bims-mistre 2025-06-08 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–06–08
sixteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity.
Exploring the Role of NLRP3 in Neurodegeneration: Cutting-Edge Therapeutic Strategies and Inhibitors.
FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function.
Oleoylethanolamide supplementation on cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials.
Ndufs4-/- mice: a testing ground for longevity interventions.
Disruption of cholesterol homeostasis triggers NLRP3-cGAS-STING axis-dependent hepatic fibrosis and honokiol intervention effects.
MitoQ for vitiligo by mitigating PARP1 translocation aberrations: Network pharmacology and experimental validation.
Mitophagy-mtROS axis contributes to anti-tuberculosis-induced liver injury through activation of the cGAS-STING pathway in rat hepatocytes.
The neurobiology of plant-based therapeutics in women's reproductive health: mechanisms, efficacy, and clinical translation.
Anti-neurodegenerative treatment in Alzheimer's disease: Multifaceted mechanisms of action of berberine.
The broccoli derivative sulforaphane extends lifespan by slowing the transcriptional aging clock.
Mechanism and implications of advanced glycation end products (AGE) and its receptor RAGE axis as crucial mediators linking inflammation and obesity.
Impairment of Tricarboxylic Acid Cycle (TCA) Cycle in Alzheimer's Disease: Mechanisms, Implications, and Potential Therapies.
Ginsenoside Rg1 Downregulates miR-9-5p Expression to Modulate SIRT1-Mediated Mitochondrial Dysfunction and Ameliorate Alzheimer's Disease.
Metformin: An Old Drug with New Tricks-Promising Role in Vascular Aging and Cardioprotection.
Ergothioneine regulates the paracrine of dermal papilla cells through SIRT1/Nrf2 pathway to antagonize oxidative stress and natural hair follicle aging.

Front Aging. 2025 ;6 1605070

Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity.

Fayaz A Mir, Arianna R S Lark, Christa J Nehs.

  The relationship between sleep and metabolism has emerged as a critical factor in aging and age-related diseases, including Alzheimer's disease and dementia. Mitochondrial oxidative phosphorylation, essential for neuronal energy production, also generates reactive oxygen species (ROS), which increase with age and contribute to oxidative stress. Sleep plays a vital role in modulating redox balance, facilitating the clearance of free radicals, and supporting mitochondrial function. Disruptions in sleep are closely linked to redox imbalances, and emerging evidence suggests that pharmacological interventions, such as dual orexin receptor antagonists and antioxidant-based therapies, may help restore redox homeostasis. Furthermore, antioxidant-rich diets and supplements have shown promise in improving both sleep quality and metabolic health in aging populations. Neurons, with their high energy demands, are particularly vulnerable to oxidative damage, making redox regulation crucial in maintaining brain integrity. This review explores the bidirectional relationship between sleep and redox metabolism through five key areas: (1) sleep's role in free radical regulation, (2) ROS as mediators of age-related sleep disturbances, (3) feedback loops between impaired sleep and brain metabolism, (4) sleep, redox, and aging in peripheral systems, and (5) therapeutic strategies to restore redox balance and improve aging outcomes. Understanding these mechanisms may provide new targets for interventions aimed at mitigating age-associated diseases.

Keywords:  antioxidants; ketones; metabolic; mitochondria; oxidative stress; sleep

DOI:  https://doi.org/10.3389/fragi.2025.1605070
Dev Neurobiol. 2025 Jul;85(3): e22982

Exploring the Role of NLRP3 in Neurodegeneration: Cutting-Edge Therapeutic Strategies and Inhibitors.

Mohammed Ahmed Mustafa, Pooja Bansal, M S Pallavi, Rajashree Panigrahi, Deepak Nathiya, Sachin Kumar, Shaker Al-Hasnaawei, Ashish Singh Chauhan, Siya Singla.

