, Xiaohu Xu, Hui Dong.

   BACKGROUND: Polycystic ovary syndrome (PCOS) has emerged as a common endocrine disorder that impacts female reproductive health. The traditional herbal formulation, Jiao-tai-wan (JTW), exhibits multiple biological activities, including improving insulin resistance, reducing oxidative stress, and mitigating inflammation. The clinical efficacy of JTW against PCOS has been reported, however, mechanistic studies remain absent.
PURPOSE: To clarify the mechanisms behind the therapeutic efficacy of JTW in PCOS.
METHODS: The PCOS rat model was established by injection of DHEA. The in vivo study consisted of two parts: Part 1 included control, PCOS, low-dose JTW, high-dose JTW, and metformin (Glucophage) groups; Part 2 included control, PCOS, and coptisine groups. The in vitro study utilized primary theca cells. The effects of JTW on ameliorating PCOS phenotypes were assessed. Key pathways were identified via RNA sequencing, and the primary constituents of JTW were identified using UPLC fingerprinting. Further mechanistic investigations were conducted using techniques including network pharmacology, cell transfection, transmission electron microscopy imaging, confocal imaging, co-immunoprecipitation, CETSA, and SPR.
RESULTS: JTW attenuated abnormal ovulation, sex hormone imbalance, glycolipid metabolism disorders, and oxidative stress in PCOS rats. RNA sequencing revealed that JTW regulated the ovarian steroidogenesis pathway. Furthermore, JTW regulated mitochondrial dynamics and inhibited StAR localization to the outer mitochondrial membrane in the ovarian theca cells. SIRT1 was identified as the key target of JTW. Coptisine, a component of JTW, reversed abnormal mitochondrial dynamics in theca cells by upregulating SIRT1 expression, which in turn suppressed mitochondrial cholesterol import, thereby alleviating LH-induced aberrant steroidogenesis. Coptisine intervention produced effects similar to SIRT1 overexpression, but SIRT1 knockdown blocked these effects. Notably, coptisine did not alter SIRT1 mRNA levels but enhanced SIRT1 protein expression by suppressing ubiquitination-mediated degradation. Coptisine weakened the interaction between the E3 ubiquitin ligase SMURF2 and SIRT1. Additionally, coptisine exhibited high affinity for SIRT1 (KD = 5.71 μM). Finally, coptisine demonstrated therapeutic effects in PCOS rats.
CONCLUSION: JTW and its component, coptisine, modulate mitochondrial dynamics by inhibiting SIRT1 ubiquitination to restrict StAR-mediated mitochondrial cholesterol import, thereby normalizing abnormal ovarian steroidogenesis and attenuating PCOS. Furthermore, this study provides novel evidence that coptisine functions as a natural stabilizer of SIRT1 protein.

Keywords:  Coptisine; Jiao-tai-wan; Ovarian steroidogenesis; Polycystic ovary syndrome; SIRT1; Theca cells

DOI:  https://doi.org/10.1016/j.phymed.2025.157446
Front Pharmacol. 2025 ;16 1630460

Sophora tonkinensis enhances activation of cGAS-STING pathway and restrains HBV replication.

Yuanyuan Guo, Jincai Wen, Xueting Wang, Xianling Wang, Yingjie Xu, Siqi Huang, Zongliang Lu, Xiaoyan Chen, Ang Huang, Zhijie Ma, Junling Cao, Xiaoyan Zhan, Zhaofang Bai.

