bims-mistre 2025-11-09 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–11–09
twenty papers selected by
Ellen Siobhan Mitchell, MitoQ

Natural products that suppress 2-deoxy-d-glucose-induced cell death as potential drug seeds for mitochondrial diseases.
β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review).
Role and mechanisms of plant polyphenols in ovarian aging.
Coenzyme Q10 attenuates age-associated neurodegeneration via modulation of autophagy and neuroinflammation in aged rats.
Melatonin mitigates polystyrene nanoplastics-induced impairment of oocyte maturation in mice.
Heat stress-induced mitochondrial damage and its impact on leukocyte function.
Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice.
Effects of exercise training on skeletal muscle mitochondrial outcomes in type 2 diabetes: a systematic review and meta-analysis.
Sestrins: a new therapeutic target for endothelial dysfunction and cardiovascular disease prevention.
Metabolic Biomarkers for Lifespan Extension and Cellular Stress in Saccharomyces cerevisiae during Calorie Restriction and Quercetin Treatment.
The auxiliary effect of oral nutritional supplements on fertility in women with diminished ovarian reserve: a systematic review and meta-analysis.
Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan.
Cerebrolysin ameliorates ketamine-mediated anxiety and cognitive impairments via modulation of mitochondrial function and CREB/PGC-1α pathway.
Effects of carnitine supplementation on glycemic markers in women with overweight and obesity: A systematic review and meta-analysis of randomized controlled trials.
Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
Stressors-induced cognitive dysfunction during aging: mechanisms and future challenges.
Bicyclol improves cognition deficits and inhibits oxidative stress-induced neuronal cell apoptosis in alzheimer's disease via Nrf2/HO-1 pathway.
Ketogenic Diets and Depression and Anxiety: A Systematic Review and Meta-Analysis.
Diagnostic and prognostic implications of growth differentiation factor 15 in heart failure with preserved ejection fraction: a systematic review and meta-analysis.
NAD+ reverses Alzheimer's neurological deficits via regulating differential alternative RNA splicing of EVA1C.

Bioorg Med Chem. 2025 Nov 02. pii: S0968-0896(25)00419-5. [Epub ahead of print]132 118478

Natural products that suppress 2-deoxy-d-glucose-induced cell death as potential drug seeds for mitochondrial diseases.

Koyo Honda, Yuki Hitora, Yusaku Sadahiro, Masahiro Wato, Yuriko Nagano, Sachiko Tsukamoto.

  Mitochondrial dysfunction is not only a known cause of mitochondrial disease but has also been implicated in diabetes and neurodegenerative diseases. Therefore, modulating mitochondrial function may provide new insights into the treatment of these diseases. In this study, we used a cancer cell-based energy metabolism restriction model with a glycolytic inhibitor and screened a natural product library and a fungal extract library to identify natural products that improve mitochondrial function. Seven compounds, including quillaic acid (1) and 20-deoxyingenol (2), were identified as mitochondrial function modulators from the Selleck natural product library. Furthermore, an extract of a fungus, Trichoderma sp., from an in-house fungal extract library suppressed 2-deoxy-d-glucose-induced cell death. Bioassay-guided fractionation of the extract afforded seven known sorbicillinoids. Among them, bisvertinol (8) did not directly affect cellular energy metabolism but appeared to protect mitochondria from oxidative stress through its antioxidant properties.

Keywords:  2-Deoxy-d-glucose; Energy metabolism; Fungus; Mitochondrial modulator; Natural product; Trichoderma sp.

DOI:  https://doi.org/10.1016/j.bmc.2025.118478
Int J Mol Med. 2026 Jan;pii: 12. [Epub ahead of print]57(1):

β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review).

Xianyi Ding, Jiabin Wu, Lian Wang, Ke Li, Haoyang Gao, Mingyu Wu, Qiuyu Zhang, Ruonan Han, Wenhong Wang, Weihua Xiao.

  Type 2 diabetes mellitus (T2DM) is a major metabolic disease that poses a threat to human health; therefore, the development of new pharmaceutical therapies for the treatment of T2DM is of great importance. β‑hydroxybutyric acid (β‑HB) is the primary ketone body present in the human body. β‑HB not only serves as an energy substrate to maintain the metabolic homeostasis of the body but also acts as a signaling molecule, exerting multiple biological functions both inside and outside cells. The present review summarizes the research progress and latest findings of β‑HB in T2DM models from the perspective of metabolism, physiological effects and potential as a therapeutic agent. Research indicates that β‑HB exerts protective effects against T2DM by regulating glucose and lipid metabolism, preserving the integrity of pancreatic β‑cells and improving insulin resistance (IR). Additionally, β‑HB can alleviate the core pathological conditions of T2DM and related complications by enhancing the stability of cellular proteins, reducing oxidative stress and controlling inflammatory responses and endoplasmic reticulum stress (ERS), while regulating mitochondrial biogenesis, autophagy and apoptosis. Furthermore, the present review also describes the application of β‑HB in clinical research on T2DM. Research indicates that regulating β‑HB levels through endogenous and exogenous ketogenesis approaches can influence body weight, fasting blood glucose levels, IR and memory ability in T2DM patients. These results suggest that β‑HB is a potential metabolite for T2DM treatment.

Keywords:  ketone body; treatment; type 2 diabetes mellitus; β‑hydroxybutyric acid

DOI:  https://doi.org/10.3892/ijmm.2025.5683
J Ovarian Res. 2025 Nov 05. 18(1): 239

Role and mechanisms of plant polyphenols in ovarian aging.

Haojie Gong, Hongye Zhang, Yan Liu, Xiangbing Mao, Jianping Wang.

