scholarly journals A Flowable Placental Formulation Prevents Bleomycin-Induced Dermal Fibrosis in Aged Mice

2020 ◽  
Vol 21 (12) ◽  
pp. 4242
Author(s):  
Sandeep Dhall ◽  
Anne Lerch ◽  
Nicholas Johnson ◽  
Vimal Jacob ◽  
Brielle Jones ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Epithelial Mesenchymal Transition ◽  
Cell Types ◽  
Treated Group ◽  
Inflammatory Factors ◽  
Control Group ◽  
Sequencing Analysis ◽  
Mesenchymal Transition ◽  
Aged Mice ◽  
Dermal Fibrosis

Fibrosis, the thickening and scarring of injured connective tissue, leads to a loss of organ function. Multiple cell types, including T-cells, macrophages, fibrocytes, and fibroblasts/myofibroblasts contribute to scar formation via secretion of inflammatory factors. This event results in an increase in oxidative stress and deposition of excessive extracellular matrix (ECM), characteristic of fibrosis. Further, aging is known to predispose connective tissue to fibrosis due to reduced tissue regeneration. In this study, we investigated the anti-fibrotic activity of a flowable placental formulation (FPF) using a bleomycin-induced dermal fibrosis model in aged mice. FPF consisted of placental amnion/chorion- and umbilical tissue-derived ECM and cells. The mice were injected with either FPF or PBS, followed by multiple doses of bleomycin. Histological assessment of FPF-treated skin samples revealed reduced dermal fibrosis, inflammation, and TGF-β signaling compared to the control group. Quantitative RT-PCR and Next Generation Sequencing analysis of miRNAs further confirmed anti-fibrotic changes in the FPF-treated group at both the gene and transcriptional levels. The observed modulation in miRNAs was associated with inflammation, TGF-β signaling, fibroblast proliferation, epithelial-mesenchymal transition and ECM deposition. These results demonstrate the potential of FPF in preventing fibrosis and may be of therapeutic benefit for those at higher risk of fibrosis due to wounds, aging, exposure to radiation and genetic predisposition.

scholarly journals L19-IL2 Immunocytokine in Combination with the Anti-Syndecan-1 46F2SIP Antibody Format: A New Targeted Treatment Approach in an Ovarian Carcinoma Model

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1232 ◽  
Author(s):  
Paola Orecchia ◽  
Enrica Balza ◽  
Gabriella Pietra ◽  
Romana Conte ◽  
Nicolò Bizzarri ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Vasculogenic Mimicry ◽  
Treated Group ◽  
Targeted Treatment ◽  
Control Group ◽  
Female Population ◽  
Mesenchymal Transition

Epithelial ovarian cancer (EOC) is the fifth most common cancer affecting the female population. At present, different targeted treatment approaches may improve currently employed therapies leading either to the delay of tumor recurrence or to disease stabilization. In this study we show that syndecan-1 (SDC1) and tumor angiogenic-associated B-fibronectin isoform (B-FN) are involved in EOC progression and we describe the prominent role of SDC1 in the vasculogenic mimicry (VM) process. We also investigate a possible employment of L19-IL2, an immunocytokine specific for B-FN, and anti-SDC1 46F2SIP (small immuno protein) antibody in combination therapy in a human ovarian carcinoma model. A tumor growth reduction of 78% was obtained in the 46F2SIP/L19-IL2-treated group compared to the control group. We observed that combined treatment was effective in modulation of epithelial-mesenchymal transition (EMT) markers, loss of stemness properties of tumor cells, and in alleviating hypoxia. These effects correlated with reduction of VM structures in tumors from treated mice. Interestingly, the improved pericyte coverage in vascular structures suggested that combined therapy could be efficacious in induction of vessel normalization. These data could pave the way for a possible use of L19-IL2 combined with 46F2SIP antibody as a novel therapeutic strategy in EOC.

scholarly journals MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1074
Author(s):  
Giuseppina Divisato ◽  
Silvia Piscitelli ◽  
Mariantonietta Elia ◽  
Emanuela Cascone ◽  
Silvia Parisi
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Cell Types ◽  
Cancer Development ◽  
Special Focus ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

YAP1 Overexpression Is Associated with Kidney Dysfunction in Lupus Nephritis

Pathobiology ◽  
2021 ◽  
pp. 1-12
Author(s):  
Ying Xie ◽  
Yuanyuan Ruan ◽  
Huimei Zou ◽  
Yixin Wang ◽  
Xin Wu ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Tissue ◽  
Mouse Kidney ◽  
Experimental Comparison ◽  
Control Group ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
Protein Levels

