scholarly journals Molecular aspects of chronic radiation enteritis

2011 ◽  
Vol 34 (3) ◽  
pp. 119 ◽  
Author(s):  
Yanfei Zhu ◽  
Jing Zhou ◽  
Guoqing Tao
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Radiation Enteritis ◽  
Intestinal Fibrosis ◽  
Chronic Radiation ◽  
Radiation Induced ◽  
Molecular Aspects ◽  
Tgf Β1

Purpose: Chronic radiation enteritis (CRE) is one of the most feared complications of abdominal or pelvic radiation therapy and the treatment of CRE is difficult and often controversial. Recent progress in molecular biology has shed some light on the pathogenesis of CRE, which is characterized by fibrosis. The purpose of this article is to summarize the current state of knowledge of molecular aspects of radiation induced intestinal fibrosis and to discuss potential therapeutic targets. Methods: A review of the up-to-date published literature involving the possible molecular cascades in radiation-induced intestinal fibrosis and prospective targets for CRE were performed using the Pub-Med search engine. Results: Fibrosis development is correlated with transforming growth factor β1 (TGF-β1) and its downstream effector Smad3, which stimulates fibrogenic downstream mediators, such as connective tissue growth factor (CTGF). Ras homologue (Rho) and Rho-associated kinase (ROCK) signaling pathway have been shown to play important roles in the development of CRE. The inhibition of these pathways ameliorated radiation-induced intestinal fibrosis in vitro and in animal studies; however, the relationship between the Smad3 and Rho signaling pathways has not been elucidated. Conclusions: Rho/ROCK and TGF-β1/Smad3 signaling pathways have been shown to play a key role in intestinal fibrogenesis, which might provide with effective possibilities for clinical intervention. Understanding the cooperation between Smad3 and Rho, may therefore be critical to our overall understanding of fibrosis development and maintenance of CRE.

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

2021 ◽  
Vol 22 (6) ◽  
pp. 2952
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western Blots ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

scholarly journals Amelioration of paraquat-induced pulmonary fibrosis in mice by regulating miR-140-5p expression with the fibrogenic inhibitor Xuebijing

2020 ◽  
Vol 34 ◽  
pp. 205873842092391 ◽  
Author(s):  
Min-na Dong ◽  
Yun Xiao ◽  
Yun-fei Li ◽  
Dong-mei Wang ◽  
Ya-ping Qu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Treatment Group ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Lavage Fluid ◽  
Tissue Growth ◽  
Control Treatment ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Tgf Β1

Intravenous Xuebijing (XBJ) therapy suppresses paraquat (PQ)-induced pulmonary fibrosis. However, the mechanism underlying this suppression remains unknown. This work aimed to analyze the miR-140-5p-induced effects of XBJ injection on PQ-induced pulmonary fibrosis in mice. The mice were arbitrarily assigned to four groups. The model group was administered with PQ only. The PQ treatment group was administered with PQ and XBJ. The control group was administered with saline only. The control treatment group was administered with XBJ only. The miR-140-5p and miR-140-5p knockout animal models were overexpressed. The gene expression levels of miR-140-5p, transglutaminase-2 (TG2), β-catenin, Wnt-1, connective tissue growth factor (CTGF), mothers against decapentaplegic homolog (Smad), and transforming growth factor-β1 (TGF-β1) in the lungs were assayed with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. The levels of TGF-β1, CTGF, and matrix metalloproteinase-9 (MMP-9) in the bronchoalveolar lavage fluid were assessed by enzyme-linked immunosorbent assay (ELISA). Hydroxyproline (Hyp) levels and pulmonary fibrosis were also scored. After 14 days of PQ induction of pulmonary fibrosis, AdCMV-miR-140-5p, and XBJ upregulated miR-140-5p expression; blocked the expressions of TG2, Wnt-1, and β-catenin; and decreased p-Smad2, p-Smad3, CTGF, MMP-9, and TGF-β1 expressions. In addition, Hyp and pulmonary fibrosis scores in XBJ-treated mice decreased. Histological results confirmed that PQ-induced pulmonary fibrosis in XBJ-treated lungs was attenuated. TG2 expression and the Wnt-1/β-catenin signaling pathway were suppressed by the elevated levels of miR-140-5p expression. This inhibition was pivotal in the protective effect of XBJ against PQ-induced pulmonary fibrosis. Thus, XBJ efficiently alleviated PQ-induced pulmonary fibrosis in mice.

scholarly journals High-Throughput Screening Assay Identifies Small Molecules Capable of Modulating the BMP-2 and TGF-β1 Signaling Pathway

2016 ◽  
Vol 22 (1) ◽  
pp. 40-50 ◽  
Author(s):  
Corina-Adriana Ghebes ◽  
Jéré van Lente ◽  
Janine Nicole Post ◽  
Daniel B. F. Saris ◽  
Hugo Fernandes
Keyword(s):  
Growth Factor ◽  
Small Molecules ◽  
Signaling Pathways ◽  
High Throughput Screening ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Bone Morphogenetic Protein 2 ◽  
Screening Assay ◽  
High Throughput Screening Assay ◽  
Tgf Β1

