bims-mistre 2026-02-01 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–02–01
33 papers selected by
Ellen Siobhan Mitchell, MitoQ

Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Aging: Current Insights and Therapeutic Advances.
Growth differentiation factor 15 as a biomarker of frailty: evidence from recent studies.
Mitochondrial Dysfunction: The Cellular Bridge from Emotional Stress to Disease Onset: A Narrative Review.
Cardiovascular Dysfunction in Polycystic Ovary Syndrome: Mitochondrial and Inflammatory Mechanisms.
Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.
Mitochondria-targeted antioxidant AntiOxBEN2 prevents metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing fatty acid oxidation and mitochondrial bioenergetics.
Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults.
Natural Vitamins and Novel Synthetic Antioxidants Targeting Mitochondria in Cognitive Health: A Scoping Review of In Vivo Evidence.
Mitochondrial protective effects of ellagic acid in a rat model of sporadic Alzheimer's disease induced by STZ.
Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
Effects of Voluntary Exercise and Acetic Acid Supplementation on Skeletal Muscle Mitochondrial Function in Ovariectomized Mice.
Mitochondria and Aging: Redox Balance Modulation as a New Approach to the Development of Innovative Geroprotectors (Fundamental and Applied Aspects).
Dapagliflozin Attenuates Atherosclerosis Under Chronic Stress by Maintaining AKT/FoxO1 Pathway Through Downregulation of REDD1.
Redox Regulation of Complement Pathway Activation in Aging and Related Diseases.
Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
Serum cell-free mitochondrial DNA under a highly standardized and controlled stress induction.
Redox signaling in the heart and brain: the roles of nitric oxide and reactive oxygen species in disease and therapy.
Growth Differentiation Factor 15 as a Link Between Obesity, Subclinical Atherosclerosis, and Heart Failure: A Systematic Review.
Creatine supplementation and exercise in aging: a narrative review of the muscle-brain axis and its impact on cognitive and physical health.
Modulating Skin Aging Molecular Targets and Longevity Drivers Through a Novel Natural Product: Rose-Derived Polydeoxyribonucleotide (Rose PDRN).
The effects of hesperidin supplementation on insulin resistance and sensitivity in adults: a systematic review and meta-analysis of randomized controlled trials.
Dietary Antioxidants, Polyphenols, and Vascular Health: Insights From Ultrasound Measurement of Carotid Intima-Media Thickness and Their Association With Cognitive Function in Aging and Neurodegenerative Diseases.
Liraglutide Modulates Zinc Release and Improves Mitochondrial Function in Insulin-Resistant Senescent Cardiomyocytes.
Antioxidant and Neuroprotective Capacity of Resveratrol-Loaded Polymeric Micelles in In Vitro and In Vivo Models with Generated Oxidative Stress.
Metabolic Reprogramming by Andrographolide: Enhanced Pentose Phosphate Pathway and Antioxidant Capacity in Cortical Astrocytes.
Baicalin Alleviates Chronic Restraint Stress-Induced Depression-like Behavior by Suppressing ROS/H2O2 Generation via a BDNF-Associated Mechanism in Mice.
Mitochondrial Metabolic Checkpoints in Human Fertility: Reactive Oxygen Species as Gatekeepers of Gamete Competence.
Ginkgolide C alleviates atherosclerosis via activating Nrf2 to inhibit ROS‑dependent NLRP3 inflammasome activation.
Effects of Probiotic Supplementation on Mental Health and the Risk of Depression in Women with Polycystic Ovary Syndrome: A Systematic Review of Randomized Controlled Trials.
Reproductive Longevity: Innovative Approaches Beyond Hormone Replacement Therapy.
Single-cell transcriptome-wide Mendelian randomization identifies mitochondrial targets in immune cells for Major Depressive Disorder.
Glycine ameliorates aging-related dysfunctions associated with Nmdmc-mediated mitochondrial one-carbon metabolism.
Microbiota-Mediated Crosstalk Between the Gut and the Vascular System: Protective Effects of Novel Postbiotic Formulations on Human Endothelial and Vascular Smooth Muscle Cells.

Biomedicines. 2026 Jan 03. pii: 100. [Epub ahead of print]14(1):

Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Aging: Current Insights and Therapeutic Advances.

Nabila Izzati Nur Azan, Norwahidah Abdul Karim, Nadiah Sulaiman, Min Hwei Ng, Asyraff Md Najib, Haniza Hassan, Ekram Alias.

  Mitochondrial dysfunction plays a central role in cardiac aging. Damaged mitochondria release excessive free radicals from the electron transport chain (ETC), leading to an increased production of reactive oxygen species (ROS). The accumulation of ROS, together with impaired ROS clearance mechanisms, results in oxidative stress, further disrupts mitochondrial dynamics, and diminishes bioenergetic capacity. Furthermore, the dysfunctional mitochondria exhibit an impaired endogenous antioxidant system, exacerbating this imbalance. These alterations drive the structural and functional deterioration of the aging heart, positioning mitochondria at the center of mechanisms underlying age-associated cardiovascular decline. In this review, we summarize the current evidence on how mitochondrial oxidative stress, mutations on mitochondrial DNA (mtDNA), and disruptions in the fission-fusion balance contribute to cardiomyocyte aging. This review also explores ways to mitigate oxidative stress, particularly with mitochondria-targeted antioxidants, and discusses the emerging potential of mitochondrial transplantation to replace dysfunctional mitochondria.

Keywords:  ROS; cardiovascular aging; mitochondria dynamics; mitochondria-targeted antioxidants; mitochondrial dysfunction; mitochondrial transplantation; oxidative stress

DOI:  https://doi.org/10.3390/biomedicines14010100
Curr Opin Clin Nutr Metab Care. 2026 Jan 29.

Growth differentiation factor 15 as a biomarker of frailty: evidence from recent studies.

Shuli Lian, Yves Rolland, Philipe de Souto Barreto.

   PURPOSE OF REVIEW: Growth differentiation factor 15 (GDF15), a stress- response protein of the TGF-β superfamily, has emerged as a potential biomarker of frailty. This review aims to summarize recent evidence on the association between GDF15 and frailty.
RECENT FINDINGS: Emerging data from 14 recent studies, including seven longitudinal and seven cross-sectional investigations, support GDF15 as a promising biomarker for frailty. Longitudinal studies indicate that elevated GDF15 levels are associated with an increased risk of developing frailty and with adverse outcomes related to frailty over follow-up periods of up to 13 years, across both community-dwelling and clinical populations, such as patients with cardiometabolic diseases or postknee replacement. The predictive value of GDF15 appears to vary depending on the frailty assessment tool used. Cross-sectional analyses corroborate longitudinal findings by showing that GDF15 levels are associated to frailty severity across diverse populations (e.g., community-dwelling, acutely hospitalized patients) in a dose--response manner.
SUMMARY: GDF15 represents a promising biomarker for frailty, reflecting physical decline and risk of future frailty. Future research should address sex-specific effects, standardize assay protocols and frailty assessments, and explore the clinical utility of GDF15 to detect people at increased risk of decline in intrinsic capacity and frailty in a life course perspective.

Keywords:  GDF15; aging; biomarker; frailty

DOI:  https://doi.org/10.1097/MCO.0000000000001213
Biomolecules. 2026 Jan 08. pii: 117. [Epub ahead of print]16(1):

Mitochondrial Dysfunction: The Cellular Bridge from Emotional Stress to Disease Onset: A Narrative Review.

Sakthipriyan Venkatesan, Cristoforo Comi, Fabiola De Marchi, Teresa Esposito, Carla Gramaglia, Carlo Smirne, Mohammad Mostafa Ola Pour, Mario Pirisi, Rosanna Vaschetto, Patrizia Zeppegno, Elena Grossini.

  Severe emotional stress constitutes a significant public-health concern associated with negative health outcomes. Although the clinical effects are well acknowledged, the specific biological mechanisms that translate emotional suffering into systemic disease remain incompletely understood. Psychological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, which directly target mitochondria and alter their bioenergetic and redox capacity. For this reason, this narrative review proposes that mitochondria serve as the primary subcellular link in the mind-body connection, as they play a pivotal role in converting neuroendocrine signals into cellular dysfunction. In particular, we focus on the concept of mitochondrial allostatic load (MALT), a framework explaining how the progressive decline in mitochondrial functions, from their initial adaptive roles in energy production, reactive oxygen species signaling, and calcium regulation, to being sources of inflammation and systemic damage, occurs when stress exceeds regulatory limits. We also, discuss how this transition turns mitochondria from adaptive responders into drivers of multi-organ disease. In subsequent sections, we examine diagnostic potentials related to MALT, including the use of biomarkers, such as growth differentiation factor 15, cell-free mitochondrial desoxyribonucleic acid, and functional respirometry. Furthermore, we evaluate mitochondria-targeted therapeutic strategies, encompassing pharmacological compounds, such as mitoquinone mesylate, Skulachev ions, and elamipretide, alongside lifestyle and psychological interventions. Here, we aim to translate MALT biology into clinical applications, positioning mitochondrial health as a target for preventing and treating stress-related disorders. We propose that MALT may serve as a quantifiable bridge between emotional stress and somatic disease, enabling future precision medicine strategies integrating mitochondrial care.

