Effect of histone deacetylase inhibitor on proliferation of biliary tract cancer cell lines

AIM： To explore the effect of histone deacetylase inhibitor, trichostatin A （TSA） on the growth of biliary tract cancer cell lines （gallbladder carcinoma cell line and cholangiocarcinoma cell line） in vivo and in vitro, and to investigate the perspective of histone deacetylase inhibitor in its clinical application. METHODS： The survival rates of gallbladder carcinoma cell line （Mz-ChA-l cell line） and cholangiocarcinoma cell lines （QBC939, KMBC and OZ cell lines） treated with various doses of TSA were detected by methylthiazoy tetrazolium （MTT） assay. A nude mouse model of transplanted gallbladder carcinoma （Mz-ChA-l cell line） was successfully established, and changes in the growth of transplanted tumor after treated with TSA were measured. RESULTS： TSA could inhibit the proliferation of gallbladder carcinoma cell line （Mz-ChA-l cell line） and cholangiocarcinoma cell lines （QBC939, KMBC and OZ cell lines） in a dose-dependent manner. After the nude mouse model of transplanted gallbladder carcinoma （Mz- ChA-l cell line） was successfully established, the growth of cancer was inhibited in the model after treated with TSA. CONCLUSION： TSA can inhibit the growth of cholangiocarcinoma and gallbladder carcinoma cell lines in vitro and in vivo.     

Improvement of cyclosporin A-induced cholestasis by tauroursodeoxycholate in a long-term study in the rat

Cyclosporin A is an essential immunosuppressive drug, but it is potentially toxic to the kidney and liver. Ursodeoxycholic acid, a hydrophilic bile acid, has been reported to improve cholestasis in liver disease in man. The purpose of this work was to examine whether tauroursodeoxycholate could reduce cyclosporin A-induced hepatic or renal injuries in the rat. After randomization into three groups (N=8), rats received daily for 17 days: cyclosporin A intraperitoneally alone (30 mg/kg) or cyclosporin A intraperitoneally and tauroursodeoxycholate (60 mg/kg) by gavage; controls received the cyclosporin A excipient. Under tauroursodeoxycholate, cholestastic parameters (bile flow, bile salt secretion, serum bile salts, serum bilirubin) improved significantly without affecting cyclosporin A blood levels, and excretion of the drug and its metabolites in bile increased by 47%. Serum creatinine levels were better preserved, although not significantly. These results show that tauroursodeoxycholate prevents cyclosporin A-induced cholestasis in long-term treatment in rats, possibly by facilitating the drug elimination in bile.This work was supported by grants from the Caisse Régionale d'Assurance Maladie du Sud-Est and Houdé Laboratories.     

Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis

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Chemotherapeutic studies on N-nitrosoacetoxymethyl-methylamine-and 1,2-dimethylhydrazine-induced colonic tumors in rats: Monotherapy with 5-fluorouracil,ftorafur, CGP 6809, and CGP 15'720A

Summary Colonic tumors were induced in male Sprague-Dawley rats by ten applications of 2 mg/kg/week N-nitrosoacetoxymethyl-methylamine (AMMN) or by three applications of 100 mg/kg/month 1,2-dimethylhydrazine (1,2-DMH). Application of AMMN and 1,2-DMH induced selective colonic tumors in 97% and 29–42% of the initial animals, respectively. Colonic-tumor-bearing animals were subjected to monotherapy with 5-fluorouracil, ftorafur, CGP 6809, and CGP 15'720A. No cures were achieved. The different therapies did not exert any clear influence on the survival time of animals, except for animals pretreated with AMMN and then subjected to ftorafur therapy.     

Strychnine poisoning. Recovery from profound lactic acidosis, hyperthermia, and rhabdomyolysis

Strychnine poisoning results in a predictable and treatable sequence of events involving blockade of the inhibitory neurotransmitter, extensor muscle spasms, seizures, and respiratory paralysis. These spasms may lead to hyperthermia, profound lactic acidosis, and rhabdomyolysis. Acidosis is primarily attributable to lactate, as indicated by the correlation between arterial pH and log of lactic acid concentration (r = -0.878). Interruption of the strychnine blockade is the primary therapy for strychnine poisoning. Phenobarbital in moderate doses should be the first intervention and anesthetic doses should be used if necessary. Suppression of convulsions will permit successful management of the complications of strychnine poisoning. Our patient survived, even though at one point he had a pH of 6.55, a lactate level of 32 mM/liter, a temperature of 43 degrees C, and rhabdomyolysis with an increased creatine phosphokinase level of 359,000 mU/ml (5,983 mumol/s/liter).     

