scholarly journals Targeting Mechano-Transcription Process as Therapeutic Intervention in Gastrointestinal Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Ramasatyaveni Geesala ◽  
You-Min Lin ◽  
Ke Zhang ◽  
Xuan-Zheng Shi
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Mechanical Stress ◽  
Tissue Growth ◽  
Visceral Hypersensitivity ◽  
Gi Tract ◽  
Functional Bowel Disorders ◽  
Transcription Process ◽  
Bowel Disorders ◽  
Inflammatory Molecules

Mechano-transcription is a process whereby mechanical stress alters gene expression. The gastrointestinal (GI) tract is composed of a series of hollow organs, often encountered by transient or persistent mechanical stress. Recent studies have revealed that persistent mechanical stress is present in obstructive, functional, and inflammatory disorders and alters gene transcription in these conditions. Mechano-transcription of inflammatory molecules, pain mediators, pro-fibrotic and growth factors has been shown to play a key role in the development of motility dysfunction, visceral hypersensitivity, inflammation, and fibrosis in the gut. In particular, mechanical stress-induced cyclooxygenase-2 (COX-2) and certain pro-inflammatory mediators in gut smooth muscle cells are responsible for motility dysfunction and inflammatory process. Mechano-transcription of pain mediators such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) may lead to visceral hypersensitivity. Emerging evidence suggests that mechanical stress in the gut also leads to up-regulation of certain proliferative and pro-fibrotic mediators such as connective tissue growth factor (CTGF) and osteopontin (OPN), which may contribute to fibrostenotic Crohn’s disease. In this review, we will discuss the pathophysiological significance of mechanical stress-induced expression of pro-inflammatory molecules, pain mediators, pro-fibrotic and growth factors in obstructive, inflammatory, and functional bowel disorders. We will also evaluate potential therapeutic targets of mechano-transcription process for the management of these disorders.

scholarly journals Growth factors in the regulation of reparative response in the presence of peritoneal damage

2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Irina A. Shurygina ◽  
Мichael G. Shurygin ◽  
Lubov V. Rodionova ◽  
Nataliya I. Ayushinova
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Extended Period ◽  
Tissue Growth ◽  
Tissue Response ◽  
Heparin Binding ◽  
Lower Quadrant ◽  
Male Wistar Rats ◽  
The Right ◽  
Endothelial Growth Factor

AbstractObjectivesTo study the expression of growth factors in the regulation of tissue repair after peritoneal damage tissue response to peritoneal damage.MethodsExperimental study in 35 male Wistar rats determining the evolution over time of the tissue response to aseptic peritoneal damage. A standardized bowel and peritoneal lesions were created in the right lower quadrant by laparotomy. Then, tissular expression of growth factors was evaluated by multiplex polymerase chain reaction at seven timepoints between 6 h and 30 days, postoperatively.ResultsTissular responses of granulocyte-stimulating factors (Csf2, Csf3), connective tissue growth factor (Ctgf), epidermal growth factors and receptor (Egf, Egfr), fibroblast growth factors (Fgf2, 7 and 10), heparin binding EGF-like growth factor (Hbegf), hepatocyte growth factor (Hgf), insulin-like growth factor-1 (Igf1), mitogenic transforming growth factors (Tgfa, Tgfb1, Tgfbr3), and vascular endothelial growth factor A (Vegfa) were biphasic with a first expression peak at day 3, followed by a more pronounced peak at day 14.ConclusionsWe observed a long-lasting, widespread response of tissular growth factors for at least two weeks after peritoneal damage. To be clinically effective, the prophylaxis of postoperative adhesions might be needed for an extended period of time.

scholarly journals The proliferative effect of cortisol on bovine endometrial epithelial cells

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Junsheng Dong ◽  
Jun Li ◽  
Jianji Li ◽  
Luying Cui ◽  
Xia Meng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Akt Signaling ◽  
Tissue Growth ◽  
Mrna Levels ◽  
Physiological Level ◽  
Endometrial Epithelial Cells

