RESUMO
Thioacetamide (TAA) within the liver generates hepatotoxic metabolites that can be induce hepatic fibrosis, similar to the clinical pathological features of chronic human liver disease. The potential protective effect of Albiflorin (ALB), a monoterpenoid glycoside found in Paeonia lactiflora Pall, against hepatic fibrosis was investigated. The mouse hepatic fibrosis model was induced with an intraperitoneal injection of TAA. Hepatic stellate cells (HSCs) were subjected to treatment with transforming growth factor-beta (TGF-ß), while lipopolysaccharide/adenosine triphosphate (LPS/ATP) was added to stimulate mouse peritoneal macrophages (MPMs), leading to the acquisition of conditioned medium. For TAA-treated mice, ALB reduced ALT, AST, HYP levels in serum or liver. The administration of ALB reduced histopathological abnormalities, and significantly regulated the expressions of nuclear receptor-related 1 protein (NURR1) and the P2X purinoceptor 7 receptor (P2×7r) in liver. ALB could suppress HSCs epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, and pro-inflammatory factor level. ALB also remarkably up-regulated NURR1, inhibited P2×7r signaling pathway, and worked as working as C-DIM12, a NURR1 agonist. Moreover, deficiency of NURR1 in activated HSCs and Kupffer cells weakened the regulatory effect of ALB on P2×7r inhibition. NURR1-mediated inhibition of inflammatory contributed to the regulation of ALB ameliorates TAA-induced hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. Therefore, ALB plays a significant part in the mitigation of TAA-induced hepatotoxicity this highlights the potential of ALB as a protective intervention for hepatic fibrosis.
Assuntos
Células Estreladas do Fígado , Cirrose Hepática , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Transdução de Sinais , Tioacetamida , Animais , Tioacetamida/toxicidade , Células Estreladas do Fígado/efeitos dos fármacos , Camundongos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Masculino , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Camundongos Endogâmicos C57BL , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacosRESUMO
Alcoholic liver disease (ALD) is the main factor that induces liver-related death worldwide and represents a common chronic hepatopathy resulting from binge or chronic alcohol consumption. This work focused on revealing the role and molecular mechanism of nodakenin (NK) in ALD associated with hepatic inflammation and lipid metabolism through the regulation of Nur77-P2X7r signaling. In this study, an ALD model was constructed through chronic feeding of Lieber-DeCarli control solution with or without NK treatment. Ethanol (EtOH) or NK was administered to AML-12 cells, after which Nur77 was silenced. HepG2 cells were exposed to ethanol (EtOH) and subsequently treated with recombinant Nur77 (rNur77). Mouse peritoneal macrophages (MPMs) were treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP) and NK, resulting in the generation of conditioned media. In vivo, histopathological alterations were markedly alleviated by NK, accompanied by reductions in serum triglyceride (TG), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels and the modulation of Lipin-1, SREBP1, and Nur77 levels in comparison to the EtOH-exposed group (p < 0.001). Additionally, NK reduced the production of P2X7r and NLRP3. NK markedly upregulated Nur77, inhibited P2X7r and Lipin-1, and promoted the function of Cytosporone B, a Nur77 agonist (p < 0.001). Moreover, Nur77 deficiency weakened the regulatory effect of NK on P2X7r and Lipin-1 inhibition (p < 0.001). In NK-exposed MPMs, cleaved caspase-1 and mature IL-1ß expression decreased following LPS/ATP treatment (p < 0.001). NK also decreased inflammatory-factor production in primary hepatocytes stimulated with MPM supernatant. NK ameliorated ETOH-induced ALD through a reduction in inflammation and lipogenesis factors, which was likely related to Nur77 activation. Hence, NK is a potential therapeutic approach to ALD.
