摘要：
Background: Dexamethasone (Dex), a synthetic glucocorticoid, is strictly controlled for use due to its serious side effects, including immune suppression. Betulinic acid (BA), an antioxidant prepared from the white birch, exhibits immunomodulation properties. To assess the implications and investigate the mechanisms of BA-elicited immunomodulation, we hypothesized that Dex induced thymocyte apoptosis via oxidative stress could be lessened by BA. Methods: Mice were given oral doses of BA (0.25, 0.5, and 1.0 mg/kg) daily for 14 days, and induced oxidative stress by giving a single dose of Dex intraperitoneal at the dosage of 25 mg/kg body weight 8 h after the last administration of BA. Results: Dex administration alone significantly decreased antioxidant enzyme activities, while significantly increased reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial dysfunctions, caspase-3 activation and cellular apoptosis. However, pretreatment with BA dose dependently mitigated Dex-induced oxidative damage after 14 days of feeding. In addition to ROS scavenging activity in Dex-induced thymocyte, BA administration decreased lipid peroxidation, up regulated antioxidant enzymes, restored mitochondrial function, increased Bcl-2 expression but reduced Bax expression, inhibited caspase-3 activation, and improved cell survival. Conclusions: These findings reveal a protective capability of BA against Dex-induced cell death by reducing oxidative stress via mitochondrial mediated signal pathway which could be the potential mechanism underlying BA-elicited immunomodulation. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
摘要：
The toxic effects of lead on normal rat kidney epithelial cells (NRK cells) may occur via various pathways. However, the role of intrinsic mitochondrial pathway in Lead-induced apoptosis in NRK cells has not been investigated. The purpose of our study was to investigate cytotoxic responses and cell apoptosis mediated by lead in NRK cells. NRK cells were treated with different concentrations of Lead acetate for 12 h to determine the cytotoxicity of lead. Mitochondrial transmembrane potential was also analyzed using a fluorescence spectrophotometer. Moreover, the activities of caspase-3 and caspase-9 were detected in the presence of lead. Finally, the lead-induced cell apoptosis was evaluated by flow cytometry in the present of caspase inhibitors Z-VAD-FMK and Ac-LEHD-FMK, respectively. The results would contribute to clarify the role of Lead in proliferation and apoptosis of NRK cells, and help to understand the underlying mechanism responsible for lead-induced cell apoptosis.
摘要：
Medicinal herbal plants have been commonly used for intervention of different diseases and health enhancement worldwide. Koumine, an alkaloid monomer found abundantly in Gelsemium plants, can be effectively used as an anti-inflammatory medication. In this study, the mechanisms associated with the preventative effect of koumine on lipopolysaccharide (LPS)-mediated inflammation in RAW264.7 macrophages were investigated. Koumine induced a decrease in the level of inducible nitric oxide synthase (iNOS) protein, concomitant reduction in the production of nitric oxide (NO) and reduction of the levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-1β. Furthermore, koumine decreased the phosphorylation of p65 and inhibited nuclear factor κ Bα (IκBα) proteins, resulting in lower production of nuclear factor (NF)-κB transactivation. Koumine also induced a decrease in the phosphorylation of extracellular-signal-regulated kinases (ERK) and p38 in RAW264 cells. In conclusion, these findings reveal that koumine decreases the productions of pro-inflammatory mediators though the suppression of p38 and ERK MAPK phosphorylation and the inhibition of NF-κB activation in RAW264.7 cells.
摘要：
T-2 toxin is a secondary metabolite produced by Fusarium genus and is a common contaminant in food and feedstuffs of cereal origin. In porcine granulosa cells(GC), T-2 toxin has been shown to inhibit the steroidogenesis; however, the mechanism has not been well understood. Gonadotropin-stimulated steroidogenesis is regulated by the cAMP-PKA pathway. In this study, we investigated potential mechanisms for T-2 toxin-induced reproductive toxicity focusing on the critical steps of the cAMP-PKA pathway affected by T-2 toxin. We first analyzed the effects of T-2 toxin on progesterone and estrogen production in rat granulosa cells. For this purpose the granulosa cells were cultured for 48 h in 10% fetal bovine serum-containing medium followed by 24 h in serum-free medium containing FSH (10 ng/ml) and androstenedione (3 ng/ml), both are required for normal steroidogenesis. Treatment of these cells with T-2 toxin dose-dependently inhibited the growth of cells and the steroid hormone production. Cellular cyclic AMP levels were dose-dependently inhibited by T-2 toxin (0, 1, 10 and 100 nM, 24 h). Furthermore, we found that although the induction of progesterone by 8-Br-cAMP (a FSH mimetic) and 22R-HC (substrate for progesterone) could both be inhibited by T-2 toxin treatment, the T-2-imposed inhibitory effects could be reversed by increasing doses of 22R-HC, while increasing 8-Br-cAMP had no effects, suggesting that T2 toxin targeted at distinct mechanisms. cAMP-stimulated steroidogenic acute regulatory protein (StAR) is a rate limiting protein in progesterone synthesis. Exposure to T2 toxin caused significant suppression of StAR expression as determined by Western blotting and semi-quantitative RT-PCR suggesting StAR is a sensitive target for T-2 toxin. Taken together, our results strongly suggest that T2 toxin inhibits steroidogenesis by suppressing cAMP-PKA pathway and StAR is a target for T-2-toxin. The antisteroidogenesis effects were observable at low T-2 dose (1 ng/ml) suggesting T-2 toxin has an endocrine disruptive effect. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
摘要：
Betulinic acid (BA) is a bioactive pentacyclic triterpene that exhibits a variety of biological activities including antioxidative and immunomodulative properties. The objective of this study was to investigate the potential splenocytes protective effect and underlying mechanism of BA using dexamethasone (Dex)-induced mice as a model system. Pretreatment with BA (0.25, 0.5, and 1.0 mg/kg) dose-dependently ameliorated Dex-induced oxidative damage and apoptosis after 14 days of feeding. In addition to reactive oxygen species scavenging activity in Dex-induced splenocytes, BA administration up-regulated antioxidant enzymes, decreased lipid peroxidation, restored mitochondrial function, decreased the expression of pro-apoptotic protein Bax, prevented the decline of anti-apoptotic protein Bcl-2, inhibited caspase-9 and caspase-3 activation, and improved cell survival. These findings reveal that BA was able to mitigate Dex-induced oxidative stress and might play an important role in repairs of oxidative damage in immunological system.
