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31.
《Cytokine》2016
Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFNγ signaling and has been implicated in the regulation of liver fibrosis. However, it is not known whether SOCS1 mediates its anti-fibrotic functions in the liver directly, or via modulating IFNγ, which has been implicated in attenuating hepatic fibrosis. Additionally, it is possible that SOCS1 controls liver fibrosis by regulating hepatic stellate cells (HSC), a key player in fibrogenic response. While the activation pathways of HSCs have been well characterized, the regulatory mechanisms are not yet clear. The goals of this study were to dissociate IFNγ-dependent and SOCS1-mediated regulation of hepatic fibrogenic response, and to elucidate the regulatory functions of SOCS1 in HSC activation. Liver fibrosis was induced in Socs1−/−Ifng−/− mice with dimethylnitrosamine or carbon tetrachloride. Ifng−/− and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs1−/−Ifng−/− mice showed elevated serum ALT levels and increased liver fibrosis compared to Ifng−/− mice. The latter group showed higher ALT levels and fibrosis than C57BL/6 controls. The livers of SOCS1-deficient mice showed bridging fibrosis, which was associated with increased accumulation of myofibroblasts and abundant collagen deposition. SOCS1-deficient livers showed increased expression of genes coding for smooth muscle actin, collagen, and enzymes involved in remodeling the extracellular matrix, namely matrix metalloproteinases and tissue inhibitor of metalloproteinases. Primary HSCs from SOCS1-deficient mice showed increased proliferation in response to growth factors such as HGF, EGF and PDGF, and the fibrotic livers of SOCS1-deficient mice showed increased expression of the Pdgfb gene. Taken together, these data indicate that SOCS1 controls liver fibrosis independently of IFNγ and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability. 相似文献
32.
Massimo Dal Monte Maurizio Cammalleri Valeria Pecci Monica Carmosino Giuseppe Procino Alessandro Pini Mario De Rosa Vincenzo Pavone Maria Svelto Paola Bagnoli 《Journal of cellular and molecular medicine》2019,23(2):1034-1049
The urokinase‐type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR ‐(s)uPAR‐ from circulation) is to regulate podocyte function through αvβ3 integrin/Rac‐1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)‐induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac‐1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ‐induced up‐regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac‐1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen‐plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR‐targeting approaches. 相似文献
33.
Anil Chekuri Katarzyna Zientara‐Rytter Angel Soto‐Hermida Shyamanga Borooah Marina Voronchikhina Pooja Biswas Virender Kumar David Goodsell Caroline Hayward Peter Shaw Chloe Stanton Donita Garland Suresh Subramani Radha Ayyagari 《Aging cell》2019,18(6)
Late‐onset retinal degeneration (L‐ORD) is an autosomal dominant macular degeneration characterized by the formation of sub‐retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L‐ORD results from mutations in the C1q‐tumor necrosis factor‐5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L‐ORD pathology, we used a human cDNA library yeast two‐hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM‐Ch) from wild‐type (Wt), heterozygous S163R Ctrp5 mutation knock‐in (Ctrp5S163R/wt), and homozygous knock‐in (Ctrp5S163R/S163R) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C‐terminal PDZ‐binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R‐CTRP5 protein also binds to HTRA1 but is resistant to HTRA1‐mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM‐Ch of Ctrp5S163R/S163R and Ctrp5S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L‐ORD pathology. 相似文献
34.
Small-angle X-ray scattering experiments were carried out to investigate the structural changes of cardiac thin filaments induced by the cardiomyopathy-causing E244D mutation in troponin T (TnT). We examined native thin filaments (NTF) from a bovine heart, reconstituted thin filaments containing human cardiac wild-type Tn (WTF), and filaments containing the E244D mutant of Tn (DTF), in the absence and presence of Ca2+. Analysis by model calculation showed that upon Ca2+-activation, tropomyosin (Tm) and Tn in the WTF and NTF moved together in a direction to expose myosin-binding sites on actin. On the other hand, Tm and Tn of the DTF moved in the opposite directions to each other upon Ca2+-activation. These movements caused Tm to expose more myosin-binding sites on actin than the WTF, suggesting that the affinity of myosin for actin is higher for the DTF. Thus, the mutation-induced structural changes in thin filaments would increase the number of myosin molecules bound to actin compared with the WTF, resulting in the force enhancement observed for the E244D mutation. 相似文献
35.
