bims-mistre 2025-05-25 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–05–25
28 papers selected by
Ellen Siobhan Mitchell, MitoQ

Targeting mitochondria with natural polyphenols for treating Neurodegenerative Diseases: a comprehensive scoping review from oxidative stress perspective.
Skeletal Muscle as a Mediator of Interorgan Crosstalk During Exercise: Implications for Aging and Obesity.
Age-Related Oxidative Stress and Mitochondrial Dysfunction in Lymph Node Stromal Cells Limit the Peripheral T Cell Homeostatic Maintenance and Function.
Ganoderma lucidum extract reduces skin aging by reducing mitochondrial stress and controlling mitochondrial numbers.
Succinate reduces biological activity and mitochondrial function of human adipose-derived stem cells.
How Do Mitochondria Manage Competing Biochemical Metabolic Processes Under Stress?
Hyperbaric Oxygen Increases Mitochondrial Biogenesis and Function with Oxidative Stress in HL-1 Cardiomyocytes.
The Conceivable Role of Metabolic Syndrome in the Pathogenesis of Alzheimer's Disease: Cellular and Subcellular Alterations in Underpinning a Tale of Two.
De novo serine biosynthesis is protective in mitochondrial disease.
Bisphenol A Induces Neuronal Apoptosis and Oxidative Stress Through TRPV4 Channel Signaling Pathways: Protective Role of Alpha-Lipoic Acid.
Peptide YY fragment PYY1-36 disrupts mitochondrial biogenesis via RBM43-dependent PGC-1α translation inhibition.
Hydroxytyrosol Inhibits BPS-Induced NF-κB Signaling Pathway Activation, Mitigates Oxidative Stress, and Reduces Neuronal Apoptosis.
Exploring the role of mitochondrial dysfunction and aging in COVID-19-Related neurological complications.
Hypercholesterolemia, oxidative stress, and low-grade inflammation: a potentially dangerous scenario to blood-brain barrier.
Apolipoprotein M delays the development of atherosclerosis by regulating autophagy and mitochondrial function.
Mitochondrial Electron Transfer Chain Activation in Atrophic Muscle: Implications for Calcium Signaling and Chondrocyte Apoptosis in Osteoarthritis.
SLC25A33-mediated mitochondrial DNA synthesis plays a critical role in the inflammatory response of M1 macrophages by contributing to mitochondrial ROS and VDAC oligomerization.
In silico screening of naturally derived dietary compounds as potential butyrylcholinesterase inhibitors for Alzheimer's disease treatment.
STING contributes to the inflammation and proliferation of Staphylococcus aureus via mitochondrial reactive oxygen species-hypoxic inducible factor 1α axis in epithelial cells.
Relationship troubles at the mitochondrial level and what it might mean for human disease.
Glycation in Alzheimer's Disease and Type 2 Diabetes: The Prospect of Dual Drug Approaches for Therapeutic Interventions.
A CoQ10 analog ameliorates cognitive impairment and early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation.
Schisandrin B ameliorates Alzheimer's disease by suppressing neuronal ferroptosis and ensuing microglia M1 polarization.
Effects of astaxanthin on the mechanisms involved in skeletal muscle lipid metabolism and oxidative stress in an experimental model of metabolic syndrome.
From powerhouse to modulator: regulating immune system responses through intracellular mitochondrial transfer.
Tea polyphenols and EGCG induce preeclampsia-like symptoms by reducing 2-methoxyestradiol.
Slow wave synchrony during NREM sleep tracks cognitive impairment in prodromal Alzheimer's disease.
Dissecting Metabolic Control of Behaviors and Physiology During Aging in Drosophila.

J Transl Med. 2025 May 23. 23(1): 572

Targeting mitochondria with natural polyphenols for treating Neurodegenerative Diseases: a comprehensive scoping review from oxidative stress perspective.

Yueyue Guan, Lei Li, Rui Yang, Yun Lu, Jun Tang.

  Neurodegenerative diseases are a class of conditions with widespread detrimental impacts, currently lacking effective therapeutic drugs. Recent studies have identified mitochondrial dysfunction and the resultant oxidative stress as crucial contributors to the pathogenesis of neurodegenerative diseases. Polyphenols, naturally occurring compounds with inherent antioxidant properties, have demonstrated the potential to target mitochondria and mitigate oxidative stress. This therapeutic potential has garnered significant attention in recent years. Investigating the mitochondrial targeting capacity of polyphenols, their role in functional regulation, and their ability to modulate oxidative stress, along with exploring novel technologies and strategies for modifying polyphenol compounds and their formulations, holds promise for providing new avenues for the treatment of neurodegenerative diseases.

Keywords:  Mitochondria; Neurodegenerative disease; Oxidative stress; Polyphenols

DOI:  https://doi.org/10.1186/s12967-025-06605-0
Circ Res. 2025 May 23. 136(11): 1407-1432

Skeletal Muscle as a Mediator of Interorgan Crosstalk During Exercise: Implications for Aging and Obesity.

Julia A Shero, Maléne E Lindholm, Marco Sandri, Kristin I Stanford.

  Physical exercise is critical for preventing and managing chronic conditions, such as cardiovascular disease, type 2 diabetes, hypertension, and sarcopenia. Regular physical activity significantly reduces cardiovascular and all-cause mortality. Exercise also enhances metabolic health by promoting muscle growth, mitochondrial biogenesis, and improved nutrient storage while preventing age-related muscle dysfunction. Key metabolic benefits include increased glucose uptake, enhanced fat oxidation, and the release of exercise-induced molecules called myokines, which mediate interorgan communication and improve overall metabolic function. These myokines and other exercise-induced signaling molecules hold promise as therapeutic targets for aging and obesity-related conditions.

Keywords:  cardiovascular diseases; epinephrine; hypertension; muscle, skeletal; sarcopenia

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325614
Aging Cell. 2025 May 21. e70100

Age-Related Oxidative Stress and Mitochondrial Dysfunction in Lymph Node Stromal Cells Limit the Peripheral T Cell Homeostatic Maintenance and Function.

Sandip Ashok Sonar, Ruchika Bhat, Heather L Thompson, Christopher P Coplen, Jennifer L Uhrlaub, Mladen Jergovic, Janko Ž Nikolich.

