Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes

Nature, Год журнала: 2022, Номер 611(7935), С. 358 - 364

Опубликована: Ноя. 2, 2022

Язык: Английский

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Metabolism of tissue macrophages in homeostasis and pathology

Cellular and Molecular Immunology, Год журнала: 2021, Номер 19(3), С. 384 - 408

Опубликована: Дек. 7, 2021

Abstract Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy structural components. The emerging field immunometabolism highlights importance maintenance activities immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that key healthy homeostasis but can also contribute pathologies such as metabolic syndrome, atherosclerosis, fibrosis cancer. Macrophage has largely been studied in vitro. However, different organs contain diverse macrophage populations specialize distinct often tissue-specific functions. This context specificity creates diverging challenges fulfill their homeostatic roles particular microenvironment conditions response pathological conditions. Here, we outline current knowledge on requirements adaptations macrophages located tissues during selected diseases.

Язык: Английский

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Dynamic Shifts in the Composition of Resident and Recruited Macrophages Influence Tissue Remodeling in NASH

Cell Reports, Год журнала: 2021, Номер 34(2), С. 108626 - 108626

Опубликована: Янв. 1, 2021

Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4pos Kupffer cells (KCs) decrease number, while monocyte-derived Tim4neg macrophages accumulate. In concert, infiltrating enter liver and consist a transitional subset that expresses Cx3cr1/Ccr2 second characterized by expression Trem2, Cd63, Cd9, Gpmnb; markers ascribed to lipid-associated (LAMs). The Cx3cr1/Ccr2-expressing macrophages, referred as C-LAMs, localize macrophage aggregates hepatic crown-like structures (hCLSs) steatotic liver. C-motif chemokine receptor 2 (Ccr2)-deficient mice, C-LAMs fail appear liver, this prevents hCLS formation, reduces LAM numbers, increases fibrosis. Taken together, our data reveal dynamic changes subsets during NASH link these shifts pathologic tissue remodeling.

Язык: Английский

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Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2020, Номер 18(1), С. 24 - 39

Опубликована: Окт. 22, 2020

Язык: Английский

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Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans

Molecular Metabolism, Год журнала: 2020, Номер 50, С. 101122 - 101122

Опубликована: Ноя. 20, 2020

Nonalcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or inflammation (nonalcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes disease. NAFLD is developing as a burgeoning health challenge, mainly due to worldwide obesity and diabetes epidemics. This review summarizes knowledge on pathogenesis underlying by focusing studies humans hypercaloric nutrition, including effects saturated fat fructose, well adipose tissue dysfunction, leading lipotoxicity, abnormal mitochondrial function, oxidative stress, highlights intestinal dysbiosis. These mechanisms are discussed context current treatments targeting metabolic pathways results related clinical trials. Recent have provided evidence that certain conditions, for example, severe insulin-resistant (SIRD) subgroup (cluster) presence an increasing number gene variants, seem predispose excessive risk its accelerated progression. trials been frequently unsuccessful halting preventing progression, perhaps partly unselected cohorts later stages NAFLD. On basis this literature review, study proposed screening individuals highest genetic acquired SIRD subgroup, treatment concepts earliest pathophysiolgical alterations, namely, adipocyte dysfunction insulin resistance.

Язык: Английский

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Indole-3-Acetic Acid Alleviates Nonalcoholic Fatty Liver Disease in Mice via Attenuation of Hepatic Lipogenesis, and Oxidative and Inflammatory Stress

Nutrients, Год журнала: 2019, Номер 11(9), С. 2062 - 2062

Опубликована: Сен. 3, 2019

Recent evidences have linked indole-3-acetic acid (IAA), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting IAA-mediated protection against nonalcoholic fatty disease (NAFLD) an in vivo study is lacking. In this study, we assessed role of IAA attenuating high-fat diet (HFD)-induced NAFLD male C57BL/6 mice. Administration (50 mg/kg body weight) by intraperitoneal injection was found alleviate HFD-induced elevation fasting blood glucose and homeostasis model assessment insulin (HOMA-IR) index as well plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), glutamic-pyruvic transaminase (GPT) activity. Histological examination further presented protective effect on damage induced HFD feeding. increase triglycerides together upregulation genes related lipogenesis including sterol regulatory element binding-protein 1 (Srebf1), steraroyl coenzyme decarboxylase (Scd1), peroxisome proliferator-activated receptor gamma (PPARγ), acetyl-CoA carboxylase (Acaca), glycerol-3-phosphate acyltransferase, mitochondrial (Gpam), which were mitigated treatment. The results reactive oxygen species (ROS) malonaldehyde (MDA) level along superoxide dismutase (SOD) activity glutathione (GSH) content tissue evidenced oxidative stress. Additionally, attenuated inflammatory response mice exposed shown reduction F4/80-positive macrophage infiltration expression monocyte chemoattractant protein-1 (MCP-1) tumor necrosis factor-α (TNF-α). conclusion, our findings uncover that alleviates hepatotoxicity mice, proves be associated amelioration resistance, lipid metabolism,