   Background: Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling pathway plays a vital role in innate immune response. Once activated, cGAS-STING pathway mediates the production of type I IFNs and pro-inflammatory cytokines, triggering antiviral response. The Chinese medicine Sophora Tonkinensis Gagnep. is a commonly used traditional Chinese medicine with the effects of clearing away heat and detoxification, subduing swelling and relieving pharynx. Modern studies have shown that it has antiviral activity, however, its mechanism of action is still not clear.
Methods: In this study, we used the botanical drug Sophora tonkinensis Gagnep. (Fabaceae) and investigated the effect of Sophorae tonkinensis extract (STE) on the activation of the cGAS-STING pathway in BMDMs and THP-1 cells, the mechanism by which STE regulates cGAS-STING pathway were studied. We also evaluated the antiviral activity of STE in an HBV mouse model by hydrodynamic injection of pAAV-HBV1.2 plasmid. The content levels of HBsAg and HBeAg in the serum of mice were detected by Elisa, and the level of HBV-DNA was detected by PCR-Fluorescence Probing in One-Tube.
Results: STE effectively promoted the activation of the cGAS-STING pathway in BMDMs and THP-1, but had no effect on cytoplasmic RNA-induced RIG-I signaling activation. Furthermore, STE can be effective, promoting 2'3'-CGAMP synthesis. Importantly, STE could effectively restrain HBV replication and promote cGAS-STING pathway activation in HBV mouse model.
Conclusion: STE could effectively promote the activation of cGAS-STING pathway by facilitating cGAMP synthesis by cGAS, exhibiting obviously inhibitory effect on HBV replication. STE might serve as an effective therapeutic approach against viral infections diseases.

Keywords:  HBV; Sophora tonkinensis gagnep. [fabaceae]; antiviral response; cGAS-STING pathway; immonology

DOI:  https://doi.org/10.3389/fphar.2025.1630460
Nat Aging. 2025 Oct 31.

Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.

Dominic Denk, Anurag Singh, Herbert G Kasler, Davide D'Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, Sibylle Loibl, Eric Verdin, Chris Rinsch, Florian R Greten.

Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day-1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8+ fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99; P = 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+ cells, increased peripheral CD56dimCD16bright NK cells, and nonclassical CD14loCD16hi monocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number: NCT05735886 .

DOI: https://doi.org/10.1038/s43587-025-00996-x
Geroscience. 2025 Oct 29.

Association between blood nicotinamide adenine dinucleotide levels and blood laboratory parameters at baseline and after nicotinamide mononucleotide supplementation in middle-aged healthy individuals: post hoc analysis of a randomized, double-blinded, placebo-controlled clinical trial.

Ajla H Kuerec, Weilan Wang, Keona D M Fokke, Lin Yi, Zhigang Lin, Aditi Vaidya, Sohal Pendse, Sornaraja Thasma, Niranjan Andhalkar, Ganesh Avhad, Vidyadhar Kumbhar, Andrea B Maier.

  To assess associations between blood nicotinamide adenine dinucleotide (NAD) levels and laboratory parameters at baseline and after 60 days of nicotinamide mononucleotide (NMN) supplementation. Post hoc analysis of a randomized, double-blind, clinical trial of daily NMN (300, 600, or 900 mg) or placebo in healthy middle-aged participants. Among the 80 participants (49.4 ± 6.8 year), the baseline NAD was 7.21 [5.5, 10.6] nM. Every 1 nM higher baseline NAD level was associated with 0.24% (95%CI: 0.05-0.44) higher lymphocytes, - 0.36% (95% CI: - 0.57 to - 0.14) lower neutrophils, 0.023% (95% CI: 0.011-0.036) higher triglycerides, - 0.009% (95% CI: - 0.015 to - 0.003) lower high-density lipoprotein, 0.02% (95% CI: 0.004-0.035) higher alanine transaminase, 0.01% (95% CI: 0.0003-0.021) aspartate transaminase. Every 1 nM increase in the NAD level was associated with an increase in hemoglobin of 0.027% (95% CI: 0.01-0.045), red blood cells (RBC) of 0.025% (95% CI: 0.009-0.042), mean corpuscular hemoglobin concentration of 0.016 g/dL (95% CI: 0.008-0.025), and uric acid of 0.02% (95%CI: 0.003-0.038). Higher baseline NAD levels are associated with inflammatory, lipid, and liver profiles. NMN-induced increases in blood NAD are associated with an increase in RBC parameters, potentially indicating enhanced oxygen-carrying capacity.

Keywords:  Aging; Blood laboratory parameters; Blood nicotinamide adenine dinucleotide levels; Nicotinamide mononucleotide supplementation

DOI:  https://doi.org/10.1007/s11357-025-01968-0
Free Radic Biol Med. 2025 Oct 23. pii: S0891-5849(25)01299-7. [Epub ahead of print]

V8, a lysosomotropic wogonin derivative, alleviates hepatic steatosis by modulating GDF15-dependent mitochondrial homeostasis.

