牛蒡低聚果糖对小鼠抗疲劳作用的研究

为研究牛蒡低聚果糖(BFOS)对小鼠的抗疲劳作用,将牛蒡低聚果糖用三个不同剂量组100、200、400mg.kg-1.d-1给小鼠灌胃,对照组为生理盐水,连续灌胃42 d,末次饲喂30 min后进行游泳实验,耐缺氧实验,测定运动耐力、血乳酸(LAC)、血尿素氮(BUN)等指标。测试结果表明三个剂量的牛蒡低聚果糖均能显著提高运动耐力和耐缺氧时间;降低运动后LAC和BUN的含量;提高肌、肝糖元含量。说明牛蒡低聚果糖具有良好的抗疲劳作用,200 mg.kg-1.d-1为最佳用量,高剂量无明显优势。     

Antiglioma activity of GoPI-sugar,a novel gold(I)–phosphole inhibitor: Chemical synthesis,mechanistic studies,and effectiveness in vivo

Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-β-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC₅₀ of 430 μM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC₅₀ 4.3 nM) and human glutathione reductase (IC₅₀ 88.5 nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.     

Edaravone inhibits acute renal injury and cyst formation in cisplatin-treated rat kidney

Background: Although cis-diamminedichloroplatinum (II) (cisplatin) is an effective anticancer agent, its clinical use is highly limited predominantly due to its adverse effects on renal functions. The present work examined the therapeutic potential of edaravone, a free radical scavenger, for inhibiting cisplatin-induced renal injury.

Methods: Edaravone, 3-methyl-1-phenyl-pyrazolin-5-one, was administrated intravenously at a dose of 30 mg/kg of body weight to male Wistar rats (200-220 g). After 30 min, cisplatin was injected intraperitoneally at a dose of 5 mg/kg of body weight. At the indicated times after the treatment, functions and histological changes of the kidney were analyzed. To test the therapeutic potential of edaravone in chemotherapy, its effect on the anticancer action of cisplatin was examined in ascites cancer-bearing rats.

Results: We found that cisplatin rapidly impaired the respiratory function and DNA of mitochondria in renal proximal tubules, thereby inducing apoptosis of tubular epithelial cells within a few days and chronic renal dysfunction associated with multiple cysts one-year after the administration. Administration of edaravone inhibited the cisplatin-induced acute injury of mitochondria and their DNA and renal epithelial cell apoptosis as well as the occurrence of chronic renal dysfunction and multiple cyst formation. The anticancer effect of cisplatin remained unaffected by intravenous administrating of edaravone.

Conclusions: These results indicate that edaravone may have therapeutic potential for inhibiting the acute and chronic injury of the kidney induced by cisplatin.     

Proteomics of rat biological fluids--the tenth anniversary update

In addition to a remarkable sexual dimorphism of serum and urine proteomes, the rat is exceptional for the wide difference between the serum patterns during an acute phase reaction vs baseline conditions. This feature allows monitoring with high sensitivity onset and progression of any pathological state that involves an inflammatory component as well as assessing the outcome of any therapeutic intervention. Reference maps have been defined for the proteomes of serum, urine, cerebrospinal fluid and bronchoalveolar lavage fluid. For both serum and urine most of the proteomic investigations have dealt with toxicological testing, for BALF with allergic or irritative reactions, whereas with CSF the main aim was the characterization of rat models of neurological disorders. When surveying more than ten years of literature on rat biological fluid proteomics, it is puzzling to see how seldom a consistent analytical plan has been set up for the comparative investigation on two or more types of sample, whether to fully characterize a disease model or to evaluate pharmacological/toxicological effects of a drug. It is also regrettable that in several cases only a negligible part of the results is discussed at length whereas most data are not even made known to the scientific community.     

Toxicity of depleted uranium on isolated rat kidney mitochondria

Background

Kidney is known as the most sensitive target organ for depleted uranium (DU) toxicity in comparison to other organs. Although the oxidative stress and mitochondrial damage induced by DU has been well investigated, the precise mechanism of DU-induced nephrotoxicity has not been thoroughly recognized yet.

