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1.
Cell Mol Gastroenterol Hepatol ; 17(6): 887-906, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38311169

RESUMO

BACKGROUND & AIMS: Hepatic fibrosis is characterized by enhanced deposition of extracellular matrix (ECM), which results from the wound healing response to chronic, repeated injury of any etiology. Upon injury, hepatic stellate cells (HSCs) activate and secrete ECM proteins, forming scar tissue, which leads to liver dysfunction. Monocyte-chemoattractant protein-induced protein 1 (MCPIP1) possesses anti-inflammatory activity, and its overexpression reduces liver injury in septic mice. In addition, mice with liver-specific deletion of Zc3h12a develop features of primary biliary cholangitis. In this study, we investigated the role of MCPIP1 in liver fibrosis and HSC activation. METHODS: We analyzed MCPIP1 levels in patients' fibrotic livers and hepatic cells isolated from fibrotic murine livers. In vitro experiments were conducted on primary HSCs, cholangiocytes, hepatocytes, and LX-2 cells with MCPIP1 overexpression or silencing. RESULTS: MCPIP1 levels are induced in patients' fibrotic livers compared with their nonfibrotic counterparts. Murine models of fibrosis revealed that its level is increased in HSCs and hepatocytes. Moreover, hepatocytes with Mcpip1 deletion trigger HSC activation via the release of connective tissue growth factor. Overexpression of MCPIP1 in LX-2 cells inhibits their activation through the regulation of TGFB1 expression, and this phenotype is reversed upon MCPIP1 silencing. CONCLUSIONS: We demonstrated that MCPIP1 is induced in human fibrotic livers and regulates the activation of HSCs in both autocrine and paracrine manners. Our results indicate that MCPIP1 could have a potential role in the development of liver fibrosis.


Assuntos
Comunicação Autócrina , Células Estreladas do Fígado , Cirrose Hepática , Comunicação Parácrina , Ribonucleases , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Animais , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Camundongos , Ribonucleases/metabolismo , Ribonucleases/genética , Masculino , Modelos Animais de Doenças , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Fígado/patologia , Fígado/metabolismo
2.
Acta Biochim Pol ; 70(4): 919-925, 2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37929720

RESUMO

Monocyte-chemoattractant protein-induced protein 1 (MCPIP1, or Regnase-1) is an endoribonuclease that degrades translationally active mRNA molecules. MCPIP1 is mostly known for its anti-inflammatory actions, but it is also an important regulator of adipogenesis and lipid metabolism. Its overexpression impairs adipogenesis by reducing mRNA levels of C/EBPß and PPARγ, key transcription factors regulating this process. Although adipocytes overexpressing MCPIP1 are characterised by impaired glucose uptake, the function of MCPIP1 in hepatocyte metabolism remains unknown. In this study, conditional deletion of Zc3h12a in murine liver epithelial cells was used to characterise the role of Mcpip1 in adaptation to 24-hour food restriction. We found that Mcpip1 deficiency in liver epithelial cells (Mcpip1fl/flAlbCre mice) resulted in higher blood glucose levels in response to fasting in comparison to Mcpip1fl/fl counterparts. Hepatic proteome analysis showed 26 down-regulated and 117 up-regulated proteins in Mcpip1fl/flAlbCre animals that were involved in cellular adhesion, extracellular matrix and metabolic processes. In conclusion, our studies provide new insight into the hepatic function of Mcpip1 and its involvement in metabolic control.


Assuntos
Metabolismo dos Lipídeos , Fígado , Animais , Camundongos , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Ribonucleases/genética , RNA Mensageiro/genética
3.
Biochim Biophys Acta Mol Basis Dis ; 1869(7): 166764, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37257731