Keywords:  allostatic load; mitochondrial dysfunction; psychosocial stress; reactive oxygen species; relationship trauma; systemic nervous system

DOI:  https://doi.org/10.3390/biom16010117
Biomed Res Int. 2026 ;2026 1110229

Cardiovascular Dysfunction in Polycystic Ovary Syndrome: Mitochondrial and Inflammatory Mechanisms.

Olabimpe Caroline Badejogbin, Mary Olaoluwa Agunloye, Ojichukwuka Ebere Chijioke-Agu, Makinde Vincent Olubiyi, Success Oluwanifesimi Olugbuyiro, Olaniyi Azeez Soetan, Opeyemi Abel Bamgbose, Tobi Opeyemi Olaleye.

   Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that significantly increases cardiovascular disease (CVD) risk in women. While insulin resistance and dyslipidemia are established contributors, growing evidence highlights mitochondrial dysfunction and chronic low-grade inflammation as central drivers of cardiovascular pathology in PCOS.
Objective: This narrative review synthesizes current evidence on how mitochondrial dysfunction and inflammation interact to promote cardiovascular complications in women with PCOS while identifying potential therapeutic targets and areas requiring further investigation.
Methods: A comprehensive review of clinical and experimental studies was conducted using PubMed, Scopus, and Web of Science databases. Relevant literature exploring mitochondrial alterations, oxidative stress, inflammatory cytokines, and endothelial function in PCOS, with emphasis on cardiovascular outcomes, was critically evaluated and summarized.
Results: Women with PCOS exhibit altered mitochondrial dynamics, reduced ATP production, and elevated reactive oxygen species (ROS), which collectively impair vascular function. These mitochondrial abnormalities compromise oocyte quality and endometrial receptivity and activate proinflammatory signaling pathways, including the NLRP3 inflammasome, contributing to endothelial dysfunction and atherogenesis, and increased long-term cardiovascular risk, particularly in women with prior pregnancy complications. Elevated levels of cytokines including TNF-α, IL-6, and CRP further exacerbate cardiovascular risk. This bidirectional relationship between mitochondrial dysfunction and inflammation establishes a vicious cycle underlying cardiovascular deterioration in PCOS.
Conclusion: Mitochondrial dysfunction and inflammation are interdependent mechanisms that contribute substantially to cardiovascular risk in women with PCOS. Targeting mitochondrial dysfunction and systemic inflammation presents a promising therapeutic strategy for reducing cardiovascular morbidity in PCOS. Future research should emphasize phenotype-specific interventions, biomarker discovery, and translational trials to improve long-term reproductive and cardiovascular outcomes.

Keywords:  cardiovascular dysfunction; chronic inflammation; insulin resistance; mitochondrial dysfunction; oxidative stress; polycystic ovary syndrome; therapeutic targets

DOI:  https://doi.org/10.1155/bmri/1110229
Biology (Basel). 2026 Jan 20. pii: 189. [Epub ahead of print]15(2):

Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.

Yanyu Bao, Guoying Miao, Nannan He, Xingting Bao, Zheng Shi, Cuilan Hu, Xiongxiong Liu, Bing Wang, Chao Sun.

  Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.

Keywords:  melatonin; mitochondrial dysfunction; mitochondrial quality control; neurodegenerative diseases; oxidative stress

DOI:  https://doi.org/10.3390/biology15020189
Biomed Pharmacother. 2026 Jan 28. pii: S0753-3322(26)00054-5. [Epub ahead of print] 119022

Mitochondria-targeted antioxidant AntiOxBEN2 prevents metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing fatty acid oxidation and mitochondrial bioenergetics.

Ricardo Amorim, Carina Magalhães, Ana I Duarte, Alexandra C de Lemos, Adriana-Marques Carvalho, Susana P Pereira, Luís F Grilo, Débora Mena, Heloísa Gerardo, Caroline Veloso, Diana Sousa, Armando Caseiro, Fernando Cagide, Fernanda Borges, Paulo Matafome, José Teixeira, Paulo J Oliveira.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30 % of the global population. Its progression is commonly linked to excessive hepatic fat accumulation, elevated oxidative stress, and impaired mitochondrial function. Given the central role of mitochondria in cellular energy metabolism and redox balance, mitochondria-targeted bioactive molecules have emerged as a promising strategy for the prevention and treatment of MASLD. To this end, we develop AntiOxBEN2, a mitochondria-targeted compound generated by conjugating the antioxidant moiety of gallic acid with the lipophilic triphenylphosphonium cation. This design enables selective accumulation of AntiOxBEN2 in the mitochondrial matrix, taking advantage of the organelle's negative membrane potential. In multiple in vitro disease models, AntiOxBEN2 has demonstrated remarkable antioxidant properties, effectively mitigating oxidative stress and preserving mitochondrial function. However, effects on cellular and mitochondrial energy metabolism in vivo remain unexplored. In the present study, we tested whether chronic peripheral administration of AntiOxBEN2 (0.5 or 2.5 mg/kg, 3x/week) could prevent MASLD development in male and female C57BL/6 J mice fed with a 30 % high-fat, 30 % high-sucrose (Western Diet, WD) diet for 16 weeks. Our results demonstrate that AntiOxBEN2 treatment significantly reduced hepatic lipid accumulation in both sexes without affecting body weight. This reduction was accompanied by improvements in mitochondrial function, including enhanced fatty acid oxidation (FAO) and increased activities of mitochondrial electron transport chain (ETC) complexes. Moreover, AntiOxBEN2 administration lowered circulating levels of hepatic damage markers (ALT and AST), as well as insulin and leptin. Notably, a clear sexual dimorphism was observed, with female mice displaying a more pronounced improvement in mitochondrial parameters. Collectively, these findings highlight the therapeutic potential of AntiOxBEN2 for the prevention and/or treatment of MASLD.

Keywords:  Fatty acid oxidation; Metabolic dysfunction-associated steatotic liver disease (MASLD); Mitochondria (dys)function; Mitochondria-targeted antioxidant AntiOxBEN(2); Oxidative stress; Western diet

DOI:  https://doi.org/10.1016/j.biopha.2026.119022
Geroscience. 2026 Jan 28.

Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults.

Malte Schmücker, Cathrine Tranberg, Jacob Borch, Mette Killerup Kaae, Michelle Damgaard, Mathias Flensted-Jensen, Ida Blom, Marco Morosetti, Sara Barbarossa, Patrick Orlando, Luca Tiano, Flemming Dela, Jørn Wulff Helge, Steen Larsen.

  Mitochondrial function is important to healthy aging, as it influences energy metabolism, oxidative stress, and physical performance. With age, mitochondrial function and biosynthesis of coenzyme Q10 (CoQ10) may change. CoQ10 serves as a key antioxidant and component of the electron transport system. Supplementation with CoQ10 may help preserve mitochondrial function and support healthy aging. Forty older community-dwelling adults (74 ± 4 years) received either daily oral CoQ10 supplementation (400 mg daily) or a placebo in a 12-week double-blinded, randomized, placebo-controlled design. Before and after the supplementation period, muscle biopsies were obtained. Subsequently, oral glucose tolerance tests (OGTT) and VO2max tests were conducted. Mitochondrial respiratory capacity (MRC), mitochondrial H2O2 emission, and mitochondrial content were assessed in both isolated mitochondria and permeabilized muscle fibers. Levels and redox status of CoQ10 were measured in plasma, muscle tissue, and isolated skeletal muscle mitochondria. Additionally, resting metabolic rate, cognitive function, and body composition were investigated. Plasma levels of CoQ10 increased significantly without changes in redox status after the intervention. No changes between groups or time were observed in muscle and isolated mitochondria regarding MRC, H2O2 emission, mitochondrial content, and levels of CoQ10. Glucose homeostasis, VO2max, and body composition were also unchanged. Twelve weeks of supplementation led to increased plasma levels of CoQ10, with unchanged levels in muscle tissue and isolated mitochondria. No differences in mitochondrial function, glucose homeostasis, and physical performance were found in a cohort of robust older adults.

Keywords:  Antioxidant; Healthy aging; Mitochondrial function; Reactive oxygen species

DOI:  https://doi.org/10.1007/s11357-025-02068-9
Antioxidants (Basel). 2026 Jan 07. pii: 78. [Epub ahead of print]15(1):

Natural Vitamins and Novel Synthetic Antioxidants Targeting Mitochondria in Cognitive Health: A Scoping Review of In Vivo Evidence.

