Background: Panduratin A is a bioactive cyclohexanyl chalcone exhibiting several pharmacological activities, such as anti-inflammatory, anti-oxidative, and anti-cancer activities. Recently, the nephroprotective effect of panduratin A in cisplatin (CDDP) treatment was revealed. The present study examined the potential of certain compounds derived from panduratin A to protect against CDDP-induced nephrotoxicity. Methods: Three derivatives of panduratin A (DD-217, DD-218, and DD-219) were semi-synthesized from panduratin A. We investigated the effects and corresponding mechanisms of the derivatives of panduratin A for preventing nephrotoxicity of CDDP in both immortalized human renal proximal tubular cells (RPTEC/TERT1 cells) and mice. Results: Treating the cell with 10 µM panduratin A significantly reduced the viability of RPTEC/TERT1 cells compared to control (panduratin A: 72% ± 4.85%). Interestingly, DD-217, DD-218, and DD-219 at the same concentration did not significantly affect cell viability (92% ± 8.44%, 90% ± 7.50%, and 87 ± 5.2%, respectively). Among those derivatives, DD-218 exhibited the most protective effect against CDDP-induced renal proximal tubular cell apoptosis (control: 57% ± 1.23%; DD-218: 19% ± 10.14%; DD-219: 33% ± 14.06%). The cytoprotective effect of DD-218 was mediated via decreases in CDDP-induced mitochondria dysfunction, intracellular reactive oxygen species (ROS) generation, activation of ERK1/2, and cleaved-caspase 3 and 7. In addition, DD-218 attenuated CDDP-induced nephrotoxicity by a decrease in renal injury and improved in renal dysfunction in C57BL/6 mice. Importantly, DD-218 did not attenuate the anti-cancer efficacy of CDDP in non-small-cell lung cancer cells or colon cancer cells. Conclusions: This finding suggests that DD-218, a derivative of panduratin A, holds promise as an adjuvant therapy in patients receiving CDDP.
Fibrosis is a final common outcome of almost progressive kidney disease; it strongly correlates with kidney insufficiency. Initiation of fibrosis is stimulated by sustain activation of injurious stimuli. This process leads to induction of epithelial to mesenchymal transition (EMT) of tubular cells. Transforming growth factor β1 is the master regulator of EMT and fibrosis. The aim of this study is to investigate the pharmacological effects of TMED‐A001, a natural product isolated from fungi, on EMT of human renal proximal tubular cells. The morphology of human renal proximal tubular cells was examined and photographed under light microscope. The protein expression of E‐cadherin, fibronectin, Smad7, phosphorylated Smad2, Smad3, and extracellular signal‐regulated kinase (ERK) 1/2 were evaluated by Western blot analysis. Incubation RPTEC/TERT1 cells, an immortalized human renal proximal tubular cells, with 10 ng/ml transforming growth factor β1 (TGF‐β1) led to change in cell morphology of renal epithelial to fibroblast‐like structure. Co‐incubation the cells with TGF‐β1 and TMED‐A001 (50 and 100 µM) prevented the morphology change. TMED‐A001 maintained the epithelial characteristics by preserving protein expression of E‐cadherin with reduction of fibronectin protein expression. TMED‐A001 significantly reduced downstream of TGF‐β1 signaling pathway including phosphorylated Smad2 and Smad3 protein expression. In contrast to Smad2 and Smad3, TMED‐A001 increased Smad7 protein expression which is the negative regulator of TGF‐β1‐Smad signaling pathway. In addition, TMED‐A001 also significantly reduced phosphorylated ERK 1/2 protein expression, a TGF‐β1‐non‐Smad signaling pathway. These results suggest that TMED‐A001 prevents EMT in human renal proximal tubular cells through the inhibition of TGF‐β1‐Smad and non‐Smad signaling pathways. In summary, TMED‐A001 presents anti‐EMT property of renal proximal tubular cells by counteracting TGF‐β1 signaling pathway. TMED‐A001 might be the therapeutic potential agent for renal fibrosis in the progressive kidney diseases.
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