Superoxide dismutases: marker in predicting reduced left ventricular ejection fraction in patients with type 2 diabetes and acute coronary syndrome.

AIM: To examine the prognostic value of superoxide dismutase (SOD) activity for monitoring reduced left ventricular ejection fraction(LVEF)in the patients with type 2 diabetes and acute coronary syndrome (ACS). METHODS: The population of this cross-sectional study included 2377 inpatients with type 2 diabetes who had an ACS admitted to the Shandong Provincial Hospital Affiliated to Shandong First Medical University from January 2016 to January 2021. RESULTS: Diabetic patients with ACS were divided into 2 subgroups based on LVEF. The mean SOD activity was significantly lower in patients with an LVEF ≤ 45% than in those with an LVEF > 45% (149.1 (146.4, 151.9) versus 161.9 (160.8, 163.0)). Using ROC statistic, a cut-off value of 148.8 U/ml indicated an LVEF ≤ 45% with a sensitivity of 51.6% and a specificity of 73.7%. SODs activity were found to be correlated with the levels of NT-proBNP, hs-cTnT, the inflammatory marker CRP and fibrinogen. Despite taking the lowest quartile as a reference (OR 0.368, 95% CI 0.493-0.825, P = 0.001) or examining 1 normalized unit increase (OR 0.651, 95% CI 0.482-0.880, P = 0.005), SOD activity was found to be a stronger predictor of reduced LVEF than CRP and fibrinogen, independent of confounding factors. CONCLUSIONS: Our cross-sectional study suggests that SOD activity might be a valuable and easily accessible tool for assessing and monitoring reduced LVEF in the diabetic patients with ACS.

Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy in patients with congenital hypogonadotropic hypogonadism: a multicentre clinical study.

BACKGROUND: Pulsatile gonadotropin-releasing hormone (GnRH) therapy may restore function of the hypothalamus-pituitary-gonad axis and induce spermatogenesis in male patients with congenital hypogonadotropic hypogonadism (CHH). The study sought to test the reliability of a newly developed Innopump® hormone pump, and to confirm the efficacy and safety of pulsatile GnRH therapy (by Innopump® hormone pump) in CHH patients. METHODS: From November 2017 to November 2018, 28 male patients with CHH were treated with pulsatile GnRH at Peking Union Medical College Hospital, Beijing Chaoyang Hospital, and Shandong Provincial Hospital. A prospective, self-controlled, 7-day clinical trial was conducted. The primary outcome measures were the efficacy and safety of pulsatile GnRH therapy (which was administered via the Innopump® hormone pump). The secondary outcome measures included total serum testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels. RESULTS: All of the patients participated the clinical study. For 7 days, a dosage prescribed by doctors was accurately administered by the Innopump® hormone pump, and recorded by the pump. During the treatment, LH and FSH levels gradually increased to 2.66±1.74 and 5.05±3.03 IU/L, respectively. Upper respiratory tract infection in 1 patient and slight nausea in another patient were reported, which were confirmed to be unrelated to the pulsatile GnRH therapy. CONCLUSIONS: The Innopump® hormone pump was found to be reliable in drug administration, and to have an accurate alarming system. It effectively and safely treated patients with CHH. Pulsatile GnRH therapy may produce a physiological pattern of GnRH secretion, and re-establish pituitary-gonad axis function by increasing gonadotropin levels.

NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic ß-cells for protection.

Sustained hyperglycaemia and hyperlipidaemia incur endoplasmic reticulum stress (ER stress) and reactive oxygen species (ROS) overproduction in pancreatic ß-cells. ER stress or ROS causes c-Jun N-terminal kinase (JNK) activation, and the activated JNK triggers apoptosis in different cells. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an inducible multi-stress response factor. The aim of this study was to explore the role of NR4A1 in counteracting JNK activation induced by ER stress or ROS and the related mechanism. qPCR, Western blotting, dual-luciferase reporter and ChIP assays were applied to detect gene expression or regulation by NR4A1. Immunofluorescence was used to detect a specific protein expression in ß-cells. Our data showed that NR4A1 reduced the phosphorylated JNK (p-JNK) in MIN6 cells encountering ER stress or ROS and reduced MKK4 protein in a proteasome-dependent manner. We found that NR4A1 increased the expression of cbl-b (an E3 ligase); knocking down cbl-b expression increased MKK4 and p-JNK levels under ER stress or ROS conditions. We elucidated that NR4A1 enhanced the transactivation of cbl-b promoter by physical association. We further confirmed that cbl-b expression in ß-cells was reduced in NR4A1-knockout mice compared with WT mice. NR4A1 down-regulates JNK activation by ER stress or ROS in ß-cells via enhancing cbl-b expression.

