scholarly journals Sulodexide Prevents Peritoneal Fibrosis by Downregulating the Expression of TGF-β1 and Its Signaling Pathway Molecules

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Zhiqiang Duan ◽  
Jia Yao ◽  
Nan Duan ◽  
Min Wang ◽  
Shiwei Wang
Keyword(s):  
Peritoneal Dialysis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Vascular Endothelial Cells ◽  
Inflammatory Factors ◽  
Control Group ◽  
Peritoneal Fibrosis ◽  
Blank Control Group ◽  
Peritoneal Tissue ◽  
Tgf Β1

Peritoneal dialysis is one of the main renal replacement treatments. However, long-term peritoneal dialysis keeps the peritoneum in contact with the sugar-containing nonphysiological peritoneal fluid, which leads to recurrent peritonitis, peritoneal fibrosis, and failure of ultrafiltration. Transforming growth factor-β1 (TGF-β1), related cytokines, and inflammatory factors are closely related to peritoneal fibrosis. Sulodexide (SLX) is a new type of glycosaminoglycan preparation, which is involved in the formation of an anionic charge barrier and can maintain the selective permeability of vascular endothelial cells. In this study, the innovative analysis of SLX specifically prevents the process of peritoneal dialysis peritoneal fibrosis by downregulating the expression of TGF-β1 and its signaling pathway molecules. We randomly divided 30 rats into three groups. The blank control group received no treatment. The peritoneal dialysis model group was injected with 4.25% peritoneal dialysate (PDF) 20 ml daily, and the SLX group was injected with 4.25% PDF 20 ml + sulodexide (SLX) 20 mg/kg daily. After 8 weeks of dialysis, the rats were sacrificed, and the peritoneal function test was performed to determine the amount of glucose transport and ultrafiltration. The thickness of peritoneal per unit area was observed under high magnification. The level of inflammation in peritoneal tissue and the expression of TGF-β1/Smad were detected. The results showed that SLX can significantly improve peritoneal tissue thickening and inflammation, can downregulate the expression of TGF-β1, Smad2, Smad3, and Smad7 in peritoneal tissue, and improve the progression of peritoneal fibrosis.

scholarly journals Curcumin ameliorates peritoneal fibrosis via inhibition of transforming growth factor-activated kinase 1 (TAK1) pathway in a rat model of peritoneal dialysis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jun-Li Zhao ◽  
Ting Zhang ◽  
Xia Shao ◽  
Jun-Jun Zhu ◽  
Mei-Zi Guo
Keyword(s):  
Peritoneal Dialysis ◽  
Peritoneal Fluid ◽  
Transforming Growth Factor ◽  
Collagen I ◽  
Control Group ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Peritoneal Fibrosis ◽  
Jnk Pathway ◽  
Tgf Β1

Abstract Background Peritoneal fibrosis (PF) remains a serious complication of long-term peritoneal dialysis (PD). The goal of this study was to investigate the anti-fibrotic effects of curcumin on the PF response to PD and its’ mechanism. Methods Male Sprague–Dawley rats were infused with 20 mL of 4.25% glucose-based standard PD fluid for 8 consecutive weeks to establish PF model and then divided into five groups: Control, received sham operation and 0.9% physiological saline; PD, received 4.25% standard PD fluid; Curcumin, PD rats injected intraperitoeally with curcumin for 8 weeks at doses of 10, 20 or 40 mg/kg. Masson’s staining was performed to evaluate the extent of PF. Peritoneal Equilibration Test (PET) was conducted to assess ultrafiltration volume (UFV) and mass transfer of glucose (MTG), quantitative RT-PCR, and immunohistochemistry or western blotting were performed to measure the expression levels of inflammation and fibrosis-associated factors. We also detected the TGF-β1 in peritoneal fluid by ELISA. Results Compared with the control group, the PD rats showed decreased UFV (2.54 ± 0.48 to 9.87 ± 0.78 mL, p < 0.05] and increased MTG (18.99 ± 0.86 to 10.85 ± 0.65 mmol/kg, p < 0.05) as well as obvious fibroproliferative response, with markedly increased peritoneal thickness (178.33 ± 4.42 to 25.26 ± 0.32um, p < 0.05) and higher expression of a-SMA, collagen I and TGF-β1. Treatment with curcumin significantly increased UFV, reduced MTG and peritoneal thickness of PD rats. The elevated TGF-β1 in peritoneal fluid of PD rats was significantly decreased by curcumin. It attenuated the increase in protein and mRNA of TGF-β1, α-SMA and collagen I in peritoneum of PD rats. The mRNA expressions of TAK1, JNK and p38, as well as the protein expressions of p-TAK1, p-JNK and p-p38 in peritoneum of PD rats were reduced by curcumin. Conclusions Present results demonstrate that curcumin showed a protective effect on PD-related PF and suggest an implication of TAK1, p38 and JNK pathway in mediating the benefical effects of curcumin.

