The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

Gregorio, Jacopo Di; Robuffo, Iole; Spalletta, Sonia; Giambuzzi, Giulia; Iuliis, Vincenzo De; Toniato, E; Martinotti, Stefano; Conti, Pio; Flati, Vincenzo

doi:10.3389/fcell.2020.607483

Cited by 99 publications

(89 citation statements)

References 322 publications

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“…TGF-β is a well-known inducer of endothelial-to-mesenchymal transition, representing a critical link in the complex interactions between inflammatory stress and endothelial dysfunction. It is involved in a variety of biological processes that drive the formation of fibrosis, accompanying many disease states [62,63]. Our microarray data suggest, for the first time, that HT treatment reduced the IL-1β up-regulated expression of TGF-β2 and β3 in endothelial cells, thus revealing another mechanistic explanation for the anti-inflammatory and vascular beneficial properties attributed to HT, including a potential antifibrotic effect.…”

Section: Discussionmentioning

confidence: 63%

Nutrigenomic Effect of Hydroxytyrosol in Vascular Endothelial Cells: A Transcriptomic Profile Analysis

et al. 2021

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Hydroxytyrosol (HT), a peculiar olive and olive oil phenolic antioxidant, plays a significant role in the endothelial and cardiovascular protection associated with olive oil consumption. However, studies examining the effects of HT on the whole-genome expression of endothelial cells, which are prominent targets for vasculo-protective effects of olive oil polyphenols, have been lacking. This study aims to comprehensively evaluate the genomic effects exerted by HT, at the transcriptional level, in endothelial cells under resting or proinflammatory conditions. Human umbilical vein endothelial cells (HUVECs) were treated with 10 µmol/L HT for 1 h and then stimulated with 5 ng/mL interleukin (IL)-1β for 3 h. Total RNA was extracted, and gene expression profile assessed with microarray analysis. Functional enrichment analysis and pathway analysis were performed by Ingenuity Pathways Analysis. Microarray data were validated by qRT-PCR. Fixing a significance threshold at 1.5-fold change, HT affected the expression of 708 and 599 genes, respectively, in HUVECs under resting and IL-1β-stimulated conditions; among these, 190 were common to both conditions. Unfolded protein response (UPR) and endoplasmic reticulum stress resulted from the two top canonical pathways common between HT and HT-IL-1β affected genes. IL-17F/A signaling was found in the top canonical pathways of HT modified genes under resting unstimulated conditions, whereas cardiac hypertrophy signaling was identified among the pathways affected by HT-IL-1β. The transcriptomic analysis allowed pinpointing immunological, inflammatory, proliferative, and metabolic-related pathways as the most affected by HT in endothelial cells. It also revealed previously unsuspected genes and related gene pathways affected by HT, thus broadening our knowledge of its biological properties. The unbiased identification of novel genes regulated by HT improves our understanding of mechanisms by which olive oil prevents or attenuates inflammatory diseases and identifies new genes to be enquired as potential contributors to the inter-individual variation in response to functional food consumption.

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Section: Discussionmentioning

confidence: 63%

Nutrigenomic Effect of Hydroxytyrosol in Vascular Endothelial Cells: A Transcriptomic Profile Analysis

et al. 2021

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“…Consistent with the previous results, the activated form of Smad2/3 significantly increased in TGF-β1-treated CCD-18Co cells. Another critical feature of TGF-β1 is the ability to sustain itself through an autocrine loop inducing its release from fibroblast [21]. TGF-β1neosynthesis in activated-CCD-18Co cells was significantly stimulated by the addition of TGF-β1; however, the Vivomixx ® lysates significantly suppressed the stimulation.…”