  The ovary is a vital organ in female animals, playing a crucial role in regulating reproductive and endocrine functions. Ovarian aging is characterized by declining oocyte quality and ovarian reserve quantity, ultimately leading to infertility and increased risk of age-related diseases. Oxidative stress, inflammation, endocrine disorders, and ovarian microenvironmental disruption are central mechanisms contributing to ovarian aging. Despite the growing incidence of delayed childbearing, there are limited effective interventions to preserve ovarian function. Plant polyphenols, a diverse group of naturally occurring compounds with potent biological activities, have emerged as promising candidates for improving ovarian function and reproductive health. However, a comprehensive synthesis of their classification, mechanisms of action, translational potential, and clinical application prospects remain lacking. In this review, we describe the mechanisms of ovarian aging, systematically classify plant polyphenols and summarize their specific bioactivities related to ovarian function. Furthermore, we highlight that these natural compounds have the potential to delay ovarian aging by alleviating oxidative stress, reducing inflammation, modulating hormone balance, and regulating gut microbiota. Consequently, they hold promise as a novel intervention strategy to mitigate the adverse outcomes of ovarian aging. While plant polyphenols hold considerable promise, several critical challenges remain unresolved, specifically inconsistent dosing regimens, poor bioavailability, and a lack of robust clinical validation. Overall, this review aims to provide a comprehensive overview of the protective roles and underlaying biological mechanisms of plant polyphenols in ovarian aging and propose future research directions for developing safe and effective plant polyphenol-based interventions for female reproductive longevity.

Keywords:  Gut microbiota; Inflammation; Ovarian aging; Oxidative stress; Plant polyphenols; Reproductive hormone

DOI:  https://doi.org/10.1186/s13048-025-01799-9
Metab Brain Dis. 2025 Nov 03. 40(8): 305

Coenzyme Q10 attenuates age-associated neurodegeneration via modulation of autophagy and neuroinflammation in aged rats.

Parisha Srivastava, Avnish Kumar Verma, Arun Kumar Yadawa, Syed Ibrahim Rizvi.

  This study investigates the neuroprotective potential of Coenzyme Q10 (CoQ10) in aging rats, with emphasis on its roles in modulating autophagy and reducing inflammaging. Male Wistar rats, both young (4 months) and aged (24 months), were orally administered CoQ10 at a dose of 20 mg/kg body weight for 28 days. Biochemical analysis revealed a significant enhancement in antioxidant defenses, as evidenced by elevated ferric reducing antioxidant power (FRAP), reduced glutathione (GSH), and increased activities of superoxide dismutase (SOD) and catalase (CAT). In parallel, levels of oxidative stress biomarkers-including malondialdehyde (MDA), advanced oxidation protein products (AOPP), protein carbonyls (PCO), and nitric oxide (NO)-were significantly reduced. CoQ10 supplementation also restored mitochondrial function, as indicated by increased activities of electron transport chain complexes in the brain. Gene expression analysis via reverse transcriptase-polymerase chain reaction (RT-PCR) showed up-regulation of autophagy markers Beclin-1 and ULK-1, alongside down-regulation of pro-inflammatory cytokines IL-6 and TNF-α, suggesting a reduction in neuroinflammation. Histopathological analysis supported these findings, demonstrating improved structural integrity of brain cells in CoQ10-treated rats. Overall, these results indicate that CoQ10 exerts multifaceted neuroprotective effects through enhancement of antioxidant defenses, restoration of mitochondrial function, activation of autophagy, and suppression of inflammation, thereby offering a promising intervention to mitigate age-associated neurodegeneration.

Keywords:  Aging; Autophagy; Coenzyme Q10 ; Inflammaging; Neuroprotection

DOI:  https://doi.org/10.1007/s11011-025-01721-8
Ecotoxicol Environ Saf. 2025 Oct 15. pii: S0147-6513(25)01618-5. [Epub ahead of print]305 119273

Melatonin mitigates polystyrene nanoplastics-induced impairment of oocyte maturation in mice.

Jingwen Qu, Wen Cai, Yajun Lu, Danhua Pu, Rongrong Tan, Jie Wu.

  The widespread contamination of polystyrene nanoparticles (PS-NPs) has emerged as a significant global concern due to its potential threats to human and animal health. Although the toxicity of PS-NPs to ovarian function has been established, how to relieve the damage of PS-NPs to oocyte maturation remains elusive. Since melatonin (MLT) plays an essential role in regulating ovarian function. This study is the first attempt to explore the protective roles of melatonin in counteracting the maturation defects of oocytes caused by PS-NPs exposure. In this investigation, the reproductive toxicity of PS-NPs was evaluated after continued exposure for 35 days. After exposure, cumulus oocyte complexes (COCs) obtained from PS-NPs exposed-mice were cultured in vitro, meanwhile the various concentration MLT were supplemented into the culture medium to determine the beneficial roles. The results revealed that PS-NPs exposure could impede the meiotic progression, fertilization competence and subsequent embryonic development of oocytes. These impairments are likely mediated through multiple mechanisms, including excessive ROS generation, reduced ATP contents, mitochondrial dysfunction and subsequent induction of early apoptosis. Besides, PS-NPs exposure was found to compromise the architecture of spindle and the alignment of chromosome via altering the key epigenetic markers (tubulin-ace and H4K12ac). Notably, these adverse effects could be alleviated after MLT administration. Further analysis demonstrated that MLT supplementation significantly enhanced antioxidant capacity and mitochondrial dynamics, which indicated by enlarged the mRNA expression levels of anti-oxidative enzyme and mitochondrial dynamics-related genes. In conclusion, MLT could rescue PS-NPs-induced oocyte quality decline by ameliorating oxidative stress, restoring mitochondrial function, and normalizing epigenetic modifications.