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

2018 ◽  
Vol 48 (6) ◽  
pp. 456-464 ◽  
Author(s):  
Jin Sug Kim ◽  
Kyung Sook Cho ◽  
Seon Hwa Park ◽  
Sang Ho Lee ◽  
Ji Hwan Lee ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Isotonic Saline ◽  
Control Group ◽  
Protective Effects ◽  
Peritoneal Fibrosis ◽  
Shh Signaling ◽  
Itraconazole Treatment

Background: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. Methods: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. Results: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-β1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. Conclusion: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.

scholarly journals Dihydromyricetin Reverses Thioacetamide-Induced Liver Fibrosis Through Inhibiting NF-κB-Mediated Inflammation and TGF-β1-Regulated of PI3K/Akt Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yingchun Zhao ◽  
Xinglong Liu ◽  
Chuanbo Ding ◽  
Yan Gu ◽  
Wencong Liu
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Histopathological Examination ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Immunofluorescence Staining ◽  
Inflammatory Factors ◽  
Tgf Β1

As a natural active substance, dihydromyricetin (DHM) has been proven to have good hepatoprotective activity. However, the therapeutic effect of DHM on liver fibrosis, which has become a liver disease threatening the health of people around the world, has not been studied to date. The purpose of this study was to investigate the effect of DHM as a new nutritional supplement on thioacetamide (TAA)-induced liver fibrosis. The liver fibrosis model was established by intraperitoneal injection of TAA (200 mg/kg, every 3 days) for 8 weeks, and oral administration of DHM (20 mg/kg and 40 mg/kg, daily) after 4 weeks of TAA-induced liver fibrosis. The results showed that DHM treatment significantly inhibited the activities of alanine aminotransferase (ALT) (37.81 ± 7.62 U/L) and aspartate aminotransferase (AST) (55.18 ± 10.94 U/L) in serum of liver fibrosis mice, and increased the levels of superoxide dismutase (SOD) and glutathione (GSH) while reversed the level of malondialdehyde (MDA). In addition, histopathological examination illustrated that TAA induced the inflammatory infiltration, apoptosis and fibroatherosclerotic deposition in liver, which was further confirmed by western-blot and immunofluorescence staining. Moreover, DHM inhibited hepatocyte apoptosis by regulating the phosphorylation level of phosphatidylinositol 3-kinase (PI3K), protein kinase-B (AKT) and its downstream apoptotic protein family. Interestingly, immunofluorescence staining showed that DHM treatment significantly inhibited alpha smooth muscle actin (α-SMA), which was a marker of hepatic stellate cell activation, and regulated the expression of transforming growth factor (TGF-β1). Importantly, supplementation with DHM significantly inhibited the release of nuclear factor kappa-B (NF-κB) signaling pathway and pro-inflammatory factors in liver tissue induced by TAA, and improved liver fiber diseases, such as tumor necrosis factor alpha (TNF-α) and recombinant rat IL-1β (IL-1β). In conclusion, the evidence of this study revealed that DHM is a potential hepatoprotective and health factor, and which also provides the possibility for the treatment of liver fibrosis.

