SOCS3 Negatively Regulates Cardiac Hypertrophy via Targeting GRP78-Mediated ER Stress During Pressure Overload.

Pressure overload-induced hypertrophic remodeling is a critical pathological process leading to heart failure (HF). Suppressor of cytokine signaling-3 (SOCS3) has been demonstrated to protect against cardiac hypertrophy and dysfunction, but its mechanisms are largely unknown. Using primary cardiomyocytes and cardiac-specific SOCS3 knockout (SOCS3cko) or overexpression mice, we demonstrated that modulation of SOCS3 level influenced cardiomyocyte hypertrophy, apoptosis and cardiac dysfunction induced by hypertrophic stimuli. We found that glucose regulatory protein 78 (GRP78) was a direct target of SOCS3, and that overexpression of SOCS3 inhibited cardiomyocyte hypertrophy and apoptosis through promoting proteasomal degradation of GRP78, thereby inhibiting activation of endoplasmic reticulum (ER) stress and mitophagy in the heart. Thus, our results uncover SOCS3-GRP78-mediated ER stress as a novel mechanism in the transition from cardiac hypertrophy to HF induced by sustained pressure overload, and suggest that modulating this pathway may provide a new therapeutic approach for hypertrophic heart diseases.

Calcium-Polystyrene Sulfonate Decreases Inter-Dialytic Hyperkalemia in Patients Undergoing Maintenance Hemodialysis: A Prospective, Randomized, Crossover Study.

Hyperkalemia is a life-threatening emergency in maintenance hemodialysis (MHD) patients. This clinical trial investigated the efficacy and safety of calcium-polystyrene sulfonate (Ca-PS) in MHD patients with interdialytic hyperkalemia. A total of 58 hemodialysis patients with hyperkalemia (≥5.5 mol/L) were selected and administered either a 3-week Ca-PS (3 × 5 g/day) or a blank control following the model of a prospective, randomized, crossover clinical trial with a 1-week washout period. All patients were followed up for another 3 weeks for safety evaluations. The primary outcome was the magnitude of the change in serum potassium levels. The secondary outcomes were electrocardiography (ECG) changes and treatment safety (volume overload, electrolyte imbalance). Compared with the control group, Ca-PS treatment significantly reduced serum potassium levels (P <0.01). More patients in the Ca-PS group had lower serum potassium levels than the safety level of <5.5 mmol/L (32% for control vs. 61% for Ca-PS, P <0.01). Peaked T-wave occurred less frequently in patients in the Ca-PS group (13.8% for Ca-PS vs. 31.03% for control, P <0.01). In addition, Ca-PS reduced serum phosphorus levels with no effects on serum levels of calcium and sodium, fluid volume, blood pressure, or interdialytic weight gain. Ca-PS treatment decreases serum levels of potassium and phosphorus in MHD patients with interdialytic hyperkalemia. Ca-PS does not induce volume overload or disrupt electrolyte balance.

Longitudinal associations of high-density lipoprotein cholesterol or low-density lipoprotein cholesterol with metabolic syndrome in the Chinese population: a prospective cohort study.

OBJECTIVE: Currently, most studies only reveal the relationship between baseline high-density lipoprotein cholesterol (HDL-c) or low-density lipoprotein cholesterol (LDL-c) levels and metabolic syndrome (MetS). The relationship between dynamic changes in HDL-c or LDL-c and MetS remains unclear. We aimed to gain a deeper understanding of the relationship between the dynamic changes in HDL-c or LDL-c and MetS. DESIGN: A prospective study. SETTING: The Medical Centre of the Second Hospital affiliated with Dalian Medical University from 2010 to 2016. PARTICIPANTS: A total of 4542 individuals who were initially MetS-free and completed at least two follow-up examinations as part of the longitudinal population were included. METHODS: The Joint Interim Statement criteria 2009 were used to define MetS. We used the Joint model to estimate the relative risks (RRs) of incident MetS. RESULTS: The cumulative incidence of MetS was 17.81% and was 14.86% in men and 5.36% in women during the 7 years of follow-up. In the Joint models, the RRs of the longitudinal decrease in HDL-c and the longitudinal increase in LDL-c for the development of MetS were 18.8781-fold (95% CI 12.5156 to 28.4900) and 1.3929-fold (95% CI 1.2283 to 1.5795), respectively. CONCLUSIONS: The results highlight that the dynamic longitudinal decrement of HDL-c or the increment of LDL-c is associated with an elevated risk of MetS.

