transforming-growth-factor-beta and piperine

Our goal was to examine the anticancer effects of piperine against the resistant human ovarian cancer cells and to explore the molecular mechanisms responsible for its anticancer effects. Our study used drug-sensitive ovarian cancer cell line W1 and its sublines resistant to paclitaxel (PAC) and topotecan (TOP). We analyzed the cytotoxic effect of piperine and cytostatic drugs using an MTT assay. The impact of piperine on protein expression was determined by immunofluorescence and Western blot. We also examined its effect on cell proliferation and migration. We noticed a different level of piperine resistance between cell lines. Piperine increases the cytotoxic effect of PAC and TOP in drug-resistant cells. We observed an increase in PTPRK expression correlated with decreased pTYR level after piperine treatment and downregulation of P-gp and BCRP expression. We also noted a decrease in COL3A1 and TGFBI expression in investigated cell lines and increased COL3A1 expression in media from W1PR2 cells. The expression of Ki67 protein and cell proliferation rate decreased after piperine treatment. Piperine markedly inhibited W1TR cell migration. Piperine can be considered a potential anticancer agent that can increase chemotherapy effectiveness in cancer patients.

Topics: Aldehyde Dehydrogenase 1 Family; Alkaloids; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Cell Survival; Collagen Type III; Drug Resistance, Neoplasm; Extracellular Matrix Proteins; Female; Humans; Ovarian Neoplasms; Paclitaxel; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Retinal Dehydrogenase; Transforming Growth Factor beta

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.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Disease Models, Animal; Female; Fibrosis; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis, Chronic; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Mitogen-activated protein kinases (MAPKs) and AMP-activated protein kinase α (AMPKα) play critical roles in the process of cardiac hypertrophy. Previous studies have demonstrated that piperine activates AMPKα and reduces the phosphorylation of extracellular signal-regulated kinase (ERK). However, the effect of piperine on cardiac hypertrophy remains completely unknown. Here, we show that piperine-treated mice had similar hypertrophic responses as mice treated with vehicle but exhibited significantly attenuated cardiac fibrosis after pressure overload or isoprenaline (ISO) injection. Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts induced by transforming growth factor-β (TGF-β) or angiotensin II (Ang II) in vitro. This anti-fibrotic effect was independent of the AMPKα and MAPK pathway. Piperine blocked activation of protein kinase B (AKT) and, downstream, glycogen synthase kinase 3β (GSK3β). The overexpression of constitutively active AKT or the knockdown of GSK3β completely abolished the piperine-mediated protection of cardiac fibroblasts. The cardioprotective effects of piperine were blocked in mice with constitutively active AKT. Pretreatment with GW9662, a specific inhibitor of peroxisome proliferator activated receptor-γ (PPAR-γ), reversed the effect elicited by piperine in vitro. In conclusion, piperine attenuated cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β.

Topics: Alkaloids; Angiotensin II; Anilides; Animals; Benzodioxoles; Cell Differentiation; Cells, Cultured; Cytochrome P-450 Enzyme Inhibitors; Fibroblasts; Fibrosis; Glycogen Synthase Kinase 3 beta; Heart; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Myocardium; Myofibroblasts; Piperidines; Polyunsaturated Alkamides; PPAR gamma; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta