bims-mistre 2025-06-15 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–06–15
nineteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Nicotinamide Adenine Dinucleotide Supplementation to Alleviate Heart Failure: A Mitochondrial Dysfunction Perspective.
Gallic Acid Ameliorates Skeletal Muscle Metabolic Inflexibility by Regulating Lactate Metabolism and Promoting Mitochondrial Function.
A Nucleic Acid Prodrug That Activates Mitochondrial Respiration, Promotes Stress Resilience, and Prolongs Lifespan.
Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances.
Aging-related dysregulation of energy metabolism and mitochondrial dynamics in microglia.
The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
Serotonergic Regulation in Alzheimer's Disease.
Restoring glucose metabolism in Alzheimer's disease by targeting integrated stress response.
Caryocar brasiliense Camb. Fruit Improves Health and Lifespan in Caenorhabditis elegans.
Molecular mechanisms and therapeutic potential of quercetin in ovarian functions.
Celastrol improves endothelial function in diet-induced obesity mice via attenuating endoplasmic reticulum stress through the activation of AMPK pathway.
Natural products for the treatment of age-related macular degeneration: New insights focusing on mitochondrial quality control and cGAS/STING pathway.
Acetyl zingerone inhibits chondrocyte pyroptosis and alleviates osteoarthritis progression by promoting mitophagy through the PINK1/parkin signaling pathway.
mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition.
Exploration of Asparagus racemosus Willd for Alzheimer's Disease Through Integrated Metabolomics and Network Pharmacology Analyses Targeting BACE1 Protein.
Characteristics of Berberine Effects on Insulin Exocytosis in Pancreatic β Cells.
Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
Repetitive Compressive Loading Downregulates Mitochondria Function and Upregulates the Cartilage Matrix Degrading Enzyme MMP-13 Through the Coactivation of NAD-Dependent Sirtuin 1 and Runx2 in Osteoarthritic Chondrocytes.
Microglial SIRT2 deficiency aggravates cognitive decline and amyloid pathology in Alzheimer's disease.

Nutrients. 2025 May 29. pii: 1855. [Epub ahead of print]17(11):

Nicotinamide Adenine Dinucleotide Supplementation to Alleviate Heart Failure: A Mitochondrial Dysfunction Perspective.

Fan Yu, Huiying Zhao, Lu Luo, Wei Wu.

  Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD+), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca2+ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD+ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD+-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD+ content, and supplementation with NAD+ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD+ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD+ in mitochondrial homeostasis and for the development of targeted therapies for heart failure.

Keywords:  ATP; heart failure; mitochondrial dysfunction; nicotinamide adenine dinucleotide; redox

DOI:  https://doi.org/10.3390/nu17111855
Mol Nutr Food Res. 2025 Jun 09. e70106

Gallic Acid Ameliorates Skeletal Muscle Metabolic Inflexibility by Regulating Lactate Metabolism and Promoting Mitochondrial Function.

Yu Wang, Feijie Wang, Juan Sun, Lamei Xue, Yujie Sun, Kuiliang Zhang, Mingcong Fan, Haifeng Qian, Binrui Yang, Jun Du, Yan Li, Li Wang.

  Obesity-induced mitochondrial dysfunction impairs skeletal muscle metabolic flexibility. Gallic acid possesses the ability to modulate metabolic homeostasis. This study aimed to investigate the impact of gallic acid on high-fat diet (HFD)-induced metabolic disorders in skeletal muscle. Twenty-four mice were randomly divided into three groups and subjected to HFD and gallic acid intervention for 12 weeks. The overall glycolipid metabolic status, exercise performance, muscle fiber type, and antioxidant capacity of skeletal muscle in HFD-fed mice treated with gallic acid were assessed. Untargeted metabolomics analysis was performed to evaluate key metabolic characteristics in skeletal muscle. Gallic acid administration effectively reduced fat accumulation, improved exercise capacity, and enhanced antioxidant capacity in HFD-fed mice. Untargeted metabolomics revealed that gallic acid positively regulated lactate metabolism and mitochondrial fatty acid oxidation. Mechanistically, gallic acid intervention increased fatty acid oxidation capacity while inhibiting lactate production and mitochondrial protein lactylation in skeletal muscle. Moreover, the role of gallic acid in enhancing mitochondrial function through the LDHA-lactate axis has been demonstrated in C2C12 cells. Collectively, gallic acid ameliorated HFD-induced metabolic disorders in skeletal muscle, indicating a novel role for gallic acid in ameliorating diet-induced skeletal muscle metabolic disorders by regulating lactate metabolism and mitochondrial function.

