Structure–activity relationship of piperine and its synthetic amide analogs for therapeutic potential to prevent experimentally induced ER stress in vitro

Abstract

Endoplasmic reticulum (ER) is the key organelle involved in protein folding and maturation. Emerging studies implicate the role of ER stress in the development of chronic kidney disease. Thus, there is an urgent need for compounds that could ameliorate ER stress and prevent CKD. Piperine and its analogs have been reported to exhibit multiple pharmacological activities; however, their efficacy against ER stress in kidney cells has not been studied yet. Hence, the goal of this study was to synthesize amide-substituted piperine analogs and screen them for pharmacological activity to relieve ER stress using an in vitro model of tunicamycininduced ER stress using normal rat kidney (NRK-52E) cells. Five amide-substituted piperine analogs were synthesized and their chemical structures were elucidated by pertinent spectroscopic techniques. An in vitro model of ER stress was developed using tunicamycin, and the compounds of interest were screened for their effect on cell viability, and the expression of ER chaperone GRP78, the pro-apoptotic ER stress marker CHOP, and apoptotic caspases 3 and 12 (via western blotting). Our findings indicate that exposure to tunicamycin (0.5 μg/ mL) for 2 h induces the expression of GRP78 and CHOP, and apoptotic markers (caspase-3 and caspase-12) and causes a significant reduction in renal cell viability. Pre-treatment of cells with piperine and its cyclohexylamino analog decreased the tunicamycin-induced upregulation of GRP78 and CHOP and cell death. Taken together, our findings demonstrate that piperine and its analogs differentially regulate ER stress, and thus represent potential therapeutic agents to treat ER stressrelated renal disorders.

Piperine pretreatment attenuates renal ischemia-reperfusion induced liver injury

“…In various studies, the antioxidant and anti-inflammatory effects of piperine have been examined. It has been reported that piperine supplement caused a significant decline in H2O2 production stimulated by puromycin [30], enhanced antioxidant capacity and reduction of lipid peroxidation [14], diminished oxidative stress of the endoplasmic reticulum [19] and reduction of MDA and elevation of superoxide dismutase and glutathione peroxidase [17]. Also, the results of other studies suggest that piperine causes diminished expression of NF-κB, TNF-α and ICAM-1 in different models of inflammation as well as ischemia-reperfusion [16].…”

“…It can also protect and reduce damages in brain ischemia-reperfusion [16], and lead acetate induced nephrotoxicity in rats [17]. Mechanistically, it has been shown that piperine decreases intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor alpha (TNF-α), indcible nitric oxide synthase (iNOS), and nuclear factor-κB (NF-κB) expression [16, 18], and inhibits cytochrome P450 activity and endoplasmic reticulum stress [19]. In a previous study, we found that piperine gavage resulted in diminished renal inflammation, oxidative stress, tissue damage, and functional disturbances following 30 min of ischemia and 24 h of reperfusion (unpublished data).…”

Protective effect of piperine in ischemia-reperfusion induced acute kidney injury through inhibition of inflammation and oxidative stress

“…In this study, piperine gavage reduced MDA and increased FRAP, reflecting its anti-oxidative properties. It has been shown that piperine supplementation considerably reduces puromycin induced H 2 O 2 production, 34 increases antioxidative capacity of tissues, decreases lipid peroxidation, 11 reduces endoplasmic reticulum oxidative stress 24 and augments superoxide dismutase and glutathione peroxidase from renal tissue following lead acetate induced nephrotoxicity. 18 Via its antioxidant effect, piperine is able to reduce the oxidative stress in renal tissue following IR, appearing as a decrease in MDA and an increase in FRAP.…”

“… 18 Several studies have been performed on the mechanism of piperine, reporting that it acts by reducing the expression of ICAM-1, TNF-α, iNOS, and NF-κB, 17 , 19 , 20 inhibiting cytochrome P450 enzymes 21 and p-glycoprotein activities, 22 , 23 and preventing endoplasmic reticulum stress. 24 However, the protective effect of piperine against functional disturbances, inflammation, oxidative stress and tissue damages induced by renal IR is yet to be fathomed. Therefore, the objective of the present study was to assess the protective effects of piperine against renal damages induced by 30-min bilateral renal ischemia followed by 24-h reperfusion in rat.…”

Piperine protects against myocardial ischemia/reperfusion injury by activating the PI3K/AKT signaling pathway

“…Myocardial H/R injury is related to the activation of ERS-induced apoptosis and PIP was indicated to be involved in ERS progression ( 3 , 18 , 19 ). As an ER chaperone, GRP78 is crucial for myocardial apoptosis during H/R, particularly since ERS can drive the apoptotic cascade, including the activation of caspase-12 in a CHOP-dependent manner ( 3 ).…”