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1.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917858

RESUMO

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
2.
PLoS One ; 15(9): e0235824, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881898

RESUMO

Pulmonary hypertension due to left heart disease (PH-LHD) is a momentous pulmonary hypertension disease, and left heart disease is the most familiar cause. Mechanical stretching may be a crucial cause of vascular remodeling. While, the underlining mechanism of mechanical stretching-induced in remodeling of pulmonary vein in the early stage of PH-LHD has not been completely elucidated. In our study, the PH-LHD model rats were successfully constructed. After 25 days, doppler echocardiography and hemodynamic examination were performed. In addition, after treatment, the levels of matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1) were determined by ELISA, immunohistochemistry and western blot assays in the pulmonary veins. Moreover, the pathological change of pulmonary tissues was evaluated by H&E staining. Our results uncovered that left ventricular insufficiency and interventricular septal shift could be observed in PH-LHD model rats, and the right ventricular systolic pressure (RVSP) and mean left atrial pressure (mLAP) were also elevated in PH-LHD model rats. Meanwhile, we found that MMP-9 and TGF-ß1 could be highly expressed in PH-LHD model rats. Besides, we revealed that stretch-activated channel (SAC)/mitogen-activated protein kinases (MAPKs) signaling pathway could be involved in the upregulations of MMP-9 and TGF-ß1 mediated by mechanical stretching in pulmonary vein. Therefore, current research revealed that mechanical stretching induced the increasing expressions of MMP-9 and TGF-ß1 in pulmonary vein, which could be mediated by activation of SAC/MAPKs signaling pathway in the early stage of PH-LHD.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Sistema de Sinalização das MAP Quinases , Metaloproteinase 9 da Matriz/metabolismo , Veias Pulmonares/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Ativação Enzimática , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Masculino , Veias Pulmonares/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Remodelação Vascular , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/metabolismo
3.
Ecotoxicol Environ Saf ; 205: 111327, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961493

RESUMO

Exposure to PM2.5 can cause serious harm to the respiratory system. Until now, although many toxicological studies have shown that pulmonary fibrosis can be caused by long-term PM2.5 exposure, there is no evidence that Endothelial-Mesenchymal Transition (EndMT) can trigger the process of pulmonary fibrosis after exposure. LncRNAs are a class of non-coding RNAs detected in mammalian cells. Nevertheless, researchers have not found whether lncRNAs participate in PM2.5 induced EndMT during pathophysiological duration. The Balb/c mouse model was exposed to PM2.5 for 4 months by dynamic intoxication. The levels of specific endothelial and mesenchymal markers were evaluated by molecular biology experiments to elucidate the mechanisms of EndMT induced by PM2.5 in lung tissues. LncRNA microarray analysis of the established mouse model of PM2.5 exposure was performed. Based on a bioinformatics analysis and RT-qPCR analysis, lncRNA Gm16410 attracted our attention. The change of lncRNA Gm16410 in mouse pulmonary vascular endothelial cells (MHCs) exposed to PM2.5 was verified, and the mechanism of lncRNA Gm16410 in EndMT was discussed. The changes of cell function were evaluated by cell migration and proliferation experiments. The molecular biology experiments proved that PM2.5 induced EndMT by activating the TGF-ß1/Smad3/p-Smad3 pathway in vitro. The relationship of EndMT and lncRNA Gm16410 was verified in mouse lung tissues and MHC cells by PM2.5 exposure. The involvement of lncRNA Gm16410 in PM2.5-induced EndMT highlights the potential of lncRNA to promote pulmonary fibrosis under environmental pollution.


Assuntos
Material Particulado/toxicidade , RNA Longo não Codificante/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Camundongos , Material Particulado/metabolismo , Fibrose Pulmonar/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3 , Fator de Crescimento Transformador beta1/metabolismo
4.
Sci Adv ; 6(35): eaba7910, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32923629

RESUMO

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Antivirais/farmacologia , Cinamatos/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , ortoaminobenzoatos/farmacologia , Células A549 , Animais , Betacoronavirus/efeitos dos fármacos , Sítios de Ligação/genética , Linhagem Celular Tumoral , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Cães , Células HEK293 , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/patologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pandemias , Pneumonia Viral/patologia , Ligação Proteica/genética , Transporte Proteico/efeitos dos fármacos , RNA Viral/genética , Receptor de Interferon alfa e beta/genética , Fator de Crescimento Transformador beta1/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Infecção por Zika virus/patologia
5.
Life Sci ; 259: 118293, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822714