Keywords:  antioxidant capacity; gallic acid; lactate; mitochondrial function; skeletal muscle

DOI:  https://doi.org/10.1002/mnfr.70106
J Am Chem Soc. 2025 Jun 13.

A Nucleic Acid Prodrug That Activates Mitochondrial Respiration, Promotes Stress Resilience, and Prolongs Lifespan.

Takahisa Anada, Michiharu Kawahara, Taisei Shimada, Ryotaro Kuroda, Hidenori Okamura, Daiki Setoyama, Fumi Nagatsugi, Yuya Kunisaki, Eriko Kage-Nakadai, Shingo Kobayashi, Masaru Tanaka.

Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan of Caenorhabditis elegans. AXP-driven stimulation of cellular energy metabolism proposed herein represents a novel geroprotective strategy and paves the way for the development of bioenergetic-molecule therapeutics.

DOI: https://doi.org/10.1021/jacs.5c06772
Signal Transduct Target Ther. 2025 Jun 11. 10(1): 190

Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances.

Xieyang Xu, Yan Pang, Xianqun Fan.

Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy.

DOI: https://doi.org/10.1038/s41392-025-02253-4
J Clin Biochem Nutr. 2025 May;76(3): 239-244

Aging-related dysregulation of energy metabolism and mitochondrial dynamics in microglia.

Yoki Nakamura, Manaya Nakano, Kazue Hisaoka-Nakashima, Norimitsu Morioka.

  Microglia, the primary immune cells of the central nervous system, play a pivotal role in maintaining brain homeostasis. Recent studies have highlighted the involvement of microglial dysfunction in the pathogenesis of various age-related neurodegenerative diseases, such as Alzheimer's disease. Moreover, the metabolic state of microglia has emerged as a key factor in these diseases. Interestingly, aging and neurodegenerative diseases are associated with impaired mitochondrial function and a metabolic shift from oxidative phosphorylation to glycolysis in microglia. This metabolic shift may contribute to sustained microglial activation and neuroinflammation. Furthermore, the leakage of mitochondrial DNA into the cytoplasm, because of mitochondrial dysfunction, has been implicated in triggering inflammatory responses and disrupting brain function. This review summarizes recent advances in understanding the role of microglial metabolic shifts, particularly glycolysis, and mitochondrial dysfunction. It also explores the potential of targeting microglial metabolism, for instance by modulating mitophagy or intervening in specific metabolic pathways, as a novel therapeutic approach for changes in brain function and neurodegenerative diseases associated with aging.

Keywords:  Alzheimer’s disease; aging; glycolysis; microglia; mitochondria

DOI:  https://doi.org/10.3164/jcbn.24-202
bioRxiv. 2025 Jun 06. pii: 2025.06.03.656903. [Epub ahead of print]

The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.

Sarah J Shemtov, Eric McGann, Lucy Carrillo, Sangmin Lee, Herbert Anson, Claire S Chung, Maria-Eleni Anagnostou, Guan-Ju D Lai, Bert M Verheijen, Junxiang Wan, Ivetta Vorobyova, Monica Sanchez-Contreras, Cheryl A Conover, Max A Thorwald, Pinchas Cohen, Scott R Kennedy, Jean-François Gout, Suraiya Haroon, Marc Vermulst.

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

DOI: https://doi.org/10.1101/2025.06.03.656903
Int J Mol Sci. 2025 May 29. pii: 5218. [Epub ahead of print]26(11):

Serotonergic Regulation in Alzheimer's Disease.

Lyudmila P Dolgacheva, Valery P Zinchenko, Alexander D Nadeev, Nikolay V Goncharov.

