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1.
Medicine (Baltimore) ; 100(35): e26774, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477116

RESUMO

ABSTRACT: Umbilical Vein Recanalization (UVR) may occur in patients with long-standing portal hypertension and liver cirrhosis. This study aimed to investigate the clinical significance of UVR.Medical records of a cohort of patients with cirrhosis (n = 247) who were hospitalized at the Digestive Medicine Center of the Second Affiliated Hospital of Nanchang University from January 2012 to October 2015 were accessed. The UVR diagnosis was made by ultrasound examination and was confirmed by computerized tomography scan.The UVR incidence was 20.2% (50/247) in the cohort. The size of UVR was 9.9 ±â€Š4.7 mm (range: 5-26.5 mm) in diameter. The UVR and non-UVR groups showed no difference in grades of hepatic encephalopathy (P = .496), Child-Pugh classification (P = .401), the incidence of moderately severe ascites (26% vs 26%, P = 1), the esophageal variceal bleeding rate (32% vs 39%, P = .402), or portal vein thrombosis (8% vs 12%, P = .580). However, the incidence of cavernous transformation of the portal vein was statistically different, that there was 0 case in the UVR group and 8 cases in the non-UVR group (P < .05).Our results suggested that UVR had little impact on the clinical manifestations of patients with liver cirrhosis, the significance of UVR as an intervention method requires further studies.


Assuntos
Cateterismo/estatística & dados numéricos , Fibrose/fisiopatologia , Veias Umbilicais , Adulto , Cateterismo/métodos , Feminino , Fibrose/classificação , Fibrose/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
2.
Phys Rev Lett ; 127(9): 098101, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34506203

RESUMO

Cardiac fibrosis is a well-known arrhythmogenic condition which can lead to sudden cardiac death. Physically, fibrosis can be viewed as a large number of small obstacles in an excitable medium, which may create nonlinear wave turbulence or reentry. The relation between the specific texture of fibrosis and the onset of reentry is of great theoretical and practical importance. Here, we present a conceptual framework which combines functional aspects of propagation manifested as conduction blocks, with reentry wavelength and geometrical clusters of fibrosis. We formulate them into the single concept of minimal functional cluster and through extensive simulations show that it characterizes the path of reexcitation accurately, and importantly its size distribution quantitatively predicts the reentry probability for different fibrosis densities and tissue excitabilities.


Assuntos
Sistema de Condução Cardíaco/fisiopatologia , Modelos Cardiovasculares , Miocárdio/patologia , Potenciais de Ação , Análise por Conglomerados , Fibrose/patologia , Fibrose/fisiopatologia , Humanos , Dinâmica não Linear
3.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(4): 634-641, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34494537

RESUMO

Discoidin domain receptor 1(DDR1)is a critical member of the receptor tyrosine kinase family.It may be related to tumor invasion and metastasis,and the abnormal activation of DDR1 can lead to the occurrence and development of malignant tumors,inflammation,and fibrosis.DDR1 are involved in cell adhesion,migration,proliferation,secretion of cytokines,and remodeling of extracellular matrix,thus playing a critical role in various pathophysiological processes of the human body.In this review,we demonstrate the research progress of DDR1 in breast cancer and other malignant tumors,in order to provide a new theoretical basis for the prevention and treatment of breast cancer and other tumors.


Assuntos
Neoplasias da Mama , Receptor com Domínio Discoidina 1 , Neoplasias da Mama/genética , Adesão Celular , Feminino , Fibrose , Humanos , Receptores Proteína Tirosina Quinases/genética
5.
Gan To Kagaku Ryoho ; 48(9): 1100-1102, 2021 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-34521784