Increased lipolysis by secretory phospholipase A(2) group V of lipoproteins in diabetic dyslipidaemia

Background. Lipolysis of lipoproteins by secretory phospholipase A₂ group V (sPLA₂‐V) promotes inflammation, lipoprotein aggregation and foam cell formation – all considered as atherogenic mechanisms. Objective. In this study, we compared the susceptibility to sPLA₂‐V lipolysis of VLDL and LDL from individuals with type 2 diabetes and the metabolic syndrome (T2D‐MetS) and from healthy controls. Design. VLDL and LDL were isolated from 38 T2D‐MetS subjects and 38 controls, treated pair‐wise. Extent of sPLA₂‐V lipolysis was measured as release of nonesterified free fatty acids (NEFA). In a subset of the subjects, lipoprotein composition was determined as a relationship between lipid and apolipoprotein components. Results. Mean paired increase in sPLA₂‐V lipolysis after 1 h for T2D‐MetS versus control was 2.0 μmol NEFA l^?1 for VLDL (P = 0.004) and 0.75 μmol NEFA l^?1 for LDL (P = 0.001). There were also substantial differences in lipoprotein composition between the groups. T2D‐MetS VLDL had higher triglyceride and cholesterol contents than control VLDL. T2D‐MetS LDL was smaller and contained more triglycerides and less cholesterol than control LDL. Both VLDL and LDL from T2D‐MetS subjects also contained more apolipoprotein CIII per particle. Conclusion. VLDL and LDL from T2D‐MetS individuals were more susceptible to sPLA₂‐V lipolysis than those from control individuals. This may result in elevated levels of NEFA and lysophosphatidylcholine, both in circulation and in LDL, possibly contributing to the elevated inflammatory state and increased risk of cardiovascular diseases seen in these individuals.     

The Genomic Regions That Contain Ochratoxin A Biosynthetic Genes Widely Differ in Aspergillus Section Circumdati Species

Aspergillus section Circumdati includes 27 species, some of which are considered ochratoxin A (OTA) producers. However, there is considerable controversy about their potential OTA synthesis ability. In this work, the complete genomes of 13 species of Aspergillus section Circumdati were analyzed in order to study the cluster of OTA biosynthetic genes and the region was compared to those previously reported in A. steynii and A. westerdijkiae. The results obtained reveal that the genomes of some species in this section, including A. affinis, A. cretensis, A. elegans, A. muricatus, A. pulvericola, A. roseoglobulosus, and A. subramanianii, contain a potentially functional OTA biosynthetic cluster. Therefore, they might be able to synthesize the toxin. On the contrary, A. melleus, A. ochraceus, A. ostianus, A. persii, A. sclerotiorum, A. sesamicola, and A. westlandensis contain a truncated version of the cluster that lacks many of the genes involved in OTA biosynthesis, which might be related to their inability to produce OTA. The gain/loss pattern is different in all species, which suggests that the genetic evolution of this region might be due to independent events.     

A型肉毒毒素对面部三叉神经痛大鼠疼痛的改善作用及对炎性介质IL-6、TNF-α表达的影响

目的 探讨A型肉毒毒素（BTA）对面部三叉神经痛（TN）大鼠疼痛的改善作用及对炎性介质IL-6、TNF-α表达的影响。方法 从50只大鼠中随机取10只为对照组,剩余大鼠用结扎眶下神经的方法建立TN模型,分为模型组、BTA低剂量组（BTA-L组）、BTA高剂量组（BTA-H组）和卡马西平组,每组各10只。BTA-L组、BTA-H组分别以9、18 μL/kg BTA溶液于手术同侧面部须垫处注射,对照组及模型组给予等量生理盐水,卡马西平组以5 mg/kg卡马西平灌胃。检测大鼠疼痛阈值,ELISA法检测血清中IL-6、TNF-α水平,HE染色观察眶下神经组织病理变化;蛋白免疫印迹法检测三叉神经节中核因子κB（NF-κB）p65、磷酸化型NF-κB p65（p-NF-κB p65）、p38丝裂原活化蛋白激酶（p38MAPK）、磷酸化型p38MAPK（p-p38MAPK）蛋白相对表达量。结果 与对照组比较,模型组注射1、2、3周时疼痛阈值降低（P均 < 0.05）;与模型组比较,BTA-L组、BTA-H组、卡马西平组注射1、2、3周时疼痛阈值升高,且BTA-L组 < BTA-H组 < 卡马西平组（P均 < 0.05）;与对照组比较,模型组血清中IL-6、TNF-α水平及p-NF-κB p65、p-p38MAPK蛋白相对表达量升高（P均< 0.05）;与模型组比较,BTA-L组、BTA-H组、卡马西平组血清中IL-6、TNF-α水平及三叉神经节中p-NF-κB p65、p-p38MAPK蛋白相对表达量降低,且卡马西平组 < BTA-H组 < BTA-L组（P均< 0.05）;HE染色显示,与模型组比较,BTA-L组、BTA-H组、卡马西平组神经纤维肿胀、排列、炎性细胞浸润等异常改变减轻,其中卡马西平组减轻更显著。结论 BTA可降低炎性介质IL-6、TNF-α水平,减轻炎症反应,改善面部疼痛,可能通过抑制NF-κB、p38MAPK信号通路发挥作用。