Statins reduce plasma low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) levels. Rosuvastatin 10 mg daily appears to be more potent in reducing LDL-C than simvastatin 40 mg, but the relative effect of these two statin doses on hsCRP is unknown.
Chinese hyperlipidaemic patients with high cardiovascular risk or familial hypercholesterolaemia (FH) were treated with rosuvastatin 10 mg and simvastatin 40 mg daily in an open-label crossover study. Lipid profiles were measured off treatment and after at least 4 weeks treatment with each of the two statins and hsCRP levels were measured on treatment with both statins.
Both treatments were well tolerated in 247 patients (age 55.7 ± 11.1 years; 100 male; 140 with FH) with good treatment compliance. There were statistically significant differences (P < 0.001) for rosuvastatin versus simvastatin for LDL-C reduction (−52.4 ± 11.9 % vs. -47.7 ± 10.8 %) and on-treatment LDL-C (2.62 ± 0.99 mmol/L vs. 2.86 ± 0.97 mmol/L), respectively, but the on-treatment hsCRP levels (1.33 ± 1.37 mg/L vs. 1.41 ± 1.57 mg/L, P > 0.05) were not significantly different. The lipid target (LDL-C <2.6 mmol/L) was achieved by 52.9 % with rosuvastatin compared with 42.6 % with simvastatin (P < 0.05). The proportions of patients attaining hsCRP targets of <2 and <1 mg/L were similar with the two statins (57.1 % and 74.6 % for rosuvastatin vs. 57.1 % and 80.1 % for simvastatin, P > 0.05).
A significantly greater proportion of patients achieved LDL-C targets with rosuvastatin 10 mg compared to simvastatin 40 mg in Chinese patients with hypercholesterolaemia, but there was no significant difference in achieving hsCRP target levels with the two statins.
High-sensitivity C-reactive protein; Statins; Low-density lipoprotein cholesterol; Chinese
The acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes DGAT1 and DGAT2 catalyze the final step in triglycerides biosynthesis. This study examined the relationships of baseline phenotypes and the common polymorphisms in DGAT1 and DGAT2 with the lipid responses to niacin.
Lipid responses in Chinese patients with dyslipidemia treated with the extended release (ER) niacin/laropiprant combination 1000/20 mg for 4 weeks and then 2000/40 mg for 8 weeks (n = 121, the primary study) or with ER niacin 1500 mg for at least 4 weeks (n = 68, the replication study) were analyzed according to genotypes of DGAT1 rs7003945 T>C and DGAT2 rs3060 T>C polymorphisms.
Treatment with ER niacin improved all lipid parameters in both studies. Absolute and percentage changes in lipids were related to their baseline levels, particularly for low-density lipoprotein cholesterol (LDL-C). The DGAT2 rs3060 T>C polymorphism was associated with lower baseline LDL-C, apoB, high-density lipoprotein cholesterol (HDL-C), and apoAI in patients on statin therapy in the primary study. Subjects with the DGAT2 rs3060 T>C variant had less reduction in LDL-C in the primary study and smaller changes in triglyceride and HDL-C in the replication study but these associations became non-significant after adjusting for baseline lipid values. The DGAT1 rs7003945 T>C polymorphism was not related to lipid baseline values or changes in either study. Concomitant statin therapy and lower body weight were also associated with greater reduction in LDL-C.
Baseline lipid levels were the main determinants of lipid responses especially for LDL-C. The DGAT2 rs3060 polymorphism might influence the lipid responses depending on baseline phenotype, but this association did not persist after adjustment for the baseline lipid levels.
Objectives. This study examined whether the increase of adiponectin associated with extended-release (ER) niacin/laropiprant combination attenuates the adverse effect of niacin on glucose and insulin resistance in Hong Kong Chinese patients with dyslipidaemia. Methods. Patients (N = 121) were treated with ER niacin/laropiprant 1 g/20 mg for 4 weeks and then the dose was doubled for an additional 8 weeks. Measurements of fasting lipids, glucose, insulin, and adiponectin were performed at baseline and during the study. Results. There were significant (P < 0.001) increases in glucose (9.4 ± 13.1%), insulin (70.2 ± 91.0%), HOMA-IR (87.8 ± 103.9%), and adiponectin (169.3 ± 111.6%). The increase in adiponectin was significantly associated with increase in glucose (r = 0.221, P < 0.05), insulin (r = 0.184, P < 0.05), and HOMA-IR (r = 0.237, P < 0.01) and the association remained significant after adjustment for changes in body weight or body fat mass. Conclusion. Treatment with ER niacin/laropiprant led to a significant increase in adiponectin levels but worsening of glucose levels and insulin resistance, and the increase in adiponectin and insulin resistance were correlated suggesting the increase in adiponectin did not ameliorate the deterioration in insulin resistance. Clinical trial is registered with number on WHO-ICTRP: ChiCTR-ONC-10001038.
