Toxic effects of Fusarium mycotoxin butenolide on rat myocardium and primary culture of cardiac myocytes.

Mycotoxin toxicosis has been implicated in the etiopathogenesis of Keshan disease (KD), an endemic cardiomyopathy prevailing in some regions of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone, CAS No. 16275-44-8), a mycotoxin produced by several Fusarium species such as Fusarium tricinctum and Fusarium graminearum, is frequently detected from the cereals in the endemic areas of KD. The present study is undertaken to investigate whether this mycotoxin can induce myocardial damage. Exposure of primary culture of cardiac myocytes to butenolide resulted in significant cytotoxicity, manifested by changes in cell morphology and decreases in cell viability. Consistent with the in vitro findings, distinct myocardial toxicity in vivo was observed after administration of rats by gavage with butenolide (10 and 20 mg/kg/day) for 2 months, and the myocardial injuries were characterized by focal necrosis of myocardium and fragmentation of myofiber. Butenolide also induced significant oxidative damage to the myocardium in vitro evidenced by a concentration-dependent lipid peroxidation in the myocardial homogenates, whereas antioxidants superoxide dismutase (SOD), N-acetylcysteine (NAC) and glutathione (GSH) provided significant protections against this oxidative effect. Taken together, these results clearly reveal that butenolide possesses the potential to induce myocardial toxicity. The present findings may reinforce the hypothesis that toxicosis by mycotoxins is one of the etiological factors for KD.     

Homocysteinylation of low-density lipoproteins (LDL) from subjects with Type 1 diabetes: effect on oxidative damage of human endothelial cells.

BACKGROUND: Homocysteine (Hcy) is an independent risk factor for cardiovascular disease (CVD). Individuals with Type 1 and Type 2 diabetes are more susceptible to the effects of homocysteine than non-diabetic subjects. The interaction between homocysteine-thiolactone (Hcy-thiolactone), a reactive product of Hcy, and low-density lipoproteins (LDL) induces the formation of homocystamide-LDL adducts (Hcy-LDL) and it has been suggested that homocysteinylation could increase atherogenicity of lipoproteins. AIM: The aim of the study was to compare the effect of in vitro homocysteinylation of LDL isolated from healthy control subjects (C-LDL) and from Type 1 diabetic patients (DM-LDL) and to investigate the effect of homocysteinylated LDL (Hcy-C-LDL and Hcy-DM-LDL) on peroxynitrite production of endothelial cells. METHODS: The in vitro homocysteinylation of LDL isolated from control (n = 12) and DM subjects (n = 12) was carried out by incubating lipoproteins with Hcy-thiolactone. The reaction was verified by quantifying the increase in sulphydryl groups (-SH groups) in Hcy-LDL with respect to control LDL. Control and homocysteinylated LDL were incubated with human aortic endothelial cells (HAEC) in culture. Peroxynitrite production in cells treated in different experimental conditions was assayed by a fluorimetric method. RESULTS: The increase in -SH groups after incubation with homocysteine was greater in LDL from diabetic subjects compared with LDL from control subjects (P < 0.001). In addition, peroxynitrite production from HAEC incubated with Hcy-LDL from diabetic patients was greater than after incubation with Hcy-LDL from control subjects and untreated LDL from diabetic patients (P < 0.001). CONCLUSIONS: These results show that LDL from diabetic patients is more susceptible to in vitro homocysteinylation than LDL from non-diabetic individuals and demonstrate that the compositional changes in Hcy-LDL from diabetic subjects have cytotoxic effects on human endothelial cells.     

Primary malignant mesodermal ovarian sarcomas

Primary malignant mesodermal ovarian sarcomas are rare tumors and have a poor prognosis. The disease is usually diagnosed at a late stage and 5-year survivals are uncommon. Most patients are treated with debulking surgery followed by adjuvant chemotherapy. We report ten patients treated at a single institution. All patients underwent surgery and 90% received adjuvant chemotherapy. The median survival was 20 months, and only one patient survived beyond 5 years. Newer treatment strategies are urgently needed in the management of this disease.     

Progression-free interval in ovarian cancer and predictive value of an ex vivo chemoresponse assay

The study objective was to determine the effectiveness of a phenotypic chemoresponse assay in predicting response to chemotherapy measured by progression-free interval (PFI) in a retrospective series of ovarian cancer patients whose tumor specimens had been tested with the ChemoFx assay. A statistically significant correlation between assay prediction of response and PFI was observed in 256 cases with an exact or partial match between drug(s) assayed and received. In 135 cases with an exact match, the hazard ratio for progression of the resistant group was 2.9 (confidence interval [CI]: 1.4-6.3; P < 0.01) compared to the sensitive group and 1.7 (CI: 1.2-2.5) for the intermediate compared to the sensitive group. The median PFI for patients treated with drugs assayed as resistant was 9 months, 14 months for those with drugs assayed as intermediately sensitive, and PFI had not been achieved for those with drugs assayed as sensitive. These data indicate that the ChemoFx assay is predictive of PFI in ovarian cancer. As the majority of ovarian cancers display different degrees of response to different chemotherapy agents ex vivo, the incorporation of assay information into treatment selection has the potential to improve clinical outcomes in ovarian cancer patients.     

