bims-mistre 2026-05-31 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–05–31
eighteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
The Oxidative Stress: Origin and Role in Aging and Diseases.
From protector to perpetrator: The cGAS-STING pathway at the intersection of neurodegeneration and neuroinflammation.
Mitochondrial dynamics in depression: friend or foe?
Carnitine deficiency alters fuel metabolism and voluntary wheel running in mice.
Pyrroloquinoline Quinone Mitigates Type 2 Diabetes-Induced Cardiac Injury Through Mitochondrial Quality Control and Inhibition of NLRP3-Dependent Pyroptosis.
Beyond reproduction: The ovary as a systemic regulator of female health and aging.
Combined Histidine and Proline Supplementation (HISPRO) Enhances Oxidative and Mitochondrial Function in Skeletal Muscle Through SIRT1-Associated Signaling.
Nicotinamide riboside and pterostilbene reduces frequency and severity of undesirable symptoms of the menopause transition: an open-label, pilot clinical trial.
Compressed residual green tea extract prevents capillary regression by inhibiting slow-to-fast muscle fiber transformation in the atrophied skeletal muscle.
Oxidative Stress in Dry Eye Disease: Molecular Mechanisms and Emerging Therapeutic Strategies.
D-Pinitol Mitigates Renal Senescence via Targeting the SARM1-cGAS-STING Signaling Axis to Restore Mitochondrial Function and Dampen Inflammatory Responses.
4-N-Furfurylcytosine, a Novel Cytosine-Derived Modulator of Mitochondrial and Redox Homeostasis to Counteract Aging: Insights from Cellular and Mouse Models.
A multilayered stress-response circuit: The mammalian mitochondrial UPR.
Reproductive Factors, Lifestyle Behaviours and Cognitive Decline in Chinese Postmenopausal Women: A Cohort Study.
Effects of Zingiberaceae-derived interventions on memory-related and other cognitive outcomes in adults: a systematic review and meta-analysis.
Mitochondrial metabolic reprogramming in diabetic cardiomyopathy.
Estrogen Replacement Therapy in Ovariectomized Rats: Complementary Roles of ER and GPR30 in Alleviating Depressive-like Behavior.

Commun Biol. 2026 May 27.

Mapping the GDF15 arm of the integrated stress response in human cells and tissues.

Janell L M Smith, Kamaryn T Tanner, Jack Devine, Anna S Monzel, Taivan Batjargal, Maxwell Z Wilson, Alan A Cohen, Martin Picard.

Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we show that the ISR has multiple arms. To quantify the GDF15 arm of ISR activation in human cells, we developed an ISRGDF15 index. We validate the ISRGDF15 index in datasets from optogenetic and small molecule activation of ISR kinases, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deploy the ISRGDF15 index across 44 postmortem human tissues, confirm its correlation with age, and report that the ISRGDF15 is upregulated in the heart of individuals with acute causes of death in the emergency room, whereas it was upregulated in the brain of individuals who died after protracted hospital inpatient stays. These data highlight distinct arms of the ISR and clarify genes related to the GDF15 ISR arm, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues.

DOI: https://doi.org/10.1038/s42003-026-10312-x
Antioxidants (Basel). 2026 May 08. pii: 597. [Epub ahead of print]15(5):

The Oxidative Stress: Origin and Role in Aging and Diseases.

D'Orazi Gabriella, Neroni Luca, Verdina Alessandra.

  Reactive oxygen species (ROS) play a dual role in biological systems: at low-to-moderate concentrations, they function as essential signaling molecules involved in processes such as cell proliferation, differentiation, and immune defense. However, excessive ROS production or impaired antioxidant defenses lead to oxidative stress, which can damage lipids, proteins, and DNA, contributing to the development and progression of various pathological conditions including cancer, cardiovascular diseases, neurodegenerative disorders, and aging. Understanding and managing oxidative stress is critical to promoting health and preventing chronic conditions. This review explores the growing body of literature surrounding this multifaceted and increasingly important area of study.

Keywords:  aging; antioxidants; cancer; cellular damage; chronic inflammatory diseases; oxidative stress; reactive oxygen species (ROS); redox balance

DOI:  https://doi.org/10.3390/antiox15050597
Brain Res Bull. 2026 May 25. pii: S0361-9230(26)00249-2. [Epub ahead of print]241 111963

From protector to perpetrator: The cGAS-STING pathway at the intersection of neurodegeneration and neuroinflammation.

Ghaleb Oriquat, Abdulqader Faris Abdulqader, Hamrayev Farid, Zarifjon Ashurov, Abduvali Sottarov, Nghm Yhya Ghafl, Neeraj Bainsal, Ritesh Singh.