Sichan Li, Shunzi Shao, Zhaokun Zhang, Zhuo Wang, Xiaolei Han, Xiaoqian Jia, Hongxin Zhang, Yuan Gao, Xiaobo Zhang.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global epidemic, leading to an unmet medical need for pharmacological interventions. This study aims to investigate the protective effect and mechanism of a synthetic wogonin derivate V8 against hepatic steatosis. Herein, we report that V8 attenuates lipid accumulation and prevents mitochondrial dysfunction in hepatocytes. Growth differentiation factor 15 (GDF15), a well-known cytokine with powerful metabolic action, mediates the effect of V8 on lipid metabolic disorders. Mechanistically, due to its lysosomotropic property, V8 promotes nuclear translocation of transcription factor EB (TFEB) and subsequent GDF15 gene transcription through activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Further analysis demonstrates GDF15 mainly improves mitochondrial homeostasis under stressful condition. Consistently, Gdf15 ablation in mice results in aggravated hepatic lipid deposition and liver injury upon high-fat diet feeding. Moreover, V8 alleviates diet-induced hepatic steatosis in a GDF15-dependent manner, and improves toxins-induced hepatic pathological phenotypes accompanying with upregulation of GDF15. Collectively, these data demonstrate the beneficial metabolic effect of V8 and highlight its utility in treating hepatic steatosis and its associated metabolic complications.

Keywords:  AMPK; GDF15; TFEB; lysosome; steatosis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.10.274
Front Nutr. 2025 ;12 1683556

The effects of trace element supplementation on glycolipid metabolism in PCOS: a systematic review and meta-analysis.

Liuzhen Yang, Yi Gao, Wei Zhao, Yuwen Qi, Xinru Duo, Huixia Wang.

   Objectives: A common endocrine and metabolic condition affecting women of reproductive age is polycystic ovarian syndrome (PCOS). The link between trace elements and PCOS has drawn more attention in recent years. However, the complete therapeutic potential of trace element supplementation in PCOS therapy is still unknown. Thus, the purpose of this study is to look at how supplementing with four trace elements- calcium, chromium, selenium and magnesium-may affect the metabolism of glycolipids and other clinical outcomes in women with PCOS.
Methods: To find randomized controlled trials (RCTs), a comprehensive literature search was carried out up until May 2025 using four internet databases: the Cochrane Library, Web of Science, Embase, and PubMed. Intervention studies that evaluated the impact of calcium, chromium, selenium and magnesium supplementation on important outcomes such as blood glucose levels, lipid profiles, oxidative stress markers, inflammatory responses, sex hormone concentrations, and body weight in PCOS patients met the inclusion criteria. Heterogeneity between studies was evaluated using the I2 statistic, a result of more than 50% indicates significant heterogeneity.
Results: A total of 25 RCTs with a combined sample size of 1,600 PCOS patients were considered. The results showed a significant decrease in fasting blood glucose levels (SMD = -0.79, 95% CI: -1.11 to -0.46). Both insulin resistance as determined by homeostasis model assessment of β-cell function (SMD = -0.68, 95% CI: -1.00 to -0.36) and fasting insulin levels were significantly lower (SMD = -0.58, 95% CI: -0.90 to -0.26). Additionally, it was discovered that taking supplements of selenium increased the QUICKI index (SMD = 0.53, 95% CI: 0.15 to 0.91) and considerably decreased fasting insulin concentrations (SMD = -0.32, 95% CI: -0.63 to -0.01). Magnesium supplementation did not show statistically significant impacts on any glucose metabolic measures, however neither fasting plasma glucose nor HOMA-IR showed any statistically significant effects. Chromium supplementation was observed to significantly lower levels of very-low-density lipoprotein (SMD = -0.59, 95% CI: -0.91 to -0.27) and triglycerides (SMD = -0.59, 95% CI: -0.91 to -0.27) in relation to lipid metabolism. Other lipid measures, such as total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, did not, however, show any statistically significant changes. Supplementing with magnesium or selenium had no statistically significant effects on any of the lipid metabolic markers. Calcium supplementation was observed to significantly lower levels of nitric oxide (SMD = -0.45, 95% CI: -0.84 to -0.06) and malondialdehyde (SMD = -0.76, 95% CI: -1.15 to -0.36) in relation to oxidative stress markers. Malondial-dehyde levels (SMD = -1.69, 95% CI: -3.10 to -0.28) and high-sensitivity C-reactive protein levels (SMD = -0.65, 95% CI: -1.05 to -0.24) were shown to be considerably reduced by chromium supplementation. Furthermore, a noteworthy rise in total antioxidant capacity was linked to it (SMD = 1.47, 95% CI: 1.02 to 1.92). Malondial-dehyde and inflammatory cytokines did not show any statistically significant changes, while selenium supplementation was shown to significantly increase total antioxidant capacity (SMD = 0.55, 95% CI: 0.16 to 0.95). None of the oxidative stress markers were significantly regulated by magnesium; The levels of sex hormones, including follicle-stimulating hormone, luteinizing hormone, dehydroepiandrosterone, sex hormone-binding globulin, testosterone, total testosterone, and the free androgen index, did not significantly improve with supplementation of chromium, calcium, magnesium, and selenium; Across all trace element supplementation regimens, no statistically significant variations were seen in weight-related measures, including body weight, waist circumference, hip circumference, and body mass index. Further high-quality randomized controlled studies are necessary to validate the low efficacy of calcium and magnesium, across the majority of outcome measures.
Conclusion: In PCOS patients, chromium has a clear therapeutic benefit in reducing oxidative stress, dyslipidemia, and glucose metabolic disorders. Selenium has demonstrated promise in raising antioxidant capacity and boosting insulin sensitivity.