<b><i>Objective:</i></b> The goal of the present study was to determine the expression of yes-associated protein 1 (YAP1) in renal tissues of mice with lupus nephritis (LN) and elucidate its role in the progression of renal fibrosis. <b><i>Methods:</i></b> C57BL/6 mice and MRL/lpr mice were selected for experimental comparison. Mouse kidney tissues were removed and sectioned for hematoxylin and eosin staining, Masson’s trichome staining, Sirius staining, and immunohistochemistry. The mRNA and protein levels of YAP1 in mouse kidney tissues were detected, and the correlation between YAP1 and fibronectin (FN) mRNA levels was analyzed. Mouse renal epithelial cells were used for in vitro experiments. After transfection and stimulation, the cells were divided into 4 groups, namely the C57BL/6 serum group (group 1), the MRL/lpr serum group (group 2), the MRL/lpr serum + siRNA-negative control group (group 3), and the MRL/lpr serum + siRNA-YAP1 group (group 4). Epithelial-mesenchymal transition (EMT) markers in each group were detected by Western blotting and immunofluorescence staining. Serum creatinine, blood urea nitrogen, and urinary protein levels were detected and assessed for their correlation with YAP1 mRNA levels by Spearman’s analysis. <b><i>Results:</i></b> Compared to C57BL/6 mice, MRL/lpr mice exhibited obvious changes in fibrosis in renal tissues. In addition, YAP1 expression was significantly higher in the renal tissues of MRL/lpr mice than in those of C57BL/6 mice, and YAP1 mRNA levels were positively correlated with those of FN. YAP1 silencing in lupus serum-stimulated cells could effectively relieve serum-induced EMT. Finally, we observed that YAP1 mRNA levels in mouse kidney tissue were significantly and positively correlated with the degree of renal function injury. <b><i>Conclusion:</i></b> YAP1 expression in the kidney tissues of LN mice was higher than that observed in normal mice, indicating that YAP1 may play an important role in the occurrence and development of LN.

scholarly journals FERMT3 mediates cigarette smoke-induced epithelial–mesenchymal transition through Wnt/β-catenin signaling

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xiaoshan Su ◽  
Junjie Chen ◽  
Xiaoping Lin ◽  
Xiaoyang Chen ◽  
Zhixing Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Migration ◽  
Cigarette Smoke ◽  
Epithelial Mesenchymal Transition ◽  
Control Group ◽  
Data Set ◽  
Mesenchymal Transition

Abstract Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Epithelial–mesenchymal transition (EMT) is an essential pathophysiological process in COPD and plays an important role in airway remodeling, fibrosis, and malignant transformation of COPD. Previous studies have indicated FERMT3 is downregulated and plays a tumor-suppressive role in lung cancer. However, the role of FERMT3 in COPD, including EMT, has not yet been investigated. Methods The present study aimed to explore the potential role of FERMT3 in COPD and its underlying molecular mechanisms. Three GEO datasets were utilized to analyse FERMT3 gene expression profiles in COPD. We then established EMT animal models and cell models through cigarette smoke (CS) or cigarette smoke extract (CSE) exposure to detect the expression of FERMT3 and EMT markers. RT-PCR, western blot, immunohistochemical, cell migration, and cell cycle were employed to investigate the potential regulatory effect of FERMT3 in CSE-induced EMT. Results Based on Gene Expression Omnibus (GEO) data set analysis, FERMT3 expression in bronchoalveolar lavage fluid was lower in COPD smokers than in non-smokers or smokers. Moreover, FERMT3 expression was significantly down-regulated in lung tissues of COPD GOLD 4 patients compared with the control group. Cigarette smoke exposure reduced the FERMT3 expression and induces EMT both in vivo and in vitro. The results showed that overexpression of FERMT3 could inhibit EMT induced by CSE in A549 cells. Furthermore, the CSE-induced cell migration and cell cycle progression were reversed by FERMT3 overexpression. Mechanistically, our study showed that overexpression of FERMT3 inhibited CSE-induced EMT through the Wnt/β-catenin signaling. Conclusions In summary, these data suggest FERMT3 regulates cigarette smoke-induced epithelial–mesenchymal transition through Wnt/β-catenin signaling. These findings indicated that FERMT3 was correlated with the development of COPD and may serve as a potential target for both COPD and lung cancer.

scholarly journals Mummy Induces Apoptosis Through Inhibiting of Epithelial-Mesenchymal Transition (EMT) in Human Breast Cancer Cells

2020 ◽  
Vol 9 ◽  
pp. 1812
Author(s):  
Solmaz Rahmani Barouji ◽  
Arman Shahabi ◽  
Mohammadali Torbati ◽  
Seyyed Mohammad Bagher Fazljou ◽  
Ahmad Yari Khosroushahi
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Control Group ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
Mcf 7

