scholarly journals Baicalin Ameliorates Pancreatic Fibrosis by Inhibiting the Activation of Pancreatic Stellate Cells in Mice with Chronic Pancreatitis

2021 ◽  
Vol 11 ◽  
Author(s):  
Jianwei Fan ◽  
Lifang Duan ◽  
Nan Wu ◽  
Xiaofan Xu ◽  
Jiaqi Xin ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Type I ◽  
Alpha Smooth Muscle Actin

Pancreatic inflammation and fibrosis are typical pathological features in chronic pancreatitis (CP). Activated pancreatic stellate cells (PSCs) have been regarded as the core event in the development of pancreatic fibrosis and are considered to be the key target for treatment of CP. Baicalin (C21H18O11), the main chemical composition of Baikal skullcap in the traditional Chinese medicines Dachaihu decoction (DCHD) and Xiaochaihu decoction (XCHD), has shown significant effects in the treatment of pancreatic fibrosis in CP mice; however, whether baicalin can inhibit the activation of PSCs and its underlying mechanism remain unclear. In this study, the influence of baicalin on activated PSCs in vitro and in vivo was investigated, and the results showed that Baicalin could significantly ameliorate the degree of pancreatic inflammation and fibrosis, while decreasing the levels of alpha-smooth muscle actin (α-SMA), F4/80 (surface markers of mouse macrophages), nuclear factor kappa-B (NF-κB), monocyte chemotactic protein 1 (MCP-1), and collagen type I alpha 1 (COL1A1)in the pancreas. Moreover, NF-κB and α-SMA were co-expressed in the pancreas of CP mice. Baicalin treatment markedly reduced the expression of co-location of α-SMA and NF-κB. In vitro, the protein expression levels of transforming growth factor-β receptor 1 (TGF-βR1), phosphorylated TGF-β activated kinase 1 p-TAK 1, and NF-κBp65 in PSCs were all remarkably reduced after treatment with baicalin. In addition, baicalin could inhibit MCP-1 mRNA expression in supernatant of activated PSCs, as well as the excessive migration of macrophages. Taken together, our findings indicated that baicalin could inhibit the TGF-β1/TGF-βR1/TAK1/NF-κB signaling pathway of activated PSCs, reduce the secretion of MCP-1, and further decrease the infiltration of macrophages and inflammation cells of the local microenvironment of the pancreas. Thus, this study provides a reliable experimental basis for baicalin in the prevention and treatment of CP.

scholarly journals mTOR inhibitors potentially reduce TGF-β2-induced fibrogenic changes in trabecular meshwork cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nozomi Igarashi ◽  
Megumi Honjo ◽  
Makoto Aihara
Keyword(s):  
Trabecular Meshwork ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Mtor Inhibitors ◽  
In Vivo Model ◽  
Type I ◽  
Fibrotic Response ◽  
Alpha Smooth Muscle Actin

AbstractWe examined the effects of mTOR inhibitors on the fibrotic response induced by transforming growth factor-beta2 (TGF-β2) in cultured human trabecular meshwork (hTM) cells. TGF-β2-induced expression of fibronectin, collagen type I, alpha 1 chain (COL1A1), and alpha-smooth muscle actin (αSMA) in hTM cells was examined in the presence or absence of mTOR inhibitors using quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The migration rates of hTM cells were examined in the presence of TGF-β2 with or without mTOR inhibitors. An in vitro study showed that the expression of fibronectin, COL1A1, and αSMA was upregulated by TGF-β2 treatment of hTM cells; such upregulation was significantly suppressed by mTOR inhibitors. The inhibitors significantly reduced the migration rate of TGF-β2-stimulated hTM cells. mTOR inhibitors may usefully reduce the fibrotic response of hTM cells and we may have to explore if it is also effective in in vivo model.

scholarly journals Eruberin A, a Natural Flavanol Glycoside, Exerts Anti-Fibrotic Action on Pancreatic Stellate Cells

2015 ◽  
Vol 36 (6) ◽  
pp. 2433-2446 ◽  
Author(s):  
Siu Wai Tsang ◽  
Hong-Jie Zhang ◽  
Ye-Gao Chen ◽  
Kathy Ka-Wai Auyeung ◽  
Zhao-Xiang Bian
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Type I ◽  
Alpha Smooth Muscle Actin ◽  
Expression Levels

Background: Eruberin A (2, 3-dehydroflavonoid), a flavanol glycoside isolated from Pronephrium penangianum, has been used as a blood-nourishing folk medicine for centuries; however, it indeed possesses a variety of other health-promoting benefits including anti-fibrotic bioactivity. Activation of pancreatic stellate cells (PSCs) is the key initiating step in pancreatic fibrosis, which is a characteristic feature associated with chronic pancreatitis and pancreatic adenocarcinoma. Methods: The anti-fibrotic effect of eruberin A and the underlying mechanisms of its anti-fibrotic action in LTC-14 cells, which retained essential characteristics and morphological features of primary PSCs, were examined by means of real-time polymerase chain reactions, Western blotting and immunostaining. Results: The application of eruberin A (20 µg/ml) effectively inhibited the expression levels of fibrotic mediators namely alpha-smooth muscle actin, fibronectin and type I-collagen, so as the sonic hedgehog signaling pathway components post transforming growth factor-beta (5 ng/ml) stimulation. Eruberin A treatment also led to a notable decrease in the activation of nuclear factor-kappaB (NF-κB) and the phosphorylation of phosphoinositide 3-kinase (PI3K)/serine-threonine kinase (AKT). Conclusion: Our results demonstrated that eruberin A significantly suppressed the expression levels of fibrotic mediators in PSCs, and we suggest that its anti-fibrotic mechanism was associated with an attenuation of the PI3K/AKT/NF-κB signaling pathway.

