Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Авг. 5, 2023

Microglia are the resident innate immune cells in brain with a major role orchestrating responses. They also provide frontline of host defense central nervous system (CNS) through their active phagocytic capability. Being professional phagocyte, microglia participate and autophagic clearance cellular waste debris as well toxic protein aggregates, which relies on optimal lysosomal acidification function. Defective microglial leads to impaired functions result perpetuation neuroinflammation progression neurodegeneration. Reacidification lysosomes has been shown reverse neurodegenerative pathology Alzheimer's disease. In this review, we summarize key factors mechanisms contributing impairment associated dysfunction microglia, how these defects contribute We further discuss techniques monitor pH therapeutic agents that can reacidify under disease conditions. Finally, propose future directions investigate lysosome-mitochondria crosstalk neuron-glia interaction for more comprehensive understanding its broader CNS physiological pathological implications.

Язык: Английский

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Therapeutic targeting of obesity-induced neuroinflammation and neurodegeneration

Frontiers in Endocrinology, Год журнала: 2025, Номер 15

Опубликована: Янв. 17, 2025

Obesity is a major modifiable risk factor leading to neuroinflammation and neurodegeneration. Excessive fat storage in obesity promotes the progressive infiltration of immune cells into adipose tissue, resulting release pro-inflammatory factors such as cytokines adipokines. These inflammatory mediators circulate through bloodstream, propagating inflammation both periphery central nervous system. Gut dysbiosis, which results leaky intestinal barrier, exacerbates plays significant role linking pathogenesis neurodegeneration gut-brain/gut-brain-liver axis. Inflammatory states within brain can lead insulin resistance, mitochondrial dysfunction, autolysosomal increased oxidative stress. disruptions impair normal neuronal function subsequently cognitive decline motor deficits, similar pathologies observed neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease. Understanding underlying disease mechanisms crucial for developing therapeutic strategies address defects these metabolic pathways. In this review, we summarize provide insights different strategies, methods alter gut lifestyle changes, dietary supplementation, well pharmacological agents derived from natural sources, that target obesity-induced

Язык: Английский

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Role of metabolic dysfunction and inflammation along the liver–brain axis in animal models with obesity-induced neurodegeneration

Neural Regeneration Research, Год журнала: 2024, Номер 20(4), С. 1069 - 1076

Опубликована: Май 17, 2024

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease Parkinson’s disease. Obesity-related conditions like type 2 diabetes non-alcoholic fatty liver exacerbate this relationship. Peripheral lipid accumulation, particularly in liver, initiates a cascade inflammatory processes that extend brain, influencing critical regulatory regions. Ceramide palmitate, key components, along with transporters lipocalin-2 apolipoprotein E, contribute neuroinflammation by disrupting blood–brain barrier integrity promoting gliosis. insulin resistance further exacerbates brain neuroinflammation. Preclinical interventions targeting peripheral metabolism signaling pathways have shown promise reducing animal models. However, translating these findings clinical practice requires investigation into human subjects. In conclusion, dysfunction, inflammation, are integral neurodegeneration. Understanding complex mechanisms holds potential for identifying novel therapeutic targets improving outcomes diseases.

Язык: Английский

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Liver diseases: epidemiology, causes, trends and predictions

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Фев. 4, 2025

Abstract As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles metabolism, detoxification, immune response. Various factors including viruses, alcohol, metabolites, toxins, other pathogenic agents can compromise function, leading to acute or chronic injury that may progress end-stage diseases. While sharing common features, diseases exhibit distinct pathophysiological, clinical, therapeutic profiles. Currently, contribute approximately 2 million deaths globally each year, imposing significant economic social burdens worldwide. However, there no cure for many kinds of diseases, partly due lack thorough understanding development these Therefore, this review provides comprehensive examination epidemiology characteristics covering spectrum from conditions manifestations. We also highlight multifaceted mechanisms underlying initiation progression spanning molecular cellular levels networks. Additionally, offers updates on innovative diagnostic techniques, current treatments, potential targets presently under clinical evaluation. Recent advances pathogenesis hold critical implications translational value novel strategies.

