Gossypin, a pentahydroxy glucosyl flavone, inhibits the transforming growth factor beta-activated kinase-1-mediated NF-kappaB activation pathway, leading to potentiation of apoptosis, suppression of invasion, and abrogation of osteoclastogenesis

Gossypin, a flavone originally isolated from Hibiscus vitifolius, has been shown to suppress angiogenesis, inflammation, and carcinogenesis. The mechanisms of these activities, however, are unknown. Because nuclear factor-kappaB (NF-kappaB) is associated with inflammation, carcinogenesis, hyperproliferation, invasion, and angiogenesis, we hypothesized that gossypin mediates its effects through modulation of NF-kappaB activation. In the present study, we demonstrate that gossypin (and not gossypetin, an aglycone analog) inhibited NF-kappaB activation induced by inflammatory stimuli and carcinogens. Constitutive NF-kappaB activation in tumor cells was also inhibited by this flavone. Inhibition of I kappa B alpha kinase by gossypin led to the suppression of I kappa B alpha phosphorylation and degradation, p65 nuclear translocation, and NF-kappaB-regulated gene expression. This, in turn, led to the down-regulation of gene products involved in cell survival (IAP2, XIAP, Bcl-2, Bcl-xL, survivin, and antiFas-associated death domain-like interleukin-1 beta-converting enzyme-inhibitory protein), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), angiogenesis (vascular endothelial growth factor), and invasion (matrix metalloprotease-9). Suppression of these gene products by gossypin enhanced apoptosis induced by tumor necrosis factor and chemotherapeutic agents, suppressed tumor necrosis factor-induced cellular invasion, abrogated receptor activator of NF-kappaB ligand-induced osteoclastogenesis, and vascular endothelial growth factor-induced migration of human umbilical vein endothelial cells. Overall, our results demonstrate that gossypin inhibits the NF-kappaB activation pathway, which may explain its role in the suppression of inflammation, carcinogenesis, and angiogenesis.     

Gambogic acid, a novel ligand for transferrin receptor, potentiates TNF-induced apoptosis through modulation of the nuclear factor-kappaB signaling pathway

Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been recently demonstrated to bind transferrin receptor and exhibit potential anticancer effects through a signaling mechanism that is not fully understood. Because of the critical role of NF-kappaB signaling pathway, we investigated the effects of GA on NF-kappaB-mediated cellular responses and NF-kappaB-regulated gene products in human leukemia cancer cells. Treatment of cells with GA enhanced apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, inhibited the expression of gene products involved in antiapoptosis (IAP1 and IAP2, Bcl-2, Bcl-x(L), and TRAF1), proliferation (cyclin D1 and c-Myc), invasion (COX-2 and MMP-9), and angiogenesis (VEGF), all of which are known to be regulated by NF-kappaB. GA suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens and this, accompanied by the inhibition of TAK1/TAB1-mediated IKK activation, inhibited IkappaBalpha phosphorylation and degradation, suppressed p65 phosphorylation and nuclear translocation, and finally abrogated NF-kappaB-dependent reporter gene expression. The NF-kappaB activation induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKKbeta was also inhibited. The effect of GA mediated through transferrin receptor as down-regulation of the receptor by RNA interference reversed its effects on NF-kappaB and apoptosis. Overall our results demonstrate that GA inhibits NF-kappaB signaling pathway and potentiates apoptosis through its interaction with the transferrin receptor.     

Small-sized liver graft does not increase the risk of hepatocellular carcinoma recurrence after living donor liver transplantation

PURPOSE: Following implantation into adult recipients, living donor liver grafts usually undergo liver regeneration. This regeneration process may provoke the growth of occult hepatocellular carcinoma (HCC) cells in the recipient body. To assess the risk of HCC recurrence, we analyzed the influence of graft-recipient weight ratio (GRWR). METHODS: The 181 recipients with HCC within the University of California at San Francisco (UCSF) criteria were divided into four groups according to GRWR: low GRWR (<0.8; n = 30), mid GRWR (0.8-1.0; n = 65), high GRWR (>1.0; n = 64), and whole liver graft group (>1.5; n = 22). RESULTS: There were no differences in overall patient survival (P = .105) and recurrence-free survival (P = .406) among these four groups. GRWR <0.8 was not a significant risk factor for HCC recurrence. Similar outcomes were obtained in HCC patients who met the Milan criteria (n = 170). CONCLUSIONS: We think that small living donor liver graft and subsequent liver regeneration do not increase the risk of posttransplant HCC recurrence when HCC is within the Milan or UCSF criteria.     