  Lymph nodes (LN) are the key organs in charge of long-term maintenance of naïve lymphocytes and their initial, primary activation upon infection. Accumulating evidence indicates that LN stromal cells undergo degenerative changes with aging that critically impair LN function, including the generation of protective primary immune responses. The nature of these defects remains incompletely understood. We here demonstrate that age-related LN stromal changes manifest themselves in mitochondrial dysfunction and oxidative stress. Ex vivo, all three major stromal cell subsets, fibroblastic reticular cells (FRC), lymphatic endothelial cells (LEC), and blood endothelial cells (BEC) exhibit elevated mitochondrial reactive oxygen species (ROS) stress, reduced mitochondrial potential, and elevated mitochondrial mass with aging. Old FRC also exhibited elevated cytoplasmic ROS production. This was accompanied by the reduced ability of old LN stromal cells to support Tn survival in vitro, a defect alleviated by pretreating old LN stroma with the general antioxidant N-acetyl cysteine (NAC) as well as by mitochondrial ROS-reducing (mitoquinone) and mitophagy-inducing (urolithin A) compounds. Mitochondrial dysfunction and, in particular, reduced mitochondrial potential in old FRC were also seen upon vaccination or infection in vivo. Consistent with these results, in vivo antioxidant treatment of old mice with NAC restored to adult levels the numbers of antigen-specific CD8+ effector T cells and their production of granzyme B in response to antigenic challenge.

Keywords:  T cell homeostasis; aging; lymph node stromal cells; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.1111/acel.70100
Fitoterapia. 2025 May 15. pii: S0367-326X(25)00252-7. [Epub ahead of print]184 106627

Ganoderma lucidum extract reduces skin aging by reducing mitochondrial stress and controlling mitochondrial numbers.

Han Wang, Meiling Tai, Wanzhao Li, Yawen Li, Zhimeng Zhang, Dongli Zhang, Lishe Gan, Junhao Li, Xiaojuan Song, Honghong Qiu, Manmei Li, Heyun Zhang, Zhong Liu.

  Mitochondrial dysfunction is one of the important signs of cellular and even individual aging. Ganoderma lucidum is a common edible and medicinal mushroom, widely used as a functional food in Asia. This study investigated the potential anti-aging effects of Ganoderma lucidum extract (GLE). Our results demonstrated that GLE alleviated cellular oxidative stress, reduced the abnormal increase of mitochondrial ROS in aging cells, and maintained mitochondrial membrane integrity and inner membrane potential. Additionally, GLE affected mitochondrial biogenesis in aging cells. In a murine photoaging model, GLE treatment mitigated UVA-induced mitochondrial dysfunction while markedly attenuating UVA-triggered epidermal thickening and dermal protein depletion. These properties may be interrelated with the presence of abundant triterpenoids identified by LC-MS analysis.

Keywords:  Ganoderma lucidum; Mitochondrial dysfunction; Photoaging; UVA

DOI:  https://doi.org/10.1016/j.fitote.2025.106627
Cell Cycle. 2025 May 20. 1-13

Succinate reduces biological activity and mitochondrial function of human adipose-derived stem cells.

Bo Wang, Xinxin Wang, Meijin Guo, Huiming Xu.

  Elevated succinate accumulation has been demonstrated to be associated with metabolic and inflammatory disorders. Our previous study revealed that adipose-derived stem cells (ADSC) from obese individuals exhibit high succinate, reduced biological activity, and mitochondrial dysfunction. However, the precise role of succinate in these processes remains unclear. Here, we investigated the effects of excess succinate on cellular biological activity, immunomodulatory capacity, and mitochondrial function of ADSC. We found that elevated succinate levels in ADSC decreased proliferation and differentiation potential, while promoting M1 macrophage polarization. Furthermore, succinate accumulation impaired mitochondrial biogenesis and metabolism, increasing in reactive oxygen species (ROS) production and inflammatory responses. Transcriptome sequencing analysis further confirmed that succinate upregulated inflammatory pathways, suppressed mitochondrial biogenesis and metabolism, and enhanced cellular apoptosis and senescence, accompanied by reduced DNA replication and repair. Overall, these findings imply that succinate accumulation in ADSC triggers inflammatory response and mitochondrial dysfunction, potentially contributing to a decline of cellular biological activity. Targeting succinate may offer therapeutic potential for metabolic disorders.

Keywords:  Succinate; adipose-derived stem cells; mitochondrial dysfunction; reduced biological activity

DOI:  https://doi.org/10.1080/15384101.2025.2508109
Curr Protein Pept Sci. 2025 May 16.

How Do Mitochondria Manage Competing Biochemical Metabolic Processes Under Stress?

Drew Hindrer, Tyler Stark, Selman Aydogdu, Cade Ward, Mohamed Eldeeb.



Keywords:  Mitochondrial fission; mitochondrial fusion; mitochondrial quality control.; mitochondrial stress; molecular metabolism; redox reactions

DOI:  https://doi.org/10.2174/0113892037381885250506091434
J Appl Physiol (1985). 2025 May 22.

Hyperbaric Oxygen Increases Mitochondrial Biogenesis and Function with Oxidative Stress in HL-1 Cardiomyocytes.

Ha-Yeong Young, Sunchul Lee, Yeo-Eun Choi, Sang-Hoon Nam, Seung-Kuy Cha, Yangsik Jeong, Hyun Kim, Tae-Min Shin, Kyu-Sang Park.

  Hyperbaric oxygen (HBO2) therapy has been used to treat various pathological conditions, including carbon monoxide poisoning and ischemia-reperfusion injury. However, the molecular mechanisms underlying these therapeutic effects remain unclear. We investigated HBO2-induced changes in mitochondrial function and biogenesis in a clonal cardiomyocyte cell line, HL-1. Cells were exposed to HBO2 (3 atmospheres, 2218 mmHg O2, 39 mmHg CO2) in a cell incubation chamber under controlled temperature and humidity conditions. Levels of reactive oxygen species (ROS), gene transcription and translation, mitochondrial membrane potential (ΔΨm), mitochondrial respiration, cellular ATP content, and spontaneous beating foci of HL-1 cells were measured. Exposure (2 or 6 h) to HBO2 increased the cytosolic and mitochondrial ROS production, followed by upregulation of stress responses, including growth differentiation factor 15 and fibroblast growth factor 21. HBO2 augmented antioxidant defence signalling through nuclear factor erythroid-2-related factor 2 and mitochondrial biogenesis through peroxisome proliferator-activated receptor-gamma coactivator-1α. HBO2 exposure also elevated mitochondrial oxygen consumption, ΔΨm, and ATP production. To assess cardiomyocyte function, live cell imaging was performed, and the findings demonstrated an increase in the number of beating clusters in HL-1 cells following exposure to HBO2. Notably, in HL-1 cells pre-treated with sublethal doses of mitochondrial electron transport chain inhibitors, further depolarisation of ΔΨm was observed after HBO2 exposure, implying exacerbation of mitochondrial dysfunction. Collectively, HBO2-induced oxidative stress enhances mitochondrial biogenesis and function, possibly through a stress-mediated response. However, in the presence of defective mitochondrial function, cells may not be able to overcome the stress caused by HBO2.

