LncRNA HOTAIR promotes endometrial fibrosis by activating TGF-β1/Smad pathway

2020 ◽  
Vol 52 (12) ◽  
pp. 1337-1347
Author(s):  
Jianhong Wu ◽  
Lingge Jin ◽  
Yudi Zhang ◽  
Aihong Duan ◽  
Juhong Liu ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Option ◽  
Quantitative Polymerase Chain Reaction ◽  
Endometrial Stromal Cells ◽  
Expression Levels ◽  
Non Coding Rna ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Abstract Homeobox transcript antisense RNA (HOTAIR) is a long non-coding RNA associated with a number of fibrosis-related diseases. The aim of this study was to investigate the specific role of HOTAIR in the development of endometrial fibrosis and to identify the molecular mechanisms underlying this process. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of HOTAIR in samples of intrauterine adhesion (IUA) tissue and in endometrial stromal cells (ESCs) that had been treated with transforming growth factor beta 1 (TGF-β1). Additionally, we transfected ESCs with either overexpression plasmid (pcDNA-HOTAIR) or silencing construct (si-HOTAIR) and then treated these cells with TGF-β1. We then performed RT-qPCR and western blot analysis, along with cell proliferation and apoptosis assays, to investigate the effects of HOTAIR on the transdifferentiation of ESCs into myofibroblasts. The results showed that the expression levels of HOTAIR were significantly elevated in IUA tissue and in ESCs that had been treated with TGF-β1. The overexpression of HOTAIR had a pro-fibrotic effect on ESCs, while the silencing of HOTAIR exerted an anti-fibrotic effect. Most importantly, the protein expression levels of p-Smad2 and p-Smad3 were significantly upregulated in TGF-β1-treated ESCs transfected with pcDNA-HOTAIR and were downregulated after transfection with si-HOTAIR constructs. These data indicate that HOTAIR promotes endometrial fibrosis by activating the TGF-β1/Smad signaling pathway, suggesting that the inhibition of HOTAIR may represent a promising therapeutic option for suppressing endometrial fibrosis.

Effect of intestinal colonisation by two Lactobacillus strains on the immune response of gnotobiotic mice

2014 ◽  
Vol 5 (4) ◽  
pp. 409-419 ◽  
Author(s):  
R.S. Steinberg ◽  
M. Lima ◽  
N.L. Gomes de Oliveira ◽  
A. Miyoshi ◽  
J.R. Nicoli ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Necrosis Factor Alpha ◽  
Interleukin 5 ◽  
Germ Free ◽  
Intestinal Colonisation ◽  
Tnf Α ◽  
Tgf Β1 ◽  
Intragastric Gavage

The effect of intestinal colonisation on the immune system was investigated in germ-free mice monoassociated with Lactobacillus strains isolated from calf faeces. Single doses of Lactobacillus acidophilus L36 or Lactobacillus salivarius L38 were administered to germ-free mice by intragastric gavage. Ten days later, the mice were euthanised. Gene expression levels of interleukin 5 (IL-5), IL-6, IL-10, IL-12b, IL-17a, gamma interferon (IFN-γ), transforming growth factor beta 1 (TGF-β1), and tumour necrosis factor alpha (TNF-α) were quantified in segments of the small and large intestines by real time quantitative polymerase chain reaction. All the mice were colonised rapidly after Lactobacillus administration with intestinal counts ranging from 6.53 to 8.26 log cfu/g. L. acidophilus L36 administration increased the expression of cytokines involved with the Th2 (IL-5, IL-6 and TGF-β1) and Th17 (IL-17a, TNF-α and IL-6) inflammatory response, whereas L. salivarius L38 appeared to stimulate a pattern of less diversified cytokines in the intestine. Intragastric gavage of L. acidophilus L36 and L. salivarius L38 induced similar levels of colonisation in the digestive tracts of germ-free mice but stimulated different immune responses in the intestinal mucosa. The different immunomodulation patterns might facilitate the potential use of these lactobacilli as probiotics to treat distinct pathological conditions, for example protection against Citrobacter rodentium infection by stimulating IL-17 production.

scholarly journals Fallopia Japonica and Prunella Vulgaris Inhibit Myopia Progression by Suppressing Akt and NFκB Mediated Inflammatory Reactions

2021 ◽  
Author(s):  
Chia-Hung Lin ◽  
Chih-Sheng Chen ◽  
Yao-Chien Wang ◽  
En-Shyh Lin ◽  
Ching-Yao Chang ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Axial Length ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Retinal Pigment Epithelial Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Myopia Progression ◽  
Rpe Cells ◽  
Expression Levels