Association Between Thyroid Nodules and Volume and Metabolic Syndrome in an Iodine-Adequate Area: A Large Community-Based Population Study.

Background: Given its high incidence, thyroid nodule (TN) warrants public attention. Thyroid volume (TV) has also been associated with multiple factors, such as iodine deficiency and supply and body mass index. It is well known that metabolic syndrome (MetS) comprises many metabolic disturbances, with insulin resistance being its major component. Materials and Methods: The aim of this study was to investigate the relationship between TN and TV and MetS and its components in an iodine-adequate area in Asia. All participants were asked to complete a questionnaire. After excluding 938 individuals based on the exclusion criteria, we reviewed data from 927 of 1865 participants. Adopting MetS diagnostic criteria, we found 437 subjects to be MetS positive [MetS(+)] and 490 subjects to be MetS negative [MetS(-)], respectively. Multivariate linear regression was used to assess the relationship between TNs and MetS. Moreover, univariate binary logistic regression analyses were used to calculate odds ratios (ORs), and 95% confidence intervals (CIs) were used to estimate the associations between different variables and TNs. Results: A total of 232 females and 205 males were MetS(+), as diagnosed using the International Diabetes Federation criteria. However, there were 330 females and 160 males in the group of MetS(-) individuals. The prevalence of TNs was 38.29% in the MetS(+) group and 17.79% in the MetS(-) group. After adjusting for systolic blood pressure, diastolic blood pressure, and gender, only high-density lipoprotein, waist circumference (WC), and age were related to TNs (OR = 0.45, 95% CI 0.27-0.75, P = 0.0023; OR = 1.04, 95% CI 1.02-1.06, P = 0.0036). The TV of all participants was 13.98 (11.24, 17.01) mL; 13.26 (10.62, 16.17) mL for females and 14.96 (11.83, 18.01) mL for males. It was found that only WC was related to TV, after controlling for sex and age (P = 0.02). Conclusions: The morbidity among TN patients in the MetS(+) group was higher than that among the MetS(-) group. High-density lipoprotein cholesterol emerged as a protective factor, and WC was a risk factor for TN. Moreover, TV was related to MetS, and WC was an independent risk factor for TV.

The Effect of Statins on Levels of Dehydroepiandrosterone (DHEA) in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND Currently, statins are used to treat polycystic ovary syndrome (PCOS). This systematic review and meta-analysis aimed to investigate the effect of statins on serum or plasma levels of dehydroepiandrosterone (DHEA) in women with PCOS. MATERIAL AND METHODS Databases that were searched included PubMed, Embase, and the Cochrane Library from their inception to August of 2018. Published randomized controlled trials (RCTs) were identified that evaluated the impact of statins on plasma DHEA levels in women with PCOS. The Cochrane risk of bias tool was used to assess the quality of the included RCTs. A random-effects model was used to analyze the pooled results. RESULTS Meta-analysis was performed on data from ten published studies that included 735 patients and showed that statin treatment could significantly reduce plasma DHEA levels when compared with controls (SMD, -0.43; 95% CI, -0.81-0.06; p=0.02; I²=82%). Statins were significantly more effective than placebo in reducing the levels of DHEAs. Subgroup analysis based on statin type showed that atorvastatin significantly reduced DHEA levels (SMD, -0.63; 95% CI, -1.20 - -0.05; p=0.03; I²=38%) but simvastatin did not significantly reduce DHEA levels (SMD: -0.14; 95% CI, -0.49-0.28; p=0.43; I²=77%). Subgroup analysis based on duration of treatment showed no significant difference between 12 weeks of statin treatment (SMD, -0.61; 95% CI, -1.23-0.02; p=0.06; I²=85%) and 24 weeks (SMD, -0.34; 95% CI -0.95-0.28; p=0.29; I²=83%). CONCLUSIONS Meta-analysis showed that statins significantly reduced the levels of DHEA when compared with placebo in patients with PCOS.

Study on the expression of p53 and MMP-2 in patients with lung cancer after interventional therapy.

