Tangshen Formula Improves Diabetes-Associated Myocardial Fibrosis by Inhibiting TGF-β/Smads and Wnt/β-Catenin Pathways.
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ABSTRACT:
SUBMITTER: Hu L
PROVIDER: S-EPMC8687440 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.
| S-EPMC7878558 | biostudies-literature
Project description:ObjectivesGastric ulcer (GU) is a prevalent chronic digestive disease affecting about 10% of the world's population leading to gastrointestinal perforation and bleeding. Genistein is a legume flavonoid with antioxidants, anti-inflammatory and antibacterial activities. Therefore, we aimed to investigate the ability of genistein to reduce experimentally induced GU in rats by affecting gastric tissue fibrosis Wnt/β-catenin/TGF-β/SMAD4 pathway.MethodsThirty rats were used. Ten rats served as control, and GU was induced in twenty rats using a single dose of indomethacin (80 mg/kg) orally. Following induction of GU, ten were treated with genistein 25 mg/kg orally. The gastric tissues were isolated to investigate markers of gastric fibrosis, Wnt, β-catenin, transforming growth factor (TGF)-β, SMAD4, and Protein kinase B (PKB). In addition, gastric sections were stained with PAS and anti-TGF-β antibodies.ResultsInvestigation GU micro-images revealed degeneration in both surface cells and glandular epithelial cells, which was improved by genistein. In addition, treatment with genistein significantly reduced the expression of Wnt, β-catenin, TGF-β, SMAD4, and PKB.ConclusionBesides antioxidant activity, genistein improves experimentally induced GU in rats, at least in part, via reduction of gastric tissue fibrosis as indicated by reduction in expression of Wnt, β-catenin, TGF-β, SMAD4, and PKB.
| S-EPMC10236962 | biostudies-literature
Project description:As renal fibrosis significantly contributes to various kinds of chronic kidney diseases, this study aimed to investigate the renal protective effects of Qingshen Buyang Formula against renal fibrosis on 5/6 nephrectomized rats, and its underlying mechanisms were explored. A total of 24 male Sprague-Dawley rats were randomly divided into sham operation group (Sham group), 5/6 nephrectomy group (5/6Nx group), and Qingshen Buyang Formula treatment group (QBF group). The intervention was intragastric administration for 12 weeks. In the end, the blood samples were collected to test renal functional parameters, urine proteins were measured, and the left kidneys were removed for histological studies, as well as mRNA and protein expression analysis. The results showed that Qingshen Buyang Formula significantly decreased BUN, Scr, and proteinuria in 5/6Nx rats. Meanwhile, it ameliorated the kidney injury and fibrosis, exemplified by the depressed expression of collagen I and fibronectin (FN), which are the main components of ECM. Furthermore, the process of EMT inhibited the Wnt/β-catenin signaling pathway related genes, such as Wnt4, TCF4, β-catenin, and p-GSK3β. Collectively, the Qingshen Buyang Formula can improve renal function and attenuate renal fibrosis, and its underlying mechanisms may be related with inhibiting EMT and Wnt/β-catenin signaling pathway.
| S-EPMC6521559 | biostudies-literature
Project description:Pulmonary fibrosis (PF) is the end stage of various chronic and progressive interstitial lung diseases. TGF-β, a profibrotic cytokine, can promote epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) accumulation, and fibroblast proliferation, which contribute to progressive lung remodeling in PF. The Wenfei Buqi Tongluo (WBT) formula has been certified to be effective in the prevention and treatment of PF in clinical practice and has inhibitory effects on EMT, inflammation, and profibrotic factors. However, the pharmacological mechanisms of WBT against PF need to be further explored. In this study, we first analyzed the chemical components of the WBT formula using the UHPLC/Q-TOF-MS analysis. The potential targets of the identified compounds from WBT were predicted by the network pharmacology, which was confirmed by in vivo and in vitro study. After screening by the PubChem database, we first identified the 36 compounds of WBT and predicted the TGF-β signaling pathway, with ECM degradation as potential mechanism of WBT against PF by the network pharmacology. Furthermore, WBT treatment inhibited the levels of TGF-β and Smad3 phosphorylation and subsequently alleviated EMT and ECM accumulation in the bleomycin-induced mouse model and TGF-β1-induced cell model. These findings indicate that WBT can block the progressive process of PF by inhibiting EMT and promoting ECM degradation via the TGF-β/Smad3 pathway. This study may provide new insights into the molecular mechanism of WBT for the prevention and treatment of PF in the clinical application.
