A non-linear relationship between triglyceride glucose waist circumference and nonalcoholic fatty liver disease in a Japanese population: a secondary analysis.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disorder associated with insulin resistance (IR). Triglyceride glucose waist circumference (TyG-WC) is a novel index of IR that reflects both visceral fat and hepatic steatosis. However, it is not known whether TyG-WC and NAFLD exhibit a nonlinear relationship in Japanese subjects with normal plasma glucose level. Thus, we examined the relationship between TyG-WC and NAFLD, in addition to determining the threshold level of TyG-WC associated with NAFLD. Methods: A secondary analysis was performed based on a previous study that extracted medical examination records from Murakami Memorial Hospital between 2004 and 2015 in order to detect chronic diseases and their risk factors. TyG-WC was determined at baseline. NAFLD is the dependent variable. Univariate and multivariate logistic regression models were used to evaluate the risk of NAFLD incidence. Based on the smoothing plot, a two-piecewise linear regression model was used to examine the threshold effect of TyG-WC on NAFLD. A subgroup analysis was carried out in order to study other factors that may influence the association between TyG-WC and NAFLD. Results: 14,280 met the criteria for inclusion in the current secondary analysis. The adjusted OR (95% CI) for NAFLD in all subjects was 1.007 (95% CI 1.006-1.009, P < 0.001). The relationship between TyG-WC and NAFLD in Japanese subjects with normal plasma glucose level is nonlinear. TyG-WC is positively associated with NAFLD when TyG-WC is ranged between 480 and 800. In subgroup analyses, there was a significant interaction between BMI and TyG-WC associated NAFLD risk (P for interaction <0.001). Discussion: The relationship between TyG-WC and NAFLD is nonlinear. TyG-WC is positively associated with NAFLD when TyG-WC is ranged between 480 and 800. There is potential clinical significance for the TyG-WC in identifying groups at high risk for NAFLD in subjects with normal plasma glucose level.

PGAM4 silencing inhibited glycolysis and chemoresistance to temozolomide in glioma cells.

Gliomas account for about 80% of malignant brain tumors. The incidence of a new brain tumor is 6.4 per 100,000 persons per year with an overall 5-year survival rate of 33.4%. Regardless of the great advances that have been made in recent years, the causes and pathogenesis of glioma remain unclear. Here we study how phosphoglycerate mutase 4 (PGAM4) contributes to glioma. Using a variety of methods to examine glioma cell viability, proliferation, apoptosis, glycolysis, as well as ChIP coanalysis with modified histone H3, we showed that PGAM4 was significantly upregulated in patients with glioma and associated with poor survival. Silencing PGAM4 attenuated cell viability, proliferation, and glycolysis in T98G cells and suppressed tumor growth in vivo, while overexpressing PGAM4 promoted cell viability, proliferation, and glycolysis in U251 cells via regulating glycolysis pathway. Study also revealed that PGAM4 was regulated by EP300-mediated modifications of H3K27ac. PGAM4 silencing inhibited cell viability and proliferation, suppressed tumor growth, and decreased chemoresistance to temozolomide in glioma cells through suppressing glycolysis.

Chemical profiling and identification of anti-osteoporosis chemical-markers of Cinnamomum cassia (L.) presl extracts using GC-MS and spectrum-activity analyses.

Cinnamomum cassia (L.) Presl (cinnamon), an important folk medicine is widely used to prevent osteoporosis for long time in China. Our study aimed to investigate the anti-osteoporosis activity and mechanisms of cinnamon extracts obtained by supercritical CO2 extraction (SFE) and identify activity associated chemical components by gas chromatography-mass spectrometry. The cinnamon SFE exhibited superior anti-osteoporosis efficacy in an ovariectomised mice model to common alcohol extracts. It could induce calcified nodules and ALP activity, upregulate the mRNA expression of ALP, BMP-2, and RUNX2 in MC3T3-E1 cells. The major chemical classes of cinnamon extracts were alcohol esters (28.2%), and terpenes (16.1%). The spectrum-activity analysis indicated that the potential chemical-markers of extracts could be (E)-Cinnamaldehyde, γ-Sitosterol, and (Z, Z)-9,12-Octadecadienoic acid, which could induce the proliferation and ALP activity in MC3T3-E1 cells. Our study revealed the promising applications of the cinnamon SFE in prevention of osteoporosis, and identified its anti-osteoporosis associated compounds.