The aim of the study was to investigate the expression of tumor suppressor gene p53 and MMP-9 in non-small cell lung cancer (NSCLC) before and after chemotherapy, and investigate its association with the effect of chemotherapy and prognosis. Fifty-eight elderly NSCLC patients comprised the observation group. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of p53 and MMP-9 in lung cancer tissues before and after chemotherapy. Immunohistochemistry and western blot analysis were used to detect the expression of p53 and MMP-9 proteins in NSCLC tissue before and after chemotherapy. Terminal deoxynucleotidyl transferase nick end-labeling (TUNEL) was used to detect apoptotic cells. The association between the effect of chemotherapy and the expression of p53 and MMP-9 in lung cancer tissues was analysed. RT-qPCR results showed that the expression of p53 and MMP-2 mRNA in the tumor tissue after chemotherapy was significantly lower than that in the tumor tissue before chemotherapy. Western blot analysis revealed that the expression of p53 and MMP-2 protein in the tumor tissue after chemotherapy was significantly decreased. The positive expression of p53 and MMP-2 in lung cancer tissues before chemotherapy was 76.25 and 71.25%, respectively, and were reduced to 27.50 and 23.75%, respectively, after chemotherapy. After chemotherapy, the positive rates of p53 and MMP-2 were significantly lower than those before chemotherapy. TUNEL results showed that the apoptosis index increased significantly after chemotherapy. Efficiency of chemotherapy in patients with a negative expression of p53 and MMP-2 in lung cancer before chemotherapy was significantly higher than that in patients with a positive p53 and MMP-2 expression. A significant difference was found in the expression levels of p53 and MMP-2 in lung cancer before and after chemotherapy. The findings of the present study indicate that the expression levels of p53 and MMP-2 can be used as a predictor of chemotherapy sensitivity.

Atherogenic Index of Plasma is Associated with Body Fat Level in Type 2 Diabetes Mellitus Patients.

OBJECTIVE: To investigate the characteristics of body fat distribution and the relationship between body fat index and Atherogenic Index of Plasma (AIP) in Type 2 Diabetes Mellitus (T2DM) patients. METHODS: A total of 316 participants were divided into a T2DM group and a non-diabetes group (controls). According to the Visceral Fat Area (VFA), all participants were further divided into VFA ≥100 cm2 and VFA <100 cm2 groups. To compare the differences of blood lipid, blood glucose, body fat index and AIP between the 2 groups, single factor correlation analysis was used to determine the correlation between the indexes and AIP, and multiple linear regression was used to analyse the correlation between the related factors and AIP. RESULTS: The body fat index (including body fat content, Percentage of Body Fat (PBF), Waist to Hip Fat Ratio (WHR) and VFA), Triglyceride (TG), Fasting Insulin (FINS), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and AIP in T2DM group were significantly higher than in the control group, while High Density Lipoprotein Cholesterol (HDL-C) level was significantly higher in the control group. In the VFA≥100 cm2 group, TG, Low Density Lipoprotein Cholesterol (LDL-C), FINS, HOMAIR and AIP were all higher than that in the VFA <100 cm2 group. There was a positive correlation between AIP and VFA, body fat content, percentage of body fat, and WHR, respectively. There was also a negative correlation between AIP and HDL-C, which was not related to age, sex, Fasting Glucose (FPG), glycosylated haemoglobin (HbA1c), Total Cholesterol (TC), LDL-C and course of disease. Compared with the VFA <100 cm2 group, the VFA ≥100 cm2 group had higher blood Uric Acid (UA) levels and UA was positively correlated with VFA. After correcting the effect of UA on AIP, VFA was still an independent related factor of AIP, and VFA increased the risk of atherosclerosis by increased UA. CONCLUSION: T2DM patients have the abnormal distribution of body fat and a high VFA, which was associated with AIP.

[Effect of Tangshenkang Granule containing serum on renal mesangial cells' proliferation and TGF-ß1/Smad2/3 pathway in the high glucose condition].