  Serotonin (5-HT) is a neurotransmitter that also plays an important role in the regulation of vascular tone and angiogenesis. This review focuses on the involvement of the 5-HT system in pathological processes leading to the development of Alzheimer's disease (AD). There is evidence that damage or dysfunction of the 5-HT system contributes to the development of AD, and different subtypes of 5-HT receptors are a potential target for the treatment of AD. A link has been established between AD, depression, stress, and 5-HT deficiency in the brain. There are new data on the role of circadian rhythms in modulating stress, depression, and the 5-HT system; amyloid β (Aβ) plaque clearance; and AD progression. Circadian disruption inhibits Aβ plaque clearance and modulates AD progression. The properties and functions of 5-HT, its receptors, and serotonergic neurons are presented. Special attention is paid to the central role of 5-HT in brain development, including neurite outgrowth, regulation of somatic morphology, motility, synaptogenesis, control of dendritic spine shape and density, neuronal plasticity determining its role in network regeneration, and changes in innervation after brain damage. The results of different studies indicate that the interaction of amyloid β oligomers (AβO) with mitochondria is a sufficient trigger for AD-related neurodegeneration. The action of 5-HT leads to an improvement in mitochondrial quality and the restoration of brain areas after traumatic brain injury, chronic stress, or developmental disorders in AD. The role of a healthy lifestyle and drugs acting on serotonin receptors in the prevention and treatment of AD is discussed.

Keywords:  Alzheimer’s disease; amyloid β oligomer; mitochondrial biogenesis; mitochondrial dysfunction; multitarget molecules; neurogenesis; serotonin; serotonin receptors

DOI:  https://doi.org/10.3390/ijms26115218
Neurotherapeutics. 2025 Jun 05. pii: S1878-7479(25)00096-0. [Epub ahead of print] e00618

Restoring glucose metabolism in Alzheimer's disease by targeting integrated stress response.

Hui Sun, Shenrui Guo, Hongfu Jin, Lin Ding, Yuanyuan Chen, Yu Zhang, Kun He, Qi Huang, Jinyuan Gu, Suyun Chen, Hui Wang, Chenglai Fu, Yafu Yin, Weiwei Cheng.

  Cerebral glucose hypometabolism has been consistently associated with Alzheimer's disease (AD). With extensive efforts to eliminate AD pathologies, including the removal of amyloid-β (Aβ) plaques and hyperphosphorylated Tau, strategies aimed at restoring glucose metabolism in the brain regions most affected by AD are believed to have significant clinical implications. In this study, we demonstrated that glucose hypometabolism preceded neuronal death in triple-transgenic AD (3xTg-AD) mice, likely attributable to reduced expression of glucose transporter type 1 (GLUT1) or glucose transporter type 3 (GLUT3). Furthermore, we observed aberrant activation of the integrated stress response (ISR) pathway in AD models, with Aβ and Tau phosphorylation contributing to the activation of the ISR and subsequent reduction in GLUT1/3 expression. Inhibiting ISR activation by utilizing the ISR inhibitor ISRIB can effectively restore GLUT1/3 expression in both in vitro and in vivo models. Importantly, ISRIB treatment improved cognitive function and brain glucose metabolism in 3xTg-AD mice. Our findings suggest that targeting the ISR pathway to restore GLUTs expression may be a potential therapeutic strategy for AD.

Keywords:  Alzheimer's disease; Glucose hypometabolism; Glucose transporters; ISRIB; Integrated stress response

DOI:  https://doi.org/10.1016/j.neurot.2025.e00618
Food Sci Nutr. 2025 Jun;13(6): e70384

Caryocar brasiliense Camb. Fruit Improves Health and Lifespan in Caenorhabditis elegans.

Laura Costa Alves de Araújo, Natasha Rios Leite, Paola Dos Santos da Rocha, Alex Santos Oliveira, Daniel Ferreira Leite, Isabella Giunco Estigarribia, Matheus Henrique Franco Alves, Alércio da Silva Soutilha, Helder Freitas Dos Santos, Debora da Silva Baldivia, Nelson Carvalho Farias Junior, Danielle Araujo Agarrayua, Daiana Silva de Ávila, Jaqueline Ferreira Campos, Kely de Picoli Souza, Edson Lucas Dos Santos.