Background: Mummy (Iranian pure shilajit) is a remedy with possessing anti-inflammatory, antioxidant and anticancer activities. This study aimed to examine mummy effects on epithelial-mesenchymal transition (EMT) and invasiveness of MCF-7 and MDA-MB-231 breast cancer (BC) cell lines with underlying its mechanism. Materials and Methods: The dose-dependent inhibitory effect of the mummy on cell proliferation in vitro was determined using the MTT assay.  Flow cytometry and 4’,6-diamidino-2-phenylindole dihydrochloride staining were respectively used for quantitative and qualitative analysis of cellular apoptosis, and gene expression analysis was conducted using real-time PCR. Results: MDA-MB-231 showed more sensitivity than the MCF-7 cell line to the anticancer activity of mummy, while mummy did not exhibit significant cell cytotoxicity against human normal cells (MCF-10A). The gene expression profile demonstrated a significant decrease in TGF-β1, TGF-βR1, TWIST1, NOTCH1, CTNNB1, SRC along with an increase in E-cadherin mRNA levels in mummy treated cells compared to the untreated control group (P≤0.05). Conclusion: Mummy triggers inhibition of EMT and metastasis in breast cancer cells mainly through the downregulation of TGFβ1 activity, and more studies required to find its specific anticancer activity with details. [GMJ.2020;9:e1812]

scholarly journals Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2413 ◽  
Author(s):  
Asunción Fernández-Barral ◽  
Pilar Bustamante-Madrid ◽  
Gemma Ferrer-Mayorga ◽  
Antonio Barbáchano ◽  
María Jesús Larriba ◽  
...  
Keyword(s):  
Vitamin D ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Cell Types ◽  
Carcinoma Cells ◽  
Dihydroxyvitamin D3 ◽  
Human Carcinoma ◽  
Mesenchymal Transition ◽  
Major Mechanism ◽  
Egf Signaling

Vitamin D3 is the precursor of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), a pleiotropic hormone that is a major regulator of the human genome. 1,25(OH)2D3 modulates the phenotype and physiology of many cell types by controlling the expression of hundreds of genes in a tissue- and cell-specific fashion. Vitamin D deficiency is common among cancer patients and numerous studies have reported that 1,25(OH)2D3 promotes the differentiation of a wide panel of cultured carcinoma cells, frequently associated with a reduction in cell proliferation and survival. A major mechanism of this action is inhibition of the epithelial–mesenchymal transition, which in turn is largely based on antagonism of the Wnt/β-catenin, TGF-β and EGF signaling pathways. In addition, 1,25(OH)2D3 controls the gene expression profile and phenotype of cancer-associated fibroblasts (CAFs), which are important players in the tumorigenic process. Moreover, recent data suggest a regulatory role of 1,25(OH)2D3 in the biology of normal and cancer stem cells (CSCs). Here, we revise the current knowledge of the molecular and genetic basis of the regulation by 1,25(OH)2D3 of the differentiation and stemness of human carcinoma cells, CAFs and CSCs. These effects support a homeostatic non-cytotoxic anticancer action of 1,25(OH)2D3 based on reprogramming of the phenotype of several cell types.

scholarly journals Involvement of Inflammatory Cytokines in Antiarrhythmic Effects of Clofibrate in Ouabain-Induced Arrhythmia in Isolated Rat Atria

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Somayeh Moradi ◽  
Vahid Nikoui ◽  
Muhammad Imran Khan ◽  
Shayan Amiri ◽  
Farahnaz Jazaeri ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Present Experiment ◽  
Treated Group ◽  
Inflammatory Factors ◽  
Control Group ◽  
Rat Atria ◽  
Beating Rate ◽  
Anti Inflammatory ◽  
Isolated Rat ◽  
Antiarrhythmic Effects

Considering the cardioprotective and anti-inflammatory properties of clofibrate, the aim of the present experiment was to investigate the involvement of local and systemic inflammatory cytokines in possible antiarrhythmic effects of clofibrate in ouabain-induced arrhythmia in rats. Rats were orally treated with clofibrate (300 mg/kg), and ouabain (0.56 mg/kg) was administered to animals intraperitoneally. After induction of anesthesia, the atria were isolated and the onset of arrhythmia and asystole was recorded. The levels of inflammatory cytokines in atria were also measured. Clofibrate significantly postponed the onset of arrhythmia and asystole when compared to control group (P≤0.05andP≤0.01, resp.). While ouabain significantly increased the atrial beating rate in control group (P≤0.05), same treatment did not show similar effect in clofibrate-treated group (P>0.05). Injection of ouabain significantly increased the atrial and systemic levels of all studied inflammatory cytokines (P≤0.05). Pretreatment with clofibrate could attenuate the ouabain-induced elevation of IL-6 and TNF-αin atria (P≤0.01andP≤0.05, resp.), as well as ouabain-induced increase in IL-6 in plasma (P≤0.05). Based on our findings, clofibrate may possess antiarrhythmic properties through mitigating the local and systemic inflammatory factors including IL-6 and TNF-α.