Keywords:  Cardiomyocytes; Hyperbaric oxygen; Mitochondrial biogenesis; Mitochondrial respiration; Reactive oxygen species; Stress response

DOI:  https://doi.org/10.1152/japplphysiol.00428.2024
Neuromolecular Med. 2025 May 16. 27(1): 35

The Conceivable Role of Metabolic Syndrome in the Pathogenesis of Alzheimer's Disease: Cellular and Subcellular Alterations in Underpinning a Tale of Two.

Ekremah A Alzarea, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Athanasios Alexiou, Marios Papadakis, Olivia N Beshay, Gaber El-Saber Batiha.

  Alzheimer's disease (AD)is an age-related neurodegenerative disease characterized by memory decline and cognitive impairment .AD is common in people aged > 65 years, though most of AD cases are sporadic, which accounts for 95%, and 1-5% of AD is caused by familial causes . The causes of AD are aging, environmental toxins, and cardiometabolic factors that induce the degeneration of cholinergic neurons. It has been shown that the metabolic syndrome which is a clustering of dissimilar constituents including insulin resistance (IR), glucose intolerance, visceral obesity, hypertension, and dyslipidemia is implicated in the pathogenesis of AD. Metabolic syndrome disapprovingly affects cognitive function and the development in AD by inducing the development of oxidative stress, neuroinflammation, and brain IR. These changes, together with brain IR, impair cerebrovascular reactivity causing cognitive impairment and dementia. Nevertheless, the fundamental mechanism by which metabolic syndrome persuades AD risk is not entirely explicated. Accordingly, this review aims to discuss the connotation between metabolic syndrome and AD. In conclusion, metabolic syndrome is regarded as a possible risk factor for the initiation of AD neuropathology by diverse signaling pathways such as brain IR, activation of inflammatory signaling pathways, neuroinflammation, defective proteostasis, and dysregulation of lipid mediators.

Keywords:  Alzheimer’s disease; Insulin resistance; Metabolic syndrome; Neuroinflammation

DOI:  https://doi.org/10.1007/s12017-025-08832-6
Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710

De novo serine biosynthesis is protective in mitochondrial disease.

Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.

  The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment

DOI:  https://doi.org/10.1016/j.celrep.2025.115710
Environ Toxicol. 2025 May 21.

Bisphenol A Induces Neuronal Apoptosis and Oxidative Stress Through TRPV4 Channel Signaling Pathways: Protective Role of Alpha-Lipoic Acid.

Ramazan Çinar, Mustafa Nazıroğlu.

  Bisphenol A (BPA), an environmental toxin, exerts adverse effects by increasing mitochondrial (mROS) and intracellular (iROS) reactive oxygen species, apoptosis, and Ca2+ influx in neurological diseases. However, antioxidants can mitigate these detrimental effects. This study aimed to investigate the protective role of antioxidant alpha-lipoic acid (ALA) against BPA-induced TRPV4 channel stimulation, oxidant, and apoptotic changes in SH-SY5Y neuronal cells. Five experimental groups were established: control, ALA, BPA, BPA + ALA, and BPA + TRPV4 antagonist (ruthenium red, RuR). BPA increased excessive Ca2+ influx and TRPV4 current density, while BPA- and TRPV4 agonist (GSK1016790A)-induced TRPV4 stimulations were downregulated following incubation with ALA and RuR. BPA-induced increases in oxidant markers (lipid peroxidation, mROS, iROS), apoptotic markers (caspase-3, -8, and -9), Zn2+, and cell death were reduced by ALA and RuR treatment. Conversely, BPA-induced reductions in cell viability, glutathione, and glutathione peroxidase levels were restored following treatment. In summary, ALA attenuated BPA-induced excess Ca2+ influx, Zn2+ accumulation, apoptosis, and oxidative neurotoxicity via TRPV4 inhibition. Therefore, ALA may offer protection against BPA-induced neuronal cell death associated with oxidative neurotoxicity.

Keywords:  TRPV4 channel; alpha‐lipoic acid; apoptosis; bisphenol A; oxidative neurotoxicity

DOI:  https://doi.org/10.1002/tox.24541
Invest New Drugs. 2025 May 22.

Peptide YY fragment PYY1-36 disrupts mitochondrial biogenesis via RBM43-dependent PGC-1α translation inhibition.

Benkun Liu, Fucheng Zhou, Bowen Shi, Yubo Yan, Yanbo Wang, Junfeng Wang, Yaoguo Lang, Shidong Xu.

  Mitochondrial dysfunction is a key driver of cancer progression, with therapies increasingly targeting metabolic weaknesses. Peptide YY (PYY), a gastrointestinal hormone, regulates cellular activity, but its influence on mitochondrial health in lung cancer remains poorly understood. We explored how PYY1-36, a bioactive fragment of PYY, affects mitochondrial stability in NCI-H1581 lung cancer cells. Using dose-response experiments, we measured oxidative stress by tracking lactate dehydrogenase (LDH) release, mitochondrial ROS levels, and oxidative DNA damage (8-OHdG). Energy production was evaluated through ATP levels, oxygen consumption rates (OCR), and Complex I activity. We also analyzed mitochondrial biogenesis markers (NRF1, TFAM, PGC-1α) and the RNA-binding protein RBM43 via qPCR and immunoblotting. Dose-dependent tests showed that PYY1-36 triggers mitochondrial oxidative damage, marked by higher LDH release and ROS spikes. These changes aligned with sharp drops in ATP production and disrupted respiratory function. Notably, PYY1-36 reduced mitochondrial mass and biogenesis, supported by weaker MitoTracker Red signals and lower mtDNA/nDNA ratios. Key regulators NRF1 and TFAM were strongly suppressed, pointing to widespread mitochondrial failure. Intriguingly, PYY1-36 blocked PGC-1α protein synthesis without altering mRNA levels, suggesting a post-transcriptional control mechanism. PYY1-36 also boosted RBM43 levels. Knocking down RBM43 reversed PYY1-36's effects on PGC-1α and mitochondrial health. Our findings reveal RBM43 as a central player in PYY1-36-induced mitochondrial dysfunction through its suppression of PGC-1α translation. Targeting RBM43 could unlock new strategies to tackle metabolic chaos in lung cancer.

Keywords:  Lung Cancer; Mitochondrial Biogenesis; PGC-1α; PYY1-36; RBM43

DOI:  https://doi.org/10.1007/s10637-025-01545-4
J Biochem Mol Toxicol. 2025 Jun;39(6): e70303

Hydroxytyrosol Inhibits BPS-Induced NF-κB Signaling Pathway Activation, Mitigates Oxidative Stress, and Reduces Neuronal Apoptosis.

Hongyu Zhang, Guoshun Lin, Yang Yang, Yifei Wang, Xiushuo Yang, Guige Hou, Zhenbo Wang, Qingguo Meng, Yun Hou.