  The Caryocar brasiliense Camb. is a native Brazilian Cerrado species, considered the symbol of this biome. This tree produces a fruit known as pequi, which is much appreciated in Brazilian traditional culinary and is also used in popular medicine. However, there is still limited knowledge about the pharmaceutical potential of the fruit of C. brasiliense. In this study, we evaluated the bioactive compounds present in the lyophilized fruit pulp of C. brasiliense (CBFP) and investigated its antioxidant properties in vitro and in vivo, as well as its effects on models of Alzheimer's disease and longevity. As a main result, we revealed that CBFP presented phenolic and flavonoid constituents, lipophilic compounds, and ascorbic acid. The in vitro antioxidant activity was observed through free radical scavenging and DNA protection against oxidative damage. In the in vivo life quality assay, no signs of CBFP-induced toxicity were observed, and nematode viability and reproductive capacity remained unaltered. Furthermore, CBFP treatment delayed paralysis in the Alzheimer's disease mutant strain and improved locomotor capacity during aging in the wild-type strain. CBFP increased the lifespan of C. elegans and enhanced resistance to oxidative and heat stresses. Together, our findings demonstrate that CBFP exhibited beneficial effects on healthspan, attributed to its antioxidant properties and the regulation of oxidative stress.

Keywords:  Pequi; antioxidant; ascorbic acid; flavonoids; functional product; lycopene; neuroprotective

DOI:  https://doi.org/10.1002/fsn3.70384
Phytomedicine. 2025 Jun 04. pii: S0944-7113(25)00583-5. [Epub ahead of print]144 156945

Molecular mechanisms and therapeutic potential of quercetin in ovarian functions.

Xiaoyu Zhang, Xuyang Cui, Fengjun Ma, Yue Zhou, Shuai Song, Yujie Li, Yuxia Ma.

   BACKGROUND: Quercetin is a naturally occurring flavonoid abundant in various fruits and vegetables, known for its broad pharmacological properties, including antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects. Emerging evidence suggests that quercetin exerts protective roles in a range of ovarian-related reproductive disorders.
PURPOSE: This review aims to comprehensively summarize and critically assess current evidence on the therapeutic potential and molecular mechanisms of quercetin in the treatment of ovarian-related reproductive conditions. The goal is to provide a scientific foundation for its prospective clinical applications in female reproductive health.
METHODS: A systematic search was conducted in major scientific databases, including PubMed, Web of Science, and ScienceDirect, covering literature published up to February 2025. The search strategy utilized a combination of keywords-"Quercetin", "Ovarian", "Polycystic Ovary Syndrome", "Premature Ovarian Failure", "Ovarian Dysfunction", "Premature Ovarian Insufficiency", and "Infertility"-combined using Boolean operators (AND, OR).
RESULTS: Quercetin has demonstrated therapeutic efficacy in multiple ovarian conditions, including ovarian aging, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), and chemotherapy-induced ovarian damage. Mechanistic studies reveal that quercetin modulates several critical biological pathways, particularly those involved in oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, and steroid hormone biosynthesis.
CONCLUSION: This review underscores the potential of quercetin as a promising therapeutic agent for managing ovarian-related reproductive disorders. Given its diverse biological activities, quercetin may offer significant clinical benefits in female reproductive medicine. Nonetheless, further investigations are warranted to determine its long-term efficacy, optimal dosing strategies, and specific molecular targets across various ovarian pathologies.

Keywords:  Infertility; Molecular mechanism; Ovarian function; Quercetin; Reproduction

DOI:  https://doi.org/10.1016/j.phymed.2025.156945
Mol Med. 2025 Jun 11. 31(1): 233

Celastrol improves endothelial function in diet-induced obesity mice via attenuating endoplasmic reticulum stress through the activation of AMPK pathway.

Cheng Yu, Weihong Lin, Jing Yang, Qiong Jiang, Wenkun Liu, Hongjin Liu, Yong Lin, Litao Wang, Lei Chen, Yu Huang, Lianglong Chen.

