bims-mistre 2026-01-11 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–01–11
24 papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial Health Through Nicotinamide Riboside and Berberine: Shared Pathways and Therapeutic Potential.
Mitochondrial Dysfunction in Inflammatory Skin Diseases: Mechanisms, Biomarkers, and Emerging Therapeutic Strategies.
Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.
Thermotolerance induced by non-lethal heat shock at 40 °C is activated by mitochondrial ROS and is Nrf2-dependent.
Chronic stress and the mitochondria-telomere axis: human evidence for a bioenergetic-debt model of early aging.
Metformin Attenuates ox-LDL-Induced Macrophage Senescence and Inflammation via NR4A1-Mediated Mitophagy Regulation.
Effect of micronutrients on fertility and aneuploidy rates in human conceptions: a systematic review and meta-analysis.
Clinical Potential of Curcuma longa Linn. as Nutraceutical/Dietary Supplement for Metabolic Syndrome: Systematic Review and Meta-Analysis of Randomized Controlled Trials.
SKQ1: a mitochondria-targeted antioxidant with therapeutic potential.
Estrogen receptor-autophagy axis protects the heart, aorta and kidneys during perimenopausal aging: Evidence from human cohort and mouse experiments.
NLRP3 inflammasome and Alzheimer's disease: bridging inflammation and neurodegeneration.
Pathophysiology of HFpEF: Insights from a Metabolic-Mitochondrial Perspective.
Oxidative Stress, Mitochondrial Homeostasis, and Sirtuins in Atrial Fibrillation.
The Emerging Role of L-Arginine and Creatine Supplementation Combined with Exercise on Hippocampal Neurogenesis, Spatial Learning, and Cognitive Flexibility in Aging and Neurodegenerative Diseases.
Kynurenine Pathway Metabolites as Mediators of Exercise-Induced Mood Enhancement, Fatigue Resistance, and Neuroprotection.
Plasma growth differentiation factor-15 is associated with cardiovascular events in patients hospitalized for acute exacerbation of COPD.
Ubiquinol in Fertility and Reproduction: A Conditionally Essential Nutrient for Critical Early-Life Stages.
Ketone monoester ingestion improves endothelial function during hyperglycemia in females with polycystic ovary syndrome.
Endothelial mitochondrial dysfunction in hypertension, diabetes and atherosclerosis.
Effects of Green Tea Extract Supplementation on Inflammatory Cytokines Among Postmenopausal Women with Overweight or Obesity-A Secondary Analysis of a Randomized Controlled Trial.
Dietary phenolics and exercise complementation to delay aging at its source: a comprehensive review highlighting mitochondrial function.
No effect of pyrroloquinoline quinone on mouse body weight and energy metabolism with the concomitant increase in mitochondrial biogenesis and antioxidant ability.
Brain Glutathione Levels Associate With Cognitive Performance in Older Adults.
The Mitochondrial Protective Mechanisms Mediated by SGLT2i: From Molecular Basis to Clinical Implications.

Int J Mol Sci. 2026 Jan 02. pii: 485. [Epub ahead of print]27(1):

Mitochondrial Health Through Nicotinamide Riboside and Berberine: Shared Pathways and Therapeutic Potential.

Federico Visalli, Matteo Capobianco, Francesco Cappellani, Lorenzo Rapisarda, Alfonso Spinello, Alessandro Avitabile, Ludovica Cannizzaro, Caterina Gagliano, Marco Zeppieri.

  Mitochondrial dysfunction represents a central hallmark of aging and a broad spectrum of chronic diseases, ranging from metabolic to neurodegenerative and ocular disorders. Nicotinamide riboside (NR), a vitamin B3 derivative and efficient precursor of NAD+ (nicotinamide adenine dinucleotide), and berberine (BBR), an isoquinoline alkaloid widely investigated in metabolic regulation, have independently emerged as promising mitochondrial modulators. NR enhances cellular NAD+ pools, thereby activating sirtuin-dependent pathways, stimulating PGC-1α-mediated mitochondrial biogenesis, and triggering the mitochondrial unfolded protein response (UPRmt). BBR, by contrast, primarily activates AMPK (AMP-activated protein kinase) and interacts with respiratory complex I, improving bioenergetics, reducing mitochondrial reactive oxygen species, and promoting mitophagy and organelle quality control. Importantly, despite distinct upstream mechanisms, NR and BBR converge on shared signaling pathways that support mitochondrial health, including redox balance, metabolic flexibility, and immunometabolic regulation. Unlike previous reviews addressing these compounds separately, this article integrates current preclinical and clinical findings to provide a unified perspective on their converging actions. We critically discuss translational opportunities as well as limitations, including heterogeneous clinical outcomes and the need for robust biomarkers of mitochondrial function. By outlining overlapping and complementary mechanisms, we highlight NR and BBR as rational combinatorial strategies to restore mitochondrial resilience. This integrative perspective may guide the design of next-generation clinical trials and advance precision approaches in mitochondrial medicine.

Keywords:  NAD+ metabolism; berberine; cardiometabolic disease; mitochondrial dysfunction; neuroprotection; nicotinamide; nicotinamide riboside; oxidative stress; retinal ganglion cells

DOI:  https://doi.org/10.3390/ijms27010485
Drug Dev Res. 2026 Feb;87(1): e70221

Mitochondrial Dysfunction in Inflammatory Skin Diseases: Mechanisms, Biomarkers, and Emerging Therapeutic Strategies.

Mei Li, Guowei Zhao, Guo-Wei Zhao, Jie Shen.

  Mitochondrial dysfunction critically underpins the pathogenesis of inflammatory skin diseases such as psoriasis, vitiligo, atopic dermatitis, and impaired wound healing. This comprehensive review synthesizes recent evidence to elucidate mechanisms, including compromised bioenergetics, excessive reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, and aberrant mitochondrial dynamics. Distinct from prior work, this analysis uncovers novel findings: mtDNA acts as a damage-associated molecular pattern, activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathways to drive type I interferon in vitiligo and IL-17A in psoriasis; succinate-mediated immune-metabolic signaling amplifies type 2 inflammation in atopic dermatitis; and subclinical mitochondrial impairments in non-lesional skin serve as early indicators of disease susceptibility across these conditions. Preclinical studies have shown that emerging therapies, including antioxidants (e.g., NMN), mitochondrial modulators (e.g., SS31), senotherapeutics, and mitochondrial transplantation, are promising strategies for restoring cellular function. Future research should focus on multi-omics to dissect mitochondrial-epigenetic interactions, validate mitochondrial metabolites like succinate as diagnostic biomarkers, and explore synergistic combination therapies. This integrative framework of mitochondrial-driven pathology provides fresh perspectives to advance diagnostic and therapeutic innovation in dermatology.