Keywords:  glucose and lipid metabolism; meta-analysis; polycystic ovarian syndrome; sex hormones; trace elements

DOI:  https://doi.org/10.3389/fnut.2025.1683556
J Womens Health (Larchmt). 2025 Oct 29.

Association Between Depressive Symptoms and Insulin Resistance and the Impact of the Menopausal Transition.

Yuqing Chen, Maria M Brooks, Samar R El Khoudary, Rebecca C Thurston, Alicia B Colvin.

  Context: Recent meta-analyses and cross-sectional studies propose that insulin resistance (IR) is not a lasting feature of depression. However, longitudinal evidence is lacking, particularly in midlife women across menopause and ethnically diverse cohorts. Objective: To assess the longitudinal association between depressive symptoms and IR among midlife women and determine if this association varies by menopausal status and ethnicity. Methods: The study population comprised 2,829 White, Black, Hispanic, Chinese, and Japanese women from the Study of Women's Health Across the Nation followed for approximately 20 years. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale, and IR was obtained from the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear mixed-effects modeling was used to estimate the association between depressive symptoms (CES-D score ≥16, indicating risk for clinical depression) and HOMA-IR, adjusting for important confounders. Results: In multivariable analyses simultaneously including current depressive symptoms and depressive symptoms from the prior visit in the model, the estimated effect of current CES-D score ≥16, but not prior CES-D score ≥16, was statistically significantly associated with higher log-HOMA-IR levels (β = 0.03, 95% confidence interval [CI]: 0.01, 0.06). The relationship between current depressive symptoms and IR was strongest among Hispanic women (interaction p = 0.005; β = 0.18, 95% CI: 0.08, 0.27). Conclusion: Current reporting of CES-D score ≥16, but not prior reporting, was associated with elevated IR over time among midlife women. This study provides longitudinal evidence in support of IR as a temporary feature of depression. Moreover, the results suggest that Hispanic women with higher depressive symptoms may be particularly susceptible to IR.

Keywords:  depressive symptoms; insulin resistance; menopausal transition; race/ethnicity

DOI:  https://doi.org/10.1177/15409996251379406
Cell Tissue Res. 2025 Oct 30.

The antioxidant, N-acetyl-L-cysteine, affects beta cell oxidative stress, insulin secretion, and intracellular signaling pathways in MIN6 cells.

Meg Schuurman, Rachel B Wilson, Nica Borradaile, Rennian Wang.

