家兔急性缺氧后左心室舒张功能和心肌细胞内钙转运及能量代谢的研究

为探讨急性缺氧对家兔左心室舒张功能、心肌细胞内钙转运和能量代谢的影响。将２３只家兔分为对照组（６只）、吸入５％低氧混合气的缺氧１组（Ｈ１）（１２只）、吸入１０％低氧混合气的缺氧２组（Ｈ２）（５只），用心导管法测定左心室压力下降最大速率（ＬＶｄｐ／ｄｔｍａｘ）和压力下降时间常数（Ｔ值）；测定心肌肌浆网（ＳＲ）钙ＡＴＰ酶活性、心肌ＳＲ摄钙量、心肌组织ＡＴＰ和磷酸肌酸（ＣｒＰ）。结果，缺氧后ＬＶｄｐ／ｄｔｍａｘ下降，Ｔ值延长；缺氧组心肌ＳＲ钙ＡＴＰ酶活性及摄钙量下降；心肌线粒体钙含量升高；心肌组织ＡＴＰ和ＣｒＰ下降，心肌组织ＡＴＰ与线粒体钙含量呈负相关。提示，急性缺氧可引起左心室舒张功能障碍并影响心肌ＳＲ钙转运和心肌能量代谢。     

PATHOLOGY OF LONG-CHAIN 3-HYDROXYACYL-COA DEHYDROGENASE DEFICIENCY CAUSED BY THE G1528C MUTATION

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is a recently discovered disorder affecting the mitochondrial-oxidation of fatty acids. There have been few reports of the pathologic findings in-oxidation defects. We examined pathologic specimens from 16 patients with this disorder (11 patients were homozygous for the common mutation G1528C, 5 patients were siblings with a similar clinical presentation). Autopsies were performed on all 15 patients who died, and liver biopsy specimens were available from 8 patients. Hepatomegaly and steatosis of the liver, found in every patient, were often combined with fibrosis or cirrhosis. Cardiomegaly and accumulation of fat in the myocardium, renal tubules, and skeletal muscle were found in many patients. A detailed neuropathologic examination was performed on six patients, and brain specimens obtained at autopsy were examined in four others. In general, neuropathologic findings were mild and unspecific, but vacuolization was detected in the deep gray matter and in the cerebellum and brain stem nuclei of five patients. In one patient the vacuolization was prominent; in the other four it was milder and more focal. The vacuoles seemed to be either in the neuropil or associated with swollen hydropic cells. The uniform pattern of histopathologic changes facilitates the diagnostics in this severe disorder, allowing opportunities for therapy and prenatal diagnosis.     

A new case of malonyl coenzyme A decarboxylase deficiency presenting with cardiomyopathy

A new case of mitochondrial malonyl coenzyme A decarboxylase deficiency is described. The patient presented with an initial episode of metabolic acidosis, seizures, hypoglycemia, and cardiac failure at 2 months of age which slowly resolved. Subsequent evaluations at 4 years of age for developmental delay revealed a prominent elevation of malonic acid in urine. Malonyl carnitine was also elevated. The activity of malonyl CoA decarboxylase in cultured fibroblasts was 7% of normal. Conclusion Malonyl CoA decarboxylase deficiency may result in inhibition of fatty acid oxidation, which may account for the cardiomyopathy. Received: 12 April 1996 / Accepted: 24 September 1996     

突发性聋与铁代谢障碍疾病关系的临床调查

对１９７９年７月至１９９６年６月的突发性聋发病情况进行前瞻性研究与回顾性分析，探讨突聋与铁代谢障碍疾病的关系，前瞻性研究的对象分为铁代谢障碍疾病组２１８例，血液病组２１５例和正常对照组４８５０例；回顾性分析为１７年间资料完整的４２９例突聋患者史的代谢障碍疾病及其他血液病的发病情况。结果表明，铁代谢障碍疾病组的突聋调整年发病率显著高于血液病组以及正常对照组，４２９例突聋患者的无贫血缺铁，缺铁性人同血     

Abrogated energy-dependent uptake of cisplatin in a cisplatin-resistant subline of the human ovarian cancer cell line IGROV-1