Mutations in the Drosophila alphaPS2 integrin subunit uncover new features of adhesion site assembly
The Drosophila alphaPS2betaPS integrin is required for diverse development events, including muscle attachment. We characterized six unusual mutations in the alphaPS2 gene that cause a subset of the null phenotype. One mutation changes a residue in alphaPS2 that is equivalent to the residue in alphaV that contacts the arginine of RGD. This change severely reduced alphaPS2betaPS affinity for soluble ligand, abolished the ability of the integrin to recruit laminin to muscle attachment sites in the embryo and caused detachment of integrins and talin from the ECM. Three mutations that alter different parts of the alphaPS2 beta-propeller, plus a fourth that eliminated a late phase of alphaPS2 expression, all led to a strong decrease in alphaPS2betaPS at muscle ends, but, surprisingly, normal levels of talin were recruited. Thus, although talin recruitment requires alphaPS2betaPS, talin levels are not simply specified by the amount of integrin at the adhesive junction. These mutations caused detachment of talin and actin from integrins, suggesting that the integrin-talin link is weaker than the ECM-integrin link. 相似文献
36.
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38.
Circular RNAs (circRNAs) are a novel type of noncoding RNAs that modulate the pathogenesis of multiple diseases. Nevertheless, the role of circRNAs in diabetic nephropathy (DN) pathogenesis is still ambiguous. In the current study, our team aims to investigate the expression profiles of circRNAs in DN and identify the function of circRNA on mesangial cells. CircRNAs microarray analysis revealed dysregulated circRNA in db/db DN mice, and circRNA_15698 was validated to be upregulated in both db/db mice and mouse mesangial cells (SV40-MES13) that were exposed to high glucose (25 mM) using real-time polymerase chain reaction. Loss-of-functional experiments showed that circRNA_15698 knockdown significantly inhibited the expression levels of collagen type I (Col. I), collagen type IV (Col. IV), and fibronectin. Moreover, the cellular localization of circRNA_15698 was mainly in the cytoplasm. Bioinformatics tools and luciferase reporter assay confirmed that circRNA_15698 acted as a ‘sponge’ of miR-185, and then positively regulated the transforming growth factor-β1 (TGF-β1) protein expression, suggesting a circRNA_15698/miR-185/TGF-β1 pathway. Further validation experiments validated that circRNA_15698/miR-185/TGF-β1 promoted extracellular matrix (ECM)-related protein synthesis. In summary, our study preliminarily investigates the role of circRNAs in mesangial cells and ECM accumulation, providing a novel insight for DN pathogenesis. 相似文献
39.
《European journal of cell biology》2019,98(2-4):65-73
Stem cell niche is a specialized and dynamic microenvironment around the stem cells which plays a critical role in maintaining the stemness properties of stem cells. Over the years, advancement in the research activity has revealed the various important aspects of stem cell niche including cell-cell interaction, cell-extracellular matrix interaction, a large number of soluble signaling factors and various biochemical and biophysical cues (such as oxygen tension, flow, and shear and pore size). Stem cells have the potential to be a powerful tool in regenerative medicine due to their self-renewal property and immense differentiation potential. Recent progresses in in vitro culture conditions of embryonic stem cells, adult stem cells and induced pluripotent stem cells have enabled the researchers to investigate and understand the role of the microenvironment in stem cell properties. The engineered artificial stem cell niche has led to a better execution of stem cells in regenerative medicine. Here we elucidate the key components of stem cell niche and their role in niche engineering and stem cell therapeutics. 相似文献
40.
The chemokine receptor CXCR2 and its ligands are implicated in the progression of tumours and various inflammatory diseases. Activation of the CXCLs/CXCR2 axis activates multiple signalling pathways, including the PI3K, p38/ERK, and JAK pathways, and regulates cell survival and migration. The CXCLs/CXCR2 axis plays a vital role in the tumour microenvironment and in recruiting neutrophils to inflammatory sites. Extensive infiltration of neutrophils during chronic inflammation is one of the most important pathogenic factors in various inflammatory diseases. Chronic inflammation is considered to be closely correlated with initiation of cancer. In addition, immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) against T cells attenuate the anti-tumour effects of T cells and promote tumour invasion and metastasis. Over the last several decades, many therapeutic strategies targeting CXCR2 have shown promising results and entered clinical trials. In this review, we focus on the features and functions of the CXCLs/CXCR2 axis and highlight its role in cancer and inflammatory diseases. We also discuss its potential use in targeted therapies. 相似文献