This letter describes the construction
of conformationally constrained
quinazoline analogues. Structure–activity relationship studies
led to the identification of the lead compound 9n. Compound 9n exhibits effective in vitro activity
against A431WT,overexpression and H1975[L858R/T790M] cancer cell lines but is significantly less effective against EGFR
negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in
vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant
EGFR kinase. Meanwhile, an oral administration of 9n at
a dose of 200 mg/kg produced a considerable antitumor effect in a
A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic
study of 9n also indicates it has good pharmacokinetic
properties, and therefore, it is a good starting point for further
Anticancer; kinase inhibitor; EGFR; conformationally constrained
A parallel solid-phase synthesis of 1,6-disubstituted-1,2,4-triazin-3-ones from MBHA resin is described. The reduction of resin-bound nitrosamino acids provides hydrazines efficiently without affecting the amide bond. The trityl protected hydrazine is then reduced with borane, and cyclized with 1,1-carbonyldiimidazole. The desired products are cleaved from their solid support and obtained in good yield and purity. This methodology is of value for the rapid parallel preparation of these potentially bioactive molecules.
solid-phase; 1,2,4-triazinones; N-nitroso; hydrazine; reduction; cyclization
Background. We for the first time examined the effects of a multiherb formula containing Crataegus pinnatifida (1 g daily), Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba on plasma lipid and glucose levels in Chinese patients with dyslipidemia. Methods. In this randomized, double-blind, placebo-controlled study, 42 patients were randomized at a ratio of 1 : 1 to receive the herbal formula or placebo for 12 weeks and 40 patients completed the study. Lipid profiles, glucose, glycated haemoglobin (HbA1c), and laboratory safety parameters were performed before and after treatment. Results. The difference in the changes in low-density lipoprotein cholesterol (LDL-C) levels between placebo and active treatment (−9%) was significantly (P < 0.05) better with active treatment. HbA1c levels significantly decreased by −3.9% in the active treatment group, but the change was not significantly different from that with placebo (−1.1%) (P = 0.098). There were no apparent adverse effects or changes in laboratory safety parameters with either treatment. Conclusions. The multiherb formula had mild beneficial effects on plasma LDL-C after 12-weeks treatment in subjects with dyslipidemia without any noticeable adverse effects.
Recent studies have demonstrated a potent anticancer potential of medicinal fungus Antrodia cinnamomea, especially against hepatocarcinoma. These studies, however, were performed with prolonged treatments, and the early anticancer events remain missing. To probe the early anticancer mechanisms of A. cinnamomea, we treated SK-Hep-1 liver cancer cell with A. cinnamomea fruiting body extract for 2 and 4 hours, sequenced RNA samples with next-generation sequencing approach, and profiled the genome-wide miRNA and mRNA transcriptomes. Results unmistakably associated the early anticancer effect of A. cinnamomea fruiting body extract with a global downregulation of miRNAs which occurred solely in the A. cinnamomea fruiting body extract-treated SK-Hep-1 cells. Moreover, the inhibitory effect of A. cinnamomea fruiting body extract upon cancer miRNAs imposed no discrimination against any particular miRNA species, with oncomirs miR-21, miR-191 and major oncogenic clusters miR-17-92 and miR-106b-25 among the most severely downregulated. Western blotting further indicated a decrease in Drosha and Dicer proteins which play a key role in miRNA biogenesis, together with an increase of XRN2 known to participate in miRNA degradation pathway. Transcriptome profiling followed by GO and pathway analyses indicated that A. cinnamomea induced apoptosis, which was tightly associated with a downregulation of PI3K/AKT and MAPK pathways. Phosphorylation assay further suggested that JNK and c-Jun were closely involved in the apoptotic process. Taken together, our data indicated that the anticancer effect of A. cinnamomea can take place within a few hours by targeting multiple proteins and the miRNA system. A. cinnamomea indiscriminately induced a global downregulation of miRNAs by simultaneously inhibiting the key enzymes involved in miRNA maturation and activating XRN2 protein involved in miRNA degradation. Collapsing of the miRNA system together with downregulation of cell growth and survival pathways and activation of JNK signaling unleash the extrinsic and intrinsic apoptosis pathways, leading to the cancer cell death.