RESUMO

Gut microbes are one of the essential components of the tumor microenvironment, the same as interstitial stroma, angiogenesis, and immunity. With the advancement of technology, it has become possible to analyze various bacterial flora without culturing microbiomes comprehensively. There are a massive amount of gut microbes in the large intestine compared with other organs. It has been reported that some species of gut microbes, such as Fusobacterium nucleatum, are involved in the progression and metastasis of colorectal cancer and resistance to chemotherapy, with multiple mechanisms. The interstitial stroma composed of an extracellular matrix is also one of the crucial components of the tumor microenvironment involved in cancer progression and metastasis. It has been reported that fibrosis in the invasive front of the primary tumor and metastatic lymph nodes is a poor prognostic factor in colorectal cancer. Gut microbes affect not only cancer cells but also various surrounding factors such as fibrosis and angiogenesis. Gut microbes produced many kinds of enzymes, including protease, elastase, and collagenase, which degrade the surrounding extracellular matrix and secreted cytokines to induce inflammation and remodel a cancer-specific environment. It is important to consider the cancer microenvironment, including gut microbes and interstitial stroma, for treating colorectal cancer.


Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Fibrose , Fusobacterium nucleatum , Humanos , Microambiente Tumoral
6.
Nat Commun ; 12(1): 5213, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480023

RESUMO

Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, p19ARF, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types. Results suggest that senolytics may provide an attractive strategy to mitigating age-dependent disc degeneration.


Assuntos
Envelhecimento/efeitos dos fármacos , Dasatinibe/uso terapêutico , Degeneração do Disco Intervertebral/tratamento farmacológico , Quercetina/uso terapêutico , Agrecanas/metabolismo , Envelhecimento/metabolismo , Animais , Anel Fibroso/efeitos dos fármacos , Anel Fibroso/metabolismo , Anel Fibroso/patologia , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrose , Inflamação , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Fenótipo , Transcriptoma/efeitos dos fármacos
7.
Int Heart J ; 62(4): 891-899, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334583

RESUMO

Long-chain noncoding RNA (lncRNA) is a new class of molecular regulators in heart development and disease. However, the role of specific lncRNA in cardiac fibrosis remains to be fully explored. This study aimed to investigate the role and potential mechanism of lncRNA MHRT in myocardial fibrosis after myocardial infarction (MI).Cardiac fibroblasts (CFs) were isolated from a mouse model of MI. The expression levels of MHRT and miR-3185 in the hearts of MI and CFs mice treated with transforming growth factor beta 1 (TGF-ß1) were analyzed by qRT-PCR. The collagen expression was assessed using qRT-PCR and Western blot. Cell proliferation was assessed by performing MTT and EdU assays. The direct interaction between lncRNA and miRNA was analyzed by luciferase assay, RNA-binding protein immunoprecipitation (RIP) assay, and RNA pull-down assay.The expression levels of MHRT were raised in MI and CFs mice treated with TGF-ß1. Overexpression of MHRT promoted collagen production and CF proliferation, while silencing of MHRT showed the opposite effect. MiR-3185 was a target gene of MHRT. In addition, overexpression of MHRT reduced the expression levels of miR-3185, and siMHRT reversed the inhibitory effect of TGF-ß1 on the expression of miR-3185. Overexpression of miR-3185 inhibited the upregulation of Col I and Col III induced by TGF-ß1.MHRT promoted cardiac fibrosis after MI through miR-3185 and increased myocardial collagen deposition and promoted myocardial fibrosis.


Assuntos
Infarto do Miocárdio/metabolismo , Miocárdio/patologia , RNA Longo não Codificante/metabolismo , Animais , Colágeno/metabolismo , Fibroblastos/metabolismo , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Ratos Sprague-Dawley
8.
Pestic Biochem Physiol ; 178: 104919, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34446195