RESUMO

MCPIP1 (called also Regnase-1) is a negative regulator of inflammation. Knockout of the Zc3h12a gene, encoding Mcpip1 in cells of myeloid origin (Mcpip1MKO), has a pathological effect on many organs. The aim of this study was to comprehensively analyze pathological changes in the skin caused by Mcpip1 deficiency in phagocytes with an emphasis on its molecular mechanism associated with microbiome dysbiosis. Mcpip1MKO mice exhibited spontaneous wound formation on the skin. On a molecular level, the Th2-type immune response was predominantly characterized by an increase in Il5 and Il13 transcript levels, as well as eosinophil and mast cell infiltration. Irritation by DNFB led to a more severe skin contact allergy in Mcpip1MKO mice. Allergic reactions on the skin were strongly influenced by gut dysbiosis and enhanced systemic dissemination of bacteria. This process was followed by activation of the C/EBP pathway in peripheral macrophages, leading to local changes in the cytokine microenvironment that promoted the Th2 response. A reduced bacterial load inhibited allergic inflammation, indicating the role of intestinal dysbiosis in the development of skin diseases. Our results clearly show that MCPIP1 in phagocytes is an essential negative regulator that controls the gut-skin axis.


Assuntos
Disbiose , Inflamação , Animais , Camundongos , Inflamação/metabolismo , Camundongos Knockout , Células Mieloides/metabolismo , Pele/metabolismo
4.
Hepatol Commun ; 7(3): e0008, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36809310

RESUMO

BACKGROUND AND AIMS: NAFLD is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called NASH, which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to life-threatening complications, such as fibrosis, cirrhosis, or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF-κB activity. METHODS: In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (hematoxylin and eosin and Oil Red-O staining), 12 patients were classified into the NAFL group, 19 into the NASH group, and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. In addition, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient body mass index or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients' PBMCs there were no differences in the expression of genes regulating ß-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG). CONCLUSION: We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Inflamação , Cirrose Hepática/patologia
5.
Postepy Biochem ; 68(3): 246-254, 2022 09 30.
Artigo em Polonês | MEDLINE | ID: mdl-36317994

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of lipids in hepatocytes. Among NAFLD patients, in 25% of them this disease progress to nonalcoholic steatohepatitis, which is characterized additionally by the development of inflammation and fibrosis of liver. Currently, it is estimated that 24% of the world's population suffers from NAFLD. MCPIP1 protein is an RNase described as a negative regulator of inflammation. Also, MCPIP1 plays a role in lipid metabolism because it inhibits the process of adipogenesis and mice with a deletion of Zc3h12a gene are characterized by dyslipidemia and reduced body fat content. In the case of ischemia-reperfusion injury in liver, MCPIP1 is protective against the inflammation and damage of this organ. Lipid accumulation by hepatocytes is associated with a decrease of Mcpip1 level. In addition, MCPIP1 may influence the PPARγ-mediated lipogenesis process. Presence of Mcpip1 in both myeloid leukocytes and liver epithelial cells is crucial for the maintenance of liver homeostasis.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/genética , Metabolismo dos Lipídeos , Inflamação , Homeostase
6.
Pharmacol Rep ; 74(2): 263-272, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35032321

RESUMO

Murine models of human diseases are of outmost importance for both studying molecular mechanisms driving their development and testing new treatment strategies. In this review, we first discuss the etiology and risk factors for autoimmune liver disease, including primary biliary cholangitis, autoimmune hepatitis and primary sclerosing cholangitis. Second, we highlight important features of murine transgenic models that make them useful for basic scientists, drug developers and clinical researchers. Next, a brief description of each disease is followed by the characterization of selected animal models.


Assuntos
Doenças Autoimunes , Hepatite Autoimune , Hepatopatias , Animais , Doenças Autoimunes/genética , Modelos Animais de Doenças , Hepatite Autoimune/genética , Humanos , Hepatopatias/genética , Camundongos , Fatores de Risco
7.
FEBS J ; 288(22): 6563-6580, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34058074

