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1.
Cardiac fibrosis critically injured the cardiac structure and function of the hypertensive patients. However, the anti‐fibrotic strategy is still far from satisfaction. This study aims to determine the effect and mechanism of Pirfenidone (PFD), an anti‐lung fibrosis medicine, in the treatment of cardiac fibrosis and heart failure induced by pressure overload. Male C57BL/6 mice were subjected to thoracic aorta constriction (TAC) or sham surgery with the vehicle, PFD (300 mg/kg/day) or Captopril (CAP, 20 mg/kg/day). After 8 weeks of surgery, mice were tested by echocardiography, and then sacrificed followed by morphological and molecular biological analysis. Compared to the sham mice, TAC mice showed a remarkable cardiac hypertrophy, interstitial and perivascular fibrosis and resultant heart failure, which were reversed by PFD and CAP significantly. The enhanced cardiac expression of TGF‐β1 and phosphorylation of Smad3 in TAC mice were both restrained by PFD. Cardiac fibroblasts isolated from adult C57BL/6 mice were treated by Angiotensin II, which led to significant increases in cellular proliferation and levels of α‐SMA, vimentin, TGF‐β1 and phosphorylated TGF‐β receptor and Smad3. These changes were markedly inhibited by pre‐treatment of PFD. Collectively, PFD attenuates myocardial fibrosis and dysfunction induced by pressure overload via inhibiting the activation of TGF‐β1/Smad3 signalling pathway.  相似文献   

2.
Skin fibrosis, which is characterized by fibroblast proliferation and increased extracellular matrix, has no effective treatment. An increasing number of studies have shown that microRNAs (miRNAs/miRs) participate in the mechanism of skin fibrosis, such as in limited cutaneous systemic sclerosis and pathological scarring. The objective of the present study was to determine the role of miR‐411‐3p in bleomycin (BLM)‐induced skin fibrosis and skin fibroblast transformation. Using Western blot analysis and real‐time quantitative polymerase chain reaction assess the expression levels of miR‐411‐3p, collagen (COLI) and transforming growth factor (TGF)‐β/Smad ubiquitin regulatory factor (Smurf)‐2/Smad signalling factors both in vitro and in vivo with or without BLM. To explore the regulatory relationship between miR‐411‐3p and Smurf2, we used the luciferase reporter assay. Furthermore, miR‐411‐3p overexpression was identified in vitro and in vivo via transfection with Lipofectamine 2000 reagent and injection. Finally, we tested the dermal layer of the skin using haematoxylin and eosin and Van Gieson''s staining. We found that miR‐411‐3p expression was decreased in bleomycin (BLM)‐induced skin fibrosis and fibroblasts. However, BLM accelerated transforming growth factor (TGF)‐β signalling and collagen production. Overexpression of miR‐411‐3p inhibited the expression of collagen, F‐actin and the TGF‐β/Smad signalling pathway factors in BLM‐induced skin fibrosis and fibroblasts. In addition, miR‐411‐3p inhibited the target Smad ubiquitin regulatory factor (Smurf)‐2. Furthermore, Smurf2 was silenced, which attenuated the expression of collagen via suppression of the TGF‐β/Smad signalling pathway. We demonstrated that miR‐411‐3p exerts antifibrotic effects by inhibiting the TGF‐β/Smad signalling pathway via targeting of Smurf2 in skin fibrosis.  相似文献   

