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1.
Biochem Biophys Res Commun ; 688: 149122, 2023 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-37951152

RESUMO

Damage-associated molecular patterns released upon hepatocyte injury ensuing non-alcoholic steatohepatitis (NASH) can stimulate innate immunity by activating NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, thereby triggering pro-inflammatory cascades in the liver. Aberrant NLRP3 activation allied to compromised autophagic clearance of its components contributes to the progression of multiple inflammatory diseases. Such intricate interplay, however, was not fully deciphered in NASH. Prior studies have illuminated the ability of vitamin D3 to temper inflammasome activation in several contexts, prompting us to probe the impact of vitamin D3, particularly its active form, calcitriol (CAL), on NLRP3 overactivation in a high-fat diet (HFD)-based NASH model and its potential dependence on autophagy. Hydroxychloroquine (HCQ), an autophagy inhibitor, was co-administered with CAL to examine the likely modulation of the NLRP3/autophagy crosstalk. Our results showed that treatment with CAL countervailed the histopathological derangement reported in the livers of HFD-fed mice that paralleled a restoration of vitamin D receptor gene expression and reduction in sterol regulatory element binding protein 1c levels. Moreover, p62 was curtailed with CAL treatment indicating autophagy induction. CAL also prompted a reduction in NLRP3, caspase-1, gasdermin D, and IL-18 protein levels along with the apoptosis-associated speck-like protein (ASC) gene expression. Treatment with CAL also reduced IL-1ß and caspase-3 immunoreactivities compared to control. Intriguingly, CAL modulatory effects on inflammasome activation were curbed in the group that received HCQ, suggesting a potential autophagy dependency. Accordingly, the current study suggests that CAL was capable of ameliorating NASH via inhibiting NLRP3 inflammasome activation in an autophagy-dependent manner.


Assuntos
Inflamassomos , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Inflamassomos/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Colecalciferol/farmacologia , Autofagia , Calcitriol/farmacologia
2.
Life Sci ; 332: 122124, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37742738

RESUMO

Vitamin D (VD) is a secosteroid hormone that is renowned for its crucial role in phospho-calcium homeostasis upon binding to the nuclear vitamin D receptor (VDR). Over and above, the pleiotropic immunomodulatory, anti-inflammatory, and metabolic roles VD plays in different disease settings started to surface in the past few decades. On the other hand, a growing body of evidence suggests a correlation between non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form non-alcoholic steatohepatitis (NASH) with vitamin D deficiency (VDD) owing to the former's ingrained link with obesity and metabolic syndrome. Accordingly, a better understanding of the contribution of disrupted VDR signalling to NAFLD incidence and progression would provide further insights into its diagnosis, treatment modalities, and prognosis. This is especially significant as, hitherto, no drug for NAFLD has been approved. This review, therefore, sought to set forth the likely contribution of VDR signalling in NAFLD and how it might influence its multiple drivers.

3.
Biomed Pharmacother ; 157: 114050, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36462310

RESUMO

Experimental and clinical evidence implicate disrupted gut barrier integrity in provoking innate immune responses, specifically macrophages, towards the progression of non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptors (PPARs), a subset of the nuclear receptor superfamily, act to fine-tune several metabolic and inflammatory processes implicated in NASH. As such, the current study was carried out to decipher the potential role of dual PPAR α/δ activation using elafibranor (ELA) on ileal macrophage polarization (MP) and its likely impact on the liver in a NASH setting. To achieve this aim, an in vitro NASH model using fat-laden HepG2 cells was first used to validate the impact of ELA on hepatic fat accumulation. Afterwards, ELA was used in a combined model of dietary NASH and chronic colitis analogous to the clinical presentation of NASH parallel with intestinal barrier dysfunction. ELA mitigated fat accumulation in vitro as evidenced by Oil Red-O staining and curbed triglyceride levels. Additionally, ELA restored the expression of tight junctional proteins, claudin-1 and occludin, along with decreasing intestinal permeability and inflammation skewing ileal macrophages towards the M2 phenotype, as indicated by boosted arginase-1 (Arg1) and curtailed inducible nitric oxide synthase (iNOS) expression levels. These changes were aligned with a modulation in hepatic toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) along with ileal interleukin-10 (IL-10)/signal transducer and activator of transcription-3 (STAT3) axes. Overall, the present findings suggest that the dual PPAR α/δ agonist, ELA, may drive MP in the ileum towards the M2 phenotype improving intestinal integrity towards alleviating NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , PPAR delta , Humanos , NF-kappa B/metabolismo , Interleucina-10/metabolismo , PPAR alfa/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , PPAR delta/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição STAT3/metabolismo
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