OBJECTIVE: To study the effect of Tangshenkang Granule (TG) containing serum on renal mesangial cells' (RMCs) proliferation and TGF-ß1/Smad2/3 pathway in the high glucose condition. METHODS: Twelve SD rats were randomly divided into four groups, i.e., the low dose TG group, the middle dose TG group, the high dose TG group, and the blank control group, 3 in each group. After 7-day gastrogavage via portal vein blood, rats were sacrificed and their serum samples were collected. RMCs were cultured in common rat serum and TG containing serum respectively. The proliferation of mesangial cells was determined by methly thiazolyl tetrazolium (MTT) assay to determine the optimal TG containing serum concentration. Expression levels of TGF-ß1 mRNA and protein were determined by real time quantitative PCR and ELISA. Smad2/3 protein expression and phosphorylation were determined by Western blot and immunofluorescence. RESULTS: TG containing serum at different doses could inhibit high glucose induced RMC cells' proliferation, TGF-ß1 over-expression and Smad2/3 phosphorylation. CONCLUSION: TG containing serum could inhibit high glucose induced RMC cells' proliferation, and its mechanism might be possibly associated with inhibiting TGF-ß1/Smad2/3 signaling pathway.

Effects of periodontal treatment on glycemic control in type 2 diabetic patients: a meta-analysis of randomized controlled trials.

The association between diabetes and inflammatory periodontal diseases has been studied extensively. However, there is a lack of robustness and homogeneity among studies describing effects of periodontal treatment on glycemic control. The aim of this study was to carry out a meta-analysis to understand whether periodontal treatment could improve glycemic control in type 2 diabetic patients. Electronic searches were carried out on MEDLINE, EMBASE and the Cochrane central register of controlled trials from 1980 to July 2012. Randomized controlled trials of periodontal therapy on glycemic control in diabetic patients with a minimum of 3 months of follow-up were included. Meta-analysis was carried out with 8 studies involving 515 participants using Stata 11.0 software. Our results showed that periodontal treatment could lead to a significant decrease in HbA1c level. The standardized mean difference between intervention groups and control groups was significant: 1.03% (95% confidence interval: 0.31% to 1.70%, P = 0.003) from baseline to 3 months, and 1.18% (95% confidence interval: 0.72% to 1.64%, P < 0.001) from baseline to 6 months. Periodontal treatment could lead to a non-significant decrease in fasting plasma glucose (FPG) levels from baseline to 3 months. The standardized mean difference between the intervention and the control group was 0.69 mg/dl (95% confidence interval: -0.27 mg/dl to 1.66 mg/dl, P = 0.158). Our analysis indicated that periodontal treatment could improve glycemic control in type 2 diabetic patients with periodontal diseases.

Chronic ethanol consumption increases the levels of chemerin in the serum and adipose tissue of humans and rats.

AIM: Chemerin is a new adipokine involved in adipogenesis and insulin resistance. Since ethanol affects the insulin sensitivity that is closely associated with adipokines. The aim of this study was to investigate the effects of ethanol on chemerin in humans and rats. METHODS: In the human study, 148 men who consumed alcohol for more than 3 years and 55 men who abstained from alcohol were included. Based on ethanol consumption per day, the drinkers were classified into 3 groups: low-dose (<15 g/d), middle-dose (15-47.9 g/d) and high-dose (≥48 g/d). Anthropometric measurements and serum parameters were collected. In the rat study, 27 male Wistar rats were randomly divided into 4 groups administered water or ethanol (0.5, 2.5, or 5 g·kg(-1)·d(-1)) for 22 weeks. The chemerin levels in the sera, visceral adipose tissue (VAT) and liver were measured using ELISA. RESULTS: In the high-dose group of humans and middle- and high-dose groups of rats, chronic ethanol consumption significantly increased the serum chemerin level. Both the middle- and high-dose ethanol significantly increased the chemerin level in the VAT of rats. In humans, triglyceride, fasting glucose, insulin and HOMA-IR were independently associated with chemerin. In rats, the serum chemerin level was positively correlated with chemerin in the VAT after adjustments for the liver chemerin (r=+0.768). High-dose ethanol significantly increased the body fat in humans and the VAT in rats. CONCLUSION: Chronic ethanol consumption dose-dependently increases the chemerin levels in the serum and VAT. The serum chemerin level is associated with metabolic parameters in humans. The increased serum chemerin level is mainly attributed to an elevation of chemerin in the VAT after the ethanol treatment.

Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes.

