Energy metabolism manipulates the fate and function of tumour myeloid-derived suppressor cells.

In recent years, a large number of studies have been carried out in the field of immune metabolism, highlighting the role of metabolic energy reprogramming in altering the function of immune cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathological conditions, such as cancer, inflammation, and infection, and show remarkable ability to suppress T-cell responses. These cells can also change their metabolic pathways in response to various pathogen-derived or inflammatory signals. In this review, we focus on the roles of glucose, fatty acid (FA), and amino acid (AA) metabolism in the differentiation and function of MDSCs in the tumour microenvironment, highlighting their potential as targets to inhibit tumour growth and enhance tumour immune surveillance by the host. We further highlight the remaining gaps in knowledge concerning the mechanisms determining the plasticity of MDSCs in different environments and their specific responses in the tumour environment. Therefore, this review should motivate further research in the field of metabolomics to identify the metabolic pathways driving the enhancement of MDSCs in order to effectively target their ability to promote tumour development and progression.

Identification of Target Genes in Hypertension and Left Ventricular Remodeling.

INTRODUCTION: Hypertension occurs profoundly in the world, and left ventricular (LV) remodeling containing functional, structural, and mechanical changes induced by uncontrolled blood pressure is a well-known complication, however the underlying mechanism is still obscure. METHODS: To determine differences in gene expression profiles of hypertension and LV remodeling consequence to hypertension, Gene Expression Omnibus 2R online tool was used to identify differently expressed genes. Publicly available databases including GeneMANIA, database for annotation, visualization and integrated discovery, search tool for the retrieva predicting associated transcription factors (TF) from annotated affinities interacting genes, Predicting Associated TF from Annotated Affinities, JASPAR and Comparative Toxicogenomics Database (CTD) were accessed to perform an integrated bioinformatic analysis. RESULTS: Twenty-one genes (SEC14L3, EML7, PSMD7, PSMA1, GLRX, CNOT10, NBR1, DUSP12, STRAP, SMIM14, RBM8A, TMEM59, TMEM87A,PSMC1, CASP4, ITGB8, DNAJA1, PINK1, PRNP, SAP30L, and EIF3M) were found overexpression in both hypertension and hypertensive LV remodeling. Biological process analysis first revealed that enrichment of these target genes correlated with regulation of cellular amino acid metabolic process, antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent and proteasome complex, 3 different expression genes (DEGs) participate significantly enriched in NFκB, WNT, and MAPK pathways, meanwhile, 47% DEGs displayed similar co-expression characteristics. Furthermore, the transcription factors associated with key DEGs were identified. Finally, the TF (HAND1, E4BP4, ESR1, VBP, ELK-1, POU3F2) associated with LV remodeling in hypertension were confirmed to act a crucial role in correlated heart diseases. CONCLUSION: The present study reveals the targeted genes probably associated with LV remodeling in hypertension by bioinformatics-based analyses, which provides clues for prognosis judgement and pharmacological therapies.

Rosuvastatin protects against endothelial cell apoptosis in vitro and alleviates atherosclerosis in ApoE-/- mice by suppressing endoplasmic reticulum stress.