  Hydroxytyrosol (HT), a primary phenolic compound in olive oil, exhibits antioxidant and antiapoptotic effects in various cell types, including cardiomyocytes and human umbilical vein endothelial cells. Contrastingly, bisphenol S (BPS) is known to induce apoptosis in myocardial and endothelial cells via oxidative stress. BPS increases reactive oxygen species (ROS) production and reduces the viability of hippocampal HT22 cells. In this study, we explored whether HT could protect neurons from BPS-induced oxidative stress and apoptosis. Our results showed that HT effectively inhibited oxidative stress responses in the brains of BPS-treated mice and significantly decreased ROS production in BPS-treated HT22 and PC12 cells. Additionally, HT reduced BPS-induced neuronal apoptosis in the cortical regions of mice as well as in HT22 and PC12 cells. Further analysis revealed that BPS activates the NF-κB signaling pathway, a key mediator of oxidative stress and neuronal apoptosis, while HT counteracted these effects. In summary, this study demonstrates the antioxidant and antiapoptotic properties of HT in BPS-exposed neurons. These findings provide compelling experimental evidence supporting the potential dietary inclusion of HT-rich compounds to alleviate oxidative stress-related neuronal damage.

Keywords:  Bisphenol S; apoptosis; hydroxytyrosol; oxidative stress

DOI:  https://doi.org/10.1002/jbt.70303
Mol Biol Rep. 2025 May 21. 52(1): 479

Exploring the role of mitochondrial dysfunction and aging in COVID-19-Related neurological complications.

Prajakta Hingole, Priya Saha, Sourav Das, Chayanika Gundu, Ashutosh Kumar.

  The COVID-19 pandemic, caused by SARS-CoV-2, posed a tremendous challenge to healthcare systems globally. Severe COVID-19 infection was reported to be associated with altered immunometabolism and cytokine storms, contributing to poor clinical outcomes and in many cases resulting in mortality. Despite promising preclinical results, many drugs have failed to show efficacy in clinical trials, highlighting the need for novel approaches to combat the virus and its severe manifestations. Mitochondria, crucial for aerobic respiration, play a pivotal role in modulating immunometabolism and neuronal function, making their compromised capability as central pathological mechanism contributing to the development of neurological complications in COVID-19. Dysregulated mitochondrial dynamics can lead to uncontrolled immune responses, underscoring the importance of mitochondrial regulation in shaping clinical outcomes. Aging further accelerates mitochondrial dysfunction, compounding immune dysregulation and neurodegeneration, making older adults particularly vulnerable to severe COVID-19 and its neurological sequelae. COVID-19 infection impairs mitochondrial oxidative phosphorylation, contributing to the long-term neurological complications associated with the disease. Additionally, recent reports also suggest that up to 30% of COVID-19 patients experience lingering neurological issues, thereby highlighting the critical need for further research into mitochondrial pathways to mitigate long-tern neurological consequences of Covid-19. This review examines the role of mitochondrial dysfunction in COVID-19-induced neurological complications, its connection to aging, and potential biomarkers for clinical diagnostics. It also discusses therapeutic strategies aimed at maintaining mitochondrial integrity to improve COVID-19 outcomes.

Keywords:  Aging; Biomarkers; COVID-19; Mitochondrial dynamics; Mitochondrial dysfunction; Neurological symptoms

DOI:  https://doi.org/10.1007/s11033-025-10586-0
Metab Brain Dis. 2025 May 17. 40(5): 205

Hypercholesterolemia, oxidative stress, and low-grade inflammation: a potentially dangerous scenario to blood-brain barrier.

Hémelin Resende Farias, Lílian Corrêa Costa-Beber, Fátima Theresinha Costa Rodrigues Guma, Jade de Oliveira.

  For more than a century, hypercholesterolemia has been linked to atherosclerotic cardiovascular disease. Notably, this metabolic condition has also been pointed out as a risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). Oxidative stress seems to be the connective factor between hypercholesterolemia and cardio and neurological disorders. By disturbing redox homeostasis, hypercholesterolemia impairs nitric oxide (NO) availability, an essential vasoprotective element, and jeopardizes endothelial function and selective permeability. The central nervous system (CNS) is partially protected from peripheral insults due to an arrangement between endothelial cells, astrocytes, microglia, and pericytes that form the blood-brain barrier (BBB). The endothelial dysfunction related to hypercholesterolemia increases the risk of developing cardiovascular diseases and also initiates BBB breakdown, which is a cause of brain damage characterized by neuroinflammation, oxidative stress, mitochondrial dysfunction, and, ultimately, neuronal and synaptic impairment. In this regard, we reviewed the mechanisms by which hypercholesterolemia-induced oxidative stress affects peripheral vessels, BBB, and leads to memory deficits. Finally, we suggest oxidative stress as the missing link between hypercholesterolemia and dementia.

Keywords:  Cholesterol; Dementia; Endothelial dysfunction; Inflammation; Mild cognitive impairment; Oxidative stress

DOI:  https://doi.org/10.1007/s11011-025-01620-y
Cardiovasc Diagn Ther. 2025 Apr 30. 15(2): 423-440

Apolipoprotein M delays the development of atherosclerosis by regulating autophagy and mitochondrial function.

Yuanping Shi, Shuang Yao, Binhua Jiang, Jun Zhang, Mingjun Cao, Jing Wu, Lu Zheng, Ning Xu, Xiaoying Zhang, Guanghou Shui, Guanghua Luo.

   Background: Apolipoprotein M (ApoM), a protein component of lipoproteins, is closely related to the development of atherosclerosis, but the specific mechanism remains elusive. Mitochondrial DNA damage can contribute to atherosclerosis, so this study was designed to investigate whether ApoM influences the structure and function of mitochondria during the progression of atherosclerosis and to explore the underlying mechanism.
Methods: Atherosclerosis models were established in male ApoM-deficient (ApoM-/- ) and wild-type (ApoM+/+ ) C57BL/6 mice fed a high-fat diet (HFD), and the development of atherosclerosis was verified by en face analysis of the aorta and Masson's trichrome staining. We utilized transmission electron microscopy (TEM) to examine the ultrastructure of the aorta, its endothelial cells and EA.hy926 cells. Mass spectrometry-based lipidomics was performed to measure lipidomes in the serum and liver tissue of ApoM- /- mice. In EA.hy926 cells, we modulated the levels of autophagy and ApoM expression, and investigated the mechanism by which ApoM influences the pathogenesis of atherosclerosis through western blotting, JC-1 staining, flow cytometry, and Seahorse extracellular flux analysis.
Results: In ApoM-/- mice fed an HFD, atherosclerotic markers such as aortic lipid accumulation, fibrosis, endothelial cell oedema, and mitochondrial swelling were observed, indicating early atherosclerotic development. Lipidomic analysis revealed that ApoM deficiency might lead to impaired autophagy and mitochondrial dysfunction. In EA.hy926 cells, overexpression of ApoM not only activated autophagy but also improved mitochondrial structure. Moreover, ApoM decreased the mitochondrial membrane potential (ΔΨm) of EA.hy926 cells, which was further reduced by autophagy activation. Additionally, overexpression of ApoM in EA.hy926 cells, which have a low basal metabolism and primarily rely on glycolysis for energy, significantly reduced basal mitochondrial respiration and adenosine triphosphate (ATP) production, suggesting that ApoM can facilitate mitochondrial fission.
Conclusions: ApoM exerts atheroprotective effects by promoting autophagy and regulating mitochondrial dynamics, thereby maintaining mitochondrial integrity and function. This study provides novel insights into the mechanisms underlying the protective role of ApoM in atherosclerosis and highlights its potential as a therapeutic target for cardiovascular diseases.