Keywords:  atopic dermatitis; emerging therapies; mitochondrial DNA (mtDNA); mitochondrial dysfunction; psoriasis; vitiligo

DOI:  https://doi.org/10.1002/ddr.70221
Glia. 2026 Mar;74(3): e70119

Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.

Surabhi D Abhyankar, Yucheng Xiao, Neha Mahajan, Qianyi Luo, Theodore R Cummins, Adrian L Oblak, Bruce T Lamb, Timothy W Corson, Ashay D Bhatwadekar.

  Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein ε4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Müller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K+ channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Müller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. MitoQ was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD.

Keywords:   APOE ; Kir4.1; Müller cells; late‐onset Alzheimer's disease; mitochondrial dysfunction

DOI:  https://doi.org/10.1002/glia.70119
Arch Biochem Biophys. 2026 Jan;pii: S0003-9861(25)00363-7. [Epub ahead of print]775 110649

Thermotolerance induced by non-lethal heat shock at 40 °C is activated by mitochondrial ROS and is Nrf2-dependent.

Georges Hraoui, Mélanie Grondin, Khadija Rezki, Diana A Averill-Bates.

  Hyperthermia is generally administered as an adjuvant to chemotherapy/radiotherapy and sensitizes tumors to these anticancer treatments. Repeated heat treatments (≥42 °C) cause development of transient thermotolerance, an adaptive survival response. This response can be mediated by upregulation of cellular defense pathways and remains unclear. We aim to clarify the mechanistic explanations behind activation of this response. In vitro, thermotolerance can be induced by mild heat stress at 40 °C and protects cells against subsequent lethal heat shock (≥42 °C). When HeLa cells were heated at 42 °C, cellular and mitochondrial superoxide and peroxide levels increased. Treatment with mitochondrial antioxidant MitoQ, or NADPH oxidase (NOX) inhibitor apocynin, decreased levels of reactive oxygen species (ROS) and apoptotic cell death, indicating that mitochondria and NOX are important sources of ROS at 42 °C. Mild heat stress at 40 °C increased production of ROS, which are thought to activate the adaptive response, and reduce subsequent cell death at 42 °C. Our results show that heat-derived ROS are linked to expression of master antioxidant regulator Nrf2. When Nrf2 was overexpressed or knocked down, Nrf2 expression was directly associated with protective ability of the adaptive response induced by mild heat stress (40 °C). Mitochondrial ROS were found to be essential in mediating Nrf2-dependent thermotolerance, because MitoQ treatment prior to exposure to 40 °C reduced Nrf2 levels and dissipated the subsequent protective effect of thermotolerance against toxicity at 42 °C. Our study demonstrates that specific sources of ROS had biologically different implications in activating Nrf2, underlining potential therapeutic targets that may contribute to thermotolerance in anticancer treatments.

Keywords:  Adaptive survival response; Heat shock; Mitochondria; Nrf2; Oxidative stress; Thermotolerance

DOI:  https://doi.org/10.1016/j.abb.2025.110649
Biogerontology. 2026 Jan 06. 27(1): 33

Chronic stress and the mitochondria-telomere axis: human evidence for a bioenergetic-debt model of early aging.

Torsak Tippairote, Pruettithada Hoonkaew, Aunchisa Suksawang, Prayfan Tippairote.

  Chronic stress has been linked to mitochondrial dysfunction and impaired telomere maintenance, yet the mechanistic relationships connecting these pathways in humans remain poorly resolved. Using longitudinal findings from the Guillén-Parra cohort as a motivating human example, this Perspective offers a reinterpreted framework that proposes a unifying energetic interpretation in which bioenergetic insufficiency-defined as a mismatch between stress-induced energetic demand and mitochondrial throughout-rather than accumulated molecular damage, forms the upstream constraint linking stress physiology, mitochondrial performance, and telomerase regulation. In this cohort, lower baseline mitochondrial energetic capacity predicted greater longitudinal declines in telomerase activity, while telomere length remained stable across the short observation window, supporting the view that telomerase activity represents an early, energy-sensitive marker of unresolved stress adaptation, whereas telomere shortening is a delayed structural consequence. Interpreted within the Exposure-Related Malnutrition (ERM) framework, these patterns suggest that repeated activation of stress-response pathways without adequate metabolic recovery limits mitochondrial throughput and progressively compromises genome maintenance. In contrast, repeated exposure to mild stressors followed by sufficient recovery promotes adaptive strengthening of mitochondrial function and telomeric maintenance, consistent with physiological hormesis. We outline a roadmap integrating telomerase activity with dynamic indices of mitochondrial and redox function, including NAD⁺ availability, and emerging biomarkers of systemic energetic strain, such as circulating cell-free mitochondrial DNA and GDF15. By reframing aging phenotypes as early-stage failures of energetic resolution, this model highlights modifiable windows of vulnerability and hormesis-informed strategies-including exercise-induced adaptive stress, circadian alignment, and nutritional sufficiency-as actionable pathways for preserving mitochondrial resilience and telomere maintenance.

Keywords:  Bioenergetic stress; Cellular senescence; Mitochondrial energetics; Psychological stress; Telomerase activity

DOI:  https://doi.org/10.1007/s10522-025-10377-x
Basic Clin Pharmacol Toxicol. 2026 Feb;138(2): e70188

Metformin Attenuates ox-LDL-Induced Macrophage Senescence and Inflammation via NR4A1-Mediated Mitophagy Regulation.

Luling Li, Xiuting Huang, Pei Li.

