scholarly journals Acute Liver Injury after CCl4 Administration Is Independent of Smad7 Expression in Myeloid Cells

2019 ◽  
Vol 20 (22) ◽  
pp. 5528 ◽  
Author(s):  
Jessica Endig ◽  
Ludmilla Unrau ◽  
Paulina Sprezyna ◽  
Sebasting Rading ◽  
Meliha Karsak ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Elevated Serum ◽  
Myeloid Cells ◽  
Transforming Growth Factor Β ◽  
Cellular Processes ◽  
Ccl4 Administration ◽  
Smad7 Expression ◽  
The Impact

Myeloid cells are essential for the initiation and termination of innate and adaptive immunity that create homeostasis in the liver. Smad7 is an inhibitor of the transforming growth factor β (TGF-β) signaling pathway, which regulates inflammatory cellular processes. Knockdown of Smad7 in hepatocytes has been shown to promote liver fibrosis, but little is known about the effects of Smad7 in myeloid cells during inflammatory responses in the liver. Using mice with a myeloid-specific knockdown of Smad7 (LysM-Cre Smad7fl/fl), we investigated the impact of Smad7 deficiency in myeloid cells on liver inflammation and regeneration using the well-established model of CCl4-mediated liver injury. Early (24/48 h) and late (7 d) time points were analyzed. We found that CCl4 induces severe liver injury, with elevated serum ALT levels, centrilobular and periportal necrosis, infiltrating myeloid cells and an increase of inflammatory cytokines in the liver. Furthermore, as expected, inflammation peaked at 24 h and subsided after 7 d. However, the knockdown of Smad7 in myeloid cells did not affect any of the investigated parameters in the CCl4-treated animals. In summary, our results suggest that the inhibition of TGF-β signaling via Smad7 expression in myeloid cells is dispensable for the induction and control of acute CCl4-induced liver injury.

scholarly journals Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl4 Exposure in Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11575
Author(s):  
Ludmilla Unrau ◽  
Jessica Endig ◽  
Diane Goltz ◽  
Paulina Sprezyna ◽  
Hanna Ulrich ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Elevated Serum ◽  
Myeloid Cells ◽  
Chronic Liver ◽  
Signalling Pathway ◽  
Liver Inflammation ◽  
Knock Down ◽  
Smad Protein ◽  
Smad7 Expression

Myeloid cells play an essential role in the maintenance of liver homeostasis, as well as the initiation and termination of innate and adaptive immune responses. In chronic hepatic inflammation, the production of transforming growth factor beta (TGF-β) is pivotal for scarring and fibrosis induction and progression. TGF-β signalling is tightly regulated via the Smad protein family. Smad7 acts as an inhibitor of the TGF-β-signalling pathway, rendering cells that express high levels of it resistant to TGF-β-dependent signal transduction. In hepatocytes, the absence of Smad7 promotes liver fibrosis. Here, we examine whether Smad7 expression in myeloid cells affects the extent of liver inflammation, injury and fibrosis induction during chronic liver inflammation. Using the well-established model of chronic carbon tetrachloride (CCl4)-mediated liver injury, we investigated the role of Smad7 in myeloid cells in LysM-Cre Smadfl/fl mice that harbour a myeloid-specific knock-down of Smad7. We found that the chronic application of CCl4 induces severe liver injury, with elevated serum alanine transaminase (ALT)/aspartate transaminase (AST) levels, centrilobular and periportal necrosis and immune-cell infiltration. However, the myeloid-specific knock-down of Smad7 did not influence these and other parameters in the CCl4-treated animals. In summary, our results suggest that, during long-term application of CCl4, Smad7 expression in myeloid cells and its potential effects on the TGF-β-signalling pathway are dispensable for regulating the extent of chronic liver injury and inflammation.

scholarly journals Hepatoprotective and antioxidant effects of Wu-Zi-Yuan-Chung-Wan against CCl4-induced oxidative damage in rats