Keywords:  Epigenetic modifications; Melatonin; Oocyte quality; Oxidative stress; PS-NPs

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119273
J Intensive Care. 2025 Nov 04. 13(1): 61

Heat stress-induced mitochondrial damage and its impact on leukocyte function.

Toshiaki Iba, Julie Helms, Isao Nagaoka, Ricard Ferrer, Jerrold H Levy.

  Heatstroke is characterized by systemic inflammation, immune dysregulation, and multiorgan failure, in which mitochondrial damage in leukocytes plays a pivotal role. This review examines the mechanisms by which heat stress induces leukocyte mitochondrial dysfunction and its downstream effects on immunity, coagulation, and organ integrity. Exposure to heat stress activates leukocytes through damage-associated molecular patterns (DAMPs), triggering the release of proinflammatory cytokines, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs). These responses disrupt endothelial integrity, promote microvascular thrombosis, and contribute to the development of disseminated intravascular coagulation (DIC). Prolonged heat exposure further shifts the immune landscape toward immunosuppression, marked by monocyte deactivation and lymphocyte apoptosis. Mitochondrial dysfunction is central to this biphasic immune response. Heat stress reduces mitochondrial membrane potential, increases ROS production, and promotes the release of mitochondrial DNA and cytochrome c, amplifying inflammation and initiating cell death pathways, including apoptosis, pyroptosis, and ferroptosis. Biomarkers such as reduced mitochondrial membrane potential (ΔΨm), elevated mitochondrial ROS, cytochrome c, circulating mitochondrial DNA (mtDNA), and altered expression of mitophagy regulators (e.g., PINK1 and Parkin) provide insights into mitochondrial integrity and function in leukocytes. In addition to immune disruption, mitochondrial injury exacerbates coagulation abnormalities by promoting platelet activation and endothelial dysfunction, fostering a prothrombotic environment. In the microcirculation, leukocyte adhesion, NET formation, and endothelial damage create a self-amplifying cycle of ischemia and inflammation, ultimately leading to organ dysfunction, including hepatic failure, acute kidney injury, acute lung injury, and gastrointestinal barrier breakdown. Therapeutic strategies aimed at preserving mitochondrial function include antioxidants (e.g., N-acetylcysteine and MitoQ), mitochondrial biogenesis inducers (e.g., PGC-1α activators), and mitophagy enhancers. Understanding the central role of leukocyte mitochondrial damage in heat stress provides a foundation for the development of targeted diagnostics and interventions to prevent organ failure and improve clinical outcomes.

Keywords:  Cell death; Heat stress; Leukocyte; Mitochondria; Organ dysfunction

DOI:  https://doi.org/10.1186/s40560-025-00832-9
Biol Sex Differ. 2025 Nov 06. 16(1): 90

Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice.

Haichang Luo, Ezequiel Marron Fernandez de Velasco, Jaeyoon Kim, Praseuth Yang, Paul Mermelstein, Joseph V Bonventre, Paul S Cooke, Kevin Wickman.

   BACKGROUND: Amyloid β oligomers (oAβ) are a key pathogenic driver in Alzheimer's Disease (AD). Neuronal G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels are important regulators of neuronal excitability and prominent somatodendritic effectors for inhibitory G protein-coupled receptors, including the γ-aminobutyric acid type B receptor (GABABR). We previously reported a male-specific suppression of GIRK channel activity in hippocampal (HPC) neurons evoked by oAβ in in vitro, ex vivo, and in vivo mouse models of AD, and showed that this adaptation correlated with synaptic and cognitive impairment. Using pharmacological approaches, we showed that this adaptation is mediated by co-activation of cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5) and requires activation of cytosolic phospholipase A2 α (cPLA2α). However, the mechanisms underlying the sex specificity was unknown. Given the clinical context that females exhibit a 2-fold higher incidence of AD than males, and the loss of neuroprotective estrogen by menopause contributes to the sex differences in AD, we postulated that estrogen-associated resilience underlies this sex dimorphism of oAβ action.
METHODS: To examine the strength of GIRK-dependent signaling in HPC neurons, we performed electrophysiology in primary HPC cultures from neonatal male and female mice and then measured whole-cell currents evoked by the direct-acting GIRK channel agonist ML297 and the GABABR-selective agonist baclofen. We used an array of genetic and pharmacological approaches to investigate the molecular mechanism(s) underlying the vulnerability and resilience of GIRK channel activity to oAβ in male and female HPC neurons, respectively.
RESULTS: We found that resilience to the oAβ-induced and PrPC/mGluR5-dependent suppression of GIRK channel activity in female HPC neurons is conferred by membrane-associated estrogen receptor α (mERα) and caveolin 1 (Cav1). When this resilience factor is blocked or absent, oAβ suppresses GIRK channel activity in female HPC neurons via the same PrPC-mGluR5-cPLA2α signaling pathway identified previously in male neurons.
CONCLUSION: As estrogen levels decline with aging and menopause, the protective influence of mERα/Cav1 may diminish, unmasking the oAβ-induced suppression of GIRK channel activity and exacerbating disease progression in females. While amyloid β plaques (Aβ) are notable hallmarks of Alzheimer's Disease (AD), cognitive impairment in the early stages of the disease tracks more closely with the level of soluble Aβ oligomers (oAβ) in the brain. oAβ promotes cognitive deficits by disrupting the balance of excitatory and inhibitory influences on neurons in brain regions important for learning and memory such as the hippocampus, but the underlying molecular targets of oAβ and its pathogenic mechanisms are not fully understood. We recently demonstrated that oAβ weakens the activity of a prominent inhibitory influence on neuronal excitability (the GIRK channel) in the hippocampus of male but not female mice. This sexually dimorphic effect of oAβ was interesting and unexpected given that women are twice as likely to develop AD than men, and because disease progression is more aggressive in women. In this study, we investigated the mechanisms underlying the resilience of GIRK channels in female hippocampal neurons to oAβ. We found that resilience is conferred by estrogen and one of its receptors. When the influence of this receptor is diminished using pharmacological or genetic interventions, oAβ weakens GIRK channel activity in female and male neurons to a similar degree, and via the same mechanism. We speculate that with the onset of menopause, the protective influence of estrogen on GIRK channel activity in the hippocampus begins to wane. This, combined with other female-specific effects of oAβ on neuronal activity, contributes to the increased incidence and severity of AD in females.

