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1.
FASEB J ; 38(16): e70014, 2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39183544

RESUMO

End-ischemic normothermic mechanical perfusion (NMP) could provide a curative treatment to reduce cholestatic liver injury from donation after circulatory death (DCD) in donors. However, the underlying mechanism remains elusive. Our previous study demonstrated that air-ventilated NMP could improve functional recovery of DCD in a preclinical NMP rat model. Here, metabolomics analysis revealed that air-ventilated NMP alleviated DCD- and cold preservation-induced cholestatic liver injury, as shown by the elevated release of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and γ-glutamyl transferase (GGT) in the perfusate (p < .05) and the reduction in the levels of bile acid metabolites, including ω-muricholic acid, glycohyodeoxycholic acid, glycocholic acid, and glycochenodeoxycholate (GCDC) in the perfused livers (p < .05). In addition, the expression of the key bile acid metabolism enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is predominantly expressed in hepatocytes, was substantially elevated in the DCD rat liver, followed by air-ventilated NMP (p < .05), and in vitro, this increase was induced by decreased GCDC and hypoxia-reoxygenation in the hepatic cells HepG2 and L02 (p < .05). Knockdown of UGT1A1 in hepatic cells by siRNA aggravated hepatic injury caused by GCDC and hypoxia-reoxygenation, as indicated by the ALT and AST levels in the supernatant. Mechanistically, UGT1A1 is transcriptionally regulated by peroxisome proliferator-activator receptor-γ (PPAR-γ) under hypoxia-physoxia. Taken together, our data revealed that air-ventilated NMP could alleviate DCD- and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis. Based on the results from this study, air-ventilated NMP confers a promising approach for predicting and alleviating cholestatic liver injury through PPAR-γ/UGT1A1 axis.


Assuntos
PPAR gama , Animais , Ratos , PPAR gama/metabolismo , PPAR gama/genética , Masculino , Humanos , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/genética , Fígado/metabolismo , Fígado/patologia , Colestase/metabolismo , Perfusão , Ratos Sprague-Dawley , Preservação de Órgãos/métodos , Transplante de Fígado
2.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(1): 24-30, 2024 Jan 20.
Artigo em Zh | MEDLINE | ID: mdl-38322521

RESUMO

Liquid-liquid phase separation (LLPS) is a reversible process, during which biological macromolecules, including proteins and nucleic acids, condense into liquid membraneless organelles under the influence of weak multivalent interactions. Currently, fluorescence recovery after photobleaching is the primary method used to detect the phase separation of biological macromolecules. Recent studies have revealed the link between abnormal LLPS and the pathogenesis and development of various human cancers. Through phase separation or abnormal phase separation, tumor-related biological macromolecules, such as mRNA, long noncoding RNAs (lncRNAs), and tumor-related proteins, can affect transcriptional translation and DNA damage repair, regulate the autophagy and ferroptosis functions of cells, and thus regulate the development of various tumors. In this review, we summarized the latest research findings on the mechanism of LLPS in the pathogenesis and progression of tumors and elaborated on the promotion or inhibition of autophagy, tumor immunity, DNA damage repair, and cell ferroptosis after abnormal phase separation of biomolecules, including mRNA, lncRNA, and proteins, which subsequently affects the pathogenesis and progression of tumors. According to published findings, many biological macromolecules can regulate transcriptional translation, expression, post-transcriptional modification, cell signal transduction, and other biological processes through phase separation. Therefore, further expansion of the research field of phase separation and in-depth investigation of its molecular mechanisms and regulatory processes hold extensive research potential.


Assuntos
Neoplasias , Separação de Fases , Humanos , Proteínas , RNA Mensageiro
3.
Hepatology ; 75(2): 338-352, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34455616

RESUMO

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is a common complication of hepatectomy and liver transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Regulator of G-protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates the G-protein and mitogen-activated protein kinase (MAPK) signaling pathways. However, the role of RGS14 in hepatic IRI remains unclear. APPROACH AND RESULTS: We found that RGS14 expression increased in mice subjected to hepatic ischemia-reperfusion (IR) surgery and during hypoxia reoxygenation in hepatocytes. We constructed global RGS14 knockout (RGS14-KO) and hepatocyte-specific RGS14 transgenic (RGS14-TG) mice to establish 70% hepatic IRI models. Histological hematoxylin and eosin staining, levels of alanine aminotransferase and aspartate aminotransferase, expression of inflammatory factors, and apoptosis were used to assess liver damage and function in these models. We found that RGS14 deficiency significantly aggravated IR-induced liver injury and activated hepatic inflammatory responses and apoptosis in vivo and in vitro. Conversely, RGS14 overexpression exerted the opposite effect of the RGS14-deficient models. Phosphorylation of TGF-ß-activated kinase 1 (TAK1) and its downstream effectors c-Jun N-terminal kinase (JNK) and p38 increased in the liver tissues of RGS14-KO mice but was repressed in those of RGS14-TG mice. Furthermore, inhibition of TAK1 phosphorylation rescued the effect of RGS14 deficiency on JNK and p38 activation, thus blocking the inflammatory responses and apoptosis. CONCLUSIONS: RGS14 plays a protective role in hepatic IR by inhibiting activation of the TAK1-JNK/p38 signaling pathway. This may be a potential therapeutic strategy for reducing incidences of hepatic IRI in the future.