Alexia Squillace, Malika G Fernando, Kirstin Sullivan, Hosen Kiat, Ralph N Martins.

  Mitochondrial dysfunction and oxidative stress are crucial contributors to the pathogenesis of Alzheimer's disease (AD) and dementia exhibiting cognitive decline at the early stage of neurodegeneration. Natural vitamin antioxidants (NVAs) and novel mitochondria-targeted antioxidants (MTAs) are proposed as potential therapeutics though conclusive evidence is lacking. Objectives were to examine in vivo evidence on NVAs and MTAs for preventing and/or treating cognitive decline leading to dementia, to identify the most promising antioxidants, and highlight translational gaps. Methods followed PRISMA-ScR guidelines. MEDLINE, EMBASE and Scopus were searched for English language in vivo experiments assessing NVAs or MTAs in AD and dementia. A total of 25 studies (13 NVAs; 12 MTAs) met inclusion criteria. NVAs (Vitamin A, B, C, E) demonstrated mixed efficacy in reducing oxidative stress and improving cognitive outcomes, with Vitamin E showing the most consistent neuroprotective effects. MTAs (MitoQ, MitoTEMPO, SS31, SkQ1) improved mitochondrial dynamics and cognitive performance and reduced dementia-related pathology. Both NVAs and MTAs improved biomarker profiles and cognitive outcomes in vivo animal models of AD and dementia, but MTAs showed more robust and consistent efficacy by directly targeting mitochondrial pathways. Given the favourable safety profiles of MTAs in other clinical conditions, early-phase human trials in dementia and AD are warranted to evaluate their long-term cognitive benefits.

Keywords:  Alzheimer’s disease; cognitive impairment; dementia; in vivo animal models; mitochondria-targeted antioxidants; oxidative stress

DOI:  https://doi.org/10.3390/antiox15010078
Sci Rep. 2026 Jan 26. 16(1): 3498

Mitochondrial protective effects of ellagic acid in a rat model of sporadic Alzheimer's disease induced by STZ.

Forouzan Khodaei, Mohammad Reza Namavar, Narges Soutodeh, Arsalan Hadipour, Freshteh Asadi, Mohmmad Javad Khoshnoud, Marzieh Rashedinia.

  Alzheimer's disease (AD) is a neurodegenerative disorder primarily affecting the elderly, characterized by mitochondrial dysfunction. Mitochondria play a dual role in AD, serving both as the main source of reactive oxygen species (ROS) generation and as a major target of oxidative damage. This study aimed to investigate the protective mechanisms of ellagic acid (EA) a natural dietary polyphenol on mitochondrial function in an intracerebroventricular (ICV) streptozotocin (STZ)-injected rat model of AD. Rats were randomly assigned to six groups: Control, Sham, STZ (1.5 mg/kg on days 1 and 3), STZ + EA 5 mg/kg, STZ + EA 50 mg/kg, and STZ + EA 100 mg/kg. On day 14, behavioral tests (Shuttle box and Step-down), histopathological evaluations, oxidative stress markers, and mitochondrial indices were assessed in brain tissue. Treatment with EA (100 mg/kg) significantly improved spatial memory, as evidenced by increased latency time in the Morris water maze test (p < 0.001). Furthermore, EA treatment mitigated hippocampal neurodegeneration, increasing neuronal density in the CA1 subfield (p < 0.001) and restoring total hippocampal volume (p < 0.01). At the biochemical level, EA markedly reduced oxidative stress levels (p < 0.001) and enhanced mitochondrial function, restoring cortical ATP levels (p < 0.001) and cytochrome c oxidase activity (p < 0.01) compared to the STZ- group. In conclusion, these findings suggest that EA may have therapeutic potential in mitigating mitochondrial dysfunction and oxidative stress in AD, offering a promising approach for addressing neurodegeneration and energy deficits associated with the disease.

Keywords:  Alzheimer’s disease; Ellagic acid; Mitochondrial function; Oxidative stress; Streptozotocin

DOI:  https://doi.org/10.1038/s41598-025-31867-5
J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):

Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.

Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.

Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.

DOI: https://doi.org/10.1083/jcb.202501023
Nutrients. 2026 Jan 20. pii: 332. [Epub ahead of print]18(2):

Effects of Voluntary Exercise and Acetic Acid Supplementation on Skeletal Muscle Mitochondrial Function in Ovariectomized Mice.

Ki-Woong Park, Yoonhwan Kim, Yuan Tan, Byung-Jun Ryu, Seung-Min Lee, Hanall Lee, Byunghun So, Jinhan Park, Junho Jang, Chounghun Kang, Taewan Kim, Jinkyung Cho, Moon-Hyon Hwang, Jae-Geun Kim, Yong Kyung Kim, Young-Min Park.

  Background: Estrogen deficiency following human menopause or rodent ovariectomy (OVX) induces adverse alterations in body composition and metabolic function. This study investigated the combined effects of acetic acid supplementation and voluntary exercise on metabolic health and skeletal muscle mitochondrial function using an OVX mouse model. Methods: Forty female C57BL/6J mice (8 weeks old) were randomly assigned to 5 groups: sham (SHM), ovariectomized control (OVX), OVX with exercise (OVX-E), OVX with acetic acid (OVX-A), and OVX with both interventions (OVX-AE). Following a 1-week recovery from OVX, a 13-week intervention was initiated: 5% sodium acetate-supplemented chow and/or voluntary wheel running. Body composition, glucose tolerance, total energy expenditure, skeletal muscle mitochondrial function, and the contents of AMPKα, PGC-1α, and carbonyl protein were assessed. Results: OVX impaired whole-body metabolism and skeletal muscle mitochondrial function, specifically in the gastrocnemius muscle. While the exercise alone failed to mitigate the OVX-induced mitochondrial dysfunction, the combined treatment of exercise and acetic acid supplementation significantly rescued from the OVX-induced mitochondrial dysfunction. Conclusions: OVX resulted in detrimental changes in whole-body metabolism, but voluntary exercise and/or acetic acid supplementation had no rescuing effects on those parameters. In gastrocnemius muscle, acetic acid supplementation during exercise enhanced mitochondrial function in OVX mice.

Keywords:  acetic acid; mitochondrial function; ovariectomy; skeletal muscle; voluntary running

DOI:  https://doi.org/10.3390/nu18020332
Int J Mol Sci. 2026 Jan 14. pii: 842. [Epub ahead of print]27(2):

Mitochondria and Aging: Redox Balance Modulation as a New Approach to the Development of Innovative Geroprotectors (Fundamental and Applied Aspects).

Ekaterina Mironova, Igor Kvetnoy, Sofya Balazovskaia, Viktor Antonov, Stanislav Poyarkov, Gianluigi Mazzoccoli.

  Redox (reduction-oxidation) processes underlie all forms of life and are a universal regulatory mechanism that maintains homeostasis and adapts the organism to changes in the internal and external environments. From capturing solar energy in photosynthesis and oxygen generation to fine-tuning cellular metabolism, redox reactions are key determinants of life activity. Proteins containing sulfur- and selenium-containing amino acid residues play a crucial role in redox regulation. Their reversible oxidation by physiological oxidants, such as hydrogen peroxide (H2O2), plays the role of molecular switches that control enzymatic activity, protein structure, and signaling cascades. This enables rapid and flexible cellular responses to a wide range of stimuli-from growth factors and nutrient signals to toxins and stressors. Mitochondria, the main energy organelles and also the major sources of reactive oxygen species (ROS), play a special role in redox balance. On the one hand, mitochondrial ROS function as signaling molecules, regulating cellular processes, including proliferation, apoptosis, and immune response, while, on the other hand, their excessive accumulation leads to oxidative stress, damage to biomolecules, and the development of pathological processes. So, mitochondria act not only as a "generator" of redox signals but also as a central link in maintaining cellular and systemic redox homeostasis. Redox signaling forms a multi-layered cybernetic system, which includes signal perception, activation of signaling pathways, the initiation of physiological responses, and feedback regulatory mechanisms. At the molecular level, this is manifested by changes in the activity of redox-regulated proteins of which the redox proteome consists, thereby affecting the epigenetic landscape and gene expression. Physiological processes at all levels of biological organization-from subcellular to systemic-are controlled by redox mechanisms. Studying these processes opens a way to understanding the universal principles of life activity and identifying the biochemical mechanisms whose disruption causes the occurrence and development of pathological reactions. It is important to emphasize that new approaches to redox balance modulation are now actively developed, ranging from antioxidant therapy and targeted intervention on mitochondria to pharmacological and nutraceutical regulation of signaling pathways. This article analyzes the pivotal role of redox balance and its regulation at various levels of living organisms-from molecular and cellular to tissue, organ, and organismal levels-with a special emphasis on the role of mitochondria and modern strategies for influencing redox homeostasis.