RESUMO

BACKGROUND: Paraquat poisoning leads to lung injury and pulmonary fibrosis. The effect of paraquat encapsulation by previously described Pectin/Chitosan/Tripolyphosphate nanoparticles on its pulmonary toxicity was investigated in present study in a rat model of poison inhalation. MATERIAL AND METHOD: The rats inhaled nebulized different formulation of paraquat (n = 5) for 30 min in various experimental groups. Lung injury and fibrosis scores, Lung tissue enzymatic activities, apoptosis markers were determined compared among groups. RESULTS: Encapsulation of paraquat significantly rescued both lung injury and fibrosis scores. Lung MDA level was reduced by encapsulation. Paraquat poisoning led to lung tissue apoptosis as was evidenced by higher Caspase-3 and Bax/Bcl2 expressions in rats subjected to paraquat inhalation instead of normal saline or free nanoparticles. Again, nanoencapsulation reduced these apoptosis markers significantly. Alpha-SMA expression was also reduced by encapsulation. Nanoparticles per se have no or little toxicity as was evidenced by inflammatory and apoptotic markers and histological scores. CONCLUSION: In a rat model of inhalation toxicity of paraquat, loading of this herbicide on PEC/CS/TPP nanoparticles reduced acute lung injury and fibrosis. The encapsulation also led to lower apoptosis, oxidative stress and alpha-SMA expression in the lung tissue.


Assuntos
Quitosana , Paraquat , Animais , Apoptose , Fibrose , Pulmão/patologia , Paraquat/toxicidade , Pectinas , Polifosfatos , Ratos
9.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445632

RESUMO

Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-ß1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-ß1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)2pD, suppresses fibrosis and mediators of the TGF-ß1 pathway in the bleomycin (BLM) model of fibrosis. Fibrosis was induced into the skin of female C57BL/6 mice by repeated injections of BLM (50 µg/100 µL) subcutaneously. Mice received daily oral gavage with either vehicle (propylene glycol) or 17,20S(OH)2pD using 5, 15, or 30 µg/kg for 21 days. The injected skin was biopsied; analyzed histologically; examined for total collagen by Sircol; and examined for mRNA expression of MMP-13, BMP-7, MCP-1, Gli1, and Gli2 by TR-PCR. Spleen was analyzed for lymphocytes using flow cytometry. Serum was analyzed for cytokines using a multiplexed ELISA. Results showed that all three doses of 17,20S(OH)2pD suppressed net total collagen production, dermal thickness, and total collagen content in the BLM fibrosis model. 17,20S(OH)2pD also increased MMP-13 expression, decreased MCP-1 and Gli-2 expression in vivo, and suppressed serum levels of IL-13, TNF-α, IL-6, IL-10, IL-17, and IL-12p70. In summary, 17,20S(OH)2pD modulates the mediators of fibrosis in vivo and suppresses total collagen production and dermal thickness. This antifibrotic property of 17,20S(OH)2pD offers new therapeutic approaches for fibrotic disorders.


Assuntos
Bleomicina/toxicidade , Colecalciferol/análogos & derivados , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Escleroderma Sistêmico/complicações , Dermatopatias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/toxicidade , Colecalciferol/farmacologia , Citocinas/metabolismo , Feminino , Fibrose/etiologia , Fibrose/patologia , Camundongos , Camundongos Endogâmicos C57BL , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/patologia , Dermatopatias/etiologia , Dermatopatias/patologia
10.
Biomolecules ; 11(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34356613

RESUMO

Renal fibrosis is a hallmark of chronic kidney disease (CKD) and a common manifestation of end-stage renal disease that is associated with multiple types of renal insults and functional loss of the kidney. Unresolved renal inflammation triggers fibrotic processes by promoting the activation and expansion of extracellular matrix-producing fibroblasts and myofibroblasts. Growing evidence now indicates that diverse T cells and macrophage subpopulations play central roles in the inflammatory microenvironment and fibrotic process. The present review aims to elucidate the role of CD8+ T cells in renal fibrosis, and identify its possible mechanisms in the inflammatory microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Rim/imunologia , Miofibroblastos/imunologia , Insuficiência Renal Crônica/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Fibrose , Humanos , Inflamação/imunologia , Inflamação/patologia , Rim/patologia , Miofibroblastos/patologia , Insuficiência Renal Crônica/patologia
11.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443591