Assuntos
MAP Quinase Quinase Quinases/metabolismo , Proteínas RGS/genética , Proteínas RGS/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Alanina Transaminase/metabolismo , Animais , Apoptose , Aspartato Aminotransferases/metabolismo , Hipóxia Celular , Células Cultivadas , Ativação Enzimática , Hepatócitos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Adv Sci (Weinh) ; 11(30): e2403148, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38874408

RESUMO

Astaxanthin (ASX) is an oxygen-containing non-vitamin A carotenoid pigment. However, the role of ASX in autoimmune hepatitis (AIH) remains unclear. In this study, a mouse model of AIH is established induced by concanavalin A (ConA). Mass cytometry and single-cell RNA sequencing (scRNA-seq) are used to analyze the potential role of ASX in regulating the immune microenvironment of AIH. ASX treatment effectively alleviated liver damage induced by ConA and downregulated pro-inflammatory cytokines production in mice. Mass cytometry and scRNA-seq analyses revealed a significant increase in the number of CD8+ T cells following ASX treatment. Functional markers of CD8+ T cells, such as CD69, MHC II, and PD-1, are significantly downregulated. Additionally, specific CD8+ T cell subclusters (subclusters 4, 13, 24, and 27) are identified, each displaying distinct changes in marker gene expression after ASX treatment. This finding suggests a modulation of CD8+ T cell function by ASX. Finally, the key transcription factors for four subclusters of CD8+ T cells are predicted and constructed a cell-to-cell communication network based on receptor-ligand interactions probability. In conclusion, ASX holds the potential to ameliorate liver damage by regulating the number and function of CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Hepatite Autoimune , Xantofilas , Animais , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/genética , Hepatite Autoimune/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Xantofilas/farmacologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Citometria de Fluxo/métodos , Camundongos Endogâmicos C57BL
5.
J Intensive Med ; 3(4): 345-351, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-38028643

RESUMO

Background: Whether a causative link exists between brain death (BD) and intestinal microbiota dysbiosis is unclear, and the distortion in liver metabolism associated with BD requires further exploration. Methods: A rat model of BD was constructed and sustained for 9 h (BD group, n=6). The sham group (n=6) underwent the same procedures, but the catheter was inserted into the epidural space without ballooning. Intestinal contents and portal vein plasma were collected for microbiota sequencing and microbial metabolite detection. Liver tissue was resected to investigate metabolic alterations, and the results were compared with those of a sham group. Results: α-diversity indexes showed that BD did not alter bacterial diversity. Microbiota dysbiosis occurred after 9 h of BD. At the family level, Peptostreptococcaceae and Bacteroidaceae were both decreased in the BD group. At the genus level, Romboutsia, Bacteroides, Erysipelotrichaceae_UCG_004, Faecalibacterium, and Barnesiella were enriched in the sham group, whereas Ruminococcaceae_UCG_007, Lachnospiraceae_ND3007_group, and Papillibacter were enriched in the BD group. Short-chain fatty acids, bile acids, and 132 other microbial metabolites remained unchanged in both the intestinal contents and portal vein plasma of the BD group. BD caused alterations in 65 metabolites in the liver, of which, carbohydrates, amino acids, and organic acids accounted for 64.6%. Additionally, 80.0% of the differential metabolites were decreased in the BD group livers. Galactose metabolism was the most significant metabolic pathway in the BD group. Conclusions: BD resulted in microbiota dysbiosis in rats; however, this dysbiosis did not alter microbial metabolites. Deterioration in liver metabolic function during extended periods of BD may reflect a continuous worsening in energy deficiency.