Keywords:  Alzheimer’s disease; Estrogen; Kir3; Sex difference; cPLA2α2α; mGluR5

DOI:  https://doi.org/10.1186/s13293-025-00776-7
Front Physiol. 2025 ;16 1671926

Effects of exercise training on skeletal muscle mitochondrial outcomes in type 2 diabetes: a systematic review and meta-analysis.

Wenning Zhu, Zhangxu Zhou, Jingyao Sun, Juncheng Si.

   Background: Skeletal muscle mitochondrial dysfunction is a key driver of insulin resistance and disease progression in type 2 diabetes mellitus (T2DM), while exercise training has shown potential to improve mitochondrial function. However, existing studies focus on single exercise modalities, lack systematic synthesis of mitochondrial mechanisms, and exhibit conflicting results, highlighting the need for a comprehensive meta-analysis.
Methods: Systematic searches were conducted in PubMed, Web of Science, and Scopus for studies involving T2DM patients (≥40 years) with exercise as the primary intervention and mitochondrial outcomes. Methodological quality was assessed via the TESTEX scale, with meta-analysis performed using Stata 17.0.
Results: A total of 18 studies (394 participants, 272 in training groups) were included. Exercise significantly enhanced mitochondrial oxidative capacity (SMD = 0.61, 95% CI [0.30, 0.92], driven by citrate synthase [CS] and COX-II), antioxidant capacity (SMD = 1.18, 95% CI [0.50, 1.86], mainly via SOD2), and fusion marker MFN2 (SMD = 0.96, 95% CI [0.63, 1.29]). It tended to increase mitochondrial content (SMD = 0.50, p = 0.091) but with no significant mtDNA/PGC-1α changes. Effective modalities included long-term moderate aerobic training, short-term HIIT, and long-term resistance/combined training. Antidiabetic medications' potential interference was underassessed.
Conclusion: Moderate-to-high intensity exercise selectively improves skeletal muscle mitochondrial function in T2DM, particularly oxidative capacity (via CS/COX-II), antioxidant capacity (via SOD2), and mitochondrial fusion (via MFN2). The effect on mitochondrial content is non-significant, and the influence of antidiabetic medications requires further investigation.
Systematic Review Registration: Identifier CRD42024579581.

Keywords:  exercise training; meta-analysis; mitochondrial function; skeletal muscle; type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fphys.2025.1671926
Ann Med. 2025 Dec;57(1): 2578729

Sestrins: a new therapeutic target for endothelial dysfunction and cardiovascular disease prevention.

Cheng Li, Xu Zhang.

   BACKGROUND: Sestrins are a highly conserved family of proteins that have garnered significant attention for their critical roles in regulating cellular stress responses, antioxidative defense, energy metabolism, and cell survival. Endothelial dysfunction, a pivotal early event in the development of cardiovascular diseases (CVDs), is strongly associated with oxidative stress, inflammation, and disruption of vascular homeostasis.
FINDINGS: Recent studies have demonstrated that Sestrins contribute to maintaining endothelial cell integrity by mitigating oxidative stress, modulating inflammatory signaling, and promoting cellular adaptation through the regulation of key pathways such as AMPK/mTOR and autophagy. Experimental evidence from cardiovascular disease models suggests that upregulation of Sestrins can improve endothelial function and attenuate vascular damage, highlighting their involvement in vascular protection and disease modulation.
CONCLUSIONS: Sestrins emerge as promising therapeutic targets for the prevention and treatment of endothelial dysfunction and cardiovascular diseases. This review underscores the potential of Sestrins in vascular biology and advocates for further research to elucidate their mechanisms and clinical applicability in cardiovascular medicine.

Keywords:  Sestrins; cardiovascular diseases; endothelial dysfunction; oxidative stress

DOI:  https://doi.org/10.1080/07853890.2025.2578729
Prev Nutr Food Sci. 2025 Oct 31. 30(5): 488-501

Metabolic Biomarkers for Lifespan Extension and Cellular Stress in Saccharomyces cerevisiae during Calorie Restriction and Quercetin Treatment.

Min-Young Mun, Ji-Sue Lee, Eun-Hee Kim, Young-Shick Hong.

