Novel and traditional anthropometric indices for identifying arterial stiffness in overweight and obese adults.

BACKGROUND: Obesity and arterial stiffness are both independently associated with cardiovascular risk. New anthropometric indices can better reflect abdominal obesity than traditional anthropometric indices. Thus, we hypothesized that compared with conventional parameters, these newly developed anthropometric parameters were more accurate to identify arterial stiffness among overweight and obesity population. METHODS: Cross-sectional data on socio-demographic, lifestyle, clinical characteristics and biochemical measurements were collected for 1442 Chinese obese and overweight adults. Six anthropometric indices including a body shape index (ABSI), body mass index (BMI), ABSI combined with BMI, body roundness index (BRI), waist circumference and waist-to-hip ratio were calculated. Carotid-femoral pulse wave velocity (cf-PWV) was detected in all subjects. Meanwhile, visceral fat area (VFA) was quantificationally measured by CT. Partial Spearman correlation coefficients were used to clarify the association between anthropometric measures with cf-PWV. Logistic regression analyses were used to identify to the association between anthropometric measures and arterial stiffness. RESULTS: After adjusting for covariates, BRI had the strongest correlation with cf-PWV and VFA in all anthropometric indices. Multivariate regression analysis showed VFA (ß = 0.322, p < 0.001) and BRI (ß = 0.307, p < 0.001) remained independently associated with cf-PWV. BRI had a highest odds ratios in all anthropometric indices (OR = 1.543, p < 0.001). ABSI only displayed a weak correlation with arterial stiffness. Meanwhile, BRI had the highest area under curve for abnormal cf-PWV, and the optimum cutoff value was a BRI ≥5.4. CONCLUSION: BRI was found to have a close relationship with arterial stiffness in overweight and obesity people. However, ABSI was weakly correlated with arterial stiffness, but not better than traditional anthropometric indices.

Tetrandrine and cepharanthine induce apoptosis through caspase cascade regulation, cell cycle arrest, MAPK activation and PI3K/Akt/mTOR signal modification in glucocorticoid resistant human leukemia Jurkat T cells.

Tetrandrine (TET) and cepharanthine (CEP) are two bisbenzylisoquinoline alkaloids isolated from the traditional herbs. Recent molecular investigations firmly supported that TET or CEP would be a potential candidate for cancer chemotherapy. Prognosis of patients with glucocorticoid resistant T cell acute lymphoblastic leukemia (T-ALL) remains poor; here we examined the anti-T-ALL effects of TET and CEP and the underlying mechanism by using the glucocorticoid resistant human leukemia Jurkat T cell line in vitro. TET and CEP significantly inhibited cell viabilities and induced apoptosis in dose- and time-dependent manner. Further investigations showed that TET or CEP not only upregulated the expression of initiator caspases such as caspase-8 and 9, but also increased the expression of effector caspases such as caspase-3 and 6. As the important markers of apoptosis, p53 and Bax were both upregulated by the treatment of TET and CEP. However, TET and CEP paradoxically increased the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1, and activated the survival protein NF-κB, leading to high expression of p-NF-κB. Cell cycle arrest at S phase accompanied by increase in the amounts of cyclin A2 and cyclin B1, and decrease in cylcin D1 amount in cells treated with TET or CEP will be another possible mechanism. During the process of apoptosis in Jurkat T cells, treatment with TET or CEP also increased the phosphorylation of JNK and p38. The PI3K/Akt/mTOR signaling pathway modification appears to play significant role in the Jurkat T cell apoptosis induced by TET or CEP. Moreover, TET and CEP seemed to downregulate the expressions of p-PI3K and mTOR in an independent way from Akt, since these two drugs strongly stimulated the p-Akt expression. These results provide fundamental insights into the clinical application of TET or CEP for the treatment of patients with relapsed T-ALL.

Plant-derived alkaloid sinomenine potentiates glucocorticoid pharmacodynamics in mitogen-activated human peripheral blood mononuclear cells by regulating the translocation of glucocorticoid receptor.