The increased global incidence of myopia requires the establishment of therapeutic approaches. Previous studies have suggested that inflammation plays an important role in the development and progression of myopia. We used human retinal pigment epithelial cell to study the molecular mechanisms on how FJE and PVE lowering the inflammation of the eye. The effect of FJE and PVE in MFD induced hamster model and explore the role of inflammation cytokines in myopia. Expression levels of IL-6, IL-8, and TNF-α were upregulated in retinal pigment epithelium (RPE) cells treated with IL-6 and TNF-α. FJ extract (FJE) + PV extract (PVE) reduced IL-6, IL-8, and TNF-α expression in RPE cells. Furthermore, FJE and PVE inhibited inflammation by attenuating the phosphorylation of protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway. In addition, we report two resveratrol + ursolic acid compounds from FJ and PV and their inhibitory activities against IL-6, IL-8, and TNF-α expression levels in RPE cells treated with IL-6 and TNF-α. FJE, PVE, and FJE + PVE were applied to MFD hamsters and their axial length was measured after 21 days. The axial length showed statistically significant differences between phosphate-buffered saline- and FJE-, PVE-, and FJE + PVE-treated MFD eyes. FJE + PVE suppressed expressions of IL-6, IL-8, and TNF-α. They also inhibited myopia-related transforming growth factor-beta (TGF)-β1, matrix metalloproteinase (MMP)-2, and NF-κB expression while increasing type Ⅰ collagen expression. Overall, these results suggest that FJE + PVE may have a therapeutic effect on myopia and be used as a potential treatment option.

The Role of TGF-β Signaling Regulatory MicroRNAs in the Pathogenesis of Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4611-4618 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Majid Khazaei ◽  
Gordon A. Ferns ◽  
Seyed H. Aghaee-Bakhtiari
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Growth Factor Beta ◽  
And Migration ◽  
Multiple Signaling ◽  
Tgf Β1

Colorectal cancer (CRC) is one of the most common cancers globally and is associated with a high mortality rate. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in normal intestinal tissue function, but has also been implicated in the development of CRC. MicroRNAs (miRNAs) have also recently emerged as important regulators of cancer development and progression. They act by targeting multiple signaling pathways including the TGF-β signaling pathway. There is growing evidence demonstrating that miRNAs target various components of the TGF-β signaling pathway, including TGF-β1, TGF-β2, regulatory SMADs (SMAD1, 2, 3, 5 and 9), co-mediator SMAD4, inhibitory SMADs (SMAD6 and 7) and the TGF-β receptors, and thereby alter the proliferation and migration of CRC cells. In this review, we summarize the data concerning the interaction between TGF-β signaling pathway and miRNAs with the aim to better understanding the CRC molecular mechanisms and hence better management of this disease.

scholarly journals Hypoxia Promotes Ectopic Adhesion Ability of Endometrial Stromal Cells via TGF-β1/Smad Signaling in Endometriosis

Endocrinology ◽  
2018 ◽  
Vol 159 (4) ◽  
pp. 1630-1641 ◽  
Author(s):  
Xiang Lin ◽  
Yongdong Dai ◽  
Wenzhi Xu ◽  
Libing Shi ◽  
Xiaoying Jin ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Integrin Expression ◽  
Normal Endometrium ◽  
Endometrial Stromal Cells ◽  
Adhesion Properties ◽  
Expression Levels ◽  
Smad Signaling ◽  
Adhesion Ability ◽  
Tgf Β1

Abstract Hypoxia plays a vital role in the progression of endometriosis. Additionally, integrin-mediated aberrant adhesion is also essential for establishment of endometriotic lesions. In this study, we sought to determine the function of hypoxia in integrin-mediated adhesion of endometrial stromal cells (ESCs) in endometriosis. The expressions of adhesion molecule integrins (integrin α5, integrin αV, integrin β3, and integrin β5) were determined in 15 normal endometria and 15 paired eutopic and ectopic endometria by immunohistochemistry. Thirteen primary ESCs from patients with peritoneal endometriosis in the proliferative phase were cultured under a hypoxic (1% O2) or normoxic (21% O2) environment, and the expression levels of hypoxia-inducible factor (HIF)-1α, transforming growth factor (TGF)-β1, and integrins were detected by quantitative reverse transcription polymerase chain reaction and western blot. The alteration of integrins in endometriotic mouse models were also explored. Our results demonstrated that HIF-1α and integrins were highly expressed in ESCs of endometriotic lesions compared with ESCs of eutopic and normal endometrium. Hypoxia treatment significantly increased ESC adhesion abilities and integrin expression, which were positively correlated with TGF-β1 expression. Both TGF-β1 and hypoxia enhanced ESC adhesion properties, whereas hypoxia combined with TGF-β1 receptor inhibitor inhibited ESC adhesion. Knockdown of HIF-1α attenuated TGF-β1/Smad signaling activation and integrin expression and reduced ESC adhesion. Higher expression levels of HIF-1α, TGF-β1, and integrins were detected in endometriotic cysts from mice models. Our findings provide a novel insight of endometriosis that the hypoxic microenvironment stimulates ESCs to produce excessive TGF-β1 and activates the TGF-β1/Smad signaling pathway, thus enhancing integrin expression and the adhesion ability of ESCs.