  The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of the innate immune system designed to combat pathogens, is now implicated as a critical driver of sterile inflammation in the brain. This review synthesizes compelling evidence that in the aging and diseased central nervous system, endogenous cytosolic DNA, sourced from genomic instability, mitochondrial dysfunction, and activated retrotransposons, hijacks this pathway. Chronic cGAS-STING activation transforms microglia into inflammatory amplifiers, instigates neurotoxic astrocyte programs, and directly compromises neuronal health, creating a self-perpetuating cycle of neuroinflammation. We dissect the cell-type specific consequences within the neurovascular unit and establish the pathway's role in the pathogenesis of ALS/FTD, Alzheimer's, Parkinson's, and Huntington's diseases. Crucially, we evaluate the therapeutic potential of targeting this axis, discussing small-molecule inhibitors, oligonucleotide therapies, and upstream interventions to quell the source of immunogenic DNA. We also explicitly examine contradictory preclinical data, including the retracted PINK1-Parkin-STING report and context-dependent neurovascular findings, to provide a balanced appraisal of STING biology in the CNS. By reconciling its dual protective and pathogenic roles, this review posits cGAS-STING as a pivotal mechanism-based therapeutic node for halting the progression of neurodegenerative disorders.

Keywords:  Innate Immunity; Mitochondrial DNA; Neurodegenerative Diseases; Neuroinflammation; cGAS-STING Pathway

DOI:  https://doi.org/10.1016/j.brainresbull.2026.111963
Metab Brain Dis. 2026 May 23. pii: 113. [Epub ahead of print]41(1):

Mitochondrial dynamics in depression: friend or foe?

Oluwagbenga M Adu, Edem E Edem, Chidubem F Emereonye, Stephanie E Areloegbe, Busayo O Oguntola, Abiola O Obisesan, Kehinde S Olaniyi.

  Depression represents a significant global health burden characterized by complex, multifactorial pathophysiology. While traditional theories have focused on monoamine neurotransmitter imbalances, emerging evidence implicates mitochondrial dysfunction as a critical contributor to depressive disorders. This review examines the bidirectional relationship between mitochondrial dynamics, fusion, fission, biogenesis, and mitophagy and depression pathophysiology. The study synthesizes recent preclinical and clinical findings demonstrating alterations in mitochondrial morphology and dynamics in depressed subjects and explores the paradoxical nature of these changes, which can serve both adaptive and maladaptive roles. The review further evaluates therapeutic approaches targeting mitochondrial dynamics, including conventional antidepressants, lifestyle interventions, and novel mitochondria-targeted compounds. Ultimately, the relationship between mitochondria and depression is explained to serve as enlightenment and to find better approaches for using mitochondrial approaches in therapy for Depression.

Keywords:  Depression; Major depressive disorder; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial fission; Mitochondrial fusion; Mitophagy; Neurotransmitter imbalance

DOI:  https://doi.org/10.1007/s11011-026-01876-y
J Lipid Res. 2026 May 22. pii: S0022-2275(26)00081-7. [Epub ahead of print] 101055

Carnitine deficiency alters fuel metabolism and voluntary wheel running in mice.

Meagan S Kingren, Daniel G Sadler, Elijah Bolin, Izak Harville, James Sikes, Renny Lan, Elisabet Børsheim, Craig Porter.

   BACKGROUND: Carnitine plays an obligatory role in energetics owing to its role in the translocation of long-chain fatty acids into the mitochondrion for oxidation. Here, we determined the metabolic and behavioral consequences of systemic carnitine deficiency (SCD) in mice.
METHODS: Female C57BL/6J mice were randomized to receive normal drinking water (control, n = 8) or drinking water supplemented with mildronate 4g.L-1 (mildronate, n = 8) for 21 days. Body composition was assessed at baseline and post treatment. Metabolic and behavioral phenotyping was performed continuously over 72 hours following 14 days of control or mildronate treatment. Stable isotope were used to assess whole-body substrate oxidation. Carnitine subfractions were quantified in skeletal muscle and liver, as was mitochondrial respiratory function. Liver and muscle samples also underwent proteomic analysis.
RESULTS: Mildronate treatment depleted total carnitine in muscle and liver by ∼97% (P < 0.001) and ∼90% (P < 0.001), respectively. Carnitine depletion was accompanied by lower total energy expenditure (P = 0.01), attributable to lower voluntary wheel running (P = 0.01). Oxidation rates of palmitate (P < 0.01) but not octanoate were lower whereas rates of glucose oxidation were greater in carnitine depleted mice (P < 0.01). Mitochondrial respiratory capacity was unaltered by carnitine deficiency. Carnitine deficiency remodeled muscle and liver proteomes to support lipid oxidation and energy production.