RESUMO

AIMS: Liver fibrosis is an inflammatory and fibrogenic process that occurs following chronic liver damage. TGFß1 is the key inducer of fibrosis. MiR-21 and miR-122 are two miRNAs that their expression changes during fibrosis. In the present study, we investigate the effects of curcumin, quercetin, and atorvastatin on the expression levels of miR-21 and miR-122 and evaluated their correlation with TGFß1 expression in bile duct ligation (BDL)-induced fibrotic rats. MATERIALS AND METHODS: Thirty two adult male Wistar rats were divided into 8 groups (n = 8 for each): Sham, Sham + curcumin (100 mg/kg/day), Sham + quercetin (30 mg/kg/day), Sham + atorvastatin (15 mg/kg/day), BDL, BDL + curcumin, BDL + quercetin, BDL + atorvastatin and treated for four weeks via oral gavage. The expression of miR-21, miR-122, and TGFß1 was evaluated via RT-qPCR. KEY FINDINGS: The expression levels of TGFß1 and miR-21 were significantly increased in the BDL group compared to the Sham group (P < 0.05), but the expression of miR-122 was significantly decreased in the BDL group compared to the Sham group (P < 0.05). Curcumin, quercetin, and atorvastatin treatment lead to down-regulation of miR-21 and TGFß1 and up-regulation of miR-122 in the BDL groups. There was no significant difference between these drugs in altering gene expression and all had the same effects. Moreover, a direct significant correlation was observed between mir-21 and TGFß1 and an inverse significant correlation between mir-122 and TGFß1 expression. SIGNIFICANCE: In summary, targeting these molecular pathways may partially prevent the progression of liver fibrosis.


Assuntos
Atorvastatina/farmacologia , Curcumina/farmacologia , Cirrose Hepática/metabolismo , MicroRNAs/metabolismo , Quercetina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
6.
PLoS One ; 15(8): e0238076, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857768

RESUMO

Epidermal lineages and injury induced regeneration are controlled by transcriptional programs coordinating cellular signaling and epigenetic regulators, but the mechanism remains unclear. Previous studies showed that conditional deletion of the transcriptional coactivator Mediator 1 (Med1) changes epidermal lineages and accelerates wound re-epithelialization. Here, we studied a molecular mechanism by which Med1 facilitates these processes, in particular, by focusing on TGFß signaling through genome wide transcriptome analysis. The expression of the TGF ligands (Tgfß1/ß2) and their downstream target genes is decreased in both normal and wounded Med1 null skin. Med1 silencing in cultured keratinocytes likewise reduces the expression of the ligands (TGFß1/ß2) and diminishes activity of TGFß signaling as shown by decreased p-Smad2/3. Silencing Med1 increases keratinocyte proliferation and migration in vitro. Epigenetic studies using chromatin immuno-precipitation and next generation DNA sequencing reveals that Med1 regulates transcription of TGFß components by forming large clusters of enhancers called super-enhancers at the regulatory regions of the TGFß ligand and SMAD3 genes. These results demonstrate that Med1 is required for the maintenance of the TGFß signaling pathway. Finally, we show that pharmacological inhibition of TGFß signaling enhances epidermal lineages and accelerates wound re-epithelialization in skin similar to that seen in the Med1 null mice, providing new insights into epidermal regeneration.


Assuntos
Subunidade 1 do Complexo Mediador/genética , Regeneração/fisiologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Animais , Linhagem da Célula , Movimento Celular , Proliferação de Células , Regulação para Baixo , Epiderme/fisiologia , Queratinócitos/citologia , Queratinócitos/metabolismo , Subunidade 1 do Complexo Mediador/antagonistas & inibidores , Subunidade 1 do Complexo Mediador/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Pele/metabolismo , Pele/patologia , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta2/genética , Regulação para Cima
7.
PLoS One ; 15(8): e0237479, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790806

