Anti-fibrotic Effects of Synthetic Oligodeoxynucleotide for TGF-β1 and Smad in an Animal Model of Liver Cirrhosis

Kim, Jung-Yeon; An, Hyun‐Jin; Kim, Woon‐Hae; Gwon, Mi‐Gyeong; Gu, Hyemin; Park, Yoon-Yub; Park, Kwan‐Kyu

doi:10.1016/j.omtn.2017.06.022

Cited by 40 publications

(45 citation statements)

References 70 publications

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“…46 CCl4-treated mouse model. 27 In our current study, we found that Nano NiO increased the contents of TGF-β1, p-Smad2, and p-Smad3, and decreased the level of Smad7, implying that TGF-β1/Smad pathway could be involved in Nano NiO-induced liver fibrosis in rats.…”

Section: Effects Of Nano Nio On Tgf-β1 Smad and Mapk Pathways Emtsupporting

confidence: 47%

“…Smad7, as an intracellular inhibitor of TGF‐β1/Smad pathway, interacts with TβRI to provide a negative feedback loop . CCl 4 causes liver fibrosis via Smad signaling pathway, in which TGF‐β1, p‐Smad2, and p‐Smad3 are up‐regulated and Smad7 is down‐regulated, but TGF‐β1/Smad oligodeoxynucleotide effectively prevents the fibrogenesis and collagen deposition in CCl4‐treated mouse model . In our current study, we found that Nano NiO increased the contents of TGF‐β1, p‐Smad2, and p‐Smad3, and decreased the level of Smad7, implying that TGF‐β1/Smad pathway could be involved in Nano NiO‐induced liver fibrosis in rats.…”

Section: Discussionmentioning

confidence: 47%

“…TGF-β1 is an essential profibrotic factor that induces hepatic fibrosis via Smad signaling pathway. 27 TGF-β1 interacts with its type II receptor (TβRII), type I receptor (TβRI), p-Smad2, p-Smad3, and Smad4, then they are all combined and transferred into the nucleus. Smad7, as an intracellular inhibitor of TGF-β1/Smad pathway, interacts with TβRI to provide a negative feedback loop.…”

Section: Effects Of Nano Nio On Tgf-β1 Smad and Mapk Pathways Emtmentioning

confidence: 99%

“…24,25 Liver fibrosis is associated with the accumulation of activated fibroblasts and EMT occurrence. 26 EMT occurrence is related to the activation of Smad-dependent pathway 27 and mitogen activated protein kinase (MAPK) pathway which is mediated by TGF-β1. 28 Smads act as central intracellular effectors of TGF-β1.…”

mentioning

confidence: 99%

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TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

Zhang

Chang

Wang

et al. 2019

Environmental Toxicology

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Nickel oxide nanoparticles (Nano NiO) bears hepatotoxicity, while whether it leads to liver fibrosis remains unclear. The aim of this study was to establish the Nano NiO‐induced hepatic fibrosis model in vivo and investigate the roles of transforming growth factor β1 (TGF‐β1) in Smad pathway activation, epithelial‐mesenchymal transition (EMT) occurrence, and extracellular matrix (ECM) deposition in vitro. Male Wistar rats were exposed to 0.015, 0.06, and 0.24 mg/kg Nano NiO by intratracheal instilling twice a week for 9 weeks. HepG2 cells were treated with 100 μg/mL Nano NiO and TGF‐β1 inhibitor (SB431542) to explore the mechanism of collagen formation. Results of Masson staining as well as the elevated levels of type I collagen (Col‐I) and Col‐III suggested that Nano NiO resulted in hepatic fibrosis in rats. Furthermore, Nano NiO increased the protein expression of TGF‐β1, p‐Smad2, p‐Smad3, alpha‐smooth muscle actin (α‐SMA), matrix metalloproteinase9 (MMP9), and tissue inhibitors of metalloproteinase1 (TIMP1), while decreased the protein content of E‐cadherin and Smad7 in rat liver and HepG2 cells. Most importantly, Nano NiO‐triggered the abnormal expression of the abovementioned proteins were all alleviated by co‐treatment with SB431542, implying that TGF‐β1‐mediated Smad pathway, EMT and MMP9/TIMP1 imbalance were involved in overproduction of collagen in HepG2 cells. In conclusion, these findings indicated that Nano NiO induced hepatic fibrosis via TGF‐β1‐mediated Smad pathway activation, EMT occurrence, and ECM deposition.

