Yi Wang,Jingwen Xu,Yihai Wang,Limin Xiang,Xiangjiu He
Multidrug resistance (MDR) is a major cause of chemotherapy failure. Adriamycin (ADR) has been widely used to treat cancer, however, as a substrate of the adenosine triphosphate binding cassette (ABC) transporter, it is easy to develop drug resistance during the treatment. Here, we demonstrated that steroidal saponin S-20 isolated from the berries of black nightshade has comparable cytotoxicity in ADR-sensitive and resistant K562 cell lines. Autophagy is generally considered to be a protective mechanism to mediate MDR during treatment. However, we found that S-20-induced cell death in K562/ADR is associated with autophagy. We further explored the underlying mechanisms and found that S-20 induces caspase-dependent apoptosis in ADR-sensitive and resistant K562 cell lines. Most importantly, S-20-induced autophagy activates the ERK pathway and then inhibits the expression of drug resistance protein, which is the main reason to overcome K562/ADR resistance, rather than apoptosis. Taken together, our findings emphasize that S-20 exerts anti-multidrug resistance activity in K562/ADR cells through autophagic cell death and ERK activation, which may be considered as an effective strategy.
Baicalein, a major bioactive flavone constituent isolated from Scutellaria baicalensis Georgi, has neuroprotective properties in several neurological disorders. Many studies suggest that oxidative stress plays a central role in the pathogenesis of Parkinson’s disease (PD). Baicalein has also been shown to have antioxidant effects. Therefore, the current study was designed to investigate whether baicalein could protect against MPP + /MPTP-induced neurotoxicity via suppressing oxidative stress in vitro and in vivo . In vitro , our results showed that baicalein increased cell viability in MPP + -treated SH-SY5Y cells. Treatment with baicalein could reversed the increased MDA and ROS levels, and the decreased GSH levels in MPP + -treated SH-SY5Y cells. In MPTP-treated mice, baicalein ameliorated MPTP-induced motor impairment and suppressed the MPTP-induced accumulation of iron and lipid peroxides. Besides, baicalein improved the neurotoxicity induced by MPTP as seen by a significant raise of tyrosine hydroxylase (TH) and simultaneous decrease of monoamine-oxidase-B (MAO-B). The inhibitory effect of baicalein on oxidative stress probably was partially governed by inhibition of ERK activation. In conclusion, our results suggest that baicalein could prevent MPP+/MPTP-induced neurotoxicity via suppressing oxidative stress.
Yong Li,Tingting Yang,Qing Yao,Songsong Li,En Fang,Yankun Li,Chao Liu,Weimin Li
Background Intestinal barrier dysfunction is a key etiologic factor of irritable bowel syndrome (IBS). Metformin improves intestinal barrier function, although the underlying mechanism has yet to be fully explained. This study evaluates the protective effect of metformin on colonic barrier integrity and explores the underlying cellular mechanisms. Methods IBS-like rats were induced by maternal separation. Metformin was administered daily by gavage at 08:30, and rat pups were then separated from their mother. Visceral hyperalgesia and depression-like behaviors were evaluated by colorectal distension, sucrose preference tests, and forced swimming tests. Intestinal integrity was analyzed using sugar probes and transmission electron microscopy. Inflammatory factors and the levels of corticotropin-releasing factor were assessed by PCR and ELISA. The number of mast cells was evaluated by toluidine blue staining. Protein expression and localization were determined using Western blot and immunochemistry. Key Results Metformin pretreatment (a) reduced visceral hypersensitivity to colorectal distension, immobility time and enhanced sucrose consumption; (b) decreased urine lactulose/mannitol ratio and sucralose output; (c) inhibited the dilation of tight junction and prevented claudin-4 translocation; (d) inhibited mast cell activation and downregulated the expression of IL-6, IL-18, tryptase, PAR-2, and ERK activation; (e) inhibited claudin-4 phosphorylation at serine sites and interactions between clau-4 and ZO-1. Conclusions & Inferences Metformin may block mast cell activation to reduce PAR-2 expression and subsequently inhibit ERK activation and clau-4 phosphorylation at serine sites to normalize the interaction of clau-4 and ZO-1 and clau-4 distribution. Metformin may be clinically beneficial for patients with IBS or IBS-like symptoms.
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