Antihyperlipidemic Effect of Curcumin and Tetrahydrocurcumin in Experimental Type 2 Diabetic Rats

Hyperlipidemia is an associated complication of diabetes mellitus. In the present study, we investigated the effect of tetrahydrocurcumin (THC), one of the active metabolites of curcumin on lipid profile in streptozotocin (STZ)-nicotinamide-induced diabetic rats. THC 80mg/kg body weight was orally administered to diabetic rats for 45 days, resulting in a significant reduction in blood glucose and a significant increase in plasma insulin in diabetic rats, which proved that THC possess an antidiabetic effect. THC also caused a significant reduction serum and liver cholesterol, triglycerides, free fatty acids, phospholipids, HMG CoA reductase activity, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol levels. The decreased serum high-density lipoprotein (HDL) cholesterol in diabetic rats was also reversed toward normalization after the treatment. These biochemical observations were supplemented by histopathological examination of liver section. The effect was compared with curcumin (80 mg/kg body weight). The results showed that THC had antihyperlipidemic action in control and experimental diabetic rats. The antidiabetic and antihyperlipidemic effects of THC are more potent than those of curcumin at the same dose.     

5α还原酶抑制剂与前列腺癌预防

5α还原酶抑制剂通过抑制5α还原酶降低双氢睾酮水平。应用5α还原酶抑制剂进行的前列腺癌预防研究显示,5α还原酶抑制剂可以降低前列腺癌发病率,但同时也出现高级别前列腺癌病例增加的现象,引起广泛关注。有研究和分析显示,5α还原酶抑制剂使前列腺体积缩小,同时也缩小Gleason评分为3分患者的前列腺癌体积,使得再次穿刺更容易发现Gleason评分为4分以上的前列腺癌。另外5α还原酶抑制剂显著提高前列腺穿刺诊断前列腺癌和高级别前列腺癌敏感度。笔者认为5α还原酶抑制剂不但不增加高级别前列腺癌的发生率,反而会帮助我们更早发现高级别前列腺癌。     

Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery

Aim: To test whether short‐term perioperative administration of oral atorvastatin could reduce incidence of postoperative acute kidney injury (AKI) in cardiac surgical patients. Methods: We conducted a double‐blind, randomized controlled trial in 100 cardiac surgical patients at increased risk of postoperative AKI. Patients were randomized to atorvastatin (40 mg once daily for 4 days starting preoperatively) or identical placebo capsule. Primary outcome was to detect a smaller absolute rise in postoperative creatinine with statin therapy. Secondary outcomes included AKI defined by the creatinine criteria of RIFLE consensus classification (RIFLE R, I or F), change in urinary neutrophil gelatinase‐associated lipocalin (NGAL) concentration, requirement for renal replacement therapy, length of stay in intensive care, length of stay in hospital and hospital mortality. Results: Study groups were well matched. For each patient maximal increase in creatinine during the 5 days after surgery was assessed; median maximal increase was 28 µmol/L in the atorvastatin group and 29.5 µmol/L in the placebo group (P = 0.62). RIFLE R or greater occurred in 26% of patients with atorvastatin and 32% with placebo (P = 0.65). Postoperatively urine NGAL changes were similar (median NGAL : creatinine ratio at intensive care unit admission: atorvastatin group 1503 ng/mg, placebo group 1101 ng/mg; P = 0.22). Treatment was well tolerated and adverse events were similar between groups. Conclusion: Short‐term perioperative atorvastatin use was not associated with a reduced incidence of postoperative AKI or smaller increases in urinary NGAL. (ClinicalTrials.gov NCT00910221).     

Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study

Study Type – Prognostic (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Previous studies used the decrease in PSA after 6 months of dutasteride treatment as a new ‘baseline’ PSA value from which subsequent rises may serve as a warning for prostate cancer; however, PSA tends to continue to decrease as dutasteride treatment continues. By comparing positive biopsy rates in the REDUCE study using any rise from nadir in the dutasteride arm and standard PSA decision criteria (NCCN) in the placebo arm, we demonstrated that the ability to detect prostate cancer and high grade prostate cancer is maintained with dutasteride treatment.

OBJECTIVES

? To determine if dutasteride‐treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. ? To analyse whether the use of treatment‐specific criteria for repeat biopsy maintains the usefulness of prostate‐specific antigen (PSA) level for detecting high grade cancers.

PATIENTS AND METHODS

? The REDUCE study was a randomized, double‐blind, placebo‐controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy‐detectable prostate cancer in men with a previous negative biopsy. ? The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. ? The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. ? Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds.

RESULTS

? Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. ? If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8–10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8–10 cancers would have been missed in the placebo group. ? In both groups, the incidence of Gleason 7 and Gleason 8–10 cancers generally increased with greater rises in PSA. ? Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7–10 cancers in men treated with dutasteride vs placebo. ? Men with Gleason 7 and Gleason 8–10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds.

CONCLUSION

? Using treatment‐specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. ? The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8–10) or higher than (Gleason 7–10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.     