Keywords:  aging; antioxidants; glutathione; mitochondria; oxidative stress; redox regulation

DOI:  https://doi.org/10.3390/ijms27020842
FASEB J. 2026 Jan 31. 40(2): e71473

Dapagliflozin Attenuates Atherosclerosis Under Chronic Stress by Maintaining AKT/FoxO1 Pathway Through Downregulation of REDD1.

Jianyi Li, Luyao Zhang, Jiapei Xu, Dishan Wu, Qinan Ma, Botao Sang, Sainan Li, Xiangfei Liu, Beidong Chen, Deping Liu.

  Chronic stress is associated with inflammatory activation and oxidative stress responses leading to endothelial dysfunction, which promotes the development of atherosclerosis (AS). SGLT2 inhibitors, such as Dapagliflozin (DAPA), exhibit a protective effect against cardiovascular diseases. However, the effects and mechanisms of DAPA on chronic stress-induced AS are largely unknown. The aim of this study was to determine whether DAPA confers a protective effect against chronic stress-induced AS and to elucidate its further molecular mechanisms. The combined high-fat diet-fed and chronic unpredictable mild stress in ApoE-/- mice and lipopolysaccharides- and corticosterone-induced human umbilical vein endothelial cells (HUVECs) were employed to evaluate the antiatherosclerotic effect of DAPA under chronic stress in vivo and in vitro. Histological staining, western blot analysis, siRNA transfection, reactive oxygen species (ROS) staining, and apoptosis assessment were used to investigate the potential mechanisms of DAPA against AS under chronic stress. The results indicate that DAPA significantly improved plaque size and increased plaque stability in the aorta under chronic stress and reduced inflammation and oxidative stress and inhibited apoptosis in the aorta and HUVECs. Chronic stress upregulated regulated in development and DNA damage response 1 (REDD1) expression, which exacerbated cellular inflammation, oxidative stress, and apoptosis levels, leading to endothelial dysfunction. In contrast, DAPA downregulated REDD1 expression and activated the AKT/FoxO1 pathway. In addition, p53 was a transcriptional regulator of REDD1 under chronic stress. More importantly, p53 agonists prevented DAPA from downregulating REDD1 and inhibited AKT/FoxO1 activation, thereby exacerbating chronic stress-induced endothelial dysfunction. These results suggest that DAPA effectively attenuates chronic stress-induced endothelial dysfunction and AS by downregulating REDD1 to activate the AKT/FoxO1 pathway.

Keywords:  atherosclerosis; chronic stress; dapagliflozin; endothelial dysfunction; sodium‐glucose cotransporter protein 2 (SGLT2) inhibitors

DOI:  https://doi.org/10.1096/fj.202502868R
Antioxidants (Basel). 2025 Dec 24. pii: 29. [Epub ahead of print]15(1):

Redox Regulation of Complement Pathway Activation in Aging and Related Diseases.

Shirin Ferdowsi, Srividya Arjuna, Sudharshan Sj, Rahima Zennadi.

  Aging is a complex degenerative process characterized by the accumulation of molecular damage and a heightened susceptibility to disease. The oxidative stress theory of aging identifies endogenous reactive oxygen species (ROS) as primary drivers of this cellular deterioration. This review provides a comprehensive analysis of the critical, yet underappreciated, interplay between oxidative stress and the complement system, a powerful effector of innate immunity. We detail the mechanistic pathways through which redox imbalance directly activates complement components and, conversely, how complement activation amplifies oxidative stress, creating a vicious cycle that accelerates tissue damage. A central focus is placed on how this redox-complement axis contributes to the pathophysiology of age-related conditions, including neurodegenerative, cardiovascular, and metabolic diseases. Furthermore, the review explores emerging therapeutic strategies that target this interaction, highlighting the potential of antioxidant and complement-inhibitory approaches to disrupt this cycle and promote healthy aging. By synthesizing current evidence, this work underscores the significance of the redox-complement network as a key mechanistic link in aging and its associated diseases.

Keywords:  aging; complement activation; complement system; oxidative damage; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox15010029
Immunology. 2026 Jan 29.

Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.

Woo Hyun Park.

  Beyond their classical role as cellular powerhouses, mitochondria are now recognised as indispensable hubs for innate immune signalling. A pivotal aspect of this function is the release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern (DAMP) that, when misplaced, acts as a powerful alarmin due to its prokaryotic origins. In response to cellular stress or infection, mtDNA translocates to the cytosol and activates intracellular protein platforms known as inflammasomes, triggering the maturation of cytokines like interleukin-1β (IL-1β) and inducing a lytic form of cell death, pyroptosis. This review synthesises current research on this intricate relationship. Whilst potassium (K+) efflux remains the canonical trigger for the NLR family pyrin domain containing 3 (NLRP3) inflammasome, emerging and debated roles of oxidised mtDNA (ox-mtDNA) as a potential direct ligand or critical upstream amplifier are explored. The manuscript elucidates mtDNA release mechanisms, such as mitochondrial permeability transition pore (mPTP) opening, and explores the role of amplifying pathways like the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis and cytidine/uridine monophosphate kinase 2 (CMPK2)-mediated mtDNA synthesis. The profound involvement of the mtDNA-inflammasome axis is surveyed across a spectrum of pathologies, including autoimmune, metabolic, neurodegenerative, and cardiovascular diseases. The compiled evidence establishes mtDNA as a universal trigger of inflammation and a unifying pathogenic driver across this diverse disease landscape, highlighting the significant therapeutic potential of modulating this fundamental immune signalling axis to treat a multitude of human diseases.

Keywords:  immunogenic cell death; inflammasome; innate immunity; mitochondrial DNA; pyroptosis; sterile inflammation

DOI:  https://doi.org/10.1111/imm.70111
Mitochondrion. 2026 Jan 25. pii: S1567-7249(26)00003-6. [Epub ahead of print]87 102113

Serum cell-free mitochondrial DNA under a highly standardized and controlled stress induction.

Benedict Herhaus, Carina Daubermann, Elmo W I Neuberger, Perikles Simon, Katja Petrowski.

  Cell-free mitochondrial DNA (ccf-mtDNA) is increasingly recognized as a biomarker of stress-related mitochondrial dysfunction. Acute psychological stress may induce ccf-mtDNA release, underscoring its potential role in stress physiology and adaptation. To further investigate this relationship, the present study examined acute stress-induced ccf-mtDNA dynamics in a controlled experimental setting. Twenty-seven healthy males (mean age: 23.78 ± 3.90 years) underwent both the Trier Social Stress Test (psychological stressor) and a resting condition. The kinetics of serum cell-free mitochondrial DNA (ccf-mtDNA) and serum cortisol were measured before and at 8 time points up to 105 min after the two stress conditions. After the TSST, ccf-mtDNA showed significant transient increases at +20 and +75 min, whereas cortisol exhibited the expected robust stress response. Our findings suggest that acute psychological stress can induce transient and heterogeneous changes in serum ccf-mtDNA, though these dynamics appear more modest and delayed than cortisol responses. Variability across studies underscores the need for standardized protocols and further research to clarify the mechanisms and moderators of ccf-mtDNA release under stress.

Keywords:  Circulating cell-free mitochondrial DNA (ccf-mtDNA); Psychological stress; Trier Social Stress Test (TSST)

DOI:  https://doi.org/10.1016/j.mito.2026.102113
Metab Brain Dis. 2026 Jan 28. 41(1): 23

Redox signaling in the heart and brain: the roles of nitric oxide and reactive oxygen species in disease and therapy.

Ramtin Naderian, Mohammad Ali Nazari, Tohid Emami Meybodi, Elham Paraandavaji, Ahmadreza Lagzian, Mahboobeh Nikandish, Majid Eslami.

  Nitric oxide (NO) and reactive oxygen species (ROS) are central to the pathophysiology of cardiovascular and neurological disorders, influencing intricate signaling pathways that manage vascular function, inflammation, and oxidative stress. NO, predominantly produced by NO-synthases, plays a vital role in maintaining vascular health by facilitating vasodilation and preventing platelet aggregation. However, its reaction with superoxide results in the formation of peroxynitrite, a highly reactive molecule that intensifies oxidative damage and impairs endothelial function. Elevated ROS levels, arising from sources like NADPH oxidases and mitochondrial activity, further heighten oxidative stress, driving the progression of conditions like atherosclerosis and neurodegenerative diseases. Therapeutic strategies aimed at restoring the balance between NO and ROS include the use of antioxidants to neutralize ROS, pharmacological methods to enhance NO bioavailability, and nanoparticle-based systems designed to address oxidative stress. Emerging research points to potential of targeting redox-sensitive pathways, such as the Keap1-Nrf2 axis, to slow disease progression. In neurological disorders, overproduction of ROS leads to neuroinflammation and neuronal apoptosis, which are central to conditions like Alzheimer's and Parkinson's disease. This review explores the complex relationship between NO and ROS in disease mechanisms, emphasizing cutting-edge therapeutic strategies that utilize redox signaling in cardiovascular and neurological conditions.

