Urate-lowering therapy exerts protective effects against hypertension development in patients with gout.

Many studies have demonstrated that hyperuricemia is associated with hypertension (HTN) development, but few studies have explored whether urate-lowering therapy (ULT), which reverses hyperuricemia, decreases the risk of incident HTN. In this retrospective cohort study, we compared the risk of incident HTN of gout patients between those undergoing and not undergoing ULT. Risks of new-onset diabetes mellitus (DM) and chronic kidney disease (CKD) were also examined. In total, 2712 gout patients from 2000 to 2012 were enrolled. Overall incidence rates of HTN, DM, and CKD were compared between 1356 patients undergoing ULT recipients and 1356 matched control patients. After adjustment for sex, age, area, comorbidities, and drugs used, the incidence rates of HTN were 4.8 and 3.0 per 100 person years for non-ULT and ULT patients, respectively. ULT patients had a lower adjusted hazard ratio (aHR) of HTN (aHR: 0.64, 95% confidence interval [CI]: 0.54-0.75, p < 0.001) than non-ULT patients. The lower risk of incident HTN after xanthine oxidase inhibitors exhibited a significant dose-response trend. ULT patients also had a lower risk of DM (aHR: 0.55, 95% CI: 0.43-0.70) than non-ULT patients. ULT patients exhibited no significant difference in CKD development (aHR: 1.04, 95% CI: 0.85-1.27) as compared with non-ULT patients. The present study revealed that ULT was associated with lower risks of incident HTN and DM, and the protective effect of xanthine oxidase inhibitors seemed to have a dose-response relationship.

Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout.

OBJECTIVES: Although studies have demonstrated the association of hyperuricemia with cardiovascular (CV) diseases, few have explored the effect of urate-lowering therapy (ULT) on the incidence of CV diseases. Therefore, we compared the risks of hospitalized coronary artery disease (CAD), stroke, heart failure (HF), and all-cause mortality between ULT users and nonusers among patients with gout. METHODS: We performed this retrospective cohort study using Taiwan's population-based National Health Insurance Research Database. In total, 5218 patients with gout were included from 2000 to 2012. We compared the incidence rates (IRs) of hospitalized CAD, stroke, HF, and all-cause mortality between ULT users and matched nonusers. RESULTS: The IRs of hospitalized stroke were 0.6 and 1.0 per 100 person-years for ULT users and nonusers, respectively, after adjusting for age, sex, residence, comorbidities, and medications. ULT users showed lower adjusted hazard ratios (aHR) for hospitalized stroke (aHR: 0.52, p < 0.001) and all-cause mortality (aHR: 0.6, p = 0.02) than nonusers. Subgroup analyses revealed that uricosuric agents and xanthine oxidase inhibitors were significantly associated with lower risks of hospitalized stroke and all-cause mortality, respectively. The effect of uricosuric agents on the decrease in hospitalized stroke risk indicated a dose-response relationship. CONCLUSIONS: Our study showed lower risks of hospitalized stroke and all-cause mortality in ULT users than in nonusers among patients with gout. Therefore, patients with gout may receive ULT to mitigate the risks of hospitalized stroke and mortality.

Urate-Lowering Therapy May Prevent the Development of Coronary Artery Disease in Patients With Gout.

Substantial evidence has demonstrated a close relationship between hyperuricemia and cardiovascular (CV) diseases, but few studies have explored the possibility of using urate-lowering therapy (ULT) to attenuate the development of CV diseases. To compare the risks of incident coronary artery disease (CAD), stroke, and heart failure (HF) between ULT users and non-users in patients with gout, we conducted a retrospective cohort study from the population-based National Health Insurance Research Database in Taiwan. In total, 4,072 patients with gout were included between 2000 and 2012. The overall incident rates of CAD, stroke, and HF were compared between 2,036 ULT users and 2,036 matched non-users. The incident rates of incident CAD were 1.3 and 1.7 per 100 person-years for ULT users and non-users. ULT users had a lower adjusted hazard ratio (aHR) for CAD [aHR: 0.7, 95% confidence interval (CI): 0.55-0.89] compared with non-users. ULT users also had a lower aHR for incident stroke (aHR: 0.68, 95% CI: 0.5-0.92) compared with non-users. ULT had a neutral effect on the risk of incident HF (aHR: 0.92, 95% CI: 0.58-1.45). Among the urate-lowering therapy, subgroup analyses indicated that uricosuric agents had a significant effect on the prevention of CAD and stroke development; and the protection against the development of CAD by uricosuric agents appeared to have a dose-response trend. Our study demonstrated that ULT associated with lower risks of incident CAD and stroke. We recommend that patients with gout receive ULT to lower the burden of CV diseases.