  Inflammasomes, particularly the NLRP3 inflammasome, play a pivotal role in mediating neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD). Recent findings indicate that the activation of the NLRP3 inflammasome in microglia and astrocytes triggers the release of pro-inflammatory cytokines, including IL-1β and IL-18, which contribute to chronic inflammation and neuronal damage. This process accelerates neurodegeneration and exacerbates disease progression. Misfolded protein aggregates, mitochondrial dysfunction, and oxidative stress are key factors in the pathological activation of the NLRP3 inflammasome in these diseases. Recent studies have highlighted that targeting the NLRP3 inflammasome, either through direct inhibitors like MCC950 or natural compounds such as oridonin and β-hydroxybutyrate, shows promise in mitigating neuroinflammation and protecting neuronal integrity. These inhibitors have demonstrated neuroprotective effects in animal models of AD, PD, and MS, presenting a new therapeutic approach for halting disease progression. However, the complexity of NLRP3 regulation requires further investigation to balance its inflammatory and protective roles. This review examines the recent advancements in NLRP3 inflammasome research and discusses potential strategies for modulating inflammasome activity to slow or prevent the progression of neurodegenerative diseases.

Keywords:  NLRP3; cytokine; inflammasome; inflammasome inhibitors; neurodegenerative diseases

DOI:  https://doi.org/10.1002/dneu.22982
JACC Basic Transl Sci. 2025 Apr 09. pii: S2452-302X(25)00012-9. [Epub ahead of print] 101222

FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function.

Xin Zhang, Wen-Sheng Dong, Kang Li, Yun-Jia Ye, Can Hu.

  Mitochondria play critical roles in maintaining oxidative metabolism and cardiac homeostasis; however, their function is compromised in aging hearts. Fibronectin type III domain-containing 4 (FNDC4) is involved in regulating mitochondrial biogenesis, energy expenditure, and metabolic balance. The present study found that aging mice exhibited a sizable decline in cardiac and plasma FNDC4 levels, and that lower FNDC4 expression also correlated with a poor cardiac function. Cardiac-specific FNDC4 overexpression alleviated, while cardiac-specific FNDC4 knockdown facilitated aging-related cardiac remodeling and dysfunction. The unbiased transcriptome analysis and untargeted metabolomics revealed that FNDC4 activated AMP-activated protein kinase α/peroxisome proliferator-activated receptor α signaling pathway to improve mitochondrial dysfunction and lipotoxicity in aging hearts.

Keywords:  AMPKα; FNDC4; PPARα; cardiac aging; mitochondrial function

DOI:  https://doi.org/10.1016/j.jacbts.2025.01.004
Front Nutr. 2025 ;12 1553288

Oleoylethanolamide supplementation on cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials.

Hossein Bahari, Mostafa Shahraki Jazinaki, Ladan Aghakhani, Alireza Hatami, Iman Rahnama, Mahsa Malekahmadi.

   Background: Oleoylethanolamide (OEA) is a naturally occurring lipid that has been studied for its potential role in weight management and metabolic health. Through comprehensive meta-analysis, we aim to clarify the potential benefits of OEA in improving inflammation, oxidative stress, and metabolic parameters.
Methods: To identify relevant randomized controlled trials (RCTs), a comprehensive search was conducted using Google Scholar and four databases: PubMed, Embase, Scopus, and Web of Science, up to November 2024. Eligible trials were detected by screening, and related data were extracted, respectively. Pooled effect sizes were calculated using meta-analyses and expressed as standard mean difference (SMD) with a 95% confidence interval (CI).
Results: Ten trials (with 11 treatment arms) were eligible for inclusion in this review. Meta-analysis revealed that OEA supplementation led to a significant improvement in C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), total antioxidant capacity (TAC), malondialdehyde (MDA), body weight, body mass index (BMI), waist circumference (WC), fat mass (FM), body fat percentage (BFP), triglycerides (TG), fasting blood glucose (FBG), insulin, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) levels. However, no significant changes were observed in interleukin 6 (IL-6), fat-free mass (FFM), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and hemoglobin A1C (HbA1c) following OEA intake.
Conclusion: Supplementation with OEA may help improve glycemic control, weight loss, waist circumference, fat mass, fat percentage, inflammation, and oxidative stress. However, further research is needed to establish definitive conclusions regarding its efficacy and long-term benefits.

Keywords:  inflammation; meta-analysis; metabolic health; obesity; oleoylethanolamide; oxidative stress

DOI:  https://doi.org/10.3389/fnut.2025.1553288
Geroscience. 2025 Jun 05.

Ndufs4-/- mice: a testing ground for longevity interventions.

Jackson Nuss, Matt Kaeberlein, Alessandro Bitto, Anthony S Grillo.

  Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the pathophysiology of mitochondrial disease and mitochondrial dysfunction in sporadic disorders. Intriguingly, longevity interventions are very effective at treating symptoms of disease in this model. Herein, we introduce the model and its notable features that may help provide insights in longevity research. We performed a retrospective analysis of historical data from our laboratories over the past 10 years regarding the use of this animal model in aging studies, the manifestation and progression of mitochondrial disease, and factors that influence their premature death. We observed a correlation between weight and lifespan in female animals and a sex-independent correlation between the onset of clasping, a typical neurodegenerative symptom, and overall survival. We observed a sexual dimorphism in lifespan with female mice being more resilient despite a similar age of onset of disease symptoms. Lastly, we report increased lifespan and delayed onset of disease symptoms following treatment with 17-alpha-estradiol, a non-feminizing estrogen which can extend lifespan in genetically heterogeneous mice. This analysis serves as a useful guide for researchers utilizing this animal in the discovery of effective interventions for longevity and to prevent the onset of disease. It suggests there may be unprecedented underlying sex-specific differences in patients with Leigh syndrome and further strengthens the connection between normative aging and mitochondrial dysfunction.

Keywords:  Interventions; Longevity; Mitochondrial dysfunction; Vertebrate models

DOI:  https://doi.org/10.1007/s11357-025-01704-8
Phytomedicine. 2025 May 24. pii: S0944-7113(25)00542-2. [Epub ahead of print]143 156904

Disruption of cholesterol homeostasis triggers NLRP3-cGAS-STING axis-dependent hepatic fibrosis and honokiol intervention effects.

Zhilei Wang, Jingwen Liu, Yu Mou, Xianglu Zhou, Wenhao Liao, Yuchen Li, Yong Liu, Jianyuan Tang.

   BACKGROUND: Maintaining cholesterol homeostasis is crucial for sustaining human health and physiological function. Although the detrimental effects of chronic cholesterol overload on hepatic injury and fibrosis are well documented, the molecular mechanisms driving this pathology remain incompletely understood.
PURPOSE: This study investigates the mechanistic role of chronic cholesterol overload in driving liver fibrosis and evaluates the therapeutic efficacy of honokiol as a targeted intervention.
STUDY DESIGN AND METHODS: High-cholesterol models induced by cholesterol and 25-hydroxycholesterol in human HepG2 cells or induced by cholesterol crystals in mouse bone marrow-derived macrophages were established. We also examined the effect of cholesterol on the livers of mice following a 20-week regimen of high-cholesterol diets.
RESULTS: Excess cholesterol interfered with normal cholesterol metabolism both in vitro and in vivo, and led to liver damage and fibrosis in vivo. Further research showed that cholesterol exposure triggered NLRP3 inflammasome activation and programmed cell death called pyroptosis; induced an increase in mitochondrial ROS and a disruption of intracellular redox homeostasis, followed by the opening of the mitochondrial permeability transition pore; and finally induced cellular DNA damage, resulting in the translocation of the double-stranded DNA fragment into the cytoplasm and the activation of the DNA-sensing adaptor STING. The activation of the NLRP3-cGAS-STING axis initiated the downstream cascade reaction and up-regulated the expression of pro-inflammatory cytokines, including IL-1β, TNF-α, and IFN-β, thus facilitating liver damage and fibrosis. Furthermore, honokiol, an active ingredient in Magnolia officinalis, could alleviate liver damage and fibrosis by blocking NLRP3 inflammasome activation, pyroptosis, and the cGAS-STING pathway.
CONCLUSION: Systematic evidence shows that cholesterol induces liver fibrosis through the activation of the NLRP3-cGAS-STING signaling axis and that honokiol demonstrates interventional efficacy in mitigating this process.

Keywords:  Cholesterol homeostasis; Honokiol; Liver fibrosis; NLRP3 inflammasome; Pyroptosis; cGAS-STING

DOI:  https://doi.org/10.1016/j.phymed.2025.156904
Biochim Biophys Acta Mol Cell Res. 2025 May 30. pii: S0167-4889(25)00100-4. [Epub ahead of print]1872(7): 119995

MitoQ for vitiligo by mitigating PARP1 translocation aberrations: Network pharmacology and experimental validation.

Renxue Xiong, Shiyu Jin, Yujie Li, Tingru Dong, Xiuzu Song, Cuiping Guan.