Sinomenine has been used as an antirheumatic drug in China. Glucocorticoid combined with sinomenine could be an alternative therapeutic approach. In this study, we evaluated the sinomenine potential effect on glucocorticoid pharmacodynamics in vitro using a human peripheral blood mononuclear cell (PBMC) culture system. We also disclosed the possible action mechanism of sinomenine with a focus on P-glycoprotein function and glucocorticoid receptor (GR) translocation into nucleus. The median (range) of methylprednisolone IC50 values against the PBMC proliferation was 3.18 (0.45-6.81) ng/mL, whereas the median (range) IC50 values of methylprednisolone combined with 0.03, 0.3, 3, and 30 µM sinomenine were 1.85 (0.05-5.15), 0.83 (0.10-3.90), 0.56(0.09-1.62), and 0.59(0.05-1.30) ng/mL, respectively. Sinomenine significantly decreased the IC50 values of methylprednisolone and enhanced the immunosuppressive effect of methylprednisolone (p < 0.05). Sinomenine alone regulated the GR translocation in both Jurkat T cells and normal human PBMCs, and the combination of sinomenine and methylprednisolone showed stronger GR-modulatory activity than methylprednisolone alone. Thus, the additive effect of sinomenine to promote the methylprednisolone immunosuppressive efficacy was suggested to be related to nuclear GR-translocation. However, sinomenine did not significantly inhibit the P-glycoprotein function in the activated PBMCs, suggesting that sinomenine's additive effect seemed to be unrelated with the P-glycoprotein inhibition.

The feasibility of two anthropometric indices to identify metabolic syndrome, insulin resistance and inflammatory factors in obese and overweight adults.

OBJECTIVES: A body shape index (ABSI) and body roundness index (BRI) were reported to predict diabetes and hypertension in general population, but their validity was regularly questioned. The aim of this study was to evaluate whether ABSI and BRI are the best anthropometric indices to reflect metabolic syndrome (MetS), insulin resistance (IR), and inflammatory factors in obese and overweight Chinese adults. METHODS: Cross-sectional data on sociodemographic, lifestyle, anthropometric indices, clinical characteristics, and biochemical measurements were collected for 1442 Chinese obese and overweight adults. Logistic regression analysis examined the associations between anthropometric indices with incidences of MetS and IR in both sexes. Furthermore, the correlation between anthropometric indices and inflammatory factors was assessed. RESULTS: Multivariate regression analysis depicting BRI and waist circumference (WC) were associated significantly with MetS and IR. BRI had the highest odds ratios (ORs) for IR and WC had the highest ORs for MetS in all anthropometric indices. However, ABSI did not exhibit any association between the MetS and IR. The ABSI adjusted regression coefficients (ß values) were 0.403 for high-sensitivity C reactive protein, 0.077 for tumor necrosis factor-α, and 0.022 for interleukin-6. BRI and WC were also significantly associated with three inflammatory factors. Comparing the lowest with the highest quintile, BRI had the largest ORs for MetS (OR, 5.778; 95% confidence interval [CI], 2.954-11.303; P < 0.01) and IR (OR, 6.212; 95% CI, 2.912-13.250; P < 0.01). CONCLUSION: Only BRI and WC, not ABSI, can significantly determine the presence of MetS and IR. BRI showed the optimal capability to identify IR in obese and overweight population.

Traditional Chinese Medicine for Refractory Nephrotic Syndrome: Strategies and Promising Treatments.

Refractory nephrotic syndrome (RNS) is an immune-related kidney disease with poor clinical outcomes. Standard treatments include corticosteroids as the initial therapy and other immunosuppressants as second-line options. A substantial proportion of patients with RNS are resistant to or dependent on immunosuppressive drugs and often experience unremitting edema and proteinuria, cycles of remission and relapse, and/or serious adverse events due to long-term immunosuppression. Traditional Chinese medicine has a long history of treating complicated kidney diseases and holds great potential for providing effective treatments for RNS. This review describes the Chinese medical theories relating to the pathogenesis of RNS and discusses the strategies and treatment options using Chinese herbal medicine. Available preclinical and clinical evidence strongly supports the integration of traditional Chinese medicine and Western medicine for improving the outcome of RNS. Herbal medicine such as Astragalus membranaceus, Stephania tetrandra S. Moore, and Tripterygium wilfordii Hook F can serve as the alternative therapy when patients fail to respond to immunosuppression or as the complementary therapy to improve therapeutic efficacy and reduce side effects of immunosuppressive agents. Wuzhi capsules (Schisandra sphenanthera extract) with tacrolimus and tetrandrine with corticosteroids are two herb-drug combinations that have shown great promise and warrant further studies.

Small dense low density lipoprotein-cholesterol and cholesterol ratios to predict arterial stiffness progression in normotensive subjects over a 5-year period.

