Piperine ameliorates the severity of fibrosis via inhibition of TGF‑β/SMAD signaling in a mouse model of chronic pancreatitis

Abstract

Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation and fibrosis. Currently, there are no drugs for the treatment of pancreatic fibrosis associated with CP. Piperine, a natural alkaloid found in black pepper, has been reported to show anti-inflammatory, anti-oxidative, and antitumor activities. Although piperine exhibits numerous properties in regards to the regulation of diverse diseases, the effects of piperine on CP have not been established. To investigate the effects of piperine on CP in vivo, we induced CP in mice through the repetitive administration of cerulein (50 µg/kg) six times at 1-h intervals, 5 times per week, for a total of 3 weeks. In the pre-treatment groups, piperine (1, 5, or 10 mg/kg) or corn oil were administrated orally at 1 h before the first cerulein injection, once a day, 5 times a week, for a total of 3 weeks. In the post-treatment groups, piperine (10 mg/kg) or corn oil was administered orally at 1 or 2 week after the first cerulein injection. Pancreases were collected for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the anti-fibrogenic effects and regulatory mechanisms of piperine. Piperine treatment significantly inhibited histological damage in the pancreas, increased the pancreatic acinar cell survival, reduced collagen deposition and reduced pro-inflammatory cytokines and chemokines. In addition, piperine treatment reduced the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, and fibronectin 1 in the pancreas and PSCs. Moreover, piperine treatment reduced the production of transforming growth factor (TGF)-β in the pancreas and PSCs. Furthermore, piperine treatment inhibited TGF-β-induced pSMAD2/3 activation but not pSMAD1/5 in the PSCs. These findings suggest that piperine treatment ameliorates pancreatic fibrosis by inhibiting TGF-β/SMAD2/3 signaling during CP.

Piperine Inhibits TGF-β Signaling Pathways and Disrupts EMT-Related Events in Human Lung Adenocarcinoma Cells

“…The EMT process is characterized by morphological, phenotypic and biochemical alterations, which together influence the behavior of tumor cells of epithelial origin [74]. In the literature, many studies have shown that piperine modulates crucial events related to EMT process, such as cell motility [22], MMP expression and activity [30], expression of mesenchymal proteins [18], as well as the activation of MAPK and SMAD signaling pathways [18,75]. However, so far, no study has demonstrated the ability of piperine to collectively compromise all of these events in cancer cells undergoing EMT.…”

“…Recently, Choi et al [18] demonstrated that in a murine study of chronic pancreatitis, piperine attenuated the production of TGF-β in the pancreas and improved the severity of fibrosis through inhibition of TGF-β/SMAD signaling pathways. The authors also demonstrated that in TGFβ-treated pancreatic stellate cells, piperine reduced the expression of the mesenchyml markers αSMA, FN and collagen.…”

“…Piperine mitigates liver damage prompted by renal ischemia-reperfusion [11] and ameliorates oxidative stress [12,13]. Piperine also has antipyretic [14], analgesic [15], anti-parasitic [16,17] and anti-inflammatory [15,18,19] activities. The anti-tumoral properties are particularly noteworthy because of the current interest in identifying useful natural products for cancer treatment.…”

“…Hwang and colleagues [32] demonstrated that piperine strongly repressed the PMA-induced phosphorylation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) in human cancer cells. More recently, it has been demonstrated that piperine treatment repressed the expression of α-smooth muscle actin (α-SMA), fibronectin (FN) and collagen in the pancreas and pancreatic stellate cells [18]. Furthermore, piperine inhibited the production of TGF-β in the pancreas and pancreatic stellate cells, as well as TGF-β-induced pSMAD 2/3 activation, suggesting that the natural amide ameliorates pancreatic fibrosis by inhibiting the TGF-β/SMAD 2/3 signaling pathway during chronic pancreatitis [18].…”

“…More recently, it has been demonstrated that piperine treatment repressed the expression of α-smooth muscle actin (α-SMA), fibronectin (FN) and collagen in the pancreas and pancreatic stellate cells [18]. Furthermore, piperine inhibited the production of TGF-β in the pancreas and pancreatic stellate cells, as well as TGF-β-induced pSMAD 2/3 activation, suggesting that the natural amide ameliorates pancreatic fibrosis by inhibiting the TGF-β/SMAD 2/3 signaling pathway during chronic pancreatitis [18]. All those events are deeply associated with the epithelial-mesenchymal transition (EMT) process [33][34][35][36], a biological phenomenon that occurs throughout the development of fibrosis, wound-healing, tumor progression, as well as in the emergence of chemotherapy-resistant cancer cells [37,38].…”