| S-EPMC8814462 | biostudies-literature
Project description:BackgroundCardiac fibrosis is the most important pathogenesis leading to cardiac remodeling and heart failure after myocardial infarction (MI). Tissue nonspecific alkaline phosphatase (TNAP) has recently been recognized as a potential prognostic factor for MI. Nevertheless, the role of TNAP in cardiac fibrosis after MI has not been explicitly delineated.MethodsA systematic review and meta-analysis was conducted to assess the effect of serum TNAP levels on mortality in patients with ischemic heart disease (IHD). A correlation analysis was performed to investigate the relationship between serum levels of TNAP and biomarkers of fibrosis. Heart biopsies from patients with MI and a mouse model of MI were used to detect the expression and distribution of TNAP. Furthermore, we established adenovirus-mediated knockdown and overexpression of TNAP, using a combination of in vivo and in vitro studies in mice, to determine the role and mechanism of TNAP in cardiac fibrosis after MI. In the in vitro studies, cardiac fibroblasts were cultured on soft plates.FindingsAfter searching the main databases and performing a detailed assessment of the full-text articles, eight studies with 14,816 individuals were included in the quantitative analysis. We found that a high serum TNAP level was associated with an increased risk of mortality in patients with IHD and MI. The correlation analysis revealed a positive correlation between serum TNAP levels and the concentration of fibrosis biomarkers (PICP/PIIINP). The expression of TNAP was upregulated in the myocardium of patients with MI and in a mouse model of MI, accompanied by fibroblast activation and the deposition of collagen fibers. In the in vivo study, TNAP knockdown ameliorated cardiac fibrosis and improved cardiac function in mice. TNAP overexpression aggravated cardiac fibrosis and worsened cardiac function. In the in vitro study, TNAP promoted cardiac fibroblast differentiation, migration and proliferation. Mechanistically, the pro-fibrotic effect of TNAP on cardiac fibroblasts was at least partially achieved by activating the TGF-β1/Smads and ERK1/2 signaling pathways.InterpretationBased on these findings, TNAP plays an important pro-fibrotic role in cardiac fibrosis after MI by activating TGF-β/Smads and ERK1/2 signaling, indicating that it functions as a potential regulator of and therapeutic target in cardiac fibrosis.FundingThis work was supported by the National Natural Science Foundation of China.
| S-EPMC8122000 | biostudies-literature
Project description:Wnts compose a family of signaling proteins that play an essential role in kidney development, but their expression in adult kidney is thought to be silenced. Here, we analyzed the expression and regulation of Wnts and their receptors and antagonists in normal and fibrotic kidneys after obstructive injury. In the normal mouse kidney, the vast majority of 19 different Wnts and 10 frizzled receptor genes was expressed at various levels. After unilateral ureteral obstruction, all members of the Wnt family except Wnt5b, Wnt8b, and Wnt9b were upregulated in the fibrotic kidney with distinct dynamics. In addition, the expression of most Fzd receptors and Wnt antagonists was also induced. Obstructive injury led to a dramatic accumulation of beta-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/beta-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal beta-catenin abundance. Delivery of the Wnt antagonist Dickkopf-1 gene significantly reduced renal beta-catenin accumulation and inhibited the expression of Wnt/beta-catenin target genes. Furthermore, gene therapy with Dickkopf-1 inhibited myofibroblast activation; suppressed expression of fibroblast-specific protein 1, type I collagen, and fibronectin; and reduced total collagen content in the model of obstructive nephropathy. In summary, these results establish a role for Wnt/beta-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target.
| S-EPMC2663839 | biostudies-other
Project description:BackgroundAdverse left ventricular remodeling after myocardial infarction (MI) compromises cardiac function and increases heart failure risk. Until now, comprehension of the role transcription factor EB (TFEB) plays after MI is limited.ObjectivesThe purpose of this study was to describe the effects of TFEB on fibroblasts differentiation and extracellular matrix expression after MI.MethodsAAV9 (adeno-associated virus) mediated up- and down-regulated TFEB expressions were generated in C57BL/6 mice two weeks before the MI modeling. Echocardiography, Masson, Sirius red staining immunofluorescence, and wheat germ agglutinin staining were performed at 3 days, and 1, 2, and 4 weeks after MI modeling. Fibroblasts collected from SD neonatal rats were transfected by adenovirus and siRNA, and cell counting kit-8 (CCK8), immunofluorescence, wound healing and Transwell assay were conducted. Myocardial fibrosis-related proteins were identified by Western blot. PNU-74654 (100 ng/mL) was used for 12 hours to inhibit β-catenin-TCF/LEF1 complex.ResultsThe up-regulation of TFEB resulted in reduced fibroblasts proliferation and its differentiation into myofibroblasts in vitro studies. A significant up-regulation of EF and down-regulation of myocyte area was shown in the AAV9-TFEB group. Meanwhile, decreased protein level of α-SMA and collagen I were observed in vitro study. TFEB didn't affect the concentration of β-catenin. Inhibition of TFEB, which promoted cell migration, proliferation and collagen I expression, was counteracted by PNU-74654.ConclusionsTFEB demonstrated potential in restraining fibrosis after MI by inhibiting the Wnt/β-catenin signaling pathway.