Keywords:  Carnitine; Energetics; Fat oxidation; Mildronate; Mitochondria; Skeletal muscle; Stable Isotopes; glucose oxidation

DOI:  https://doi.org/10.1016/j.jlr.2026.101055
Metabolites. 2026 May 19. pii: 340. [Epub ahead of print]16(5):

Pyrroloquinoline Quinone Mitigates Type 2 Diabetes-Induced Cardiac Injury Through Mitochondrial Quality Control and Inhibition of NLRP3-Dependent Pyroptosis.

Xue Zhang, Wei Liu, Zhijing Fu, Zhuoling Chen, Qixin Chen, Yanan Shen, Yukai Jin, Dengfeng Xu, Yin Wang, Xuefeng Qu, Yangjunna Zhang.

  Background: Pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor with potent antioxidant and anti-inflammatory properties, has been shown to protect against cardiac injury. However, its therapeutic potential in diabetic cardiomyopathy (DCM) induced by Type 2 diabetes mellitus (T2DM) and the underlying mechanisms remain poorly understood. Methods: A T2DM mouse model was established via a high-fat diet and low-dose STZ. We investigated the cardioprotective effects of 12-week oral PQQ administration, assessing fasting blood glucose, oral glucose tolerance, cardiac function, myocardial histopathology, blood biochemistry, mitophagy, and NLRP3 inflammasome activation. In vitro experiments using AC16 cardiomyocytes exposed to palmitic acid and high glucose were also conducted. Results: Results showed PQQ significantly improved cardiac function, attenuated remodeling, and reduced proinflammatory cytokines in mice with T2DM, regulated key mitophagy-related proteins (Parkin, Beclin-1, LC3B-II, p62), and downregulated NLRP3 inflammasome pathway components (Caspase-1, NLRP3, IL-1β, IL-18). In vitro experiments demonstrated that PQQ reduced reactive oxygen species (ROS) production, improved mitochondrial membrane potential, promoted mitophagy, and inhibited NLRP3 inflammasome-mediated pyroptosis. Conclusions: PQQ alleviates DCM in mice with T2DM by improving mitochondrial quality control, promoting mitophagy, and subsequently inhibiting NLRP3 inflammasome-mediated pyroptosis, highlighting its potential as a promising therapeutic agent for T2DM-associated cardiomyopathy.

Keywords:  NLRP3 inflammasome; diabetic cardiomyopathy; mitochondrial quality control; pyrroloquinoline quinone; type 2 diabetes

DOI:  https://doi.org/10.3390/metabo16050340
PLoS Biol. 2026 May;24(5): e3003800

Beyond reproduction: The ovary as a systemic regulator of female health and aging.

Jennifer L Garrison.

Classifying ovaries solely as reproductive organs has obscured their role as systemic regulators of female physiology. This Perspective makes the case that ovarian aging is a primary determinant of healthspan and belongs at the center of geroscience.

DOI: https://doi.org/10.1371/journal.pbio.3003800
Cells. 2026 May 13. pii: 887. [Epub ahead of print]15(10):

Combined Histidine and Proline Supplementation (HISPRO) Enhances Oxidative and Mitochondrial Function in Skeletal Muscle Through SIRT1-Associated Signaling.

Dohyun Lee, Jongsu Jeon, Gyuwon Huh, Seoyeong Baek, Daehun Kim, Hyeon-Ji Kang, Hoyul Lee, In-Kyu Lee, Jae-Han Jeon, Hoe-Yune Jung.

  Amino acids are key regulators of metabolism, their coordinated effects on skeletal muscle signaling and metabolic remodeling under physiological conditions remain incompletely understood. Here, we investigated whether 14 weeks of combined histidine and proline supplementation (HISPRO; 700 mg/kg) enhances skeletal muscle function through metabolic reprogramming in normal ICR mice. HISPRO significantly improved muscle performance compared with the control group, including grip strength, rota-rod, and treadmill. Histological and biochemical analyses revealed a shift toward oxidative muscle phenotype compared with the control group, with larger muscle fibers and succinate dehydrogenase-positive fibers. Consistently, HISPRO promoted mitochondrial biogenesis and oxidative metabolism compared with the control group, as evidenced by upregulation of mitochondrial regulatory genes, mitochondrial DNA copy number, citrate synthase activity, and oxidative phosphorylation (OXPHOS) complex levels in skeletal muscles. Mechanistically, HISPRO was associated with activation of the SIRT1-PGC1α-AMPK signaling axis compared with the control group, as evidenced by increased Nampt and Nmnat1 expression, an elevated NAD+/NADH ratio, and enhanced AMPK phosphorylation. SIRT1 inhibition markedly attenuated HISPRO-induced increases in mitochondrial biogenesis markers but did not fully suppress OXPHOS protein expression, suggesting the involvement of both SIRT1-dependent and -independent mechanisms. Notably, HISPRO also improved muscle function in dexamethasone-induced muscle atrophy model. It restored mitochondrial biogenesis and function, and suppressed atrophy-related markers compared with the dexamethasone-treated group. HISPRO may contribute to improving muscle quality through coordinated metabolic regulation and could represent a complementary nutritional for supporting muscle metabolic health.