Abstract Background Bovine endometrial epithelial cells (BEECs) undergo regular regeneration after calving. Elevated cortisol concentrations have been reported in postpartum cattle due to various stresses. However, the effects of the physiological level of cortisol on proliferation in BEECs have not been reported. The aim of this study was to investigate whether cortisol can influence the proliferation properties of BEECs and to clarify the possible underlying mechanism. Methods BEECs were treated with different concentrations of cortisol (5, 15 and 30 ng/mL). The mRNA expression of various growth factors was detected by quantitative reverse transcription-polymerase chain reaction (qPCR), progression of the cell cycle in BEECs was measured using flow cytometric analysis, and the activation of the Wnt/β-catenin and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways was detected with Western blot and immunofluorescence. Results Cortisol treatment resulted in upregulated mRNA levels of vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF); however, it had no influence on transforming growth factor-beta1 (TGF-β1). Cortisol (15 ng/mL) accelerated the cell cycle transition from the G0/G1 to the S phase. Cortisol upregulated the expression of β-catenin, c-Myc, and cyclinD1 and promoted the phosphorylation of PI3K and AKT. Conclusions These results demonstrated that cortisol may promote proliferation in BEECs by increasing the expression of some growth factors and activating the Wnt/β-catenin and PI3K/AKT signaling pathways.

Cytokines and Growth Factors Involved in Peritoneal Fibrosis of Peritoneal Dialysis Patients

2005 ◽  
Vol 28 (2) ◽  
pp. 129-134 ◽  
Author(s):  
K.-H. Oh ◽  
P.J. Margetts
Keyword(s):  
Peritoneal Dialysis ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Fibroblast Growth Factors ◽  
Tissue Growth ◽  
Platelet Derived Growth Factor ◽  
Fibroblast Growth ◽  
Dialysis Patients ◽  
Peritoneal Fibrosis

Peritoneal fibrosis is initiated by exposure of peritoneal tissues to numerous harmful agents encountered during peritoneal dialysis. These agents interact with cells within the peritoneum to induce growth factors and cytokines that are important in the initiation, progression and maintenance of fibrosis. Some of the mediators implicated in the pathogenesis of peritoneal fibrosis include transforming growth factor (TGF) ß, connective tissue growth factor (CTGF), fibroblast growth factors (FGF), and platelet derived growth factor (PDGF).

TGF-β and CTGF have overlapping and distinct fibrogenic effects on human renal cells

2002 ◽  
Vol 283 (4) ◽  
pp. F707-F716 ◽  
Author(s):  
Elizabeth Gore-Hyer ◽  
Daniel Shegogue ◽  
Malgorzata Markiewicz ◽  
Shianlen Lo ◽  
Debra Hazen-Martin ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Growth Factors ◽  
Growth Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Mrna Levels ◽  
Potent Inducer ◽  
Collagen Promoter

Transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) are ubiquitously expressed in various forms of tissue fibrosis, including fibrotic diseases of the kidney. To clarify the common and divergent roles of these growth factors in the cells responsible for pathological extracellular matrix (ECM) deposition in renal fibrosis, the effects of TGF-β and CTGF on ECM expression in primary human mesangial (HMCs) and human proximal tubule epithelial cells (HTECs) were studied. Both TGF-β and CTGF significantly induced collagen protein expression with similar potency in HMCs. Additionally, α2(I)-collagen promoter activity and mRNA levels were similarly induced by TGF-β and CTGF in HMCs. However, only TGF-β stimulated collagenous protein synthesis in HTECs. HTEC expression of tenascin-C (TN-C) was increased by TGF-β and CTGF, although TGF-β was the more potent inducer. Thus both growth factors elicit similar profibrogenic effects on ECM production in HMCs, while promoting divergent effects in HTECs. CTGF induction of TN-C, a marker of epithelial-mesenchymal transdifferentiation (EMT), with no significant induction of collagenous protein synthesis in HTECs, may suggest a more predominant role for CTGF in EMT rather than induction of excessive collagen deposition by HTECs during renal fibrosis.

Role of Connective Tissue Growth Factor In Endothelin-Mediated Endothelial Cell Activation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2107-2107
Author(s):  
Anna J Hernandez ◽  
Sonia Henriquez ◽  
Enrique R Maldonado ◽  
Rodeler Youte ◽  
Gregory N Prado ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Connective Tissue ◽  
Cell Activation ◽  
Fold Increase ◽  
Tissue Growth ◽  
Vegf Expression ◽  
Endothelial Cell Activation