The source of circulating selenoprotein S and its association with type 2 diabetes mellitus and atherosclerosis: a preliminary study.

BACKGROUND: Selenoprotein S (SelS) is a transmembrane protein that is expressed in the liver, skeletal muscle, adipose tissue, pancreatic islets, kidney, and blood vessels. In addition to its transmembrane localization, SelS is also secreted from hepatoma HepG2 cells (but not L6 skeletal muscle cells, 3T3-L1 adipocytes, Min6 pancreatic ß cells and human embryonic kidney 293 cells) and has been detected in the serum of some human subjects, with a detection rate of 31.1 %. These findings prove that serum SelS is secreted by hepatocytes. However, whether vascularly expressed SelS can be secreted has not been reported. Transmembrane SelS has been suggested to play different roles in the pathogenesis and progression of diabetes mellitus (DM) and atherosclerosis (AS), but the association of secreted SelS with DM and macroangiopathy remains unclear. RESEARCH DESIGN AND METHODS: Supernatants were collected from human umbilical vein endothelial cells (HUVECs), human aortic vascular smooth muscle cells (HA/VSMCs) and human hepatoma HepG2 cells that were untransfected or transfected with the indicated plasmid and concentrated for western blotting. Serum samples were collected from 158 human subjects with or without type 2 DM (T2DM) and/or AS. Serum SelS levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Secreted SelS was only detected in the supernatants of hepatoma HepG2 cells. The SelS detection rate among the 158 human serum samples was 100 %, and the average SelS level was 64.81 ng/dl. The serum SelS level in the isolated DM subjects was lower than the level in the healthy control subjects (52.66 ± 20.53 vs 70.40 ± 21.38 ng/dl). The serum SelS levels in the DM complicated with SAS subjects (67.73 ± 21.41 ng/dl) and AS subjects (71.69 ± 27.00 ng/dl) were significantly increased compared with the serum SelS level in the isolated DM subjects. There was a positive interaction effect between T2DM and AS on the serum SelS level (P = 0.002). Spearman correlation analysis showed that the serum SelS level was negatively correlated with fasting plasma glucose. CONCLUSIONS: Vascular endothelial and vascular smooth muscle cells could not secrete SelS. Serum SelS was primarily secreted by hepatocytes. SelS was universally detected in human serum samples, and the serum SelS level was associated with T2DM and its macrovascular complications. Thus, regulating liver and serum SelS levels might become a new strategy for the prevention and treatment of DM and its macrovascular complications.

Birth defects data from surveillance hospitals in Dalian city, China, 2006-2010.

OBJECTIVE: The objective of this study is to disclose characteristics of birth defects in perinatal infants in Dalian and provide an epidemiological basis for controlling birth defects. METHODS: Data used in this study were collected from surveillance hospitals in Dalian during 2006-2010. Comparison analysis and trend analysis were conducted by performing Chi-square tests. RESULTS: The perinatal prevalence of birth defects from 2006 to 2010 was 101.14 per 10 000 live births and was decreased by about 29% from 115.49 per 10 000 live births in 2006 to 81.16 per 10 000 live births in 2010. The prevalence in urban was higher than that in rural areas significantly. The three leading birth defects were congenital heart disease, cleft lip and/or palate, and polydactyly or syndactyly. About 572 cases identified by antenatal diagnosis were terminated pregnancy before 28 weeks of gestation, so the prevalence of birth defects would decrease from 126.29/10 000 to 101.14/10 000. CONCLUSIONS: Dalian has experienced a decreasing temporal trend of birth defects' prevalence; however, it is still confronted with the challenge to reduce the prevalence of birth defects. Congenital heart diseases are the focus to prevent birth defects. It is necessary to keep the surveillance system function properly, provide preconception health care service extensively, and improve the ability of prenatal diagnosis.

Primary prevention of macroangiopathy in patients with short-duration type 2 diabetes by intensified multifactorial intervention: seven-year follow-up of diabetes complications in Chinese.