Methods

Kidney mitochondria were obtained using differential centrifugation from Wistar rats and mitochondrial toxicity endpoints were then determined in both in vivo and in vitro uranyl acetate (UA) exposure cases.

Results

Single injection of UA (0, 0.5, 1 and 2 mg/kg, i.p.) caused a significant increase in blood urea nitrogen and creatinine levels. Isolated mitochondria from the UA-treated rat kidney showed a marked elevation in oxidative stress accompanied by mitochondrial membrane potential (MMP) collapse as compared to control group. Incubation of isolated kidney mitochondria with UA (50, 100 and 200 μM) manifested that UA can disrupt the electron transfer chain at complex II and III that leads to induction of reactive oxygen species (ROS) formation, lipid peroxidation, and glutathione oxidation. Disturbances in oxidative phosphorylation were also demonstrated through decreased ATP concentration and ATP/ADP ratio in UA-treated mitochondria. In addition, UA induced a significant damage in mitochondrial outer membrane. Moreover, MMP collapse, mitochondrial swelling and cytochrome c release were observed following the UA treatment in isolated mitochondria.

General significance

Both our in vivo and in vitro results showed that UA-induced nephrotoxicity is linked to the impairment of electron transfer chain especially at complex II and III which leads to subsequent oxidative stress.     

Identification of a novel duplication CFTRdup2 and functional impact of large rearrangements identified in the CFTR gene

The aim of this study was to investigate associations of two candidate gene SNPs of the endocannabinoid receptor type 1 gene (CNR1) with overweight, obesity and obesity-related traits in Chinese retired women. The study subjects were a subsample of the Taizhou Retiree Women Cohort, consisting of 2812 retired women aged 50-64 years recruited from Taizhou, Jiangsu, China. Neither rs2023239 nor rs806381 polymorphism was significantly associated with body mass index-defined overweight and obesity or waist-to-hip-ratio-defined obesity. For obesity-related traits, rs2023239 was significantly associated with glutamate pyruvate transaminase (GPT) (median, 18.00 vs 17.00 for TT and TC genotypes, respectively, P=0.043). The rs806381 also showed significant association with triglyceride (TG) (mean±SD, 1.46±0.20 vs 1.53±0.20 for GA and GG+AA genotypes, respectively, P=0.013) under the dominant genetic model. In conclusion, the rs2023239 and rs806381 polymorphisms of CNR1 were not associated with increased overweight and obesity risk. But the rs2023239 polymorphism was significantly associated with GPT, and the rs806381 polymorphism was significantly associated with TG.     

Effects of dietary crude protein on fertility: Meta-analysis and meta-regression

Studies used to evaluate effects of dietary intervention on fertility may be subject to confounding because modification of one nutritional input requires a change in at least one other input. Meta-analytical modeling allows examination of a main intervention for a series of studies, but also an examination of a series of related effects through use of meta-regression. Effects of dietary crude protein (CP) on fertility were examined using this approach. We obtained 21 studies containing 32 comparisons that had pregnancy or conception data and met the eligibility criteria for meta-analysis of randomized controlled experiments providing information on diets used. Publications that contained data on prospective, randomized controlled experiments examining effects of dietary CP, either concentrations or degradability, or effects of a specific feed ingredient intervention on fertility were identified. Details on dietary formulation and diet intake were extracted from the publications, as were measures of urea in blood or plasma. Estimated fixed and random effects relative risks showed that risk of conception was lower in cows fed higher CP or more degradable CP diets (fixed effect (Mantel-Haenszel Relative Risk) = 0.91 (95% CI 0.84-0.98); P=0.019). This effect was homogenous (I² = 0) and not influenced by difference in blood urea N, duration of intervention, breed, parity, milk production or type of diet delivery. Significant associations among CP components of the diet and carbohydrate fractions supported the hypothesized potential for confounding, but only the amount of soluble CP eaten was a significant meta-regression covariate that reduced risk of conception. There was no evidence that the significant reduction in fiber or non-fiber carbohydrate (NFC) fractions of the diets associated with increased concentration of CP, soluble CP or rumen degradable fractions or soyabean products content of the diet influenced conception rates. Results support findings of experiments showing that increased intake of soluble CP reduced conception rates, and provides strong evidence that increased concentrations of CP or increased degradability of CP, within the ranges evaluated in the studies contributing to this meta-analysis, reduce the risk of conception in lactating dairy cattle.     