   BACKGROUND: Diet-induced obesity (DIO) is a significant factor in endothelial dysfunction. Celastrol, a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has shown promise as a protective agent against cardiovascular disease. However, the specific protective effects and mechanisms of celastrol in preventing endothelial dysfunction in diet-induced obesity are not yet fully understood.
METHODS AND RESULTS: In this study, eight-week-old C57BL/6 mice were fed a normal or high-fat diet and treated with or without celastrol for 8 weeks. We measured acetylcholine-induced endothelium-dependent relaxation (EDR) in the aortae using a wire myograph. The results revealed that EDR was impaired in DIO mice, along with decreased AMPK phosphorylation, increased endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) in the aortae. These effects were reversed by celastrol treatment. Celastrol also reversed tunicamycin-induced ER stress, decreased nitric oxide (NO) production, and impaired EDR in mouse aortae. The protective effects of celastrol were negated by co-treatment with an AMPK inhibitor (Compound C). Furthermore, in AMPKα deficient mice, the beneficial effects of celastrol on EDR were significantly reduced.
CONCLUSIONS: These findings suggest that celastrol improves endothelial function by inhibiting ER stress and increasing NO production through the activation of the AMPK pathway in DIO mice.

Keywords:  AMPK; Celastrol; Endoplasmic reticulum stress; Endothelial function; Obesity

DOI:  https://doi.org/10.1186/s10020-025-01259-6
J Pharm Anal. 2025 May;15(5): 101145

Natural products for the treatment of age-related macular degeneration: New insights focusing on mitochondrial quality control and cGAS/STING pathway.

Xuelu Xie, Shan Lian, Wenyong Yang, Sheng He, Jingqiu He, Yuke Wang, Yan Zeng, Fang Lu, Jingwen Jiang.

  Age-related macular degeneration (AMD) is a disease that affects the vision of elderly individuals worldwide. Although current therapeutics have shown effectiveness against AMD, some patients may remain unresponsive and continue to experience disease progression. Therefore, in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment. Recently, studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species (ROS) and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) innate immunity pathways, ultimately resulting in sterile inflammation and cell death in various cells, such as cardiomyocytes and macrophages. Therefore, combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management. Notably, emerging evidence indicates that natural products targeting mitochondrial quality control (MQC) and the cGAS/STING innate immunity pathways exhibit promise in treating AMD. Here, we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways, as well as their interconnected mediators, which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses, thereby hoping to offer new insights into therapeutic interventions for AMD treatment.

Keywords:  Age-related macular degeneration; Mitochondrial biogenesis; Mitochondrial quality control; Mitophagy; Phytochemicals; cGAS/STING

DOI:  https://doi.org/10.1016/j.jpha.2024.101145
Int Immunopharmacol. 2025 Jun 09. pii: S1567-5769(25)01045-8. [Epub ahead of print]161 115055

Acetyl zingerone inhibits chondrocyte pyroptosis and alleviates osteoarthritis progression by promoting mitophagy through the PINK1/parkin signaling pathway.

Zhuangzhuang Zhang, Tianyue Huang, Xu Chen, Jie Chen, Hang Yuan, Ning Yi, Chunbao Miao, Rongbin Sun, Su Ni.

  Osteoarthritis (OA) is a common chronic degenerative joint disease, characterized by osteophyte formation and cartilage degeneration. A growing number of studies have found that nod-like receptor pyrin domain 3 (NLRP3) inflammasome-mediated chondrocyte pyroptosis plays a crucial role in the development of OA. Acetyl zingerone (AZ) is a small molecule compound, chemically synthesized to retain the key functional properties of curcumin and zingerone, while exhibiting enhanced anti-inflammatory, antioxidant, and anti-aging effects. Previous studies in our group have found an inhibitory effect on ferroptosis in AZ osteoarthritis. However, its specific mechanism of action has not been fully explained. Therefore, we further delved into whether AZ could alleviate OA in mice by affecting mitophagy and pyroptosis. In an in vitro study, we observed that AZ alleviated LPS + ATP-induced pyroptosis in chondrocytes and inhibited the activation of the NLRP3 inflammasome, a key factor in pyroptosis. Moreover, by using the mitophagy activators Resveratrol, the autophagy lysosome inhibitor chloroquine (CQ) and siPINK1 to knock down PINK1, we demonstrated that AZ promoted PINK1/Parkin-mediated mitophagy. AZ enhanced PINK1/Parkin-mediated mitophagy, facilitating the clearance of damaged mitochondria, thereby reducing reactive oxygen species (ROS) production and suppressing NLRP3 inflammasome activation. This cascade mitigated chondrocyte pyroptosis and promoted collagen synthesis. Moreover, AZ demonstrated a comparable pro-regenerative effect on the extracellular matrix to that observed with the standard osteoarthritis treatment, rapamycin. In animal experiments, intra-articular administration of AZ similarly promoted mitophagy and inhibited chondrocyte pyroptosis, alleviating osteoid formation and cartilage damage. Collectively, these findings suggest that AZ may mitigate OA progression by activating mitophagy and attenuating pyroptosis, highlighting its potential as a preventive therapeutic approach for OA.