RESUMO

OBJECTIVE: As native cartilage consists of different phenotypical zones, this study aims to fabricate different types of neocartilage constructs from collagen hydrogels and human mesenchymal stromal cells (MSCs) genetically modified to express different chondrogenic factors. DESIGN: Human MSCs derived from bone-marrow of osteoarthritis (OA) hips were genetically modified using adenoviral vectors encoding sex-determining region Y-type high-mobility-group-box (SOX) 9, transforming growth factor beta (TGFB) 1 or bone morphogenetic protein (BMP) 2 cDNA, placed in type I collagen hydrogels and maintained in serum-free chondrogenic media for three weeks. Control constructs contained unmodified MSCs or MSCs expressing GFP. The respective constructs were analyzed histologically, immunohistochemically, biochemically, and by qRT-PCR for chondrogenesis and hypertrophy. RESULTS: Chondrogenesis in MSCs was consistently and strongly induced in collagen I hydrogels by the transgenes SOX9, TGFB1 and BMP2 as evidenced by positive staining for proteoglycans, chondroitin-4-sulfate (CS4) and collagen (COL) type II, increased levels of glycosaminoglycan (GAG) synthesis, and expression of mRNAs associated with chondrogenesis. The control groups were entirely non-chondrogenic. The levels of hypertrophy, as judged by expression of alkaline phosphatase (ALP) and COL X on both the protein and mRNA levels revealed different stages of hypertrophy within the chondrogenic groups (BMP2>TGFB1>SOX9). CONCLUSIONS: Different types of neocartilage with varying levels of hypertrophy could be generated from human MSCs in collagen hydrogels by transfer of genes encoding the chondrogenic factors SOX9, TGFB1 and BMP2. This technology may be harnessed for regeneration of specific zones of native cartilage upon damage.


Assuntos
Proteína Morfogenética Óssea 2/genética , Hidrogéis/química , Fatores de Transcrição SOX9/genética , Fator de Crescimento Transformador beta1/genética , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Cartilagem/citologia , Cartilagem/metabolismo , Cartilagem/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Condrogênese/genética , Colágeno Tipo I/química , Colágeno Tipo X/genética , Meios de Cultura Livres de Soro/química , Glicosaminoglicanos/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , RNA Mensageiro/metabolismo , Fatores de Transcrição SOX9/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
8.
Nat Commun ; 11(1): 4254, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848143

RESUMO

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFß1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFß1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.


Assuntos
Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Bleomicina/toxicidade , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Deleção de Genes , Humanos , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isomerases de Dissulfetos de Proteínas/genética , Dobramento de Proteína , Estabilidade Proteica , Fibrose Pulmonar/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Transdução de Sinais , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Regulação para Cima
9.
Nat Commun ; 11(1): 4075, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796847

RESUMO

Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFß signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFß signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFß-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.


Assuntos
Envelhecimento/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interleucina-6/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Envelhecimento/genética , Animais , Medula Óssea , Ciclo Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Células Precursoras Eritroides , Eritropoese/genética , Eritropoese/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hematopoese , Interleucina-6/genética , Linfopoese/genética , Linfopoese/fisiologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Transdução de Sinais , Nicho de Células-Tronco , Fator de Crescimento Transformador beta1/genética
10.
Life Sci ; 258: 118029, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32619495

RESUMO

OBJECTIVE: Hepatitis B virus (HBV) infection causes liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) development, but the underlying mechanism remains poorly understood. This study aimed to investigate the roles and molecular mechanisms of Dystrobrevin-α (DTNA) in HBV-induced liver cirrhosis and HCC pathogenesis. METHODS: DTNA expression was bioinformatically analyzed using the GEO database. DTNA expression was silenced by transfection with shRNAs. Cell proliferation and apoptosis were evaluated by MTT and flow cytometry respectively. The expression of genes in mRNA or protein levels was assessed by quantitative RT-PCR and western blotting. The interaction between proteins was predicted with the String and GCBI online softwares, and then confirmed by co-immunoprecipitation. Animal models were established by injecting nude mice with AVV8-HBV1.3 vector. RESULTS: Bioinformatics analysis showed a significantly increase in DTNA expression in HBV-positive liver cirrhosis and HCC patients. HBV infection caused a significantly increase in DTNA expression in HCC cell lines HepAD38 and HepG2.2.15. DTNA knockdown suppressed proliferation and promoted apoptosis of HBV-infected HepAD38 and HepG2.2.15 cells. HBV induced elevated expression of fibrosis-related genes Collagen II and TGFß1 in LO-2 cells, which were suppressed by DTNA knockdown. DTNA directly binded with STAT3 protein to promote STAT3 phosphorylation and TGFß1 expression and repress P53 expression in HBV-infected HepAD38 and LO-2 cells. The DTNA/STAT3 axis was activated during HBV-induced fibrosis, cirrhosis and HCC development in mouse model. CONCLUSION: DTNA binds with and further activates STAT3 to induce TGFß1 expression and repress P53 expression, thus promoting HBV-induced liver fibrosis, cirrhosis and hepatocellular carcinoma progression.