2021 ◽  
Vol 19 ◽  
pp. 205873922110140
Author(s):  
Hao-Yuan Cheng ◽  
Jung Chao ◽  
Chuan-Sung Chiu ◽  
I-Chien Hsieh ◽  
Hui-Chi Huang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Transforming Growth Factor Β ◽  
Hepatoprotective Activity ◽  
Chronic Liver ◽  
Control Group ◽  
Antioxidant Enzyme Activities ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

This study was designed to investigate the hepatoprotective potentials of the Wu-Zi-Yuan-Chung-Wan (WZYCW) using an animal model of carbon tetrachloride (CCl4) induced liver injury. CCl4 induced chronic liver hepatotoxicity in adult Sprague-Dawley rats. Excluding the control group, all of the rats with chronic liver fibrosis received 0.4% CCl4 (1.5 mL/kg of body weight, ip) twice per week for 8 weeks. WZYCW (20, 100, and 500 mg/kg) and silymarin (200 mg/kg) were administered five times per week for 8 weeks. After 8 weeks, the rats were sacrificed, blood samples were obtained, and liver histological examinations were performed for subsequent assays. These results suggest that WZYCW considerably reduced Glutamic Oxaloacetic Transaminase (GOT), Glutamic Pyruvic Transaminase (GPT), Triglyceride (TG); and cholesterol activity; and the levels of malonaldehyde (MDA), nitric oxide (NO), and transforming growth factor-β1 (TGF-β1) in the liver. WZYCW also increased the level of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in liver tissue. WZYCW produced hepatoprotective and antifibrotic effects. This is the first study to demonstrate that WZYCW expressed hepatoprotective activity against CCl4 induced acute hepatotoxicity in rat. In addition, the primary compound of WZCYW was analyzed using HPLC. The major peaks of WZCYW, including schizandrin. The results indicate that WZYCW not only enhances hepatic antioxidant enzyme activities and inhibits lipid peroxidation but also suppresses inflammatory responses in CCl4 induced liver damage. Our findings provide evidence that WZYCW possesses a hepatoprotective activity to ameliorate chronic liver injury.

scholarly journals Elevated Serum Transforming Growth Factor β1 Levels in Epstein-Barr Virus-Associated Diseases and Their Correlation with Virus-Specific Immunoglobulin A (IgA) and IgM

2000 ◽  
Vol 74 (5) ◽  
pp. 2443-2446 ◽  
Author(s):  
Jingwu Xu ◽  
Ali Ahmad ◽  
James F. Jones ◽  
Riccardo Dolcetti ◽  
Emanuela Vaccher ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epstein Barr Virus ◽  
Transforming Growth Factor ◽  
Immunoglobulin A ◽  
Elevated Serum ◽  
Transforming Growth Factor Β ◽  
Serum Levels ◽  
Barr Virus ◽  
Associated Diseases ◽  
Epstein Barr

ABSTRACT Transforming growth factor β (TGF-β) is an immunosuppressive cytokine which can induce immunoglobulin A (IgA) switch and Epstein-Barr virus (EBV) replication in latently infected cells. Here we report elevated serum levels of TGF-β in various EBV-associated diseases correlating positively with EBV-specific IgA titers and negatively with IgM titers, suggesting a role for this cytokine in the pathogenesis of these diseases.

scholarly journals ROS and TGFβ: from pancreatic tumour growth to metastasis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Chao-Hui Chang ◽  
Siim Pauklin
Keyword(s):  
Tumour Growth ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Cancer Therapeutics ◽  
Transforming Growth Factor Β ◽  
Ductal Adenocarcinoma ◽  
Cellular Processes ◽  
Tumour Development ◽  
Pancreatic Tumour ◽  
Tgfβ Signalling