   PURPOSE: Oxidative stress plays a significant role in the development of vitiligo. Although the specific mechanism of the mitochondria-targeted antioxidant mitoquinone (MitoQ) in vitiligo remains unclear, it has shown promise in the treatment of various diseases.
METHODS: In this study, we employed network pharmacology, molecular docking, transcriptomic approaches, and experimental verification to investigate the potential targets of MitoQ in vitiligo.
RESULTS: Molecular docking results identified four possible crucial targets of MitoQ in vitiligo treatment: poly (ADP-ribose) polymerase 1 (PARP1), prostaglandin-endoperoxide synthase 2 (PTGS2), estrogen receptor 1 (ESR1), and C-X-C motif chemokine receptor 3 (CXCR3). MitoQ alleviated oxidative stress-induced PARP1 nuclear mislocalization, attenuated ROS accumulation, restored mitochondrial membrane potential, and enhanced ATP synthesis in vitro analysis. Transcriptomic analysis demonstrated that MitoQ reduced the expression of DNA damage genes and genes involved in the PI3K-AKT and MAPK signaling pathways. The protein-protein interaction network indicated a potential relationship between PARP1 and DNA damage-related genes, suggesting that MitoQ could interfere with abnormal PARP1 activation. Notably, MitoQ reduced cellular senescence by decreasing CDKN1A/p21 protein through PARP1, and the knockdown of PARP1 reduced oxidative damage.
CONCLUSION: These results indicate that PARP1 decreases cellular senescence and offers a potential target for therapeutic research in the management of vitiligo.

Keywords:  Melanocyte; Oxidative stress; Vitiligo; p21

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119995
Int Immunopharmacol. 2025 May 30. pii: S1567-5769(25)00974-9. [Epub ahead of print]160 114984

Mitophagy-mtROS axis contributes to anti-tuberculosis-induced liver injury through activation of the cGAS-STING pathway in rat hepatocytes.

Wenyan Chen, Chenjunlei Luo, He Zhou, Zhenhui Liu, Junfei Huang, Yining Liu, Mingdan You, Guanghong Yang.

  Tuberculosis (TB) remains a major worldwide healthcare issue, with anti-TB drugs playing a pivotal role in its treatment. However, the emergence of anti-TB drug-induced liver injury (ATB-DILI) poses a considerable challenge, undermining treatment efficacy and patient survival. This study investigates the underlying mechanisms of ATB-DILI, focusing on reactive oxygen species (ROS), mitophagy, lysosomal function, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. A rat hepatocyte model treated with standard anti-TB drugs was established to assess liver inflammation, oxidative stress biomarkers, mitochondrial function, and mitophagy processes. The results indicate that anti-TB drug administration induced significant inflammatory injury, characterized by elevated IL-6 and reduced IL-4 and IL-10 levels. ROS overproduction predominantly originates in the mitochondrial level, consequently resulting in oxidative stress and impaired mitochondrial function. A noticeable decline in both the oxygen consumption rate and ATP production is indicative of this phenomenon. Although mitophagy was activated, impaired lysosomal function hindered mitophagic flux, leading to the buildup of damaged mitochondria and ROS. Pharmacological intervention with mitoTEMPO alleviated mitochondrial dysfunction, while clioquinol restored lysosomal function and improved mitophagy. Additionally, the cGAS-STING signaling pathway was found to regulate inflammation in ATB-DILI, with both mitoTEMPO and clioquinol alleviating its effects. These findings elucidate the crucial impact of lysosome-mediated mitophagy dysfunction and mitochondrial ROS in ATB-DILI, highlighting potential therapeutic targets to enhance liver protection during anti-TB treatment.

Keywords:  Anti-tuberculosis drugs; Liver injury; Lysosomal dysfunction; Mitophagy; Reactive oxygen species; cGAS-STING

DOI:  https://doi.org/10.1016/j.intimp.2025.114984
Front Nutr. 2025 ;12 1591534

The neurobiology of plant-based therapeutics in women's reproductive health: mechanisms, efficacy, and clinical translation.

Xue Liu, Chengli Bin, Zehui Zhou, Tongtong Zeng, Kun Wu, Yiping Luo, Qun Liu, Shaobin Wei.