RESUMO

Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NFκB activity. Moreover, it was demonstrated that MCPIP1 regulates lipid metabolism both in adipose tissue and in hepatocytes. In this study, we investigated the effects of tissue-specific Mcpip1 deletion on the regulation of hepatic metabolism and development of nonalcoholic fatty liver disease (NAFLD). We used control Mcpip1fl/fl mice and animals with deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/fl LysMCre ) and in hepatocytes (Mcpip1fl/fl AlbCre ), which were fed chow or a high-fat diet (HFD) for 12 weeks. Mcpip1fl/fl LysMCre mice fed a chow diet were characterized by a significantly reduced hepatic expression of genes regulating lipid and glucose metabolism, which subsequently resulted in low plasma glucose level and dyslipidemia. These animals also displayed systemic inflammation, demonstrated by increased concentrations of cytokines in the plasma and high Tnfa, Il6, IL1b mRNA levels in the liver and brown adipose tissue (BAT). Proinflammatory leukocyte infiltration into BAT, together with low expression of Ucp1 and Ppargc1a, resulted in hypothermia of 22-week-old Mcpip1fl/fl LysMCre mice. On the other hand, there were no significant changes in phenotype in Mcpip1fl/fl AlbCre mice. Although we detected a reduced hepatic expression of genes regulating glucose metabolism and ß-oxidation in these mice, they remained asymptomatic. Upon feeding with a HFD, Mcpip1fl/fl LysMCre mice did not develop obesity, glucose intolerance, nor hepatic steatosis, but were characterized by low plasma glucose level and dyslipidemia, along with proinflammatory phenotype. Mcpip1fl/fl AlbCre animals, following a HFD, became hypercholesterolemic, but accumulated lipids in the liver at the same level as Mcpip1fl/fl mice, and no changes in the level of soluble factors tested in the plasma were detected. We have demonstrated that Mcpip1 protein plays an important role in the liver homeostasis. Depletion of Mcpip1 in myeloid leukocytes, followed by systemic inflammation, has a more pronounced effect on controlling liver metabolism and homeostasis than the depletion of Mcpip1 in hepatocytes.


Assuntos
Fígado Gorduroso/metabolismo , Fígado/metabolismo , Células Mieloides/metabolismo , Obesidade/metabolismo , Ribonucleases/metabolismo , Animais , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ribonucleases/sangue , Ribonucleases/deficiência
8.
Dis Model Mech ; 14(3)2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737335

RESUMO

Myeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.


Assuntos
Autoimunidade , Linfócitos B/imunologia , Diferenciação Celular , Células Mieloides/imunologia , Ribonucleases/metabolismo , Animais , Células Apresentadoras de Antígenos/metabolismo , Autoanticorpos/imunologia , Proliferação de Células , Citocinas/metabolismo , Terapia de Imunossupressão , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Rim/patologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Nefrite/imunologia , Nefrite/patologia , Plasmócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Baço/imunologia , Células Th17/imunologia , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo
9.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525359

RESUMO

Nonalcoholic fatty liver disease is defined as the accumulation of excessive fat in the liver in the absence of excessive alcohol consumption or any secondary cause. Although the disease generally remains asymptomatic, chronic liver inflammation leads to fibrosis, liver cirrhosis, and even to the development of hepatocellular carcinoma (HCC). Fibrosis results from epithelial-mesenchymal transition (EMT), which leads to dedifferentiation of epithelial cells into cells with a mesenchymal-like phenotype. During EMT, epithelial cells with high expression of E-cadherin, influenced by growth factors, cytokines, and inflammatory processes, undergo morphological changes via enhanced expression of, e.g., vimentin, fibronectin, and N-cadherin. An inducer of EMT and, consequently, of fibrosis development is transforming growth factor beta (TGFß), a pleiotropic cytokine associated with the progression of hepatocarcinogenesis. However, the understanding of the molecular events that direct the development of steatosis into steatohepatitis and liver fibrosis remains incomplete. Our study revealed that both prolonged exposure of hepatocarcinoma cells to fatty acids in vitro and high-fat diet in mice (20 weeks) result in inflammation. Prolonged treatment with fatty acids increased the levels of TGFß, MMP9, and ß-catenin, important EMT inducers. Moreover, the livers of mice fed a high-fat diet exhibited features of liver fibrosis with increased TGFß and IL-1 levels. Increased expression of IL-1 correlated with a decrease in monocyte chemoattractant protein-induced protein 1 (MCPIP1), a negative regulator of the inflammatory response that regulates the stability of proinflammatory transcripts encoding IL-1. Our study showed that a high-fat diet induced EMT by increasing the levels of EMT-activating transcription factors, including Zeb1, Zeb2, and Snail and changed the protein profile to a profile characteristic of the mesenchymal phenotype.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/genética , Fator de Crescimento Transformador beta/genética , beta Catenina/genética , Animais , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Oleico/farmacologia , Ribonucleases/genética , Ribonucleases/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/agonistas , Fator de Crescimento Transformador beta/metabolismo , Vimentina/genética , Vimentina/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , beta Catenina/agonistas , beta Catenina/metabolismo
10.
Biochim Biophys Acta Mol Basis Dis ; 1867(5): 166086, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513427

