Abstract
The aim of this study was to explore the protective effects of bioactive compounds from the fruit of the mulberry tree (Morus alba L.) against cisplatin-induced apoptosis in LLC-PK1 pig kidney epithelial cells. Morus alba fruit is a well-known edible fruit commonly used in traditional folk medicine. Chemical investigation of M. alba fruit resulted in the isolation and identification of six phytosterols (1–6). Their structures were determined as 7-ketositosterol (1), stigmast-4-en-3β-ol-6-one (2), (3β,6α)-stigmast-4-ene-3,6-diol (3), stigmast-4-ene-3β,6β-diol (4), 7β-hydroxysitosterol 3-O-β-d-glucoside (5), and 7α-hydroxysitosterol 3-O-β-d-glucoside (6) by analyzing their physical and spectroscopic data as well as liquid chromatography/mass spectrometry data. All compounds displayed protective effects against cisplatin-induced LLC-PK1 cell damage, improving cisplatin-induced cytotoxicity to more than 80% of the control value. Compound 1 displayed the best effect at a relatively low concentration by inhibiting the percentage of apoptotic cells following cisplatin treatment. Its molecular mechanisms were identified using Western blot assays. Treatment of LLC-PK1 cells with compound 1 decreased the upregulated phosphorylation of p38 and c-Jun N-terminal kinase (JNK) following cisplatin treatment. In addition, compound 1 significantly suppressed cleaved caspase-3 in cisplatin-induced LLC-PK1 cells. Taken together, these findings indicated that cisplatin-induced apoptosis was significantly inhibited by compound 1 in LLC-PK1 cells, thereby supporting the potential of 7-ketositosterol (1) as an adjuvant candidate for treating cisplatin-induced nephrotoxicity.
Highlights
IntroductionIn more than 30% of patients taking cisplatin, a variety of side effects, including allergic reactions, ototoxicity, myelotoxicity, nephrotoxicity, and gastrotoxicity, have been reported [2]
AVANCE III 700 nuclear magnetic resonance (NMR) spectrometer operating at 700 MHz (1 H) and 175 MHz (13 C) (Bruker, Karlsruhe, Germany) with chemical shifts reported in parts per million (δ)
Dried and pulverized M. alba fruit was extracted with 70% ethanol three times at room temperature
Summary
In more than 30% of patients taking cisplatin, a variety of side effects, including allergic reactions, ototoxicity, myelotoxicity, nephrotoxicity, and gastrotoxicity, have been reported [2]. Of these side effects, nephrotoxicity is a dose-limiting one that makes patients unable to continue cisplatin treatment [3]. Cisplatin can seriously damage the S3 segment of the proximal tubules, causing kidney dysfunction [4]. Magnesium supplementation, and kidney-protective therapeutic approaches using enzymes and compounds that can help treat or prevent cisplatin-induced nephrotoxicity was reported [5]
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