| S-EPMC10441526 | biostudies-literature
Project description:BackgroundSystemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. So far, no Western medicine treatment can completely inhibit or reverse the progress of SSc, while at the same time, our previous series of studies have shown that the treatment of SSc by the Wenyang Huazhuo Tongluo formula (WYHZTL), a Chinese herbal decoction, shows a delightful prospect. The aim of this study is to further investigate the mechanism of anti-fibrosis of WYHZTL formula in SSc mouse model.MethodsThe Bleomycin-induced SSc mouse model was treated with saline (BLM), high-dosage of WYHZTL formula (WYHZTL-H), medium-dosage of WYHZTL formula (WYHZTL-M), low-dosage of WYHZTL formula (WYHZTL-L) and XAV-939, a small molecule inhibitor of Wnt/β-catenin signaling pathway, by the intragastric administration and intraperitoneal injection, respectively. The mRNA and protein levels of Wnt/β-catenin signaling pathway associated genes, fibrosis markers and histopathology were detected by reverse transcription-quantitative polymerase chain reaction, Western blotting and hematoxylin/eosin-staining. The levels of Wnt1, CTGF and DKK1 protein in serum were detected by enzyme-linked immunosorbent assay.ResultsCompared with BLM group, the WYHZTL formula and XAV-939 could significantly inhibit the thickness of the skin tissue of the SSc mouse model. The mRNA expression levels of GSK3β and DKK1 in the WYHZTL formula and XAV-939-treated group were significantly higher than those in the BLM group, while Wnt1, β-catenin, TCF4, cyclin D1, survivin, VEGF, CTGF, FN1, collagen I/III were decreased. Compared with BLM group, the protein expression levels of GSK3β and DKK1 in the WYHZTL formula and XAV-939-treated group were upregulated, while Wnt1, β-catenin, cyclin D1, survivin, CTGF, FN1, collagen I/III were downregulated. WYHZTL formula and XAV-939 could inhibit expression of Wnt1 and CTGF, but promoted DKK1 in serum. Furthermore, WYHZTL-H seemed more effective than WYHZTL-M and/or XAV-939 on regulating Wnt1, β-catenin, TCF4, GSK3β, DKK1, cyclin D1, survivin, VEGF, CTGF, FN1 and collagen I/III.ConclusionThis present study demonstrates that WYHZTL formula has anti-fibrosis effect in Bleomycin-induced SSc mouse model in a dosage-dependent manner, and the molecular mechanism may be related to the inhibition of Wnt/β-catenin signaling pathway.
| S-EPMC5870182 | biostudies-literature
Project description:TGF-β is a key profibrotic factor, but targeting TGF-β to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-β signaling by preventing downstream profibrotic interaction of β-catenin with T cell factor (TCF), thereby enhancing the interaction of β-catenin with Foxo, a transcription factor that controls differentiation of TGF-β induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-β In iTregs derived from EL4 T cells treated with recombinant human TGF-β1 (rhTGF-β1) in vitro, inhibition of β-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of β-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of β-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3gfp Ly5.1/5.2 mice revealed that coadministration of rhTGF-β1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-β1 treatment alone. Coadministration of rhTGF-β1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF-β1. Together, our results show that diversion of β-catenin from TCF- to Foxo-mediated transcription inhibits the β-catenin/TCF-mediated profibrotic effects of TGF-β while enhancing the β-catenin/Foxo-mediated anti-inflammatory effects. Targeting β-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.
| S-EPMC5791062 | biostudies-literature
Project description:BackgroundTransforming growth factor-β (TGF-β) is a key cytokine during differentiation of mesenchymal stem cells (MSC) into vascular smooth muscle cells (VSMC). High phosphate induces a phenotypic transformation of vascular smooth muscle cells (VSMC) into osteogenic-like cells. This study was aimed to evaluate signaling pathways involved during VSMC differentiation of MSC in presence or not of high phosphate.ResultsOur results showed that TGF-β induced nuclear translocation of Smad3 as well as the expression of vascular smooth muscle markers, such as smooth muscle alpha actin, SM22α, myocardin, and smooth muscle-myosin heavy chain. The addition of high phosphate to MSC promoted nuclear translocation of Smad1/5/8 and the activation of canonical Wnt/β-catenin in addition to an increase in BMP-2 expression, calcium deposition and alkaline phosphatase activity. The administration of TGF-β to MSC treated with high phosphate abolished all these effects by inhibiting canonical Wnt, BMP and TGF-β pathways. A similar outcome was observed in high phosphate-treated cells after the inhibition of canonical Wnt signaling with Dkk-1. Conversely, addition of both Wnt/β-catenin activators CHIR98014 and lithium chloride enhanced the effect of high phosphate on BMP-2, calcium deposition and alkaline phosphatase activity.ConclusionsFull VSMC differentiation induced by TGF-β may not be achieved when extracellular phosphate levels are high. Moreover, TGF-β prevents high phosphate-induced osteogenesis by decreasing the nuclear translocation of Smad 1/5/8 and avoiding the activation of Wnt/β-catenin pathway.
| S-EPMC3937350 | biostudies-literature