  This review examines the neurobiological mechanisms by which plant-derived compounds influence women's reproductive health through the neuroendocrine-reproductive axis. Gynecological disorders frequently present with neurological manifestations, including cognitive decline in perimenopause, anxiety and depression in polycystic ovary syndrome (PCOS), and central sensitization in endometriosis. Bioactive compounds from medicinal plants, including polyphenols and phytoestrogens, demonstrate therapeutic potential through their anti-inflammatory, antioxidant, and neuromodulatory properties. These multi-target compounds offer advantages over conventional single-target therapies by simultaneously regulating multiple physiological processes. The review explores applications in specific gynecological conditions and discusses the development of dietary supplements and functional foods incorporating these plant-derived ingredients. The growing market for these products presents opportunities for innovative formulations with enhanced bioavailability and personalized approaches. Future research directions include integrating neuroimaging with herbal research, improving clinical translation, and establishing regulatory frameworks for the global application of these plant-derived interventions to enhance female neuroendocrine-reproductive health.

Keywords:  functional foods; neuroendocrine-reproductive axis; phytoestrogens; plant-derived compounds; women's health

DOI:  https://doi.org/10.3389/fnut.2025.1591534
Int J Clin Pharmacol Ther. 2025 Jun 02.

Anti-neurodegenerative treatment in Alzheimer's disease: Multifaceted mechanisms of action of berberine.

Dandan Song, Congmin Zhang.

BACKGROUND: Berberine, a traditional Chinese medicine, has demonstrated significant therapeutic influences in treating diabetes, obesity, and diarrhea, among other conditions. It has exhibited potential therapeutic benefits for various neurodegenerative diseases, namely, Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD).
AIMS: This study aims to elucidate the mechanism behind berberine pharmacological action in treating AD.
MATERIALS AND METHODS: We search the articles published in PubMed and CNKI and summarize the mechanism of berberine in AD.
RESULTS: In recent years, as research into the pharmacology of berberine has deepened, researchers have discovered its strong neuroprotective properties. The ability of berberine to enhance cognitive function is thought to result from inhibiting the spread of AD-related proteins, reducing oxidative stress and inflammation, increasing choline levels, and regulating autophagy.
CONCLUSION: This review explores the latest research on berberine in AD, suggesting that berberine and its analogs may offer a promising new approach to treating the condition.

DOI: https://doi.org/10.5414/CP204725
bioRxiv. 2025 May 15. pii: 2025.05.11.653363. [Epub ahead of print]

The broccoli derivative sulforaphane extends lifespan by slowing the transcriptional aging clock.

Christine A Sedore, Erik Segerdell, Anna L Coleman-Hulbert, Erik Johnson, Jonathan N Levi, Gordon J Lithgow, Monica Driscoll, Patrick C Phillips.

Sulforaphane, an organosulfur isothiocyanate derived from cruciferous vegetables, has been shown to inhibit inflammation, oxidative stress, and cancer cell growth. To explore the potential of sulforaphane as a candidate natural compound for promoting longevity more generally, we tested the dose and age-specific effects of sulforaphane on C. elegans longevity, finding that it can extend lifespan by more than 50% at the most efficacious doses, but that treatment must be initiated early in life to be effective. We then created a novel, gene-specific, transcriptional aging clock, which demonstrated that sulforaphane-treated individuals exhibited a "transcriptional age" that was approximately four days younger than age-matched controls, representing a nearly 20% reduction in biological age. The clearest transcriptional responses were detoxification pathways, which, together with the shape of the dose-response curve, indicates a likely hormetic response to sulforaphane. These results support the idea that robust longevity-extending interventions can act via global effects across the organism, as revealed by systems level changes in gene expression.

DOI: https://doi.org/10.1101/2025.05.11.653363
Mol Biol Rep. 2025 Jun 05. 52(1): 556

Mechanism and implications of advanced glycation end products (AGE) and its receptor RAGE axis as crucial mediators linking inflammation and obesity.

Sajani Arunkumar Kavitha, Sara Zainab, Yadav Sangeeta Muthyalaiah, Cordelia Mano John, Sumathy Arockiasamy.

