Genistein mitigates senescence of bone marrow mesenchymal stem cells via ERRα-mediated mitochondrial biogenesis and mitophagy in ovariectomized rats

Redox Biology, Journal Year: 2023, Volume and Issue: 61, P. 102649 - 102649

Published: Feb. 27, 2023

Senescence of bone marrow mesenchymal stem cells (BMMSCs) induced by chronic oxidative stress is an important factor contributes to the postmenopausal osteoporosis (PMOP). Mitochondrial quality control takes a pivotal role in regulating and cell senescence. Genistein major isoflavone soy products, which best known for its ability inhibit loss both women ovariectomized (OVX) rodents. Here we show that OVX-BMMSCs displayed premature senescence, elevated reactive oxygen species (ROS) level mitochondria dysfunction, while genistein rescued these phenotypes. Using network pharmacology molecular docking, identified estrogen-related receptor α (ERRα) as potential target genistein. Knockdown ERRα greatly abolished anti-senescence effect on OVX-BMMSCs. Further, mitochondrial biogenesis mitophagy were inhibited knockdown In vivo, trabecular p16INK4a expression, upregulated sirtuin 3 (SIRT3) peroxisome proliferator-activated gamma coactivator one alpha (PGC1α) expression area proximal tibia OVX rats. Together, this study revealed ameliorates senescence through ERRα-mediated mitophagy, provided basis advancement development therapeutic strategies against PMOP.

Language: Английский

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Estrogen and cardiovascular disease

Progress in Cardiovascular Diseases, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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Spaceflight induces changes in gene expression profiles linked to insulin and estrogen

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: June 11, 2024

Abstract Organismal adaptations to spaceflight have been characterized at the molecular level in model organisms, including Drosophila and C. elegans . Here, we extend work energy metabolism sex hormone signaling mice humans. We found induced changes insulin estrogen rodents Murine were most prominent liver, where observed inhibition of receptor with concomitant hepatic resistance steatosis. Based on metabolic demand, pathways mediated by vary among muscles, specifically between soleus extensor digitorum longus. In humans, related genes pathways. Pathway analysis demonstrated resistance, signaling, stress response, viral infection. These data strongly suggest need for further research reproductive endocrinologic effects space travel, if are become a successful interplanetary species.

Language: Английский

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Mechanisms underlying sex differences in autoimmunity

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(18)

Published: Sept. 16, 2024

Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune occur more often in women than men, with rheumatic being among those most highly expressed women. Several key factors, identified mainly animal models and cell culture experiments, important increasing disease females. These include sex hormones, immune genes including found on the X chromosome, sex-specific epigenetic effects by estrogen environment, regulation messenger RNA microRNAs extracellular vesicles. Evidence is also emerging that viruses as well drugs or toxins damage mitochondria may contribute to increased levels autoantibodies against nuclear mitochondrial antigens, which common many diseases. The purpose this Review summarize our current understanding mechanisms determine differences disease.

Language: Английский

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Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 100053 - 100053

Published: March 1, 2025

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson Huntington amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due intricate pathogenesis substantial variability among patients, including differences in environmental exposures genetic predispositions. One of the defining characteristics NDs is widely reported be buildup misfolded proteins. For example, disease marked by amyloid beta hyperphosphorylated Tau aggregates, whereas exhibits α-synuclein aggregates. Amyotrophic sclerosis dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, fused-in sarcoma involves mutant huntingtin polyglutamine These proteins key biomarkers also serve potential therapeutic targets, they can addressed through autophagy, a process that removes excess cellular inclusions maintain homeostasis. Various forms macroautophagy, chaperone-mediated microautophagy, hold promise eliminating toxic implicated NDs. In this review, we focus on elucidating regulatory connections between autophagy NDs, summarizing cause exploring impact mechanisms, discussing how regulate aggregation. Moreover, underscore activation strategy across different small molecules capable activating pathways, rapamycin targeting mTOR pathway clear Sertraline AMPK/mTOR/RPS6KB1 Tau, further illustrate NDs' intervention. Together, these findings would provide new insights into current research trends propose small-molecule drugs promising strategies future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview eliminate aggregates neurodegenerative diseases. It elucidates fascinating interrelationships "chasing escaping" phenomenon. discusses progress utilizing activate improve efficacy therapies removing

Language: Английский

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Breakdown and repair of metabolism in the aging brain