  Metformin alleviates oxidized low-density lipoprotein (ox-LDL)-induced macrophage senescence, a key process in atherosclerosis. Our in vitro findings demonstrate that metformin suppresses ox-LDL-induced overexpression of the nuclear receptor NR4A1 in macrophages. This inhibition subsequently reduces excessive mitophagy, improves mitochondrial membrane potential and decreases reactive oxygen species (ROS) production. The amelioration of this mitochondrial dysfunction directly attenuated cellular senescence markers and reduced the secretion of inflammatory cytokines. Furthermore, we identified Caveolin-1 as a critical regulator of metformin's protective effects. Overexpression of Caveolin-1 was shown to reverse metformin-mediated improvements in mitochondrial function. These results establish that metformin mitigates macrophage senescence by targeting the NR4A1-mitophagy pathway, with Caveolin-1 serving as an essential modulator. This NR4A1-mitophagy axis represents a promising therapeutic target, positioning metformin as a potential candidate for slowing atherosclerosis progression by preserving mitochondrial health in macrophages.

Keywords:  atherosclerosis; inflammation; macrophage senescence; metformin; ox‐LDL

DOI:  https://doi.org/10.1111/bcpt.70188
Reprod Biomed Online. 2025 Sep 10. pii: S1472-6483(25)00468-7. [Epub ahead of print]52(2): 105261

Effect of micronutrients on fertility and aneuploidy rates in human conceptions: a systematic review and meta-analysis.

David Schütz, Kirstine Huong Lettorp, Isa Amalie Olofsson, Eva R Hoffmann.

  In order to make clinical recommendations based on uncertain evidence, a systematic review and meta-analysis on the influence of micronutrient supplementation on preclinical and clinical reproductive outcomes was undertaken. PubMed and Scopus were searched until 12 November 2024. Parallel-grouped intervention studies with women undergoing fertility treatment with micronutrient supplementation or addition of micronutrient to in-vitro maturation media were included. The primary outcomes were oocyte maturation and chromosome aneuploidy rates, pregnancy rate, miscarriage rate, and live birth rate. Five of 1810 studies were included. In three clinical studies, 326 women underwent fertility treatment with coenzyme Q10 (CoQ10) or control treatment. CoQ10 increased oocyte retrieval and live birth rates for women diagnosed with poor ovarian response (POR; OR = 2.28), and increased the pregnancy rate for women diagnosed with POR or polycystic ovary syndrome (PCOS) (OR = 2.20 and 13.26, respectively). CoQ10 had no effect on the miscarriage rate. In two in-vitro studies, 127 women donated 241 immature oocytes which were matured with CoQ10 or resveratrol. CoQ10 increased the oocyte maturation rate (OR = 2.73), and decreased oocyte and chromosome aneuploidy rates (OR = 0.31 and 0.57, respectively) for women of advanced maternal age (AMA). Resveratrol had no effect. Women of AMA and women diagnosed with POR or PCOS gained greater benefit from CoQ10 supplementation.

Keywords:  Aneuploidy; CoQ10; Coenzyme Q10; Fertility; Micronutrients; Resveratrol

DOI:  https://doi.org/10.1016/j.rbmo.2025.105261
Foods. 2025 Dec 24. pii: 60. [Epub ahead of print]15(1):

Clinical Potential of Curcuma longa Linn. as Nutraceutical/Dietary Supplement for Metabolic Syndrome: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Samuel Abiodun Kehinde, Zahid Naeem Qaisrani, Rinrada Pattanayaiying, Bo Bo Lay, Khin Yadanar Phyo, Wai Phyo Lin, Myat Mon San, Nurulhusna Awaeloh, Sasithon Aunsorn, Ran Kitkangplu, Sasitorn Chusri.

  Metabolic syndrome (MetS) and its associated conditions, namely, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), obesity, and polycystic ovary syndrome (PCOS) are characterized by insulin resistance, dyslipidemia, and low-grade inflammation. Curcumin, a polyphenolic compound derived from Curcuma longa Linn., exhibits pleiotropic metabolic and anti-inflammatory properties and has thus been evaluated as a nutraceutical intervention for these conditions, but findings remain inconsistent. This systematic review and meta-analysis evaluated the clinical efficacy of Curcuma longa supplementation on anthropometric, glycemic, lipid, inflammatory, and oxidative stress parameters in adults with MetS or related disorders. A comprehensive search of databases (PubMed, Scopus, AMED, LILACS, and Google Scholar) identified 104 eligible randomized controlled trials (RCTs). The included trials primarily assessed standardized oral turmeric/curcumin supplements and bioavailability-enhanced formulations rather than whole culinary turmeric. Pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were computed using random-effects models. Subgroup analyses were conducted by disease category, dose, and formulation. Risk of bias was assessed using the Cochrane RoB 2 tool. Curcumin supplementation significantly reduced fasting blood sugar (SMD = -0.54, 95% CI -0.72 to -0.36) and HbA1c (SMD = -0.41, 95% CI -0.60 to -0.23) in T2DM; decreased triglycerides (SMD = -0.48; 95% CI: -0.70 to -0.25), and LDL cholesterol (SMD = -0.39; 95% CI: -0.59 to -0.18) while elevating HDL cholesterol (SMD = 0.45; 95% CI: 0.25 to 0.65) and total antioxidant capacity (SMD = 0.73; 95% CI: 0.51 to 0.94). Curcuma longa also attenuated systemic inflammation, lowering C-reactive protein (SMD = -0.62; 95% CI: -0.81 to -0.43), TNF-α (SMD = -0.57; 95% CI: -0.80 to -0.34), and IL-6 (SMD = -0.50; 95% CI: -0.70 to -0.29). Heterogeneity was moderate-to-high, reflecting some differences in the formulation, dosage, and duration. Collectively, these findings affirm that Curcuma longa exerts measurable, clinically relevant improvements on glycemic regulation, lipid metabolism, and inflammatory-oxidative balance, supporting its role as a nutraceutical adjunct in metabolic health management, while its bioavailability-enhanced formulations show superior efficacy. Larger, long-term, multicenter RCTs are warranted to confirm durability, optimal dosing, and safety.

Keywords:  Curcuma longa; antioxidant; curcumin; inflammation; lipid profile; metabolic syndrome; nutraceuticals; randomized controlled trial; type 2 diabetes

DOI:  https://doi.org/10.3390/foods15010060
J Drug Target. 2026 Jan 06. 1-32

SKQ1: a mitochondria-targeted antioxidant with therapeutic potential.

Ruolan Wu, Yuan Wu.