Assuntos
Carcinoma Hepatocelular/virologia , Progressão da Doença , Proteínas Associadas à Distrofina/metabolismo , Vírus da Hepatite B/fisiologia , Neoplasias Hepáticas/virologia , Neuropeptídeos/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Carcinoma Hepatocelular/patologia , Proliferação de Células , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Células Hep G2 , Hepatite B , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica , Transdução de Sinais
11.
PLoS One ; 15(7): e0232307, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32667911

RESUMO

In the mammalian gut CD103+ve myeloid DCs are known to suppress inflammation threatened by luminal bacteria, but stimuli driving DC precursor maturation towards this beneficial phenotype are incompletely understood. We isolated CD11+ve DCs from mesenteric lymph nodes (MLNs) of healthy mice; CD103+ve DCs were 8-24 fold more likely than CD103-ve DCs to exhibit extensive of prior phagocytosis of apoptotic intestinal epithelial cells. However, CD103+ve and CD103-ve MLN DCs exhibited similar ex vivo capacity to ingest apoptotic cells, indicating that apoptotic cells might drive immature DC maturation towards the CD103+ve phenotype. When cultured with apoptotic cells, myeloid DC precursors isolated from murine bone marrow and characterised as lineage-ve CD103-ve, displayed enhanced expression of CD103 and ß8 integrin and acquired increased capacity to induce T regulatory lymphocytes (Tregs) after 7d in vitro. However, DC precursors isolated from αv-tie2 mice lacking αv integrins in the myeloid line exhibited reduced binding of apoptotic cells and complete deficiency in the capacity of apoptotic cells and/or latent TGF-ß1 to enhance CD103 expression in culture, whereas active TGF-ß1 increased DC precursor CD103 expression irrespective of αv expression. Fluorescence microscopy revealed clustering of αv integrin chains and latent TGF-ß1 at points of contact between DC precursors and apoptotic cells. We conclude that myeloid DC precursors can deploy αv integrin to orchestrate binding of apoptotic cells, activation of latent TGF-ß1 and acquisition of the immunoregulatory CD103+ve ß8+ve DC phenotype. This implies that a hitherto unrecognised consequence of apoptotic cell interaction with myeloid phagocytes is programming that prevents inflammation.


Assuntos
Antígenos CD/metabolismo , Apoptose , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Imunomodulação , Cadeias alfa de Integrinas/metabolismo , Integrina alfaV/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Células Mieloides/citologia , Fagocitose , Linfócitos T Reguladores/imunologia
12.
Life Sci ; 256: 117887, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32497629

RESUMO

Vascular complications are a leading cause of morbidity and mortality among diabetic patients. This work aimed to investigate possible influences of dimethyl fumarate (DMF) on streptozotocin (STZ) diabetes-associated vascular complications in rats, exploring its potential to modulate ROS-TXNIP-NLRP3 inflammasome pathway. Two weeks after induction of diabetes (via a single injection of 50 mg/kg STZ, i.p.), diabetic rats were administered either DMF (25 mg/kg/day) or its vehicle for further eight weeks. Age-matched normal and DMF-administered non-diabetic rats served as controls. DMF treatment elicited a mild ameliorative effect on diabetic glycemia. DMF reduced serum TG and AGE levels and enhanced serum HDL-C concentrations in diabetic rats. Moreover, DMF significantly diminished aortic levels of ROS and MDA and restored aortic GSH, SOD and Nrf2 to near-normal levels in STZ rats. Aortic mRNA levels of TXNIP, NLRP3 and NF-κB p65 in diabetic rats were significantly reduced by DMF treatment. Serum and aortic protein levels of TXNIP and aortic contents of IL-1ß, iNOS, NLRP3 and TGF-ß1 were significantly lower in DMF-diabetic animals than non-treated diabetic rats. Furthermore, protein expression of TNF-α and caspase-3 in diabetic aortas was greatly attenuated by DMF administration. DMF enhanced eNOS mRNA and protein levels and increased bioavailable NO in diabetic aortas. Functionally, DMF attenuated contractile responses of diabetic aortic rings to KCl and phenylephrine and enhanced their relaxant responses to acetylcholine. DMF also mitigated diabetes-induced fibrous tissue proliferation in aortic tunica media. Collectively, these findings demonstrate that DMF offered vasculoprotective influences on diabetic aortas via attenuation of ROS-TXNIP-NLRP3 inflammasome pathway.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Fumarato de Dimetilo/uso terapêutico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Biomarcadores/metabolismo , Caspase 3/metabolismo , Proteínas de Ciclo Celular/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Angiopatias Diabéticas/sangue , Fumarato de Dimetilo/farmacologia , Interleucina-1beta/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Oxirredução , Ratos Sprague-Dawley , Estreptozocina , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Life Sci ; 256: 117966, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32535079