Keywords:  Apolipoprotein M (ApoM); atherosclerosis; autophagy; lipid metabolism; mitochondria

DOI:  https://doi.org/10.21037/cdt-2024-614
Free Radic Biol Med. 2025 May 20. pii: S0891-5849(25)00681-1. [Epub ahead of print]

Mitochondrial Electron Transfer Chain Activation in Atrophic Muscle: Implications for Calcium Signaling and Chondrocyte Apoptosis in Osteoarthritis.

Ailin Li, Tingting Pang, Jie Yang, Yunli Wang, Li Dong, Zhenwei Zhou, Yunfei Li, Xiangyang Leng, Haisi Dong, Yufeng Wang.

  Skeletal muscle wasting directly impacts the stability of the knee joint, leading to the development of osteoarthritis (OA). However, the underlying mechanism of the interaction between skeletal muscle and cartilage remains unclear. Therefore, the cross-talk between skeletal muscle and cartilage was investigated in rat models of muscle atrophy and the combination of OA and muscle atrophy through gait analysis, grip strength testing, micro-CT, and histological staining. The underlying mechanism was identified through metabolomics, RNA-sequencing, and verification experiments. It is first confirmed that skeletal muscle wasting induces reduction of joint function and the acceleration of cartilage injury. Furthermore, OA chondrocytes exhibited worsened injury when co-cultured with atrophied muscle. Mechanistically, metabolomics revealed the differential metabolites in muscle mainly enriched mitochondrial electron transport chain signaling pathway, which is the primary source of reactive oxygen species (ROS). RNA-sequencing of cartilage combined with verification experiments further indicated that the calcium signaling pathway in injured cartilage was activated, leading to the increase in chondrocyte apoptosis and inflammation, which attributed to the elevated levels of ROS in muscle atrophy, which stimulates synovium to further produce ROS and then release it into knee joint fluid. These observations suggest that elevated ROS levels in atrophied muscle may activate the calcium signaling pathway, leading to the increase of chondrocyte apoptosis, and ultimately exacerbate OA, which have potential to be a novel therapeutic target for OA treatment.

Keywords:  ROS; atrophied muscle; calcium signaling pathway; osteoarthritis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.398
Int J Biol Sci. 2025 ;21(7): 2935-2953

SLC25A33-mediated mitochondrial DNA synthesis plays a critical role in the inflammatory response of M1 macrophages by contributing to mitochondrial ROS and VDAC oligomerization.

Daehoon Kim, Jonghwa Jin, Yu-Rim Lee, Dong-Ho Kim, Soo-Young Park, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.

M1 macrophage polarization is modulated by the release of mitochondrial DNA (mtDNA) and induces the inflammatory immune response, which is further increased by the generation of mitochondrial reactive oxygen species (mtROS). The pyrimidine nucleotide carrier SLC25A33 is located in the mitochondrial inner membrane and is linked to mtDNA synthesis, but its role in the M1 macrophage inflammatory immune response remains unclear. Here, we elucidate the regulatory mechanisms responsible for upregulation of SLC25A33 expression during M1 macrophage polarization, SLC25A33-mediated mtROS production, and the inflammatory response. SLC25A33 expression was significantly elevated in CD14+ monocytes derived from patients with sepsis and LPS/interferon-gamma (IFN-γ)-stimulated peritoneal macrophages (PMs). SLC25A33 was upregulated by ATF4 through the MyD88-PI3K-mTORC1 pathway in LPS/IFN-γ-stimulated PMs. Furthermore, SLC25A33 increased mtDNA synthesis and the release of mtDNA into the cytosol, which was facilitated by mtROS-mediated voltage-dependent anion channel (VDAC) oligomer formation, thereby contributing to activation of the cGAS-STING inflammatory pathway. Conversely, SLC25A33 knockdown and pyridoxal 5'-phosphate treatment, which inhibits SLC25A33 activity, decreased mtDNA release and reduced M1 macrophage polarization and associated inflammatory responses. These findings were consistent across in vitro and in vivo sepsis models, as well as in septic patients with liver abscesses. Our findings underscore the significant role of SLC25A33 in inflammation, suggesting that targeting of SLC25A33 could be a promising therapeutic strategy for the management of M1 macrophage-mediated inflammatory diseases, including sepsis.

DOI: https://doi.org/10.7150/ijbs.96563
Sci Rep. 2025 May 17. 15(1): 17134

In silico screening of naturally derived dietary compounds as potential butyrylcholinesterase inhibitors for Alzheimer's disease treatment.

Md Tarikul Islam, Md Aktaruzzaman, Chandan Barai, Farhan Ishrak Rafi, Al Riyad Hasan, Tasfiah Tasnim, Parvej Sarder, Ghadeer M Albadrani, Muath Q Al-Ghadi, Amany A Sayed, Mohamed M Abdel-Daim, Humayra Afroz Dona, Kishore Kumar Sarkar, Md Obayed Raihan.

  Alzheimer's disease (AD) is a progressive neurodegenerative condition that causes a substantial decline in cognitive functions and affects memory, thinking abilities, and daily behavior. The most prominent hallmark of AD pathogenesis is the formation of amyloid-β plaques, among other associated pathways such as neurofibrillary tangles, mitochondrial dysfunction, neuroinflammation, and oxidative stress. Butyrylcholinesterase (BuChE), an acetylcholine-degrading enzyme, plays a critical role in the progression of Alzheimer's disease, particularly through its involvement in amyloid-β plaque formation. Thus, the inhibition of BuChE is considered a valuable therapeutic strategy for the management of AD. The present study aimed to identify potential bioactive chemicals from naturally occurring dietary compounds that could improve neurocognitive function and appear as a viable treatment for AD by inhibiting the function of BuChE. A small library of 44 natural dietary chemicals from a variety of dietary plants was subjected to comprehensive in silico studies, including molecular docking, molecular mechanics generalized born surface area (MM-GBSA) calculations, pharmacokinetics assessments, toxicity profiles, molecular dynamics (MD) simulation, and density functional theory (DFT) analysis. These studies revealed that CID 129886986 and CID 115269 showed stronger binding affinities with drug-likeness and no toxicity than the FDA-approved standard drug, Donepezil. Additionally, they exhibited strong structural stability with fewer fluctuations throughout the simulation, making them promising candidates for Alzheimer's disease treatment.