3.
Radiation‐induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy. RILI can be divided into radiation pneumonia (RP) and radiation‐induced lung fibrosis (RILF). Once RILF occurs, patients will eventually develop irreversible respiratory failure; thus, a new treatment strategy to prevent RILI is urgently needed. This study explored the therapeutic effect of pirfenidone (PFD), a Food and Drug Administration (FDA)‐approved drug for (IPF) treatment, and its mechanism in the treatment of RILF. In vivo, C57BL/6 mice received a 50 Gy dose of X‐ray radiation to the whole thorax with or without the administration of PFD. Collagen deposition and fibrosis in the lung were reversed by PFD treatment, which was associated with reduced M2 macrophage infiltration and inhibition of the transforming growth factor‐β1 (TGF‐β1)/Drosophila mothers against the decapentaplegic 3 (Smad3) signalling pathway. Moreover, PFD treatment decreased the radiation‐induced expression of TGF‐β1 and phosphorylation of Smad3 in alveolar epithelial cells (AECs) and vascular endothelial cells (VECs). Furthermore, IL‐4–induced M2 macrophage polarization and IL‐13–induced M2 macrophage polarization were suppressed by PFD treatment in vitro, resulting in reductions in the release of arginase‐1 (ARG‐1), chitinase 3‐like 3 (YM‐1) and TGF‐β1. Notably, the PFD‐induced inhibitory effects on M2 macrophage polarization were associated with downregulation of nuclear factor kappa‐B (NF‐κB) p50 activity. Additionally, PFD could significantly inhibit ionizing radiation‐induced chemokine secretion in MLE‐12 cells and consequently impair the migration of RAW264.7 cells. PFD could also eliminate TGF‐β1 from M2 macrophages by attenuating the activation of TGF‐β1/Smad3. In conclusion, PFD is a potential therapeutic agent to ameliorate fibrosis in RILF by reducing M2 macrophage infiltration and inhibiting the activation of TGF‐β1/Smad3.  相似文献   

4.
This study is to investigate the inhibitory effects and mechanisms of DEK‐targeting aptamer (DTA‐64) on epithelial mesenchymaltransition (EMT)‐mediated airway remodelling in mice and human bronchial epithelial cell line BEAS‐2B. In the ovalbumin (OVA)‐induced asthmatic mice, DTA‐64 significantly reduced the infiltration of eosinophils and neutrophils in lung tissue, attenuated the airway resistance and the proliferation of goblet cells. In addition, DTA‐64 reduced collagen deposition, transforming growth factor 1 (TGF‐β1) level in BALF and IgE levels in serum, balanced Th1/Th2/Th17 ratio, and decreased mesenchymal proteins (vimentin and α‐SMA), as well as weekend matrix metalloproteinases (MMP‐2 and MMP‐9) and NF‐κB p65 activity. In the in vitro experiments, we used TGF‐β1 to induce EMT in the human epithelial cell line BEAS‐2B. DEK overexpression (ovDEK) or silencing (shDEK) up‐regulated or down‐regulated TGF‐β1 expression, respectively, on the contrary, TGF‐β1 exposure had no effect on DEK expression. Furthermore, ovDEK and TGF‐β1 synergistically promoted EMT, whereas shDEK significantly reduced mesenchymal markers and increased epithelial markers, thus inhibiting EMT. Additionally, shDEK inhibited key proteins in TGF‐β1‐mediated signalling pathways, including Smad2/3, Smad4, p38 MAPK, ERK1/2, JNK and PI3K/AKT/mTOR. In conclusion, the effects of DTA‐64 against EMT of asthmatic mice and BEAS‐2B might partially be achieved through suppressing TGF‐β1/Smad, MAPK and PI3K signalling pathways. DTA‐64 may be a new therapeutic option for the management of airway remodelling in asthma patients.  相似文献   

5.
Epithelial‐mesenchymal transition (EMT) has been contributed to increase migration and invasion of cancer cells. However, the correlate of Naa10p and IKKα with EMT in oral squamous cell carcinoma (OSCC) is not yet fully understood. In our present study, we found N‐α‐acetyltransferase 10 protein (Naa10p) and IκB kinase α (IKKα) were abnormally abundant in oral squamous cell carcinoma (OSCC). Bioinformatic results indicate that the expression of Naa10p and IKKα is correlated with TGF‐β1/Smad and EMT‐related molecules. The Transwell migration, invasion, qRT‐PCR and Western blot assay indicated that Naa10p repressed OSCC cell migration, invasion and EMT, whereas IKKα promoted TGF‐β1–mediated OSCC cell migration, invasion and EMT. Mechanistically, Naa10p inhibited IKKα activation of Smad3 through the interaction with IKKα directly in OSCC cells after TGF‐β1 stimulation. Notably, knockdown of Naa10p reversed the IKKα‐induced change in the migration, invasion and EMT‐related molecules in OSCC cells after TGF‐β1 stimulation. These findings suggest that Naa10p interacted with IKKα mediates EMT in OSCC cells through TGF‐β1/Smad, a novel pathway for preventing OSCC.  相似文献   

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Renal fibrosis is a major factor in the progression of chronic kidney diseases. Obstructive nephropathy is a common cause of renal fibrosis, which is also accompanied by inflammation. To explore the effect of human‐specific CHRFAM7A expression, an inflammation‐related gene, on renal fibrosis during obstructive nephropathy, we studied CHRFAM7A transgenic mice and wild type mice that underwent unilateral ureteral obstruction (UUO) injury. Transgenic overexpression of CHRFAM7A gene inhibited UUO‐induced renal fibrosis, which was demonstrated by decreased fibrotic gene expression and collagen deposition. Furthermore, kidneys from transgenic mice had reduced TGF‐β1 and Smad2/3 expression following UUO compared with those from wild type mice with UUO. In addition, the overexpression of CHRFAM7A decreased release of inflammatory cytokines in the kidneys of UUO‐injured mice. In vitro, the overexpression of CHRFAM7A inhibited TGF‐β1‐induced increase in expression of fibrosis‐related genes in human renal tubular epithelial cells (HK‐2 cells). Additionally, up‐regulated expression of CHRFAM7A in HK‐2 cells decreased TGF‐β1‐induced epithelial‐mesenchymal transition (EMT) and inhibited activation f TGF‐β1/Smad2/3 signalling pathways. Collectively, our findings demonstrate that overexpression of the human‐specific CHRFAM7A gene can reduce UUO‐induced renal fibrosis by inhibiting TGF‐β1/Smad2/3 signalling pathway to reduce inflammatory reactions and EMT of renal tubular epithelial cells.  相似文献   

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High fructose intake is a risk factor for liver fibrosis. Polydatin is a main constituent of the rhizome of Polygonum cuspidatum, which has been used in traditional Chinese medicine to treat liver fibrosis. However, the underlying mechanisms of fructose‐driven liver fibrosis as well as the actions of polydatin are not fully understood. In this study, fructose was found to promote zinc finger E‐box binding homeobox 1 (ZEB1) nuclear translocation, decrease microRNA‐203 (miR‐203) expression, increase survivin, activate transforming growth factor β1 (TGF‐β1)/Smad signalling, down‐regulate E‐cadherin, and up‐regulate fibroblast specific protein 1 (FSP1), vimentin, N‐cadherin and collagen I (COL1A1) in rat livers and BRL‐3A cells, in parallel with fructose‐induced liver fibrosis. Furthermore, ZEB1 nuclear translocation‐mediated miR‐203 low‐expression was found to target survivin to activate TGF‐β1/Smad signalling, causing the EMT in fructose‐exposed BRL‐3A cells. Polydatin antagonized ZEB1 nuclear translocation to up‐regulate miR‐203, subsequently blocked survivin‐activated TGF‐β1/Smad signalling, which were consistent with its protection against fructose‐induced EMT and liver fibrosis. These results suggest that ZEB1 nuclear translocation may play an essential role in fructose‐induced EMT in liver fibrosis by targeting survivin to activate TGF‐β1/Smad signalling. The suppression of ZEB1 nuclear translocation by polydatin may be a novel strategy for attenuating the EMT in liver fibrosis associated with high fructose diet.  相似文献   

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The persistent transactivation of epidermal growth factor receptor (EGFR) causes subsequent activation of the TGF‐β/Smad3 pathway, which is closely associated with fibrosis and cell proliferation in diabetic nephropathy (DN), but the exact mechanism of persistent EGFR transactivation in DN remains unclear. ARAP1, a susceptibility gene for type 2 diabetes, can regulate the endocytosis and ubiquitination of membrane receptors, but the effect of ARAP1 and its natural antisense long non‐coding RNA (lncRNA), ARAP1‐AS2, on the ubiquitination of EGFR in DN is not clear. In this study, we verified that the expression of ARAP1 and ARAP1‐AS2 was significantly up‐regulated in high glucose‐induced human proximal tubular epithelial cells (HK‐2 cells). Moreover, we found that overexpression or knockdown of ARAP1‐AS2 could regulate fibrosis and HK‐2 cell proliferation through EGFR/TGF‐β/Smad3 signalling. RNA pulldown assays revealed that ARAP1‐AS2 directly interacts with ARAP1. Coimmunoprecipitation, dual‐immunofluorescence and ubiquitination assays showed that ARAP1 may maintain persistent EGFR activation by reducing EGFR ubiquitination through competing with Cbl for CIN85 binding. Taken together, our results suggest that the lncRNA ARAP1‐AS2 may promote high glucose‐induced proximal tubular cell injury via persistent EGFR/TGF‐β/Smad3 pathway activation by interacting with ARAP1.  相似文献   