Frontiers in Science, Journal Year: 2025, Volume and Issue: 3

Published: March 25, 2025

Age-related neurodegenerative disorders, including dementia, are a major global health concern. This article describes the first comprehensive, data-driven molecular model of neuro-glia-vascular system to explore complex relationships between aging brain, energy metabolism, blood flow, and neuronal activity. Comprising 16,800 interaction pathways, includes all key enzymes, transporters, metabolites, circulatory factors vital for electrical We found significant alterations in metabolite concentrations differential effects on adenosine triphosphate (ATP) supply neurons astrocytes within subcellular compartments aged brains identified reduced sodium/potassium triphosphatase (Na + /K -ATPase) activity as leading cause impaired action potentials. The predicts that metabolic pathways cluster more closely suggesting loss robustness adaptability. Additionally, displays flexibility, undermining its capacity efficiently respond stimuli recover from damage. Through transcription factor analysis, estrogen-related receptor alpha (ESRRA) emerged central target connected these aging-related changes. An unguided optimization search pinpointed potential interventions capable restoring brain’s flexibility generation. These strategies include increasing nicotinamide adenine dinucleotide (NADH) cytosol-mitochondria shuttle, NAD pool, ketone β-hydroxybutyrate, lactate, Na -ATPase, while reducing glucose levels. is open sourced help guide further research into brain metabolism.

Language: Английский

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Protective effect of genistein on nonalcoholic fatty liver disease (NAFLD)

Biomedicine & Pharmacotherapy, Journal Year: 2019, Volume and Issue: 117, P. 109047 - 109047

Published: June 5, 2019

NAFLD is a vital health problem worldwide; however, no effective treatment currently available for NAFLD. Intensive studies have indicated the efficacy of genistein (GE), bioactive isoflavone extracted from soy, in treating In addition to its oestrogen-like effects, GE known multiple molecular instance, lipid and glucose metabolism-promoting effects activities against peroxidation, inflammation, fibrosis, NAFLD-related tumours. Here, this review summarizes potential role prevention some targets signalling pathways

Language: Английский

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COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Oxidative Medicine and Cellular Longevity, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 34

Published: Sept. 16, 2020

Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing large innate immune response associated with cytokine storm and acute respiratory distress syndrome (ARDS). This at the molecular level decreased energy metabolism, altered redox state, oxidative damage, cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as ketogenic diet or consuming exogenous ketones, should restore metabolism state. R-BHB activates anti-inflammatory GPR109A signaling inhibits NLRP3 inflammasome histone deacetylases, while has been shown protect mice from influenza virus through protective γδ T increasing electron transport chain gene expression metabolism. During virus-induced storm, metabolic flexibility compromised increased reactive oxygen species (ROS) nitrogen (RNS) downregulate, inactivate many enzymes central including pyruvate dehydrogenase complex (PDC). leads an crisis decreases B proliferation results in production It hypothesized moderately high-fat together ketone supplementation first signs will mitochondrial bypassing block PDC. R-BHB-mediated restoration nucleotide coenzyme ratios state decrease ROS RNS blunt allowing cells responsible for adaptive immunity. Limitations proposed therapy include following: it unknown if human lung functions are enhanced ketosis, risk ketoacidosis must be assessed prior initiating treatment, permissive dietary fat carbohydrate ketones boost function not yet established. The third limitation could addressed studies influenza-infected mice. A clinical study warranted where COVID-19 consume combined ester raise blood 1 2 mM measured outcomes symptom severity, length infection, case fatality rate.

Language: Английский

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Obesogens: How They Are Identified and Molecular Mechanisms Underlying Their Action

Frontiers in Endocrinology, Journal Year: 2021, Volume and Issue: 12

Published: Nov. 25, 2021

Adult and childhood obesity have reached pandemic level proportions. The idea that caloric excess insufficient levels of physical activity leads to is a commonly accepted answer for unwanted weight gain. This paradigm offers an inconclusive explanation as the world continually moves towards unhealthier heavier existence irrespective energy balance. Endocrine disrupting chemicals (EDCs) are resemble natural hormones disrupt endocrine function by interfering with body’s endogenous hormones. A subset EDCs called obesogens been found cause metabolic disruptions such increased fat storage, in vivo . Obesogens act on system through multiple avenues affect homeostasis variety systems gut microbiome adipose tissue functioning. Obesogenic compounds shown disturbances later life can even pass into future generations, post exposure. rising rates related disease demanding increasing attention chemical screening efforts worldwide preventative strategies keep public generations safe. review addresses most current findings known their effects system, mechanisms action which they upon, were identified with. interplay between obesogens, brown tissue, major topics will be covered.

Language: Английский

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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

The American Journal of Human Genetics, Journal Year: 2022, Volume and Issue: 109(8), P. 1366 - 1387

Published: Aug. 1, 2022

Language: Английский

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