scholarly journals MicroRNA-485 Modulates the TGF-β/ Smads Signaling Pathway in Chronic Asthmatic Mice by Targeting Smurf2

2018 ◽  
Vol 51 (2) ◽  
pp. 692-710 ◽  
Author(s):  
Jing Wang ◽  
Hong-Yan Li ◽  
Hu-Shan Wang ◽  
Zhen-Bo  Su
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Transforming Growth Factor Β ◽  
Airway Smooth Muscle Cell ◽  
Cell Cycle Distribution ◽  
Chronic Asthma ◽  
Expression Levels ◽  
Tgf Β1

Background/Aims: Chronic respiratory conditions continue to plague millions of people worldwide. We aimed to elucidate the detailed mechanisms of microRNA-485 (miR-485) in airway smooth muscle cell (ASMC) proliferation and apoptosis in chronic asthmatic mice. Methods: A mouse model of chronic asthma was established. Ovalbumin was used to induce chronic asthma in the mice. The levels of transforming growth factor β (TGF-β), interleukin (IL)-4, IL-5, IL-13 and IL-17 in bronchoalveolar lavage fluid in mice were measured by enzyme-linked immunoassays (ELISAs). ASMCs were transfected with miR-485 mimic, miR-485 inhibitor and siRNA-Smurf2. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analyses were applied to detect the mRNA and protein levels of Smurf2, α-SMA, TGF-β1 and decapentaplegic homolog (Smads). The MTT assay was utilized for cell proliferation, while flow cytometry was conducted to assess cell cycle distribution and apoptosis. Results: Lower expression of miR-485 and higher expression levels of TGF-β1, IL-4, IL-5, IL-13 and IL-17 were detected in mice with chronic asthma. Smurf2 was identified as the target gene of miR-485. Upregulation of miR-485 mimic and downregulation of Smurf2 decreased expression levels of Smurf2, α-SMA, TGF-β1 and Smad3, inhibited cell proliferation and increased apoptosis, while contrary results were observed in ASMCs transfected with miR-485 inhibitor. Conclusion: Overexpressed miR-485 inhibits cell proliferation and promotes apoptosis of ASMCs through the Smurf2-mediated TGF-β/Smads signaling pathway in mice with chronic asthma.

scholarly journals TGF-β1 and Its Signal Transduction Pathways: Are They Corelated With The Elastic Characteristics of Breast Lesions?

2021 ◽  
Author(s):  
Meng Ke Zhang ◽  
Shi Yu Li ◽  
Bo Wang ◽  
Gang Liu ◽  
Zhi Li Wang
Keyword(s):  
Signal Transduction ◽  
P38 Mapk ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Shear Wave Elastography ◽  
Signal Transduction Pathways ◽  
Breast Lesions ◽  
Expression Levels ◽  
Tgf Β1 ◽  
Elastic Characteristics