Keywords:  Cardiovascular diseases; Hypoxic; Neurological diseases; Nitric oxide (NO); Oxidative stress; ROS pathways

DOI:  https://doi.org/10.1007/s11011-025-01775-8
Medicina (Kaunas). 2026 Jan 08. pii: 132. [Epub ahead of print]62(1):

Growth Differentiation Factor 15 as a Link Between Obesity, Subclinical Atherosclerosis, and Heart Failure: A Systematic Review.

Raluca-Elena Alexa, Alexandr Ceasovschih, Bianca Codrina Morărașu, Andreea Asaftei, Mihai Constantin, Alexandra-Diana Diaconu, Anastasia Balta, Raluca Ecaterina Haliga, Victorița Șorodoc, Laurențiu Șorodoc.

  Background and Objectives: Obesity, heart failure (HF), and atherosclerosis have common pathways, including chronic inflammation, immune cells activation, and metabolic disturbances. These pathways often coexist and overlap, increasing cardiometabolic risk. Growth differentiation factor 15 (GDF-15) is an emerging cytokine linked to inflammation, oxidative stress, and metabolic dysregulation, which are common pathways between heart failure, obesity and atherosclerosis. Beyond its established prognostic value in cardiovascular diseases (CVD) and HF, recent evidence suggests that GDF-15 may also reflect subclinical atherosclerosis, potentially improving early risk stratification in obese and HF populations. The aim of this review is to synthesize current evidence on the association between GDF-15 and markers of subclinical atherosclerosis, and to evaluate whether GDF-15 may serve as an integrative biomarker reflecting shared cardiometabolic pathways. Materials and Methods: We conducted a systematic review following PRISMA recommendations registered by CRD420251267457 number on PROSPERO. PubMed, Embase, Scopus, and Web of Science were searched for human studies evaluating the correlation between markers of subclinical atherosclerosis and GDF-15 concentration. We excluded the studies not published in English, not involving human participants, and not meeting the inclusion criteria. We assessed the risk of bias using the Joanna Briggs Institute appraisal tool. Due to the heterogeneity of studies, a narrative synthesis was performed. Result: The review included 18 studies, which evaluated the association between GDF-15 and subclinical atherosclerosis markers, such as intima media thickness, coronary artery calcium score, ankle-brachial index, and atherosclerotic plaques. Studies included patients with metabolic disorders, chronic inflammatory diseases, HIV cohorts, and general population samples. Most of the studies reported that GDF-15 levels were associated with greater atherosclerotic burden; however, results were frequently influenced by confounders. Methodological limitations, such as limited or highly specified samples, cross-sectional designs, variability in atherosclerotic-imaging technique, and inconsistent adjustment for confounders, restrict generalization of the results. Conclusions: Current evidence supports GDF-15 as a biomarker integrating inflammatory and metabolic stress signals, indirectly linking obesity, HF and subclinical atherosclerosis. While current data supports its prognostic relevance, further studies are needed to confirm its clinical utility in routine assessment and preventive cardiovascular care.

Keywords:  GDF-15; atherosclerosis; growth differentiation factor 15; heart failure; obesity

DOI:  https://doi.org/10.3390/medicina62010132
Front Nutr. 2025 ;12 1687719

Creatine supplementation and exercise in aging: a narrative review of the muscle-brain axis and its impact on cognitive and physical health.

Nana Li.

   Background/Aim: Aging is associated with progressive declines in neuromuscular and cognitive functions, which negatively impact independence and quality of life. The muscle-brain axis has emerged as a key pathway linking skeletal muscle health to cognitive performance. This review aimed to evaluate the effects of creatine supplementation combined with exercise on physical and cognitive outcomes in older adults.
Methods: A narrative review was conducted summarizing evidence from clinical and preclinical studies, including randomized controlled trials and meta-analyses, on creatine supplementation and exercise interventions targeting aging populations.
Results: Creatine supplementation, particularly when combined with resistance training, significantly improves muscle strength, lean body mass, and functional capacity in older adults. Cognitive outcomes show modest improvements in memory, processing speed, and executive function, especially in individuals with lower baseline creatine levels. Mechanistically, creatine supports energy metabolism, mitochondrial stability, and antioxidant defenses, while exercise promotes neuroplasticity through myokines, collectively reinforcing the muscle-brain axis.
Conclusion: The combination of creatine supplementation and structured exercise appears to be a safe and promising strategy to counteract age-related declines in both physical and cognitive functions. However, further large-scale studies are required to establish long-term benefits and optimize dosing protocols.

Keywords:  aging; cognitive function; creatine; exercise; neuroprotection

DOI:  https://doi.org/10.3389/fnut.2025.1687719
Curr Issues Mol Biol. 2025 Nov 23. pii: 971. [Epub ahead of print]47(12):

Modulating Skin Aging Molecular Targets and Longevity Drivers Through a Novel Natural Product: Rose-Derived Polydeoxyribonucleotide (Rose PDRN).

Andrea Cavagnino, Gayané Azadiguian, Lionel Breton, Martin Baraibar, Annie F Black.

  Environmental stressors such as pollution and ultraviolet (UV) radiation contribute significantly to skin aging and skin photo-aging, alongside intrinsic chronological factors. Recent insights into longevity science have emphasized mitochondrial health, proteostasis, and autophagic balance as critical processes for maintaining skin integrity. This study investigates the protective potential of a natural product, Rose-derived PolyDeoxyRiboNucleotide (PDRN), against mitochondrial dysfunction and dysregulated autophagy in primary human keratinocytes subjected to environmental stress (benzo-a-pyrene and UV-A). PDRN was evaluated at 0.1%, 0.05%, and 0.01% concentrations. Mitochondrial function was assessed through membrane polarization, ATP/ADP ratio, Complex V (CV-ATP5A) levels, and citrate synthase levels. LAMP2A levels were quantified to evaluate the autophagic pathway. Complementary analyses were performed on ex vivo human skin explants, evaluating oxidative protein damage (carbonylation), Collagen I/III integrity, MMP1 and IL1a levels, and mitophagy markers (PINK1, PARK2). The results confirm significant protection of mitochondrial function, attenuation of oxidative stress, and modulation of autophagy-related pathways by PDRN across all models tested. These findings underscore the capacity of this novel natural product, a plant-derived PDRN, to mitigate environmental skin aging (and photo-aging) through mitochondrial maintenance and proteostasis regulation, positioning Rose-PDRN as a key active ingredient for dermocosmetic formulations targeting skin longevity biomarkers.

Keywords:  PDRN; autophagy; mitochondrial function; natural product; proteostasis; skin aging; skin longevity; skin photo-aging

DOI:  https://doi.org/10.3390/cimb47120971
Front Nutr. 2025 ;12 1724786

The effects of hesperidin supplementation on insulin resistance and sensitivity in adults: a systematic review and meta-analysis of randomized controlled trials.

Wen Li, Yuyin Liu, Kun Zhu, Lijiao Wu, Meixi Liu, Qiu Chen.

  This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effects of hesperidin supplementation on insulin resistance and sensitivity in adults. Two authors independently searched electronic databases, including PubMed, Scopus, Embase, Web of Science, and the Cochrane Library, from their inception to July 2025 for relevant RCTs. The quality of the included studies was assessed using the Cochrane Collaboration's tool for assessing the risk of bias. Heterogeneity among the included studies was evaluated using Cochrane's Q test and the I2 statistic. A meta-analysis of eligible studies was conducted using either fixed- or random-effects models, with the weighted mean difference (WMD) serving as the overall effect size. Pre-specified subgroup and sensitivity analyses were performed to explore potential sources of heterogeneity. This meta-analysis included 16 studies, comprising 845 participants and assessing five outcome measures. We found that hesperidin supplementation significantly reduced the homeostatic model assessment of insulin resistance (HOMA-IR) (WMD: -0.43, 95%CI: -0.82, -0.03; p = 0.034) and increased the quantitative insulin sensitivity check index (WMD: 0.05, 95%CI: 0.01, 0.08; p = 0.005). However, no significant effects were observed on insulin, fasting blood glucose, or glycated hemoglobin A1c. Subgroup analyses indicated that supplementation with high-dose, long-duration purified hesperidin, particularly in individuals with metabolic disorders and obesity, had a positive effect on insulin levels. However, subsequent trial sequential analysis revealed that hesperidin confers no statistically significant improvement in HOMA-IR. In conclusion, the current body of evidence does not support hesperidin as an effective intervention for ameliorating insulin resistance or enhancing glycemic control. Future investigations are warranted to explore its potential efficacy in specific populations or subgroups.
Systematic review registration: PROSPERO, identifier (CRD420251102342).