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Myocardial ischemia/reperfusion injury (MI/RI) is the main cause of deaths in the worldwide, leading to severe cardiac dysfunction. Resveratrol (RSV) is a polyphenol plant‐derived compound. Our study aimed to elucidate the underlying molecular mechanism of preconditioning RSV in protecting against MI/RI. Mice were ligated and re‐perfused by the left anterior descending branch with or without RSV (30 mg/kg·ip) for 7 days. Firstly, we found that RSV pretreatment significantly alleviated myocardial infarct size, improved cardiac function and decreased oxidative stress. Furthermore, RSV activated p‐AMPK and SIRT1, ameliorated inflammation including the level of TNF‐α and IL‐1β, and promoting autophagy level. Moreover, neonatal rat ventricular myocytes (NRVMs) and H9c2 cells with knockdown the expression of AMPK, SIRT1 or FOXO1 were used to uncover the underlying molecular mechanism for the cardio‐protection of RSV. In NRVMs, RSV increased cellular viability, decreased LDH release and reduced oxidative stress. Importantly, Compound C(CpC) and EX527 reversed the effect of RSV against MI/RI in vivo and in vitro and counteracted the autophagy level induced by RSV. Together, our study indicated that RSV could alleviate oxidative stress in cardiomyocytes through activating AMPK/SIRT1‐FOXO1 signallingpathway and enhanced autophagy level, thus presenting high potential protection on MI/RI.  相似文献   

15.
Systemic Sclerosis (SSc) is a rare fibrotic autoimmune disorder for which no curative treatments currently exist. Metabolic remodelling has recently been implicated in other autoimmune diseases; however, its potential role in SSc has received little attention. Here, we aimed to determine whether changes to glycolysis and glutaminolysis are important features of skin fibrosis. TGF‐β1, the quintessential pro‐fibrotic stimulus, was used to activate fibrotic pathways in NHDFs in vitro. Dermal fibroblasts derived from lesions of SSc patients were also used for in vitro experiments. Parameters of glycolytic function were assessed using by measuring extracellular acidification in response to glycolytic activators/inhibitors, whilst markers of fibrosis were measured by Western blotting following the use of the glycolysis inhibitors 2‐dg and 3PO and the glutaminolysis inhibitor G968. Succinate was also measured after TGF‐β1 stimulation. Itaconate was added to SSc fibroblasts and collagen examined. TGF‐β1 up‐regulates glycolysis in dermal fibroblasts, and inhibition of glycolysis attenuates its pro‐fibrotic effects. Furthermore, inhibition of glutamine metabolism also reverses TGF‐β1‐induced fibrosis, whilst glutaminase expression is up‐regulated in dermal fibroblasts derived from SSc patient skin lesions, suggesting that enhanced glutamine metabolism is another aspect of the pro‐fibrotic metabolic phenotype in skin fibrosis. TGF‐β1 was also able to enhance succinate production, with increased succinate shown to be associated with increased collagen expression. Incubation of SSc cells with itaconate, an important metabolite, reduced collagen expression. TGF‐β1 activation of glycolysis is a key feature of the fibrotic phenotype induced by TGF‐B1 in skin cells, whilst increased glutaminolysis is also evident in SSc fibroblasts.  相似文献   

16.
ObjectivesIdiopathic pulmonary fibrosis (IPF) is marked by the excessive accumulation of extracellular matrix, which participates in a variety of chronic diseases or injuries and seriously threatens human health. Due to the side effects of clinical drugs, there is still a need to develop novel and less toxic drugs to treat pulmonary fibrosis.Materials and MethodsSKLB‐YTH‐60 was developed through computer‐aided drug design, de novo synthesis and high‐throughput screening. We employed the bleomycin (BLM)‐induced lung fibrosis animal models and used TGF‐β1 to induce the epithelial‐mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the α‐smooth muscle actin (α‐SMA), E‐cadherin, p‐FGFR1, p‐PLCγ, p‐Smad2/3 and p‐Erk1/2 was detected by western blot.ResultsYTH‐60 has obvious anti‐proliferative activity on fibroblasts and A549 cells. Moreover, YTH‐60 could impair the EMT of A549 cells and suppressed fibrosis by inhibiting FGFR and TGF‐β/Smad‐dependent pathways. Intraperitoneal administration of preventive YTH‐60 could significantly reduce the degree of fibrosis in mice and regulate the imbalance of the immune microenvironment. In addition, we observed that therapeutic YTH‐60 treatment attenuated fibrotic changes in mice during the period of fibrosis. Importantly, YTH‐60 has shown an acceptable oral bioavailability (F = 17.86%) and appropriate eliminated half‐life time (T 1/2 = 8.03 hours).ConclusionsTaken together, these preclinical evaluations suggested that YTH‐60 could be a promising drug candidate for treating IPF.  相似文献   