Modulating the bone morphogenetic protein 2 (BMP-2) and transforming growth factor–β1 (TGF-β1) signaling pathways is essential during tendon/ligament (T/L) healing. Unfortunately, growth factor delivery in situ is far from trivial and, in many cases, the necessary growth factors are not approved for clinical use. Here we used a BMP-2 and a TGF-β1 reporter cell line to screen a library of 1280 Food and Drug Administration–approved small molecules and identify modulators of both signaling pathways. We identified four compounds capable of modulating BMP and TGF signaling on primary human tendon–derived cells (huTCs) and describe their effects on proliferation and differentiation of these cells.

Calycosin Inhibits Intestinal Fibrosis on CCD-18Co Cells via Modulating Transforming Growth Factor-β/Smad Signaling Pathway

Pharmacology ◽  
2019 ◽  
Vol 104 (1-2) ◽  
pp. 81-89 ◽  
Author(s):  
Jing Liu ◽  
Tan Deng ◽  
Yaxin Wang ◽  
Mengmeng Zhang ◽  
Guannan Zhu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Collagen I ◽  
Smad Pathway ◽  
Smad Signaling ◽  
Intestinal Fibrosis ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Background: Intestinal fibrosis is the major complication of Crohn’s disease (CD). There are no other good treatments for CD except surgery and remains a refractory disease. Calycosin (CA), the active component of astragalus membranaceus, has been reported the potential effect on lung fibrosis and renal fibrosis. In this study, we aim to explore the effect of CA on intestinal fibrosis in vitro and the possible signal pathway. Methods: The antifibrotic effect of CA is investigated in human intestinal fibroblasts (CCD-18Co) cells induced by transforming growth factor-β1 (TGF-β1). MTT method was used to screen the concentration of CA. Real-time polymerase chain reaction and western blot analysis were used to evaluate the expression of α-smooth muscle actin (α-SMA), collagen I, and TGF-β/Smad pathway. Results: The results showed that the concentration of CA was 12.5, 25, 50 μmol/L. CA could inhibit the expression of α-SMA and collagen I. In addition, CA regulated the expression of TGF-β/Smad signaling pathway. Conclusion: This study demonstrated that CA could inhibit the activation of CCD-18Co cells and reduce the expression of extracellular matrix. Our study highlighted that CA-inhibited TGF-β/Smad pathway through inhibiting the expression of p-Smad2, p-Smad3, Smad4, and TGF-β1 and raised the Smad7 expression. Therefore, CA might inhibit intestinal fibrosis by inhibiting the TGF-β/Smad pathway.

Connective tissue growth factor antagonizes transforming growth factor-β1/Smad signalling in renal mesangial cells

2011 ◽  
Vol 441 (1) ◽  
pp. 499-510 ◽  
Author(s):  
Helen C. O'Donovan ◽  
Fionnuala Hickey ◽  
Derek P. Brazil ◽  
David H. Kavanagh ◽  
Noelynn Oliver ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Transcriptional Responses ◽  
Cell Contractility ◽  
Tgf Β1

The critical involvement of TGF-β1 (transforming growth factor-β1) in DN (diabetic nephropathy) is well established. However, the role of CTGF (connective tissue growth factor) in regulating the complex interplay of TGF-β1 signalling networks is poorly understood. The purpose of the present study was to investigate co-operative signalling between CTGF and TGF-β1 and its physiological significance. CTGF was determined to bind directly to the TβRIII (TGF-β type III receptor) and antagonize TGF-β1-induced Smad phosphorylation and transcriptional responses via its N-terminal half. Furthermore, TGF-β1 binding to its receptor was inhibited by CTGF. A consequent shift towards non-canonical TGF-β1 signalling and expression of a unique profile of differentially regulated genes was observed in CTGF/TGF-β1-treated mesangial cells. Decreased levels of Smad2/3 phosphorylation were evident in STZ (streptozotocin)-induced diabetic mice, concomitant with increased levels of CTGF. Knockdown of TβRIII restored TGF-β1-mediated Smad signalling and cell contractility, suggesting that TβRIII is key for CTGF-mediated regulation of TGF-β1. Comparison of gene expression profiles from CTGF/TGF-β1-treated mesangial cells and human renal biopsy material with histological diagnosis of DN revealed significant correlation among gene clusters. In summary, mesangial cell responses to TGF-β1 are regulated by cross-talk with CTGF, emphasizing the potential utility of targeting CTGF in DN.

scholarly journals Antenatal glucocorticoids counteract LPS changes in TGF-β pathway and caveolin-1 in ovine fetal lung