Язык: Английский

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Editorial: Lipid metabolism dysregulation in obesity-related diseases and neurodegeneration

Frontiers in Endocrinology, Год журнала: 2025, Номер 16

Опубликована: Фев. 11, 2025

Editorial: Lipid Metabolism Dysregulation in Obesity-Related Diseases and Neurodegeneration Provisionally accepted

Язык: Английский

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Lysosomal acidification impairment in astrocyte-mediated neuroinflammation

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Март 10, 2025

Abstract Astrocytes are a major cell type in the central nervous system (CNS) that play key role regulating homeostatic functions, responding to injuries, and maintaining blood-brain barrier. also regulate neuronal functions survival by modulating myelination degradation of pathological toxic protein aggregates. have recently been proposed possess both autophagic activity active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete cellular cargos. Defective lysosomal acidification astrocytes impairs their resulting accumulation debris, excessive myelin lipids, aggregates, ultimately contributes propagation neuroinflammation neurodegenerative pathology. Restoration impaired represent new neuroprotective strategy therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, lipid mediated toxicity, contribute impairment associated dysfunction astrocytes. We discuss astrocyte-mediated primarily context diseases along with other brain injuries. then highlight re-acidification as restore well degradative capacity conclude providing future perspectives phagocytes crosstalk CNS cells impart or effects.

Язык: Английский

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Nanotechnology applications in the regulation of metabolic diseases

Coordination Chemistry Reviews, Год журнала: 2025, Номер 538, С. 216736 - 216736

Опубликована: Апрель 22, 2025

Язык: Английский

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Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 5, 2024

Abstract Current research efforts in polymer and nanotechnology applications are primarily focused on cargo delivery to enhance the therapeutic index, with limited attention being paid self‐molecularly targeted nanoparticles, which may also exhibit significant potential. Long‐term anomalous lipid accumulation liver is a highly relevant factor contributing diseases. However, development of reliable medications their pharmacological mechanisms remain insufficient. Herein, polyguanide nanoinhibitors (PGNI) depot constructed by copolymerizing biguanide derivatives different proportions onto prepolymers. The for ability ameliorate vitro vivo screened, subsequently demonstrated that covalently polymeric guanidine chains superior efficacy ameliorating hepatic via heterogeneous compared small‐molecule guanidine. It found PGNIs stabilize metabolism liver, preferably biosafety. More importantly, PGNI ingested localized hepatocyte lysosomes locked interact vesicular adenosine triphosphatase (V‐ATPase) lysosomes, leading inhibition V‐ATPase lysosomal acidification, thereby activating AMPK pathway, reducing fatty acid synthesis, enhancing lipolysis oxidation. These results imply polymer‐formed nanoparticles can serve as inhibitors, offering novel approach applications.

Язык: Английский

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Succinic Acid Improves the Metabolism of High-Fat Diet-Induced Mice and Promotes White Adipose Browning

Nutrients, Год журнала: 2024, Номер 16(22), С. 3828 - 3828

Опубликована: Ноя. 8, 2024

Succinic acid plays a crucial role as an essential intermediate in the mitochondrial tricarboxylic cycle mitochondria. In recent years, growing evidence has supported important of succinic fat metabolism. Therefore, we aimed to investigate effects on adipose tissue metabolism and insulin sensitivity high-fat diet (HFD)-induced obese mice try explore its potential mechanism. We found that addition (40 mM) drinking water inhibited hypertrophy inguinal white (iWAT) HFD-induced mice. Furthermore, supplementation enhanced improved their glucose tolerance Interestingly, lipid HFD-fed mice, shown by decreased serum levels TG, TC, LDL-C, increased HDL-C. addition, expression browning markers mitochondria-related genes iWAT. Further studies showed promotes iWAT activating PI3K-AKT/MAPK signaling pathway. These results suggest be used effective component for dietary intervention may, therefore, play ameliorating preventing obesity associated metabolic diseases caused HFD.

Язык: Английский

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Exploring the heterogeneity of hepatic and pancreatic fat deposition in obesity: implications for metabolic health

Frontiers in Endocrinology, Год журнала: 2024, Номер 15

Опубликована: Окт. 8, 2024

Objective This retrospective observational study investigates the heterogeneity of hepatic and pancreatic fat deposition its implications for metabolic health in individuals with obesity. Methods A total 706 patients obesity underwent an MRI to quantify liver fat. Patients were classified into four groups based on deposition: no (None), fatty pancreas only (NAFPD), (NAFLD), both conditions (NAFLD+NAFPD). Biochemical profiles, insulin resistance (Homeostatic Model Assessment Insulin Resistance, HOMA-IR), β-cell function analyzed. series multiple linear regressions used investigate independent effects characteristics glucose, insulin, C-peptide at 0h. Another regression was performed evaluate basic average fat, mean visceral Results The majority (76.63%) exhibited NAFLD NAFPD, highlighting among Groups displayed significantly higher fasting C-peptide, HOMA-IR levels than those without (P < 0.01). Fatty alone did not influence these parameters > 0.05). underscores greater impact compared Conclusions confirms complex obesity, being a more influential factor disturbances pancreas. prevalent co-occurrence NAFPD this population need targeted management strategies focusing reduction mitigate risk.

Язык: Английский

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