BACKGROUND: Small dense low density lipoprotein-cholesterol (sdLDL-C), cholesterol ratios and carotid-femoral pulse wave velocity (cf-PWV) impart risk for all-cause morbidity and mortality independently of conventional cardiovascular disease (CVD) risk factors. This study was designed to identify feasible indicators for predicting arterial stiffness progression. METHODS: We followed up 816 normotensive participants without diabetes or CVD for nearly 5.0 years. Cholesterol parameters, ratios and other clinical and laboratory data were collected at baseline. cf-PWV were measured at baseline and the end of follow-up. RESULTS: PWV progression subjects had higher levels of PWV parameters, sdLDL-C and TG/HDL-C ratio. sdLDL-C and TG/HDL-C were significantly correlated with all PWV parameters. Multiple regression models showed that sdLDL-C was closely associated with follow-up PWV (ß = 0.222, p < 0.001) and △PWV (ß = 0.275, p < 0.001). TG/HDL-C was only one cholesterol ratios that associated with all PWV parameters. sdLDL-C (OR = 2.070, 95%CI: 1.162 to 3.688, p = 0.014) and TG/HDL-C (OR = 1.355, 95%CI: 1.136 to 1.617, p = 0.001) could significantly determine the progression of PWV after correction for covariates. High sd-LDL-C quantiles subjects were more likely to develop arterial stiffness progression than low quantiles (Tertiles 3 vs Tertiles1, RR = 2.867, 95%CI: 1.106 to 7.434, p = 0.03). CONCLUSION: We founded that sdLDL-C and TG/HDL-C ratio can independently predict arterial stiffness progression in normotensive subjects, and high level sdLDL-C and TG/HDL-C ratio were associated with a higher risk of arterial stiffness.

Autoantibodies against AT1 and α1-adrenergic receptors predict arterial stiffness progression in normotensive subjects over a 5-year period.

Arterial stiffness is an independent indicator of cardiovascular risk. Autoantibodies (AAs) against angiotensin AT1 receptor (AT1-AAs) and α1-adrenergic receptor (α1-AAs) are important in the pathogenesis of hypertension. We identified the types of AT1-AAs and α1-AAs in normotensive subjects, with the aim of determining whether these antibodies predict aortic stiffness progression. Carotid-femoral pulse wave velocity (cf-PWV) was used to measure aortic stiffness. Overall, 816 subjects (71% of those invited) underwent a medical examination and evaluation of aortic stiffness. The types of AT1-AAs and α1-AAs were measured at baseline. Meanwhile, plasma renin, angiotensin II (Ang II), and norepinephrine (NE) concentrations were measured at baseline and follow-up. Baseline mean cf-PWV was 9.90 ± 0.84 m/s and follow-up was 10.51 ± 1.12 m/s. The annualized ΔPWV was 0.12 ± 0.08 m/s/year. At the end of follow-up, 129 normotensive subjects developed hypertension and 144 subjects had PWV progression. After adjustment for covariates, AA type was independently associated with ΔPWV, annualized ΔPWV, and abnormal PWV. In our study, the risk of developing hypertension (RR =2.028, 95% CI: 1.227-3.351, P=0.006) and PWV progression (RR =2.910, 95% CI: 1.612-5.253, P<0.001) in AA-positive subjects was significantly higher than that in AA-negative subjects. Receiver operating characteristic (ROC) curve showed AA had an identify power to discriminate subjects with or without PWV and hypertension progression. We have shown for the first time that the types of A1-AAs and α1-AAs are independent predictors for aortic stiffness progression in normotensive subjects. Our data collectively support the utility of these AAs as potential markers of aortic stiffness.

Immunosuppressive efficacy of tetrandrine combined with methylprednisolone against mitogen-activated peripheral blood mononuclear cells of haemodialysis patients.

Immunosuppressive therapy for prevention of acute rejection episode occasionally causes serious adverse effects, and thus it is important to develop new therapeutic approach for renal transplant recipients. This study evaluated the immunosuppressive pharmacodynamics of tetrandrine (TET) and/or methylprednisolone (MP) in haemodialysis patients in vitro by using the peripheral blood mononuclear cells (PBMCs) isolated from whole blood of haemodialysis patients. The median (range) of MP IC50 values against the proliferation of patients PBMCs was 7.04 (2.30-500.00) ng/mL. In contrast, the median (range) of MP IC50 values against the proliferation of healthy PBMCs was 4.44 (3.19-5.08) ng/mL. The median (range) of TET IC50 values against the proliferation of patients PBMCs was 1.61 (1.04-4.79) µmol/L. Lower concentrations of TET (0.3-300 nmol/L) were able to decrease the IC50 values of MP and thus potentiate the MP immunosuppressive effect on patient PBMCs. The median (range) of MP IC50 values in combination with 0.3, 3, 30, and 300 nmol/L TET were 0.92 (0.49-8.39), 2.10 (0.45-20.00), 0.35 (0.092-1.05), and 0.14 (0.05-6.78) ng/mL, respectively. TET potentiates the MP immunosuppressive pharmacodynamics and thus, it was possible to use the combination of MP and TET to attenuate MP side effects. There were significant correlations between the IC50 values of TET and stimulation indices (P=0.04, r=.58), the IC50 values of TET and the haemodialysis periods (P=0.04, r=.57), or the IC50 values of MP combined with 0.3 nmol/L TET and C-reactive protein concentrations (P=0.04, r=.64), respectively.