RESUMO

AIM: The present study aims to investigate the protective effects of artemisinin (ATZ) on early renal damage in experimental diabetic rats and its probable mechanism. METHODS: Models of diabetic nephropathy (DN) rats was established utilizing streptozotocin (STZ)-injection intraperitoneally (55 mg/kg) method. All rats were subsequently divided into normal control group, model group and ATZ (25, 50, 75 mg/kg) group randomly. Biochemical parameters including body weight, kidney index, blood glucose, 24 h UAER, Scr, BUN, T-SOD, GSH-Px and MDA were comprehensively determined after 8-week consecutive administrations. HE and PAS stainings were performed to observe the histopathological alterations of kidney. Western blot was conducted to detect the expressions of TGF-ß1, Nrf2, HQ-1 and NQO1. KEY FINDINGS: ATZ at three concentrations in ATZ group significantly increased the body weight. Biochemical parameters altered significantly between model group and ATZ group. Moreover, ATZ inhibited TGF-ß1 protein expression and activated the Nrf2 signaling pathway. Pathological histology results revealed the alterations including mesangial cells proliferation, thickness of glomerular capillary basement membrane, extracellular matrix (ECM) and the 24 h UAER. Western blot analysis demonstrated the increase of antioxidant proteins HO-1 and NQO1 and Nrf2-related proteins. SIGNIFICANCE: ATZ could reduce early renal oxidative stress damage in DN rats by inhibiting TGF-ß1 protein expression in kidney tissues as well as activating the Nrf2 signaling pathway and enhancing the expression of antioxidant proteins, thereby exerting the protective effects on DN kidney. The current study is the first report of ATZ on attenuating effects on kidney of DN rats, which could lay solid theoretical foundations on clinical application of ATZ to treat DN.


Assuntos
Artemisininas/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Rim/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Animais , Artemisininas/farmacologia , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Nefropatias Diabéticas/sangue , Heme Oxigenase-1/metabolismo , Rim/efeitos dos fármacos , Masculino , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
14.
Life Sci ; 256: 117909, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512009

RESUMO

Hepatic fibrosis (HF) is a wound-healing response that occurs during chronic liver injury and features by an excessive accumulation of extracellular matrix (ECM) components. Activation of hepatic stellate cell (HSC), the leading effector in HF, is responsible for overproduction of ECM. It has been documented that transforming growth factor-ß1 (TGF-ß1) stimulates superfluous accumulation of ECM and triggers HSCs activation mainly via canonical Smad-dependent pathway. Also, the pro-fibrogenic TGF-ß1 is correlated with generation of reactive oxygen species (ROS) and inhibition of antioxidant mechanisms. Moreover, involvement of oxidative stress (OS) can be clearly elucidated as a fundamental event in liver fibrogenesis. Nuclear factor erythroid 2-related factor 2-antioxidant response elements (Nrf2-AREs) pathway, a group of OS-mediated transcription factors with diverse downstream targets, is associated with the induction of diverse detoxifying enzymes and the most pivotal endogenous antioxidative system. More specifically, Nrf2-AREs pathway has recently assigned as a new therapeutic target for cure of HF. The overall goal of this review will focus on recent findings about activation of Nrf2-AREs-mediated antioxidant and suppression of profibrotic TGF-ß1/Smad3 pathway in the liver, providing an overview of recent advances in transcriptional repressors that dislocated during HF formation, and highlighting possible novel therapeutic targets for liver fibrosis.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antioxidantes/metabolismo , Descoberta de Drogas , Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Humanos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
15.
Clin Sci (Lond) ; 134(12): 1433-1448, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32478392

