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1.
Int J Biol Sci ; 20(7): 2422-2439, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725842

RESUMO

Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.


Assuntos
Células Estreladas do Fígado , Cirrose Hepática , MicroRNAs , Estresse Oxidativo , Complexo Correpressor Histona Desacetilase e Sin3 , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Humanos , Masculino , Camundongos , Tetracloreto de Carbono , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , MicroRNAs/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Complexo Correpressor Histona Desacetilase e Sin3/metabolismo
2.
Cell Mol Gastroenterol Hepatol ; 13(1): 151-171, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34390865

RESUMO

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH also is associated with adipose tissue inflammation, but the role of adipose tissue inflammation in NASH pathogenesis remains obscure. The aim of this study was to investigate the interplay between neutrophil recruitment in adipose tissue and the progression of NASH. METHODS: A mouse model of NASH was obtained by high-fat diet (HFD) feeding plus adenovirus-Cxcl1 overexpression (HFD+AdCxcl1). Genetic deletion of E-selectin (Sele) and treatment with an S100A9 inhibitor (Paquinimod) were investigated using this model. RESULTS: By analyzing transcriptomic data sets of adipose tissue from NASH patients, we found that E-selectin, a key adhesion molecule for neutrophils, is the highest up-regulated gene among neutrophil recruitment-related factors in adipose tissue of NASH patients compared with those in patients with simple steatosis. A marked up-regulation of Sele in adipose tissue also was observed in HFD+AdCxcl1 mice. The HFD+AdCxcl1-induced NASH phenotype was ameliorated in Sele knockout mice and was accompanied by reduced lipolysis and inflammation in adipose tissue, which resulted in decreased serum free fatty acids and proinflammatory adipokines. S100A8/A9, a major proinflammatory protein secreted by neutrophils, was highly increased in adipose tissue of HFD+AdCxcl1 mice. This increase was blunted in the Sele knockout mice. Therapeutically, treatment with the S100A9 inhibitor Paquinimod reduced lipolysis, inflammation, and adipokine production, ameliorating the NASH phenotype in mice. CONCLUSIONS: E-selectin plays an important role in inducing neutrophil recruitment in adipose tissue, which subsequently promotes inflammation and lipolysis via the production of S100A8/A9, thereby exacerbating the steatosis-to-NASH progression. Targeting adipose tissue inflammation therefore may represent a potential novel therapy for treatment of NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Tecido Adiposo/metabolismo , Animais , Selectina E/metabolismo , Humanos , Inflamação/patologia , Lipólise , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia
3.
Cell Mol Immunol ; 18(1): 18-37, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33203939

RESUMO

Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma. The progression of liver disease is controlled by a variety of factors, including liver injury, inflammatory cells, inflammatory mediators, cytokines, and the gut microbiome. In the current review, we discuss recent data on a large number of cytokines that play important roles in regulating liver injury, inflammation, fibrosis, and regeneration, with a focus on interferons and T helper (Th) 1, Th2, Th9, Th17, interleukin (IL)-1 family, IL-6 family, and IL-20 family cytokines. Hepatocytes can also produce certain cytokines (such as IL-7, IL-11, and IL-33), and the functions of these cytokines in the liver are briefly summarized. Several cytokines have great therapeutic potential, and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases, which are also described.


Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/patologia , Hepatopatias/terapia , Animais , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Hepatopatias/imunologia , Hepatopatias/metabolismo , Hepatopatias/patologia
4.
J Clin Invest ; 131(9)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33724957

RESUMO

Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. Using microdissection and next-generation RNA-Seq, we identified 5 genes, including Mapk8ip2, Cdkn1a, Itgb6, Rgs4, and Ccl2, that were most upregulated in proliferating BECs after acute injury. Immunohistochemical analyses confirmed robust upregulation of integrin αvß6 (ITGß6) expression in this BEC injury model, after bile duct ligation, and in patients with chronic cholangiopathies. Deletion of the Itgb6 gene attenuated BEC proliferation after acute bile duct injury. Macrophage depletion or Ccr2 deficiency impaired ITGß6 expression and BEC proliferation. In vitro experiments revealed that bile acid-activated monocytes promoted BEC proliferation through ITGß6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGß6, which work together to promote BEC proliferation and therefore represent potential therapeutic targets for cholangiopathies.


Assuntos
Antígenos de Neoplasias/biossíntese , Ácidos e Sais Biliares/metabolismo , Sistema Biliar/metabolismo , Proliferação de Células , Células Epiteliais/metabolismo , Integrinas/biossíntese , Ativação de Macrófagos , Macrófagos/metabolismo , Regulação para Cima , Animais , Antígenos de Neoplasias/genética , Ácidos e Sais Biliares/genética , Feminino , Humanos , Integrinas/genética , Masculino , Camundongos , Camundongos Transgênicos , RNA-Seq
5.
World J Clin Cases ; 7(12): 1529-1534, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31363483

RESUMO

BACKGROUND: Paragangliomas in the mediastinum are rare, accounting for only 1%-2% of all paragangliomas and < 0.3% of all mediastinal tumors. Most paragangliomas are nonfunctional, therefore, asymptomatic functional paragangliomas in the left posterior mediastinum are extremely rare. Perioperative management including preoperative preparation, careful intraoperative procedures, and strict postoperative care is important, and one-stage surgical resection should be performed only after appropriate perioperative measures are undertaken. Because those tumors are rare, it is necessary to report known cases to raise awareness regarding them. CASE SUMMARY: We report the case of a 47-year-old male who was admitted to our hospital with the chief complaints of intermittent tearing pain on the left side of the chest and back for more than 10 mo. A chest contrast-enhanced computed tomography scan revealed a round, solid mass in the left posterior mediastinum, with low-density cystic lesions in the middle, and no enlarged lymph nodes in the hilum or mediastinum (Figure 1). After the diagnosis of paraganglioma, the patient was preoperatively given an oral adrenoceptor blocking drug (phenoxybenzamine), and intravenous fluid resuscitation for two weeks, subsequently the patient underwent a one-stage resection of lesions via left thoracotomy. The patient's blood pressure increased to 220/120 mmHg when the tumor was touched, which could be relieved by symptomatic treatment such as accelerating liquid transfusion or other intervention to lower blood pressure. The patient recovered uneventfully after surgery, with no abnormal blood pressure or recurrence during one year of follow-up visits. CONCLUSION: Surgical resection is the preferred treatment for asymptomatic functional paragangliomas.

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