CCL2 activates AKT signaling to promote glycolysis and chemoresistance in glioma cells.

The incidence of gliomas is increasing. Although great progress in glioma treatment has been made, the clinical outcome remains unsatisfactory. Chemokine (C-C motif) ligand 2 (CCL2) plays a key role in different types of cancers, including glioma. However, the function of CCL2 in glioma chemoresistance is not fully understood. In the current study, CCL2 was significantly upregulated in glioma. More importantly, CCL2 and CCR2 were significantly upregulated in temozolomide (TMZ)-resistant glioma. TMZ-resistant malignant glioblastoma cells (U251/TMZ) had higher expressions of CCL2 and CCR2 and a higher level of glycolysis as compared to its parental cell line U251. Silencing of CCL2 in U251/TMZ cells inhibited glycolysis. Overexpression of CCL2 reduced TMZ-induced apoptosis through activation of the AKT pathway and promotion of glycolysis. Moreover, overexpression of CCL2 significantly reduced the antitumor effect of TMZ in vivo. In conclusion, CCL2 overexpression reduced the antitumor effect of TMZ by enhancing glycolysis through activation of AKT signaling. The findings highlighted the importance of CCL2/CCR2/glycolysis and its potential value in developing new treatment for glioma.

Valtrate as a novel therapeutic agent exhibits potent anti-pancreatic cancer activity by inhibiting Stat3 signaling.

BACKGROUND: Valtrate is a novel epoxy iridoid ester isolated from Chinese herbal medicine Valeriana jatamansi Jones with anti-proliferative activity against various human cancer cell lines. However, its efficacy and molecular mechanisms against pancreatic cancer (PC) cells are largely unclear. PURPOSE: To investigate the anti-cancer effects of valtrate on PC cell lines and its underlying mechanisms. METHODS: MTT assay was first performed to detect the effect of valtrate on cell viability in human PC cell lines and normal pancreatic epithelial cells HPDE. Cell apoptosis and cycle phase assay were detected by flow cytometry. The relative mRNA expressions of Bax, Bcl-2, c-Myc, and CyclinB1 were tested by quantitative PCR (qPCR) assay. The expression of relative proteins was detected by Western blotting (WB). A PANC-1luc cells xenograft mouse model in nu/nu female mice was used to elucidate the effect of valtrate on tumor growth in vivo. RESULTS: Valtrate significantly inhibited the growth of PC cells without affecting the growth of normal pancreatic epithelial cells HPDE, induced significant apoptosis and cell cycle arrest in G2/M phase. Moreover, valtrate inhibited the tumor growth of PC cell PANC-1 in xenograft mice by 61%. Further mechanism study demonstrated that valtrate could increase the expression level of Bax, suppress Bcl-2 as well as c-Myc and Cyclin B1, inhibit the transcriptional activity of Stat3, while valtrate decreased the expression level of Stat3 and phosphated-Stat3 (Tyr705) and induced the high molecular aggregation of Stat3. Molecular docking analysis predicted that valtrate might interact with Cys712 of Stat3 protein. Valtrate could also induce a transient depleted intracellular glutathione (GSH) level and increased reactive oxygen species (ROS). NAC (N-acetylcysteine), a reducer reversed valtrate-induced the depletion of Stat3, p-Stat3, c-Myc, and Cyclin B1. CONCLUSION: Valtrate exerts anti-cancer activity against PC cells by directly targeting Stat3 through a covalent linkage to inhibit Stat3 activity, which causes apoptosis and cell cycle arrest.

Association of body mass index, waist circumference, and metabolic syndrome with serum cystatin C in a Chinese population.