OBJECTIVE: To explore whether intensified, multifactorial intervention could prevent macrovascular disease in patients with recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 150 type 2 diabetic patients, with disease duration of <1 year and without clinical arteriosclerotic disease or subclinical atherosclerotic signs confirmed by ultrasonographic scanning of three conducting arteries, were randomized into an intensive intervention group and a conventional intervention group. They then received intensive, multifactorial intervention or conventional intervention over 7 years of follow-up. The patients' common carotid intima-media thicknesses (CC-IMTs) were measured every year. The primary outcome was the time to the first occurrence of CC-IMTs ≥1.0 mm and/or development of atherosclerosis plaques in the carotid artery. The secondary outcome was clinical evidence of cardiovascular disease. RESULTS: A total of 70 patients in the intensive group and 68 patients in the conventional group completed the 7-year follow-up. Subclinical macrovascular (primary) outcomes occurred in seven cases in the intensive group and 22 cases in the conventional group for a cumulative prevalence of 10.00 and 32.35%, respectively (P < 0.05). No significant differences between the two groups were observed regarding the secondary outcome. CONCLUSIONS: Primary prevention of macrovascular diseases can be achieved through intensified, multifactorial intervention in patients with short-duration type 2 diabetes. Type 2 diabetic patients should undergo intensive multifactorial interventions with individual targets for the prevention of macrovascular diseases.

[Relationship of amyloid-ß with vascular endothelial cell damage induced by diabetic serum].

OBJECTIVE: To explore the relationship of the impairment of human umbilical vein endothelial cell (HUVEC) with amyloid-ß. METHODS: HUVECs were cultured in the serum of patients with type 2 diabetes mellitus (DM) or serum of healthy control (HC), while fetal bovine serum (FBS) was used as a negative control. The proliferative activity of HUVEC were assessed by thiazolyl blue tetrazolium bromide (MTT) after 72 h. The supernatant concentrations of superoxide dismutase (SOD), maleic dialdehyde (MDA), nitric oxide (NO), amyloid-ß40 (Aß40) and Aß42 were measured after 0.5, 3 and 72 h respectively. RESULTS: Glycosylated hemoglobin values, fasting plasma glucose and fasting plasma Aß40 concentrations of diabetic patients were higher than those of healthy counterparts (P < 0.01). Proliferative activity of HUVECs in group DM were significantly lower than that of group HC. Both group and the time of intervention had crossover effects on the levels of MDA, SOD, NO and Aß40 ((163 ± 64), (207 ± 69), (286 ± 75) ng/L in group DM; (146 ± 76), (154 ± 75), (161 ± 72) ng/L in group HC after 0.5, 3 and 72 h, P < 0.05) and Aß42 ((48 ± 46), (54 ± 43), (79 ± 44) ng/L in group DM; (41 ± 12), (44 ± 16), (48 ± 12) ng/L in group HC after 0.5, 3 and 72 h, P < 0.05). With the elongating time of intervention, the levels of SOD and NO decreased significantly in group DM and reached the lowest after 72 h while increased significantly in groups HC and FBS and peaked after 72 h. The concentrations of MDA, Aß40 and Aß42 increased significantly in all three groups while the fastest and marked increments were found in group DM (P < 0.01). Pearson correlation analysis showed that SOD was negatively correlated with Aß40 (r = -0.482, P = 0.02) and Aß42 (r = -0.422, P = 0.02) while MDA positively with Aß40 (r = 0.418, P < 0.05) and Aß42 (r = 0.833, P < 0.05) after 72 h. CONCLUSION: Oxidative stress of vascular endothelial cells may be correlated with Aß40 and Aß42 in diabetes.

Dynamic anthropometric changes in children as shown by longitudinal data for 2004-2009 from the city of Dalian, China.

BACKGROUND: The physical development of children and adolescents always attracts widespread attention in society. AIM: The goal of the present study was to systematically analyse the dynamic changes in some anthropometric characteristics among primary school age children. SUBJECTS AND METHODS: Using a longitudinal study design, this study monitored physical growth annually in 933 pupils of Dalian, China, from 2004-2009.Longitudinal multi-level modelling (mixed model) was used to analyse the trajectory of growth from ages 7-12 years by gender. Height, weight and BMI were transformed into Z-scores relative to the WHO 2007 references. RESULTS: Height, weight and BMI were all higher for boys than for girls. Due to the interaction of age and gender, boys and girls exhibited different growth models. Average heights and weights for children of 7-12 years old in Dalian were higher than the WHO 2007 references. BMI z-scores for boys were significantly greater than the WHO 2007 references. CONCLUSION: Height, weight and BMI z-scores among boys and girls of 7-12 years old in Dalian were generally greater than the WHO standards. The major reasons for the differences may be due to rapid socioeconomic development and improvements in nutrition and living conditions.

