Protective effect of alizarin on vascular endothelial dysfunction via inhibiting the type 2 diabetes-induced synthesis of THBS1 and activating the AMPK signaling pathway.

BACKGROUND: In this study, we investigated the protective effects of alizarin (AZ) on endothelial dysfunction (ED). AZ has inhibition of the type 2 diabetes mellitus (T2DM)-induced synthesis of thrombospondin 1 (THBS1). Adenosine 5'-monophosphate- activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. PURPOSE: The aim of this study was to investigate the ameliorative effect of AZ on vascular injury caused by T2DM and to reveal the potential mechanism of AZ in high glucose (HG)-stimulated human umbilical vein endothelial cells (HUVECs) and diabetic model rats. STUDY DESIGN: HUVECs, rats and AMPK-/- transgenic mice were used to investigate the mitigating effects of AZ on vascular endothelial dysfunction caused by T2DM and its in vitro and in vivo molecular mechanisms. METHODS: In type 2 diabetes mellitus rats and HUVECs, the inhibitory effect of alizarin on THBS1 synthesis was verified by immunohistochemistry (IHC), immunofluorescence (IF) and Western blot (WB) so that increase endothelial nitric oxide synthase (eNOS) content in vitro and in vivo. In addition, we verified protein interactions with immunoprecipitation (IP). To probe the mechanism, we also performed AMPKα2 transfection. AMPK's pivotal role in AZ-mediated prevention against T2DM-induced vascular endothelial dysfunction was tested using AMPKα2-/- mice. RESULTS: We first demonstrated that THBS1 and AMPK are targets of AZ. In T2DM, THBS1 was robustly induced by high glucose and inhibited by AZ. Furthermore, AZ activates the AMPK signaling pathway, and recoupled eNOS in stressed endothelial cells which plays a protective role in vascular endothelial dysfunction. CONCLUSIONS: The main finding of this study is that AZ can play a role in different pathways of vascular injury due to T2DM. Mechanistically, alizarin inhibits the increase in THBS1 protein synthesis after high glucose induction and activates AMPKα2, which increases NO release from eNOS, which is essential in the prevention of vascular endothelial dysfunction caused by T2DM.

Amorphous selenium inhibits oxidative stress injury of neurons in vascular dementia rats by activating NMDAR pathway.

Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.

Amorphous nano-selenium quantum dots prevent pulmonary arterial hypertension through recoupling endothelial nitric oxide synthase.

AIMS: We have previously reported that nano-selenium quantum dots (SeQDs) prevented endothelial dysfunction in atherosclerosis. This study is to investigate whether amorphous SeQDs (A-SeQDs) increase endogenous tetrahydrobiopterin biosynthesis to alleviate pulmonary arterial hypertension. RESULTS: Both A-SeQDs and C-SeQDs were stable under physiological conditions, while the size of A-SeQDs was smaller than C-SeQDs by high resolution-transmission electron microscopy scanning. In monocrotaline-injected mice, oral administration of A-SeQDs was more effective to decrease pulmonary arterial pressure, compared to C-SeQDs and organic selenium. Further, A-SeQDs increased both nitric oxide productions and intracellular BH4 levels, upregulated dihydrofolate reductase activity in lungs, and improved pulmonary arterial remodeling. Gene deletion of dihydrofolate reductase abolished these effects produced by A-SeQDs in mice. Finally, the blood levels of tetrahydrobiopterin and selenium were decreased in patients with pulmonary arterial hypertension. CONCLUSION: A-SeQDs increase intracellular tetrahydrobiopterin to prevent pulmonary arterial hypertension through recoupling endothelial nitric oxide synthase. METHODS: Two polymorphs of SeQDs and A-SeQDs, and a crystalline form of SeQDs (C-SeQDs) were prepared through self-redox decomposition of selenosulfate precursor. Mice were injected with monocrotaline to induce pulmonary arterial hypertension in vivo. Pulmonary arterial pressure was measured.

Floralozone Ameliorated Atherosclerosis in Experimental Atherosclerotic Rats Involved with Sphingosine 1-Phosphate 1 Enhancement.

Atherosclerosis (AS) is a chronical pathological process of the arterial narrows due to the AS plaque formation. The aim of this study was to explore the therapeutic effect and the underlying mechanism of Floralozone on experimental atherosclerotic model rats. Experimental atherosclerotic model rats were induced by the right carotid artery balloon injury and intraperitoneal injection of vitamin D3 in rats after 4 weeks high-fat diet. The results exhibited that Floralozone could ameliorate vascular injury and vasorelaxation of descending aortas and increase the superoxide dismutase activity and the expression of sphingosine 1-phosphate (S1P) 1 and reduce the intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, interleukin (IL)-1, IL-6 level, and the malondialdehyde activity in experimental atherosclerotic rats. However, Fingolimod, an S1P1 inhibitor, could reverse these Floralozone effects in experimental atherosclerotic rats. Our results indicated that Floralozone could inhibit the atherosclerotic plaque formation and improves arterial stenosis and reduces endothelial dysfunction in experimental atherosclerotic rats, which might be involved with S1P1 enhancement.

Amorphous nano-selenium quantum dots improve endothelial dysfunction in rats and prevent atherosclerosis in mice through Na+/H+ exchanger 1 inhibition.