  As life expectancy increases, age-related diseases pose significant challenges in modern medicine. The molecular mechanisms of aging have been widely explored in mice, nematodes, human cells, and yeast. The budding yeast Saccharomyces cerevisiae has become the most widely employed eukaryotic model due to its short lifespan and well-characterized genetic and molecular profiles. However, research into the metabolite perturbations associated with lifespan extension has tended to focus on mutant or engineered yeast cells, and information regarding these processes in normal yeast cells remains scant. In this study, therefore, we investigated how aging affects the intracellular metabolites of S. cerevisiae during its growth and how these changes relate to lifespan extension induced by calorie restriction (CR) and quercetin treatment using a 1H nuclear magnetic resonance (NMR)-based metabolomic approach. The results revealed clear relationships between intracellular metabolites and aging, CR, and quercetin treatment in yeast cells. The intracellular trehalose levels were found to increase with aging, CR, and dimethyl sulfoxide (DMSO) treatment, indicating that yeast cells activate protective responses against cellular stress. Meanwhile, quercetin treatment was able to clear the metabolic stress caused by DMSO treatment. The treatment of both CR and quercetin significantly increased the intracellular proline levels, which are known to regulate mitochondrial function and decline with age. The findings of this study suggest that CR and quercetin promote the longevity of S. cerevisiae through a shared metabolic pathway and highlight intracellular trehalose and proline as potentially valuable biomarkers of cellular stress and longevity in yeast cells.

Keywords:  calorie restriction; longevity; metabolomics; quercetin; yeasts

DOI:  https://doi.org/10.3746/pnf.2025.30.5.488
Ann Med. 2025 Dec;57(1): 2583330

The auxiliary effect of oral nutritional supplements on fertility in women with diminished ovarian reserve: a systematic review and meta-analysis.

Xuanling Li, Qian Zhao, Guangyao Lin, Lianwei Xu.

   OBJECTIVE: Evaluate the adjuvant effects of oral nutritional supplements including vitamins, coenzyme Q10, and dehydroepiandrosterone (DHEA) on fertility in patients with diminished ovarian reserve (DOR).
METHODS: We conducted a generalized explore of 9 databases established as of September 1, 2024. Mainly studing and analyzing outcomes including serum follicle stimulating hormone (FSH) levels, anti Mullerian hormone (AMH) levels, antral follicle count (AFC), retrieved oocytes, and clinical pregnancy rate with the methodology of a systematic review and meta-analysis. The inclusion quality of each experiment was evaluated through the Newcastle Ottawa Scale (NOS).
RESULTS: The meta-analysis consisted of 16 studies with 2773 participants. A review of existing evidence suggested that oral nutritional supplements, including vitamins, coenzyme Q10, and DHEA, could significantly lower FSH levels (SMD = -0.67, 95% CI [-0.94, -0.40], p < 0.0001), rise AMH levels (SMD = 0.35, 95% CI [0.02, 0.69], p = 0.04), AFC counts (MD = 0.99, 95% CI [0.28, 1.69], p = 0.006), retrieved oocyte counts (MD = 0.88, 95% CI [0.54, 1.23], p < 0.0001), and clinical pregnancy rate (OR = 1.70, 95% CI = [1.35, 2.13], p < 0.0001). Oral nutritional supplements for more than 2 months have a better effect on lowering FSH levels, raising AMH levels, and oocyte numbers (p < 0.05). In addition, we found that the use of coenzyme Q10 alone was more effective than the use of DHEA alone through subgroup analysis. There was a remarkable correlation (p < 0.05) between the use of both nutritional supplements and the decrease of FSH, as well as the increase of AMH, AFC, and oocytes retrieved. We used sensitivity analysis to conclude that our summary results are robust.
CONCLUSIONS: Oral nutritional supplements, including vitamins, coenzyme Q10, and DHEA may be a simple and relatively low-risk treatment option to assist in improving fertility in women with DOR.
REGISTRATION NUMBER: CRD42024580831.

Keywords:  Auxiliary effect; diminished ovarian reserve; fertility; meta-analysis; oral nutritional supplements; review

DOI:  https://doi.org/10.1080/07853890.2025.2583330
Front Endocrinol (Lausanne). 2025 ;16 1682231

Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan.

Angel A Lee, Laura J Den Hartigh.

  The aged population, expected to double by 2050, makes up a large proportion of people living with metabolic disease. Obesity rates in the elderly are rapidly increasing, with estimates that nearly 40% of men and women over the age of 60 are classified as obese. White adipose tissue (WAT) is a highly metabolically active organ that undergoes significant changes during both obesity and aging, and metabolic dysfunction in WAT is a major cause for elevated diabetes risk. A marked difference in fat distribution is often reported between men and women. Many studies suggest that pre-menopausal women are protected from the accumulation of visceral adiposity due to gonadal estrogen, which exerts cardiometabolic benefits. Men with obesity harbor a disproportionately higher volume of intra-abdominal fat than premenopausal age-matched women with obesity, an effect that is negated by menopause as women begin to gain intra-abdominal fat. Post-menopausal women are at increased risk of developing diabetes, which can be mitigated by estrogen replacement therapy, suggesting an important role for sex steroids in diabetes risk. In addition to being highly responsive to gonadal estrogens, WAT has the capacity to convert androgens into estrogens, which may similarly impact WAT distribution and metabolism. Estrogens, comprised primarily of estrone (E1) and estradiol (E2) within WAT, are biosynthesized from circulating androgens androstenedione (A4) and testosterone (T) by aromatase (CYP19A1), which is highly expressed in human and mouse adipose tissue. In post-menopausal women, WAT becomes the predominant source of estrogen production, with age-associated increases in WAT aromatase expression that are mirrored by obesity. In contrast to ovarian estrogen production, in which E2 is the predominant estrogen type, E1 tends to be the predominant estrogen post-menopause. To date, little is known about WAT-derived estrogens and their impact on metabolic health, but emerging evidence suggests that increased E1 levels may contribute to metabolic dysfunction in aging. This review will introduce known sex differences in adipose metabolism associated with aging, obesity, and diabetes, and discuss the impact of WAT-derived sex hormones on local and systemic metabolism.

