Vincamine Ameliorates Epithelial-Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis in Rats; Targeting TGF-β/MAPK/Snai1 Pathway

Abstract

Idiopathic pulmonary fibrosis is a progressive, irreversible lung disease that leads to respiratory failure and death. Vincamine is an indole alkaloid obtained from the leaves of Vinca minor and acts as a vasodilator. The present study aims to investigate the protective activity of vincamine against EMT in bleomycin (BLM)-induced pulmonary fibrosis via assessing the apoptotic and TGF-β1/p38 MAPK/ERK1/2 signaling pathways. In bronchoalveolar lavage fluid, protein content, total cell count, and LDH activity were evaluated. N-cadherin, fibronectin, collagen, SOD, GPX, and MDA levels were determined in lung tissue using ELISA. Bax, p53, bcl2, TWIST, Snai1, and Slug mRNA levels were examined using qRT-PCR. Western blotting was used to assess the expression of TGF-β1, p38 MAPK, ERK1/2, and cleaved caspase 3 proteins. H & E and Masson’s trichrome staining were used to analyze histopathology. In BLM-induced pulmonary fibrosis, vincamine reduced LDH activity, total protein content, and total and differential cell count. SOD and GPX were also increased following vincamine treatment, while MDA levels were decreased. Additionally, vincamine suppressed the expression of p53, Bax, TWIST, Snail, and Slug genes as well as the expression of factors such as TGF-β1, p/t p38 MAPK, p/t ERK1/2, and cleaved caspase 3 proteins, and, at the same time, vincamine increased bcl2 gene expression. Moreover, vincamine restored fibronectin, N-Catherine, and collagen protein elevation due to BLM-induced lung fibrosis. In addition, the histopathological examination of lung tissues revealed that vincamine attenuated the fibrotic and inflammatory conditions. In conclusion, vincamine suppressed bleomycin-induced EMT by attenuating TGF-β1/p38 MAPK/ERK1/2/TWIST/Snai1/Slug/fibronectin/N-cadherin pathway. Moreover, it exerted anti-apoptotic activity in bleomycin-induced pulmonary fibrosis.

Betanin protects against bleomycin-induced pulmonary fibrosis by regulating the NLRP3/IL-1β/TGF-β1 pathway-mediated epithelial-to-mesenchymal transition

“…These results are in agreement with previous studies. 28,29 Moreover, LDH activity in BALF was increased in BLM rats indicating interstitial lung injury, which is in line with previous studies. 29,30 Surprisingly, BET revealed an anti-inflammatory effect emphasized by attenuating total and differential cell counts (neutrophils and lymphocytes counts) and LDH activity.…”

“…28,29 Moreover, LDH activity in BALF was increased in BLM rats indicating interstitial lung injury, which is in line with previous studies. 29,30 Surprisingly, BET revealed an anti-inflammatory effect emphasized by attenuating total and differential cell counts (neutrophils and lymphocytes counts) and LDH activity. This is in harmony with the reported anti-inflammatory effect of BET in lipopolysaccharide-induced acute lung injury in mice.…”

Nebivolol ameliorates sepsis-evoked kidney dysfunction by targeting oxidative stress and TGF-β/Smad/p53 pathway

“…It disclaimed that an elevation in ROS generates sepsispersuaded kidney damage by decreasing the host's anti-oxidant defense mechanisms, leading to cell damage 51,53 . www.nature.com/scientificreports/ Numerous pro-inflammatory and pro-fibrotic signaling networks, including TGF-β1, NF-κB, p53, and MAPK family members, are activated more strongly by ROS and oxidative stress [53][54][55][56] . It was implicated that TGF-β1 has a crucial function in generating EMT and is the driver of kidney fibrogenesis through TGF-β1/Smad/p53 signaling pathways [57][58][59][60] .…”

“…Numerous pro-inflammatory and pro-fibrotic signaling networks, including TGF-β1, NF-κB, p53, and MAPK family members, are activated more strongly by ROS and oxidative stress 53 – 56 . It was implicated that TGF-β1 has a crucial function in generating EMT and is the driver of kidney fibrogenesis through TGF-β1/Smad/p53 signaling pathways 57 – 60 .…”

Insights into the Role of Glutathione Peroxidase 3 in Non-Neoplastic Diseases

“…In vivo models of IPF induced by bleomycin, a chemotherapeutic agent known to cause pulmonary fibrosis via ROS production, have shown a significant reduction in GPX levels in treated groups compared to controls [ 124 , 125 ]. Research by Zeng et al indicated that GPX3 expression is downregulated in the lung tissues of IPF patients, leading to increased oxidative stress and exacerbating the fibrotic phenotype [ 126 ].…”