Emerging evidence has shown that p53gene participates in human carcinogenesis as tumor suppressors. Polymorphism of p53 gene codon 72 Arg/Pro (rs1042522) may influence the function of p53 protein and then affect the processing of carcinogenesis. It has been suggested that p53 codon 72 Arg/Pro polymorphism is associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To examine the validity of the association between the polymorphism and HCC risk, we performed this meta-analysis.
We have conducted a search of case–control studies on the associations of p53 codon 72 polymorphism with susceptibility to HCC in PubMed, ScienceDirect, Bio-Med central, Springer-link, EBSCO, Wanfang databases and Chinese National Knowledge Infrastructure (CNKI) databases. A total of 15 studies were identified with 3704 cases and 4559 controls for codon 72 Arg/Pro polymorphism. The result did support a significant genetic association between Pro allele and susceptibility to HCC in all the genetic models. Similarly, subgroup analysis showed significant associations between the Arg/Pro polymorphism and susceptibility to HCC when stratifying by race, gender, source of controls and hepatitis virus infection status.
This meta-analysis suggests that p53 codon 72 Arg/Pro polymorphism may be associated with the risk of HCC, especially in subgroup analysis of Asian and Caucasian population, hospital-based population, the female, and the individuals infected with hepatitis virus. However, well-designed studies based on different ethnic groups with larger sample size and more detailed data are needed to confirm these conclusions.
HCC, hepatocellular carcinoma; CNKI, Chinese National Knowledge Infrastructure; HBV, hepatitis B virus; HCV, hepatitis C virus; AFB1, aflatoxin B1; HWE, Hardy–Weinberg equilibrium; CIs, confidence intervals; PCR–RFLP, polymerase chain reaction–restriction fragment length polymorphism; PCR–ASP, polymerase chain reaction–allele specific polymerase chain reaction; PCR–SSCP, polymerase chain reaction–Single strand conformation polymorphism analysis; PH, between-study heterogeneity; p53; codon 72; rs1042522; Hepatocellular carcinoma
Emerging evidence has shown that microRNAs (miRNAs) participate in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphism (SNP) located in the miRNAs may influence the function of mature miRNAs and then affect the processing of carcinogenesis. It has been suggested that two common SNPs rs2910164 in miR-146a and rs3746444 in miR-499 are associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To acquire a more precise effect of the association between these polymorphisms and HCC risk, we performed this meta-analysis.
We have conducted a search of case-control studies on the associations of SNPs rs2910164 and/or rs3746444 with susceptibility to HCC in PubMed, ScienceDirect, Cochrane Central Register of Controlled Trials, and Chinese National Knowledge Infrastructure databases for the period up to Sep 10th, 2012. A total of 6 studies were identified with 2071 cases and 2350 controls for miR-146a rs2910164 polymorphism, 667 cases and 1006 controls for miR-499 rs3746444 polymorphism. It was found that neither allele frequency nor genotype distribution of the two polymorphisms was associated with risk of HCC in all genetic models. Similarly, subgroup analysis in Asian population showed no associations between the two SNPs and the susceptibility to HCC.
This meta-analysis suggests that miR-146a rs2910164 and miR-499 rs3746444 polymorphisms may not be associated with the risk of HCC, especially for Asian population. However, well-designed studies with larger sample size and more detailed data are needed to confirm these conclusions.
Cisplain, a platinum-containing anticancer drug, has been shown to enhance DNA repair and to inhibit cell apoptosis, leading to drug resistance. Thus, the combination of anticancer drugs with nutritional factors is a potential strategy for improving the efficacy of cisplatin chemotherapy. In this study, we investigated the anti-proliferative effects of a combination of fucoxanthin, the major non-provitamin A carotenoid found in Undaria Pinnatifida, and cisplatin in human hepatoma HepG2 cells. We found that fucoxanthin (1–10 μΜ) pretreatment for 24 h followed by cisplatin (10 μΜ) for 24 h significantly decreased cell proliferation, as compared with cisplatin treatment alone. Mechanistically, we showed that fucoxanthin attenuated cisplatin-induced NFκB expression and enhanced the NFκB-regulated Bax/Bcl-2 mRNA ratio. Cisplatin alone induced mRNA expression of excision repair cross complementation 1 (ERCC1) and thymidine phosphorylase (TP) through phosphorylation of ERK, p38 and PI3K/AKT pathways. However, fucoxanthin pretreatment significantly attenuated cisplatin-induced ERCC1 and TP mRNA expression, leading to improvement of chemotherapeutic efficacy of cisplatin. The results suggest that a combined treatment with fucoxanthin and cisplatin could lead to a potentially important new therapeutic strategy against human hepatoma cells.