Keywords:  adipocyte; aromatase; estradiol; estrone; menopause; obesity; sex hormones; sex steroids

DOI:  https://doi.org/10.3389/fendo.2025.1682231
Mol Brain. 2025 Nov 07. 18(1): 84

Cerebrolysin ameliorates ketamine-mediated anxiety and cognitive impairments via modulation of mitochondrial function and CREB/PGC-1α pathway.

Leila Hosseini, Nasrin Abolhasanpour, Fatemehsadat Seyedaghamiri, Parisa Hassanzadeh, Parviz Shahabi, Vida Mafikandi, Parinaz Kalejahi, Mojgan Rajabi, Zahra Shokri, Ali Fakhari.

  Schizophrenia is known as a complex and devastating mental disorder due to its profound impact on individuals, families, and society. Emerging evidence proposes that mitochondria play a central role in schizophrenia. Here, we investigated whether cerebrolysin (CBL) can alleviate anxiety-like behaviors and cognitive deficits through a mechanism involving the CREB/PGC-1α pathway. In this study, 30 male BALB/c mice were randomly assigned to three different groups: Control, Ketamine, and Ketamine + CBL. Intraperitoneal injection of ketamine was performed at 20 mg/kg for 14 consecutive days. CBL was delivered intraperitoneally at 2.5 mL/kg once daily for seven days, starting from the 8th day to the 14th day of the experiment. The novel object recognition and elevated plus-maze tests were used to assess episodic-like memory and anxiety, respectively. Hippocampal tissue was examined not only for alterations in mitochondrial activity, encompassing ATP production and levels of reactive oxygen species (ROS), but also for estimating CREB, p-CREB, and PGC-1α protein levels. Behavioral results indicated that treatment with CBL reversed anxiety-like behavior and cognitive dysfunction caused by ketamine. Additionally, ketamine increased the production of ROS and reduced ATP levels in the hippocampus, while CBL treatment restored these changes. Furthermore, CBL therapy upregulated the hippocampal expression of the proteins CREB, p-CREB, and PGC-1α compared with the ketamine-treated animals. It is speculated that treatment with CBL can attenuate ketamine-induced cognitive deficits and anxiety-like behaviors through the upregulation of the CREB/PGC-1α pathway and the improvement of mitochondrial function.

Keywords:  Anxiety; Cerebrolysin; Memory; Mitochondrial function; Schizophrenia

DOI:  https://doi.org/10.1186/s13041-025-01255-1
Diabetes Res Clin Pract. 2025 Oct 31. pii: S0168-8227(25)00995-7. [Epub ahead of print] 112981

Effects of carnitine supplementation on glycemic markers in women with overweight and obesity: A systematic review and meta-analysis of randomized controlled trials.

Huiyu Liu, Hongjun Zhang, Bin Zhao, Kousalya Prabahar, Hamed Kord-Varkaneh, Xia Liu.

  Women with overweight or obesity face heightened risks of insulin resistance, metabolic syndrome, and type 2 diabetes. L-carnitine, a key mediator of mitochondrial fatty acid transport, has been proposed to improve glycemic regulation, yet evidence in this subgroup remains unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of carnitine supplementation versus placebo on glycemic markers in overweight or obese women. Major databases were searched through October 2025. Weighted mean differences (WMDs) with 95 % confidence intervals (CIs) were calculated using random-effects models. Predefined subgroup analyses explored dose and intervention duration effects. A total of eight studies comprising nine randomized controlled trial (RCT) arms were included. Carnitine supplementation significantly reduced fasting blood sugar (FBS; WMD -2.93 mg/dL, 95 % CI -5.20 to -0.65), fasting insulin (WMD -3.54 μU/mL, 95 % CI -7.00 to -0.07), and HOMA-IR (WMD -0.69, 95 % CI -1.26 to -0.13), but had no significant effect on QUICKI. Subgroup analyses indicated stronger effects at higher doses (≥2000 mg/day) and longer durations (≥12 weeks). Sensitivity analyses confirmed the robustness of findings, with no evidence of publication bias. Carnitine supplementation yields modest but clinically meaningful improvements in fasting glucose, insulin levels, and insulin resistance among overweight and obese women, particularly with higher dosages and longer interventions. These results highlight carnitine's potential as an adjunctive nutritional strategy.

Keywords:  Carnitine; Fasting blood sugar; HOMA-IR; Insulin resistance; Obesity; QUICKI; Women

DOI:  https://doi.org/10.1016/j.diabres.2025.112981
Nat Metab. 2025 Nov 04.

Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.

Daniel Barnett, Till S Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M Meadows, Haopeng Xiao, Man Ying Wong, Wenjie Luo, Li Gan, Edward T Chouchani, Anna G Orr, Adam L Orr.

Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.

DOI: https://doi.org/10.1038/s42255-025-01390-y
Front Aging Neurosci. 2025 ;17 1630982

Stressors-induced cognitive dysfunction during aging: mechanisms and future challenges.

Yizhe Zhang, Xiao Zhang, Jiaxi Guo, Wanbing Dai, Sifan Chen, Lili Huang, Xuwu Xiang, Weifeng Yu, Diansan Su.