The development of abnormal lipid-induced atherosclerosis is initiated with endothelial cell apoptosis. Vascular endothelial cells possess highly developed endoplasmic reticulum (ER), which is involved in lipid metabolism, indicating that ER stress may contribute chiefly to the induction of endothelial cell apoptosis. Based on its ability to reduce cholesterol levels, rosuvastatin may play an endothelial and vascular protective role by regulating ER stress. In the present study, the involvement of the inhibition of the ER stress-induced endothelial injury was investigated in combination with the lipid lowering effects of rosuvastatin. This compound can be used to inhibit cholesterol synthesis in atherosclerosis. Rosuvastatin decreased the apoptotic rates of human umbilical vascular endothelial cells (HUVECs) that had been stimulated with ox-low density lipoprotein (LDL) in vitro and repressed the mRNA levels of CHOP, sXBP1 and caspase-12, and decreased caspase-12 activity, as well as the content of glucose-regulated protein 78 (GRP78), phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-inositol-requiring protein 1α (IRE1α) and p-eIF2α proteins. In addition, ApoE-/- mice were fed with atherogenic chow for 8 weeks for atherosclerosis induction and rosuvastatin was provided by intragastric administration for an additional 4 weeks. Subsequently, the atherosclerotic plaque formation in the aorta was evaluated by Oil Red O and hematoxylin and eosin staining, and the serum LDL, high-density lipoprotein, total cholesterol (TC) and triacylglycerol (TG) levels were measured. In addition, the induction of apoptosis of endothelial cells and the expression levels of GRP78, p-PERK, p-IRE1α and p-eIF2α were assessed in the aorta. Rosuvastatin repressed atherosclerotic plaque formation and endothelial apoptosis in the aorta and decreased LDL and TG levels in the serum, as determined by in vivo results. Furthermore, it downregulated the expression levels of protein chaperone GRP78, p-PERK, p-IRE1α and p-eIF2α in the aortic intima. The data indicated that rosuvastatin could protect HUVECs from ER stress-induced apoptosis triggered by oxidized LDL. It could also inhibit atherosclerosis formation in ApoE-/- mice aorta by regulating the PERK/eIF2α/C/EBPα-homologous protein and IRE1α/sXBP1 signaling pathways. Taken collectively, the present study demonstrated the preventive and therapeutic effects of rosuvastatin in protecting from the development of endothelial cell dysfunction diseases.

Rosuvastatin protects against oxidized low­density lipoprotein­induced endothelial cell injury of atherosclerosis in vitro.

Atherosclerosis­induced cardiovascular diseases (CVDs) are accompanied by substantial morbidity and mortality. The loss and injury of endothelial cells is the primary cause of atherosclerosis. Rosuvastatin is an alternative agent used to reduce the risk of cardiovascular disease. Subsequently, the present study aimed to investigate the protective effects of rosuvastatin on oxidized­low­density lipoprotein (ox­LDL)­induced human umbilical vein endothelial cell (HUVEC) injury. The viability of ox­LDL­cultured HUVECs with or without rosuvastatin (0.01, 0.1 and 1 µmol/l) pretreatment, and pretreatment at different time points (3, 6, 12 and 24 h) was determined using an MTT assay. Morphological changes and the extent of apoptosis were detected; the anti­oxidase activity, including superoxide dismutase (SOD) and catalase (CAT), was examined, and the contents of malondiahdehyde (MDA) and nitric oxide (NO) were measured. The phosphorylation levels of endothelial nitric oxide synthase (eNOS), protein kinase B (Akt) and phosphoinositide 3 kinase (PI3K) were detected using western blot analysis. The results demonstrated that pretreatment with 0.01­1 µmol/l rosuvastatin decreased cell apoptosis caused by ox­LDL. Notably, pretreatment with 1 µmol/l rosuvastatin for >12 h increased cell viability. Additionally, DAPI staining revealed that rosuvastatin inhibited HUVEC apoptosis. Rosuvastatin treatment also resulted in increased SOD and CAT activities and decreased MDA content in ox­LDL­stimulated HUVECs. Furthermore, pretreatment with 0.01­1 µmol/l rosuvastatin significantly increased` the NO content compared with HUVECs treated with ox­LDL alone. Western blot analyses demonstrated that rosuvastatin upregulated the phosphorylation of eNOS, Akt and PI3K. These findings indicated that rosuvastatin could protect HUVECs against ox­LDL­induced injury through its anti­oxidant effect and its ability to upregulate the expression of vascular endotheliocyte­protecting factors.

Hypolipidemic effects of total flavonoide extracted from the leaves of Actinidiakolomikta in rats fed a high-fat diet.