AbstractTransforming growth factor β (TGFβ) signalling pathway switches between anti-tumorigenic function at early stages of cancer formation and pro-tumorigenic effects at later stages promoting cancer metastasis. A similar contrasting role has been uncovered for reactive oxygen species (ROS) in pancreatic tumorigenesis. Down-regulation of ROS favours premalignant tumour development, while increasing ROS level in pancreatic ductal adenocarcinoma (PDAC) enhances metastasis. Given the functional resemblance, we propose that ROS-mediated processes converge with the spatial and temporal activation of TGFβ signalling and thereby differentially impact early tumour growth versus metastatic dissemination. TGFβ signalling and ROS could extensively orchestrate cellular processes and this concerted function can be utilized by cancer cells to facilitate their malignancy. In this article, we revisit the interplay of canonical and non-canonical TGFβ signalling with ROS throughout pancreatic tumorigenesis and metastasis. We also discuss recent insight that helps to understand their conflicting effects on different stages of tumour development. These considerations open new strategies in cancer therapeutics.

scholarly journals Serological level of transforming growth factor-β as a predictive biomarker of aortic enlargement in patients with Marfan syndrome

2017 ◽  
Vol 8 (1) ◽  
pp. 61-66
Author(s):  
Andrey S Rudoy ◽  
Alexey M Uryvaev
Keyword(s):  
Risk Factors ◽  
Growth Factor ◽  
Marfan Syndrome ◽  
Aortic Root ◽  
Transforming Growth Factor ◽  
Aortic Rupture ◽  
Imaging Techniques ◽  
Elevated Serum ◽  
Transforming Growth Factor Β ◽  
Absolute Size

Marfan syndrome - an inherited, autosomal dominant disease with an expected rate of 3-5/10 000 or fraction of 20-25% of new mutations, accompanied by violation of the connective tissue that occurs as a result of gene mutations FBN1, coding for the synthesis of fibrillin-1, performing the most important role in the modulation physiological bioavailability TGF-β (transforming growth factor-β). Prediction of aortic rupture is based on the identification of risk factors: family history, the absolute size of the aortic root, the rate of expansion of the aorta, which are based on the results of the history and techniques of imaging ultrasound, CT, MRI. At the same time there is a chance of developing aortic rupture under normal aortic root size and the absence of any risk factors, as well as after the prophylactic prosthetic aortic root. This makes it necessary to search for alternative prognostic markers, threatening bundle and rupture of the aorta. Article verified the predictive role of TGF-β as a serological biomarker for assessing the extension of the aortic root in patients with Marfan syndrome (n = 23, F : M / 7 : 16; 33 ± 9.3 years). The article describes the patterns between TGF-β and the size and the reconstruction of the aneurysm of the thoracic aorta. It was found that elevated levels of serum TGF-β1 (49.1 ng/ml Vs 29.15 ng/ml in the control, p < 0.05) in patients with MS diagnosed with an extension of the aortic root (Z > 1.96) can serve as a serological marker to poor prognosis, accompanied by an increase in the size of the aortic root. In patients with normal-sized aorta, and after aortic reconstruction serum TGFβ1 not elevated. Serum TGFβ may be a promising target for therapeutic, diagnostic and prognostic tactics which are not based on imaging techniques.

Adipolin/CTRP12 protects against pathological vascular remodelling through suppression of smooth muscle cell growth and macrophage inflammatory response

2019 ◽  
Vol 116 (1) ◽  
pp. 237-249 ◽  
Author(s):  
Hayato Ogawa ◽  
Koji Ohashi ◽  
Masanori Ito ◽  
Rei Shibata ◽  
Noriyoshi Kanemura ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Transforming Growth Factor Β ◽  
Vascular Remodelling ◽  
Vsmc Proliferation ◽  
Protein Levels ◽  
Β Receptor