Section: Discussionmentioning

confidence: 99%

Soluble Fraction from Lysate of a High Concentration Multi-Strain Probiotic Formulation Inhibits TGF-β1-Induced Intestinal Fibrosis on CCD-18Co Cells

et al. 2021

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Fibrosis is a severe complication of chronic inflammatory disorders, such as inflammatory bowel disease (IBD). Current strategies are not fully effective in treating fibrosis; therefore, innovative anti-fibrotic approaches are urgently needed. TGF-β1 plays a central role in the fibrotic process by inducing myofibroblast differentiation and excessive extracellular matrix (ECM) protein deposition. Here, we explored the potential anti-fibrotic impact of two high concentration multi-strain probiotic formulations on TGF-β1-activated human intestinal colonic myofibroblast CCD-18Co. Human colonic fibroblast CCD-18Co cells were cultured in the presence of TGF-β1 to develop a fibrotic phenotype. Cell viability and growth were measured using the Trypan Blue dye exclusion test. The collagen-I, α-SMA, and pSmad2/3 expression levels were evaluated by Western blot analysis. Fibrosis markers were also analyzed by immunofluorescence and microscopy. The levels of TGF-β1 in the culture medium were assessed by ELISA. The effects of commercially available probiotic products VSL#3® and Vivomixx® were evaluated as the soluble fraction of bacterial lysates. The results suggested that the soluble fraction of Vivomixx® formulation, but not VSL#3®, was able to antagonize the pro-fibrotic effects of TGF-β1 on CCD-18Co cells, being able to prevent all of the cellular and molecular parameters that are related to the fibrotic phenotype. The mechanism underlying the observed effect appeared to be associated with inhibition of the TGF-β1/Smad signaling pathway. To our knowledge, this study provides the first experimental evidence that Vivomixx® could be considered to be a promising candidate against intestinal fibrosis, being able to antagonize TGF-β1 pro-fibrotic effects. The differences that were observed in our fibrosis model between the two probiotics used could be attributable to the different number of strains in different proportions.

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“…Elevated levels of WISP-1 in the renal tubular epithelium of rats were shown to increase the production of fibrotic substances induced by TGFβ ( Yang et al, 2020 ). By upregulating the nuclear expression of bone marrow mesenchymal genes (such as Zeb1, Pai1, and α-SMA) ( DiGregorio, et al, 2020 ), WISP-1 can also promote renal fibrosis and mediate TGF signaling. TGFβ activates Wnt signals by down-regulating the production of DKK-1 ( Akhmetshina et al, 2012 ).…”

Section: Wnt Signaling Pathway and Renal Fibrosismentioning

confidence: 99%

The Wnt Signaling Pathway in Diabetic Nephropathy

Wang

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Diabetic nephropathy (DN) is a serious kidney-related complication of both type 1 and type 2 diabetes mellitus (T1DM, T2DM) and the second major cause of end-stage kidney disease. DN can lead to hypertension, edema, and proteinuria. In some cases, DN can even progress to kidney failure, a life-threatening condition. The precise etiology and pathogenesis of DN remain unknown, although multiple factors are believed to be involved. The main pathological manifestations of DN include mesangial expansion, thickening of the glomerular basement membrane, and podocyte injury. Eventually, these pathological manifestations will lead to glomerulosclerosis, thus affecting renal function. There is an urgent need to develop new strategies for the prevention and treatment of DN. Existing evidence shows that the Wnt signaling cascade plays a key role in regulating the development of DN. Previous studies focused on the role of the Wnt canonical signaling pathway in DN. Subsequently, accumulated evidence on the mechanism of the Wnt non-canonical signaling indicated that Wnt/Ca2+ and Wnt/PCP also have essential roles in the progression of DN. In this review, we summarize the specific mechanisms of Wnt signaling in the occurrence and development of DN in podocyte injury, mesangial cell injury, and renal fibrosis. Also, to elucidate the significance of the Wnt canonical pathway in the process of DN, we uncovered evidence supporting that both Wnt/PCP and Wnt/Ca2+ signaling are critical for DN development.

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The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

Cited by 99 publications

References 322 publications

Nutrigenomic Effect of Hydroxytyrosol in Vascular Endothelial Cells: A Transcriptomic Profile Analysis

Nutrigenomic Effect of Hydroxytyrosol in Vascular Endothelial Cells: A Transcriptomic Profile Analysis

Soluble Fraction from Lysate of a High Concentration Multi-Strain Probiotic Formulation Inhibits TGF-β1-Induced Intestinal Fibrosis on CCD-18Co Cells

The Wnt Signaling Pathway in Diabetic Nephropathy

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