  Mitochondria-targeted antioxidants can selectively accumulate within mitochondria at low doses, thereby significantly enhancing therapeutic efficiency while minimizing potential side effects. SKQ1, a novel mitochondria-targeted antioxidant, operates through a well-defined mechanism: a lipophilic cation enables mitochondrial targeting, while plastoquinone exerts antioxidant activity. SKQ1 primarily exerts its potent antioxidative effects by directly neutralizing reactive oxygen species (ROS), thereby protecting mitochondrial function. Numerous studies have explored the biological functions of SKQ1, identifying its significant potential in anti-aging, immune regulation, and antimicrobial activity. In this review, we summarize all available therapeutic evidence of SKQ1. We propose that SKQ1 represents a promising candidate for treating mitochondrial dysfunction-related diseases; however, its safety profile warrants further investigation.

Keywords:  Aging; MitoQ; Mitochondria-targeted antioxidants; ROS; SKQ1

DOI:  https://doi.org/10.1080/1061186X.2026.2613054
Life Sci. 2026 Jan 03. pii: S0024-3205(25)00819-7. [Epub ahead of print]387 124183

Estrogen receptor-autophagy axis protects the heart, aorta and kidneys during perimenopausal aging: Evidence from human cohort and mouse experiments.

Xiuting Xiang, Weizhou Jiang, Praneetha Palasuberniama, M Tanveer Hossain Parash, Rahmawati Pare, Yunjun Ruan.

   AIM: The gradual decline in estrogen levels during perimenopause is strongly associated with an increased risk of metabolic and cardiovascular diseases. However, the specific relationship and underlying mechanisms remain incompletely understood. This study combines population data, network pharmacology, and mouse models to explore the detailed mechanisms underlying estrogen's organ-protective effects.
MATERIALS AND METHODS: We utilized data from the National Health and Nutrition Examination Survey (NHANES) to analyze the correlation between estradiol levels and conditions such as hypertension, kidney disease, diabetes, and hypercholesterolemia. A perimenopausal mouse model was established to assess the impact of estrogen replacement therapy on various organs, including the heart, aorta, and kidneys. Network pharmacology was used to identify molecular targets, and receptor-specific inhibitors along with autophagy inhibitors were applied for functional validation in estrogen-treated mice.
KEY FINDINGS: Lower estradiol levels were significantly associated with an increased risk of hypertension, kidney disease, diabetes, and hypercholesterolemia. Estrogen treatment markedly reduced fibrosis in the heart, aorta, and kidneys, and promoted weight gain in mice, which mirrored BMI trends observed in human cohorts. Network pharmacology identified key molecular targets involved in estradiol-mediated pathways and mTOR-regulated autophagy. Functional validation confirmed that estrogen's protective effects depend on receptor activation and downstream autophagy signaling.
SIGNIFICANCE: This study underscores the crucial role of the estrogen receptor-autophagy axis in metabolic regulation and organ protection during perimenopause. It provides new mechanistic insights that could inform precision hormone therapy strategies aimed at preventing aging-related diseases in women.

Keywords:  Autophagy; Estrogen receptor; Histopathologic; Multiorgan; Perimenopause

DOI:  https://doi.org/10.1016/j.lfs.2025.124183
Inflammopharmacology. 2026 Jan 05.

NLRP3 inflammasome and Alzheimer's disease: bridging inflammation and neurodegeneration.

Rufaida Wasim, Sumaiya Azmi, Asad Ahmad, Akash Srivastava.

  The progressive neurodegenerative disease known as Alzheimer's disease (AD) is characterized by widespread neuronal death, memory loss, and cognitive decline. The NLRP3 inflammasome has emerged as a key modulator of neuroinflammation, which is increasingly implicated in the pathophysiology of AD. In response to endogenous and pathogenic danger signals, the innate immune system's multiprotein complex known as the NLRP3 inflammasome is activated. Pyroptosis and neuroinflammatory cascades are eventually triggered by its activation, which causes caspase-1 to be cleaved and pro-inflammatory cytokines like interleukin-1β and interleukin-18 to be released. NLRP3 activation is strongly stimulated by tau aggregation and β-amyloid plaques in AD, which accelerates neuronal damage and prolongs chronic inflammation. The control and activation of inflammasomes are involved in both canonical and non-canonical pathways as well as mitochondrial dysfunction. Significantly, animal models indicate that NLRP3's therapeutic potential is highlighted by the reduction of amyloid burden and amelioration of cognitive decline that results from its inhibition or genetic deletion. Small-molecule inhibitors and natural substances that can alter NLRP3 activity have been discovered recently, providing intriguing approaches to AD treatment. Despite tremendous advancements, issues with medication selectivity and blood-brain barrier penetration still need to be resolved before these discoveries can be used in clinical settings. Comprehending the complex relationship between NLRP3 activation and Alzheimer's pathology may open the door to new, focused treatments meant to slow or stop the progression of the illness.

Keywords:  Alzheimer’s disease; Amyloid-β; Mitochondrial dysfunction; NLRP3 inflammasome; Neuroinflammation; Therapeutic targets

DOI:  https://doi.org/10.1007/s10787-025-02092-3
Int J Mol Sci. 2025 Dec 26. pii: 284. [Epub ahead of print]27(1):

Pathophysiology of HFpEF: Insights from a Metabolic-Mitochondrial Perspective.

Cristina Gatto, Maria Rosaria Rusciano, Valeria Visco, Carmine Vecchione, Michele Ciccarelli.

  Heart failure with preserved ejection fraction (HFpEF) represents a growing clinical challenge, accounting for more than half of all cases of heart failure, for which there are currently no effective treatments. Emerging evidence identifies mitochondrial dysfunction as a central mechanism linking metabolic comorbidities, systemic inflammation, and energy failure in HFpEF. This review provides a comprehensive overview of the metabolic-mitochondrial mechanisms underlying the pathophysiology of HFpEF. Loss of metabolic flexibility, characterized by reduced fatty acid and glucose oxidation, leads to energy inefficiency, lipid accumulation, and oxidative stress. Structural and functional mitochondrial abnormalities, including damaged cristae, altered fission-fusion dynamics, and impaired oxidative phosphorylation, contribute to diastolic dysfunction and ventricular remodeling. In parallel, chronic inflammation and redox imbalance amplify mitochondrial damage through cytokine- and ROS-mediated pathways, creating a cycle of bioenergetic failure. From a therapeutic perspective, strategies aimed at restoring mitochondrial homeostasis, such as physical training, metabolic modulation, SGLT2 inhibition, ketone supplementation, and mitochondria-targeted antioxidants, show promising preclinical results. However, clinical translation remains limited. Deepening the understanding of mitochondrial metabolism could enable the development of personalized treatments capable of improving outcomes for HFpEF patients.