Keywords:  Alzheimer’s disease; Butyrylcholinesterase; Density functional theory; MM-GBSA; Molecular docking; Molecular dynamics simulations; Pharmacokinetics

DOI:  https://doi.org/10.1038/s41598-025-98092-y
Infect Immun. 2025 May 19. e0013825

STING contributes to the inflammation and proliferation of Staphylococcus aureus via mitochondrial reactive oxygen species-hypoxic inducible factor 1α axis in epithelial cells.

Xing Gao, Binfeng Wu, Yawei Qiu, Shiyuan Feng, Jinqiu Zhang, Jinfeng Miao.

  Staphylococcus aureus infection poses a serious threat to the dairy industry and public health safety. The stimulator of interferon gene (STING) signaling pathway has been well established as effective in defending against viral infections. However, the role of STING is controversial during bacterial infections. Herein, we provide an insight into the role of STING during S. aureus infection. Our data revealed that the STING signaling pathway was activated in S. aureus-infected cells. In vitro investigations demonstrated that inhibiting STING reduced inflammation, hypoxia-inducible factor-1 alpha (HIF1α) expression, and mitochondrial reactive oxygen species (mROS) production. Interestingly, blocking HIF1α eliminated the escalation of inflammation associated with STING. Additionally, suppressing mROS production significantly reduced HIF1α expression and inflammation levels, while elevating mROS had the opposite effect. These results indicate that STING promoted inflammation through the mROS-HIF1α pathway. Given that glycolysis is driven by HIF1α, we investigated the role of glycolysis during infection. As expected, STING-elevated inflammation was linked with HIF1α-driven glycolysis. In terms of pathogenesis, STING contributed to S. aureus proliferation within cells and mouse mammary glands. Collectively, our findings demonstrate that STING facilitates infection via the mROS-HIF1α-glycolysis axis, highlighting its potential as a promising anti-inflammatory target.

Keywords:  STING; Staphylococcus aureus; glycolysis; mROS-HIF1α; mastitis

DOI:  https://doi.org/10.1128/iai.00138-25
Open Biol. 2025 May;15(5): 240331

Relationship troubles at the mitochondrial level and what it might mean for human disease.

Rachel James.

  Understanding and treating disease depend upon our knowledge of how the body works. The biomedical approach to disease describes health purely in terms of biological factors, with a focus on the genome as the molecular basis for cellular function and dysfunction in disease. However, the eukaryotic cell has evolved as a partnership between prokaryotic cells with mitochondria being crucial to this relationship. Aside from their role as bioenergetic and biosynthetic hubs, mitochondria are also involved in cell signalling and cell fate pathways, playing a multifaceted role in cell function and health. Crucially, mitochondria are implicated in most diseases. Perhaps then, visualizing biomedical function on the backdrop of endosymbiosis may provide another viewpoint for explaining and treating disease.

Keywords:  endosymbiosis; eukaryotic cell; genome; human disease; mitochondria

DOI:  https://doi.org/10.1098/rsob.240331
Mol Neurobiol. 2025 May 22.

Glycation in Alzheimer's Disease and Type 2 Diabetes: The Prospect of Dual Drug Approaches for Therapeutic Interventions.

Sama Ayoub, Maryam Arabi, Yousef Al-Najjar, Ibrahim Laswi, Tiago F Outeiro, Ali Chaari.

  As global life expectancy increases, the prevalence of neurodegenerative diseases like Alzheimer's disease (AD) continues to rise. Since therapeutic options are minimal, a deeper understanding of the pathophysiology is essential for improved diagnosis and treatments. AD is marked by the aggregation of Aβ proteins, tau hyperphosphorylation, and progressive neuronal loss, though its precise origins remain poorly understood. Meanwhile, type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia, leading to the formation of advanced glycation end products (AGEs), which are implicated in tissue damage and neurotoxicity. These AGEs can be resistant to proteolysis and, therefore, accumulate, exacerbating AD pathology and accelerating neurodegeneration. Insulin resistance, a hallmark of T2DM, further complicates AD pathogenesis by promoting tau hyperphosphorylation and Aβ plaque accumulation. Additionally, gut microbiome dysbiosis in T2DM fosters AGE accumulation and neuroinflammation, underscoring the intricate relationship between metabolic disorders, gut health, and neurodegenerative processes. This complex interplay presents both a challenge and a potential avenue for therapeutic intervention. Emerging evidence suggests that antidiabetic medications may offer cognitive benefits in AD, as well as in other neurodegenerative conditions, pointing to a shared pathophysiology. Thus, we posit that targeting AGEs, insulin signaling, and gut microbiota dynamics presents promising opportunities for innovative treatment approaches in AD and T2DM.

Keywords:  Advanced glycation end products (AGEs); Alzheimer’s disease; Dual drugs; Type 2 diabetes

DOI:  https://doi.org/10.1007/s12035-025-05051-9
Redox Biol. 2025 May 16. pii: S2213-2317(25)00197-1. [Epub ahead of print]84 103684

A CoQ10 analog ameliorates cognitive impairment and early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation.

Junhui Chen, Zhonghua Shi, Yuhua Chen, Kun Xiong, Yuhai Wang, Hongqi Zhang.

  Subarachnoid hemorrhage (SAH) represents a stroke subtype that can lead to prolonged cognitive deficits as well as death or disability. Prior investigation has suggested that CoQ10 analogs can mitigate oxidative stress and inflammation and promote mitochondrial biogenesis in the context of brain injury and neurodegenerative disorders. However, the precise mechanisms underlying early brain injury (EBI) following SAH remain incompletely understood, and the detailed molecular processes have yet to be completely clarified. This investigation examined the neuroprotective properties of a CoQ10 analog concerning EBI post-SAH and identified potential mechanistic pathways. Our findings indicate that SAH led to alterations in innate and learned behaviors in aged C57BL/6J mice while also triggering ferroptosis and neuroinflammation within hippocampal neurons. Additionally, SAH was associated with reduced ferroptosis-related proteins, exacerbation of iron accumulation, elevation of lipid ROS, and decreased FSP1, HO-1, and NQO1 levels. The CoQ10 analog idebenone (IDB) demonstrated a capacity to alleviate EBI, as evidenced by improvements in both innate and learned behaviors, alongside a reduction in ferroptosis-related gene/protein expression. Silencing of FSP1 exacerbated EBI, ferroptosis, and neuroinflammation, and partially counteracted the neuroprotective effects of the CoQ10 analog. These results suggest that IDB may enhance the recovery from SAH-induced EBI in aged mice by modulating FSP1 protein stability via NMT-mediated N-myristoylation, thereby inhibiting both ferroptosis and neuroinflammation. The potential therapeutic application of IDB as a clinical intervention for EBI following SAH is also highlighted.

