Pharmacological inhibition of STING signaling attenu-ates MPTP-induced neuroinflammation and neurode-generation in experimental models of Parkinson's disease / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effects of pharmacological inhibition of STING by C-176,a STING selective inhibitor,in experimental model of Parkinson's disease.METHODS The acute and sub-acute mice mod-els of Parkinson's disease(PD)were established by in-traperitoneal injection of 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydrophine(MPTP).The selective STING inhibitor C-176 was administered by intraperitoneal injec-tion.The potential neuroprotective effects of C-176 were evaluated by behavioral test,tyrosine hydroxylase(TH)immunostaining,Nissl staining,Western blotting,qPCR and immunofluorescence.For in vitro study,the effects of C-176 on LPS/MPP+-induced inflammatory responses in BV2 microglial cells were determined by real time RT-PCR and Western blotting analysis.RESULTS Our study revealed that C-176 significantly inhibited STING signaling activation,ameliorated MPTP-induced dopami-nergic neurotoxicity,motor deficit and associated neuroin-flammation.Furthermore,pharmacological inhibition of STING in BV2 microglia treated with LPS/MPP+ exhibited decreased inflammatory responses.More importantly,C176 also reduced NLRP3 inflammasome activation both in vitro and in vivo.CONCLUSION The results of our study suggest that pharmacologic inhibition of STING protects against neuroinflammation that may act at least in part through suppressing NLRP3 inflammasome acti-vation and thus ameliorated dopaminergic neurodegener-ation.STING signaling may holds great promise for the development of new treatment strategy for PD as an effective therapeutic target.

Metabonomic Characterization of The Low-grade Human Astrocytomas and Meningiomas Using Magic-angle Spinning 1H Nuclear Magnetic Resonance Spectroscopy and Principal Component Analysis / 生物化学与生物物理进展

Metabolic characteristics of 39 human brain tumor tissues, including 15 astrocytomas, 13 fibroblastic meningiomas and 11 transitional meningiomas from 39 individual patients, have been studied using high resolution magic-angle spinning (HRMAS) 1H NMR spectroscopy in conjunction with principal component analysis (PCA). With rich metabolite information, 1H NMR spectra showed that the tumor-tissuc metabonome was dominated by lipids, lactate, myo-inositol, ereatine, choline metabolites such as choline, phosphocholine and glycerophosphocholine, amino acids such as alanine, glutamate, glutamine, taurine, N-acetyl-aspartate and glutathione. PCA of the tumor NMR spectra clearly showed metabonomic differences between low-grade astrocytomas and meningiomas whereas such differences were more moderate between fibroblastic and transitional meningiomas. Compared with meningiomas, the low-grade astrocytomas had higher levels of glycerophosphocholine, phosphocholine, myo-inositol and creatine but lower levels of alanine, glutamate, glutamine, glutathione and taurine. The N-acetyl-aspartate level was low but detectable in low-grade astrocytomas whereas it was not detectable in meningiomas. It is concluded that tissue metabonomics technology consisting of HRMAS 1H NMR spectroscopy and multivariate data analysis (MVDA) offers a useful tool (1) for distinguishing different types of brain tumors, (2) for providing the metabolic information for human brain tumors, which are potentially useful for understanding biochemistry of tumor progression.

Hydroxyethylpuerarin attenuates focal cerebral ischemia-reperfusion injury in rats by decreasing TNF-α expression and NF-κB activity / 药学学报

This study is to investigate the effect of hydroxyethylpuerarin on the expression of tumor necrosis factor-alpha (TNF-α) and activity of nuclear factor kappa B (NF-κB) after middle cerebral artery occlusion (MCAO) in rats. Rats were subjected to cerebral ischemia-reperfusion injury induced by MCAO. Hydroxyethylpuerarin (10, 20, 40 mg·kg-1, iv) was administered just 30 min before occlusion and immediately after reperfusion. After a 24 h reperfusion following 2 h of MCAO, the number of viable neurons in hippocampal CA1 region was counted by hematoxylin and eosin (HE) staining. TNF-α protein and its mRNA expression were examined with radioimmunoassay (RIA) and reverse transcriptase-polymerase chain reaction (RT-PCR) respectively. NF-κB activity was observed by electrophoretic mobility shift assay (EMSA), and inhibition of NF-κB α (IκBα) protein expression was evaluated by Western blotting analysis. Animals treated with hydroxyethylpuerarin had a significant increase in neuronal survival in comparison with vehicle-treated group. Hydroxyethylpuerarin significantly reduced the protein and mRNA expression of TNF-α following 2 h of ischemia with 24 h of reperfusion. NF-κB DNA binding activity and the degradation of IκBα in the cytoplasm also decreased by hydroxyethylpuerarin treatment. The protective effects of hydroxyethylpuerarin against ischemia-reperfusion injury may be mediated by decreasing the expression of TNF-α and the activity of NF-κB in rats.