fucoxanthin; cisplatin; NFκB; DNA repair; MAPK; PI3K/AKT
Statins are widely used and have been proven to be effective in the prevention of atherosclerotic vascular disease events, primarily by reducing plasma low-density lipoprotein cholesterol concentrations. Although statins are generally well tolerated and present an excellent safety profile, adverse effects from muscle toxicity and liver enzyme abnormalities may occur in some patients. Myopathy and rhabdomyolysis are rare with statin monotherapy at the approved dose ranges, but the risk increases with use of higher doses, interacting drugs and genetic predisposition. Asymptomatic increases in liver transaminases with statin treatment do not seem to be associated with an increased risk of liver disease. Therefore, statin treatment can be safely used in patients with mild to moderately abnormal liver tests that are potentially attributable to nonalcoholic fatty liver disease and can improve liver tests and reduce cardiovascular morbidity in this group of patients. The risks of other unfavorable effects such as the slightly increased risk of new-onset diabetes and potentially increased risk of haemorrhagic stroke are much smaller than the cardiovascular benefits with the use of statins.
cardiovascular disease; drug safety; myopathy; rhabdomyolysis; statins
Inconsistent expression and regulation of drug-metabolizing enzymes (DMEs) are common causes of adverse drug effects in some drugs with a narrow therapeutic index (TI). An important cytochrome, cytochrome P450 3A4 (CYP3A4), is predominantly regulated by a nuclear receptor, pregnane X receptor (PXR). Sesamin, a major lignan constituent in sesame seeds and oil, exhibits a variety of biological functions; however, the effect of sesamin on the modulation of CYP3A4 is not well understood. In this study, the effects of sesamin on the PXR-CYP3A4 pathway were characterized, as well as the underlying mechanisms of those effects. Sesamin potently attenuated CYP3A4 induction in a dose-dependent manner by blocking the activation of PXR. The PXR inducer-mediated inhibition of CYP3A4 was further evidenced by the ability of sesamin to attenuate the effects of several PXR ligands in the CYP3A4 reporter assay. Further mechanistic studies showed that sesamin inhibited PXR by interrupting the interacting with coregulators. These results may lead to the development of new therapeutic and dietary approaches to reduce the frequency of inducer-drug interaction. Sesamin was established as a novel inhibitor of PXR and may be useful for modulating DMEs expression and drug efficacies. Modification of CYP3A4 expression and activity by consumption of sesamin may have important implications for drug safety.
Pregnane X receptor (PXR) has been reported to regulate the expression of drug-metabolizing enzymes, such as the cytochrome P450 3A (CYP3A) family and transporters, such as multiple drug resistance 1 (MDR1). Fucoxanthin, the major carotenoid in brown sea algae, is a putative chemopreventive agent. In this study, we determined whether fucoxanthin could overcome drug resistance through attenuation of rifampin-induced CYP3A4 and MDR1 gene expression by PXR-mediated pathways in HepG2 hepatoma cells. We found that fucoxanthin (1–10 μM) significantly attenuated rifampin (20 μM)-induced CYP3A4, MDR1 mRNA and CYP3A4 protein expression at 24 h of incubation. Mechanistically, fucoxanthin strongly attenuated the PXR-mediated CYP3A4 promoter activity in HepG2 cells. In addition, fucoxanthin attenuated constitutive androstane receptor (CAR)- and rPXR-mediated CYP3A4 promoter activity in this cell line. Using the mammalian two-hybrid assay, we found that fucoxanthin significantly decreased the interaction between PXR and SRC-1, a PXR co-activator. Thus, fucoxanthin can decrease rifampin-induced CYP3A4 and MDR1 expression through attenuation of PXR-mediated CYP3A4 promoter activation and interaction between PXR and co-activator. These findings could lead to potentially important new therapeutic and dietary approaches to reduce the frequency of adverse drug reactions.
fucoxanthin; PXR; CYP3A4; MDR1; drug resistance; rifampin
To investigate the effects of darapladib, a specific inhibitor of lipoprotein-associated phospholipase A2 (lp-PLA2), on inflammation and atherosclerotic formation in the low density lipoprotein receptor (LDLR)-deficient mice.