Keywords:  hesperidin; insulin resistance; insulin sensitivity; meta-analysis; randomized controlled trial

DOI:  https://doi.org/10.3389/fnut.2025.1724786
Phytother Res. 2026 Jan 26.

Dietary Antioxidants, Polyphenols, and Vascular Health: Insights From Ultrasound Measurement of Carotid Intima-Media Thickness and Their Association With Cognitive Function in Aging and Neurodegenerative Diseases.

Lei Wang, Zhiyu Luo, Dan Liu.

  Carotid intima-media thickness (CIMT), measured by ultrasound, is a validated marker of subclinical atherosclerosis and an early predictor of cardiovascular and cerebrovascular disease. Increasing evidence links vascular aging and oxidative stress to cognitive decline, particularly among older adults and individuals with neurodegenerative disorders. Dietary antioxidants and polyphenols-abundant in fruits, vegetables, olive oil, tea, and red wine-exert protective effects on vascular and brain health through anti-inflammatory, antioxidant, and endothelial-supportive mechanisms. This narrative review synthesizes current evidence on the influence of dietary antioxidants and polyphenols on ultrasound-measured CIMT and cognitive function, with emphasis on aging and early neurodegenerative disease. A narrative review of clinical trials, cohort studies, and mechanistic investigations published between 2000 and 2024 was conducted. Studies exploring antioxidant-rich diets and individual polyphenols (e.g., resveratrol, epigallocatechin gallate, punicalagin) and their effects on CIMT, oxidative stress, neuroinflammation, and cognitive outcomes were included. Evidence from randomized controlled and observational studies shows that polyphenol-rich interventions-such as the Mediterranean diet and pomegranate juice-are associated with reductions in CIMT and improvements in cognitive domains, including memory, attention, and executive function. These benefits are mediated through reduced oxidative stress, suppression of pro-inflammatory cytokines, improved lipid metabolism, and enhanced nitric oxide bioavailability. Some studies also demonstrate favorable changes in brain imaging biomarkers and cerebrovascular perfusion. Dietary antioxidants and polyphenols show potential to mitigate vascular aging and cognitive decline. These nutritional strategies may serve as safe, cost-effective adjuncts in preventing atherosclerosis and neurodegenerative disorders. However, further long-term, high-quality studies are needed to define optimal doses, formulations, and personalized dietary approaches.

Keywords:  antioxidants; carotid intima‐media thickness; cognitive function; neurodegeneration; polyphenols; ultrasound measurement; vascular aging

DOI:  https://doi.org/10.1002/ptr.70198
Cardiovasc Toxicol. 2026 Jan 28. 26(2): 22

Liraglutide Modulates Zinc Release and Improves Mitochondrial Function in Insulin-Resistant Senescent Cardiomyocytes.

Fatemeh Hosseinpourshirazi, Umur D Mendes, Zeynep B Aksoy, Dunya Aydos, Merve Sözer, Lubne Aljaser, Manolya Gundogdu, Suatnur Sık, Erkan Tuncay, Belma Turan, Yusuf Olgar.

  Aging and insulin resistance are intertwined factors in the development of metabolic diseases such as type 2 diabetes and cardiovascular disorders. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising cardioprotective effects in preclinical and clinical studies of metabolic diseases. Yet, its action on insulin-resistant aged subjects is not clearly defined. This study aimed to investigate the effects of liraglutide on intracellular zinc levels, including its modulation of oxidative stress, mitochondrial function, and Endoplasmic Reticulum (ER) stress in a novel insulin-resistant senescent model. Insulin resistance and senescence were confirmed by reduced glucose uptake and increased β-Galactosidase Staining and increased p-H2A.X (Ser139) levels after 24 h of co-incubation with bovine serum albumin (BSA) conjugated palmitic acid (PA; 50 µM) and 278 mM D-galactose (D-Gal) in human AC16 cells. Our findings showed upregulated expression of ER and mitochondrial proteostasis markers in the early minutes of liraglutide treatment. In addition, chronic but not acute liraglutide treatment significantly increased intracellular zinc levels, accompanied by improved mitochondrial membrane potential and reduced reactive oxygen species in the insulin-resistant senescent model. Casein kinase 2 inhibition completely abolished liraglutide-induced zinc elevation and mitochondrial improvements in the chronic context, highlighting the role of casein kinase 2 in the subcellular signaling of liraglutide. These findings indicate that liraglutide alters intracellular zinc and modulates endoplasmic reticulum-mitochondria communication, giving insight into its therapeutic potential in metabolic cardiomyopathies linked to insulin resistance and aging.

Keywords:  Casein kinase; Insulin resistance; Liraglutide; Mitochondrial function; Senescent cardiomyocytes; Zinc homeostasis

DOI:  https://doi.org/10.1007/s12012-026-10095-x
Biomedicines. 2025 Dec 27. pii: 63. [Epub ahead of print]14(1):

Antioxidant and Neuroprotective Capacity of Resveratrol-Loaded Polymeric Micelles in In Vitro and In Vivo Models with Generated Oxidative Stress.

Maria Lazarova, Elina Tsvetanova, Almira Georgieva, Miroslava Stefanova, Krasimira Tasheva, Lyubomira Radeva, Magdalena Kondeva-Burdina, Krassimira Yoncheva.

  Background: Resveratrol (3,5,4'-trihydroxy-trans-stilbene, RVT) is one of the most extensively studied natural polyphenols, with numerous health benefits documented in the literature. One of its most characterized biological properties is the strong antioxidant capacity. However, its poor biopharmaceutical properties limit its in vivo applicability. In this study, we conducted a detailed comparative analysis of the antioxidant and protective capacity of pure and loaded into Pluronic micelles resveratrol. Methods: Various in vitro antioxidant assays, such as DPPH, ABTS, superoxide anion radical scavenging, ferric (FRAP), and copper-reducing power assay (CUPPRAC), and iron-induced lipid peroxidation were performed. In addition, the in vitro 6-OHDA model of neurotoxicity in brain synaptosomes and the in vivo scopolamine (Sco)-induced model of cognitive impairment in rats were also employed. The main antioxidant biomarkers-the levels of lipid peroxidation (LPO) and total glutathione (GSH), as well as activities of superoxide dismutase, catalase, and glutathione peroxidase-were measured in the cortex and hippocampus. Results: The results from the in vitro tests demonstrated better ferric-reducing power activity and better neuroprotective capacity of the micellar resveratrol (mRVT), as evidenced by preserved synaptosomal viability and maintained GSH levels in a concentration-dependent manner in 6-OHDA-induced neurotoxicity. Regarding the in vivo results, mRVT (10 µM concentration) was the most effective treatment in supporting recognition memory formation in dementia rats. Further, mRVT demonstrated better LPO protective capacity in the hippocampus and GSH preserving activity in the cortex than the pure drug. Conclusions: The incorporation of resveratrol in polymeric micelles could enhance its antioxidant and neuroprotective effects.

Keywords:  antioxidant properties; micelles; neurodegeneration; neurotoxicity; resveratrol

DOI:  https://doi.org/10.3390/biomedicines14010063
Pharmaceuticals (Basel). 2026 Jan 12. pii: 133. [Epub ahead of print]19(1):

Metabolic Reprogramming by Andrographolide: Enhanced Pentose Phosphate Pathway and Antioxidant Capacity in Cortical Astrocytes.

Pedro Cisternas, Paulina Ormazabal, Camila Gherardelli, Marianela Bastías-Pérez, Jose Brito-Valenzuela, Nibaldo C Inestrosa.

  Background/Objectives: Astrocytes are key regulators of brain energy homeostasis, integrating glucose metabolism with antioxidant support for neuronal function. Dysregulation of these processes contributes to neurodegenerative diseases, including Alzheimer's disease. Andrographolide, a bioactive diterpenoid from Andrographis paniculata, has been reported to exert neuroprotective effects through the modulation of Wnt/β-catenin signaling and neuronal metabolism; however, its actions on astrocytic metabolic pathways remain insufficiently characterized. Methods: Here, we investigated the effects of andrographolide on metabolic and redox parameters in primary mouse cortical astrocytes. Results: Andrographolide increased glucose uptake and antioxidant capacity without affecting AMPK activation or the activity of core glycolytic enzymes. Instead, it selectively enhanced glucose-6-phosphate dehydrogenase activity, promoting glucose flux through the pentose phosphate pathway in a partially Wnt-dependent manner. This metabolic reprogramming was associated with increased NADPH availability and glutathione levels, together with a reduced ATP/ADP ratio, consistent with a shift toward redox maintenance rather than maximal energy production. Conclusions: Collectively, these findings highlight astrocytic metabolic plasticity as a relevant and underexplored target of andrographolide and support the concept that natural compounds can enhance brain resilience by modulating glial redox metabolism.