RESUMO

Recent identification of an RNA-binding protein (HuR) that regulates mRNA turnover and translation of numerous transcripts via binding to an ARE in their 3'-UTR involved in inflammation and is abnormally elevated in varied kidney diseases offers a novel target for the treatment of renal inflammation and subsequent fibrosis. Thus, we hypothesized that treatment with a selective inhibition of HuR function with a small molecule, KH-3, would down-regulate HuR-targeted proinflammatory transcripts thereby improving glomerulosclerosis in experimental nephritis, where glomerular cellular HuR is elevated. Three experimental groups included normal and diseased rats treated with or without KH-3. Disease was induced by the monoclonal anti-Thy 1.1 antibody. KH-3 was given via daily intraperitoneal injection from day 1 after disease induction to day 5 at the dose of 50 mg/kg BW/day. At day 6, diseased animals treated with KH-3 showed significant reduction in glomerular HuR levels, proteinuria, podocyte injury determined by ameliorated podocyte loss and podocin expression, glomerular staining for periodic acid-Schiff positive extracellular matrix proteins, fibronectin and collagen IV and mRNA and protein levels of profibrotic markers, compared with untreated disease rats. KH-3 treatment also reduced disease-induced increases in renal TGFß1 and PAI-1 transcripts. Additionally, a marked increase in renal NF-κB-p65, Nox4, and glomerular macrophage cell infiltration observed in disease control group was largely reversed by KH-3 treatment. These results strongly support our hypothesis that down-regulation of HuR function with KH-3 has therapeutic potential for reversing glomerulosclerosis by reducing abundance of pro-inflammatory transcripts and related inflammation.


Assuntos
Proteína Semelhante a ELAV 1/antagonistas & inibidores , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Nefrite/metabolismo , Nefrite/patologia , Animais , Biomarcadores/metabolismo , Peso Corporal , Polaridade Celular , Colágeno/genética , Colágeno/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Matriz Extracelular/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Humanos , Inflamação/patologia , Testes de Função Renal , Glomérulos Renais/fisiopatologia , Macrófagos/metabolismo , Masculino , Monócitos/metabolismo , NADPH Oxidase 4/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Antígenos Thy-1 , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
16.
Transl Res ; 224: 16-25, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32504824

RESUMO

Epidemiological studies found that increases in the concentrations of airborne particulate matter (PM) smaller than 10 microns diameter (PM10) in the ambient air due to desert dust outbreaks contribute to global burden of diseases, primarily as a result of increased risk of cardiovascular morbidity and mortality. No studies have investigated the possible association between desert dust inhalation and airway inflammation in patients with ischemic heart disease (IHD). Induced sputum was collected in 38 patients and analyzed to determine markers of airway inflammation (Transforming Growth Factor-ß1 [TGF-ß1] and hydroxyproline) concentrations. For the purpose of the investigation, PM10 and reactive gases concentrations measured in the European Air Quality Network implemented in the Canary Islands were also used. We identified Saharan desert dust using meteorology and dust models. Patients affected by smoking, chronic obstructive pulmonary disease (COPD), asthma, pulmonary abnormalities, acute bronchial or pulmonary disease were excluded. The median of age of patients was 64.71 years (56.35-71.54) and 14 (38.84%) of them were women. TGF-ß1 and hydroxyproline in sputum were highly associated to PM10 inhalation from the Saharan desert. According to a regression model, an increase of 1 µg/m3 of PM10 concentrations due to desert dust, results in an increase of 3.84 pg/gwt of TGF-ß1 (R2 adjusted = 89.69%) and of 0.80 µg/gwt of hydroxyproline (R2 adjusted = 85.28%) in the sputum of patients. The results of this study indicate that the exposure to high PM10 concentrations due to Saharan dust events are associated with intense inflammatory reaction in the airway mucosae of IHD-patients.


Assuntos
Poluição do Ar/análise , Poeira/análise , Exposição Ambiental , Inflamação/etiologia , Pulmão/patologia , Isquemia Miocárdica/complicações , África do Norte , Idoso , Feminino , Humanos , Hidroxiprolina/metabolismo , Masculino , Pessoa de Meia-Idade , Material Particulado/efeitos adversos , Fatores de Risco , Espanha , Escarro , Fator de Crescimento Transformador beta1/metabolismo
17.
Life Sci ; 257: 118010, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32598932