RESUMO

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by progressive destruction of the intrahepatic bile ducts. The immunopathology of PBC involves excessive inflammation; therefore, negative regulators of inflammatory response, such as Monocyte Chemoattractant Protein-1-Induced Protein-1 (MCPIP1) may play important roles in the development of PBC. The aim of this work was to verify whether Mcpip1 expression protects against development of PBC. Genetic deletion of Zc3h12a was used to characterize the role of Mcpip1 in the pathogenesis of PBC in 6-52-week-old mice. We found that Mcpip1 deficiency in the liver (Mcpip1fl/flAlbCre) recapitulates most of the features of human PBC, in contrast to mice with Mcpip1 deficiency in myeloid cells (Mcpip1fl/flLysMCre mice), which present with robust myeloid cell-driven systemic inflammation. In Mcpip1fl/flAlbCre livers, intrahepatic bile ducts displayed proliferative changes with inflammatory infiltration, bile duct destruction, and fibrosis leading to cholestasis. In plasma, increased concentrations of IgG, IgM, and AMA autoantibodies (anti-PDC-E2) were detected. Interestingly, the phenotype of Mcpip1fl/flAlbCre mice was robust in 6-week-old, but milder in 12-24-week-old mice. Hepatic transcriptome analysis of 6-week-old and 24-week-old Mcpip1fl/flAlbCre mice showed 812 and 8 differentially expressed genes, respectively, compared with age-matched control mice, and revealed a distinct set of genes compared to those previously associated with development of PBC. In conclusion, Mcpip1fl/flAlbCre mice display early postnatal phenotype that recapitulates most of the features of human PBC.


Assuntos
Autoanticorpos/imunologia , Imunoglobulinas/imunologia , Inflamação/patologia , Cirrose Hepática Biliar/patologia , Cirrose Hepática/patologia , Fenótipo , Ribonucleases/fisiologia , Animais , Feminino , Inflamação/etiologia , Inflamação/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática Biliar/etiologia , Cirrose Hepática Biliar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
Antioxidants (Basel) ; 9(12)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287312

RESUMO

OBJECTIVE: Heme oxygenase-1 (HO-1) is a cytoprotective, proangiogenic and anti-inflammatory enzyme that is often upregulated in tumors. Overexpression of HO-1 in melanoma cells leads to enhanced tumor growth, augmented angiogenesis and resistance to anticancer treatment. The effect of HO-1 in host cells on tumor development is, however, hardly known. METHODS AND RESULTS: To clarify the effect of HO-1 expression in host cells on melanoma progression, C57BL/6xFvB mice of different HO-1 genotypes, HO-1+/+, HO-1+/-, and HO-1-/-, were injected with the syngeneic wild-type murine melanoma B16(F10) cell line. Lack of HO-1 in host cells did not significantly influence the host survival. Nevertheless, in comparison to the wild-type counterparts, the HO-1+/- and HO-1-/- males formed bigger tumors, and more numerous lung nodules; in addition, more of them had liver and spleen micrometastases. Females of all genotypes developed at least 10 times smaller tumors than males. Of importance, the growth of primary and secondary tumors was completely blocked in HO-1+/+ females. This was related to the increased infiltration of leukocytes (mainly lymphocytes T) in primary tumors. CONCLUSIONS: Although HO-1 overexpression in melanoma cells can enhance tumor progression in mice, its presence in host cells, including immune cells, can reduce growth and metastasis of melanoma.