Keywords:  HFpEF; inflammation; metabolic flexibility; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/ijms27010284
Int J Mol Sci. 2025 Dec 23. pii: 175. [Epub ahead of print]27(1):

Oxidative Stress, Mitochondrial Homeostasis, and Sirtuins in Atrial Fibrillation.

Jan Krekora, Elzbieta Pawlowska, Marcin Derwich, Jarosław Drożdż, Janusz Blasiak.

  Atrial fibrillation (AF) is the most common cardiac arrhythmia. Yet, its treatment has serious challenges and is unsuccessful in a considerable fraction of patients. One reason may be a limited understanding of the molecular mechanisms underlying AF. Recent studies suggest that oxidative stress is involved in AF pathogenesis. Enhanced oxidative stress is largely determined by disrupted mitochondrial homeostasis, as cardiomyocytes heavily rely on mitochondrial energy production and calcium transfer between mitochondria and the sarcoplasmic reticulum. Atrial fibrillation involves metabolic, structural, and electrical remodeling, all of which are influenced by mitochondrial mechanisms. Mitochondrial homeostasis is controlled by mitochondrial quality control (mtQC), which is a multi-pathway mechanism to maintain integrity and functionality of mitochondria. Impaired mtQC may result in disturbed mitochondria-related calcium handling, decreased energy production, mitochondria-related inflammation and fibrosis, and impaired mitophagy. Sirtuins (SIRTs) are a family of seven members of histone deacetylases which have antioxidant properties, and three of them are localized to mitochondria. Therefore, at least some SIRTs may ameliorate enhanced oxidative stress related to damaged mitochondria. SIRTs have shown potential to improve AF outcomes in studies on AF patients and animal models. Therefore, SIRTs may have potential to ameliorate AF by decreasing oxidative stress and restoring mitochondrial homeostasis disrupted in AF. In this narrative review, we provide information on how mitochondrial dysfunctions, expressed as a disturbance in mtQC, contribute to AF through oxidative stress, calcium handling abnormalities, energy deficiency, inflammation and fibrosis, and genetic changes. In addition, we present the protective potential of sirtuins in AF.

Keywords:  AF; atrial fibrillation; calcium handling; fibrosis; inflammation; metabolic remodeling; mitochondrial quality control; mitophagy; oxidative stress; sirtuins

DOI:  https://doi.org/10.3390/ijms27010175
Mol Neurobiol. 2026 Jan 10. 63(1): 355

The Emerging Role of L-Arginine and Creatine Supplementation Combined with Exercise on Hippocampal Neurogenesis, Spatial Learning, and Cognitive Flexibility in Aging and Neurodegenerative Diseases.

Yarui Zhang, Yubing Peng, Jiangjiang Pu.

  Hippocampal neurogenesis is a pivotal process for cognitive adaptability, memory consolidation, and the regulation of emotions, all of which exhibit a decline as individual's age and contribute to the onset of neurodegenerative and mood disorders. The disruption of neurogenesis adversely affects these cognitive functions, establishing a connection between memory impairments and emotional disturbances, including anxiety and depression. Recent empirical studies underscore the promising effects of creatine and L-arginine supplementation, in conjunction with physical exercise, in enhancing hippocampal neuroplasticity and fostering neurogenesis. Creatine, recognized for its critical involvement in energy metabolism, plays a supportive role in neuronal integrity and cognitive performance, while L-arginine enhances nitric oxide-mediated neurovascular coupling and trophic support, and physical exercise activates neurogenic pathways and elevates mood. This review delineates the intricate interactions among hippocampal neurogenesis, cognitive flexibility, memory, and emotional functionality in the context of aging-related pathologies. This discourse examines the potential synergistic effects of creatine, L-arginine, and physical exercise in combating age-associated cognitive and emotional deterioration by influencing neurogenic and metabolic processes within the hippocampal region. While previous literature has scrutinized these interventions in isolation, no research to date has amalgamated their collective mechanistic impacts on hippocampal neurogenesis. This review distinctly integrates bioenergetic and neurotrophic pathways to furnish a coherent viewpoint on the interplay between exercise and creatine in the context of cognitive aging. Grasping these interrelations yields novel insights into therapeutic modalities designed to enhance cerebral resilience and psychological well-being among the elderly population. This comprehensive framework presents promising opportunities for the prevention and management of cognitive deficits and mood disturbances via lifestyle modifications and nutritional strategies.

Keywords:  Aging; Creatine; Exercise; Hippocampal neurogenesis; L-Arginine; Memory

DOI:  https://doi.org/10.1007/s12035-025-05586-x
Int J Mol Sci. 2025 Dec 22. pii: 129. [Epub ahead of print]27(1):

Kynurenine Pathway Metabolites as Mediators of Exercise-Induced Mood Enhancement, Fatigue Resistance, and Neuroprotection.

Amelia Tero-Vescan, Ruxandra Ștefănescu, Amalia Pușcaș, Mădălina Buț, Bianca-Eugenia Ősz, Mark Slevin.

  Major depressive disorder is increasingly recognized as a metabolic-immune disorder in which chronic inflammation diverts tryptophan (Trp) metabolism toward the kynurenine pathway (KP), reducing serotonin synthesis and producing neurotoxic metabolites such as quinolinic acid (QA). Elevated kynurenine (KYN)/Trp ratios and an altered QA/kynurenic acid (KYNA) balance have been consistently reported in depressed individuals, implicating the KP as a key therapeutic target. Exercise provides a unique, translationally relevant intervention: unlike pharmacological agents acting directly on neurotransmission, contracting skeletal muscle acts as a "kynurenine sink" by inducing kynurenine aminotransferases that convert circulating KYN into neuroprotective KYNA, thereby reducing brain KYN uptake and mitigating excitotoxicity. Clinical studies and meta-analyses confirm that aerobic, resistance, and high-intensity training produce antidepressant effects comparable to pharmacotherapy, while also improving cognition, fatigue tolerance, and cardiometabolic function. Beyond KP remodeling, exercise-induced myokines (irisin, IL-6, BDNF, apelin, FGF21) and adipokines (adiponectin, leptin modulators) coordinate systemic anti-inflammatory and neurotrophic adaptations that enhance resilience and brain plasticity. Furthermore, pharmacological "exercise mimetics" and metabolic modulators, such as PPAR agonists, AMPK activators, NAD+ boosters, meldonium, trimetazidine, and adiponectin receptor agonists, may be promising adjuncts for patients with low exercise capacity or metabolic comorbidities. This review provides a novel concept, positioning exercise as a systemic antidepressant that breaks the kynurenine lock of depression. Through proper interpretation of skeletal muscle as an endocrine organ of resilience, we integrate molecular, clinical, and translational findings to show how exercise remodels Trp-KYN metabolism and inflammatory signaling and how pharmacological mimetics may extend these benefits. This perspective consolidates scattered mechanistic and clinical data and outlines a forward-looking therapeutic framework that links exercise and lifestyle, metabolism, and drug discovery. We highlight that re-consideration of our understanding of depression, as a whole-body disorder, should provide new opportunities for precision interventions.

