Background and purpose: Accumulated evidence suggests that oxidative stress is involved in amyloid b (Ab)-induced cognitive dysfunction. Silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), has been shown to have antioxidative properties; however, it remains unclear whether silibinin improves Ab-induced neurotoxicity. In the present study, we examined the effect of silibinin on the memory impairment and accumulation of oxidative stress induced by Ab25-35 in mice. , once a day, p.o.) was started immediately after the injection of Ab25-35. Locomotor activity was evaluated 6 days after the Ab25-35 treatment, and cognitive function was evaluated in a Y-maze and novel object recognition tests 6-11 days after the Ab25-35 treatment. The levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus were measured 7 days after the Ab25-35 injection. Key results: Silibinin prevented the memory impairment induced by Ab25-35 in the Y-maze and novel object recognition tests. Repeated treatment with silibinin attenuated the Ab25-35-induced accumulation of malondialdehyde and depletion of glutathione in the hippocampus. Conclusions and implications:Silibinin prevents memory impairment and oxidative damage induced by Ab25-35 and may be a potential therapeutic agent for Alzheimer's disease.

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BackgroundHuman major histocompatibility complex class I-related chain A (MICA) plays a dual role in adaptive and innate immune responses. Increasing evidence demonstrates that MICA is closely correlated with acute and chronic kidney allograft rejection. Therefore, understanding the activation mechanisms of MICA is important in kidney transplantation. We previously demonstrated that ischemia/reperfusion injury (IRI) could up-regulate MICA expression on mouse kidney allografts. Since hypoxia-inducible factor-1 (HIF-1) is the master regulator of cellular adaptive responses to hypoxia during IRI, here we investigate whether HIF-1 could up-regulate MICA expression and its influence on NK cell cytotoxicity.ResultsWe find that HIF-1alpha plays an important role in up-regulating MICA expression, inducing IFNgamma secretion and NK cell cytotoxicity during hypoxia/reoxygenation. First, we generated a HIF-1alphaDELTAODD-expressing adenovirus to stably and functionally express HIF-1alpha in human renal proximal tubular epithelial (HK-2) cells under normoxia conditions. HIF-1alpha over-expression in HK-2 cells induces MICA expression and enhances NK cell cytotoxic activity towards cells that express HIF-1alpha. Second, we used a hypoxia/reoxygenation cell model to simulate IRI in vitro and found that the suppression of HIF-1alpha by RNAi induces down-regulation of MICA expression and inhibits NK cytotoxicity. In antibody blocking experiments, an anti-MICA mAb was able to down-regulate NK cell cytotoxic activity towards HK-2 cells that over-expressed HIF-1alpha. Moreover, when NK cells were co-cultured with the HK-2 cells expressing MICA, which was up-regulated by over-expression of HIF-1alpha, there was a significant increase in the secretion of IFNgamma. In the presence of the blocking MICA mAb, IFNgamma secretion was significantly decreased.ConclusionsThese results demonstrate that hypoxia/reoxygenation-promoted MICA expression on HK-2 cells is through a HIF-1 pathway. The increased IFNgamma secretion and enhanced NK cell cytotoxicity was mainly due to the surface expression of MICA induced by over-expression of HIF-1alpha. This study enhances our understanding of MICA activation mechanisms during kidney transplantation and provides insights into how IRI can influence transplant outcome. Moreover, these findings might be also important for developing strategies to reduce the effect of MICA in kidney transplant outcomes in the future.

In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Silibinin (silybin), a flavonoid derived from the herb milk thistle, has potent anti-inflammatory and antioxidant activities. However, it remains unclear whether silibinin improves amyloid ␤ (A␤) peptide-induced neurotoxicity. In this study, we examined the effect of silibinin on the fear-conditioning memory deficits, inflammatory response, and oxidative stress induced by the intracerebroventricular injection of A␤ peptide [25][26][27][28][29][30][31][32][33][34][35] (A␤ [25][26][27][28][29][30][31][32][33][34][35] ) in mice. Mice were treated with silibinin (2, 20, and 200 mg/kg p.o., once a day for 8 days) from the day of the A␤ 25-35 injection (day 0). Memory function was evaluated in cued and contextual fear-conditioning tests (day 6). Nitrotyrosine levels in the hippocampus and amygdala were examined (day 8). The mRNA expression of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor-␣ (TNF-␣) in the hippocampus and amygdala was measured 2 h after the A␤ 25-35 injection. We found that silibinin significantly attenuated memory deficits caused by A␤ [25][26][27][28][29][30][31][32][33][34][35] in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by A␤ [25][26][27][28][29][30][31][32][33][34][35] . Nitrotyrosine levels in these regions were negatively correlated with memory performance. Moreover, real-time RT-PCR revealed that silibinin inhibited the overexpression of iNOS and TNF-␣ mRNA in the hippocampus and amygdala induced by A␤ [25][26][27][28][29][30][31][32][33][34][35] . These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by A␤ [25][26][27][28][29][30][31][32][33][34][35] and (ii) may be a potential candidate for an AD medication.