Keywords:  Alzheimer disease; andrographolide; astrocytes; glucose metabolism; neuroprotection

DOI:  https://doi.org/10.3390/ph19010133
Antioxidants (Basel). 2026 Jan 21. pii: 139. [Epub ahead of print]15(1):

Baicalin Alleviates Chronic Restraint Stress-Induced Depression-like Behavior by Suppressing ROS/H2O2 Generation via a BDNF-Associated Mechanism in Mice.

Yu-Ning Teng, Tien-Wei Hsu, Wei-Hao Peng, Cheng-Chun Wu, Tian-Huei Chu, Yung-Kuo Lee, Ming Tatt Lee, Yu-Cheng Ho.

  Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Scutellaria baicalensis, exhibits antioxidant, anti-inflammatory, and neuroprotective properties and has recently gained attention for its potential to improve cognitive deficits and mood disorders. In this study, we investigated baicalin's antidepressant potential and its underlying mechanisms across multiple experimental levels. We found that oral administration of baicalin produced antidepressant-like effects in both naïve mice and those subjected to chronic restraint stress (CRS). CRS impaired hippocampal long-term potentiation (LTP), whereas baicalin restored these synaptic deficits. Importantly, intra-dorsal hippocampal microinjection of the TrkB receptor antagonist ANA-12 abolished baicalin's antidepressant effects, indicating the involvement of BDNF-TrkB signaling. Baicalin also reduced reactive oxygen species (ROS)/H2O2 production in a BDNF-associated manner, demonstrating clear antioxidant activity. Molecular docking further suggested that baicalin binds more effectively to the TrkB receptor than ANA-12, supporting its capacity to activate TrkB-mediated signaling. By integrating in vivo, ex vivo, in vitro, and in silico approaches, our study shows that baicalin exerts robust antioxidant in vitro and antidepressant effects in vivo. These benefits are primarily mediated through activation of BDNF-TrkB signaling, leading to reduced ROS/H2O2 accumulation and alleviation of CRS-induced depression-like behaviors.

Keywords:  ROS; baicalin; chronic stress; depression; hippocampus; long-term potentiation

DOI:  https://doi.org/10.3390/antiox15010139
Cells. 2026 Jan 14. pii: 149. [Epub ahead of print]15(2):

Mitochondrial Metabolic Checkpoints in Human Fertility: Reactive Oxygen Species as Gatekeepers of Gamete Competence.

Sofoklis Stavros, Nikolaos Thomakos, Efthalia Moustakli, Nikoleta Daponte, Dimos Sioutis, Nikolaos Kathopoulis, Athanasios Zikopoulos, Ismini Anagnostaki, Chrysi Christodoulaki, Themos Grigoriadis, Ekaterini Domali, Anastasios Potiris.

  Crucial regulators of gamete metabolism and signaling, mitochondria synchronize energy generation with redox equilibrium and developmental proficiency. Once thought of as hazardous byproducts, reactive oxygen species (ROS) are now understood to be vital signaling molecules that provide a "redox window of competence" that is required for oocyte maturation, sperm capacitation, and early embryo development. This review presents the idea of mitochondrial metabolic checkpoints, which are phases that govern gamete quality and fertilization potential by interacting with cellular signaling, redox balance, and mitochondrial activity. Recent research shows that oocytes may sustain a nearly ROS-free metabolic state by blocking specific respiratory-chain components, highlighting the importance of mitochondrial remodeling in gamete competence. Evidence from in vitro and in vivo studies shows that ROS act as dynamic gatekeepers at critical points in oogenesis, spermatogenesis, fertilization, and early embryogenesis. However, assisted reproductive technologies (ARTs) may inadvertently disrupt this redox-metabolic equilibrium. Potential translational benefits can be obtained via targeted techniques that optimize mitochondrial function, such as modifying oxygen tension, employing mitochondria-directed antioxidants like MitoQ and SS-31, and supplementing with nutraceuticals like melatonin, CoQ10, and resveratrol. Understanding ROS-mediated checkpoints forms the basis for developing biomarkers of gamete competence and precision therapies to improve ART outcomes. By highlighting mitochondria as both metabolic sensors and redox regulators, this review links fundamental mitochondrial biology to clinical reproductive medicine.

Keywords:  ART; OS; ROS; gamete competence; mitochondria; oocyte maturation; sperm capacitation

DOI:  https://doi.org/10.3390/cells15020149
Int J Mol Med. 2026 Mar;pii: 75. [Epub ahead of print]57(3):

Ginkgolide C alleviates atherosclerosis via activating Nrf2 to inhibit ROS‑dependent NLRP3 inflammasome activation.

Rui Zhang.

  Atherosclerosis (AS), a chronic vascular pathology characterized by endothelial dysfunction, arises from the interplay of lipid dysregulation, oxidative stress, and inflammatory activation. Reactive oxygen species (ROS) overproduction triggers Nod‑like receptor protein 3 (NLRP3) inflammasome signaling, exacerbating inflammatory cascades that drive plaque progression. The nuclear factor erythroid 2‑related factor 2 (Nrf2)‑mediated antioxidant pathway serves as a critical counterbalance to ROS/NLRP3 axis dysregulation, positioning pharmacological Nrf2 activation as a promising therapeutic strategy. The present study investigated the anti‑atherosclerotic potential of ginkgolide C (GC), a terpene lactone from Ginkgo biloba with established anti‑inflammatory and anti‑ischemia/reperfusion injury properties, through coordinated modulation of redox‑inflammatory pathways. Complementary in vivo (high‑fat diet/vitamin D3‑treated ApoE-/- mice) and in vitro (oxidized‑low density lipoprotein‑stimulated aortic endothelial cells) models were established. Comprehensive analyses included histopathological characterization, lipid profiling, ultrastructural examination, redox‑inflammatory biomarker quantification, and molecular pathway validation. GC significantly attenuated hyperlipidemia and plaque progression while preserving vascular ultrastructure. Mechanistically, GC enhanced endothelial survival through dual pathway modulation: i) Nrf2 nuclear translocation upregulated antioxidant enzymes [heme oxygenase‑1/NAD(P)H quinone oxidoreductase 1/glutamate‑cysteine ligase modifier subunit], restoring redox homeostasis; ii) NLRP3 inflammasome inhibition via Caspase‑1 suppression mitigated inflammatory cytokine release. The present study demonstrated GC's dual‑target therapeutic efficacy against AS through Nrf2‑mediated oxidative stress resolution and NLRP3 inflammasome inactivation, offering new insights into phytochemical‑based cardiovascular interventions.

Keywords:  Nod‑like receptor protein 3; atherosclerosis; ginkgolide C; nuclear factor erythroid 2‑related factor 2; reactive oxygen species

DOI:  https://doi.org/10.3892/ijmm.2026.5746
Nutrients. 2026 Jan 19. pii: 307. [Epub ahead of print]18(2):

Effects of Probiotic Supplementation on Mental Health and the Risk of Depression in Women with Polycystic Ovary Syndrome: A Systematic Review of Randomized Controlled Trials.

Karolina Łagowska, Dagmara Ptaszyńska.

  Background: Polycystic ovary syndrome (PCOS) is commonly associated with psychological disorders, including depression and anxiety. Women with PCOS also tend to experience poorer sleep quality and greater daytime sleepiness than healthy individuals. To the best of our knowledge, no systematic reviews have investigated the impact of probiotic supplementation on mental health and sleep patterns in women with PCOS. Emerging evidence indicates that probiotic therapy may be a promising adjunct for enhancing mental well-being and sleep quality within this population. Objectives: This systematic review aimed to evaluate the effects of probiotic supplementation on depression, anxiety, and sleep quality in adult women with PCOS. Methods: PubMed, Cochrane, and Scopus were searched for randomized controlled trials (RCTs) involving women aged 18-45 years old, with diagnosed PCOS, who received probiotic/synbiotic supplements and enriched foods compared with placebo. Studies had to assess mental health, depressive symptoms, or sleep disorders using validated questionnaires. Five publications met the Population, Intervention, Comparison, and Outcome inclusion criteria (PICO) and were included in the final analysis. Results: Probiotic supplementation was associated with significant improvements in sleep quality (assessed by Pittsburgh Sleep Quality Index, PSQI), depressive symptoms (assessed by Depression, Anxiety and Stress Scale, DASS 21) and some domains of quality of life (measured by Polycystic Ovary Syndrome Health Related Quality of Life Questionnaire, PCOSQ-26). Conclusions: Although probiotic supplementation may benefit mental health and sleep parameters in women with PCOS, this evidence is limited due to the small number of studies, modest sample sizes, and methodological variability. Further research with larger, more rigorous studies is needed to confirm these findings.