Tetrandrine potentiates the glucocorticoid pharmacodynamics via inhibiting P-glycoprotein and mitogen-activated protein kinase in mitogen-activated human peripheral blood mononuclear cells.

Glucocorticoids play significant roles in treatments of inflammatory and autoimmune diseases. Some patients show a poor or absent response even to high doses of glucocorticoids. The purpose of this study was to explore whether tetrandrine combined with glucocorticoids could be a new treatment strategy to resolve glucocorticoids resistance. Information on glucocorticoids sensitivity was usually obtained through mitogen-activated human peripheral blood mononuclear cells in cell culture procedures. Thus, human peripheral blood mononuclear cells was chosen as a model to study the immunosuppressive effect of methylprednisolone combined with tetrandrine, including the possible action mechanisms. Tetrandrine decreased the IC50 value of methylprednisolone significantly, but it showed little toxic effect on the concanavalin A-activated human peripheral blood mononuclear cells. Both tetrandrine and methylprednisolone inhibited the secretion of pro-inflammatory cytokines TNFα and IL-6 significantly and the combination showed stronger inhibitory ability. Tetrandrine and/or methylprednisolone did not increase the percentage of CD4+ CD25+ Foxp3+ regulatory T cells in CD4+ T cells. However tetrandrine with or without methylprednisolone significantly inhibited the function of drug efflux pump P-glycoprotein 170 of CD4+, CD8+ T cells and lymphocytes. Tetrandrine tended to suppress the phosphorylation of mitogen-activated protein kinase and this effect was potentiated by methylprednisolone. These tetrandrine effects were suggested to be beneficial for improving the immunosuppressive efficacy of glucocorticoids. Glucocorticoids combined with tetrandrine could be a new therapeutic approach to resolve glucocorticoids-resistance possibly via inhibiting the function of P-glycoprotein and blocking mitogen-activated protein kinase signaling pathway from but not affecting on CD4+ CD25+ Foxp3+ regulatory cells.

Genetic polymorphism of CYP11B2 gene and stroke in the Han Chinese population and a meta-analysis.

OBJECTIVE: The renin-angiotensin-aldosterone system is important for cerebrovascular research because it influences blood pressure, vasoconstriction, thrombosis, and vessel wall damage. We hypothesized that genetic variations in CYP11B2 gene might contribute to the susceptibility for stroke. METHODS AND RESULTS: Here, we present genetic association analyses on CYP11B2 gene variants in two independent ischemic stroke (IS) cohorts. Four single nucleotide polymorphisms (SNPs) from CYP11B2 gene were genotyped in 558 Chinese patients and 557 matched controls. Another replication was conducted in an independent sample of 525 IS cases and 694 controls. In addition, meta-analyses was performed to assess the association between the rs1799998 (-344C/T) CYP11B2 polymorphism and IS. Only one SNP rs1799998 (-344C/T)showed association with overall IS in the first study (P(dominant)=0.003, P(additive)=0.003, respectively), but this was not replicated in our second cohort. No associations were found for the rest of SNPs in both the studies. Meta-analyses (including our study) revealed that-344C/T of CYP11B2 was associated with IS both in a dominant effect (odds ratio=1.51, 95% CI: 1.06-2.16, P=0.023) and a recessive effect (odds ratio=1.57, 95% CI:1.14-2.16). Above all, our results suggest that genetic variation rs1799998 (-344C/T) of CYP11B2 gene may contribute to the risk of IS with moderate effect in Han Chinese population.

Exploring epistatic relationships of NO biosynthesis pathway genes in susceptibility to CHD.