Does Enalapril Prevent Peritoneal Fibrosis Induced by Hypertonic (3.86%) Peritoneal Dialysis Solution?

2001 ◽  
Vol 21 (2) ◽  
pp. 219-225 ◽  
Author(s):  
Soner Duman ◽  
Ali Ihsan Günal ◽  
Sait Sen ◽  
Gülay Asçi ◽  
Mehmet Özkahya ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Transforming Growth Factor ◽  
Isotonic Saline ◽  
Control Group ◽  
Peritoneal Fibrosis ◽  
Protein Loss ◽  
Cancer Antigen 125 ◽  
Converting Enzyme Inhibitors ◽  
Plasma Urea ◽  
Peritoneal Function

Objective Peritoneal fibrosis (PF) is one of the most serious causes of failure in continuous ambulatory peritoneal dialysis (PD). Although the underlying mechanism responsible for the genesis of PF is still unknown, transforming growth factor p (TGFβ1) has been shown to be associated with PF. Angiotensin converting enzyme inhibitors have been shown to prevent the stimulating effect of growth factors. The aim of the present study was to investigate the effect of enalapril on peritoneal function and morphology in a rat model of experimental PF. Methods Twenty-one albino Wistar rats were divided into three groups: ( 1 ) the control group (C) received 10 mL isotonic saline intraperitoneally (IP), ( 2 ) the dextrose (Dx) group 10 mL 3.86% dextrose PD solution IP, and ( 3 ) the enalapril-treated group (ENA) 10 cc 3.86% dextrose PD solution IP plus 100 mg/L enalapril in drinking water. After 4 weeks, a 1-hour peritoneal equilibration test was performed with 20 mL 2.27% dextrose PD solution. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D1/D0 glucose), ultrafiltration (UF) volume, and levels of dialysate protein, TGFβ1, and cancer antigen 125 (CA125) were determined. The parietal peritoneum was evaluated histologically by light microscopy. Results Administration of enalapril resulted in preserved UF (-0.2 ± 0.7 mL vs 1.7 ± 0.3 mL, p < 0.05), protein loss (2.3 ± 0.5 g/L vs 1.6 ± 0.2 g/L, p > 0.05), and peritoneal thickness (77 ± 7 μ vs 38 ± 5 μ, p < 0.001). D/P urea increased significantly in the Dx group ( p < 0.05). Both higher levels of TGFβ1 (undetectable vs 298 ± 43 pg/mL, p < 0.001) and lower levels of CA125 in dialysate effluent (0.94 ± 0.5 U/L vs 0.11 ± 0.1 U/L, p > 0.05) were determined in the Dx group. Conclusion These findings show that peritoneal morphology and function tests were dramatically deranged in the Dx group. The same properties were partially preserved in the ENA group. The production of TGFβ1 was significantly reduced but peritoneal thickness was not completely inhibited. In conclusion, by inhibiting the production of TGFβ1, enalapril can preserve peritoneal histology, peritoneal function, and remodeling of mesothelial cells.

scholarly journals Glycyrrhetinic acid alleviates radiation-induced lung injury in mice

2017 ◽  
Vol 58 (1) ◽  
pp. 41-47 ◽  
Author(s):  
Jinmei Chen ◽  
Weijian Zhang ◽  
Lurong Zhang ◽  
Jiemin Zhang ◽  
Xiuying Chen ◽  
...  
Keyword(s):  
Lung Injury ◽  
Signaling Pathway ◽  
Lung Tissue ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Glycyrrhetinic Acid ◽  
Control Group ◽  
X Rays ◽  
Radiation Induced ◽  
Tgf Β1