Keywords:  anxiety; depression; polycystic ovary syndrome; probiotic supplementation; sleep quality

DOI:  https://doi.org/10.3390/nu18020307
Medicina (Kaunas). 2026 Jan 13. pii: 157. [Epub ahead of print]62(1):

Reproductive Longevity: Innovative Approaches Beyond Hormone Replacement Therapy.

Nida Jugulytė, Daiva Bartkevičienė.

  With increasing life expectancy driven by rapid biomedical science advancement, reproductive longevity has become a key concept in women's health. Preventing reproductive senescence is important not only to extend fertility potential but also to preserve endocrine health, enhance quality of life, and promote healthy aging. The end of ovarian function and fertility is symbolized by menopause, as the most eminent index of reproductive aging. Hormone replacement therapy (HRT) remains the mainstay for managing menopausal symptoms. However, as the use of HRT is often limited, there is a need for safe and effective alternatives. This narrative review summarizes current and emerging approaches targeting different stages of reproductive aging. Both hormonal and non-hormonal therapies for vasomotor and genitourinary symptoms are discussed alongside developing fertility preservation techniques, including oocyte vitrification, ovarian tissue cryopreservation, in vitro follicle maturation, and artificial ovary engineering. Furthermore, evolving and experimental ovarian regenerative strategies, such as stem cell transplantation, intraovarian platelet-rich plasma (PRP) injections, antioxidants, metabolic modulators, telomerase activators, and stem cell-derived extracellular vesicles, offer new prospects for delaying or reversing ovarian aging. Overall, personalized regenerative strategies and innovative solutions may reshape the future of women's reproductive health and longevity.

Keywords:  fertility preservation; menopause; ovarian aging; reproductive longevity

DOI:  https://doi.org/10.3390/medicina62010157
Front Immunol. 2025 ;16 1700604

Single-cell transcriptome-wide Mendelian randomization identifies mitochondrial targets in immune cells for Major Depressive Disorder.

Yangyi Zhang, Fei Zhang, Xingyi Shen, Maoyuan Ni, Jiayi Zhang, Shunling Zhang, Jingwen Lin, Zhaoyang Yang, Huangwei Lei.

   Background: A critical need exists for objective biomarkers and novel therapeutic targets in major depressive disorder (MDD). Although dysfunction in mitochondrial immunometabolism is implicated in MDD, the specific causal genes suitable for clinical translation remain largely unidentified. This study aimed to bridge this gap by identifying mitochondria-related genes that have a causal impact on MDD risk through their expression in specific immune cells.
Methods: We integrated multi-omics data with machine learning to pinpoint key mitochondria-related energy metabolism genes (MEMRGs) linked to immune cell infiltration, assessed via ssGSEA and CIBERSORT algorithms. Cell-type-specific two-sample Mendelian randomization (MR) was employed to evaluate causal relationships between gene expression and MDD risk. Findings were validated in a chronic unpredictable mild stress (CUMS) rat model.
Results: Our analysis identified five genes-HK2, NDUFS4, NEU1, SOD1, and UCP2-whose expression in distinct immune populations had significant causal effects on MDD risk. Notably, HK2, NDUFS4, and NEU1 were identified as protective factors, while UCP2 and SOD1 were risk factors in specific cell types. The clinical relevance of this panel was supported by its diagnostic performance in an independent cohort, and the upregulation of the principal risk gene, UCP2, was confirmed in the hippocampus of CUMS rats.
Conclusion: This study provides robust genetic evidence establishing a causal link between the expression of specific mitochondrial genes in immune cells and the risk of MDD. By prioritizing UCP2, SOD1, HK2, NDUFS4, and NEU1, our findings highlight novel, immune-mediated pathways in depression and nominate promising targets for future diagnosis and therapeutic intervention.

Keywords:  Major Depressive Disorder; Mendelian randomization; immune cell eQTL; machine learning; mitochondrial energy metabolism

DOI:  https://doi.org/10.3389/fimmu.2025.1700604
Free Radic Biol Med. 2026 Jan 27. pii: S0891-5849(26)00070-5. [Epub ahead of print]

Glycine ameliorates aging-related dysfunctions associated with Nmdmc-mediated mitochondrial one-carbon metabolism.

Jiaying Yu, Yiran Wang, Nan Wang, Yizhi Zhang, Qi Yu, Jingjing Li, Runan Zhang, Fanyun Wang, Qianru Zhang, Jiaqi Zhang, Jiayu Zhu, Weili Xu, Bo Peng, Bo Qu, Liyan Liu, Rennan Feng.

   INTRODUCTION: Aging is characterized by the progressive decline of physiological integrity, and its driving factors include mitochondrial dysfunction, epigenetic changes and metabolic imbalance. Although some studies have shown that glycine (Gly) has anti-aging protection, its mechanism has not been clarified.
OBJECTIVES: The purpose of this study is to explore the mechanism of Gly in anti-aging and improving aging-related phenotype, and to clarify the molecular pathway of Gly promoting healthy aging.
METHODS: Fruit fly and aged rat models were used to evaluate the effect of Gly supplementation. Life span, stress resistance and functional phenotype were evaluated in fruit flies, and biochemical, histological and physiological indexes related to aging were detected in aged rats. Transcriptomic and metabolomic profiling, along with gene knockdown approaches, were used to identify key pathways and targets involved in Gly-mediated effects.
RESULTS: In fruit flies, Gly extended lifespan and ameliorating aging-related phenotypes, with Gly dose-dependently upregulated the expression of Nmdmc, whose knockdown abolished these beneficial effects, indicating the essential role of Nmdmc in Gly-mediated activation of one-carbon metabolism (OCM). Metabolomic identified glyceric acid as a key metabolite linked to improved mitochondrial energy metabolism. In aged rats, Gly also upregulated Mthfd2 (the mammalian ortholog of Nmdmc) and reduced neuronal damage in the hippocampus, restored hepatic cell architecture, and increased muscle fiber density, accompanied by enhanced mitochondrial biogenesis and methylation markers.
CONCLUSION: Gly supplementation alleviated aging-related dysfunction by up-regulating Nmdmc and remodeling mitochondrial OCM, which could help to improve DNA repair, mitochondrial function and oxidative stress resistance.

Keywords:  Nmdmc; aging; fruit flies; glyceric acid; glycine; one carbon metabolism

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.050
Int J Mol Sci. 2026 Jan 20. pii: 1011. [Epub ahead of print]27(2):

Microbiota-Mediated Crosstalk Between the Gut and the Vascular System: Protective Effects of Novel Postbiotic Formulations on Human Endothelial and Vascular Smooth Muscle Cells.

Lorenzo Flori, Diletta Francesca Squarzanti, Marta Lo Re, Patrizia Malfa, Alma Martelli, Vincenzo Calderone.

  The close connections between the intestine and distal systems, known as axes, are a growing focus of scientific research; however, the gut-vascular axis, particularly as a target of microbial metabolites, remains underexplored. In this study, three supernatants derived from probiotic formulations composed of Lactobacillus and Bifidobacterium strains (MIX-1, MIX-2, and MIX-3) were evaluated in counteracting vascular alterations associated with dysbiosis. Human aortic smooth muscle (HASMCs) and endothelial (HAECs) cells were exposed to pro-oxidative (H2O2) and pro-inflammatory (TMAO) stimuli. Concentrations up to 5-10% (v/v) were tolerated in both cell lines, with MIX-1 and MIX-3 showing the greatest protective efficacy. These formulations exerted antioxidant effects by reducing H2O2-induced ROS production and cell viability loss, and anti-inflammatory effects by limiting TMAO-induced IL-1β release. MIX-1 also attenuated TMAO-induced IL-6 release. Further analyses indicated a partial involvement of the SIRT1-pathway in its vascular antioxidant effects. Chromatographic profiling revealed comparable qualitative metabolites among the probiotic supernatants, while quantitative differences were observed, with higher lactate levels in MIX-1 and MIX-3 compared to MIX-2. Finally, we have determined that Limosilactobacillus reuteri-PBS072 is mainly responsible for the antioxidant effect of MIX-1 and MIX-3. Overall, these findings highlight the potential of probiotic-derived metabolites in modulating the gut-vascular axis and promoting vascular protection.

Keywords:  TMAO; crosstalk; dysbiosis; gut; gut-vascular axis; lactate; microbiota; postbiotic; probiotic; vascular

DOI:  https://doi.org/10.3390/ijms27021011