RESUMO

The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial benefits of resveratrol with sacubitril/valsartan alongside an active comparator valsartan in MI-induced male Sprague Dawley rats. MI-induced and sham-operated animals received vehicle, resveratrol, sacubitril/valsartan, valsartan alone or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint to assess cardiac structure and function. Cardiac oxidative stress, inflammation, fibrosis, brain natriuretic peptide (BNP), creatinine and neutrophil gelatinase associated lipocalin were measured. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented left ventricular (LV) dilatation and improved LV ejection fraction in MI-induced rats. All treatments also significantly reduced myocardial tissue oxidative stress, inflammation and fibrosis, as well as BNP. Treatment with the combination of sacubitril/valsartan and resveratrol did not show additive effects. In conclusion, resveratrol, sacubitril/valsartan, and valsartan significantly prevented cardiac remodeling and dysfunction in MI-induced rats. The reduction in cardiac remodeling and dysfunction in MI-induced rats was mediated by a reduction in cardiac oxidative stress, inflammation and fibrosis.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Resveratrol/farmacologia , Valsartana/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Combinação de Medicamentos , Interações Medicamentosas , Fibrose , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacos
12.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445305

RESUMO

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1ß, IL-6, TNF-α, NFκB p65, Iκß, TGF-ß, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-ß were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1ß, and Cd68 in the lung. In addition, TGF-ß, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-ß. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.


Assuntos
Anti-Inflamatórios/uso terapêutico , Dissulfetos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Ácidos Sulfínicos/uso terapêutico , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Citocinas/genética , Citocinas/metabolismo , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Wistar , Proteína Smad5/genética , Proteína Smad5/metabolismo
13.
Stem Cell Res Ther ; 12(1): 435, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34348793

RESUMO

Fibrosis is likely to occur in many tissues and organs to induce cicatrisation and dysfunction. The therapeutic regimens for delaying and even reversing fibrosis are quite limited at present. In nearly a decade, mesenchymal stem cells (MSCs) have been widely acknowledged as useful in treating fibrotic diseases in preclinical and clinical trials. Further preclinical studies indicated that the effects of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are probably superior to that of MSCs. At present, MSC-EVs have attracted much attention in treating fibrosis of lung, liver, kidney, skin, and heart. By contrast, a significant knowledge-gap remains in treating fibrosis of other tissues and organs (including uterus, gastrointestinal tract, and peritoneum) with the aid of MSC-EVs. This review summarises the preclinical research status of MSC-EVs in treating fibrotic diseases and proposes solutions to existing problems, which contribute to further clinical research on the treatment of fibrotic diseases with MSC-EVs in the future.


Assuntos
Vesículas Extracelulares , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Feminino , Fibrose , Humanos , Rim
14.
Sci Transl Med ; 13(605)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349032

RESUMO

Transforming growth factor-ß (TGFß) is a key driver of fibrogenesis. Three TGFß isoforms (TGFß1, TGFß2, and TGFß3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFß2 and TGFß3 have not been well characterized. Here, we show that the latent forms of TGFß2 and TGFß3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFß1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFß2 and TGFß3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFß isoform-selective antibodies demonstrated that TGFß2 and TGFß3 are independently involved in mouse fibrosis models in vivo, and selective TGFß2 and TGFß3 inhibition does not lead to the increased inflammation observed with pan-TGFß isoform inhibition. A cocrystal structure of a TGFß2-anti-TGFß2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFß2 and/or TGFß3 while sparing TGFß1 may alleviate fibrosis without toxicity concerns associated with pan-TGFß blockade.