scholarly journals BMP2 inhibits TGF-β-induced pancreatic stellate cell activation and extracellular matrix formation

2013 ◽  
Vol 304 (9) ◽  
pp. G804-G813 ◽  
Author(s):  
Xuxia Gao ◽  
Yanna Cao ◽  
Wenli Yang ◽  
Chaojun Duan ◽  
Judith F. Aronson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Steady Increase ◽  
Pathological Feature

Activation of pancreatic stellate cells (PSCs) by transforming growth factor (TGF)-β is the key step in the development of pancreatic fibrosis, a common pathological feature of chronic pancreatitis (CP). Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have anti-fibrogenic functions, in contrast to TGF-β, in the kidney, lung, and liver. However, it is not known whether BMPs have an anti-fibrogenic role in the pancreas. The current study was designed to investigate the potential anti-fibrogenic role of BMPs in the pancreas using an in vivo CP model and an in vitro PSC model. CP was induced by repetitive intraperitoneal injections of cerulein in adult Swiss Webster mice. The control mice received saline injections. Compared with the control, cerulein injections induced a time-dependent increase in acinar injury and progression of fibrosis and a steady increase in inflammation. Cerulein injections also induced increases of the extracellular matrix (ECM) protein fibronectin and of α-smooth muscle actin (α-SMA)-positive stellate cells (PSCs). The mice receiving cerulein injections showed increased BMP2 protein levels and phosphorylated Smad1 levels up to 4 wk and then declined at 8 wk to similar levels as the control. In vitro, the isolated mouse and human PSCs were cultured and pretreated with BMP2 followed by TGF-β treatment. BMP2 pretreatment inhibited TGF-β-induced α-SMA, fibronectin, and collagen type Ia expression. Knocking down Smad1 with small-interfering RNA reversed the inhibitory effect of BMP2 on TGF-β-induced α-SMA and fibronectin expression. Thus, BMP2 opposes the fibrogenic function of TGF-β in PSCs through the Smad1 signaling pathway.

scholarly journals Conophylline Suppresses Pancreatic Stellate Cells and Improves Islet Fibrosis in Goto-Kakizaki Rats

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 621-630 ◽  
Author(s):  
Rie Saito ◽  
Satoko Yamada ◽  
Yoritsuna Yamamoto ◽  
Tsutomu Kodera ◽  
Akemi Hara ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Activin A ◽  
Pancreatic Stellate Cells ◽  
Muscle Actin ◽  
Β Cell ◽  
Gk Rats

Activin A is a differentiation factor for β-cells and is effective to promote β-cell neogenesis. Activin A is also an autocrine activator of pancreatic stellate cells, which play a critical role in fibrogenesis of the pancreas. Conophylline (CnP) is a natural compound, which reproduces the effect of activin on β-cell differentiation and promotes β-cell neogenesis when administered in vivo. However, its effect on stellate cells is not known. We therefore investigated the effect of CnP on stellate cells both in vitro and in vivo. Unlike activin A, CnP inhibited activation of cultured stellate cells and reduced the production of collagen. We then analyzed the involvement of stellate cells in islet fibrosis in Goto-Kakizaki (GK) rats, a model of type 2 diabetes mellitus. In pancreatic sections obtained from 6-wk-old GK rats, CD68-positive macrophages and glial fibrillary acidic protein- and α-smooth muscle actin-positive stellate cells infiltrated into islets. Later, the number of macrophages was increased, and the α-smooth muscle actin staining of stellate cells became stronger, indicating the involvement of stellate cells in islet fibrosis in GK rats. When CnP was administered orally for 4 wk, starting from 6 wk of age, invasion of stellate cells and macrophages was markedly reduced and islet fibrosis was significantly improved. The insulin content was twice as high in CnP-treated rats. These results indicate that CnP exerts antifibrotic actions both in vitro and in vivo and improves islet fibrosis in Goto-Kakizaki rats.

scholarly journals Phosphocreatine Attenuates Isoproterenol-Induced Cardiac Fibrosis and Cardiomyocyte Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Hui Dai ◽  
Liang Chen ◽  
Dongyue Gao ◽  
Aihua Fei
Keyword(s):  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Cardiomyocyte Apoptosis ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Type I ◽  
Alpha Smooth Muscle Actin