Population pharmacokinetics of valproic acid concentrations in elderly nursing home residents

The objective of this study was to identify factors that affect valproic acid (VPA) apparent clearance (CL/F) in elderly nursing home residents. Inclusion criteria included residency in a nursing home for at least 2 months, aged 65 years or older, a stable dosing regimen of VPA for at least 4 weeks, VPA concentration, and complete dosing information. CL/F was analyzed by a nonlinear mixed effects model. A one-compartment model with first-order absorption and elimination was used. Both volume and absorption rate constant were fixed (14 L and 1 hr, respectively). Covariates were tested by forward inclusion and backward elimination. Interindividual variability in clearance was estimated using an exponential error model and expressed as a coefficient of variation. Residual error was estimated using a combined additive and constant coefficient of variation error model. The study consisted of 405 observations from 146 (52 men, 94 women) elderly nursing home residents. CL/F was not affected by age or weight. The population CL/F was 0.843 L/hr. CL/F was 1) 27% lower in female residents; 2) 41% greater when the resident was on concomitant metabolic inducers carbamazepine or phenytoin cotherapy; and 3) 25% greater when the syrup formulation was used. Variability in CL/F was 32.9%. Coefficient of variation and standard deviation of the residual error were 18.2% and 10.6 mg/L, respectively. The increased CL/F in patients taking VPA syrup may be the result of a decreased bioavailability (F) rather than an increased CL that could be associated with pathology requiring use of the syrup rather than an inherent property of the drug formulation. The results from this study may be useful for individualizing dose regimens in the nursing home population based on patient-specific factors.     

Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized,double-blind,active-controlled,multicenter phase 3 trial

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are −19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and −11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.     

Risk of bleeding-related complications after kidney biopsy in patients with systemic lupus erythematosus

Clinical Rheumatology - Kidney biopsy is essential for the diagnosis and classification of lupus nephritis. Percutaneous biopsy has a risk of bleeding-related complications; however, data on the...     

Incidence and Risk of Venous Thromboembolism in Bisphosphonates and Selective Estrogen Receptor Modulators Treatment in Korea

BackgroundSelective estrogen receptor modulators (SERMs) were associated with an increased risk of venous thromboembolism (VTE) due to the estrogen effect. In this study, we investigated the effect of SERMs on VTE compared to bisphosphonates (BPs) using the Korean National Health Insurance claims database.MethodsThis was a retrospective cohort study. Women over 50 years old who were first prescribed BPs or SERMs for osteoporosis treatment in 2012 were included. The difference in VTE incidence between the SERMs and BP groups was compared. Both groups were followed up for VTE or PE occurrence, death, or until December 2016. The study population was analyzed by 3:1 matching according to age using a multivariate Cox model.ResultsThe hazard ratio (HR) for VTE was 0.72 (95% confidence interval [CI], 0.40–1.28) in the SERMs group compared to BP group. Older age (60–69 vs. 50–59 years: HR, 3.77; 95% CI, 2.07–6.86 and 70–79 vs. 50–59 years: HR, 5.88; 95% CI, 3.14–11.02), major osteoporotic fracture (HR, 1.77; 95% CI, 1.16- 2.70), atrial fibrillation (HR, 3.31; 95% CI, 1.35–8.11), and estrogen replacement (HR, 3.40; 95% CI, 2.01–5.73) all increased VTE risk. In subgroup analysis of the SERMs group, past hospitalization (HR, 2.24; 95% CI, 1.02–4.92), estrogen replacement (HR, 5.75; 95% CI, 2.29–14.39), and glucocorticoid replacement (HR, 2.71; 95% CI, 1.05–7.0) increased VTE risk.ConclusionSERMs did not increase the risk of VTE compared to BPs in Koreans with osteoporosis. However, old age and estrogen replacement both increased VTE risk.