AbstractAimsSecreted factors produced by adipose tissue are involved in the pathogenesis of cardiovascular disease. We previously identified adipolin, also known as C1q/TNF-related protein 12, as an insulin-sensitizing adipokine. However, the role of adipolin in vascular disease remains unknown. Here, we investigated whether adipolin modulates pathological vascular remodelling.Methods and resultsAdipolin-knockout (APL-KO) and wild-type (WT) mice were subjected to wire-induced injury of the femoral artery. APL-KO mice showed increased neointimal thickening after vascular injury compared with WT mice, which was accompanied by an enhanced inflammatory response and vascular cell proliferation in injured arteries. Adipolin deficiency also led to a reduction in transforming growth factor-β (TGF-β) 1 protein levels in injured arteries. Treatment of cultured macrophages with adipolin protein led to a reduction in lipopolysaccharide-stimulated expression of inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin (IL) 6, and monocyte chemotactic protein (MCP)-1. These effects were reversed by inhibition of TGF-β receptor II (TGF-βRII)/Smad2 signalling. Adipolin also reduced platelet-derived growth factor (PDGF)-BB-stimulated proliferation of vascular smooth muscle cells (VSMCs) through a TGF-βRII/Smad2-dependent pathway. Furthermore, adipolin treatment significantly increased TGF-β1 concentration in media from cultured VSMCs and macrophages.ConclusionThese data indicate that adipolin protects against the development of pathological vascular remodelling by attenuating macrophage inflammatory responses and VSMC proliferation.

scholarly journals P1196AN INIHIBITOR OF KRUPPEL-LIKE FACTOR 5 SUPPRESSES PERITONEAL FIBROSIS IN MICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Kumiko Muta ◽  
Yuka Nakazawa ◽  
Yoko Obata ◽  
Hiro Inoue ◽  
Kenta Torigoe ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Retinoic Acid Receptor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Peritoneal Fibrosis ◽  
Retinoic Acid Receptor Α ◽  
Klf5 Expression

Abstract Background and Aims We presented previously that Am80, a synthetic retinoic acid receptor α specific agonist, inhibited the expression of Krüppel-like transcription factor 5 (KLF5) and reduced peritoneal fibrosis in mice. Now, we examined further detail about the mechanism to inhibit peritoneal fibrosis. Method Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) into peritoneal cavity of ICR mice. Am80 was administered orally for every day from the start of CG injection. After 3 weeks of treatment, peritoneal tissues were examined using serial sections by immunohistochemistry to identify what kind of cells expressed KLF5. We also examined the effect of Am80 to inhibit peritoneal fibrosis in vitro. Results While KLF5 was expressed in the thickened submesothelial area of CG injected mice, Am80 treatment reduced KLF5 expression and remarkably attenuated peritoneal thickening. The numbers of transforming growth factor β positive cells, α-smooth muscle actin (αSMA) or F4/80 positive cells were significantly decreased in Am80 treated group. KLF5 was expressed in αSMA, F4/80 or CD31 positive cells. Conclusion These results indicate the KLF5 might not only associate phenotypical differentiation from fibroblasts to myofibroblasts but also regulate inflammatory responses and angiogenesis in peritoneal fibrosis model. Am80 can suppress peritoneal fibrosis through inhibiting these mechanisms. In vitro experiments are ongoing.

scholarly journals Modulation of the TGF-β signaling pathway by long noncoding RNA in hepatocellular carcinoma

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Mengzhen Han ◽  
Zhibin Liao ◽  
Furong Liu ◽  
Xiaoping Chen ◽  
Bixiang Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Processes ◽  
Therapy Targets ◽  
Non Coding Rnas