RESUMO

Podocyte injury is an early event and core in the development of focal segmental glomerular sclerosis (FSGS) that induces poor prognosis. Epithelial-mesenchymal transition (EMT) as a response of podocyte to injury leads to podocyte depletion and proteinuria. The abnormally reactivated NOTCH pathway may be involved in podocyte EMT. Baicalin, as a natural flavonoid compound, had significant inhibitory activity on tissue fibrosis and tumor cell invasion. However, its potential role and molecular mechanisms to injured podocyte in FSGS are little known. Here we found that baicalin could inhibit podocyte EMT markers expression and cell migration induced by TGF-ß1, accompanied by the up-regulated expression of slit diaphragm (SD) proteins and cell-cell adhesion molecule. Further investigation revealed that EMT inhibition of baicalin on injured podocyte is mainly mediated by the reduction of notch1 activation and its downstream Snail expression. Using the adriamycin-induced FSGS model, we determined that baicalin suppresses the Notch1-Snail axis activation in podocytes, relieves glomerulus structural disruption and dysfunction, and reduces proteinuria. Altogether, these findings suggest that baicalin is a novel renoprotective agent against podocyte EMT in FSGS and indicate its underlying mechanism that involves in negative regulation of the Notch1-Snail axis.


Assuntos
Flavonoides/farmacologia , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Proteinúria/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Doxorrubicina/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Flavonoides/metabolismo , Glomerulosclerose Segmentar e Focal/metabolismo , Glomérulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Podócitos/metabolismo , Proteinúria/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
18.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 67-72, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476375

RESUMO

OBJECTIVE: Effects of Yiqi Huashi Tongluo Formula on oxidative stress and renal fibrosis of residual kidney were investigated in five/sixth nephrectomy rats. METHODS: The rat model of chronic renal failure after nephrectomy was established by Platt method. Two weeks after the operation, the rats were randomly divided into model group, Yiqi Huashi Tongluo Formula (YHT) group, benazepril online (BH) group and sham group, with 8 rats in each group. Treatment was initiated once a day for 12 weeks after successful modeling. Animals were treated once a day with intragastric administration for 12 weeks. (Aqueous solution of free decoction granules in YHT group was 0.276 g/100 g·d. BH group benazepril hydrochloride tablet aqueous solution 0.09 mg/100 g·d gavage; sham group and model group were gavage with 1 ml/100 g normal saline). Urine was collected with a metabolic cage at the end of the 12th week, and urine protein content was detected for 24 hours. The rats were then anesthetized to extract blood from the abdominal aorta and the kidneys. The pathological changes of left kidney were observed by HE staining and Masson staining. The activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in kidney homogenate were determined by colorimetry. Western blot assay was used to detect the expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), kelch-like ech-associated protein-1 (Keap1), NADPH oxidase 4 (Nox4), transforming growth factor-binding 1(TGF-ß1), type I collagen (Collagen1) and Nrf2 in the nucleus in renal tissue. RESULTS: Compared with sham group, model group rats had severe glomerular injury and obvious fibrosis. Levels of Scr, BUN, MDA and 24-hour urine protein excretion, protein expressions of Keap1, Nox4, TGF-ß1 and Collagen1 were significantly increased (P<0.01), while SOD activity and Nrf2 expression were significantly decreased (P<0.01).Compared with the model group, the degree of glomerular lesion was reduced and fibrosis was less after YHT or BH intervention, and the levels of Scr, BUN, MDA, 24-hour urine protein excretion, protein expressions of Keap1, Nox4, TGF-ß1 and Collagen1 were significantly decreased (P<0.01), while SOD activity and Nrf2 expression were significantly increased (P<0.01). CONCLUSION: Through affecting the Nrf2/Keap1 signaling pathway and down-regulating the expression of TGF-ß1 protein, Yiqi Huashi Tongluo Formula improved the oxidative stress damage and fibrosis degree of residual kidney in the model rats with renal failure.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Nefropatias/tratamento farmacológico , Estresse Oxidativo , Animais , Fibrose , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo
19.
Medicine (Baltimore) ; 99(24): e20253, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541451