Keywords:  Acetyl zingerone; Mitophagy; NLRP3 inflammasome; Osteoarthritis; Pyroptosis

DOI:  https://doi.org/10.1016/j.intimp.2025.115055
Eur J Immunol. 2025 Jun;55(6): e51176

mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition.

Alvaro González-Dominguez, Shuling Zhang, Daniel Boy-Ruiz, Daniel Connors, Raquel de la Varga-Martínez, Beverly A Mock, Mario D Cordero.

The NLRP3 inflammasome has emerged as an unexpected sensor of metabolic danger and stress. Their enhanced activation has been implicated in the development of major diseases such as gout, Type 2 diabetes, obesity, cancer, and neurodegenerative and cardiovascular diseases. In this study, we showed that mammalian target of rapamycin (mTOR) regulates NLRP3 inflammasome activation in the nucleus of macrophages. mTOR binds to NLRP3 under basal conditions, and this binding is reduced after lipopolysaccharides (LPS) or LPS + adenosine triphosphate (ATP) treatment. Furthermore, rapamycin-induced downregulation of mTOR expression has an inhibitory effect on NLRP3 inflammasome activation. mTOR knockdown (KD) mice exhibit reduced protein levels of inflammasome components, and their macrophages fail to activate the NLRP3 inflammasome after LPS + ATP treatment. From a mechanistic point of view, LPS + ATP treatment induced the nuclear translocation of mTOR, leading to enhanced NLRP3 inflammasome activation. However, the mTOR inhibition by rapamycin treatment increased phosphorylation of STAT1 which repressed NLRP3 activation. When rapamycin was combined with the STAT1 inhibitor fludarabine, NLRP3 inflammasome activity was restored. Taken together, these findings suggest a role for mTOR in NLRP3 regulation and identify a potential therapeutic option for controlling inflammasome activation.

DOI: https://doi.org/10.1002/eji.202451176
Neurochem Res. 2025 Jun 08. 50(3): 190

Exploration of Asparagus racemosus Willd for Alzheimer's Disease Through Integrated Metabolomics and Network Pharmacology Analyses Targeting BACE1 Protein.

Vineetha Shaji, S Amrutha, Ravishankar Pervaje, Chandran S Abhinand, Rajesh Raju, Thottethodi Subrahmanya Keshava Prasad, Prashant Kumar Modi.

  Asparagus racemosus Willd, an Ayurvedic medicine, is known for its antioxidant, antiviral, immune-boosting, and neuro-nutraceutical benefits, particularly in female health. However, its metabolites, mechanisms of action, and target proteins are yet to be fully understood. The present study aimed to identify the metabolite constitution and metabolite-associated proteins in neuroprotective mechanisms in neurodegenerative disease. Mass spectrometry-based untargeted metabolomics and network pharmacology approaches were used to identify metabolites in A. racemosus root extract. In vitro studies, including oxidative stress regulation, neuronal apoptosis, and western blot analysis, were conducted to assess the plant's impact on Alzheimer's disease (AD). We identified 44,014 spectra in positive and negative modes, corresponding to 31,931 non-redundant metabolites at the MS1 level and 5,608 at the MS2 level, from A. racemosus root extract, which include metabolites belonging to phenols, lipids, flavonoids, isoprenoids, and fatty acyls. Novel and known compounds were identified, such as asparagine, sitosterol, arginine, muzanzagenin, pinene, flavone, and kaempferol. Network pharmacology predicted 44 potential human protein targets linked to Alzheimer's disease from these metabolites. These proteins belong to neuromodulator classes, including BACE1, CHRM3, APP, MAP2K1, GSK3B, and TNF, and some of the metabolites of A. racemosus including muzanzagenin interact with BACE1 protein. In vitro validation showed that A. racemosus regulates ROS levels, apoptosis pathways, and BACE1 expression in Alzheimer's disease (AD), highlighting its therapeutic potential. This study integrates network pharmacology and metabolomics, paving the way for clinical research into the neuropharmacological effects of A. racemosus on neurological disorders.