AIM: Selenium, a trace element involved in important enzymatic activities inside the body, has protective effects against cardiovascular diseases including atherosclerosis. The safe dose of selenium in the organism is very narrow, limiting the supplementation of selenium in diet. The aim of this study is to explore whether selenium quantum dots (SeQDs) prevent atherosclerosis and to investigate the potential mechanisms. METHODS: An amorphous form of SeQDs (A-SeQDs) and a crystalline form of SeQDs (C-SeQDs) were prepared through self-redox decomposition of selenosulfate precursor. Endothelial dysfunction was induced by balloon injury plus high fat diet (HFD) in rats. Atherosclerotic model was established by feeding Apoe-/- mice with HFD. RESULTS: Administrations of A-SeQDs but not C-SeQDs dramatically improved endothelium-dependent relaxation, and accelerated would healing in primary endothelial cells isolated from rats, which was comprised by co-treatment of LiCl. Lentivirus-mediated knockdown of Na+/H+ exchanger 1 (NHE1) abolished LiCl-induced endothelial dysfunction in rats. In cultured endothelial cells, A-SeQDs, as well as cariporide, inhibited NHE1 activities, decreased intracellular pH value and Ca2+ concentration, and reduced calpain activity increased by ox-LDL. These protective effects of A-SeQDs were reversed by LiCl treatment in endothelial cells. In Apoe-/- mice feeding with HFD, A-SeQDs prevented endothelial dysfunction and reduced the size of atherosclerotic plaque in aortic arteries. Further, lentivirus-mediated NHE1 gene overexpression abolished the protective effects of A-SeQDs against endothelial dysfunction and atherosclerosis in Apoe-/- mice. CONCLUSION: A-SeQDs prevents endothelial dysfunction and the growth of atherosclerotic plaque through NHE1 inhibition and subsequent inactivation of Ca2+/calpain signaling. Clinically, the administration of A-SeQDs is an effective approach to treat atherosclerosis.

Traditional Chinese medicine Ka-Sai-Ping suppresses the growths of gastric cancers via induction of autophagy.

Traditional Chinese medication is increasingly used to treat a wide range of human chronic diseases like cardiovascular diseases and cancers. This study was designed to explore whether ka-sai-ping (KSP), a novel traditional Chinese medicine developed by us, prevents gastric cancer growths and to investigate the underlying mechanism. The xenograft model of mouse gastric cancer was established by injecting MFCs into nude mouse subcutaneously. Cell autophagy was assessed by MDC staining. Lysosome and mitochondria were detected by Lyso-Tracker Red and Mito-Traker Green staining. Incubation of cultured mouse gastric cancer cell line MFCs with KSP for 48 hours, concentration-dependently reduced cell survivals and activated autophagy, which were accompanied with damaged lysosomes and mitochondria. In vivo studies indicated that KSP therapy (20 ml/kg/day) for two weeks suppressed the growth of gastric cancer, increased the protein levels of LC3-II, beclin-1, cathepsin L, bcl-2, p53, and capase-3 in tumor tissues from the xenograft model of mouse gastric cancer. Importantly, all these effects induced by KSP were abolished by co-administration of autophagy inhibitor 3-MA. In conclusion, KSP activates cell autophagy to suppress gastric cancer growths. Clinically, KSP is potentially considered as a medicine to treat patients with gastric cancer.

Traditional Chinese medicine xin-mai-jia recouples endothelial nitric oxide synthase to prevent atherosclerosis in vivo.

Endothelial dysfunction, which is caused by endothelial nitric oxide synthase (eNOS) uncoupling, is an initial step in atherosclerosis. This study was designed to explore whether Chinese medicine xin-mai-jia (XMJ) recouples eNOS to exert anti-atherosclerotic effects. Pretreatment of XMJ (25, 50, 100 µg/ml) for 30 minutes concentration-dependently activated eNOS, improved cell viabilities, increased NO generations, and reduced ROS productions in human umbilical vein endothelial cells incubated with H2O2 for 2 hours, accompanied with restoration of BH4. Importantly, these protective effects produced by XMJ were abolished by eNOS inhibitor L-NAME or specific eNOS siRNA in H2O2-treated cells. In ex vivo experiments, exposure of isolated aortic rings from rats to H2O2 for 6 hours dramatically impaired acetylcholine-induced vasorelaxation, reduced NO levels and increased ROS productions, which were ablated by XMJ in concentration-dependent manner. In vivo analysis indicated that administration of XMJ (0.6, 2.0, 6.0 g/kg/d) for 12 weeks remarkably recoupled eNOS and reduced the size of carotid atherosclerotic plaque in rats feeding with high fat diet plus balloon injury. In conclusion, XMJ recouples eNOS to prevent the growth of atherosclerosis in rats. Clinically, XMJ is potentially considered as a medicine to treat patients with atherosclerosis.

Protective effect of Xingnaojia formulation on rats with brain and liver damage caused by chronic alcoholism.

The aim of this study was to observe the effect of a formulation of traditional Chinese medicine extracts known as Xingnaojia (XNJ) on the liver function, learning ability and memory of rats with chronic alcoholism and to verify the mechanism by which it protects the brain and liver. A rat model of chronic alcoholism was used in the study. The spatial learning ability and memory of the rats were tested. The rats were then sacrificed and their brains and hepatic tissues were isolated. The activity of superoxide dismutase (SOD) and levels of glutamate (Glu), N-methyl D-aspartate receptor subtype 2B (NR2B), cyclin-dependent kinase 5 (CDK5) and cannabinoid receptor 1 (CB1) in the hippocampus were analyzed. The ultrastructure of the hepatic tissue was observed by electron microscopy. In addition, the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in serum were tested and the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG) and total cholesterol (TCHOL) were analyzed. XNJ enhanced the learning and memory of rats with chronic alcoholism. Treatment with XNJ increased the activity of SOD, and decreased the expression levels of NR2B mRNA and NR2B, CB1 and CDK5 proteins in the brain tissues compared with those in the model rats. It also increased the activity of ALDH in the serum and liver, decreased the serum levels of LDL, TG and TCHOL and increased the serum level of HDL. These results indicate that XNJ exhibited a protective effect against brain and liver damage in rats with chronic alcoholism.