6.
Int Immunopharmacol ; 113(Pt B): 109469, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36435062

RESUMO

Timely treatment of acute inflammatory reactions induced by fungi or bacteria is essential to prevent infectious damage. Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor which is used to treat various lymphoid cancers. It is also known that BTK plays important roles in innate immunity and inflammatory response. In the present study, we investigated the regulatory effects of Ibrutinib on the activation of neutrophils and macrophages and its therapeutic effects on acute peritonitis. In addition, we also studied its anti-inflammatory mechanisms. The results showed that Ibrutinib inhibited the expression and secretion of inflammatory factors in macrophages induced by multiple Toll-like receptor (TLR) agonists. In the study of neutrophils, Ibrutinib selectively suppressed the activation, superoxide release, and calcium influx of neutrophils stimulated by zymosan. Furthermore, in zymosan-induced mice acute peritonitis, Ibrutinib significantly reduced the infiltration of neutrophils into peritoneal cavity, the release of myeloperoxidase (MPO) and ß-glucuronidase as well as the production of inflammatory factors in peritoneal cavity. In mechanism study, Ibrutinib selectively inhibited the phosphorylation of PLCγ2, PKCδ, and ERK1/2 in neutrophils induced by zymosan. Collectively, Ibrutinib can significantly inhibit the activation of neutrophils and macrophages by inhibiting BTK-PLCγ2-PKC signaling pathway, and has great potential to be developed into therapeutic drug for acute inflammatory diseases.


Assuntos
Neutrófilos , Peritonite , Animais , Camundongos , Zimosan , Fosfolipase C gama , Macrófagos , Adjuvantes Imunológicos , Peritonite/induzido quimicamente , Peritonite/tratamento farmacológico
7.
Cell Adh Migr ; 16(1): 94-106, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35880618

RESUMO

Fluid shear stress (FSS) regulates the metastasis of hepatocellular carcinoma (HCC), but the role of the RhoA-YAP1-autophagy pathway in HCC remains unclear. Due to the core role of liver cancer stem cells (LCSCs) in HCC metastasis and recurrence, we explored the RhoA-YAP1-autophagy pathway in LCSCs under FSS. Our results indicate that LCSCs have stronger proliferation and cell spheroidization abilities. FSS (1 dyn/cm2) upregulated the migration of LCSCs and autophagy protein markers, inducing LC3B aggregation and autophagosome formation in LCSCs. Mechanistically, FSS promoted YAP1 dephosphorylation and transport to the nucleus, which is mediated by RhoA, inducing autophagy. Finally, inhibition of autophagy suppressed cell migration in LCSCs under FSS. In conclusion, FSS promoted the migration of LCSCs via the RhoA-YAP1-autophagy pathway.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Autofagia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Humanos , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas de Sinalização YAP , Proteína rhoA de Ligação ao GTP/metabolismo
8.
Math Biosci Eng ; 18(5): 6652-6671, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34517550

RESUMO

The image super-resolution reconstruction method can improve the image quality in the Internet of Things (IoT). It improves the data transmission efficiency, and is of great significance to data transmission encryption. Aiming at the problem of low image quality in image super-resolution using neural networks, a self-attention-based image reconstruction method is proposed for secure data transmission in IoT environment. The network model is improved, and the residual network structure and sub-pixel convolution are used to extract the feature of the image. The self-attention module is used extract detailed information in the image. Using generative confrontation method and image feature perception method to improve the image reconstruction effect. The experimental results on the public data set show that the improved network model improves the quality of the reconstructed image and can effectively restore the details of the image.


Assuntos
Processamento de Imagem Assistida por Computador , Internet das Coisas , Redes Neurais de Computação
9.
Int Immunopharmacol ; 101(Pt B): 108294, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34749250

RESUMO

Oxidative stress following liver ischemia/reperfusion (I/R) is an important pathological mechanism responsible for liver injury. Veratric acid (VA) is a phenolic benzoic acid that has been reported to have antioxidant properties. However, whether VA has protective effects against liver I/R injury remains unclear. In the present study, a mouse liver I/R injury model was established. VA was administered intragastrically for one week before liver I/R. Biochemical indicators, histological analysis, cell apoptosis, oxidative stress, and pathway proteins were tested to evaluate the protective effects of VA on liver I/R injury. Furthermore, a mouse AML12 hepatocyte hypoxia/reoxygenation (H/R) model was used to explore the underlying mechanism. VA alleviated liver I/R injury, as manifested by decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver necrotic area, oxidative stress, and hepatocyte apoptosis. VA pretreatment increased the expression of Nrf2 and its downstream antioxidant proteins heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO-1). In addition, VA pretreatment increased AML12 cell activity and decreased oxidative stress; it also decreased the apoptosis induced by H/R. Moreover, the protective effect of VA on hepatocytes was related to the activation of the Nrf2 signaling pathway, and to increases in the Nrf2, HO-1, and NQO-1 protein expression. The inhibition of Nrf2 with ML385 offseted VA-mediated protection in AML12 cells. In conclusion, these results suggest that VA protects the liver from oxidative stress and apoptosis induced by liver I/R injury by activating the Nrf2 signaling pathway.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Hepatócitos/efeitos dos fármacos , Fígado/patologia , Hepatopatias/patologia , Masculino , Camundongos , NAD(P)H Desidrogenase (Quinona) , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Ácido Vanílico/análogos & derivados
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