Effect of compound EXP-2528 on angiotensin Ⅱ-induced E-selectin and VCAM-1 expression in rat brain microvascular endothelial cells in vitro / 药学学报

The aim of this study is to investigate the effect and mechanism of angiotensin (Ang) II on E-selectin and vascular cell adhesion molecule-1 (VCAM-1) expression in rat brain microvascular endothelial cells (BMEC) and evaluate the effect of compound EXP-2528, a novel Ang Ⅱ type 1 (AT1) receptor antagonist. The experiment was performed in cultured BMEC of rat. The mRNA and protein expression of E-selectin and VCAM-1 in BMEC was analyzed by RT-PCR and Western blotting, respectively. The results showed that the mRNA and protein expression of E-selectin and VCAM-1 in BMEC were significantly upregulated by 4 h or 18 h exposure to 1×10-7 mol·L-1 Ang Ⅱ. These effects were abolished by pretreatment with the selective AT1 receptor antagonists losartan and compound EXP-2528, but not with the AT2 selective antagonist PD123319. Combining losartan with PD123319 also significantly inhibited Ang Ⅱ-induced E-selectin and VCAM-1 expression in BMEC, but there was no significant difference compared with losartan group. These findings indicated that Ang Ⅱ upregulated E-selectin and VCAM-1 in BMEC by activating AT1 receptor and then involved in the development of cerebrovascular disease.

Compared study of hippocampus pathological lesion with magnetic resonance spectroscopy in experimental cerebral ischemic rats / 中国病理生理杂志

AIM: By Applying magnetic resonance spectroscopy(MRS) to distinguish delayed neuronal death and reactive glial proliferation in ipsilateral hippocampus of MCAO reperfusion rats.METHODS: Sixteen adult Wistar rats with MCA occlusion for 1 h then perfusion through remove the embolus were used in the experiment.10 pseudooperaton rats were served as control.MRS and pathologic examination were performed six weeks after operation.The hippocampus modality,cell density and immunohistochemical results with N-acetylaspartate,creatine and myo-inositol changes were compared.RESULTS: The values of NAA,Cr and NAA/Cr ratio of ipsilateral hippocampus lesion in MCAO reperfusion rats(2.05?0.33,2.42?0.41 and 0.86?0.10) were decreased distinctly than those in opposite side(3.45?0.58,3.10?0.93,1.18?0.32) and control group(3.42?0.43,3.57?0.47,0.98?0.14).MI value and mI/Cr ratio in ischemic hippocampus(1.47,1.30) were visible increased than those in control group(0.15,0.15).CONCLUSIONS: MRS is a perfect technique for observing the cellular metabolic changes in CA1 region.Decrease in NAA resulted from neuron delayed injury and increase in mI resulted from reactive astrocytes proliferation can be matched respectively.However,the decrease in NAA is not perfectly corresponded to the degree of neuron lost.This change has closed correlation with reactive astrocytes proliferation.

Effects of Weiankang on immune function in mice / 中成药

Objective:To study the effects of WAK on immune function in mice.Methods: After different doses of WAK were given to mice ig, its effects on delayed type hypersensitivity (DTH), hemolysin production, NK and LAK cell killing activity were observed.Results: WAK could enhance DTH and hemolysin production in immunosuppressive mice and improve NK and LAK cell killing activity in mice.Conclusions: WAK could exhibit its antitumor effect by increasing immune function.

Protective effects of carvedilol on oxidative stress injury induced by hydrogen peroxide in vascular endothelial cells / 中国药理学通报

Aim To observe the influence of carvedilol on the injury and expression of intercellular adhesion molecule-1 induced by hydrogen peroxide in ECV-304 cells and investigate the anti-atherosclerotic effect of carvedilol.Methods: The viability of ECV-304 cells was detected by MTT assay.Morphological changes of ECV-304 cells were observed under converse microscope.The level of lactate dehydrogenase released to the extracellular medium,the intracellular superoxide dismutase activity and the extracellular and intracellular Malondialdelyde level were determined using automatic biochemistry analyser.The expression of ICAM-1 in protein level and mRNA level was detected with flow cytometric technique and RT-PCR.Results Pretreated with carvidilol(1.0?10~(-5)～1.0?10~(-9)mol?L~(-1)) for 24 h,the cell survival rate was increased significantly in a concentration-dependent manner.Pre-incubation for 24 h with carvedilol results in a significant concentration-dependent decline of LDH release from hydrogen peroxide(1.0?10~(-6)mol?L~(-1))injured cells.While ECV-304 cells were pre-incubated with carvedilol,the level of MDA decreased and the activity of SOD increased significantly.Carvedilol produced a concentration-dependent inhibition of the expression of ICAM-1 protein and mRNA in hydrogen peroxide injured ECV-304 cells in a similar manner.Conclusion: These experiments demonstrated that carvedilol was able to protect ECV-304 cells from the oxidative stress injury and inhibit ICAM-1expression in ECV-304 cells induced by hydrogen peroxide.Therefore,we can consider that carvedilol maintains and improves the function of endothelium damaged by hydrogen peroxide from many aspects,which does indicate extensive antioxidant effects on the hydrogen peroxide-injured vascular endothelial cells and suggest promising effects in atherogenesis process.