Hallmarks of Health

Cell, Год журнала: 2020, Номер 184(1), С. 33 - 63

Опубликована: Дек. 18, 2020

Язык: Английский

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Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 15, 2023

Abstract The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or “proteostasis”. quality control systems involve ER-associated degradation, chaperons, and autophagy. ER stress is activated when proteostasis broken with an accumulation of misfolded unfolded proteins in the ER. activates adaptive response to restore by initiating kinase R-like kinase, activating transcription factor 6, inositol requiring enzyme 1. multifaceted, acts on aspects at epigenetic level, including processing. Accumulated data indicates its key role homeostasis other diverse involved various ocular diseases, such glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, tumors, surface myopia. This review summarizes molecular mechanisms underlying aforementioned diseases from perspective. Drugs (chemicals, neurotrophic factors, nanoparticles), gene therapy, stem cell therapy are used treat alleviating stress. We delineate advancement targeting provide new treatment strategies diseases.

Язык: Английский

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Signaling pathways in obesity: mechanisms and therapeutic interventions

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Авг. 28, 2022

Abstract Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases risk of several diseases, such as type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver linked to lower life expectancy. Although lifestyle intervention (diet exercise) has remarkable effects on weight management, achieving long-term success at loss extremely challenging, prevalence continues rise worldwide. Over past decades, pathophysiology been extensively investigated, an increasing number signal transduction pathways have implicated obesity, making it possible fight more effective precise way. In this review, we summarize recent advances pathogenesis from both experimental clinical studies, focusing signaling their roles regulation food intake, glucose homeostasis, adipogenesis, thermogenesis, inflammation. We also discuss current anti-obesity drugs, well compounds trials, that target these signals. The evolving knowledge may shed light future direction research, move into new era precision medicine.

Язык: Английский

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The role of leptin and ghrelin in the regulation of appetite in obesity

Peptides, Год журнала: 2025, Номер 186, С. 171367 - 171367

Опубликована: Фев. 19, 2025

Язык: Английский

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N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor

Journal of Medicinal Chemistry, Год журнала: 2018, Номер 62(2), С. 965 - 973

Опубликована: Дек. 13, 2018

The ghrelin receptor or growth hormone secretagogue (GHSR) is a G-protein-coupled that controls and insulin secretion, food intake, reward-seeking behaviors. Liver-expressed antimicrobial peptide 2 (LEAP2) was recently described as an endogenous antagonist of GHSR. Here, we present study aimed at delineating the structural determinants required for LEAP2 activity toward We demonstrate entire sequence not necessary its actions. Indeed, N-terminal part alone confers binding to LEAP2. found both behave inverse agonists GHSR competitive antagonists ghrelin-induced inositol phosphate production calcium mobilization. Accordingly, region able inhibit intake in mice. These data unexpected pharmacological likely have important role control response under normal pathological conditions.

Язык: Английский

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Regulation of GH and GH Signaling by Nutrients

Cells, Год журнала: 2021, Номер 10(6), С. 1376 - 1376

Опубликована: Июнь 2, 2021

Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, body maintenance, conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, the aim preserve protein storages survival. IGF-I/insulin signaling was also first one identified regulation lifespan relation nutrient-sensing. Indeed, nutrients crucial modifiers GH/IGF-I axis, these regulate complex orchestration utilization cell tissues. The this review is summarize current knowledge on reciprocal among macro micronutrients, dietary regimens, including caloric restriction. Expanding depth information topic could open perspectives nutrition management, prevention, treatment deficiency or excess during life.

Язык: Английский

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Ghrelin’s Relationship to Blood Glucose

Endocrinology, Год журнала: 2019, Номер 160(5), С. 1247 - 1261

Опубликована: Март 15, 2019

Much effort has been directed at studying the orexigenic actions of administered ghrelin and potential effects endogenous system on food intake, reward, body weight, adiposity, energy expenditure. Although ghrelin's some these processes remain ambiguous, its glucoregulatory have emerged as well-recognized features during extreme metabolic conditions. The blood glucose-raising are beneficial starvation-like conditions, defending against life-threatening falls in glucose, but they seemingly detrimental obese states certain monogenic forms diabetes, contributing to hyperglycemia. Also interest, glucose negatively regulates secretion. This article reviews literature suggesting existence a glucose-ghrelin axis highlights factors that mediate ghrelin, especially extremes such starvation diabetes.

Язык: Английский

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Liver-expressed antimicrobial peptide 2 antagonizes the effect of ghrelin in rodents

Journal of Endocrinology, Год журнала: 2019, Номер 244(1), С. 13 - 23

Опубликована: Сен. 20, 2019

Ghrelin, a stomach-derived peptide, promotes feeding and growth hormone (GH) secretion. A recent study identified liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inhibitor of ghrelin-induced GH secretion, but the effect LEAP2 in brain remained unknown. In this study, we showed that intracerebroventricular (i.c.v.) administration to rats suppressed central ghrelin functions including Fos expression hypothalamic nuclei, promotion food intake, blood glucose elevation, body temperature reduction. did not inhibit neuropeptide Y (NPY)-induced intake or des-acyl reduction temperature, indicating inhibitory effects were specific for GHSR. Plasma levels varied according status seemed be dependent on hepatic Leap2 expression. Furthermore, via AMPK activation. Together, these results reveal inhibits crosstalk between liver stomach.

Язык: Английский

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Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Авг. 19, 2020

Abstract Ghrelin is a gastric peptide hormone with important physiological functions. The unique feature of ghrelin its Serine 3 acyl-modification, which essential for ghrelin’s activity. However, it remains to be elucidated why the acyl-modification necessary To address these questions, we solved crystal structure receptor bound antagonist. ligand-binding pocket bifurcated by salt bridge between E124 and R283. A striking wide gap (crevasse) TM6 TM7 bundles that rich in hydrophobic amino acids, including cluster phenylalanine residues. Mutagenesis analyses suggest interaction acyl acid moiety may participate transforming into an active conformation.

Язык: Английский

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Gut-brain communication and obesity: understanding functions of the vagus nerve

Journal of Clinical Investigation, Год журнала: 2021, Номер 131(10)

Опубликована: Май 16, 2021

Given the crucial role of gastrointestinal tract and associated organs in handling nutrient assimilation metabolism, it has long been known that its communication with brain is important for control ingestive behavior body weight regulation. It also clear gut-brain bidirectional utilizes both rapid neural slower humoral mechanisms pathways. However, progress understanding these leveraging them treatment obesity metabolic disease hindered by enormous dimension gut mucosa, complexity signaling systems, lack specific tools. With ascent modern neurobiological technology, our vagal afferents begun to change. The first function-specific populations providing nutritional feedback as well feed-forward signals have identified genetics-guided methodology, hoped extension methodology other pathways will follow soon. Currently, efficient clinical treat limited a few hormones, but more complete projection-specific neuronal should make possible develop selective effective neuromodulation approaches.

Язык: Английский

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