Assuntos
Fator de Crescimento Transformador beta2 , Fator de Crescimento Transformador beta3 , Animais , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Camundongos , Isoformas de Proteínas/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta3/metabolismo
15.
Clin Immunol ; 230: 108827, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34428741

RESUMO

BAL cellularity and lymphocyte immunophenotyping offer insights into lung inflammatory status. Natural killer (NK) cells are efficient effector cells, producing pro-inflammatory cytokines. A better understanding of the biology of NK cells in BAL in the lungs is necessary to improve the pathogenesis of fibrotic ILD and develop prospective targeted treatments. Our aim was to analyse NK and NKT-like cell percentages in BAL from 159 patients with different ILD: f-HP, f-NSIP, IPF and CTD-ILD, to evaluate their potential diagnostic/prognostic role. BAL NK cell percentages showed significantly higher values in IPF than in f-HP and f-NSIP, while BAL NKT-like cells showed significantly lower values in the f-NSIP than the f-HP and IPF. A cut-off of 4%NK cells in BAL of IPF showed a significant difference in survival rate. It suggests a possible new marker of survival and raises the possibility of new targeted approach in treatment and management of IPF.


Assuntos
Células Matadoras Naturais/imunologia , Doenças Pulmonares Intersticiais/imunologia , Idoso , Idoso de 80 Anos ou mais , Alveolite Alérgica Extrínseca/imunologia , Alveolite Alérgica Extrínseca/patologia , Alveolite Alérgica Extrínseca/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Doenças do Tecido Conjuntivo/imunologia , Doenças do Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/fisiopatologia , Feminino , Fibrose , Humanos , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/fisiopatologia , Imunofenotipagem , Estimativa de Kaplan-Meier , Células Matadoras Naturais/classificação , Células Matadoras Naturais/patologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/classificação , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Prognóstico , Testes de Função Respiratória
16.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445567

RESUMO

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Fibrose/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/tratamento farmacológico , Mioblastos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Animais , Fibrose/metabolismo , Fibrose/patologia , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mioblastos/metabolismo , Mioblastos/patologia , Receptores de Lisoesfingolipídeo
18.
Clin Immunol ; 230: 108823, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34400321

RESUMO

Chronic graft-versus-host disease (cGVHD) is an immune-mediated disorder characterized by chronic inflammation and fibrosis. Rho-associated coiled-coil-containing protein kinases (ROCKs) are key coordinators of tissue response to injury, regulating multiple functions, such as gene expression and cell migration, proliferation and survival. Relevant to cGVHD and autoimmunity, only the ROCK2 isoform drives a pro-inflammatory type 17 helper T (Th17) cell response. Moreover, ROCK2 inhibition shifts the Th17/regulatory T (Treg) cell balance toward Treg cells and restores immune homeostasis in animal models of autoimmunity and cGVHD. Furthermore, the selective inhibition of ROCK2 by belumosudil reduces fibrosis by downregulating both transforming growth factor-ß signaling and profibrotic gene expression, thereby impeding the creation of focal adhesions. Consistent with its anti-inflammatory and antifibrotic activities, belumosudil has demonstrated efficacy in clinical studies, resulting in an overall response rate of >70% in patients with cGVHD who failed 2 to 5 prior lines of systemic therapy. In summary, selective ROCK2 inhibition has emerged as a promising novel therapeutic approach for treating cGVHD and other immunologic diseases with unique mechanisms of action, targeting both immune imbalance and detrimental fibrotic responses.


Assuntos
Doença Enxerto-Hospedeiro/enzimologia , Quinases Associadas a rho/imunologia , Acetamidas/farmacologia , Animais , Doença Crônica , Modelos Animais de Doenças , Fibrose , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Imunomodulação , Modelos Imunológicos , Inibidores de Proteínas Quinases/farmacologia , Linfócitos T Reguladores/imunologia , Quinases Associadas a rho/antagonistas & inibidores
19.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445337

RESUMO

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFß2 and IL1ß. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.


Assuntos
Transdiferenciação Celular/genética , Rim/patologia , MicroRNAs/fisiologia , Miocárdio/patologia , Animais , Células Cultivadas , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Fibrose/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Rim/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia
20.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445377

RESUMO

Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called "ER stress". Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.


Assuntos
Proteostase/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Fibrose , Humanos , Terapia de Alvo Molecular , Insuficiência Renal Crônica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/uso terapêutico , Resposta a Proteínas não Dobradas/efeitos dos fármacos
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