Effects of five-year intensive multifactorial intervention on the serum amyloid A and macroangiopathy in patients with short-duration type 2 diabetes mellitus.

BACKGROUND: A five-year follow-up study of intensive multifactorial intervention was undertaken to assess the changes of circulating serum amyloid A (SAA) levels and the incidence of atherosclerosis (AS) in patients with short-duration type 2 diabetes mellitus (T2DM) without macroangiopathy, and whether intensive multifactorial intervention could prevent or at least postpone the occurrence of macroangiopathy. METHODS: Among 150 patients with short-duration T2DM, 75 were assigned to receive conventional outpatient treatment (conventional group) and the others underwent intensive multifactorial integrated therapy targeting hyperglycemia, hypertension, dyslipidemia and received aspirin simultaneously (intensive group). RESULTS: Plasma SAA levels were higher in diabetic patients than those in healthy control subjects, and decreased obviously after intensive multifactorial intervention. The levels of SAA were positively correlated with body mass index (BMI), waist hip ratio (WHR), triglyceride (TG), high sensitive C-reactive protein (hs-CRP) and common carotid intima-media thickness (CC-IMT). The standard-reaching rates of glycemia, blood pressure and lipidemia were significantly higher in intensive group than those of conventional group. The incidence of macroangiopathy decreased by 58.96% in intensive group compared with conventional group. CONCLUSIONS: Intensive multifactorial intervention may significantly reduce the SAA levels and prevent the occurrence of AS in short-duration patients with T2DM. SAA might be one of the risk factors of T2DM combined with AS.

Association of SelS mRNA expression in omental adipose tissue with Homa-IR and serum amyloid A in patients with type 2 diabetes mellitus.

BACKGROUND: Tanis was reported as a putative receptor for serum amyloid A (SAA) involving glucose regulated protein in insulin regulated resistance. It was found to be dysregulated in diabetic rats (Psammomys obesus, Israeli sand rat) and its homologue for humans is SelS/AD-015. The present study analyzed mRNA expression of SelS in omental adipose tissue biopsies from patients with type 2 diabetes mellitus (T2DM), and age- and weight-matched nondiabetic patients, the relationship of SelS mRNA with Homa-IR and serum SAA level. METHODS: Human omental adipose tissues from ten cases of type 2 diabetic patients and twelve cases of nondiabetic individuals were analyzed for the expression level of SelS mRNA by semiquantitative polymerase chain reaction (PCR), Homa-IR estimated by standard formula and SAA level by enzyme-linked immunosorbent assay (ELISA). RESULTS: SelS mRNA expression, Homa-IR and serum SAA were higher in T2DM sufferers than in nondiabetic control group. SelS mRNA level was positively correlated with Homa-IR and SAA level in each group. CONCLUSIONS: SelS protein may be involved in insulin resistance in Chinese with T2DM by acting as the SAA receptor, thus playing an important role in the development of T2DM and atherosclerosis.

[Effects of Ginkgo biloba extract against excitotoxicity induced by NMDA receptors and mechanism thereof].