Keywords:  AMPK; HISPRO; SIRT1; histidine; mitochondrial biogenesis; muscle atrophy; oxidative metabolism; proline; skeletal muscle

DOI:  https://doi.org/10.3390/cells15100887
Front Aging. 2026 ;7 1773667

Nicotinamide riboside and pterostilbene reduces frequency and severity of undesirable symptoms of the menopause transition: an open-label, pilot clinical trial.

Holly E Holmes, Kamal Srivastava, Jennifer M Scalici, Jyothi Dhuguru, Allyson E Shea, Marie E Migaud, Ryan W Dellinger.

   Introduction: Nicotinamide adenine dinucleotide (NAD+) is a metabolite of vitamin B3 necessary for the production of key hormones like estradiol. Both NAD+ and estradiol levels decrease with age. Reduced estradiol levels have been associated with undesirable symptoms of the menopause transition. Previous clinical trials have demonstrated that oral supplementation with NRPT, a combination of the NAD+ precursor nicotinamide riboside (NR) plus pterostilbene (PT), significantly increases NAD+ levels. In the present study, the effects of a 7-day supplementation of NRPT on undesirable symptoms of the menopause transition were examined.
Methods: An open-label, pilot clinical trial (ClinicalTrials.gov identifier NCT04841499) was conducted to assess the efficacy of NRPT supplementation (commercially known as Basis; a combination of nicotinamide riboside and pterostilbene) in 40 healthy women over 35 years of age, 32 of which self-reported symptoms associated with the menopause transition (MS group) and eight women who were not experiencing any (or minimal) symptoms associated with menopause (No-MS group). All 40 women were given the recommended dose of NRPT (250 mg NR and 50  mg PT) daily for 7 days. A menopausal symptom survey was taken at baseline and at the end of the 7-day intervention. Urine was also collected at baseline and after 7 days to assess levels of estrone (E1) and estradiol (E2) and the changes in the vitamin B3 catabolome stemming from NRPT supplementation.
Results: At the end of the study, significant decreases in both the frequency and magnitude of bloating, hot flashes, and poor sleep were reported in the MS group as compared to baseline. This was accompanied by a significant increase in the E2/E1 ratio. The No-MS group did not report any significant changes in these endpoints. As anticipated NRPT intake significantly increased urinary levels of methyl-nicotinamide (Me-NAM) as well as the methylated pyridone carboxamides (Me-PYs) in all groups. A significant time x menopausal status interaction was observed for nicotinuric acid (NUA). No other significant changes occurred for the other nicotinamide catabolites, such as nicotinamide N-oxide (NAM-N-Oxide), and a newly characterized NAD+ catabolite, N-methyl-nicotinuric acid (Me-NUA).
Discussion: This study demonstrates that NRPT is effective in significantly decreasing the frequency and magnitude of undesirable symptoms of the menopause transition and significantly increases the E2/E1 ratio in menopausal women.

Keywords:  NAD+ catabolome; NAD+ supplementation; estradiol; estrone; hot flashes; menopause; nicotinamide riboside; pterostilbene

DOI:  https://doi.org/10.3389/fragi.2026.1773667
Biomed Res. 2026 ;47(3): 113-120

Compressed residual green tea extract prevents capillary regression by inhibiting slow-to-fast muscle fiber transformation in the atrophied skeletal muscle.

Nao Fujino, Pan Han, Hiroyo Kondo, Jihao Xing, Hao Lin, Noriaki Maeshige, Hidemi Fujino.

  Disuse induces capillary regression in skeletal muscle, which is associated with excessive production of reactive oxygen species (ROS), impaired mitochondrial oxidative capacity, and a shift from slow- to fast-twitch muscle fibers. Green tea is rich in catechins with potent antioxidant properties. We hypothesized that compressed residual green tea extract, a byproduct of green tea manufacturing, may attenuate capillary regression during muscle disuse. Twenty female Wistar rats were randomly assigned to four groups: control (CON), compressed residual green tea supplementation (GTs), hindlimb unloading (HU), and hindlimb unloading with compressed residual green tea supplementation (HU+GTs). Hindlimb unloading was performed for 2 weeks. Compressed residual green tea extract (850 mg/kg/day) or distilled water was administered orally. HU induced significant reductions in soleus muscle mass, capillary-to-fiber (C/F) ratio, slow-twitch fiber proportion, and succinate dehydrogenase (SDH) activity, along with increased ROS production. Compressed residual green tea supplementation significantly attenuated capillary regression, preserved slow fiber composition, restored SDH activity, and suppressed ROS overproduction under unloaded conditions. These findings suggest that compressed residual green tea may serve as a practical nutritional strategy to maintain skeletal muscle capillarity during disuse by preserving oxidative fiber phenotype and mitochondrial function.