Язык: Английский

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Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

Hepatology, Год журнала: 2020, Номер 72(2), С. 729 - 741

Опубликована: Март 16, 2020

The cross‐linking of structural extracellular matrix (ECM) components, especially fibrillar collagens and elastin, is strongly implicated in fibrosis progression resistance to reversal. Lysyl oxidase family members (LOX LOXL1 [lysyl oxidase‐like 1], LOXL2 2], LOXL3 3], LOXL4 like 4]) are copper‐dependent enzymes that play a key role ECM cross‐linking, but have also other intracellular functions relevant carcinogenesis. Although the expression most LOX elevated experimental liver diverse etiologies, their individual contribution incompletely understood. Inhibition as whole LOX, LOXL1, specifically has been shown suppress accelerate its reversal rodent models cardiac, renal, pulmonary, fibrosis. Recent disappointing clinical trials with monoclonal antibody against (simtuzumab) patients pulmonary dampened enthusiasm for member inhibition. However, this unexpected negative outcome may be related inefficient antibody, rather than LOXL2, not qualifying antifibrotic target. Moreover, prove attractive therapeutic targets. In review, we summarize hallmarks, patterns, covalent activities, modes regulation discuss potential inhibition treat general particular.

Язык: Английский

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Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2023, Номер 20(8), С. 487 - 503

Опубликована: Март 17, 2023

Язык: Английский

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Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases

Frontiers in Immunology, Год журнала: 2019, Номер 10

Опубликована: Дек. 3, 2019

Hepatic macrophages play a central role in maintaining homeostasis the liver, as well initiation and progression of liver diseases. can mainly derive from resident hepatic called Kupffer cells or circulating bone marrow-derived monocytes. are self-renewing typically non-migrating stationed sinusoids contrast to originating regulate by mediating immunity against non-pathogenic blood-borne molecules, while participating coordinated immune responses leading pathogen clearance, leukocyte recruitment antigen presentation lymphocytes present vasculature. Monocyte-derived infiltrate into tissue when metabolic toxic damage instigates likely dispensable for replenishing macrophage population homeostasis. In recent years, different populations have been identified with distinct phenotypes discrete functions, far beyond dogma M1 M2 macrophages. pathogenesis acute chronic failure, fibrosis, non-alcoholic fatty disease, alcoholic viral hepatitis, hepatocellular carcinoma, disease resolution. The understanding diseases provides opportunities development targeted therapeutics respective malignancies. This review will summarize current knowledge macrophages, their origin, critical resolution Furthermore, we provide comprehensive overview therapeutic targeting strategies developed treatment

Язык: Английский

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Herbal drug discovery for the treatment of nonalcoholic fatty liver disease

Acta Pharmaceutica Sinica B, Год журнала: 2019, Номер 10(1), С. 3 - 18

Опубликована: Дек. 10, 2019

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver (NAFLD) and its progressive stage, steatohepatitis (NASH). Traditional herbal medicines (THM) have been used centuries to treat indigenous people with various symptoms but without clarified modern-defined types mechanisms. In modern times, NAFLD was defined as a common chronic leading more studies understand NAFLD/NASH pathology progression. THM garnered increased attention providing therapeutic candidates treating NAFLD. this review, new model called "multiple organs-multiple hits" is proposed explain mechanisms NASH Against model, effects frequently-studied THM-yielded single anti-NAFLD drug multiple herb reviewed, among which silymarin berberine already under U.S. FDA-sanctioned phase 4 clinical studies. Furthermore, experimental designs discovery from in discussed. The opportunities challenges reverse pharmacology pharmacokinetic concepts-guided strategies modernization global recognition highlighted. Increasing mechanistic evidence being generated support beneficial role discovery.

Язык: Английский

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