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Section: Effects Of Nano Nio On Tgf-β1 Smad and Mapk Pathways Emtsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 47%

Section: Effects Of Nano Nio On Tgf-β1 Smad and Mapk Pathways Emtmentioning

confidence: 99%

mentioning

confidence: 99%

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TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

Zhang

Chang

Wang

et al. 2019

Environmental Toxicology

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“…A few researches were conducted in vitro based on activated HSCs (Li et al, ; Sun, Zhang, Li, Yu, & Fu, ). Furthermore, transforming growth factor β1 (TGF‐β1) was regarded as a multifunctional cytokine demonstrating pro‐fibrotic effects through activation of Smad signaling pathways (Kim et al, ). In this study, we investigated the anti‐fibrotic ability of miR‐182 and its underlying mechanism using TGF‐β1 activated LX‐2 cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of miR‐182 on hepatic fibrosis induced by Schistosomiasis japonica by targeting FOXO1 through PI3K/AKT signaling pathway

Huang

Fan

Tao

et al. 2018

Journal Cellular Physiology

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The study aimed to investigate the impact of miR-182 and FOXO1 on S. japonica-induced hepatic fibrosis. Microarray analysis was performed to screen out differential expressed miRNAs and mRNAs. Rat hepatic fibrosis model and human hepatocellular cell line LX-2 were used to study the effect of miR-182 and FOXO1. qRT-PCR and Western blot were used to detect the expression of miR-182, FOXO1 or other fibrosis markers. The targeting relationship between FOXO1 and miR-182 was verified by luciferase reporter assay. Immunohistochemistry or immunofluorescence staining was conducted to detect FOXO1 or α-SMA in rat hepatic tissues. Cell viability and apoptosis were detected by MTT assay and flow cytometry. The expression of PI3K/AKT pathway-related proteins was detected by Western blot. miR-182 was highly expressed in liver fibrosis samples, and FOXO1 expression was negatively correlated with miR-182 expression. After transfection of miR-182, FOXO1 expression was down-regulated, with the results of LX-2 cells proliferation inhibition and apoptosis induction, as well as the aggravation of rat hepatic fibrosis. The expression of p-AKT/AKT and p-S6/S6 was increased, meaning that the PI3K/AKT signal pathway was activated. The results were reversed when treated with Wortmannin (PI3K inhibitor). After transfection of miR-182 inhibitor, FOXO1 expression was up-regulated, LX-2 cell proliferation was inhibited, and apoptosis rate was increased. High-expressed miR-182 and low-expressed FOXO1 promoted proliferation and inhibiting apoptosis on liver fibrosis cells, stimulating the development of S. japonica-induced hepatic fibrosis through feeding back to PI3K/AKT signaling pathway.

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Mechanism of epithelial‐mesenchymal transition in cancer and its regulation by natural compounds

Ang

Mohan

Shanmugam

et al. 2023

Medicinal Research Reviews

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Epithelial‐mesenchymal transition (EMT) is a complex process with a primordial role in cellular transformation whereby an epithelial cell transforms and acquires a mesenchymal phenotype. This transformation plays a pivotal role in tumor progression and self‐renewal, and exacerbates resistance to apoptosis and chemotherapy. EMT can be initiated and promoted by deregulated oncogenic signaling pathways, hypoxia, and cells in the tumor microenvironment, resulting in a loss‐of‐epithelial cell polarity, cell–cell adhesion, and enhanced invasive/migratory properties. Numerous transcriptional regulators, such as Snail, Slug, Twist, and ZEB1/ZEB2 induce EMT through the downregulation of epithelial markers and gain‐of‐expression of the mesenchymal markers. Additionally, signaling cascades such as Wnt/β‐catenin, Notch, Sonic hedgehog, nuclear factor kappa B, receptor tyrosine kinases, PI3K/AKT/mTOR, Hippo, and transforming growth factor‐β pathways regulate EMT whereas they are often deregulated in cancers leading to aberrant EMT. Furthermore, noncoding RNAs, tumor‐derived exosomes, and epigenetic alterations are also involved in the modulation of EMT. Therefore, the regulation of EMT is a vital strategy to control the aggressive metastatic characteristics of tumor cells. Despite the vast amount of preclinical data on EMT in cancer progression, there is a lack of clinical translation at the therapeutic level. In this review, we have discussed thoroughly the role of the aforementioned transcription factors, noncoding RNAs (microRNAs, long noncoding RNA, circular RNA), signaling pathways, epigenetic modifications, and tumor‐derived exosomes in the regulation of EMT in cancers. We have also emphasized the contribution of EMT to drug resistance and possible therapeutic interventions using plant‐derived natural products, their semi‐synthetic derivatives, and nano‐formulations that are described as promising EMT blockers.

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Anti-fibrotic Effects of Synthetic Oligodeoxynucleotide for TGF-β1 and Smad in an Animal Model of Liver Cirrhosis

Cited by 40 publications

References 70 publications

TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

Effect of miR‐182 on hepatic fibrosis induced by Schistosomiasis japonica by targeting FOXO1 through PI3K/AKT signaling pathway

Mechanism of epithelial‐mesenchymal transition in cancer and its regulation by natural compounds

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