Abstract Background: Shear wave elastography (SWE) can evaluate the tissue stiffness. Previous studies showed that the elastic characteristics of breast lesions were related to the components of extracellular matrix (ECM) which was directly or indirectly regulated by transforming growth factor beta 1(TGF-β1). However, it is rarely reported whether there is a correlation between TGF-β1 and the elastic characteristics of breast lesions. The purpose of this study was to investigate the relationship between TGF-β1 with its signal transduction pathways and the elastic characteristics of breast lesions.Methods: 135 breast lesions in 130 patients were included. Before operation or biopsy, SWE was performed. Elastic characteristics such as the maximum, mean, minimum and standard deviation (SD) of elastic modulus (Emax, Emean, Emin, Esd), the elastic ratio of the lesions to the peripheral tissue (Eratio) and the "stiff rim sign" were recorded. The expression levels of TGF-β1, Smad2/3, Erk1/2, p38 MAPK, JNK2, PI3K and AKT were detected by immunohistochemistry. The elastic characteristics and the expression levels of the above-mentioned indexes of benign lesions were were analyzed.Results: Emax, Emean, Esd, Eratio, “stiff rim sign” detection rate and the expression levels of TGF- β 1, et al. of benign were lower than those of malignant lesions (P＜0.0001). The expression levels of TGF- β 1, Smad2/3, Erk1/2, p38 MAPK, JNK2, PI3K and AKT were correlated with Emax, Emean, Esd, Eratio of breast lesions, the expression levels of TGF- β 1, et al. of lesions with “stiff rim sign” were higher than those of lesions without “stiff rim sign” (P＜0.05). And the expression levels of Smad2/3, Erk1/2, p38 MAPK, JNK2, PI3K and AKT were corelated with that of TGF- β 1 (r=0.678, 0.633, 0.645, 0.611, 0.589, 0.663, P＜0.0001).Conclusions: The expression levels of TGF-β1, et al. of breast lesions were corelated with the elastic characteristics, the expression levels of Smad2/3, Erk1/2, p38 MAPK, JNK2, PI3K and AKT were corelated with that of TGF- β 1, which speculated that TGF- β 1 might play an important role in the stiffness regulation of breast lesions through multiple signal transduction pathways.

Cryptolepine derivative-6h inhibits liver fibrosis in TGF-β1-induced HSC-T6 cells by targeting the Shh pathway

2016 ◽  
Vol 94 (9) ◽  
pp. 987-995 ◽  
Author(s):  
Ying-Hua He ◽  
Zeng Li ◽  
Ming-Ming Ni ◽  
Xing-Yan Zhang ◽  
Ming-Fang Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Type I ◽  
African Countries ◽  
Shh Pathway ◽  
Tgf Β1

Liver fibrosis is a worldwide problem with a significant morbidity and mortality. Cryptolepis sanguinolenta (family Periplocaceae) is widely used in West African countries for the treatment of malaria, as well as for some other diseases. However, the role of C. sanguinolenta in hepatic fibrosis is still unknown. It has been reported that Methyl-CpG binding protein 2 (MeCP2) had a high expression in liver fibrosis and played a central role in its pathobiology. Interestingly, we found that a cryptolepine derivative (HZ-6h) could inhibit liver fibrosis by reducing MeCP2 expression, as evidenced by the dramatic downregulation of α-smooth muscle actin (α-SMA) and type I collagen alpha-1 (Col1α1) in protein levels in vitro. Meanwhile, we also found that HZ-6h could reduce the cell viability and promote apoptosis of hepatic stellate cells (HSCs) treated with transforming growth factor beta 1(TGF-β1). Then, we investigated the potential molecular mechanisms and found that HZ-6h blocked Shh signaling in HSC-T6 cells, resulting in the decreased protein expression of Patched-1 (PTCH-1), Sonic hedgehog (Shh), and glioma-associated oncogene homolog 1 (GLI1). In short, these results indicate that HZ-6h inhibits liver fibrosis by downregulating MeCP2 through the Shh pathway in TGF-β1-induced HSC-T6 cells.

scholarly journals Microcurrent Stimulation Triggers MAPK Signaling and TGF-β1 Release in Fibroblast and Osteoblast-Like Cell Lines

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1924
Author(s):  
Evangelia Konstantinou ◽  
Zoi Zagoriti ◽  
Anastasia Pyriochou ◽  
Konstantinos Poulas
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor Beta ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Healing Process ◽  
Mapk Signaling ◽  
Tgf Β1

Wound healing constitutes an essential process for all organisms and involves a sequence of three phases. The disruption or elongation of any of these phases can lead to a chronic or non-healing wound. Electrical stimulation accelerates wound healing by mimicking the current that is generated in the skin after any injury. Here, we sought to identify the molecular mechanisms involved in the healing process following in vitro microcurrent stimulation—a type of electrotherapy. Our results concluded that microcurrents promote cell proliferation and migration in an ERK 1/2- or p38-dependent way. Furthermore, microcurrents induce the secretion of transforming growth factor-beta-1 (TGF-β1) in fibroblasts and osteoblast-like cells. Interestingly, transcriptomic analysis uncovered that microcurrents enhance the transcriptional activation of genes implicated in Hedgehog, TGF-β1 and MAPK signaling pathways. Overall, our results demonstrate that microcurrents may enhance wound closure through a combination of signal transductions, via MAPK’s phosphorylation, and the transcriptional activation of specific genes involved in the healing process. These mechanisms should be further examined in vivo, in order to verify the beneficial effects of microcurrents in wound or fracture healing.