Abstract Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy, but efficacious therapy for RILI is lacking. This study ascertained whether glycyrrhetinic acid (GA; a functional hydrolyzed product of glycyrrhizic acid, which is extracted from herb licorice) can protect against RILI and investigated its relationship to the transforming growth factor (TGF)-β1/Smads signaling pathway. C57BL/6 mice were divided into four groups: a control group, a GA group and two irradiation (IR) groups. IR groups were exposed to a single fraction of X-rays (12 Gy) to the thorax and administered normal saline (IR + NS group) or GA (IR + GA group). Two days and 17 days after irradiation, histologic analyses were performed to assess the degree of lung injury, and the expression of TGF-β1, Smad2, Smad3 and Smad7 was recorded. GA administration mitigated the histologic changes of lung injury 2 days and 17 days after irradiation. Protein and mRNA expression of TGF-β1, Smad2 and Smad3, and the mRNA level of Smad7, in lung tissue were significantly elevated after irradiation. GA decreased expression of TGF-β1, Smad2 and Smad3 in lung tissue, but did not increase Smad7 expression. GA can protect against early-stage RILI. This protective effect may be associated with inhibition of the TGF-β1/Smads signaling pathway.

scholarly journals Dendrobium Mixture Improved Diabetic Nephropathy in db/db Mice by Regulating TGF-β1/Smads Signal Transduction

2021 ◽  
Author(s):  
Yong Chen ◽  
Xiaohui Lin ◽  
Yanfang Zheng ◽  
Wenzhen Yu ◽  
Fan Lin ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Diabetic Nephropathy ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Fasting Blood Glucose ◽  
Blood Lipid ◽  
Control Group ◽  
Tgf Β1

Abstract BackgroundDendrobium mixture (DMix) is an effective treatment for diabetic nephropathy (DN), but the underlying molecular mechanism remains unclear. In this study, we investigated whether DMix regulates the transforming growth factor-β1 (TGF-β1)/Smads signal transduction pathway. MethodsTwenty-four db/db mice were randomly divided into three groups: the model, DMix, and gliquidone groups, while eight db/m mice were selected as the normal control group. The drug was administered by continuous gavage for 8 weeks. Body weight (BW), kidney weight (KW), kidney index, fasting blood glucose (FBG), blood lipid, 24-hour urinary albumin excretion rate, blood urea nitrogen, and serum creatinine levels were measured. Pathological changes in the renal tissue were observed using a light microscope. Real-time quantitative PCR and immunohistochemical staining were used to detect mRNA expression of TGF-β1 and alpha-smooth muscle actin (α-SMA) genes and proteins, respectively, in renal tissues. TGF-β1, Smad2, p-Smad2, Smad3, p-Smad3, and α-SMA expression levels were measured using western blotting. ResultsDMix significantly reduced FBG level, BW, KW, and blood lipid level, and improved renal function in db/db mice. Histopathology showed that DMix alleviated glomerular mesangial cell proliferation and renal interstitial fibrosis in db/db mice. Additionally, DMix reduced protein and mRNA expression of TGF-β1 and α-SMA, and inhibited Smad2 and Smad3 phosphorylation. ConclusionsThe findings suggest that DMix may inhibit renal fibrosis and delay the progression of DN by regulating the TGF-β1/Smads signaling pathway. Key words: Diabetic nephropathy, Dendrobium mixture, TGF-β1/Smads signaling pathway

scholarly journals TGF-β1-VEGF-A pathway induces neoangiogenesis with peritoneal fibrosis in patients undergoing peritoneal dialysis

2018 ◽  
Vol 314 (2) ◽  
pp. F167-F180 ◽  
Author(s):  
Tetsuyoshi Kariya ◽  
Hayato Nishimura ◽  
Masashi Mizuno ◽  
Yasuhiro Suzuki ◽  
Yoshihisa Matsukawa ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Growth Factor ◽  
Cell Lines ◽  
Transforming Growth Factor ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Mrna Levels ◽  
Peritoneal Fibrosis ◽  
Ultrafiltration Failure ◽  
Tgf Β1