Abstract Abstract 2107 Endothelial cell activation and elevated levels of circulating Endothelin-1 (ET-1) have been reported in patients with atherosclerosis and sickle cell disease (SCD). ET-1 is a well-described vasoconstrictor, mitogen and regulator of endothelial cells migration that has been shown to promote structural changes in blood vessels. ET-1 is produced in response to increases in vasoactive hormones, growth factors, hypoxia, shear stress and free radicals, events that are commonly observed in patients with SCD. Endothelial cell activation is in part characterized by increases of cytokines such as monocyte chemotactic protein-1 (MCP-1) and growth factors that are important in vascular maintenance and fibrogenesis such as connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). CTGF and VEGF are important for blood vessel remodeling, fibrogenesis and angiogenesis. Indeed there is evidence that incubation of smooth muscle cells with ET-1 leads to increases in CTGF and VEGF levels. However, the relationship between ET-1 and CTGF in endothelial cell activation is unclear. We hypothesize that increasing ET-1 would stimulate CTGF production and endothelial cell activation. We studied the effects of ET-1 on the human endothelial cell line, EA.hy926 (EA), as well as in primary cultures of mouse aortic endothelial cells (MAEC). We performed gene expression time course experiments (0, 2, 4, 8, 16, 24 Hr) on EA cells following incubation with 100nM ET-1 using quantitative RT-PCR with Taqman chemistries and GAPDH and beta-actin as endogenous controls. We observed increases of CTGF and VEGF expression between 4 and 8 hr for CTGF (1.74 fold increase vs time 0, n=6, P<0.03) and 4 hr for VEGF (2.14 fold increase vs time 0, n=3, P<0.04). Additional experiments on EA cells showed that incubation with 100nM ET-1 for 4 hr in the presence of BQ123 and BQ788, two inhibitors of ET-1 type A and B receptors, respectively, blocked the ET-1 stimulated rises in CTGF and VEGF as well as MCP-1 expression. We then performed western blot analyses (Abcam-CTGF antibody ab6992; Abcam VEGF antibody ab1316) and showed increases in cell associated CTGF protein levels following incubation of EA cells with 100nM ET-1 for 24 hr. The ET-1 stimulated rise in CTGF levels were significantly blunted by pre-incubation of EA cells with both BQ788 and BQ123. To study whether the effects of ET-1 were unique to EA cells, we also analyzed the effects of ET-1 on early cultures of MAEC isolated from C57BLJ mice. Consistent with our observations in human endothelial cells, incubation of MAEC with 100nM ET-1 for 4 hr were associated with increases of CTGF and VEGF expression (1.86 fold vs vehicle, n=3, P<0.03; 1.73 fold vs vehicle, n=3 P<0.04 respectively). Furthermore, ET-1 stimulated rises in CTGF and VEGF expressions were likewise blocked by pre-incubation with BQ123 andBQ788. We conclude that addition of ET-1 leads to activation of endothelial cells and increases in CTGF and VEGF from human and mouse endothelial cells. Thus we suggest that therapies designed to block ET-1 receptors will reduce endothelial cell activation in part by reducing CTGF production leading to alterations in cellular and tissue architecture. This work was supported by NIH R01HL090632 to AR and R01HL096518 to JRR. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Development of Normal and Cleft Palate: A Central Role for Connective Tissue Growth Factor (CTGF)/CCN2

2018 ◽  
Vol 6 (3) ◽  
pp. 18 ◽  
Author(s):  
Joseph Tarr ◽  
Alex Lambi ◽  
James Bradley ◽  
Mary Barbe ◽  
Steven Popoff
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Connective Tissue ◽  
Cleft Palate ◽  
Signaling Pathways ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Altered Expression ◽  
Palate Development ◽  
Wnt Proteins

Development of the palate is the result of an organized series of events that require exquisite spatial and temporal regulation at the cellular level. There are a myriad of growth factors, receptors and signaling pathways that have been shown to play an important role in growth, elevation and/or fusion of the palatal shelves. Altered expression or activation of a number of these factors, receptors and signaling pathways have been shown to cause cleft palate in humans or mice with varying degrees of penetrance. This review will focus on connective tissue growth factor (CTGF) or CCN2, which was recently shown to play an essential role in formation of the secondary palate. Specifically, the absence of CCN2 in KO mice results in defective cellular processes that contribute to failure of palatal shelf growth, elevation and/or fusion. CCN2 is unique in that it has been shown to interact with a number of other factors important for palate development, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), epidermal growth factor (EGF), Wnt proteins and transforming growth factor-βs (TGF-βs), thereby influencing their ability to bind to their receptors and mediate intracellular signaling. The role that these factors play in palate development and their specific interactions with CCN2 will also be reviewed. Future studies to elucidate the precise mechanisms of action for CCN2 and its interactions with other regulatory proteins during palatogenesis are expected to provide novel information with the potential for development of new pharmacologic or genetic treatment strategies for clinical intervention of cleft palate during development.

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