12.
Pharmacol Rep ; 72(1): 1-12, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016853

RESUMO

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Globally, it is currently the most common liver disease and is estimated to affect up to 25% of the population. In the first stage, NAFLD is characterized by simple hepatic steatosis (NAFL, nonalcoholic fatty liver) that might progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular carcinoma. In this review, we discuss the global burden of NAFLD, together with future perspectives on how this epidemic could be restrained. There is also an urgent need for the development of new medical strategies for NAFLD patients. We aim to present the beneficial effects of life-style modifications that should be advised to both non-obese and obese NAFLD patients. Since there are currently no medications directly used for the treatment of more advanced NAFLD stages, the central part of this review summarizes ongoing and recently completed clinical trials testing promising drugs for NASH resolution. The marketing of new therapeutic agents would greatly increase the odds of reducing the global burden of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/complicações , Animais , Carcinoma Hepatocelular/etiologia , Progressão da Doença , Humanos , Estilo de Vida , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Prevalência
13.
J Exp Clin Cancer Res ; 38(1): 421, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639017

RESUMO

The monocyte chemoattractant protein-induced protein (MCPIP) family consists of 4 members (MCPIP1-4) encoded by the ZC3h12A-D genes, which are located at different loci. The common features of MCPIP proteins are the zinc finger domain, consisting of three cysteines and one histidine (CCCH), and the N-terminal domain of the PilT protein (PilT-N-terminal domain (PIN domain)). All family members act as endonucleases controlling the half-life of mRNA and microRNA (miRNA). The best-studied member of this family is MCPIP1 (also known as Regnase-1).In this review, we discuss the current knowledge on the role of MCPIP1 in cancer-related processes. Because the characteristics of MCPIP1 as a fundamental negative regulator of immune processes have been comprehensively described in numerous studies, we focus on the function of MCPIP1 in modulating apoptosis, angiogenesis and metastasis.


Assuntos
MicroRNAs/metabolismo , Neoplasias/genética , Ribonucleases/genética , Fatores de Transcrição/genética , Apoptose , Proliferação de Células , Humanos
14.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(10): 1458-1471, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185306

RESUMO

Monocyte chemoattractant protein-1-induced protein-1 (MCPIP1) acts as an endonuclease that degrades selected mRNAs, viral RNAs and pre-miRNAs. MCPIP1 inhibits adipogenesis by degradation of C/EBPß mRNA and adipogenesis-related miRNA, however its role in the regulation of hepatic lipid homeostasis is unknown. In this study, we investigated the role of MCPIP1 in the regulation of lipid metabolism in hepatocytes. C57BL/6 mice were fed a high-fat diet (HFD) for 2-20 weeks and next primary hepatocytes and adipose tissue were isolated. For in vitro experiments we used murine primary hepatocytes, control HepG2 cells and HepG2 with overexpressed or silenced MCPIP1. We found that Mcpip1 levels were lower in primary hepatocytes isolated from HFD-fed mice than in control cells starting at 4 weeks of a HFD. Level of Mcpip1 was also depleted in visceral fat isolated from obese and glucose-intolerant mice characterized by fatty liver disease. We showed that MCPIP1 overexpression in HepG2 cells treated with oleate induces the level and activity of peroxisome proliferator-activated receptor γ (PPARγ). This phenotype was reverted upon silencing of MCPIP1 in HepG2 cells and in primary hepatocytes lacking Mcpip1 protein. MCPIP1 activated the PPARγ transcription factor via the thioredoxin-interacting protein (TXNIP)/peroxisome proliferator-activated receptor γ coactivator 1- α (PGC-1α) pathway. MCPIP1 contributes to lipid metabolism in hepatocytes by regulating the TXNIP/PGC-1α/PPARγ pathway.