  Stressful events can lead to transient impairments in learning and memory, a phenomenon more pronounced in the elderly. As global life expectancy rises, the shift toward an aging society underscores the urgent need for effective preventive strategies against stress-induced cognitive dysfunction. Elucidating its pathogenesis is essential for developing neuroprotective interventions and mitigating medical and societal impacts. In this study, male C57BL/6 mice aged 2 and 18 months were subjected to restraint stress (2 h/day for 14 days). Spontaneous activity and anxiety-like behavior were evaluated using the open field test, and cognitive performance was assessed via the novel object recognition test. mRNA sequencing revealed differentially expressed genes, which were further analyzed using Gene Ontology enrichment through the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. Key molecular findings were validated by Quantitative Polymerase Chain Reaction (RT-qPCR), Western blot, and immunofluorescence. Additionally, a literature review was conducted to identify emerging research directions. Our results reveal that aged mice exhibit impaired upregulation of protective Endoplasmic Reticulum (ER) stress genes and show downregulation of mitochondrial expression and translation pathways, in contrast to young mice in which stress primarily upregulated genes involved in mitochondrial organization and Adenosine Triphosphate (ATP) metabolism. These age-specific vulnerabilities highlight ER stress and mitochondrial dysfunction as potential intervention targets.

Keywords:  ER stress; aging; cognitive dysfunctions; mitochondria; stress

DOI:  https://doi.org/10.3389/fnagi.2025.1630982
Metab Brain Dis. 2025 Nov 06. 40(8): 310

Bicyclol improves cognition deficits and inhibits oxidative stress-induced neuronal cell apoptosis in alzheimer's disease via Nrf2/HO-1 pathway.

Shuyue Li, Ya Gao, Xiangjian Zhang, Jiadong Lang, Xiang Liu, Yidan Zhang, Jian Zhang, Yuan Zhao, Cui Chang, Xuan Gao, Jin Zhou, Donghua Yu, Guofeng Yang.

  Alzheimer's disease (AD) is identified as the prevalent neurodegenerative condition globally, ultimately resulting in dementia. Currently, the mechanisms that contribute to AD are not well comprehended, and there are few therapeutic alternatives available. Bicyclol, a substance extracted from the Chinese herb Schisandra Chinensis, has shown remarkable antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective characteristics. However, there is a shortage of research focusing on the therapeutic effects of bicyclol on AD as well as the molecular pathways that may be involved. This study sought to evaluate the effects of bicyclol on cognitive impairments in a mouse model of AD, explore its neuroprotective benefits associated with antioxidant functions and apoptosis suppression, and reveal the mechanisms involved. In this study, APP/PS1 mice underwent a 2-month treatment with bicyclol administered via gavage, after which their cognitive abilities were evaluated through behavioral assessments. The apoptosis of cortical neurons was evaluated using TUNEL staining and immunofluorescence techniques. N2A cells, which were exposed to Aβ1-42 oligomers, received a pretreatment with bicyclol, and their viability was subsequently measured. The expression levels of proteins such as nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P) H-quinine oxidoreductase-1 (NQO1), BCL2 associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2), and Cleaved caspase-3 were quantified in vitro and in vivo using western blotting and qPCR methods. Moreover, N2A cells lacking Nrf2 were utilized to investigate the underlying mechanisms through which bicyclol exerts its effects in Alzheimer's disease. Bicyclol has been shown to enhance cognitive function while simultaneously reducing the levels of cortical Aβ1-40 and Aβ1-42, and it also protects against neuronal degeneration in the APP/PS1 mouse model. Moreover, it increases the activity of cortical SOD and GSH-Px, concurrently decreasing levels of ROS and MDA in vivo. Additionally, bicyclol significantly lessened oxidative stress and apoptosis induced by Aβ1-42 in N2A cells. It further elevated the expression of proteins such as Nrf2, HO-1, and NQO1, along with mRNA levels in both in vitro and in vivo experiments. Furthermore, the silencing of Nrf2 via siRNA transfection counteracted the regulatory effects of bicyclol on apoptotic markers including Bax, Bcl-2, and Cleaved caspase-3 in vitro. Our study provides compelling evidence that bicyclol effectively alleviates cognitive impairments observed in APP/PS1 mice. Furthermore, our findings indicate that bicyclol plays a significant role in reducing oxidative stress-induced injury and neuronal apoptosis. This protective effect is associated with the activation of the Nrf2/HO-1 signaling pathway. These results suggest that bicyclol has the potential to be developed as a therapeutic agent for the treatment of Alzheimer's disease, highlighting its promise in addressing the cognitive decline associated with this debilitating condition.

Keywords:  Alzheimer’s disease; Apoptosis; Bicyclol; Nrf2/HO-1; Oxidative stress

DOI:  https://doi.org/10.1007/s11011-025-01738-z
JAMA Psychiatry. 2025 Nov 05.

Ketogenic Diets and Depression and Anxiety: A Systematic Review and Meta-Analysis.

Reinhard Janssen-Aguilar, Tulassi Vije, Malika Peera, Huda F Al-Shamali, Shakila Meshkat, Qiaowei Lin, Wendy Lou, Hugo Laviada-Molina, Mary L Phillips, Venkat Bhat.

