An update on the regulatory mechanisms of NLRP3 inflammasome activation

Cellular and Molecular Immunology, Год журнала: 2021, Номер 18(5), С. 1141 - 1160

Опубликована: Апрель 13, 2021

Abstract The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β triggering pyroptosis, which paramount importance variety physiological pathological conditions. Over past decade, considerable advances have been made elucidating molecular mechanisms underlying priming/licensing (Signal 1) assembly 2) NLRP3 activation. Recently, number studies indicated that step regulated by complicated at both transcriptional posttranslational levels. In this review, we discuss current understanding mechanistic details activation with particular emphasis on protein-protein interactions, modifications, spatiotemporal regulation machinery. We also present detailed summary multiple positive and/or negative regulatory pathways providing upstream signals culminate assembly. A better will provide opportunities for development methods prevention treatment inflammasome-related diseases.

Язык: Английский

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Transcription factors: Bridge between cell signaling and gene regulation

PROTEOMICS, Год журнала: 2021, Номер 21(23-24)

Опубликована: Июль 27, 2021

Transcription factors (TFs) are key regulators of intrinsic cellular processes, such as differentiation and development, the response to external perturbation through signaling pathways. In this review we focus on role TFs a link between pathways gene regulation. Cell tends result in modulation set that then lead changes cell's transcriptional program. We highlight molecular layers at which TF activity can be measured associated technical conceptual challenges. These include post-translational modifications (PTMs) TF, regulation binding DNA chromatin accessibility epigenetics, expression target genes. large number understudied both studies, our knowledge about known targets has strong literature bias. argue serve perfect bridge fields signaling, separating these hinders understanding cell functions. Multi-omics approaches measure multiple dimensions ideally suited study interplay using anchor two fields.

Язык: Английский

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Farnesoid X receptor (FXR): Structures and ligands

Computational and Structural Biotechnology Journal, Год журнала: 2021, Номер 19, С. 2148 - 2159

Опубликована: Янв. 1, 2021

Farnesoid X receptor (FXR) is a bile acid activated nuclear (BAR) and mainly expressed in the liver intestine. Upon ligand binding, FXR regulates key genes involved metabolic process of synthesis, transport reabsorption also metabolism carbohydrates lipids. Because its important functions, considered as promising drug target for therapy acid-related diseases. With approval obeticholic (OCA) first small molecule to FXR, many other molecules are being evaluated clinical trials. This review summarizes structures especially binding domain, development (including agonists antagonists) targeting FXR.

Язык: Английский

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Vitamin D and Its Target Genes

Nutrients, Год журнала: 2022, Номер 14(7), С. 1354 - 1354

Опубликована: Март 24, 2022

The vitamin D metabolite 1α,25-dihydroxyvitamin D3 is the natural, high-affinity ligand of transcription factor receptor (VDR). In many tissues and cell types, VDR binds in a ligand-dependent fashion to thousands genomic loci modulates, via local chromatin changes, expression hundreds primary target genes. Thus, epigenome transcriptome VDR-expressing cells directly affected by D. Vitamin genes encode for proteins with large variety physiological functions, ranging from control calcium homeostasis, innate adaptive immunity, cellular differentiation. This review will discuss VDR’s binding DNA, as well its genome-wide locations interaction partner proteins, context chromatin. information be integrated into model signaling, explaining regulation

Язык: Английский

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Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(11), С. 6046 - 6046

Опубликована: Май 27, 2022

Bile acids (BAs) are a group of amphiphilic molecules consisting rigid steroid core attached to hydroxyl with varying number, position, and orientation, hydrophilic side chain. While BAs act as detergents solubilize lipophilic nutrients in the small intestine during digestion absorption, they also hormones. Farnesoid X receptor (FXR) is nuclear that forms heterodimer retinoid α (RXRα), activated by enterohepatic circulation reabsorbed via transporters ileum colon, plays critical role regulating gene expression involved cholesterol, BA, lipid metabolism liver. The FXR/RXRα exists distal regulates production fibroblast growth factor (FGF) 15/FGF19, hormone traveling activates hepatic FGF 4 (FGFR4)-β-klotho complex metabolism, well those cell proliferation. Agonists for FXR analogs FGF15/19 currently recognized promising therapeutic target metabolic syndrome cholestatic diseases.