Keywords:  Kinases; Metabolites; Neuroprotection; Protein targets; Therapeutic targets; Untargeted metabolomics

DOI:  https://doi.org/10.1007/s11064-025-04440-9
FASEB J. 2025 Jun 15. 39(11): e70718

Characteristics of Berberine Effects on Insulin Exocytosis in Pancreatic β Cells.

Ze-Ju Jiang, Yan-Li Liu, Zi-Lu Wang, Hao Wang.

  The Coptis chinensis (Franch) is widely used in diabetes therapies in traditional folk medicine from China, and we previously reported that its main active component, berberine (BBR), acted as an insulin secretagogue through blocking the KCNH6 potassium channel. However, the specific actions of BBR on insulin secretory granule (ISG) dynamics are largely unknown. Here, we analyzed the docking and fusion of ISGs from β-cells exposed to either short-term or long-term treatment with BBR. Under short-term treatment, at 8.3 mmol/L glucose, BBR slightly induced insulin secretion with a gradually increasing second phase only, showing an increased number of ISGs fused without stable docking to the plasma membrane. However, in the presence of 16.7 mmol/L glucose, biphasic insulin secretion by BBR was augmented significantly. The intracellular Ca2+ level increased during the second phase by BBR, suggesting that the Ca2+ dynamics contribute to the dynamics of insulin exocytosis. Under long-term BBR treatment for db/db mice, BBR restored impaired biphasic phases of insulin secretion by recovering the number of ISGs fused with or without predocking to the plasma membrane. In addition, BBR enhanced the docking capacity and increased biphasic Ca2+ concentration after glucose stimulation. Further research revealed that the short-term treatment with BBR primarily promoted the fusion of ISGs through blocking KCNH6 channels, whereas the long-term treatment with BBR improved the docking and fusion of ISGs by an additional effect on activating the cAMP-PKA-CREB pathway. Hence, our study indicated that short-term and long-term treatment with BBR promoted insulin exocytosis through different mechanisms in pancreatic β cells. BBR could be a dual-action antidiabetic agent, acutely enhancing insulin secretion in response to glucose and chronically improving β-cell function in T2D.

Keywords:  KCNH6; berberine; insulin exocytosis; insulin secretory granule; total internal reflection fluorescence microscopy

DOI:  https://doi.org/10.1096/fj.202501267R
bioRxiv. 2025 May 29. pii: 2025.05.28.656437. [Epub ahead of print]

Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.

Yash Flora, Dhriti Shastri, K Adam Bohnert.

Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans , and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: mitochondria. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF- 16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11- defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.

DOI: https://doi.org/10.1101/2025.05.28.656437
Int J Mol Sci. 2025 May 22. pii: 4967. [Epub ahead of print]26(11):

Repetitive Compressive Loading Downregulates Mitochondria Function and Upregulates the Cartilage Matrix Degrading Enzyme MMP-13 Through the Coactivation of NAD-Dependent Sirtuin 1 and Runx2 in Osteoarthritic Chondrocytes.

Masahiro Takemoto, Yodo Sugishita, Yuki Takahashi-Suzuki, Hiroto Fujiya, Hisateru Niki, Kazuo Yudoh.