Keywords:  CoQ10 analog; EBI; FSP1; Ferroptosis; Idebenone; Neuroinflammation

DOI:  https://doi.org/10.1016/j.redox.2025.103684
Phytomedicine. 2025 May 16. pii: S0944-7113(25)00418-0. [Epub ahead of print]142 156780

Schisandrin B ameliorates Alzheimer's disease by suppressing neuronal ferroptosis and ensuing microglia M1 polarization.

Tao Ding, Meiying Song, Yongshi Wu, Zhu Li, Shanshan Zhang, Xiang Fan.

   BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal damage, with poor prognosis and limited therapeutic options. Inhibition of neuronal ferroptosis has shown promise as a potential treatment for AD. Schisandrin B (Sch B), a major active component of Schisandra chinensis, exhibits potential neuroprotective effects. However, whether Sch B inhibits neuronal ferroptosis remains unclear.
PURPOSE: To investigate the mechanisms underlying the effects of Sch B on the GSK3β/Nrf2/GPX4 and FSP1 signaling pathways, which are the suppression of neuronal ferroptosis and the potential therapeutic intervention in AD.
METHODS: We employed the 3 × Tg mouse model in vivo, and utilized the erastin-induced ferroptosis model in SH-SY5Y/APP695swe cells in vitro. Nissl staining was conducted to facilitate histopathological assessment. Assessment of neuronal ferroptosis was performed utilizing a lipid peroxidation and ferroptosis marker assay kit. Furthermore, bioinformatic analysis was executed with the application of the GEO database. Immunofluorescence and Western blot analyses were performed to quantify protein expression levels within the cellular context. ELISA was utilized to determine cytokine concentrations within the supernatant of cell cultures. RT-PCR was executed to evaluate mRNA expression levels.
RESULTS: Sch B suppresses the activation of GSK3β, modulating the Nrf2/GPX4 signaling pathway and consequently inhibiting ferroptosis in neurons, which results in amelioration of cognitive impairment and pathological damage in 3 × Tg mice. Sch B also inhibits GSK3β activation, thereby modulating the Nrf2/GPX4 signaling pathway to prevent erastin-induced ferroptosis in SH-SY5Y695swe cells in vitro. Furthermore, Sch B modulates FSP1, enhancing its synergistic interaction with the GSK3β/Nrf2/GPX4 pathway to suppress neuronal ferroptosis. Sch B can also inhibit TNF-α release from neurons undergoing ferroptosis, thus impeding the activation of M1-type microglia, suggesting a multifaceted neuroprotective strategy against neuroinflammatory processes.
CONCLUSION: Sch B modulates the GSK3β/Nrf2/GPX4 pathway in conjunction with FSP1 to inhibit neuronal ferroptosis and the subsequent microglial M1 polarization mediated by neuronal ferroptosis, thereby improving cognitive impairment and pathological damage in AD.

Keywords:  Alzheimer's disease; FSP1; Ferroptosis; GSK3β; Polarization of microglia; Schisandrin B

DOI:  https://doi.org/10.1016/j.phymed.2025.156780
Food Funct. 2025 May 23.

Effects of astaxanthin on the mechanisms involved in skeletal muscle lipid metabolism and oxidative stress in an experimental model of metabolic syndrome.

María Eugenia Oliva, Valentina Degrave, Paola Ingaramo, Pablo Collins, María Eugenia D'Alessandro.

This study aimed to evaluate the mechanisms involved in skeletal muscle lipotoxicity, impaired lipid metabolism, and oxidative stress induced by a sucrose-rich diet (SRD) that mimics human Metabolic Syndrome (MS), and to assess the preventive effects and molecular mechanisms of astaxanthin (AXT) extracted from freshwater crabs (Dilocarcinus pagei) on these alterations. Male Wistar rats received a reference diet (RD), RD + AXT, SRD, or SRD + AXT (10 mg kg-1 day-1 orally) for 90 days. Serum glucose, triglycerides, and cholesterol were measured. In skeletal muscle, triglyceride content, activities of lipogenic enzymes [fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), malic enzyme (ME), glucose-6-phosphate dehydrogenase (G-6-PDH)] and mitochondrial β-oxidation enzyme [carnitine palmitoyltransferase-1 (CPT-1)] were assessed, along with the expression of transcription factors sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor-α (PPARα) by qPCR. Oxidative stress was evaluated by reactive oxygen species (ROS), glutathione (GSH), and antioxidant enzymes (CAT, GPx, GR), as well as pNFκB p65 and NrF2 protein levels. SRD feeding induced dyslipidemia, intramuscular triglyceride accumulation, increased de novo lipogenesis and SREBP-1c expression, and reduced CPT-1 activity and PPARα expression in skeletal muscle. Oxidative stress was evidenced by elevated ROS and decreased GSH and antioxidant enzyme activities, with reduced NrF2 and increased pNFκB p65 levels. AXT supplementation attenuated these alterations by downregulating lipogenic enzymes and SREBP-1c, enhancing CPT-1 and PPARα expression, and modulating NrF2 and pNFκB p65, thus improving lipid metabolism and redox balance in skeletal muscle. This study revealed new aspects of skeletal muscle lipid accumulation, lipid metabolism, and oxidative stress in SRD-fed rats. We demonstrated the novel properties and molecular mechanisms of AXT extracted from freshwater crabs on these parameters in the skeletal muscle of an experimental model of MS.

DOI: https://doi.org/10.1039/d5fo02156a
Cell Commun Signal. 2025 May 20. 23(1): 232

From powerhouse to modulator: regulating immune system responses through intracellular mitochondrial transfer.

Mostafa Changaei, Zahra Azimzadeh Tabrizi, Mozhdeh Karimi, Seyed Adnan Kashfi, Tina Koochaki Chahardeh, Seyed Mahmoud Hashemi, Sara Soudi.

  Mitochondria are traditionally known as the cells' powerhouses; however, their roles go far beyond energy suppliers. They are involved in intracellular signaling and thus play a crucial role in shaping cells' destiny and functionality, including immune cells. Mitochondria can be actively exchanged between immune and non-immune cells via mechanisms such as nanotubes and extracellular vesicles. The mitochondria transfer from immune cells to different cells is associated with physiological and pathological processes, including inflammatory disorders, cardiovascular diseases, diabetes, and cancer. On the other hand, mitochondrial transfer from mesenchymal stem cells, bone marrow-derived stem cells, and adipocytes to immune cells significantly affects their functions. Mitochondrial transfer can prevent exhaustion/senescence in immune cells through intracellular signaling pathways and metabolic reprogramming. Thus, it is emerging as a promising therapeutic strategy for immune system diseases, especially those involving inflammation and autoimmune components. Transferring healthy mitochondria into damaged or dysfunctional cells can restore mitochondrial function, which is crucial for cellular energy production, immune regulation, and inflammation control. Also, mitochondrial transfer may enhance the potential of current therapeutic immune cell-based therapies such as CAR-T cell therapy.