Keywords:  capillary regression; compressed residual green tea; slow muscle fiber

DOI:  https://doi.org/10.2220/biomedres.47.113
Biomolecules. 2026 May 13. pii: 718. [Epub ahead of print]16(5):

Oxidative Stress in Dry Eye Disease: Molecular Mechanisms and Emerging Therapeutic Strategies.

Tingting Tang, Jiaxin Yang, Hongbo Yin.

  Dry eye disease (DED) is a chronic inflammatory disorder of the ocular surface, characterized by tear film homeostasis imbalance, with aging being identified as a crucial independent risk factor. Oxidative stress, which refers to the excessive production of reactive oxygen species (ROS) and reactive nitrogen substances during mitochondrial metabolism and the weakened protective effect of antioxidants, plays a central role in this process. With aging, the mitochondrial function of ocular surface tissues, such as the corneal epithelium, meibomian glands, and lacrimal glands, declines. Concurrently, the activity of endogenous antioxidant enzymes (such as superoxide dismutase and glutathione peroxidase) decreases, and the levels of tear antioxidants such as lactoferrin also decrease. These age-related changes collectively lead to excessive accumulation of ROS, triggering oxidative stress that directly damages biomacromolecules in ocular surface cells and impairs the stability of the tear film. Furthermore, we have summarized the current therapeutic strategies for oxidative stress in DED, including both conventional antioxidants and emerging approaches such as eye drops based on nanoenzymes, thermosensitive hydrogels, intense pulsed light therapy, and drug-eluting contact lenses. By combining the new progress in the delivery systems of biomaterials-based drugs with mechanism-guided interventions, this review systematically establishes the intimate functional linkages between mitochondrial dysfunction, oxidative stress, and the pathogenesis of DED and focuses on elaborating the translational potential of advanced biomaterials-based antioxidant regimens, aiming to provide novel foundations and insights theoretical for the development of more effective and precise therapeutic strategies for DED.

Keywords:  antioxidant treatments; dry eye disease; nanozymes; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.3390/biom16050718
Biomedicines. 2026 May 12. pii: 1092. [Epub ahead of print]14(5):

D-Pinitol Mitigates Renal Senescence via Targeting the SARM1-cGAS-STING Signaling Axis to Restore Mitochondrial Function and Dampen Inflammatory Responses.

Xiaofan Yin, Kaizhi Wen, Kena Yu, Zhengxin Liu, Weiming He.

  Background: Renal aging represents a pivotal contributor to the pathogenesis and progression of age-related kidney disorders. D-Pinitol (DP), a bioactive cyclitol naturally present in food plants, exhibits multiple beneficial biological activities. Nevertheless, its role in counteracting renal aging remains unclear. Methods: This study employed both in vitro (HK-2 cells) and in vivo (C57BL/6J mice) models of D-galactose (DG)-induced renal aging. A panel of experimental approaches was applied to characterize the protective effects and molecular mechanisms of DP against renal aging, including Western blot, qPCR, ELISA, transcriptomic profiling, transmission electron microscopy, surface plasmon resonance (SPR), immunohistochemistry, and immunofluorescence staining. Results: DP significantly attenuated DG-induced renal aging-like changes in vitro and in vivo by preserving mitochondrial function and alleviating inflammatory responses. Transcriptomic analysis suggested SARM1 as a potential key target responsible for the beneficial effects of DP. In DG-induced aging models, SARM1 was remarkably upregulated in a tubule-specific pattern and acted as a critical mediator of mitochondrial dysfunction. Damaged mitochondria released mtDNA, which further activated the cGAS-STING innate immune signaling pathway, consequently promoting the senescence-associated secretory phenotype (SASP) and renal inflammation. Mechanistically, molecular docking and related assays suggested that DP may stabilize the auto-inhibitory conformation of SARM1, thereby potentially preventing its activation. Conclusions: DP attenuates DG-induced renal aging-like changes via suppressing the SARM1-cGAS-STING axis, thereby restoring mitochondrial homeostasis and mitigating inflammation. Given the lack of effective interventions targeting renal aging, these findings suggest SARM1 as a novel potential therapeutic target for renal aging and highlight DP as a promising food-derived anti-aging ingredient for renal protection.