  There is intense public interest in the potential of antioxidant supplements as a preventative treatment for conditions associated with increased oxidative stress, such as type 2 diabetes mellitus. However, there is limited evidence regarding the effects of antioxidants on beta cells during physiological and pathological conditions. We examined the direct effects of N-acetyl-L-cysteine (NAC) supplementation on the MIN6 beta cell line under physiological and fatty acid stress conditions. MIN6 cells were cultured in growth medium with or without NAC (physiological conditions) or growth medium plus palmitate with or without NAC (fatty acid stress conditions). We observed that MIN6 cells receiving NAC, under physiological or fatty acid stress conditions, displayed significantly reduced cellular ATP content and oxidative stress without changes to markers of cell proliferation or apoptosis. Regardless of the treatment conditions, NAC lowered basal insulin release with no change to cellular insulin content, yet improved high glucose-stimulated insulin secretion (GSIS) was only observed under physiological conditions. Importantly, phosphorylated AKT was significantly reduced with NAC supplementation under physiological and fatty acid stress conditions, which was inversely proportional to ERK1/2Thr202/Tyr204 phosphorylation during fatty acid stress. Our findings provided evidence that NAC directly impacts ATP production and insulin signaling pathways in MIN6 cells. This study highlights the importance of investigating ROS balance in pancreatic beta cells under physiological and pathological conditions to determine if antioxidant therapies can improve functionality without interfering with essential signaling processes.

Keywords:  Beta-cell ATP content; Insulin secretion and GSIS; N-acetyl-L-cysteine (NAC)

DOI:  https://doi.org/10.1007/s00441-025-04020-x
Ecotoxicol Environ Saf. 2025 Oct 30. pii: S0147-6513(25)01643-4. [Epub ahead of print]306 119298

Alleviating effect of ellagic acid on ovarian reserve function injury induced by zearalenone and its mechanism.

Jiafu Zhao, Zhiren Pan, Xiaoyan Wen, Wei Zhang, Yi Chen, Xilu Zhang, Qingmei Lu, Bin Liu, Mingshuai Zhou, Xiang Chen, Xiaoli Shi.

   PURPOSE: Zearalenone (ZEA), a widespread mycotoxin, harms reproductive health in humans and animals. Ellagic acid (EA), a plant-derived polyphenol, can reduce such damage. This study explores how EA helps repair ZEA's effects on goat ovarian granulosa cells (OGCs) and murine ovarian.
METHODS: The detoxifying effects of EA on ZEA were examined both in vitro and in vivo.
PRINCIPAL RESULTS: In Vitro Studies: EA ameliorated ZEA-induced oxidative stress, mitochondrial dysfunction, and apoptosis in OGCs. Specifically, EA downregulated the expression of endoplasmic reticulum stress (ERS) genes (ERN1, XBP1, ATF6), reduced ROS and MDA levels, while restoring SOD and T-AOC to control levels. Furthermore, EA upregulated mitochondrial function genes (ATP5A1, CLPP) and restored mitochondrial membrane potential (MMP). Concurrently, EA downregulated the expression of apoptosis-associated proteins (caspase-9, caspase-3), elevated PCNA protein expression, Bcl-2/Bax ratio, and ultimately reduced the cellular apoptosis rate. Additionally, EA mitigated ZEA-induced estrogen secretion dysfunction in OGCs by downregulating ZEA-elevated E2 synthesis-related proteins (3β-HSD, CYP17A1), the estrogen receptor gene (ESR1) expression, and E2 secretion levels.
IN VIVO STUDIES: EA alleviated ZEA-induced oxidative damage and reproductive toxicity in mice. Treatment with EA elevated ZEA-reduced levels of IL-10, T-SOD, and GPX. Conversely, EA reduced ZEA-elevated levels of MDA, TNF-α, and key reproductive hormones (GnRH, LH, FSH, E2, P4).
CONCLUSIONS: The collective results of in vitro and in vivo experiments demonstrate that ZEA exerts significant detrimental effects on reproductive cells and ovarian function by inducing oxidative stress, ERS, diminishing mitochondrial function, and disrupting sex hormone secretion. EA alleviates these ZEA-induced toxic effects.

Keywords:  Antioxidant factors; Apoptosis; Ellagic acid; Estradiol; Ovarian granulosa cells; Zearalenone

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119298
Int J Mol Sci. 2025 Oct 13. pii: 9948. [Epub ahead of print]26(20):

Estrogenic Effect of Probiotics on Anxiety and Depression: A Narrative Review.