Keywords:  Immune system; Immunometabolism; Immunotherapy; Mitochondria; Mitochondria Transfer; Organelle therapy

DOI:  https://doi.org/10.1186/s12964-025-02237-5
J Steroid Biochem Mol Biol. 2025 May 21. pii: S0960-0760(25)00117-7. [Epub ahead of print] 106789

Tea polyphenols and EGCG induce preeclampsia-like symptoms by reducing 2-methoxyestradiol.

Yi Duan, Chen Jin, Jiaqi Wang, Pan Wang.

  Preeclampsia (PE), a severe pregnancy-specific disorder, poses significant health risks to both mothers and fetuses. Certain dietary habits, such as tea consumption, may affect the activity of enzymes involved in hormone metabolism, leading to alterations in the levels of important pregnancy-related hormone metabolites, such as 2-methoxyestradiol (2-MeO-E2), which may contribute to the development of PE. To investigate the effect of tea intake on pregnancy, we conducted both in vivo and in vitro experiments. Pregnant rats were administered tea polyphenols and epigallocatechin gallate (EGCG) by gavage starting from pregnancy day 10. We found that tea polyphenols and EGCG intake during pregnancy induced PE-like symptoms in the rats such as hypertension, proteinuria and growth restriction of fetuses. These symptoms could be rescued by cotreatment of 2-MeO-E2. Notably, the levels of the estrogen metabolite 2-MeO-E2 in rat blood were significantly reduced, and the activity of the enzyme responsible for its metabolism, catechol-O-methyltransferase (COMT), was also inhibited. Furthermore, EGCG impaired the migration ability of HTR8/SVneo cells, which could be alleviated by 2-MeO-E2 supplementation. These findings indicate that tea polyphenols intake during pregnancy can cause PE-like symptoms by inhibiting COMT activity and production of 2-MeO-E2.

Keywords:  2-methoxyestradiol; COMT; EGCG; Preeclampsia; tea polyphenols

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106789
Alzheimers Dement. 2025 May;21(5): e70247

Slow wave synchrony during NREM sleep tracks cognitive impairment in prodromal Alzheimer's disease.

Omer Sharon, Vladislav Zhelezniakov, Yael Gat, Rotem Falach, Darya Narbayev, Tamara Shiner, Matthew P Walker, Riva Tauman, Noa Bregman, Yuval Nir.

   INTRODUCTION: Alzheimer's disease (AD) disrupts human sleep architecture more severely than normal aging. However, it remains unclear how AD changes oscillatory neural activity during sleep, and whether such changes foreshadow cognitive decline in AD.
METHODS: We used high-density electroencephalography sleep recordings in 55 participants: (1) 21 healthy older adults, (2) 28 patients with amnestic mild cognitive impairment (aMCI)-a prodromal AD stage, and (3) 6 AD patients.
RESULTS: Cognitive performance robustly decreases with the slow wave (SW) trough amplitude and its synchronization across broad frontocentral cortical areas. Thus, across the AD spectrum, slow wave synchrony declines with cognition, as in normal aging, but at an accelerated pace. Moreover, delayed rapid eye movement (REM) sleep onset in aMCI and AD patients was associated with deficient SW activity, suggesting insufficiently restorative non-REM sleep.
DISCUSSION: These findings suggest that impaired slow waves are closely linked to cognitive impairment and mark disrupted neural activity in AD progression.
HIGHLIGHTS: Detailed analysis of high-density sleep electroencephalography was performed in amnestic mild cognitive impairment and Alzheimer's disease (AD) patients. Cognitive status robustly correlates with slow wave trough and its cortical spread. Delayed rapid eye movement sleep onset associated with AD correlates with diminished slow wave troughs. Impaired slow waves mark progressively disrupted neural activity in prodromal AD.

Keywords:  amnestic mild cognitive impairment; electroencephalography; memory; mild cognitive impairment; neurodegeneration; slow oscillation; slow wave

DOI:  https://doi.org/10.1002/alz.70247
Res Sq. 2025 May 09. pii: rs.3.rs-6550812. [Epub ahead of print]

Dissecting Metabolic Control of Behaviors and Physiology During Aging in Drosophila.

Elizabeth S Pasam, Kishore Madamanchi, Girish C Melkani.

  Aging disrupts physiological and behavioral homeostasis, largely driven by one-carbon metabolism, mitochondrial dysfunction, energy sensing, and metabolic imbalance. To elucidate the roles of conserved metabolic, energy sensing, and mitochondrial genes in age-related decline, we employed genetic manipulations in vivo using Drosophila melanogaster models, in a cell-autonomous and non-cell-autonomous manner. By using panneuronal and indirect flight muscle (IFM)- specific drivers, we assessed the impact of gene knockdown or overexpression on sleep-circadian rhythms, locomotion, and lipid metabolism in a cell-autonomous and non-cell-autonomous manner to address bidirectional neuro-muscle communications. Knockdown of genes such as SdhD, Marf, and Gnmt leads to decrease in flight performance especially in 6 weeks with both the drivers. Which demonstrates cell-autonomous and non-cell autonomous effects of these genes. Negative geotaxis with panneuronal knockdown of Adsl, Gnmt, SdhD, Marf genes showed reduced locomotor performance in age-dependent manner consolidating their non-cell autonomous role and neuro-muscular interaction. Whereas mAcon1, LSD2, Ampkα, Ald, Adsl genes showed reduced flight performance with only IFM specific driver emphasizing the cell-autonomous role. Panneuronal knockdown of Ald, GlyP, mAcon1, and Gnmt genes showed increased total sleep, reduced activity, while Adsl and Ogdh knockdown led to sleep fragmentation, in a mid-age suggests cell autonomous impact. Functional analysis of AMPK signaling via overexpression and knockdown of Ampkα, as well as expression of the yeast ortholog SNF1A and its kinase-dead mutant, revealed kinase-dependent, age- and tissue-specific modulation of sleep and activity rhythms. Lipid analysis showed that panneuronal overexpression of Ampkα altered lipid droplet number and size in the brain, indicating disrupted lipid homeostasis during aging. These findings establish Ampkα as a central regulator of behavioral and metabolic aging, linking neuronal energy sensing, motor function, and lipid dynamics, and offer mechanistic insights into tissue-specific metabolic regulation with potential relevance for interventions targeting age-related decline and neurodegeneration.

Keywords:  Aging; circadian rhythm; lipid metabolism; mitochondrial dysfunction; sleep fragmentation

DOI:  https://doi.org/10.21203/rs.3.rs-6550812/v1