A potent peptide as adiponectin receptor 1 agonist to against fibrosis

Abstract

Fibrotic diseases have become a major cause of death in the developed world. AdipoR1 agonists are potent inhibitors of fibrotic responses. Here, we focused on the in silico identification of novel AdipoR1 peptide agonists. A homology model was constructed to predict the 3D structure of AdipoR1. By docking to known active peptides, the putative active site of the model was further explored. A virtual screening study was then carried out with a set of manually designed peptides using molecular docking. Peptides with high docking scores were then evaluated for their anti-fibrotic properties. The data indicated that the novel peptide Pep70 significantly inhibited the proliferation of hepatic stellate cells (HSC) and NIH-3T3 cells (18.33% and 27.80%) and resulted in favouring cell-cycle arrest through increasing the accumulation of cells in the G0/G1 phase by 17.08% and 15.86%, thereby reducing the cell population in the G2/M phase by 11.25% and 15.95%, respectively. Additionally, Pep70 exhibited the most marked suppression on the expression of α-smooth muscle actin (α-SMA), collagen type I alpha1 (COL1A1) and TGF-β1. Therefore, the peptide Pep70 was ultimately identified as an inhibitor of fibrotic responses and as a potential AdipoR1 agonist.

Hydrogen inhalation attenuated bleomycin‐induced pulmonary fibrosis by inhibiting transforming growth factor‐β1 and relevant oxidative stress and epithelial‐to‐mesenchymal transition

“…Several profibrogenic cytokines, such as TGF‐β (the major profibrotic mediator) and TNF‐α (a cytokine essential for the induction of the fibrotic response), have been reported to be involved in the aberrant wound‐healing responses and can lead to the development of fibrosis by inducing the differentiation of lung fibroblasts into myofibroblasts, stimulating the accumulation of ECM and the progression of EMT (Ma et al., ; Thakur et al., ). We detected the contents of TGF‐β and TNF‐α in BLM‐induced lung injury after different durations of H 2 inhalation (2, 4 or 8 h per day).…”

“…Inflammation, expressed as an increase in macrophage infiltration and enhanced TNF‐α secretion, plays a fundamental role in the pathogenesis of fibrosis and is closely correlated with the profibrotic effects of many molecules, e.g. angiotensin II, TGF‐β and connective tissue growth factor (Ma et al., ; Qi, Jia, Li, Li, & Du, ). In the present study, upregulated TNF‐α levels were detected in BLM‐induced lung tissues.…”

“…Meanwhile, TGF‐β1 induces ECM protein synthesis and suppresses collagen degradation, leading to collagen deposition and a transition from fibroblasts to myofibroblasts. Thus, TGF‐β1 serves a vital role in promoting the progression of fibrosis (Ma et al., ). Notably, in BLM‐induced pulmonary fibrosis, the content of TGF‐β1 was significantly increased; however, H 2 inhalation attenuated the expression of TGF‐β1 at mRNA and protein levels in pulmonary fibrosis, indicating that TGF‐β1 acts as a positive feedback loop in the progression of BLM‐induced lung fibrosis, and the administration of H 2 by inhalation significantly attenuates the oxidative stress and TGF‐β1 expression.…”

“…TNF‐α, an important pro‐inflammatory factor during chronic tissue injury and inflammation, can stimulate uncontrolled ECM protein deposition, ultimately resulting in fibrosis and organ failure (Thakur, Pritchard, McMullen, & Nagy, ). TGF‐β1 overexpression leads to an increase in fibrosis‐associated gene ( α‐SMA and COL1A1 ) expression, collagen production and ECM deposition in fibrotic tissue (Ma et al., ). Thus, in addition to regulating oxidative stress, TGF‐β1 also promotes EMT, a progression centrally involved in activation of fibroblasts, to accelerate the occurrence and development of fibrosis.…”

“…TNF-, an important pro-inflammatory factor during chronic tissue injury and inflammation, can stimulate uncontrolled ECM protein deposition, ultimately resulting in fibrosis and organ failure (Thakur, Pritchard, McMullen, & Nagy, 2006). TGF-1 overexpression leads to an increase in fibrosis-associated gene ( -SMA and COL1A1) expression, collagen production and ECM deposition in fibrotic tissue (Ma et al, 2017).…”