Protective effects of coenzyme q(10) on decreased oxidative stress resistance induced by simvastatin

The effects of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), on oxidative stress resistance and the protective effects of coenzyme Q (CoQ) were investigated. When simvastatin was administered orally to mice, the levels of oxidized and reduced CoQ(9) and CoQ(10) in serum, liver, and heart, decreased significantly when compared to those of control. The levels of thiobarbituric acid reactive substances induced by Fe(2+)-ascorbate in liver and heart mitochondria also increased significantly with simvastatin. Furthermore, cultured cardiac myocytes treated with simvastatin exhibited less resistance to oxidative stress, decreased time to the cessation of spontaneous beating in response to H(2)O(2) addition, and decreased responsiveness to electrical field stimulation. These results suggested that oral administration of simvastatin suppresses the biosynthesis of CoQ, which shares the same biosynthesis pathway as cholesterol up to farnesyl pyrophosphate, thus compromising the physiological function of reduced CoQ, which possesses antioxidant activity. However, these undesirable effects induced by simvastatin were alleviated by coadministering CoQ(10) with simvastatin to mice. Simvastatin also reduced the activity of NADPH-CoQ reductase, a biological enzyme that converts oxidized CoQ to the corresponding reduced CoQ, while CoQ(10) administration improved it. These findings may also support the efficacy of coadministering CoQ(10) with statins.     

佛山市汉族人群叶酸代谢通路关键酶基因MTHFR C677T多态性分布特征调查

目的 调查佛山市体检人群叶酸代谢障碍关键酶基因5,10-亚甲基四氢叶酸还原酶(MTHFR)C677T位点基因多态性分布情况。方法 以佛山市182位女性和120位男性为研究对象,均为汉族人群,检测其MTHFR C677T基因位点多态性,分析性别、地域与基因多态性分布特征的关系。结果 调查的302例佛山市汉族人群MTHFR C677T位点CC、CT、TT基因型所占比例分别为62.6%、31.8%、5.6%,等位基因C、T所占比例分别为78.5%、21.5%。佛山市汉族男性与汉族女性MTHFR C677T位点多态性分布情况差异无统计学意义(P＞0.05)。佛山市汉族人群与已有数据报道的武汉、西安、长治、青岛、北京、乌鲁木齐等地的汉族人群的MTHFR C677T位点基因型、等位基因的分布情况差异均有统计学意义(P＜0.05)。佛山市汉族人群与回族、蒙族、维吾尔族、苗族MTHFR C677T位点基因型、等位基因的分布情况差异有统计学意义(P＜0.05),与布依族差异无统计学意义(P＞0.05)。结论 佛山市汉族人群MTHFR C677T位点多态性分布情况与其他地区、其他民族有显著差异,在实施个性化日常保健措施时可将遗传因素纳入考虑。     

细菌硝酸盐还原中的关键酶影响细菌耐药性的研究进展

硝酸盐的还原是细菌氮代谢中最重要的生化反应之一.随着对细菌耐药机制的不断探索,氮代谢过程尤其是某些代谢酶对细菌耐药性的影响得以揭示.作为硝酸盐还原过程中的关键代谢酶,硝酸还原酶(nitrate reductase,NR)与亚硝酸还原酶(nitrite reductase,NiR)不仅催化着细菌体内硝酸盐的一系列还原反应,还从多方面影响了细菌的耐药性.本文综述了NR/NiR与细菌耐药性之间关系的最新研究进展,以期为新药物靶标的发现及提出新治疗措施提供依据.     

Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin

Loxoprofen (LX) is a prodrug‐type non‐steroidal anti‐inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans‐alcohol form of LX (trans‐OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans‐OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both the permeation of LX and the formation of the trans‐OH form increased in a time‐ and dose‐dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans‐OH form were examined by a mathematical pharmacokinetic model. The K_m value was calculated to be 10.3 mm in the human in vitro skin. The predominant enzyme which generates the trans‐OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti‐human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the K_m and V_max values were 7.30 mm and 402 nmol/min/mg protein, respectively. In addition, it was found that no unknown metabolites were generated in the human in vitro skin. This is the first report in which LX is bioactivated to the trans‐OH form in human skin by CBR1. Copyright © 2015 John Wiley & Sons, Ltd.     

Role of pharmacogenomics and pharmacodynamics in the treatment of acute lymphoblastic leukaemia

Pharmacodynamic studies have been used to establish the relationships between the administered dosage and the concentration of drugs and metabolites in the blood or tissues and that between these concentrations and pharmacological effects. Polymorphisms in the genes that encode drug-metabolizing enzymes, drug transporters and drug targets can affect a person's response to therapy and may affect the development of de novo or therapy-related leukaemias. The burgeoning field of pharmacogenomics elucidates inherited differences in drug metabolism and treatment response. Increasingly, pharmacodynamic and pharmacogenomic studies are being used to individualize therapy to enhance efficacy and reduce toxicity.