Keywords:  D-Pinitol; SARM1; cGAS-STING pathway; mitochondrion; renal aging

DOI:  https://doi.org/10.3390/biomedicines14051092
Free Radic Biol Med. 2026 May 22. pii: S0891-5849(26)00798-7. [Epub ahead of print]

4-N-Furfurylcytosine, a Novel Cytosine-Derived Modulator of Mitochondrial and Redox Homeostasis to Counteract Aging: Insights from Cellular and Mouse Models.

Agnieszka Fedoruk-Wyszomirska, Paweł Pawelczak, Marta Orlicka-Płocka, Dorota Gurda-Woźna, Małgorzata Giel-Pietraszuk, Łukasz Przybył, Grzegorz Framski, Karol Pasternak, Agata Chmurzynska, Eliza Wyszko.

  Mitochondrial dysfunction and redox imbalance are key features of aging that drive cellular senescence, metabolic decline, and tissue degeneration. 4-N-furfurylcytosine (FC), a cytosine derivative with redox-modulating properties, has been proposed to counteract age-associated oxidative damage, however, its effects in mammalian aging remain unexplored. The anti-aging potential of FC was investigated using a translational approach integrating in vitro and in vivo models. Human fibroblasts (MRC-5) and keratinocytes (HaCaT) subjected to physiological and stress-induced senescence were used to assess mitochondrial function, redox balance, and proteostasis, while aged C57BL/6J mice, long-term supplemented with FC were evaluated for systemic metabolic, molecular, and behavioral outcomes. FC enhanced cell survival and mitigated key hallmarks of senescence, including β-galactosidase activity and p16 expression. Moreover, FC reduced intracellular reactive oxygen species and oxidative damage, as evidenced by decreased levels of 8-oxo-dG, protein carbonyls, and lipid peroxidation. FC improved mitochondrial membrane polarization and increased ATP levels while reducing oxygen consumption, indicating an altered bioenergetic state. Proteomic profiling revealed enrichment of pathways related to mitochondrial maintenance, antioxidant defense, and proteostasis, consistent with enhanced metabolic adaptability. In aged mice, FC supplementation preserved lean body mass, improved coordination and endurance, stabilized lipid and glucose metabolism, maintained telomere integrity, increased mtDNA:nDNA ratio, and reduced systemic oxidative stress markers, indicating delayed molecular aging and preserved mitochondrial function without no overt adverse effects detected in the measured readouts. 4-N-furfurylcytosine modulates redox- and mitochondria-associated aging phenotypes in cellular and mouse models, with effects consistent with remodeling of mitochondrial homeostasis and improved resilience to oxidative stress. These findings support FC as a promising candidate for further investigation as a modulator of aging-related processes.

Keywords:  4-N-furfurylcytosine; aging; anti-aging activity; epigenetic regulation; mitochondrial quality control; redox homeostasis; telomere maintenance

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.312
FEBS J. 2026 May 29.

A multilayered stress-response circuit: The mammalian mitochondrial UPR.

Paulina Czechowicz, Anna Więch-Walów, Sylwia Kozioł, Jakub Dudzik, James F Collawn, Rafal Bartoszewski.

  Mitochondrial proteotoxic stress activates the mammalian UPRmt through a multilayered mechanistic architecture rather than a linear pathway. At its core lies an import-gated sensing logic: reduced preprotein import and mito-nuclear stoichiometric imbalance activates the integrated stress response (ISR) toward the translation of ATF4, CHOP, and the mitochondria-targeted transcription factor ATF5. These factors cooperatively reprogram transcription to expand the chaperone-protease capacity while transiently reducing the nuclear-encoded OXPHOS load. Parallel translational mechanisms that include eIF2α-dependent repression, stress-granule triage, and miRNA-driven selective silencing reduce the mitochondrial precursor import and maintain proteostatic symmetry between the cytosol and mitochondria. Within the organelle, LONP1- and CLPP-dependent proteolysis, mitoribosome pausing, and tRNA-processing checkpoints further dampen nascent chain pressure. Epigenetic licensing by demethylases and acetyltransferases links metabolic and bioenergetic status to promoter accessibility at UPRmt loci. Together, these import-gated, translational, and epigenetic control layers form a coherent mechanistic circuit ensuring that mitochondrial recovery is matched to folding, assembly, and metabolic capacity. We propose a unified framework explaining how these layers cooperate to determine adaptive versus maladaptive outcomes.

Keywords:  Integrated stress response (ISR); Mitochondrial protein import stress; Mitochondrial proteostasis; Mitochondrial stress signaling; Mitochondrial unfolded protein response (UPRmt)

DOI:  https://doi.org/10.1111/febs.70607
BJOG. 2026 May 26.

Reproductive Factors, Lifestyle Behaviours and Cognitive Decline in Chinese Postmenopausal Women: A Cohort Study.