BACKGROUND: The aim of the study was to evaluate the association of body mass index (BMI), waist circumference (WC), and metabolic syndrome (MetS) with serum cystatin C (CysC) in a Chinese population. METHODS: The population was composed of 5866 subjects. MetS was diagnosed using the American Heart Association/National Heart, Lung, and Blood Institute 2005 (NCEP-R) criteria. Covariates were analyzed using logistic regression and Spearman partial correlation. RESULTS: In this population, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), high sensitivity C-reactive protein (hs-CRP), BMI, WC, systolic blood pressure (SBP), diastolic blood pressure (DBP), serum creatinine (Scr), and CysC were significantly higher, and HDL-C and the estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration) (eGFRCKD-EPI) were significantly lower in the MetS than in the non-MetS group. TG, LDL-C, FPG, hs-CRP, BMI, WC, SBP, DBP, and Scr were significantly higher, and HDL-C and eGFRCKD-EPI were significantly lower in the 4th quartile than in the 1st quartile of CysC. Logistic regression analysis showed that sex, age, hs-CRP, and CysC were independently associated with the presence of MetS (OR = 3.732, 1.028, 1.051, and 3.334, respectively; P < 0.05). No significant association between the presence of MetS and either Scr or eGFRCKD-EPI was observed. After adjustment for age and sex, BMI, WC, hs-CRP, and Scr were all positively correlated, whereas eGFRCKD-EPI was negatively correlated with CysC (r = 0.029, 0.061, 0.189, 0.227, and -0.210, respectively; P < 0.05). CONCLUSION: The present study revealed that the CysC was more closely associated with the presence of MetS, as compared Scr or eGFRCKD-EPI. CysC was positively correlated with BMI, and more strongly, positively correlated with WC and inflammation.

Coix seed emulsion synergistically enhances the antitumor activity of gemcitabine in pancreatic cancer through abrogation of NF-κB signaling.

Clinical outcomes in patients with pancreatic cancer (PC) continue to be dismal, in part due to de novo and acquired chemoresistance. In the present study, we provide preclinical evidence that pre-treatment with coix seed emulsion, an injectable agent extracted from coix seeds, synergistically sensitized PC cell lines (BxPC-3, PANC-1 and AsPC-1) to gemcitabine, both in vitro and in vivo. Such pretreatment led to significant induction of pro-apoptosis proteins, including caspase-3, cleaved-PARP and Bax (P<0.05), after lower doses of gemcitabine compared to monotherapy. We also showed that coix seed emulsion suppressed the constitutive and gemcitabine-induced activation of nuclear factor-κB (NF-κB), as shown with the use of electrophoretic mobility shift, reporter and immunoblotting analyses. Coix seed emulsion pretreatment also downregulated the NF-κB-dependent anti­apoptotic molecules Bcl-2, survivin and cyclooxygenase-2. In vivo, coix seed emulsion combined with gemcitabine had a much greater antitumor effect than the effect of either agent alone, consistent with the downregulation of the proliferation index, and the results of immunostaining for Ki-67, or for the NF-κB subunit p65. Overall, our data demonstrated that coix seed emulsion abrogated gemcitabine-induced activation of NF-κB, and synergistically sensitized PC cells to gemcitabine therapy.

Pharmacokinetics of propafenone hydrochloride sustained-release capsules in male beagle dogs.

This paper describes the development and validation of a liquid chromatography-mass spectrometric assay for propafenone and its application to a pharmacokinetic study of propafenone administered as a new propafenone hydrochloride sustained-release capsule (SR-test), as an instant-release tablet (IR-reference) and as the market leader sustained-release capsule (Rythmol, SR-reference) in male beagle dogs (n=8). In Study A comparing SR-test with IR-reference in a crossover design T max and t 1/2 of propafenone for SR-test were significantly higher than those for IR-reference while C max and AUC were lower demonstrating the sustained release properties of the new formulation. In Study B comparing SR-test with SR-reference the observed C max and AUC of propafenone for SR-test (124.5±140.0 ng/mL and 612.0±699.2 ng·h/mL, respectively) were higher than for SR-reference (78.52±72.92 ng/mL and 423.6±431.6 ng·h/mL, respectively) although the differences were not significant. Overall, the new formulation has as good if not better sustained release characteristics to the market leader formulation.