2013 ◽  
Vol 304 (6) ◽  
pp. L438-L444 ◽  
Author(s):  
Jennifer J. P. Collins ◽  
Steffen Kunzmann ◽  
Elke Kuypers ◽  
Matthew W. Kemp ◽  
Christian P. Speer ◽  
...  
Keyword(s):  
Growth Factor ◽  
Western Blot ◽  
Transforming Growth Factor ◽  
Fetal Lung ◽  
Tissue Growth ◽  
Caveolin 1 ◽  
Protein Levels ◽  
Smad2 Phosphorylation ◽  
Ovine Fetal ◽  
Tgf Β1

Inflammation and antenatal glucocorticoids, the latter given to mothers at risk for preterm birth, affect lung development and may contribute to the development of bronchopulmonary dysplasia (BPD). The effects of the combined exposures on inflammation and antenatal glucocorticoids on transforming growth factor (TGF)-β signaling are unknown. TGF-β and its downstream mediators are implicated in the etiology of BPD. Therefore, we asked whether glucocorticoids altered intra-amniotic lipopolysaccharide (LPS) effects on TGF-β expression, its signaling molecule phosphorylated sma and mothers against decapentaplegic homolog 2 (pSmad2), and the downstream mediators connective tissue growth factor (CTGF) and caveolin-1 (Cav-1). Ovine singleton fetuses were randomized to receive either an intra-amniotic injection of LPS and/or maternal betamethasone (BTM) intramuscularly 7 and/or 14 days before delivery at 120 days gestational age (GA; term = 150 days GA). Saline was used for controls. Protein levels of TGF-β1 and -β2 were measured by ELISA. Smad2 phosphorylation was assessed by immunohistochemistry and Western blot. CTGF and Cav-1 mRNA and protein levels were determined by RT-PCR and Western blot. Free TGF-β1 and -β2 and total TGF-β1 levels were unchanged after LPS and/or BTM exposure, although total TGF-β2 increased in animals exposed to BTM 7 days before LPS. pSmad2 immunostaining increased 7 days after LPS exposure although pSmad2 protein expression did not increase. Similarly, CTGF mRNA and protein levels increased 7 days after LPS exposure as Cav-1 mRNA and protein levels decreased. BTM exposure before LPS prevented CTGF induction and Cav-1 downregulation. This study demonstrated that the intrauterine inflammation-induced TGF-β signaling can be inhibited by antenatal glucocorticoids in fetal lungs.

scholarly journals Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy

2018 ◽  
Vol 132 (21) ◽  
pp. 2299-2322 ◽  
Author(s):  
Jinfang Bao ◽  
Yingfeng Shi ◽  
Min Tao ◽  
Na Liu ◽  
Shougang Zhuang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Growth Factor Receptor ◽  
Nuclear Factor Κb ◽  
Transforming Growth Factor Β1 ◽  
Renal Tissue ◽  
Tgf Β1

Autophagy has been identified as a cellular process of bulk degradation of cytoplasmic components and its persistent activation is critically involved in the renal damage induced by ureteral obstruction. However, the role and underlying mechanisms of autophagy in hyperuricemic nephropathy (HN) remain unknown. In the present study, we observed that inhibition of autophagy by 3-methyladenine (3-MA) abolished uric acid-induced differentiation of renal fibroblasts to myofibroblasts and activation of transforming growth factor-β1 (TGF-β1), epidermal growth factor receptor (EGFR), and Wnt signaling pathways in cultured renal interstitial fibroblasts. Treatment with 3-MA also abrogated the development of HN in vivo as evidenced by improving renal function, preserving renal tissue architecture, reducing the number of autophagic vacuoles, and decreasing microalbuminuria. Moreover, 3-MA was effective in attenuating renal deposition of extracellular matrix (ECM) proteins and expression of α-smooth muscle actin (α-SMA) and reducing renal epithelial cells arrested at the G2/M phase of cell cycle. Injury to the kidney resulted in increased expression of TGF-β1 and TGFβ receptor I, phosphorylation of Smad3 and TGF-β-activated kinase 1 (TAK1), and activation of multiple cell signaling pathways associated with renal fibrogenesis, including Wnt, Notch, EGFR, and nuclear factor-κB (NF-κB). 3-MA treatment remarkably inhibited all these responses. In addition, 3-MA effectively suppressed infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney. Collectively, these findings indicate that hyperuricemia-induced autophagy is critically involved in the activation of renal fibroblasts and development of renal fibrosis and suggest that inhibition of autophagy may represent a potential therapeutic strategy for HN.

Transforming growth factor-β1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways

2018 ◽  
Vol 96 (5) ◽  
pp. 527-534 ◽  
Author(s):  
Brice Ongali ◽  
Nektaria Nicolakakis ◽  
Xin-Kang Tong ◽  
Clotilde Lecrux ◽  
Hans Imboden ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cerebrovascular Reactivity ◽  
Cerebrovascular Dysfunction ◽  
Tgf Β1

Transgenic mice constitutively overexpressing the cytokine transforming growth factor-β1 (TGF-β1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-β1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-β1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.

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