The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis in vivo. Isoproterenol (ISO) was used to induce cardiac fibrosis in rats. PCr administration ameliorated fibrosis by reducing collagen accumulation and fibrosis-related signals, including transforming growth factor beta 1 (TGF-β1), alpha smooth muscle actin (α-SMA), collagen type I, and collagen type III. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways, including p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p65, were highly activated by ISO and blocked by PCr. Moreover, PCr decreased ISO-induced matrix metalloproteinase-9 (MMP-9) and increased the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. Furthermore, PCr suppressed cardiomyocyte apoptosis induced by ISO, as shown by downregulated expression of the proapoptotic caspase-3, Bax, and upregulated expression of the antiapoptotic Bcl-2. Taken together, PCr can be an effective agent for preventing cardiac fibrosis and cardiomyocyte apoptosis.

scholarly journals Hic-5 is required for activation of pancreatic stellate cells and development of pancreatic fibrosis in chronic pancreatitis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lin Gao ◽  
Xiao-Feng Lei ◽  
Aya Miyauchi ◽  
Masahito Noguchi ◽  
Tomokatsu Omoto ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Matrix Proteins ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Pathological Conditions ◽  
Potential Marker ◽  
Actin Expression ◽  
Tgf Β1

Abstract Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.

Gypenosides Ameliorate Carbon Tetrachloride-Induced Liver Fibrosis by Inhibiting the Differentiation of Hepatic Progenitor Cells into Myofibroblasts

2017 ◽  
Vol 45 (05) ◽  
pp. 1061-1074 ◽  
Author(s):  
Jiamei Chen ◽  
Xuewei Li ◽  
Yonghong Hu ◽  
Wei Liu ◽  
Qun Zhou ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Progenitor Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Cytokeratin 19 ◽  
Type I ◽  
Alpha Smooth Muscle Actin

Gypenosides (GPs), the predominant components of Gynostemma pentaphyllum, exert antifibrotic effects; however, the mechanisms underlying their ability to ameliorate liver fibrosis are unclear. Liver fibrosis was induced in C57BL/6 mice via subcutaneous injection of 10% carbon tetrachloride (CCl[Formula: see text] three times a week for two weeks. Then, CCl4 was administered in conjunction with intragastric GPs for another three weeks. For in vitro analyses, WB-F344, hepatatic progenitor cells (HPCs) were treated with transforming growth factor beta 1 (TGF-[Formula: see text]1) with or without GPs for 48[Formula: see text]h. The results showed that alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, deposition of collagen, hydroxyproline content, and expression of alpha-smooth muscle actin ([Formula: see text]-SMA) and collagen type I (Col I) were significantly decreased after treatment with GPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]). In the 5M CCl4 group, the expression of HPC markers, Sox9 and cytokeratin 19 (CK19), was significantly increased compared with the normal or GPs-treated group ([Formula: see text], [Formula: see text]). Immunostaining showed that the number of Sox9 and [Formula: see text]-SMA double-positive cells was higher in the 5M CCl4 group than in the normal group, but the addition of GPs caused this cell number to decrease. In WB-F344 cells, the expression of [Formula: see text]-SMA and Col I was significantly increased after treatment with TGF-[Formula: see text], whereas in the GPs treatment group, expression was markedly decreased ([Formula: see text]). The levels of TGF-[Formula: see text] and TGF-[Formula: see text]R1 were markedly reduced after GPs treatment both in vivo and in vitro. In conclusion, GPs ameliorated CCl4-induced liver fibrosis via the inhibition of TGF-[Formula: see text] signaling, consequently inhibiting the differentiation of HPCs into myofibroblasts.

scholarly journals New aspects of formation and progression of pancreatic fibrosis in pancreatitis

2019 ◽  
Vol 43 (2) ◽  
pp. 20-24
Author(s):  
V. A. Akhmedov ◽  
O. V. Gaus
Keyword(s):  
Extracellular Matrix ◽  
Chronic Pancreatitis ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Main Components ◽  
Acute And Chronic Pancreatitis

Fibrosis formation is a dynamic process during which the formation of an extracellular matrix takes place in interstitial spaces and areas where the main components of exocrine pancreatic function (acinar cells) are damaged. According to studies, the biggest role in the formation of pancreatic fibrosis upon chronic pancreatitis is played by various types of effector cells, such as fibroblasts, myofibroblasts and fibrocytes, while fibroblasts and myofibroblasts are the key fibrosis cells responsible for the secretion of extracellular matrix. Activated pancreatic stellate cells become main components of fibrosis formation in patients with chronic pancreatitis, synthesizing transforming growth factor-β, fibroblast growth factor, which leads to enhanced synthesis of extracellular matrix. The presented review highlights molecular mechanisms (Rho-kinase, mitogen-activating protein kinase, transforming growth factor-β, associated with the protein encoded by SMAD in humans, phosphatidylinositol-3 kinase), which play an important role in the activation of pancreatic stellate cells and launching the phenomenon of pancreatic fibrogenesis. The presented data opens up prospects for the development of diagnostic areas with the search for new markers for the diagnosis of acute and chronic pancreatitis along with development of new therapeutic options for the pathogenetic therapy of patients with acute and chronic pancreatitis based on the results obtained.

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