Association between Insulin Resistance, Metabolic Syndrome and Nonalcoholic Fatty Liver Disease in Chinese Adults.

BACKGROUND: The aim of this study was to assess the association between insulin resistance, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in Chinese adults. METHODS: Fifty five subjects with NAFLD and 55 controls were enrolled for the study. Waist circumference, blood pressure, plasma triglyceride, high density lipoprotein cholesterol and fasting plasma glucose concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) values as an index used to quantify insulin resistance were measured and analyzed. Logistic regression was analyzed to predict independent risk factors of NAFLD. RESULTS: The prevalence of metabolic syndrome in NAFLD group was obviously higher than in controls group (47.3% VS 3.6%, P<0.001). There were all significant differences of each component of metabolic syndrome and HOMA-IR values in comparison of nonalcoholic fatty liver disease (NAFLD) and controls group. In a logistic regression analysis, age, diastolic blood pressure, waist circumference and HOMA-IR were the covariates independently associated with the presence of NAFLD (Odds Ratio=1.107, 1.083, 1.218 and 16.836; 95% CI: 1.011∼1.211, 1.001∼1.173, 1.083∼1.370 and 3.626∼78.168, respectively; P<0.05) CONCLUSION: NAFLD was closely associated with metabolic syndrome and insulin resistance was a very strong predictor of NAFLD.

Association of the apolipoprotein B/apolipoprotein A-I ratio and low-density lipoprotein cholesterol with insulin resistance in a Chinese population with abdominal obesity.

The aim of this study is to assess the relationships among the apolipoprotein B/apolipoprotein A-I ratio (apoB/apoA-I ratio), low-density lipoprotein cholesterol (LDL-C) and insulin resistance (IR) in a Chinese population with abdominal obesity. This is a population-based, cross-sectional study of 3,945 men and 2,141 women with abdominal obesity. Individuals were referred to a primary health service and recruited for analysis. IR was measured using a homeostasis model assessment of insulin resistance (HOMA2-IR) with a HOMA2 calculator. Metabolic syndrome (MetS) was diagnosed using International Diabetes Federation (IDF) criteria. Comparing the apoB/apoA-I ratio and lipid indices using the HOMA2-IR showed that the ratio, LDL-C, total cholesterol level (TC) and triglyceride level (TG) were higher; and the high-density lipoprotein cholesterol level (HDL-C) was lower in the fourth than in the first quartile in both sexes (p ≤ 0.001). After adjustment for age, HOMA2-IR was positively correlated with the apoB/apoA-I ratio, LDL-C, TC and TG; and negatively correlated with HDL-C in men (all p < 0.0001). HOMA2-IR was also positively correlated with the apoB/apoA-I ratio, LDL-C, TC and TG; and negatively correlated with HDL-C in women (all p < 0.01). After adjustment for age and LDL-C, HOMA2-IR was found to be correlated with the apoB/apoA-I ratio in both men and women (r = 0.066 and 0.116, p < 0.0001). After adjustment for age and the apoB/apoA-I ratio, HOMA2-IR was correlated with LDL-C in men and women (r = 0.063 and 0.044, p < 0.0001 and p = 0.0431, respectively). Gender, age, LDL-C, BMI, HOMA2-IR and apoB/apoA-I were the covariates independently associated with presence of the MetS (Odds ratio, OR: 2.183, 1.034, 1.013, 1.157, 1.726 and 1.570, respectively; all p < 0.05). In conclusion, the study showed that the apoB/apoA-I ratio and LDL-C were positively correlated with IR. Excluding reciprocal interactions, the apoB/apoA-I ratio and LDL-C were still significantly correlated with IR, but the apoB/apoA-I ratio showed a greater correlation with IR than LDL-C in women with abdominal obesity, compared with men with abdominal obesity. Both LDL-C and apoB/apoA-I were independent risk factors of MetS, and the apoB/apoA-I ratio was stronger in this regard than LDL-C for this obese population.