Assuntos
Hepatócitos/metabolismo , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas de Transporte/metabolismo , Células Hep G2 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais
15.
Front Genet ; 10: 140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863427

RESUMO

NF-κB signaling, acting through NFKB1 dependent canonical and NFKB2 dependent non-canonical pathways plays a critical role in inflammatory and immune responses. Recent studies have associated mutations in these two genes with a common variable immunodeficiency (CVID). While evaluating a female patient seeking a diagnosis explaining her recurrent infections, we found a novel heterozygous c.1831C > T (p.Arg611∗) nonsense mutation in the NFKB2 gene which introduces a Stop codon in the ankyrin repeat domain of p100. Whole exome sequencing (WES) analysis, followed by Sanger sequencing, identified this previously unknown mutation in two other family members. Penetrance of the c.1831C > T variant was assessed by flow-cytometry and protein expression in peripheral blood mononuclear cells (PBMC); whereas, activation of the NF-κB2 signaling pathway was examined through immunoblotting and real-time PCR. Heterozygous c.1831C > T variant led to the expansion of lymphocyte B subpopulations with concomitant reduction of plasmablasts, low IgG levels, and accumulation of p52 in PBMC. On the other hand, tested subjects had normal levels of IgM, IgA, IgE and no impairment in lymphocytes proliferation. Although evaluated patients did not fulfill all clinical features of CVID, their health should be monitored in the future for possible late manifestation of the disease. In conclusion, we showed that NFKB2 haplodeficiency caused by c.1831C > T nonsense mutation is asymptomatic, possibly due to the compensatory mechanisms and allele redundancy.

16.
Cells ; 8(3)2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909397

RESUMO

C-Met tyrosine kinase receptor plays an important role under normal and pathological conditions. In tumor cells' overexpression or incorrect activation of c-Met, this leads to stimulation of proliferation, survival and increase of motile activity. This receptor is also described as a marker of cancer initiating cells. The latest research shows that the c-Met receptor has an influence on the development of resistance to targeted cancer treatment. High c-Met expression and activation in renal cell carcinomas is associated with the progression of the disease and poor survival of patients. C-Met receptor has become a therapeutic target in kidney cancer. However, the therapies used so far using c-Met tyrosine kinase inhibitors demonstrate resistance to treatment. On the other hand, the c-Met pathway may act as an alternative target pathway in tumors that are resistant to other therapies. Combination treatment together with c-Met inhibitor reduces tumor growth, vascularization and pro-metastatic behavior and results in suppressed mesenchymal phenotype and vascular endothelial growth factor (VEGF) secretion. Recently, it has been shown that the acquirement of mesenchymal phenotype or lack of cell differentiation might be related to the presence of the c-Met receptor and is consequently responsible for therapy resistance. This review presents the results from recent studies identifying c-Met as an important factor in renal carcinomas being responsible for tumor growth, progression and metastasis, indicating the role of c-Met in resistance to antitumor therapy and demonstrating the pivotal role of c-Met in supporting mesenchymal cell phenotype.


Assuntos
Diferenciação Celular , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Renais/metabolismo , Fenótipo
17.
Front Physiol ; 10: 6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809151

RESUMO

Healthy liver sinusoidal endothelial cells (LSECs) maintain liver homeostasis, while LSEC dysfunction was suggested to coincide with defenestration. Here, we have revisited the relationship between LSEC pro-inflammatory response, defenestration, and impairment of LSEC bioenergetics in non-alcoholic fatty liver disease (NAFLD) in mice. We characterized inflammatory response, morphology as well as bioenergetics of LSECs in early and late phases of high fat diet (HFD)-induced NAFLD. LSEC phenotype was evaluated at early (2-8 week) and late (15-20 week) stages of NAFLD progression induced by HFD in male C57Bl/6 mice. NAFLD progression was monitored by insulin resistance, liver steatosis and obesity. LSEC phenotype was determined in isolated, primary LSECs by immunocytochemistry, mRNA gene expression (qRT-PCR), secreted prostanoids (LC/MS/MS) and bioenergetics (Seahorse FX Analyzer). LSEC morphology was examined using SEM and AFM techniques. Early phase of NAFLD, characterized by significant liver steatosis and prominent insulin resistance, was related with LSEC pro-inflammatory phenotype as evidenced by elevated ICAM-1, E-selectin and PECAM-1 expression. Transiently impaired mitochondrial phosphorylation in LSECs was compensated by increased glycolysis. Late stage of NAFLD was featured by prominent activation of pro-inflammatory LSEC phenotype (ICAM-1, E-selectin, PECAM-1 expression, increased COX-2, IL-6, and NOX-2 mRNA expression), activation of pro-inflammatory prostaglandins release (PGE2 and PGF2α) and preserved LSEC bioenergetics. Neither in the early nor in the late phase of NAFLD, were LSEC fenestrae compromised. In the early and late phases of NAFLD, despite metabolic and pro-inflammatory burden linked to HFD, LSEC fenestrae and bioenergetics are functionally preserved. These results suggest prominent adaptive capacity of LSECs that might mitigate NAFLD progression.