Keywords:  HIIT; adiponectin; exercise; exercise mimetics; irisin; kynurenic acid; kynurenine pathway; leptin; major depressive disorder; quinolinic acid

DOI:  https://doi.org/10.3390/ijms27010129
Sci Rep. 2026 Jan 07. 16(1): 898

Plasma growth differentiation factor-15 is associated with cardiovascular events in patients hospitalized for acute exacerbation of COPD.

Pradeesh Sivapalan, Daniel Alexander Ackermann, Anna Kubel Vognsen, Ruth Frikke-Schmidt, Jens P Goetze, Thérèse Lappere, Christina Christoffersen, Jon Torgny Wilcke, Charlotte S Ulrik, Niklas Dyrby Johansen, Mats C Højbjerg Andersen, Alexander G Mathioudakis, Jørgen Vestbo, Manan Pareek, Tor Biering Sørensen, Jens-Ulrik Jensen.

  Patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are at increased risk of major adverse cardiovascular events (MACE) and death. Growth differentiation factor-15 (GDF-15), a marker of cellular stress and inflammation, and Syndecan-1, a marker of endothelial dysfunction, have been suggested as prognostic biomarkers in plasma for MACE. We aimed to assess their association with a combined outcome of MACE or all-cause mortality over a 5-year period. This sub-study was embedded within the randomized controlled trial CORTICOsteroid reduction in COPD (CORTICO-COP), which investigated the effects of eosinophil-guided corticosteroid therapy in patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). A total of 299 patients hospitalized with AECOPD were included in this analysis. Baseline plasma concentrations of growth differentiation factor 15 (GDF-15) and Syndecan-1 were measured and stored in a biobank for later analysis. The primary outcome was MACE or all-cause mortality, secondary outcomes included heart failure, re-AECOPD, and all-cause mortality. Hazard ratios (HRs) between low and high biomarker levels were adjusted for age, smoking, sex, GOLD class, and kidney insufficiency. The area under the receiver operating curve (AUC) was reported for each model after 6 months and two years respectively. Among the 299 hospitalized AECOPD patients included in this sub-study of the randomized controlled trial CORTICOsteroid reduction in COPD (CORTICO-COP), higher baseline concentrations of GDF-15 were associated with an increased risk of the combined outcome of MACE or all-cause mortality (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.16-2.44, p = 0.007), as well as all-cause mortality alone (HR 1.5, 95% CI 1.07-2.19, p = 0.02). GDF-15 showed moderate discriminative ability for survival, with an AUC of 64% at 6 months and 60% at 2 years. No significant associations were observed between GDF-15 and heart failure or hospital re-admission due to respiratory disease. Syndecan-1 concentrations were not associated with the combined endpoint or any of the secondary outcomes. GDF-15 may identify AECOPD patients at risk of MACE and all-cause mortality. Syndecan-1 has no predictive value in AECOPD patients.

Keywords:  AECOPD; Biomarker; COPD; Cardiovascular Risk; GDF-15; Syndecan-1

DOI:  https://doi.org/10.1038/s41598-025-27988-6
Nutrients. 2026 Jan 02. pii: 156. [Epub ahead of print]18(1):

Ubiquinol in Fertility and Reproduction: A Conditionally Essential Nutrient for Critical Early-Life Stages.

Emma J Derbyshire, Sergej M Ostojic, Ahmed T Alahmar.

  Background/Objectives: Infertility is a multifactorial condition with an etiopathology that remains largely unclear. Although substantial evidence implicates oxidative stress (OS) as a key contributor to both male and female infertility, targeted strategies for OS-mediated reproductive dysfunction are still not well defined and require further investigation. Ubiquinol is the reduced form of Coenzyme Q10 involved in mitochondrial bioenergetics. It can be synthesized by humans endogenously or provided by dietary sources-typically egg yolks, oily fish, organ meats, and in smaller amounts in nuts and seeds and leafy green vegetables. The present article reviews possible mechanisms through which Ubiquinol plays a role in the regulation of fertility and reproduction, discussing why it could be positioned as a conditionally essential nutrient. Several questions and areas for further inquiry are also proposed. Methods: The present position paper narratively summarizes evidence related to Ubiquinol fertility and reproduction, focusing on the literature from PubMed, Science Direct, and Semantic Scholar. Results: Research advancements suggest that when physiological demands rise during certain life stages, e.g., the reproductive years, the amount of Ubiquinol produced internally may not be enough to meet heightened needs, particularly with advanced maternal/paternal age. This places a heavier reliance on obtaining Ubiquinol from the diet, thus presenting itself as a conditionally essential nutrient during certain life stages. Conclusions: Overall, Ubiquinol appears to enhance mitochondrial energy production and antioxidant defense in gametes, a process that appears to aid sperm function, oocyte quality, and early embryo development. Collectively, these data indicate a key physiological role for Ubiquinol in male and female fertility, especially given its age-related decline.

Keywords:  advancing age; coenzyme Q10; conception; embryo development; fertility; infertility; oocyte quality; sperm function; ubiquinol

DOI:  https://doi.org/10.3390/nu18010156
Am J Physiol Endocrinol Metab. 2026 Jan 06.

Ketone monoester ingestion improves endothelial function during hyperglycemia in females with polycystic ovary syndrome.

Danielle E Berbrier, Will Huckins, Shannon I Delage, Emily K Van Berkel, Sarkis J Hannaian, Raychel Myara, Oluwakanyisola N Okafor, Ta Heh Chung, Togas Tulandi, Shauna L Reinblatt, Rachel N Lord, Tyler A Churchward-Venne, Charlotte W Usselman.