Arsenic trioxide–loaded, microemulsion-enhanced cytotoxicity on MDAH 2774 ovarian carcinoma cell line

The antiproliferative effect of As(2)O(3)-loaded microemulsion (As(2)O(3)-M) on human MDAH 2774 ovarian cancer cells was compared with a regular solution of the As(2)O(3). We used MDAH 2774 as model cell lines for ovarian cancer. The (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) (XTT) and trypane blue dye exclusion tests were used to evaluate cytotoxicity. Apoptotic effect of solutions was evaluated using cell death detection kit. Standard microemulsion formulation used in this experiment contains 5 x 10(-6) M As(2)O(3). It was clearly demonstrated that As(2)O(3)-M had a significant cytotoxic effect on MDAH 2774 cell line, and the cytotoxic effect of As(2)O(3)-M was significantly higher than that of regular As(2)O(3) solutions. Even approximately 6000 times diluted microemulsion formulation loaded with 5 x 10(-6) M As(2)O(3) showed a cytotoxic effect. As a result, this diluted concentration (approximately 8 x 10(-10) M) was found to be approximately 6000 times more effective than regular As(2)O(3) solutions (5 x 10(-6) M). Moreover, this diluted concentration resulted in 1.5-fold enhancement of apoptosis. According to the in vitro cytotoxicity studies, we concluded that by incorporating As(2)O(3) into the microemulsion (As(2)O(3)-M), which is a new drug carrier system, it is possible to increase antiproliferative effect of regular As(2)O(3) on MDAH 2774 cells. Translating these results to in vivo conditions would open new windows in the treatment of ovarian cancer.     

Hormonal profiles and follicular growth in cycles with imminent ovarian hyperstimulation

Ovarian hyperstimulation syndrome is a common and serious complication of human menopausal gonadotrophin/human chorionic gonadotrophin treatment. We evaluated the changes in the pituitary and ovarian hormone profiles and ultrasonographic follicular regression in 12 patients in whom human menopausal gonadotrophin was discontinued due to 'imminent' ovarian hyperstimulation. Following discontinuation, three distinct periods were observed: (i) days 1-2, the levels of oestradiol, testosterone and prolactin, and the total number of follicles continued to rise; (ii) days 3-6, the levels of oestradiol, testosterone and prolactin declined sharply and the total number of follicles was reduced significantly, while the large and medium sized follicles continued to increase. Levels of follicle-stimulating hormone and luteinizing hormone gradually declined to reach their lowest levels by days 5-6 and then increased. (iii) Thereafter the number of follicles and steroid output declined to early follicular phase levels. We conclude that discontinuation of human menopausal gonadotrophin and withholding human chorionic gonadotrophin in cycles with laboratory signs of 'imminent' ovarian hyperstimulation syndrome, allows regression of the ovarian ultrasonographic finding and prevents the development of clinical symptoms. However, if rescue of the cycle is attempted, human chorionic gonadotrophin should be given during the first 4 days after discontinuation of stimulation.     

UVA对人角质形成细胞的氧化损伤作用

①目的　探讨紫外线A(UVA)对人角质形成细胞氧化损伤的机制。②方法　用 5J/cm2 UVA照射角质形成细胞 ,酶生化法检测活性氧 (ROS)的含量及超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GSH PX)活性的变化 ,流式细胞仪测定紫外线对角质形成细胞凋亡的影响 ,原位杂交技术观察 p2 1mRNA的变化 ,并与非照射组比较。③结果　与对照组比较 ,UVA照射组ROS含量升高 (t =113.6 8,P <0 .0 0 1) ,SOD、GSH PX活性下降 (t =5 7.2 3、19.0 4 ,P <0 .0 0 1) ,细胞凋亡率升高 (t=5 3.2 8,P <0 .0 0 1) ,p2 1mRNA表达增强。④结论　UVA对人角质形成细胞的损伤与氧自由基生成增多及细胞抗氧化能力抑制有关     

Increased response of renal perfusion to the antioxidant vitamin C in type 2 diabetes.

BACKGROUND: Reactive oxygen species play a major role in the development of endothelial dysfunction. It is as yet unspecified whether increased oxidative stress contributes to endothelial dysfunction of the renal vasculature in patients with type 2 diabetes. METHODS: Renal haemodynamics were studied in 20 patients with type 2 diabetes and arterial hypertension (age 62 +/- 5 years) and 20 non-diabetic hypertensive patients at baseline and following infusions of the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg); the substrate of nitric oxide synthase, L-arginine (100 mg/kg); and the antioxidant, vitamin C (3 g, co-infused with L-arginine 100 mg/kg). RESULTS: The response of renal plasma flow (RPF) to L-NMMA (-54 +/- 62 and -45 +/- 42 ml/min/1.73 m(2); P = NS) and L-arginine (+46 +/- 36 and +49 +/- 25 ml/min/1.73 m(2); P = NS) was not different between diabetic and non-diabetic patients. In contrast, vitamin C induced a more pronounced increase in RPF in diabetic than in non-diabetic patients when co-infused with L-arginine (+71+/-47 and +43+/-33 ml/min/1.73 m(2); P<0.05). CONCLUSIONS: The difference in the response of renal perfusion to an antioxidant suggests increased formation of reactive oxygen species and thereby reduced nitric oxide bioavailability in the renal vasculature of patients with type 2 diabetes.