Dihydromyricetin confers cerebroprotection against subarachnoid hemorrhage via the Nrf2-dependent Prx2 signaling cascade.

BACKGROUND: Several clinical and experimental studies have shown that therapeutic strategies targeting oxidative damage are beneficial for subarachnoid hemorrhage (SAH). A brain-permeable flavonoid, dihydromyricetin (DHM), can modulate redox/oxidative stress and has cerebroprotective effects in several neurological disorders. The effects of DHM on post-SAH early brain injury (EBI) and the underlying mechanism have yet to be clarified. PURPOSE: This work investigated a potential role for DHM in SAH, together with the underlying mechanisms. METHODS: Cerebroprotection by DHM was studied using a SAH rat model and primary cortical neurons. Atorvastatin (Ato) was a positive control drug in this investigation. The effects of DHM on behavior after SAH were evaluated by performing the neurological rotarod and Morris water maze tests, as well as by examining its effects on brain morphology and on the molecular and functional phenotypes of primary cortical neurons using dichlorodihydrofluorescein diacetate (DCFH-DA), immunofluorescent staining, biochemical analysis, and Western blot. RESULTS: DHM was found to significantly reduce the amount of reactive oxygen species (ROS), suppress mitochondrial disruption, and increase intrinsic antioxidant enzymatic activity following SAH. DHM also significantly reduced neuronal apoptosis in SAH rats and improved short- and long-term neurological functions. DHM induced significant increases in peroxiredoxin 2 (Prx2) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, while decreasing phosphorylation of p38 and apoptotic signal-regulated kinase 1 (ASK1). In contrast, reduction of Prx2 expression using small interfering ribonucleic acid or by inhibiting Nrf2 with ML385 attenuated the neuroprotective effect of DHM against SAH. Moreover, DHM dose-dependently inhibited oxidative damage, decreased neuronal apoptosis, and increased the viability of primary cultured neurons in vitro. These positive effects were associated with Nrf2 activation and stimulation of Prx2 signaling, whereas ML385 attenuated the beneficial effects. CONCLUSION: These results reveal that DHM protects against SAH primarily by modulating the Prx2 signaling cascade through the Nrf2-dependent pathway. Hence, DHM could be a valuable therapeutic candidate for SAH treatment.

Ulinastatin prevents acute lung injury led by liver transplantation.

BACKGROUND: Little is known regarding the effect of ulinastatin (UTI) on acute lung injury (ALI) induced by orthotopic liver transplantation. This study aims to investigate the protective effect of UTI on ALI induced by orthotopic autologous liver transplantation (OALT) in a rat model and to explore the potential underlying mechanism. MATERIALS AND METHODS: Rats were randomly allocated into the following four groups (n = 8 each): (i) sham control group (group sham); (ii) model group (underwent OALT) (group model); (iii) low-dose UTI-treated group (group u1), with UTI (50 U/g) administered intravenously both before the portal vein was occluded and after liver reperfusion started; and (iv) high-dose UTI-treated group (group uh), with UTI (100 U/g) given in the same way as group ul. The lung pathologic parameters, lung water content, and levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, malondialdehyde (MDA), superoxide dismutase (SOD) activity, RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1), and peroxiredoxin-2 (Prx-2) were assessed 8 h after OALT was performed. RESULTS: According to histology, there was severe damage in the lung of group model accompanied by increases in the TNF-α, IL-1ß, IL-6, and MDA levels and decreases in SOD activity and the expression of RBCK1 and Prx-2. UTI treatment significantly reduced the pathologic scores, lung water content, and TNF-α, IL-1ß, IL-6, and MDA levels while restoring the SOD activity and expression of RBCK1 and Prx-2. Furthermore, compared with group u1, treatment with a high dose of UTI resulted in a better protective effect on the lung when assessed by the TNF-α, IL-1ß, IL-6, and MDA levels and SOD activity. CONCLUSIONS: UTI dose-dependently attenuates ALI that is induced by OALT in this rat model, which is mainly due to the suppression of the inflammatory response and oxidant stress, which may, in turn, be mediated by the upregulation of RBCK1 and Prx-2 expression.