scholarly journals Transcriptomic responses to hypoxia in endometrial and decidual stromal cells

2019 ◽  
Author(s):  
Kalle T. Rytkönen ◽  
Taija Heinosalo ◽  
Mehrad Mahmoudian ◽  
Xinghong Ma ◽  
Antti Perheentupa ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Stromal Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cell Types ◽  
Core Gene ◽  
Stromal Fibroblasts ◽  
Mesenchymal Transition ◽  
The Core ◽  
Transcriptomic Responses ◽  
Upregulated Genes

AbstractHuman reproductive success depends on a properly decidualized uterine endometrium that allows implantation and the formation of the placenta. At the core of the decidualization process are endometrial stromal fibroblasts (ESF) that differentiate to decidual stromal cells (DSC). As variations in oxygen levels are functionally relevant in endometrium both upon menstruation and during placentation, we assessed the transcriptomic responses to hypoxia in ESF and DSC. In both cell types hypoxia upregulated genes in classical hypoxia pathways such as glycolysis and the epithelial mesenchymal transition. In DSC hypoxia restored an ESF like transcriptional state for a subset of transcription factors that are known targets of the progesterone receptor, suggesting that hypoxia partially interferes with progesterone signaling. In both cell types hypoxia modified transcription of several inflammatory transcription factors that are known regulators of decidualization, including decreased transcription of STATs and increased transcription of CEBPs. We observed that hypoxia upregulated genes had a significant overlap with genes previously detected to be upregulated in endometriotic stromal cells. Promoter analysis of the genes in this overlap suggested the hypoxia upregulated Jun/Fos and CEBP transcription factors as potential drivers of endometriosis-associated transcription. Using immunohistochemistry we observed increased expression of JUND and CEBPD in endometriosis lesions compared to healthy endometria. Overall the findings suggest that hypoxic stress establishes distinct transcriptional states in ESF and DSC, and that hypoxia influences the expression of genes that contribute to the core gene regulation of endometriotic stromal cells.

scholarly journals Effect and Mechanism of TL1A Expression on Epithelial-Mesenchymal Transition during Chronic Colitis-Related Intestinal Fibrosis

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Jia Wenxiu ◽  
Yang Mingyue ◽  
Han Fei ◽  
Luo Yuxin ◽  
Wu Mengyao ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tumor Necrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Intestinal Inflammation ◽  
Epithelial Mesenchymal Transition ◽  
Lymphoid Cells ◽  
Inflammatory Factors ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis

Background and Aims. Recent evidences reveal that epithelial to mesenchymal transition (EMT) exacerbates the process of intestinal fibrosis. Tumor necrosis factor-like ligand 1A (TL1A) is a member of the tumor necrosis family (TNF), which can take part in the development of colonic inflammation and fibrosis by regulating immune response or inflammatory factors. The purpose of this study was to elucidate the possible contribution of TL1A in onset and progression of intestinal inflammation and fibrosis through EMT. Methods. Colonic specimens were obtained from patients with inflammatory bowel disease (IBD) and control individuals. The expression levels of TL1A and EMT-related markers in intestinal tissues were evaluated. Furthermore, the human colorectal adenocarcinoma cell line, HT-29, was stimulated with TL1A, anti-TL1A antibody, or BMP-7 to assess EMT process. In addition, transgenic mice expressing high levels of TL1A in lymphoid cells were used to further investigate the mechanism of TL1A in intestinal fibrosis. Results. High levels of TL1A expression were detected in the intestinal specimens of patients with ulcerative colitis and Crohn’s disease and were negatively associated with the expression of an epithelial marker (E-cadherin), while it was positively associated with the expression of interstitial markers (FSP1 and α-SMA). Transgenic mice with high expression of TL1A were more sensitive to dextran sodium sulfate and exhibited severe intestinal inflammation and fibrosis. Additionally, the TGF-β1/Smad3 pathway may be involved in TL1A-induced EMT, and the expression of IL-13 and EMT-related transcriptional molecules (e.g., ZEB1 and Snail1) was increased in the intestinal specimens of the transgenic mice. Furthermore, TL1A-induced EMT can be influenced by anti-TL1A antibody or BMP-7 in vitro. Conclusions. TL1A participates in the formation and process of EMT in intestinal fibrosis. This new knowledge enables us to better understand the pathogenesis of intestinal fibrosis and identify new therapeutic targets for its treatment.

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