scholarly journals Comparison of Cellular Responses to TGF-β1 and BMP-2 Between Healthy and Torn Tendons

2021 ◽  
Vol 49 (7) ◽  
pp. 1892-1903
Author(s):  
Wataru Morita ◽  
Sarah J.B. Snelling ◽  
Kim Wheway ◽  
Bridget Watkins ◽  
Louise Appleton ◽  
...  
Keyword(s):  
Cell Signaling ◽  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cruciate Ligament ◽  
Quantitative Polymerase Chain Reaction ◽  
Tendon Healing ◽  
Reaction Cell ◽  
Isolated Cells ◽  
Tgf Β1

Background: Tendons heal by fibrotic repair, increasing the likelihood of reinjury. Animal tendon injury and overuse models have identified transforming growth factor beta (TGF-β) and bone morphogenetic proteins (BMPs) as growth factors actively involved in the development of fibrosis, by mediating extracellular matrix synthesis and cell differentiation. Purpose: To understand how TGF-β and BMPs contribute to fibrotic processes using tendon-derived cells isolated from healthy and diseased human tendons. Study Design: Controlled laboratory study. Methods: Tendon-derived cells were isolated from patients with a chronic rotator cuff tendon tear (large to massive, diseased) and healthy hamstring tendons of patients undergoing anterior cruciate ligament repair. Isolated cells were incubated with TGF-β1 (10 ng/mL) or BMP-2 (100 ng/mL) for 3 days. Gene expression was measured by real-time quantitative polymerase chain reaction. Cell signaling pathway activation was determined by Western blotting. Results: TGF-β1 treatment induced ACAN mRNA expression in both cell types but less in the diseased compared with healthy cells ( P < .05). BMP-2 treatment induced BGN mRNA expression in healthy but not diseased cells ( P < .01). In the diseased cells, TGF-β1 treatment induced increased ACTA2 mRNA expression ( P < .01) and increased small mothers against decapentaplegic (SMAD) signaling ( P < .05) compared with those of healthy cells. Moreover, BMP-2 treatment induced ACTA2 mRNA expression in the diseased cells only ( P < .05). Conclusion: Diseased tendon–derived cells show reduced expression of the proteoglycans aggrecan and biglycan in response to TGF-β1 and BMP-2 treatments. These same treatments induced enhanced fibrotic differentiation and canonical SMAD cell signaling in diseased compared with healthy cells. Clinical Relevance: Findings from this study suggest that diseased tendon–derived cells respond differently than healthy cells in the presence of TGF-β1 and BMP-2. The altered responses of diseased cells may influence fibrotic repair processes during tendon healing.

scholarly journals The Expression of BNP, ET-1, and TGF-β1 in Myocardium of Rats with Ventricular Arrhythmias

2019 ◽  
Vol 20 (23) ◽  
pp. 5845 ◽  
Author(s):  
Tian ◽  
Xiao ◽  
Xue ◽  
Zhang ◽  
Jia ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Type I ◽  
Rat Myocardium ◽  
Novel Biomarkers ◽  
Growth Factor Beta ◽  
Polymerase Chain ◽  
Tgf Β1

Ventricular arrhythmia (VA) is a major component of sudden cardiac death (SCD). To investigate the expression of brain natriuretic peptide (BNP), endothelin-1 (ET-1), and transforming growth factor-beta 1 (TGF-β1) during VA, we established a rat model of VA induced by BaCl2 solution through a microinjector pump. PD142893 (ET-1 receptor blocker) and SB431542 (TGF-β1 receptor type I blocker) were used to explore the effect of ET-1 and TGF-β1 on BNP expression in the myocardium after VA. BNP, ET-1, and TGF-β1 in rat myocardium were assayed by western blot and immunohistochemical staining for proteins, and real-time quantitative polymerase chain reaction for mRNAs. We found increased expression of BNP and ET-1 in rat myocardium that was associated with the duration of VA. However, TGF-β1 protein expression remained unchanged. Such early increases in BNP and ET-1 may be attributed to fatal arrhythmias associated with SCD, suggesting these may be novel biomarkers of this disease. After intraperitoneal injection of PD142893 and SB431542, respectively, BNP was downregulated in the myocardium of the left ventricle; however, this was abrogated by co-application of the two inhibitors. These results suggested that both ET-1 and TGF-β1, by specifically binding to their receptors, might be involved in the myocardial synthesis of BNP during VA in vivo.

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