Xiaoqi Tang, Huiting Yang, Shuning Tang, Junling Gao, Qianyi Xiao.

   OBJECTIVE: To investigate the association of reproductive factors and their joint effects with lifestyle behaviours with cognitive decline in Chinese postmenopausal women.
DESIGN: Community-based cohort study.
SETTING: Shanghai, China.
POPULATION OR SAMPLE: We prospectively followed 1379 cognitively normal postmenopausal women aged ≥ 60 years for 1.8 years on average.
METHODS: Menopausal age, menarche age, parity, age at first live birth and breastfeeding duration were assessed at baseline. Associations between reproductive factors or their joint effects with lifestyle behaviours and cognitive decline were examined using logistic regression. The additive interaction was evaluated by the relative excess risk due to interaction (RERI) and the attributable proportion due to interaction (AP).
MAIN OUTCOME MEASURES: Cognitive decline was defined as an annual decline in Mini-Mental State (MMSE) Examination score exceeding mean decline by 1.0 SD.
RESULTS: The ORs (95% CIs) for cognitive decline were 2.55 (1.07, 6.06) for menopausal age < 46 years and 2.32 (1.11, 4.83) for menopausal age 46-50 years compared with menopausal age > 55 years. Meanwhile breastfeeding > 35 months (2.15, 1.02-4.51) and breastfeeding 24-35 months (2.31, 1.13-4.71) had higher risks of cognitive decline than breastfeeding < 12 months. Moreover, the combination of early menopause (≤ 50 years) and insufficient vegetable intake (1.84, 1.12-3.01), physical inactivity (2.11, 1.28-3.48), suboptimal sleep duration (2.15, 1.32-3.51), or an unfavourable composite lifestyle index (CLI) (1.76, 1.06-2.94) was associated with an increased risk of cognitive decline compared with the combination of late menopause (> 50 years) and each favourable lifestyle behaviour. Similarly, prolonged breastfeeding duration (> 23 months) combined with physical inactivity (2.10, 1.23-3.59), suboptimal sleep (2.11, 1.26-3.55), or an unfavourable CLI (2.16, 1.19-3.91) showed elevated risks compared with the combination of short breastfeeding duration (≤ 23 months) and each favourable lifestyle behaviour. In addition, we found additive interactions between early menopause and physical inactivity (RERI = 1.08, 95% CI: 0.37-1.80; AP = 0.51, 95% CI: 0.19-0.83), as well as between long breastfeeding duration and physical inactivity (RERI = 0.89, 95% CI: 0.15-1.63; AP = 0.42, 95% CI: 0.07-0.78).
CONCLUSIONS: Unhealthy lifestyle behaviours may exacerbate cognitive decline in women with adverse reproductive factors.

Keywords:  cognitive decline; lifestyle behaviour; postmenopausal women; reproductive factors

DOI:  https://doi.org/10.1111/1471-0528.70270
Front Nutr. 2026 ;13 1834167

Effects of Zingiberaceae-derived interventions on memory-related and other cognitive outcomes in adults: a systematic review and meta-analysis.

Desirée Victoria-Montesinos, Pilar Zafrilla, Pura Ballester, Ana María García-Muñoz.

   Introduction: Cognitive impairment and age-related cognitive decline are major public health concerns, and nutraceutical strategies targeting modifiable biological pathways have attracted growing interest. Compounds derived from the Zingiberaceae family, including curcumin, turmeric, ginger, and related preparations, have been investigated for their potential neuroprotective effects, but their clinical impact on specific cognitive domains remains unclear. This systematic review and meta-analysis aimed to evaluate the effects of Zingiberaceae-derived interventions on memory-related and other cognitive outcomes in adults.
Methods: A systematic search was conducted in MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from inception to March 2026. Randomized controlled trials evaluating orally administered Zingiberaceae-derived interventions in adults and reporting validated cognitive outcomes were included. Cognitive outcomes were grouped into memory-related outcomes, executive function and processing speed, global cognition, and attention or inhibitory control, with memory-related outcomes prespecified as the primary outcome.
Results: Eighteen randomized, double-blind, placebo-controlled clinical trials were included in the qualitative synthesis, and domain-specific meta-analyses were performed when at least three studies were available. In the pooled analysis, Zingiberaceae-derived interventions showed a statistically significant improvement in memory-related outcomes (standardized mean difference = 0.57; 95% confidence interval: 0.13 to 1.02), whereas no significant pooled effects were observed for executive function and processing speed, global cognition, or attention or inhibitory control. Sensitivity analyses were consistent with the main findings.
Discussion: Overall, Zingiberaceae-derived interventions may improve memory-related outcomes, but the evidence is very uncertain due to substantial heterogeneity, the small number of studies, risk of bias in some trials, and variability in populations, formulations, and outcome measures. These findings indicate that their cognitive effects may be domain-specific and context-dependent, highlighting the need for larger, well-designed trials using standardized cognitive endpoints and bioavailable formulations.
Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261325966, identifier CRD420261325966.