The characteristic features of chronic peritoneal injury with peritoneal dialysis (PD) are submesothelial fibrosis and neoangiogenesis. Transforming growth factor (TGF)β and vascular endothelial growth factor (VEGF)-A are the main mediators of fibrosis and neoangiogenesis, respectively; however, the effect of the interaction between them on the peritoneum is not well known. In this study, we investigated the relationship between TGF-β1 and VEGF-A in inducing peritoneal fibrosis by use of human tissues and dialysate, cultured cells, and animal models. The VEGF-A concentration correlated with the dialysate-to-plasma ratio of creatinine (D/P Cr) ( P < 0.001) and TGF-β1 ( P < 0.001) in human PD effluent. VEGF-A mRNA levels increased significantly in the peritoneal tissues of human ultrafiltration failure (UFF) patients and correlated with number of vessels ( P < 0.01) and peritoneal thickness ( P < 0.001). TGF-β1 increased VEGF-A production in human mesothelial cell lines and fibroblast cell lines, and TGF-β1-induced VEGF-A was suppressed by TGF-β receptor I (TGFβR-I) inhibitor. Incremental peak values of VEGF-A mRNA stimulated by TGF-β1 in human cultured mesothelial cells derived from PD patients with a range of peritoneal membrane functions correlated with D/P Cr ( P < 0.05). To evaluate the regulatory mechanisms of VEGF-A and neoangiogenesis in vivo, we administered TGFβR-I inhibitor intraperitoneally in a rat chlorhexidine-induced peritoneal injury (CG) model. TGFβR-I inhibitor administration in the CG model decreased peritoneal thickness ( P < 0.001), the number of vessels ( P < 0.001), and VEGF-A levels ( P < 0.05). These results suggest that neoangiogenesis is associated with fibrosis through the TGF-β1-VEGF-A pathway in mesothelial cells and fibroblasts. These findings are important when considering the strategy for management of UFF in PD patients.

scholarly journals Dendrobium Mixture Ameliorates Diabetic Nephropathy in db/db Mice by Regulating the TGF-β1/Smads Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yong Chen ◽  
Xiaohui Lin ◽  
Yanfang Zheng ◽  
Wenzhen Yu ◽  
Fan Lin ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Lipid Level ◽  
Fasting Blood Glucose ◽  
Blood Lipid ◽  
Control Group ◽  
Expression Levels ◽  
Tgf Β1

Dendrobium mixture (DMix) is an effective treatment for diabetic nephropathy (DN), but the molecular mechanism underlying its action remains unclear. In this study, we investigated whether DMix regulates the transforming growth factor-β1 (TGF-β1)/Smads signal transduction pathway. Twenty-four db/db mice were randomly divided into three groups: the model, DMix, and gliquidone groups, while eight db/m mice were selected as the normal control group. The drug was administered by continuous gavage for 8 weeks. Body weight (BW), kidney weight (KW), kidney index, fasting blood glucose (FBG), blood lipid, 24-hour urinary albumin excretion rate, blood urea nitrogen, and serum creatinine levels were measured. Pathological changes in the renal tissue were observed under a light microscope. Real-time quantitative PCR and immunohistochemical staining were used to detect the mRNA and protein expression levels of TGF-β1 and alpha-smooth muscle actin (α-SMA), respectively, in renal tissues. TGF-β1, Smad2, p-Smad2, Smad3, p-Smad3, and α-SMA expression levels were measured using western blotting. The results showed that DMix significantly reduced the FBG level, BW, KW, and blood lipid level and improved renal function in db/db mice. Histopathology showed that DMix alleviated glomerular mesangial cell proliferation and renal interstitial fibrosis in db/db mice. Additionally, DMix reduced the protein and mRNA expression levels of TGF-β1 and α-SMA and inhibited Smad2 and Smad3 phosphorylation. We conclude that DMix may inhibit renal fibrosis and delay the progression of DN by regulating the TGF-β1/Smads signaling pathway.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

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