Язык: Английский

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Roles of Estrogen, Estrogen Receptors, and Estrogen-Related Receptors in Skeletal Muscle: Regulation of Mitochondrial Function

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(3), С. 1853 - 1853

Опубликована: Янв. 17, 2023

Estrogen is an essential sex steroid hormone that functions primarily in female reproductive system, as well a variety of tissues and organs with pleiotropic effects, such cardiovascular, nervous, immune, musculoskeletal systems. Women low estrogen, exemplified by those postmenopause, are therefore prone to suffer from various disorders, i.e., cardiovascular disease, dementia, metabolic syndrome, osteoporosis, sarcopenia, frailty, so on. regulates the expression its target genes binding cognate receptors, estrogen receptors (ERs) α β. Notably, estrogen-related (ERRs) α, β, γ originally identified orphan share substantial structural homology common transcriptional targets ERs. Accumulating evidence suggests ERs ERRs play crucial roles skeletal muscles, muscle mass maintenance, exercise physiology, regeneration. In this article, we review potential regulatory particularly regard mitochondrial function metabolism.

Язык: Английский

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Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 28, 2025

Abstract Nuclear receptors (NRs) are thought to dynamically alternate between transcriptionally active and repressive conformations, which stabilized upon ligand binding. Most NR series exhibit limited bias, primarily consisting of agonists or neutral antagonists, but not inverse agonists—a limitation that restricts understanding the functional conformational ensemble. Here, we report a for peroxisome proliferator-activated receptor gamma (PPARγ) spans pharmacological spectrum from repression (inverse agonism) activation (agonism) where subtle structural modifications switch compound activity. While crystal structures provide snapshots fully state, NMR spectroscopy conformation-activity relationship analysis reveals compounds within shift PPARγ ensemble conformations natively populated in apo/ligand-free Our findings reveal molecular framework minimal chemical enhance agonism elucidate their influence on dynamic

Язык: Английский

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Nuclear receptors are the major targets of endocrine disrupting chemicals

Molecular and Cellular Endocrinology, Год журнала: 2019, Номер 502, С. 110665 - 110665

Опубликована: Ноя. 21, 2019

Язык: Английский

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Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease

Acta Pharmaceutica Sinica B, Год журнала: 2021, Номер 11(10), С. 3015 - 3034

Опубликована: Фев. 26, 2021

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to health elderly. The current treatment has been demonstrated relieve symptoms, and discovery new small-molecule compounds regarded promising strategy. Of note, homeostasis autolysosome pathway (ALP) closely associated with PD, impaired autophagy may cause death neurons thereby accelerating progress PD. Thus, pharmacological targeting drawn rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERRα, C-Abelson, well their relevant in PD models, which will shed light clue exploiting more potential targeted drugs tracking near future.

Язык: Английский

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Xenobiotic metabolism and transport in Caenorhabditis elegans

Journal of Toxicology and Environmental Health Part B, Год журнала: 2021, Номер 24(2), С. 51 - 94

Опубликована: Фев. 17, 2021

Caenorhabditis elegans has emerged as a major model in biomedical and environmental toxicology. Numerous papers on toxicology pharmacology C. have been published, this species now adopted by investigators academic toxicology, pharmacology, drug discovery labs. also attracted the interest of governmental regulatory agencies charged with evaluating safety chemicals. However, major, fundamental aspect toxicological science remains underdeveloped elegans: xenobiotic metabolism transport processes that are critical to understanding toxicokinetics toxicodynamics, extrapolation other species. The aim review was initially briefly describe history trajectory use pharmacological studies. Subsequently, physical barriers chemical uptake role worm microbiome transformation were described. Then what is not known regarding classic Phase I, II, III performed. In addition, following discussed (1) regulation metabolism; (2) published for specific chemicals; (3) genetic diversity these elegans. Finally, placed an evolutionary context; key areas future research highlighted; implications extrapolating toxicity results discussed.

Язык: Английский

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