Gilberto Uriel Rosas-Sánchez, León Jesús Germán-Ponciano, Juan Francisco Rodríguez-Landa, Herlinda Bonilla-Jaime, Ofelia Limón-Morales, Rosa Isela García-Ríos, José Luis Muñoz-Carrillo, Oscar Gutiérrez-Coronado, Paola Trinidad Villalobos-Gutiérrez, César Soria-Fregozo.

  Anxiety and depression are mental disorders with significant global impact, and are especially prominent in women during times of hormonal fluctuations. The microbiota-gut-brain axis (MGB axis) has emerged as a crucial pathway in the pathogenesis of these disorders, as it directly influences the production of neurotransmitters such as serotonin (5-HT), gamma-aminobutyric acid (GABA) and dopamine (DA). In addition, they have shown estrogenic effects through enzymes such as β-glucuronidase, which modulate hormone metabolism and consequently mood. A comprehensive search of recent preclinical studies has found that probiotic intake in female rats led to significant improvements in anxiety- and depression-related behaviors. Similarly, clinical trials in certain populations, particularly women with hormonal imbalances during menopause or premenstrual syndrome, have shown promising results. However, there are still significant problems, such as the individual variability of responses and the need for controlled long-term studies. The development of specific probiotics for hormonal modulation and the implementation of personalized approaches integrating omics and neuroimaging technologies to optimize therapeutic interventions in the field of mental health are promising. Accordingly, a comprehensive search was conducted in scientific databases such as PubMed, ScienceDirect, Scopus and Web of Science. Preclinical studies investigating the estrogenic effects of different probiotic strains in animal models and in controlled clinical trials during chronic treatment were selected, excluding those studies that did not provide access to full text.

Keywords:  Bifidobacterium; Lactobacillus; MGB axis; anxiety; depression; estrogen

DOI:  https://doi.org/10.3390/ijms26209948
Pharmaceuticals (Basel). 2025 Oct 18. pii: 1575. [Epub ahead of print]18(10):

Targeting Polycystic Ovary Syndrome (PCOS) Pathophysiology with Flavonoids: From Adipokine-Cytokine Crosstalk to Insulin Resistance and Reproductive Dysfunctions.

Sulagna Dutta, Pallav Sengupta, Sowmya Rao, Ghada Elsayed Elgarawany, Antony Vincent Samrot, Israel Maldonado Rosas, Shubhadeep Roychoudhury.

  Polycystic ovary syndrome (PCOS) represents one of the most prevalent endocrine-metabolic disorder in women of reproductive age, which includes but not restricted to reproductive disruptions, insulin resistance (IR), hyperandrogenism, and chronic low-grade inflammation. Its heterogeneous pathophysiology arises from the interplay of metabolic, endocrine, and immune factors, including dysregulated adipokine secretion, cytokine-mediated inflammation, oxidative stress (OS), and mitochondrial dysfunction. Current pharmacological therapies, such as metformin, clomiphene, and oral contraceptives, often provide partial benefits and are limited by side effects, necessitating the exploration of safer, multi-target strategies. Flavonoids, a structurally diverse class of plant-derived polyphenols, have gained attention as promising therapeutic candidates in PCOS due to their antioxidant, anti-inflammatory, insulin-sensitizing, and hormone-modulating properties. Preclinical studies in rodent PCOS models consistently demonstrate improvements in insulin sensitivity, normalization of ovarian morphology, restoration of ovulation, and reduction in hyperandrogenism. Human clinical studies, though limited in scale and heterogeneity, report favorable effects of flavonoids such as quercetin, isoflavones, and catechins on glucose metabolism, adipokine balance, inflammatory markers, and reproductive functions. This evidence-based study critically synthesizes mechanistic insights into how flavonoids modulate insulin signaling, adipokine-cytokine crosstalk, OS, and androgen excess, while highlighting translational evidence and emerging delivery systems aimed at overcoming bioavailability barriers. Collectively, flavonoids represent a promising class of nutraceuticals and adjuncts to conventional therapies, offering an integrative strategy for the management of PCOS.

Keywords:  adipokine secretion; catechins; cytokine-mediated inflammation; insulin resistance; isoflavones; polycystic ovary; quercetin

DOI:  https://doi.org/10.3390/ph18101575