Six-week-old LDLR-deficient mice were fed an atherogenic high-fat diet for 17 weeks and then randomly divided into two groups. One group was administered darapladib (50 mg·kg−1·d−1; po) for 6 weeks. The other group was administered saline as a control. Serum lipid levels were measured using the corresponding kits, and three inflammatory markers — interleukin-6 (IL-6), C reactive protein (hs-CRP), and platelet activating factor (PAF) — were determined using ELISA. Atherosclerotic plaque areas were stained with Sudan IV, and inflammatory gene expression at the lesions was evaluated using quantitative real-time PCR.
The body weight and serum lipid level between the two groups were similar at the end of the dietary period. The serum lp-PLA2 activity, hs-CRP and IL-6 levels, however, were significantly reduced in the darpladib group. The inhibition of lp-PLA2 did not alter the serum PAF level. Furthermore, the plaque area, from the aortic arch to the abdominal aorta, was significantly reduced in the darpladib group. Additionally, the expression of inflammatory genes monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) was significantly reduced at the lesions in the darapladib group.
Inhibition of lp-PLA2 by darapladib decreases the inflammatory burden and atherosclerotic plaque formation in LDLR-deficient mice, which may be a new strategy for the treatment of atherosclerosis.
atherosclerosis; lp-PLA2; darapladib; LDLR-deficient mice; inflammation; high-sensitivity C-reactive protein; interleukin-6; monocyte chemotactic protein-1; vascular cell adhesion molecule-1
Cardiovascular diseases are the major cause of morbidity and mortality worldwide, and there is considerable interest in the role of dietary constituents and supplements in the prevention and treatment of these disorders. We reviewed the major publications related to potential effects on cardiovascular risk factors and outcomes of some common dietary constituents: carotenoids, flavonoid-rich cocoa, tea, red wine and grapes, coffee, omega-3 fatty acids, and garlic. Increased intake of some of these has been associated with reduced all-cause mortality or reduced incidence of myocardial infraction, stroke, and hypertension. However, although the evidence from observational studies is supportive of beneficial effects for most of these foodstuffs taken as part of the diet, potential benefits from the use of supplements derived from these natural products remain largely inconclusive.
Studies on the relationship between obesity and bone have recently become widespread. The aim of this study was to investigate the effect of obesity on bone, utilizing a diet-induced obese mouse model, and to explore the role of free fatty acids (FFAs) in the osteogenesis/adipogenesis of mouse bone marrow-derived mesenchymal stem cells (BMSCs). An obese mouse model was established by a high-fat diet (HFD). Proximal femurs were collected at sacrifice, and bone mineral density (BMD) in the proximal femurs was measured by dual-energy X-ray absorptiometry. Bone histomorphometry was performed using undecalcified sections of the proximal femurs. The effect of obesity on the differentiation of mouse BMSCs was assessed by colony formation assays and gene expression analysis. In vitro, various osteogenic and adipogenic genes were determined by real-time quantitative PCR in mouse BMSCs after exposure to conditioned medium (CM) from FFA-treated 3T3-L1 adipocytes. Western blotting was further performed to analyze the representative protein expression of PPARγ and Runx2. BMD and trabecular thickness were significantly greater in the HFD mice than in the control mice. CFU-osteo assay showed significantly increased osteogenesis of BMSCs. The mRNA level of Runx2 was significantly higher, while PPARγ and Pref-1 were significantly lower in BMSCs from the HFD mice compared to the control mice. In mouse BMSCs, the Sox9 and Runx2 genes were significantly up-regulated after exposure to CM from FFA-treated adipocytes, while PPARγ and CEBP-α were significantly down-regulated. Osteogenesis was significantly increased, while adipogenesis was significantly decreased. In conclusion, HFD-induced obesity may play a protective role in bone formation by concomitantly promoting osteogenic and suppressing adipogenic differentiation of BMSCs through factors secreted by FFA-treated adipocytes.
mesenchymal stem cells; free fatty acids; obesity; osteogenesis; adipogenesis
The title CuII complex, [CuBr2(C21H15N3)]·0.5H2O, was obtained by the hydrothermal reaction of copper(II) bromide, 4′-phenyl-2,2′:6′,2′′-terpyridyl (4′-Ph-terpy or L) and sodium citrate in water in 31% yield. There are two unique complex molecules and a water molecule in the asymmetric unit. The CuII cation is ligated by three N atoms of L and two bromide anions, forming an irregular CuN3Br2 polyhedron with a distorted square-pyramidal coordination geometry. In the crystal structure, O—H⋯Br hydrogen bonds link the molecules in a three-dimensional network.