Importance: Ketogenic diets (KDs) have been hypothesized to influence mental health through pathways involving mitochondrial function, inflammation, and neurotransmitters, but their therapeutic value in psychiatric populations remains uncertain.
Objective: To assess the associations between KDs and mental health outcomes in adults, with a focus on depressive and anxiety symptoms.
Data Sources: MEDLINE, Embase, and APA PsycINFO were searched on April 18, 2025. Additional studies were identified through manual searches and clinical trial registries.
Study Selection: Studies involving adults aged 18 years or older receiving a KD (<26% energy from carbohydrates or <50 g/day) and assessed with validated psychiatric scales were eligible. Designs included randomized clinical trials (RCTs), quasi-experimental (QSE) studies, cross-sectional studies, case series, and case reports.
Data Extraction and Synthesis: Data were extracted by 1 reviewer and verified by 2 others. Risk of bias was assessed using critical appraisal tools from the Joanna Briggs Institute. Random-effects meta-analyses were run separately for RCTs and QSEs.
Main Outcomes and Measures: The primary outcome was changes in psychiatric symptom severity measured by standardized scales, reported as standardized mean differences (SMDs) or standardized mean change using change scores (SMCCs).
Results: A total of 50 studies (41 718 participants) were included. Ten RCTs on KD for depressive symptoms vs control diets showed a significant association (SMD, -0.48; 95% CI, -0.87 to -0.10; I2 = 67.2%), with stronger associations in studies using ketone monitoring, nonobese participants, very low-carbohydrate interventions, and non-high-carbohydrate comparators. Nine RCTs on anxiety showed no significant association (SMD, -0.03; 95% CI, -0.18 to 0.12; I2 = 41%). In QSEs, 9 on depressive symptoms showed a consistent association (SMCC, -0.66; 95% CI, -0.83 to -0.50; I2 = 0%), and 6 on anxiety showed similar results (SMCC, -0.58; 95% CI, -0.81 to -0.36; I2 = 0%).
Conclusions and Relevance: In this systematic review and meta-analysis, KDs were associated with modest improvements in depressive symptoms, particularly with biochemical ketosis verification, while anxiety evidence was inconclusive. Given heterogeneity, comparators, and short follow-up, well-powered trials with standardized, verified protocols, structured support, and prespecified outcomes are needed to confirm efficacy and durability.

DOI: https://doi.org/10.1001/jamapsychiatry.2025.3261
PeerJ. 2025 ;13 e20168

Diagnostic and prognostic implications of growth differentiation factor 15 in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

Iwan Dakota, Matthew Aldo Wijayanto, Annisa Salsabilla Dwi Nugrahani, Angela Felicia Sunjaya, Shela Rachmayanti, Enny Yuliana Indah, Natasya Naomi, Wilbert Huang, Christopher Daniel Tristan, Mira Fauziah, Hary Sakti Muliawan, Bambang Budi Siswanto.

   Background: Growth differentiation factor-15 (GDF-15), an emerging biomarker associated with chronic inflammation and oxidative stress, shows potential diagnostic and prognostic significance for heart failure with preserved ejection fraction (HFpEF). This study aimed to assess the diagnostic and prognostic value of GDF-15 in HFpEF.
Methods: Three databases (PubMed, Scopus, and ScienceDirect) were used to search for relevant literature published before August 6, 2024. Quality assessment was conducted using the Newcastle-Ottawa scale and its adaptation for cross-sectional studies. Statistical analysis was performed using RStudio version 4.4.1. All meta-analyses employed a random-effects model. Sensitivity analysis was conducted using the leave-one-out technique to evaluate the influence of individual studies on pooled estimates. This study protocol was registered in PROSPERO (CRD42024569609).
Results: A total of 5,696 HFpEF patients were identified from 28,193 individuals across 12 observational studies. GDF-15 levels were consistently elevated in HFpEF patients, with a pooled mean difference (MD) of 647.60 pg/mL (95% CI [148.43-1,146.77]; p = 0.01). Sensitivity analysis confirmed the robustness of this finding, with a slightly higher MD observed when studies involving HFpEF patients with atrial fibrillation were excluded. Qualitative analysis suggested that the overall diagnostic performance of GDF-15 in HFpEF is slightly superior to conventional biomarkers. GDF-15 showed a pooled area under the curve (AUC) of 0.82 (95% CI [0.72-0.91]), indicating good diagnostic accuracy. Additionally, GDF-15 was associated with increased risk of all-cause mortality and heart failure hospitalisation, with pooled hazard ratios (HR) of 1.46 (95% CI [1.30-1.62]; p < 0.01) and 1.76 (95% CI [1.30-2.38]; p < 0.01), respectively.
Conclusion: GDF-15 demonstrates significant diagnostic and prognostic potential for HFpEF. Elevated GDF-15 levels are associated with increased risk of all-cause mortality and heart failure hospitalisation.

Keywords:  Biomarker; Growth differentiation factor-15; Heart failure with preserved ejection fraction; Meta-analysis; Systematic review

DOI:  https://doi.org/10.7717/peerj.20168
Sci Adv. 2025 Nov 07. 11(45): eady9811

NAD+ reverses Alzheimer's neurological deficits via regulating differential alternative RNA splicing of EVA1C.

Ruixue Ai, Lipeng Mao, Xurui Jin, Carlos Campos-Marques, Shi-Qi Zhang, Junping Pan, Maria Jose Lagartos-Donate, Shu-Qin Cao, Beatriz Barros-Santos, Rita Nóbrega-Martins, Filippos Katsaitis, Guang Yang, Chenglong Xie, Xiongbin Kang, Pingjie Wang, Manuele Novello, Yang Hu, Linda Hildegard Bergersen, Jon Storm-Mathisen, Hidehito Kuroyanagi, Beatriz Escobar-Doncel, Noemí Villaseca González, Farrukh Abbas Chaudhry, Zeyuan Wang, Qiang Zhang, Guang Lu, Ioannis Sotiropoulos, Zhangming Niu, Guobing Chen, Rajeevkumar Raveendran Nair, Joana Margarida Silva, Oscar Junhong Luo, Evandro Fei Fang.

Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer's disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD+) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD+ enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD+ augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD+-induced memory retention is partially dependent on EVA1C, as adeno-associated virus-based Eva1c knockdown in the hippocampal CA1 region annuls NAD+-induced memory improvement in pathological Tau-bearing mice. We propose that NAD+ reduces AD pathologies, at least partially, via amplification of the NAD+-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.

DOI: https://doi.org/10.1126/sciadv.ady9811