  Postprandial hyperglycemia transiently impairs endothelial function. Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction and impaired glucose tolerance - both risk factors for cardiometabolic diseases - but the effects of hyperglycemia on endothelial function have yet to be assessed in PCOS. Exogenous ketone monoester (KME) supplementation lowers blood glucose and improves endothelial function in individuals predisposed to cardiometabolic diseases but has yet to be assessed in PCOS. Thus, we investigated whether oral glucose tolerance test (OGTT)-induced hyperglycemia impairs endothelial function in PCOS, and whether acute KME mitigates these impairments. Ten females with PCOS (age: 27±5yr, BMI: 23.8±2.7kg/m2) and 10 age- and BMI-matched controls (CTRL; age: 27±4yr, BMI: 23.7±2.0kg/m2) completed a randomized, double-blind, placebo controlled, crossover study. In the overnight post-absorptive state, participants consumed KME ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 482mg/kg) or a taste-matched placebo 30-min prior to a 75g OGTT. Endothelial function was assessed via flow-mediated dilation (%FMD) pre-OGTT and at 0, 60, and 120-min post-bolus. Following placebo, %FMD was lower in PCOS than CTRL (effect of group, P<0.01). %FMD declined from baseline to 60-min post-OGTT bolus in both groups (PCOS: 6.3±0.4 vs. 4.2±0.4%, P<0.01; CTRL: 9.7±0.9 vs. 6.6±0.9%, P<0.01), with sustained impairments at 120-min in PCOS only (6.3±0.4 vs. 4.0±0.5%, P<0.01). In both groups, KME reduced plasma glucose AUC (P<0.01) and improved %FMD across the OGTT (P<0.01). These data indicate that OGTT-induced endothelial dysfunction is exacerbated in PCOS, and that acute KME improved endothelial function during the OGTT. Overall, these data KME supplementation as a potential means of reducing cardiometabolic risk in PCOS.

Keywords:  Polycystic ovary syndrome; acute ketone monoester; endothelial function; flow-mediated dilation; oral glucose tolerance test

DOI:  https://doi.org/10.1152/ajpendo.00453.2025
Cardiovasc Res. 2026 Jan 05. pii: cvaf282. [Epub ahead of print]

Endothelial mitochondrial dysfunction in hypertension, diabetes and atherosclerosis.

Jaideep Singh, Christopher Peter Stanley, Mary Meltem Kavurma.

Mitochondria are essential organelles that generate adenosine triphosphate during oxidative phosphorylation by the electron transport chain. Beyond energy production, mitochondria regulate intracellular calcium homeostasis, generate signalling molecules, modulate metabolic pathways, and control cell survival. Mitochondrial dysfunction is characterised by excessive reactive oxygen species production, loss of membrane potential, calcium leakage, and structural abnormalities, ultimately lead to cell death. In endothelial cells, mitochondrial dysfunction drives endothelial impairment and contributes to cardiovascular diseases. This review explores the mechanisms underlying endothelial mitochondrial dysfunction and examines its role in the development and progression of hypertension, atherosclerosis, and diabetes.

DOI: https://doi.org/10.1093/cvr/cvaf282
Nutrients. 2026 Jan 01. pii: 143. [Epub ahead of print]18(1):

Effects of Green Tea Extract Supplementation on Inflammatory Cytokines Among Postmenopausal Women with Overweight or Obesity-A Secondary Analysis of a Randomized Controlled Trial.

Anca Cunningham, Allison Gomes, Lingqiong Meng, Sue Shapses, Laura Byham-Gray, Hamed Samavat.

  Background: Excess adiposity induces low-grade inflammation, including increased C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Green tea contains epigallocatechin gallate (EGCG), with anti-inflammatory potential. EGCG metabolism is influenced by individual variations in catechol-O-methyltransferase (COMT) genotypes. Objectives: To evaluate the effect of green tea extract (GTE) supplementation on circulating inflammatory cytokines among postmenopausal women with overweight or obesity and differing COMT genotypes. Methods: This study is a secondary analysis of a random subset (N = 97) from the Minnesota Green Tea Trial (MGTT), a randomized double-blinded placebo-controlled trial. The intervention was a high-dose GTE supplement (843 ± 44 mg EGCG/day) or placebo for 1 year. Serum CRP, TNF-α, and IL-6 were measured at 0, 6, and 12 months. Absolute changes in inflammatory cytokines from baseline to month 12 were evaluated using linear mixed-effects models adjusted for age, body mass index (BMI), smoking history, physical activity, and vitamin supplement use. Results: The changes from month 0 to month 12 were not statistically different between the groups for any of the inflammatory cytokines measured. The overall treatment effect was not statistically significant for CRP (p = 0.24), IL-6 (p = 0.59), TNF-α (p = 0.36), nor for the interaction between treatment group and time (all Ps > 0.40). There was no significant interaction between treatment group and COMT genotype for the stated markers. Conclusions: A high-dose GTE supplement consumed daily for one year did not significantly decrease inflammatory cytokines among postmenopausal women with overweight or obesity. The COMT genotype did not modify the effects of GTE supplementation on inflammatory cytokines. Future studies with a larger sample size among those at high risk of systemic inflammation are warranted.

Keywords:  C-reactive protein; catechol-O-methyltransferase; epigallocatechin gallate; green tea extract; inflammation; interleukin-6; obesity; postmenopausal

DOI:  https://doi.org/10.3390/nu18010143
Front Aging. 2025 ;6 1693043

Dietary phenolics and exercise complementation to delay aging at its source: a comprehensive review highlighting mitochondrial function.

Jiong Zhang, Wen-Wen Zhu, Yong-Yao Huang, Chuan-He Tang.

   Background: Currently, aging issues are becoming more prominent, and the aging population is expanding. The reliance on medical or pharmaceutical means of combating aging and disease raises concerns about the long-term safety and economic impact. Therefore, sustainable and friendly strategies need to be explored urgently. Phenolic-rich antioxidant dietary regimens and exercise integrated into daily habits contain great anti-aging potential. Research on natural laws for anti-aging based on phenolics and exercise is in full swing.
Scope and approach: The review first outlines the current status of aging and elucidates the root causes of aging. Second, the anti-aging mechanisms at the source through daily behaviors such as phenolic diets and exercise are introduced. Then, the combined anti-aging strategy of dietary phenolic supplements and exercise is proposed, providing a feasible basis for resource synergy between the two. Finally, constructive comments are made to guide practical implementation and future development.
Key findings and conclusions: Mitochondrial dysfunction and its ROS accumulation are the essence of aging pathogenicity, and its causes include lifestyle habits, age, and genes. The precise action on mitochondria through phenolics and exercise to ameliorate oxidative stress and maintain anti-aging function is in line with contemporary concepts of anti-aging. Although research on the combined effects of phenolics and exercise for anti-aging is scarce and faces multiple challenges, this new strategy is likely to be adopted as these issues are gradually resolved.