  Advanced glycation end products (AGEs) are heterogenous compounds that play a central role in various chronic diseases, such as diabetes, neurodegenerative disorders, cardiovascular diseases, and cancer. These are formed by non-enzymatic reaction between reducing sugar and amino group of proteins, lipids and nucleic acids. Elevated levels of AGEs are associated with obesity, which is linked to hyperglycemia, dyslipidemia and insulin resistance, contributing to metabolic syndrome and diabetes. Both dietary and endogenous AGEs contribute to persistent oxidative stress and inflammation directly through glycated biomolecules and indirectly through its receptor, receptor for advanced glycation end products, RAGE. In this context, inflammation is a sustained, systemic immune response with macrophage infiltration into adipose tissues, high pro- inflammatory cytokines leading to immune dysregulation, activation of key inflammatory pathways such as NF-kB and JNK signaling, increase oxidative stress, insulin resistance suggesting inflammation as both a cause and consequence of metabolic dysfunction. Persistent oxidative stress and inflammation accelerates AGEs formation, disrupt cellular signaling, alter extracellular matrix integrity, impair release of enzymes and hormones. Also, AGE-induced gut microbiome imbalance elicits conditions such as systemic inflammation, intestinal barrier dysfunction and metabolic imbalance, promoting obesity and its complications. This review explores the central role of AGEs in obesity-associated inflammation, emphasizing AGE-RAGE signaling, epigenetic regulation and gut microbiome dysfunction. Understanding this interplay mediated by AGEs is critical for identifying potential biomarkers of metabolic risk and strategize means to prevent AGEs formation, block AGE-RAGE interaction and signaling, thus mitigating the effects of obesity and its associated diseases.

Keywords:  Advanced glycation end products (AGEs); Inflammation; Metabolic syndrome; Obesity; Receptor for advanced glycation end products RAGE

DOI:  https://doi.org/10.1007/s11033-025-10632-x
Aging Dis. 2025 Jun 02.

Impairment of Tricarboxylic Acid Cycle (TCA) Cycle in Alzheimer's Disease: Mechanisms, Implications, and Potential Therapies.

Gudimetla Susmitha Mohan, Rahul Kumar.

Alzheimer's disease (AD) is a neurodegenerative condition defined by the gradual impairment of cognitive functions, synaptic disarray, and extensive neuronal loss. Emerging evidence suggests that metabolic impairment, specifically within tricarboxylic acid (TCA) cycle, is instrumental in the AD pathophysiology. TCA cycle represents an indispensable pathway in metabolism that is responsible for energy production, and the maintenance of cellular homeostasis, particularly in neurons. Several in vitro, clinical, and in vivo studies reported that several TCA cycle enzymes disrupt during AD. Disruption in TCA cycle enzymes exhibits more pronounced impact on the brain owing to its high metabolic activity and continuous demand for energy, where any reduction in ATP production can severely impair neuronal function, synaptic plasticity, and overall cognitive processes. The current review explores the mechanisms underlying AD related impairment in TCA cycle, focussing on the molecular alterations of TCA enzymes. We also discussed potential activators and inhibitors of TCA cycle enzymes as a potential therapeutic intervention to restore AD related metabolic balance.

DOI: https://doi.org/10.14336/AD.2025.0472
Mol Neurobiol. 2025 Jun 06.

Ginsenoside Rg1 Downregulates miR-9-5p Expression to Modulate SIRT1-Mediated Mitochondrial Dysfunction and Ameliorate Alzheimer's Disease.

Yunliang Wang, Xiangyun Sun, Biao He, Shaowen Yu.

  This study aimed to investigate the mechanism of ginsenoside Rg1 in Alzheimer's disease (AD) via miR-9-5p/SIRT1-mediated mitochondrial function. The cognitive function of AD mice was assessed by Morris water maze experiment. The histopathological changes in the CA1 region were observed by H&E staining. TUNEL staining combined with the neuronal marker NeuN was used to detect neuronal apoptosis in hippocampal tissues. Aβ1-42 induced HT-22 cells were used as AD in vitro models. MiR-9-5p expression was detected by qRT-PCR, and SIRT1 protein and autophagy-related proteins (LC3B II/I, Beclin-1) levels were measured by western blot. The binding of miR-9-5p with SIRT1 was predicted and validated. Ginsenoside Rg1 treatment in AD mice reduced miR-9-5p expression, increased SIRT1 level, attenuated mitochondrial dysfunction, and effectively improved AD symptoms in mice, while such effect can be either reversed by miR-9-5p agomir or SIRT1 inhibitor (EX527). In vitro, Aβ1-42-induced HT-22 cell activity was reduced, cell death was significantly increased, and mitochondrial dysfunction was progressed, but treatment of HT-22 cells with Aβ1-42 and ginsenoside Rg1 attenuated mitochondrial dysfunction and improved Aβ1-42-induced HT-22 cell damage. Ginsenoside Rg1 ameliorated Aβ1-42-induced HT-22 cell damage by down-regulating miR-9-5p to regulate SIRT1-mediated mitochondrial dysfunction. miR-9-5p negatively regulates SIRT1. Inhibition of mitochondrial autophagy partially reversed the ameliorative effect of ginsenoside Rg1 on mitochondrial dysfunction and cellular damage in HT-22 cells. Ginsenoside Rg1 down-regulates miR-9-5p expression to modulate SIRT1-mediated mitochondrial dysfunction, hereby attenuating Aβ1-42 induced cell injury in HT-22 cells and alleviating AD in mice.