AIM: The roles of AMP-activated protein kinase (AMPK) and myocyte enhancer factor 2 isoforms (MEF2A, D) as mediators of the effects of ethanol on glucose transporter 4 (GLUT4) expression are unclear. We studied the effects of ethanol in adipocytes in vivo and in vitro. METHODS: Thirty-six male Wistar rats were divided into three groups and given ethanol in a single daily dose of 0, 0.5, or 5 g/kg for 22 weeks. The expression of AMPK, MEF2 isoforms A and D, and GLUT4 was measured and compared in the three groups. The existence of the AMPK/MEF2/GLUT4 pathway in adipocytes and the effects of ethanol on this pathway were studied in (a) epididymal adipose tissue from six male Wistar rats subcutaneously injected with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, an AMPK activator) or with 0.9% NaCl (control); and (b) isolated rat and human adipocytes treated with or without ethanol, AICAR, and compound C (a selective AMPK inhibitor). Expression of AMPK, MEF2, and GLUT4 was measured by RT-PCR and Western blotting. RESULTS: (1) Long-term ethanol exposure decreased activated AMPK, MEF2A, MEF2D, and GLUT4 expression in rat adipose tissue. (2) In rat and human adipocytes, AICAR-induced AMPK activation, with subsequent elevation of MEF2 and GLUT4 expression, was inhibited by compound C. (3) In vitro ethanol-treatment suppressed the AMPK/MEF2/GLUT4 pathway. CONCLUSION: The AMPK/MEF2/GLUT4 pathway exists in both rat and human adipocytes, and activated AMPK may positively regulate MEF2 and GLUT4 expression. Ethanol inhibition of this pathway leads to decreased GLUT4 expression, thus reducing insulin sensitivity and glucose tolerance.

[Genotype analysis of killer cell immunoglobulin-like receptors in Graves' disease patients].

AIM: Killer cell immunoglobulin-like receptor (KIR) can modulate the activity of NK and T lymphocyte. To investigate whether the KIR genotype possessing a susceptibility to Graves disease (GD). METHODS: Using PCR-SSP to detect KIR genotype in 96 GD patients and 96 randomly selected healthy controls. RESULTS: The genotype frequency of 2DS2-, 2DL2-, 2DL3+, 2DL1+, 3DL1+, 3DS1-, 2DL5-, 2DS3-, 2DS5-, 2DS1-, 2DS4- was significantly higher in the patient group compared to that of the control group (6.25% vs 0%, P<0.05). Genotype of 2DS2-, 2DL2-, 2DL3+, 2DL1+, 3DL1+, 3DS1-, 2DL5-, 2DS3-, 2DS5-, 2DS1-, 2DS4+ is the most prevalent in the controls (28.13% vs 10.42%, P<0.01). Genotypes without activating KIR genes have higher frequency in patient group. CONCLUSION: The difference of KIR genotypes between GD patients and healthy controls may explain the pathogenesis of GD.

Insulin-like growth factor-1 promotes cell cycle progression via upregulation of cyclin D1 expression through the phosphatidylinositol 3-kinase/nuclear factor-kappaB signaling pathway in FRTL thyroid cells.

AIM: Insulin-like growth factor-1 (IGF-1) is an important hypertrophic and cell cycle progression factor for a number of cell types. It has been proven that IGF-1 is involved in the regulation of thyroid proliferation and cell cycle progression; however, the exact mechanism of this regulation has not been fully elucidated. In the present study, we investigated the effect of IGF-1 on the expression of cyclin D1, an important cell cycle regulatory protein, and a signaling pathway involved in IGF-1's effect on cyclinD1 expression in FRTL thyroid cells. METHODS: FRTL thyroid cells were treated with IGF-1 or vector control for 24 h. As appropriate to individual experiments, a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and/or a nuclear factor-kappaB (NF-kappaB) inhibitor, BAY11-7082, were added 1 h prior to IGF-1 treatment. Western blotting was used to detect cyclin D1 protein expression. Immunofluorescence was performed to analyze the expression of IkappaBalpha, an NF-kappaB inhibitory protein. Cell cycle analysis was performed by fluorescence activated cell sorting (FACS). RESULTS: IGF-1 increased the cyclin D1 expression in thyroid cells. This increase was blocked by pretreatment with LY294002 or BAY11-7082. Further studies showed that IGF-1 specifically induced NF-kappaB activity. Treatment with IGF-1 could accelerate cell cycle progression from G(0)/G(1) to S phase, whereas this progression was inhibited by the presence of LY294002 or BAY11-7082. CONCLUSION: In summary, the results of the present study show that in FRTL cells, IGF-1 promotes cell cycle progression via an upregulation of cyclin D1 expression, at least partially through the PI3K/NF-kappaB signaling pathway.