18.
Mediators Inflamm ; 2016: 5365209, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27881904

RESUMO

Ribonucleic acids (RNAs) are very complex and their all functions have yet to be fully clarified. Noncoding genes (noncoding RNA, sequences, and pseudogenes) comprise 67% of all genes and they are represented by housekeeping noncoding RNAs (transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), and small nucleolar RNA (snoRNA)) that are engaged in basic cellular processes and by regulatory noncoding RNA (short and long noncoding RNA (ncRNA)) that are important for gene expression/transcript stability. In this review, we summarize data concerning the significance of long noncoding RNAs (lncRNAs) in metabolic syndrome related disorders, focusing on adipose tissue and pancreatic islands.


Assuntos
Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Humanos , RNA Longo não Codificante/genética , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , RNA Nuclear Pequeno/genética , RNA Nuclear Pequeno/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo
19.
J Diabetes Res ; 2016: 8492353, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28053991

RESUMO

We summarize the current knowledge concerning PPARγ function in angiogenesis. We discuss the mechanisms of action for PPARγ and its role in vasculature development and homeostasis, focusing on endothelial cells, endothelial progenitor cells, and bone marrow-derived proangiogenic cells.


Assuntos
Neovascularização Patológica , PPAR gama/fisiologia , Animais , Células da Medula Óssea/citologia , Movimento Celular , Células Endoteliais/citologia , Homeostase , Humanos , Ligantes , Camundongos , Camundongos Knockout , PPAR gama/metabolismo , Células-Tronco/citologia , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Free Radic Biol Med ; 89: 147-57, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26393425

RESUMO

Lung mucoepidermoid carcinoma (MEC) is a very poorly characterized rare subtype of non-small-cell lung cancer (NSCLC) associated with more favorable prognoses than other forms of intrathoracic malignancies. We have previously identified that heme oxygenase-1 (HO-1, encoded by HMOX1) inhibits MEC tumor growth and modulates the transcriptome of microRNAs. Here we investigate the role of a major upstream regulator of HO-1 and a master regulator of cellular antioxidant responses, transcription factor Nrf2, in MEC biology. Nrf2 overexpression in the NCI-H292 MEC cell line mimicked the phenotype of HO-1 overexpressing cells, leading to inhibition of cell proliferation and migration and down-regulation of oncogenic miR-378. HMOX1 silencing identified HO-1 as a major mediator of Nrf2 action. Nrf2- and HO-1 overexpressing cells exhibited strongly diminished expression of multiple matrix metalloproteinases and inflammatory cytokine interleukin-1ß, which was confirmed in an NCI-HO-1 xenograft model. Overexpression of HO-1 altered not only human MMP levels in tumor cells but also murine MMP levels within tumor microenvironment and metastatic niche. This could possibly contribute to decreased metastasis to the lungs and inhibitory effects of HO-1 on MEC tumor growth. Our profound transcriptome analysis and molecular characterization of the mucoepidermoid lung carcinoma helps to understand the specific clinical presentations of these tumors, emphasizing a unique antitumoral role of the Nrf2-HO-1 axis.


Assuntos
Carcinoma Mucoepidermoide/prevenção & controle , Regulação Neoplásica da Expressão Gênica , Heme Oxigenase-1/metabolismo , Neoplasias Pulmonares/prevenção & controle , Metaloproteinases da Matriz/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Apoptose , Western Blotting , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/prevenção & controle , Proliferação de Células , Regulação para Baixo , Imunofluorescência , Perfilação da Expressão Gênica , Heme Oxigenase-1/genética , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
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