AbstractHepatocellular carcinoma (HCC) is a type of liver cancer with poor prognosis. There have been demonstrated to exist many possible mechanisms in HCC tumorigenesis, and recent investigations have provided some promising therapy targets. However, further mechanisms remain to be researched to improve the therapeutic strategy and diagnosis of HCC. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which plays critical roles in networks of different cellular processes, and TGF-β signaling has been found to participate in tumor initiation and development of HCC in recent years. Moreover, among the molecules and signaling pathways, researchers paid more attention to lncRNAs (long non-coding RNAs), but the connection between lncRNAs and TGF-βremain poorly understood. In this review, we conclude the malignant procedure which lncRNAs and TGF-β involved in, and summarize the mechanisms of lncRNAs and TGF-βin HCC initiation and development. Furthermore, the interaction between lncRNA and TGF-β are paid more attention, and the potential therapy targets are mentioned.

scholarly journals Polyubiquitination Events Mediate Polymethylmethacrylate (PMMA) Particle Activation of NF-κB Pathway

2011 ◽  
Vol 286 (27) ◽  
pp. 23735-23741 ◽  
Author(s):  
Yasuhiro Yamanaka ◽  
Kannan Karuppaiah ◽  
Yousef Abu-Amer
Keyword(s):  
Map Kinases ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Transforming Growth Factor Β ◽  
Secreted Factors ◽  
Ikk Complex ◽  
Particle Activation ◽  
Activation Pathways ◽  
Pmma Particles ◽  
Implant Wear

The pathologic response to implant wear-debris constitutes a major component of inflammatory osteolysis and remains under intense investigation. Polymethylmethacrylate (PMMA) particles, which are released during implant wear and loosening, constitute a major culprit by virtue of inducing inflammatory and osteolytic responses by macrophages and osteoclasts, respectively. Recent work by several groups has identified important cellular entities and secreted factors that contribute to inflammatory osteolysis. In previous work, we have shown that PMMA particles contribute to inflammatory osteolysis through stimulation of major pathways in monocytes/macrophages, primarily NF-κB and MAP kinases. The former pathway requires assembly of large IKK complex encompassing IKK1, IKK2, and IKKγ/NEMO. We have shown recently that interfering with the NF-κB and MAPK activation pathways, through introduction of inhibitors and decoy molecules, impedes PMMA-induced inflammation and osteolysis in mouse models of experimental calvarial osteolysis and inflammatory arthritis. In this study, we report that PMMA particles activate the upstream transforming growth factor β-activated kinase-1 (TAK1), which is a key regulator of signal transduction cascades leading to activation of NF-κB and AP-1 factors. More importantly, we found that PMMA particles induce TAK1 binding to NEMO and UBC13. In addition, we show that PMMA particles induce TRAF6 and UBC13 binding to NEMO and that lack of TRAF6 significantly attenuates NEMO ubiquitination. Altogether, these observations suggest that PMMA particles induce ubiquitination of NEMO, an event likely mediated by TRAF6, TAK1, and UBC13. Our findings provide important information for better understanding of the mechanisms underlying PMMA particle-induced inflammatory responses.

scholarly journals Suppressive Effects of Sulforaphane on TGFBIp-mediated Sepsis

2017 ◽  
Vol 12 (10) ◽  
pp. 1934578X1701201 ◽  
Author(s):  
In-Chul Lee ◽  
Jong-Sup Bae
Keyword(s):  
Endothelial Cells ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
Cecal Ligation ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Experimental Sepsis

Sulforaphane (SFN) is produced when the enzyme myrosinase transforms glucoraphanin upon damage to the plant such as from chewing and effective in preventing carcinogenesis, diabetes, and inflammatory responses. Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein whose expression in several cell types is greatly increased by TGF-β. TGFBIp is released by human umbilical vein endothelial cells (HUVECs) and functions as a mediator of experimental sepsis. We hypothesized that SFN could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here, we investigated the anti-septic effects and underlying mechanisms of SFN against TGFBIp-mediated septic responses. SFN effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, SFN suppressed cecal ligation and puncture (CLP)-induced sepsis lethality and pulmonary injury. In conclusion, SFN suppressed TGFBIp-mediated and CLP-induced septic responses. Therefore, SFN could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the TGFBIp signaling pathway.

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