Keywords:  aging; combined anti-aging; dietary phenolics; exercise; mitochondria

DOI:  https://doi.org/10.3389/fragi.2025.1693043
Metabol Open. 2026 Mar;29 100433

No effect of pyrroloquinoline quinone on mouse body weight and energy metabolism with the concomitant increase in mitochondrial biogenesis and antioxidant ability.

Lijun Zhang, Yimin Xu, Yanyan Zhao, Xiaochun Zhang, Xiangyan Liang, Zhuo Sun, Ying Zhou, Huan Liu, Jinrui Chang, Man Shi, Yufeng Zhao.

  Pyrroloquinoline quinone (PQQ) stimulates mitochondrial biogenesis and exhibits antioxidant properties. Since mitochondria play a crucial role in energy generation and metabolism, the present study aims to clarify whether PQQ is able to modulate energy expenditure and the development of obesity by regulating mitochondrial biogenesis. Male mice fed normal chow diet (NCD) or high fat diet (HFD) were supplemented with PQQ through drinking water for three months. Throughout this period, food and water intake, body weight, energy metabolic rate and the autonomous activity of the mice were measured. Then, the mice were sacrificed and the tissues were collected. Mitochondrial biogenesis, antioxidant capacity, and changes in gene expression were measured in liver tissue. The results showed that PQQ supplementation did not result in significant alterations in the food and water intake, body weight, and energy metabolic rate of the mice fed NCD or HFD although it significantly enhanced mitochondrial biogenesis and antioxidant capabilities of liver and promoted autonomous activity in NCD mice. Moreover, it had no impact on the adipose tissue mass in mice fed NCD or HFD. While PQQ supplementation induced the changes in metabolism-related genes such as CPT1a, SCD1, FABP1, HK2, HK3 and PGK1 in liver, it is suggested PQQ supplementation may influence lipid and glucose metabolism. However, PQQ-induced changes in hepatic gene expression and mitochondrial biogenesis are unable to alter systemic energy metabolism and adipose tissue accumulation in male mice.

Keywords:  Body weight; Energy metabolism; Pyrroloquinoline quinone

DOI:  https://doi.org/10.1016/j.metop.2025.100433
J Neurochem. 2026 Jan;170(1): e70343

Brain Glutathione Levels Associate With Cognitive Performance in Older Adults.

Phil Lee, Kirk I Erickson, Chaeryon Kang, Jeffrey M Burns, Charles H Hillman, Arthur F Kramer, George Grove, Eric D Vidoni, Haiqing Huang, Edward McAuley, Lu Wan, Lauren E Oberlin, Bradley P Sutton, Anna L Marsland, In-Young Choi.

  Glutathione (GSH), the brain's primary endogenous antioxidant, is integral to the cerebral antioxidant defense system and essential for maintaining redox homeostasis and neuronal health. Brain GSH levels naturally decrease with age, potentially contributing to cognitive vulnerability through diminished antioxidant capacity. Currently, the relationship between brain GSH and cognitive function in humans remains poorly understood. Using multiple quantum chemical shift imaging, we measured brain GSH levels in 206 cognitively unimpaired older adults (mean age 69.8 ± 3.9 years) and assessed cognitive performance across five core domains: working memory, episodic memory, visuospatial processing, executive function/attentional control, and processing speed. We hypothesized that higher GSH would be associated with better cognitive performance across all five domains, reflecting the putative role of antioxidant capacity in cognitive function. Using multiple regression with age, sex, years of education, and study site as covariates in the model, we found that higher regional brain GSH levels, including frontal and parietal regions, were associated with better working memory (p = 0.008), episodic memory (p = 0.040), and visuospatial processing (p = 0.001), but not with executive function/attentional control or processing speed. These findings highlight the critical neuroprotective role of GSH within the cerebral antioxidant defense system in supporting cognitive health in late adulthood.

Keywords:  antioxidant; brain aging; cognitive function; glutathione; magnetic resonance spectroscopy; older adults

DOI:  https://doi.org/10.1111/jnc.70343
Xenobiotica. 2026 Jan 06. 1-31

The Mitochondrial Protective Mechanisms Mediated by SGLT2i: From Molecular Basis to Clinical Implications.

Jianing Chen, Fengqi Wan, Kaiyue Wu, Xinling Xie, Tingting Wu.

  1.
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycemic agents that selectively inhibit glucose reabsorption in the renal proximal tubules, thereby promoting urinary glucose excretion and reducing blood glucose levels. In recent years, accumulating evidence from large-scale clinical trials has demonstrated that SGLT2i not only exert robust glucose-lowering effects but also confer significant protective benefits on the cardiovascular, renal, and nervous systems. However, the precise molecular mechanisms underlying these multi-system benefits remain incompletely understood.2.
RATIONALE: Mitochondria are central organelles responsible for cellular energy metabolism, redox homeostasis, and calcium handling, and they play a pivotal role in the pathogenesis and progression of various chronic diseases.3.
MECHANISMS: Emerging studies indicate that SGLT2i can markedly improve mitochondrial function through multiple mechanisms, including enhancement of mitochondrial quality control, modulation of mitochondrial energy metabolism, reinforcement of antioxidant defenses, and improvement of calcium homeostasis.4.
CONCLUSIONS: These mitochondria-centered mechanisms may underlie the protective effects of SGLT2i on the cardiovascular, renal, and neurological systems. In this review, we systematically summarize the regulatory effects of SGLT2i on mitochondrial function and discuss their potential therapeutic implications in related diseases, aiming to provide novel insights and a theoretical foundation for future basic research and clinical applications.

Keywords:  Cardiorenal protection; Mitochondrial function; Molecular mechanism; SGLT2i

DOI:  https://doi.org/10.1080/00498254.2026.2613138