AIM: To assess the epistatic relationships of nitric oxide (NO) biosynthesis pathway genes in susceptibility to coronary heart disease (CHD). METHODS: A total of 2142 subjects enrolled in two case-control studies was genotyped for 7 single-nucleotide polymorphisms (SNP) within NO biosynthesis pathway genes using TaqMan assays. The association analyses were performed at both SNP and haplotype levels. Two-way SNP-SNP interactions and high-order interactions were tested using multiple unconditional logistic regression analyses and generalized multifactor dimensionality reduction (GMDR) analyses, respectively. RESULTS: Two alleles (rs1049255*C and rs841*A) were identified that were significantly associated with increased risk of CHD after adjusting for all confounders (OR=1.21, 95% CI: 1.06-1.39, combined P=0.001, P(corr)=0.007 and OR=1.30, 95% CI 1.12-1.50, combined P<0.001, P(corr)<0.001, respectively). Significant two-way SNP-SNP interactions were found between SNP rs2297518 and these two significant polymorphisms, affecting the risk of CHD (P<0.001 for both). No significant high-order interactions were identified. CONCLUSION: The results suggested that two-way SNP-SNP interactions of polymorphisms within NO biosynthesis pathway genes contribute to CHD risk.

Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population.

OBJECTIVE: 20-Hydroxyeicosatetraenoic acid has been shown to play an important role in cerebral vascular function. We hypothesized that polymorphisms in genes encoding 20-Hydroxyeicosatetraenoic acid synthesizing enzymes might confer susceptibility to stroke. METHODS AND RESULTS: To test the hypothesis, haplotype tagging single nucleotide polymorphisms and potential functional polymorphisms of CYP4A11 and CYP4F2 genes were genotyped in 558 ischemic stroke patients, 221 hemorrhagic stroke patients and 557 controls. The association analyses were performed at both single nucleotide polymorphism and haplotype levels. We further verified our findings in an independent cohort of 551 ischemic stroke cases and 48 hemorrhagic stroke cases and 694 unaffected controls. We identified CYP4A11 C-296T and CYP4F2 V433M were associated with significantly increased risk of ischemic stroke (CT+TT vs. CC, adjusted odds ratio: 1.50, 95% confidence interval: 1.17-1.93, Pcombined=0.001, Pcorr=0.008; V/M+M/M vs. V/V, odds ratio: 1.38, 95% confidence interval: 1.15-1.65, Pcombined=5.6x10, Pcorr=0.005, respectively). Interestingly, the effects of CYP4F2 V433M on ischemic stroke in our study was only evident in male individuals. CONCLUSION: Our results suggest that genetic variation in CYP4A11 and CYP4F2 alters susceptibility to stroke in the Han Chinese population.

9p21 is a shared susceptibility locus strongly for coronary artery disease and weakly for ischemic stroke in Chinese Han population.

BACKGROUND: Recent studies on genome-wide association have identified common variants on chromosome 9p21 associated with coronary artery disease (CAD). Given that ischemic stroke and CAD share several aspects of etiology and pathogenesis, we investigated the association of variants on chromosome 9p21 with ischemic stroke and CAD in the Chinese Han population by capturing the majority of diversity in this locus using haplotype-tagging single-nucleotide polymorphisms. METHODS AND RESULTS: We performed a shared control-cases study using 15 tagging single-nucleotide polymorphisms and 2 previously reported susceptibility single-nucleotide polymorphisms spanning 58 kb of the chromosome of 9p21 in a set of 558 patients with ischemic stroke, 510 patients with CAD, and 557 unaffected participants (controls) in the Chinese Han population. The association analyses were performed at both SNP and haplotype levels. We further verified our findings in an independent cohort of 442 ischemic stroke cases and 502 control subjects. In the first study, rs2383206, rs1004638, and rs10757278 in block 3 were significantly associated with CAD but not with ischemic stroke independent of traditional cardiovascular risk factors in additive model (P = 0.002 to 0.0001, q = 0.026 to 0.004). Analysis from all blocks revealed that haplotype profiles of block 3 on 9p21 were significantly different between shared control and cases of CAD (P = 1.3 x 10(-10), q = 1.2 x 10(-9)) and ischemic stroke (P = 1.7 x 10(-6), q = 7.7 x 10(-6)). In the expanded second case-control study, block 3 on 9p21 remained associated with ischemic stroke (P = 2.6 x 10(-4), q = 6.3 x 10(-4)). CONCLUSIONS: Our results suggest for the first time that 9p21 is a shared susceptibility locus, strongly for CAD and weakly for ischemic stroke, in a Chinese Han population.