Keywords:  Zingiberaceae; cognition; cognitive aging; curcumin; ginger; meta-analysis

DOI:  https://doi.org/10.3389/fnut.2026.1834167
Biomed Pharmacother. 2026 May 28. pii: S0753-3322(26)00595-0. [Epub ahead of print]200 119559

Mitochondrial metabolic reprogramming in diabetic cardiomyopathy.

Yuting Zhou, Hao Tian, Zhongyuan Xia, Yonghong Xiong.

  Diabetes mellitus represents a major global health challenge and is strongly associated with cardiovascular complications, among which diabetic cardiomyopathy (DCM) is a major contributor to heart failure. Increasing evidence indicates that mitochondrial dysfunction plays a central role in DCM pathogenesis. However, mitochondrial abnormalities in the diabetic heart reflect not merely cellular injury but a coordinated process of mitochondrial metabolic reprogramming, characterized by altered substrate utilization, impaired oxidative phosphorylation, and disruption of mitochondrial quality control. Under diabetic conditions, chronic hyperglycemia, insulin resistance, and lipid overload induce profound metabolic remodeling in cardiomyocytes. These disturbances promote excessive reactive oxygen species production, mitochondrial DNA damage, and dysfunction of the electron transport chain. Concurrently, cardiomyocytes undergo a shift in substrate preference, including enhanced glycolysis, dysregulated fatty acid oxidation, and altered amino acid metabolism. Such metabolic inflexibility compromises ATP production and contributes to lipotoxicity, oxidative stress, and cardiomyocyte apoptosis. Recent studies have revealed that mitochondrial metabolic reprogramming is governed by complex regulatory networks, including signaling pathways such as AMPK/PGC-1α, PI3K/Akt/mTOR, hypoxia-inducible factor-1α, and TGF-β/Smad, together with epigenetic mechanisms and mitochondrial quality control processes. Disruption of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis further promotes the accumulation of dysfunctional mitochondria and accelerates disease progression. In this review, we summarize current advances in the mechanisms underlying mitochondrial metabolic reprogramming in diabetic cardiomyopathy and discuss emerging therapeutic strategies targeting mitochondrial metabolism. By integrating mitochondrial biology with cardiovascular metabolism, this review provides a comprehensive framework for understanding DCM pathogenesis and highlights potential directions for precision therapeutic intervention.

Keywords:  Diabetic cardiomyopathy; Mitochondrial metabolic reprogramming; Mitochondrial quality control; Oxidative phosphorylation; Substrate utilization

DOI:  https://doi.org/10.1016/j.biopha.2026.119559
Curr Issues Mol Biol. 2026 May 16. pii: 519. [Epub ahead of print]48(5):

Estrogen Replacement Therapy in Ovariectomized Rats: Complementary Roles of ER and GPR30 in Alleviating Depressive-like Behavior.

Siyi He, Zhongyu Ren, Lan Wu, Yinping Xie, Limin Sun, Ling Xiao, Gaohua Wang.

  Women are twice as likely to suffer from major depressive disorder (MDD). The underlying mechanism between estrogen and depression is still unknown. We used ovariectomized rats to simulate menopausal status and established a depression model of chronic and acute stress. The therapeutic effects of estrogen were systematically studied through behavioral testing, Western blotting, ELISA, LC-MS, and cell experiments. In chronic stress, OVX rats showed depressive-like behaviors, and elevated hippocampal ER, BDNF, IL-1β/IL-18, and body weight. ERT reduced depression-like behavior by 64% to 76% in the behavioral test. ERT also reversed the molecules without affecting GPR30. In acute stress, ERT reduced depression-like behavior by 20% to 58% in the behavioral test. OVX decreased ER, BDNF, P2X7, IL-1β/IL-18, spine density, and microglia and increased the expression of GPR30. ERT reversed all the above. ERT normalized metabolic abnormalities caused by CUMS. Our study demonstrates that estrogen deficiency contributes to the onset and progression of depression in a rat model of menopause-like estrogen deficiency. Estrogen replacement therapy appears to alleviate depressive-like behaviors by reducing brain inflammation and supporting the brain's adaptive capacities through ER. Furthermore, the dual function positions GPR30 as a promising potential target for future treatments of menopausal depression, and GPR30 regulates neuroinflammation and neuroplasticity through the NLRP3/P2X7/IL-1β pathway.

Keywords:  GPR30; estrogen; major depressive disorder; neuroinflammation; short-term stress

DOI:  https://doi.org/10.3390/cimb48050519