Alcohol, which is predominantly metabolized in the liver, is a major hepatic toxicant that readily induces hepatic steatosis. The expression of CCAAT enhancer binding protein (C/EBP), especially the C/EBP delta variety, is increased in the early phase of adipogenesis. However, the role of C/EBP delta in ethanol-induced hepatosteatosis is unclear.
Male C57BL/6J mice were randomized to one of four groups: a control group, a group receiving orally administered ethanol (4 g ethanol/kg body weight) (EtOH), a high-fat-diet (HF) group and an EtOH+HF group. Mice were sacrificed after 5 or 10 weeks for various measurements. The in vitro effect of ethanol on the expression of C/EBP alpha, beta and delta was studied in HepG2 cells.
By week 5, ethanol treatment had significantly increased liver C/EBP delta and beta protein expression (by 2.3- and 1.4-fold, respectively), which then returned to the control level by week 10. In contrast, the expression of C/EBP alpha was evident only at week 10. The in vitro study shows that C/EBP delta expression was elevated significantly at 24 h but not at 48 or 72 h. C/EBP beta expression was highest at 48 h, whereas C/EBP alpha expression was highest at 72 h. We also found that a low concentration of ethanol plus oleic acid enhanced C/EBP delta expression in HepG2 cells.
C/EBP delta expression appears to play an important role in the early phase of ethanol-induced hepatosteatosis in mice and in ethanol-treated HepG2 cells. In addition, EtOH+HF enhances the expression of C/EBP delta in HepG2 cells. Thus, C/EBP delta might be a therapeutic target in alcoholic hepatosteatosis.
C/EBP delta; ethanol; hepatosteatosis; adipogenesis
Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insufficiency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout flares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the first major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and efficacy is required.
febuxostat; TEI-6720; TMX-67; gout; hyperuricemia; xanthine oxidase inhibitor
The title complex, [Ag2(C7H7O3S)2(C25H22P2)2]·H2O, was obtained by the reaction of silver toluenesulfonate with diphenylphosphinomethane (dppm) in acetonitrile. There are two unique half-molecules of the complex in the asymmetric unit, together with one water molecule, which is disordered over two positions with site occupancy factors of 0.6 and 0.4. In each centrosymmetric neutral dimeric molecule, two Ag atoms are bridged by a pair of dppm ligands to give an eight-membered Ag2P4C2 ring with a distorted AgOP2 trigonal–planar environment. The Ag—Ag distances of 2.9215 (9) and 3.027 (1) Å indicate a direct bonding interaction.
AIM: To explore the effects of H pylori infection on gap-junctional intercellular communication (GJIC) and proliferation of gastric epithelial cells in vitro.
METHODS: A human gastric epithelial cell line (SGC-7901) cultured on coverslips was exposed overnight to intact H pylori (CagA+ or CagA- strains) and sonicated extracts, respectively. GJIC between the cells was detected by fluorescence redistribution after photobleaching (FRAP) technique. Proliferation of SGC cells was determined by methylthiazolyl tetrazolium (MTT) assay.
RESULTS: When compared with control in which cells were cultured with simple medium alone, both CagA+ and CagA-
H pylori isolates could inhibit GJIC (CagA+: F = 57.98, P < 0.01; CagA-: F = 29.59, P < 0.01) and proliferation (CagA+: F = 42.65, P < 0.01; CagA-: F = 58.14, P < 0.01) of SGC-7901 cells. Compared with CagA- strains, CagA+
H pylori more significantly down-regulated GJIC of gastric cells (intact H pylori: t = 13.86, P < 0.01; sonicated extracts: t = 11.87, P < 0.01) and inhibited proliferation gastric cells to a lesser extent in vitro (intact H pylori: t = 3.06, P < 0.05; sonicated extracts: t = 3.94, P < 0.01).
CONCLUSION: Compared with CagA-
H pylori strains, CagA+ strains down-regulate GJIC of gastric epithelial cells more significantly and inhibit proliferation of gastric cells to a lesser extent in vitro. H pylori, especially CagA+ strains, may play an important role in gastric carcinogenesis.
H pylori; Gap-junctional intercellular communication; Gastric epithelial cell; CagA; Fluorescence redistribution after photobleaching; Methylthiazolyl tetrazolium assay