Nanog expression is negatively regulated by protein kinase C activities in human cancer cell lines.

Nanog is a transcription factor that is essential for the maintenance of pluripotency of the embryonic stem cells. Nanog has been shown to be expressed in various kinds of human tumors, suggesting a role in tumorigenesis. In this study, we found that Nanog expression was upregulated by inhibition of protein kinase C (PKC) activity in six human cancer cell lines examined. In a Nanog non-expressing human nasopharyngeal carcinoma cell line, NPC-076, Nanog mRNA level and protein level were both induced and dose-dependently promoted by exposure to PKC inhibitors. Knockdown experiments showed that PKCα and PKCδ were two subtypes exerted most of the effect. The reporter assay showed that Nanog promoter activity was promoted by exposure of the cells to PKC inhibitors and the effect was dependent on the presence of the Octamer-Sox composite element. The involvement of Octamer-Sox composite element was further supported by the observation that silencing of Oct4 and Sox2 in NPC-076 cells attenuated the effects of PKC inhibitors. In Nanog-expressing human embryonal carcinoma cell lines, NT2/D1 and NCCIT, Nanog expression was suppressed by exposure to PKC activator Phorbol-12-myristate-13-acetate (PMA). Further study showed that overexpression of PKCα elicited a repressive effect on Nanog expression in NT2/D1 cells. Consistently, mutation of the Octamer-Sox composite element abolished the suppressive effect by PKC activator. Nanog expression was of cellular significance in that ectopic expression in NPC-076 stimulated cell proliferation and knockdown of the endogenous Nanog expression in NT2/D1-suppressed cell proliferation.

Glycogen synthase kinase-3beta regulates DeltaNp63 gene transcription through the beta-catenin signaling pathway.

Overexpression of DeltaNp63 has been observed in a number of human cancers, suggesting a role for DeltaNp63 in carcinogenesis. In the present study, we show that inhibition of glycogen synthase kinase-3beta (GSK-3beta) by lithium chloride (LiCl) elicited a stimulatory effect on DeltaNp63 promoter activity in HEK 293T cells. Exposure to LiCl induced DeltaNp63 promoter activation as well as DeltaNp63 protein expression in the cells. The effect of GSK-3beta on DeltaNp63 expression was further confirmed by the use of two highly specific GSK-3beta inhibitors, SB216763 and SB415286. Further study showed the presence of a putative beta-catenin responsive element (beta-catenin-RE) in the DeltaNp63 promoter region, and the stimulation of DeltaNp63 promoter activity by GSK-3beta inhibitor is markedly abolished by mutation or deletion of the putative beta-catenin-RE. Data are also presented to show that beta-catenin acts together with Lef-1 to influence DeltaNp63 promoter activity and protein expression.

Transcriptional activity of the DeltaNp63 promoter is regulated by STAT3.

The N terminus-truncated splicing variant of TAp63 is known as DeltaNp63. DeltaNp63 lacks transactivation function and is thought to antagonize the transcriptional regulation of the p53 and TAp63 target genes. Overexpression of DeltaNp63 has been observed in a number of human cancers, suggesting a role in carcinogenesis. In the present study we present data showing that the DeltaNp63 gene promoter activity is positively regulated by DeltaNp63alpha, and such positive autoregulation is mediated via activation of STAT3 activity. We show that expression of DeltaNp63alpha in Hep3B cells induces Stat3 phosphorylation on Tyr-705 and Ser-727. A putative STAT3-responsive element (STAT3-RE) is identified in the DeltaNp63 promoter region. Electrophoretic mobility shift and avidin biotin-Conjugated DNA assays show direct binding of STAT3 to STAT3-RE of the DeltaNp63 promoter, and such binding is stimulated by DeltaNp63alpha. Binding of the endogenous STAT3 to the DeltaNp63 promoter in Hep3B cells was demonstrated by a chromatin immunoprecipitation assay. The stimulation of the DeltaNp63 transcriptional activity by DeltaNp63alpha is abolished by Janus kinase 2 (JAK2)/STAT3 inhibitor AG490, dominant-negative STAT3, STAT3 small interfering RNA, and deletion of the STAT3-RE sequence from DeltaNp63 promoter. Taken together these observations clearly indicated that autoregulation of DeltaNp63 gene transcription is mediated through activation of STAT3 and its subsequent binding to the STAT3RE. Because the activation of STAT3 by interleukin-6 also leads to DeltaNp63 up-regulation and the blockade of DeltaNp63 or STAT3 expression by siRNA leads to repression of the cell growth, the identified regulatory pathway is presumably of cell physiological significance.