血清Cys-C 及RBP水平联合检测在早期糖尿病肾病诊断中的应用

目的:探讨血清胱抑素C(Cys-C)和视黄醇结合蛋白(RBP)水平联合检测在早期糖尿病肾病(DN)诊断中的应用价值。方法:选择2010年9月到2014年9月在我院诊疗的150例DN患者,依照24 h尿清蛋白排泄率(UAER)分为DM组(n=60例)、早期DN组(n=46例)和临床DN组(n=44例),同期选择82例健康体检者作为对照组。检测所有患者血清Cys-C、RBP、尿素氮(BUN)和肌酐(Cr)的浓度,比较各指标的阳性检测率和早期DN组各指标单一、联合检测的灵敏度。结果:早期DN组和临床DN组血清Cys-C、RBP浓度明显高于DM组和对照组(P0.05);临床DN组血清Cys-C、RBP浓度明显高于早期DN组(P0.05)。早期DN组血清BUN、Cr浓度与DM组和对照组相比,无显著性差异(P0.05);临床DN组血清BUN、Cr浓度明显高于DM组和对照组(P0.05)。早期DN组和临床DN组血清Cys-C、RBP、BUN及Cr阳性检出率比较无显著性差异(P0.05);早期DN组和临床DN组血清Cys-C、RBP阳性检出率明显高于血清BUN、Cr(P0.05)。早期DN组血清Cys-C+RBP联合检测灵敏度明显高于血清Cys-C、RBP、BUN、Cr的单一检测灵敏度和血清BUN+Cr联合检测灵敏度(P0.05)。结论:血清Cys-C和RBP水平联合检测较BUN、Cr检测早期DN,阳性检出率和灵敏度高,值得在临床上推广应用。     

Curcumin prevents Cr(VI)-induced renal oxidant damage by a mitochondrial pathway

We report the role of mitochondria in the protective effects of curcumin, a well-known direct and indirect antioxidant, against the renal oxidant damage induced by the hexavalent chromium [Cr(VI)] compound potassium dichromate (K₂Cr₂O₇) in rats. Curcumin was given daily by gavage using three different schemes: (1) complete treatment (100, 200, and 400 mg/kg bw 10 days before and 2 days after K₂Cr₂O₇ injection), (2) pretreatment (400 mg/kg bw for 10 days before K₂Cr₂O₇ injection), and (3) posttreatment (400 mg/kg bw 2 days after K₂Cr₂O₇ injection). Rats were sacrificed 48 h later after a single K₂Cr₂O₇ injection (15 mg/kg, sc) to evaluate renal and mitochondrial function and oxidant stress. Curcumin treatment (schemes 1 and 2) attenuated K₂Cr₂O₇-induced renal dysfunction, histological damage, oxidant stress, and the decrease in antioxidant enzyme activity both in kidney tissue and in mitochondria. Curcumin pretreatment attenuated K₂Cr₂O₇-induced mitochondrial dysfunction (alterations in oxygen consumption, ATP content, calcium retention, and mitochondrial membrane potential and decreased activity of complexes I, II, II-III, and V) but was unable to modify renal and mitochondrial Cr(VI) content or to chelate chromium. Curcumin posttreatment was unable to prevent K₂Cr₂O₇-induced renal dysfunction. In further experiments performed in curcumin (400 mg/kg)-pretreated rats it was found that this antioxidant accumulated in kidney and activated Nrf2 at the time when K₂Cr₂O₇ was injected, suggesting that both direct and indirect antioxidant effects are involved in the protective effects of curcumin. These findings suggest that the preservation of mitochondrial function plays a key role in the protective effects of curcumin pretreatment against K₂Cr₂O₇-induced renal oxidant damage.