  Mechanical stress is known to be a pivotal risk factor in the development of OA. However, the involvement of repetitive compressive loading in mitochondrial dysfunction in chondrocytes remains unclear. The aim of this study was to investigate whether physiologic levels of repetitive mechanical force affect the regulation of energy metabolism and activities of mitochondrial function regulators, sirtuin 1 and nicotinamide adenine dinucleotide (NAD) in chondrocytes, and to clarify any correlation with chondrocyte catabolic activity. Repetitive physiological mechanical stress was applied in a 3D chondrocyte-collagen scaffold construct, and the 3D cultured tissues were collected at different time points by collagenase treatment to collect cellular proteins. Changes in chondrocyte activity (cell proliferation, MMP-13 production), energy metabolism regulator levels (sirtuin 1), mitochondrial function (ATP production, NAD level), and the expression level of the osteogenic and hypertrophic chondrogenic transcription factor, runt-related transcription factor 2 (Runx2), were measured. Treatment with repetitive compressive loading resulted in no significant change in the cell viability of chondrocytes. In the repetitive mechanical loading group, there were statistically significant increases in MMP-13 production and expression of both sirtuin 1 and Runx2 in chondrocytes relative to the non-loading control group. Furthermore, ATP production and NAD activity in mitochondria decreased in the repetitive mechanical loading group. Our present study reveals that in chondrocytes, repetitive compressive loading accelerated sirtuin activation, which requires and consumes NAD within mitochondria, leading to a decrease of NAD and ultimately in reduced mitochondrial ATP production. Additionally, since sirtuin 1 is known to positively regulate Runx2 activity in chondrocytes, the activation of sirtuin 1 by repetitive load stimulation may induce an increase in the expression of Runx2, which promotes the expression of MMP-13, and subsequently enhances MMP-13 production. Our findings indicate that repetitive compression loading-mediated mitochondrial dysfunction plays a pivotal role in the progression of OA, primarily by driving the downregulation of ATP production and promoting the expression of the matrix-degrading enzyme MMP-13.

Keywords:  chondrocyte; matrix metalloprotease (MMP)-13; mitochondria activity; nicotinamide adenine dinucleotide (NAD); osteoarthritis; repetitive mechanical stress; runt-related transcription factor (Runx) 2; sirtuin 1

DOI:  https://doi.org/10.3390/ijms26114967
Brain Behav Immun. 2025 Jun 09. pii: S0889-1591(25)00227-2. [Epub ahead of print]

Microglial SIRT2 deficiency aggravates cognitive decline and amyloid pathology in Alzheimer's disease.

Noemi Sola-Sevilla, Maider Garmendia-Berges, Mikel Aleixo, MCarmen Mera-Delgado, Maite Solas, Rosa M Tordera, Lucía García-Carracedo, Sara Expósito, Elena Anaya-Cubero, Joaquín Fernández-Irigoyen, Elisabeth Guruceaga, Enrique Santamaria, Eduardo D Martin, Elena Puerta.

  Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, has been implicated in aging and neurodegenerative diseases such as Alzheimer's disease (AD). While global SIRT2 inhibition has shown promise in reducing amyloid-beta pathology and cognitive deficits in different mouse models of AD, peripheral SIRT2 inhibition has been associated with adverse effects, such as increased inflammation. This suggests that targeted inhibition of specific cellular populations within the brain may represent a more precise and effective approach for the treatment of AD. To explore this hypothesis, we generated a conditional microglial SIRT2 knockout mouse model in the context of AD. Our results reveal that microglial SIRT2 reduction does not confer protective effects in the APP/PS1 model; rather, it aggravates cognitive decline, accelerates amyloid plaque deposition, and increases levels of pro-inflammatory cytokines at early stages of AD pathology. Transcriptomic analysis further indicates that SIRT2-deficient microglia exhibit altered expression of genes associated with aging and synaptic dysfunction. This phenotype was accompanied by increased phagocytosis of PSD95 and impaired long-term potentiation. These findings suggest that while SIRT2 inhibition in some contexts may be beneficial, targeted inhibition within microglia could accelerate AD progression, underscoring the need for cell-specific approaches when considering SIRT2 as a therapeutic target.

Keywords:  Aging; Alzheimer’s disease; Microglia; Neurodegenerative diseases; Neuroinflammation; Sirtuin 2

DOI:  https://doi.org/10.1016/j.bbi.2025.06.016