RESUMO

This study is to explore the molecular mechanism of benign bile duct hypertrophic scar formation.Differential proteins between the normal fibroblast (NFB) and scar fibroblast (SCFB) were screened by protein chip assay, and analyzed by pathway-enrichment analysis and function-enrichment analysis. The differential proteins were further tested by ELISA. SiRNA-Act B was transfected to SCFB to down-regulate the expression of Act B. NFB was incubated with rh-Act B. The cell apoptosis and cell cycle were determined by flow cytometry. The expression of Act B, Smad2/3, transforming growth factor-ß1 (TGF-ß1), endothelin-1 (ET-1), thrombospondin-1 (Tsp-1), and Oncostatin M (OSM) were detected by Western blot.A total of 37 differential proteins were identified in SCFBs by microarray (P < .05), including 27 up-regulated proteins and 10 down-regulated proteins (P < .05). Their function were associated with Activin signaling, synthesis and degradation of extracellular matrix, formation and activation of cytokine, inflammatory reaction, immunoreaction, tissue damage reaction, cell cycle, migration, apoptosis, and secretion, etc. ELISA results showed that the expression of Act B, TGF-ß1, ET-1 were higher in SCFBs, while the expression of Tsp-1 and OSM were lower in SCFBs (P < .05). After interfered by siRNA-Act B, the expression of Act B mRNA decreased (P < .05). The percentage of early apoptosis increased (P < .05). The expression of Act B, Smad2/3, TGF-ß1 were decreased and Tsp-1, OSM were increased (P < .05). After treatment with rh-Act B, the percentage of G0/G1 phase of NFBs was decreased and that of S phase was increased without significance (P > .05). The expression of Act B, Smad2/3, TGF-ß1 were increased (P < .05) and Tsp-1, OSM were decreased (P < .01).There are differentially expressed proteins between SCFBs and NFBs. Activin B signal plays an important role in the process of NFB transforming to SCFB, and TGF-ß1, Smad2/3, Tsp-1, and OSM are important participants.


Assuntos
Ativinas/metabolismo , Ductos Biliares/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Transdução de Sinais/fisiologia , Adulto , Apoptose/fisiologia , Ciclo Celular/fisiologia , Cicatriz Hipertrófica , Endotelina-1/metabolismo , Matriz Extracelular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncostatina M/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Proteína Smad2/metabolismo , Trombospondina 1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
20.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G989-G999, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32363890

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. However, NAFLD patients generally do not respond to treatment with testosterone alone. We investigated the innate immune mechanisms underlying the effects of treatment with testosterone alone, estrogen alone, or combined testosterone and estrogen on high-fat diet (HFD)-induced NAFLD due to testosterone deficiency. Orchiectomized (OCX) male Rag2-/- mice were used as a model of testosterone deficiency. To assess NAFLD severity, NAFLD activity score (NAS) is adopted. Moreover, immunological change was analyzed by multicolor flow cytometry. Treatment with both testosterone and estrogen significantly decreased body weight to that of the sham mice/normal diet (ND). NAS and liver fibrosis in OCX-HFD mice were significantly deteriorated, and treatment with testosterone and estrogen improved same as sham-ND mice. HFD increased the ratio of both type 2 and 3 innate lymphoid cells (ILC2s and ILC3s) to CD45-positive cells in the liver. Treatment with testosterone alone decreased the ratio of ILC2 to CD45 but not the ILC3-to-CD45 ratio. Addition of estrogen to the treatment reduced the ratios of ILC2-to-CD45 and ILC3-to-CD45 to the same level observed in sham-HFD mice. Moreover, OCX-HFD mice had a decreased proportion of M2 macrophages compared with sham-ND mice. Treatment with testosterone alone did not restore the proportion of M2 macrophages; however, combination treatment with both estrogen and testosterone increased that to the same level as that in sham-HFD mice. Treatment with both testosterone and estrogen improves liver fibrosis and decreases ILC3 and increases M2 macrophage abundance in the liver.NEW & NOTEWORTHY The progression of nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. NAFLD patients generally do not respond to treatment with testosterone alone. In animal studies, treatment with testosterone and estrogen reduced the ratios of ILC2:CD45 and ILC3:CD45 and increased M2 macrophages in liver. Our study suggests, based on our immunological data, that a combination of estrogen and testosterone may be clinically relevant for the treatment of NAFLD in patients with male menopause.


Assuntos
Estradiol/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Testosterona/farmacologia , Aminoácidos , Animais , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Cromo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo , Estradiol/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Insulina , Cirrose Hepática , Neoplasias Hepáticas , Masculino , Camundongos , Camundongos Knockout , Ácidos Nicotínicos , Hepatopatia Gordurosa não Alcoólica/patologia , Orquiectomia , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Testosterona/administração & dosagem , Testosterona/deficiência , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
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