Keywords:  Alzheimer disease; Ginsenoside Rg1; MiR-9-5p; Mitochondrial autophagy; Mitochondrial dysfunction; SIRT1

DOI:  https://doi.org/10.1007/s12035-025-05073-3
Drugs Aging. 2025 Jun 05.

Metformin: An Old Drug with New Tricks-Promising Role in Vascular Aging and Cardioprotection.

Rooban Sivakumar, K A Arul Senghor, V M Vinodhini, Janardhanan S Kumar.

Metformin, traditionally promoted for its efficacy in diabetes, is increasingly appreciated for its geroprotective potential in the development of vascular aging, a key contributor to cardiovascular morbidity. This review aims at understanding the spectrum of mechanisms that govern the amelioration of degenerative processes associated with vascular aging by metformin. Central to this therapeutic promise is the activation of AMPK, which reduces metabolic dysregulation and hence slows vascular senescence. Oxidative stress has been identified as an important mechanism thought to be enhanced by metformin in the preservation of endothelial function and attenuation of arterial stiffening. Besides, metformin has lipid-lowering and antiinflammatory activity, which is critical for reducing arterial rigidity and the development of atherosclerotic plaque. In recent times, both clinical and preclinical studies revealed empirical data that confirmed the effectiveness of metformin in the improvement of endothelial function and the decreasing of arterial stiffness as a part of a reduction in the rates of cardiovascular events. The therapeutic action of the drug goes beyond glycemic control, rendering it a geroprotector potentially suitable for broader application in age-related vascular decline. In light of these findings, the clinical acceptance of metformin as an intervention in vascular aging should be possible and promising. Carefully monitored follow-up studies are needed to optimize dosing, delineate the broad biological effects, and verify long-term benefits, which will underpin metformin's role in the paradigm against age-associated vascular diseases.

DOI: https://doi.org/10.1007/s40266-025-01215-3
Free Radic Biol Med. 2025 May 29. pii: S0891-5849(25)00725-7. [Epub ahead of print]

Ergothioneine regulates the paracrine of dermal papilla cells through SIRT1/Nrf2 pathway to antagonize oxidative stress and natural hair follicle aging.

Hailin Wang, Yueying Wang, Xin Li, Jiayang Ma, Zhiqi Hu, Qian Qu, Yong Miao.

  Hair graying and loss are significant indicators of aging, and oxidative stress plays an essential role in this progression. Ergothioneine (EGT), potent antioxidant from edible fungi and certain prokaryotes, regulates the antioxidant defense system. However, its anti-aging effects on hair follicles (HFs) are remain obscure. We used dermal papilla cells (DPCs) co-culture system, HFs organ culture system, aged mice and H2O2-induced gray hair mice to explore the antioxidative functions and mechanisms of EGT on HFs. Research demonstrated that EGT mitigated H2O2-induced DPCs damage, reduced the secretion of inflammatory factors (IL-6, IL-1β, and TNF-α) and enhanced the production of pigmentation promoting factors (SCF and SDF1) through the SIRT1/Nrf2 pathway in DPCs. In vitro experiments of co-culture system indicated that EGT-treated DPCs remarkably alleviated oxidative damages and promoted cell proliferation in A-375 and HaCaT. Furthermore, it increased tyrosinase activity, melanin content and the expression of key melanin synthesis genes in A-375. Meanwhile, it promoted the expression of K19 and K14 in HaCaT. In vivo experiments revealed that EGT exhibited excellent effects on reducing pigmentation disfunction and hair loss in aged mice and H2O2-induced gray hair mice. In the HFs organ culture, the EGT promoted hair growth and pigmentation via SIRT1/Nrf2 partly. Our research indicated that EGT had potent antioxidant and anti-aging functions for HFs. This not only provided new applications for EGT but also opened up new therapeutic avenues for hair aging.

Keywords:  Aging; Dermal papilla cells; Ergothioneine; Hair follicle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.427