OBJECTIVE: To observe the effects of Ginkgo biloba extract (GBE) on N-methyl-D-aspartate (NMDA) excitotoxicity and focal cerebral ischemia, and further explore the neuroprotective mechanisms of GBE. METHODS: Neonatal SD rat hippocampus was taken out to make into cell suspension. immunohistochemistry with neuron nucleoprotein monoclonal antibody (NeuN) was used to calculate the percentage of NeuN positive cells. Twelve days after incubation the suspension of neurons were randomly divided into 4 groups: normal control group (exposed to normal saline for 15 min and then to DMEM without NMDA and glycine for 24 h), NMDA group (exposed to culture fluid with NMDA of the terminal concentration of 100 micromol/L and glycine of the terminal concentration of 10 micromol/L for 15 min and then to DMEM without NMDA and glycine for 24 h), MK-801 group (exposed to MK-801, an NMDAR antagonist, for 2 min, to culture fluid with NMDA for 15 min, and then to DMEM without NMDA and glycine for 24 h), and GBE pretreatment group (exposed to GBE of the terminal concentration of 150 microg/ml for 3 d, culture fluid with NMDS for 15 min, and then to DMEM without NMDA and glycine foe 24 h). Trypan blue staining was used to calculate the survival rate of the neurons. The lactic dehydrogenase (LDH) level in the supernatant of cultured cell suspension was detected. Whole-cell patch clamp recording was carried out to evaluate the modulatory effects of GBE on NMDA-activated currents in the rat hippocampal neurons. 108 SD rats were randomly divided into 5 groups: sham operation group (n = 12), standard middle cerebral artery occlusion (MCAO) group (n = 24, undergoing MCAO and then reperfusion), MK-801 acute administration group (n = 24, undergoing MCAO and immediate peritoneal administration of MK-801 1 mg/kg), GBE acute administration group (n = 24, undergoing peritoneal injection of GBE 100 mg/kg immediately after the MCAO), and GBE pretreatment group (n = 24, undergoing peritoneal administration of GBE every day for 7 days before the MCAO). The 4 groups were re-divided into 4 subgroups with 3 approximately 4 rats: 0.5 h ischemia, and 3 h, 1 d, and 7 d ischemia-reperfusion (IR) subgroups. The neurological symptoms were evaluated by Longa's scoring after the rats became conscious. The rats were killed at different time-points, their brains were taken out to undergo 2, 3, 5-triphenyl-tetrazolium chloride staining, the areas of cerebral infarction were calculated, and immunohistochemistry was used to evaluate the contents of NeuN and microtubule-associated protein (MAP-2). RESULTS: The cell viability of the GBE group was 85% +/- 5%, significantly higher than that of the NMDA group (39.8% +/- 2.1%, P < 0.01), and significantly lower than that of the MK-801 group (93.8% +/- 2.7%, P < 0.05). The LDH efflux of the GBE group was 87 U/L +/- 8 U/L, significantly lower than that of the NMDA group (138 U/L +/- 12 U/L, P < 0.01) and significantly higher than that of the MK-801 group (47 U/L +/- 7 U/L, P < 0.05). The inward current (I(NMDA)) of the NMDA group was significantly activated, The inhibitory rate of the NMDA-activated I(NMDA) of the GBE group was 40% +/- 17%, significantly lower than that of the MK-801 group (78% +/- 18%, P < 0.05); After washing out with standard extracellular solution, the I(NMDA) could recover to 91% +/- 8% in the GBE group, but not in the MK-801 group (P < 0.05), which indicated that GBE had lower affinity to NMDA receptor than MK-801. The Longa's scores of the 3 h and 24 h IR subgroups of the GBS pretreatment group were all significantly lower than those of the corresponding subgroups of the standard MCAO and GBE acute administration groups. The symptoms of the MK-801 were the most severe. Cerebral infarction began to appear in the 1-day subgroups. The cerebral infarction areas of the 1 d subgroups of the GBF pretreatment and MK-801 groups were 11.5% +/- 1.3% and 6.5% +/- 0.9% respectively, both significantly smaller than those of the MCAO and GBE acute administration groups (24.5% +/- % and 22.9% +/- 1.3% respectively, both P < 0.01), however, there was no significant difference in the cerebral infarction area between the GBE acute administration and MCAO group. It was true too for the cerebral infarction areas of the 7 d subgroups. Except in the control group, loss of NeuN positive neuron was seen in all groups, especially the MCAO and GBE acute administration groups. Except in the control group, the MAP-2 positive neurons were decreased in all groups, especially the MCAO and GBE acute administration groups, and 1 day and 7 days after the IR MAP-2 positive neurons were almost unseen in the MCAO and GBE acute administration groups, however, could be seen in small amounts in the GBE and MK-801 groups (all P < 0.01). CONCLUSION: GBE pretreatment protects the neurons from excitotoxicity induced by over-activated NMDA receptor and focal cerebral ischemia, which can be explained by the mild blocking effect of GBE on NMDA receptor with low affinity, comparing with MK-801, and GBE is expected to interfere in excitotoxicity in clinic without neurotoxic behaviors.