17.
The role of alveolar macrophages (AMs) in chronic obstructive pulmonary disease is unclear. We characterized the function of AMs in rats chronically exposed to biomass fuel smoke (BMF) and studied the signal pathways that regulate AMs polarization. One hundred and eighty male Sprague‐Dawley rats were divided into BMF group and clean air control (CON) group. After BMF smoke exposure for 4 days, 1 month and 6 months, the cytokine secretion and function of AMs were determined by flow cytometry, quantitative polymerase chain reaction, Western blotting and immunofluorescence. Bone marrow‐derived macrophages were cultured and exposed to particulate matter (PM) from the smoke. Exposure initially promoted pro‐inflammatory factors, but pro‐inflammatory macrophages shared features of anti‐inflammatory macrophages. Consistent with IL‐4 upregulated in bronchoalveolar lavage fluid, p‐Stat6 and peroxisome proliferator‐activated receptor γ (PPARγ) in AMs elevated at 4 days of exposure. After 6 months of exposure, CD206, TGF‐β1 and p‐Smad3 were significantly higher than the control groups. PPARγ reversed the M1 phenotype induced by PM in vitro and drove the macrophages into the M2 phenotype. Altogether, the study demonstrates the dynamic phenotype and functional changes in AMs during exposure to BMF smoke.  相似文献   

18.
Orai family are a calcium channel of cell membrane extracellular Ca2+ influx which participates in tissue fibrosis. But the roles of Orai3 have less attention on the mechanism of regulating lung fibrosis. In this study, we found that Orai3 expression was increased significantly in BLM‐induced lung fibrosis. The knockdown of Orai3 decreased TGF‐β1‐induced fibroblast proliferation, ECM production, activation of NFAT1 and Calpain/ERK signal pathway and glycolysis levels. Orai3 interacting with Orai1 was increased in BLM‐induced lung fibrosis and TGF‐β1‐induced fibroblast, while the Stim1 interacting with Orai1 and SOCE activity was suppressed, leading in a high and stable extracellular Ca2+ influx. Furthermore, the over‐expression of Orai3 did not enhance Orai3 interacting with Orai1 under TGF‐β1 free fibroblast. And then, the deeper mechanism of TGF‐β1‐induced increased SEPTIN4 promoted Orai3 interacting with Orai1. Our results indicated that Orai3 could be one of the therapy targets for PF in which remodels Orai channel, suppresses SOCE activity and activated fibroblast to alleviate fibrosis progress.  相似文献   

19.
Acute kidney injury (AKI) is a substantial worldwide public health concern with no specific and effective therapies in clinic. NAD+ is a pivotal determinant of cellular energy metabolism involved in the progression of AKI; however, its mechanism in kidney injury remains poorly understood. Sirtuin 1 (SIRT1) is an NAD+‐dependent deacetylase associated with renal protection and acute stress resistance. In this study, we have investigated the role of NAD+ in AKI and the potential mechanism(s) involved in its renoprotective effect. NAD+ was notably decreased and negatively correlated with kidney dysfunction in AKI, restoring NAD+ with NMN significantly ameliorates LPS‐induced oxidative stress and apoptosis and attenuates renal damage. We also found that the protection of NAD+ is associated with SIRT1 expressions and performs in a SIRT1‐dependent manner. Inhibition of SIRT1 blunted the protective effect of NAD+ and up‐regulated the activity of glycogen synthase kinase‐3β (GSK‐3β) that was concomitant with mitigated Nrf2 nuclear accumulation, thereby exacerbates AKI. These findings suggest that NAD+/SIRT1/GSK‐3β/Nrf2 axis is an important mechanism that can protect against AKI which might be a potential therapeutic target for the treatment of AKI.  相似文献   

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