Assuntos
Cumarínicos , Glucosídeos , Lipopolissacarídeos , Hepatopatias Alcoólicas , Animais , Camundongos , Lipopolissacarídeos/farmacologia , Hepatopatias Alcoólicas/metabolismo , Fígado , Etanol/metabolismo , Inflamação/metabolismo , Transdução de Sinais/fisiologia , Trifosfato de Adenosina/metabolismo , Camundongos Endogâmicos C57BL , Compostos OrgânicosRESUMO
Due to the highly stable structure of keratin, the extraction and dissolution steps of animal medicines rich in keratin are complex, which seriously restricts the detection efficiency and flux. Therefore, this study simplified the pre-treatment steps of horn samples and optimized the detection methods of characteristic peptides to improve the efficiency of identifying the specificity of horn-derived animal medicines. For detection of the characteristic peptides in horn-derived animal medicines treated with/without iodoace-tamide(IAA), the ion pair conditions of the characteristic peptides were optimized, and the retention time, intensity and other data of the specific peptides were compared between the samples treated with/without IAA. Two pre-treatment methods, direct enzymatic hydrolysis and total protein extraction followed by enzymatic hydrolysis, were used to prepare horn-derived animal medicine samples. The effects of different methods on the detection of specific peptides in the samples of Saiga antelope horn, water buffalo horn, goat horn, and yak horn were compared regarding the retention time of specific peptides and ion intensity. The results indicated that after direct enzymatic hydrolysis, the specific peptides in the samples without IAA treatment can be detected. Compared with the characteristic peptides in the samples treated with IAA, their retention time shifted back and the mass spectrometry response slightly decreased. The specific peptides of the samples without IAA treatment had good specificity and did not affect the specificity identification of horn-derived animal medicines. Overall, the process of direct enzymatic hydrolysis can be used to treat horn samples, omitting the steps of protein extraction and dithiothreitol and IAA treatment, significantly improving the pre-treatment efficiency without affecting the specificity identification of horn-derived animal medicines. This study provides ideas for quality research and standard improvement of horn-derived animal medicines.
Assuntos
Cornos , Queratinas , Peptídeos , Animais , Cornos/química , Peptídeos/química , Queratinas/química , Bovinos , Cabras , Búfalos , Cromatografia Líquida de Alta PressãoRESUMO
OBJECTIVE: To explore the relationship of the exposure to phthalate esters (PAE) and polycyclic aromatic hydrocarbons (PAH) with clinical premature delivery during early pregnancy. METHODS: We conducted a baseline questionnaire survey among 821 pregnant women undergoing prenatal examination in Hubei Provincial Maternal and Child Health Care Hospital, collected their morning urine samples and followed them up to the outcomes of pregnancy. We quantitatively analyzed 10 PAE and 10 PAH metabolites in the urine samples, followed by Mann-Whitney U test, chi-square test, and logistic regression analysis. RESULTS: The detection rate of the 5 factors exposed to was >80% while that of phthalic acid monobenzyl ester (MBzP) was <50% in PAEs; that of the 5 factors exposed to was >80%, that of 3-hydroxyphene (3-OHPHE) was 86.91% while that of 4-hydroxyphene (4-OHPHE) was <50% in PAHs. Logistic regression analysis showed that the risk of premature delivery was higher in the high MBzP- than in the low MBzP-exposure group (aOR = 2.26, 95% CI: 1.17ï¼4.39). CONCLUSION: High MBzP-exposure may be a risk factor for premature delivery.
Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Criança , Humanos , Feminino , Gravidez , Estudos de Coortes , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/urina , Fatores de Risco , Família , ÉsteresRESUMO
Neural radiance fields (NeRF) have achieved great success in novel view synthesis and 3D representation for static scenarios. Existing dynamic NeRFs usually exploit a locally dense grid to fit the deformation fields; however, they fail to capture the global dynamics and concomitantly yield models of heavy parameters. We observe that the 4D space is inherently sparse. Firstly, the deformation fields are sparse in spatial but dense in temporal due to the continuity of motion. Secondly, the radiance fields are only valid on the surface of the underlying scene, usually occupying a small fraction of the whole space. We thus represent the 4D scene using a learnable sparse latent space, a.k.a. SLS4D. Specifically, SLS4D first uses dense learnable time slot features to depict the temporal space, from which the deformation fields are fitted with linear multi-layer perceptions (MLP) to predict the displacement of a 3D position at any time. It then learns the spatial features of a 3D position using another sparse latent space. This is achieved by learning the adaptive weights of each latent feature with the attention mechanism. Extensive experiments demonstrate the effectiveness of our SLS4D: It achieves the best 4D novel view synthesis using only about 6% parameters of the most recent work.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ligustrum lucidum W.T. Aiton is a traditional Chinese medicine that has long been used with high hepatoprotective therapeutic and condition value. Specnuezhenide (SP), the standard prominent secoiridoid compound of Fructus Ligustri Lucidi may ameliorate hepatic inflammation in chronic liver diseases. AIM OF THE STUDY: Regulating inflammation through SIRT6-P2X7R axis has caused the emergence of novel molecular mechanism strategies for reversing hepatic fibrosis. This study focused on the mechanism of SP in modulating the liver inflammatory microenvironment in hepatic fibrosis. MATERIALS AND METHODS: C57BL/6 mice with hepatic fibrosis were stimulated with thioacetamide (TAA) prior to administration of SP. Hepatic stellate cells (HSCs) or normal mouse primary hepatocytes were exposed to transforming growth factor-ß (TGF-ß) treatment. Meanwhile, normal mouse bone marrow-derived macrophages (BMDMs) were treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP), aiming to obtain the conditioned medium. HSCs and hepatocytes were transfected with SIRT6 knockdown vector (siRNA-SIRT6) to estimate the impact of SP on the SIRT6-P2X7R/NLRP3 signaling pathway. RESULTS: SP suppressed the HSCs extracellular matrix (ECM) deposition as well as pro-inflammatory cytokine levels induced by the medium of BMDMs or TGF-ß. In addition, SP also significantly up-regulated SIRT6, inhibited P2X7R-NLRP3 inflammasome in HSCs and hepatocytes, and functioned as MDL-800 (a SIRT6 agonist). SP reduced the hepatocytes pyroptosis and further prevented the occurrence of inflammatory response in the liver. SP could inhibit the activation of BMDMs and impede IL-1ß and IL-18 from entering extracellular regions. Moreover, deficiency of SIRT6 in HSCs or hepatocytes reduced SP's regulation of P2X7R suppression. For TAA-treated mice, SP mitigated histopathological changes, ECM accumulation, EMT process, and NETs formation in hepatic fibrosis. CONCLUSIONS: Therefore, SP decreased inflammatory response via SIRT6-P2X7R/NLRP3 pathway and suppressed fibrillogenesis. These findings supported SP as the novel candidate to treat hepatic fibrosis.
RESUMO
HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition plays a key role in the progression of hepatic ï¬brosis. The present study focused on the hepatoprotective effect of Ginsenoside Rc (Rc), one of the protopanaxadiol type ginsenoside, which has contributed to reverse activated HSCs to improve hepatic fibrosis via regulating Nur77-TLR4/MyD88 signaling pathway. We established the hepatic fibrosis model by intraperitoneal injection of carbon tetrachloride (CCl4). And HSCs were stimulated with TGF-ß, followed by silencing of Nur77, and then incubated in Rc. Rc significantly alleviated histopathological changes, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Rc could upregulate the Nur77 and downregulate ï¬brosis markers in the liver of mice, including decreasing the expressions of α-SMA, Collagen-I, the ratio of TIMP-1/MMP-13. Rc significantly increased the expression of Nur77 and suppressed the production of ECM in HSCs. Rc inhibited TLR4 signaling pathway, consequently reversing the inï¬ammatory response, including the production of MyD88, IRAK1, IRAK4 and IL-23. When Nur77 was knocked in TGF-ß-stimulated HSCs, TLR4 and α-SMA production were increased. Rc suppressed these activatory eï¬ects in Nur77 knockdown HSCs. Rc reduced inflammatory reaction by regulating the Nur77-TLR4 signaling pathway while suppressing the fibrogenesis suggesting, underscoring a promising approach of Rc for the treatment in hepatic fibrosis. Targeting Nur77-TLR4 signaling in HSCs would be the potential strategy for Rc against hepatic fibrosis.