OBJECTIVES: This study was to investigate the antihyperlipidemic and antioxidant effect of total flavonoid extract from Actinidiakolomikta (TFAK) in hyperlipidemia induced by a high-fat diet. MATERIALS AND METHODS: Male SD rats were randomly divided into 6 groups: normal group, model (hyperlipidemic diet) group, hyperlipedemic diet supplemented with TFAK (50, 100 and 200 mg/kg) and simvastatin (30 mg/kg) groups. The rats were administrated TFAK by oral for 28 days. Body weight, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), superoxide dismutase (SOD), catalase(CAT), glutathione peroxidase(GSH-Px) and malondialdehyde (MDA) were measured. The atherogenic index (AI) and coronary risk index (CRI) were calculated. The activity of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in hepatic tissue was examined. Histopathologic changes were also checked. RESULTS: The levels of TC, TG and LDL-c were increased in model group. Compared to the model group, TFAK reduced significantly the body weight, TC, TG, LDL-c, AI, CRI and elevated the level of HDL-c. Moreover, the activity of SOD was elevated significantly, whereas the content of MDA decreased. The activity of HMG-CoA reductase was also decreased. Morphological evaluation found that rats in model group developed a severe steatosis, but the severity of liver steatosis was ameliorated in TFAK treated groups. The possible mechanism may be associated with decrease HMG-CoA reductase activity. CONCLUSION: Our results suggest that TFAK exerts strong antioxidant and lipid-lowering effects, prevents hepatic fatty deposition and regulates the HMG-CoA reductase.

Effect of metformin on insulin-resistant endothelial cell function.

The aim of the present study was to investigate the effect of metformin on the function of insulin-resistant (IR) endothelial cells. A model of IR endothelial cells was established by incubating cells with 30 mM glucose, 1 µM dexamethasone and various concentrations of insulin. The nitric oxide (NO) content of the endothelial cells was determined by measuring the rate of nitroreductase production; the endothelin (ET) concentration was examined by enzyme-linked immunosorbent assay; and the expression levels of endothelial nitric oxide synthase (eNOS) were detected using western blotting. The optimal conditions for inducing insulin resistance in endothelial cells were a combination treatment of 10-4 mmol/l insulin, 30 mM glucose and 1 µM dexamethasone for 48 h. Notably, metformin administration significantly increased the NO content and reduced the ET-1 concentration in the IR cells compared with the non-treated control cells (P<0.05); furthermore, metformin significantly increased the intracellular eNOS protein expression in IR endothelial cells compared with the non-treated control cells (P<0.05), with an optimal metformin concentration of 10-3 mmol/l. Thus, the present study identified that metformin improves the function of IR endothelial cells, possibly through promoting eNOS protein expression and increasing the NO content.

Beneficial effects of 20(S)-protopanaxadiol on antitumor activity and toxicity of cyclophosphamide in tumor-bearing mice.

20(S)-protopanaxadiol (PPD) is an extract of Panax quinquefolius L. The aim of this study was to investigate the effect of PPD on the antitumor activity and toxicity of cyclophosphamide (CTX) in tumor-bearing mice. C57BL/6 mice bearing Lewis lung carcinoma cells were treated with PPD (50 mg/kg) alone, CTX (20 mg/kg) alone or PPD (50 mg/kg) in combination with CTX (20 mg/kg), respectively. The results showed that PPD alone has no significant antitumor activity but synergistically enhanced the antitumor activity of CTX. PPD significantly increased the peripheral white blood cell count, bone marrow cell count, interleukin-2 and interferon-γ in CTX-treated tumor-bearing mice. The lowered levels of spleen index, splenocyte proliferation and natural killer cell activity in tumor-bearing mice following CTX treatment were also increased by PPD administration. PPD may be a beneficial supplement during CTX chemotherapy for enhancing the antitumor efficacy and reducing the toxicity of CTX.

[Risk factors of pulmonary embolism among 303 patients in the First Clinical Hospital of Jilin University].

OBJECTIVE: To study the trend and changes regarding risk factors of pulmonary embolism among inpatients in the last 10 years from the First Clinical Hospital of Jilin University. METHODS: 303 cases of pulmonary embolism inpatients in our hospital from 2001 - 2010 were included and analyzed on related incidence, mortality and risk factors. RESULTS: Data showed that: (1) the incidence of pulmonary embolism increased from 0.09‰ to 1.12‰ while the mortality dropped from 73.3% to 12.0%; (2) major risk factors would include thrombosis of deep veins, surgical operations, heart diseases, varicosity or phlebitis of lower extremities, trauma and fracture etc., according to the order of incidence rates. Surgical operations had become the second major risk factor in the last 10 years. CONCLUSION: The incidence of pulmonary embolism in our hospital showed a gradual drop while the mortality had a remarkable drop. Surgical operations had become one of the major risk factors of pulmonary embolism.