The parental IGROV-1 human ovarian adenocarcinoma cell line was intermittently exposed to increasing concentrations of cisplatin to obtain resistant sublines. A stable resistant subline with a resistance factor of 8.4 had been developed after 9 months and 28 passages, which was denoted IGROV_CDDP. A high correlation coefficient of 0.97 was found between the log cell survival and the DNA-adduct peak level during the process of resistance development. IGROV_CDDP was strongly cross-resistant to carboplatin and doxorubicin and moderately cross-resistant to etoposide, docetaxel, and topotecan. Only minor resistance against 5-fluorouracil was observed, whereas IGROV_CDDP was not cross-resistant to methotrexate. Intracellular accumulation of cisplatin was 65% lower in IGROV_CDDP as compared with parental IGROV-1 at 37  °C under normal conditions. Coincubation of cisplatin with the Na⁺/K⁺-ATPase inhibitor ouabain resulted in a more pronounced decrease in platinum accumulation in IGROV-1 (44% decrease) than in IGROV_CDDP (26% decrease). Under energy-depleting conditions the accumulation of cisplatin in the parental cell line was approximately 60% lower than that observed under normal (energy [i.e., ATP] rich) culture conditions. In contrast, the accumulation in IGROV_CDDP was not affected by ATP-depletion. There appeared to be no significant difference between the intracellular accumulation of platinum in the resistant and sensitive cells under conditions of energy deprivation or when the uptake was studied at 0  °C. In conclusion, abrogation of energy-dependent accumulation in IGROV_CDDP seems to be a major mechanism of resistance to cisplatin in this cell line. Received: 21 January 1997 / Accepted: 22 July 1997     

绞股蓝总甙复合国产1号避孕片对健康妇女脂类代谢及血压的影响

本研究将180名已婚、一孩、年龄33±5岁,需要使用避孕措施的健康妇女随机分成6组,即IUD组、绞股蓝总甙加IUD组、1号OC片组、40mg、60mg、80mg绞股蓝总甙分别与1号OC片复合的3个试验组.用双盲法给药,连续服用6个月观察脂类代谢和血压的变化.结果显示:以IUD组和1号OC片组的数据为参比值.服用不同剂量绞股蓝总甙复合口服避孕药后无升高TG和TC的趋势,有显著升高HDL-C作用和使APOA_1水平上升的趋势;亦存在降低收缩压的趋势,对舒张压无明显影响,但在服药后3个月时HDL-C水平曾发生暂时性下降.     

促甲状腺素释放激素对烧伤休克大鼠脂质过氧化的影响

目的 探讨促甲状腺素释放激素(Thyrotropin-releasing hormone, TRH)对烧伤休克大鼠氧自由基所引起的脂质过氧化损伤的作用.方法 复制大鼠40% TBSAⅡ°烧伤休克动物模型,烧伤后0.5 h给予TRH(5 mg.kg-1体重),观察烧伤前后平均动脉压的动态变化,烧伤后生存时间,烧伤后1、3、5 h血浆、心、肝、肺、肾SOD活力和MDA含量的变化.结果 TRH能提高烧伤休克大鼠的血压并维持在高水平,明显抑制生命器官组织MDA含量的上升,提高SOD活力,大鼠的生存时间明显延长.结论 TRH在抗大鼠烧伤休克的同时,具有良好的抗脂质过氧化损伤作用,适合于烧伤早期应用.     

1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is toxic to dopaminergic neuroblastoma SH-SY5Y cells via impairment of cellular energy metabolism

The endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3, 4-tetrahydroisoquinoline (salsolinol), which is structurally similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has been reported to inhibit mitochondrial complex I (NADH-Q reductase) activity as does the MPTP metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)). However, the mechanism of salsolinol leading to neuronal cell death is still unknown. Thus, we correlated indices of cellular energy production and cell viability in human dopaminergic neuroblastoma SH-SY5Y cells after exposure to salsolinol and compared these results with data obtained with MPP(+). Both toxins induce time and dose-dependent decrease in cell survival with IC(50) values of 34 microM and 94 microM after 72 h for salsolinol and MPP(+), respectively. Furthermore, salsolinol and MPP(+) produce a decrease of intracellular net ATP content with IC(50) values of 62 microM and 66 microM after 48 h, respectively. In contrast to MPP(+), salsolinol does not induce an increase of intracellular net NADH content. In addition, enhancing glycolysis by adding D-glucose to the culture medium protects the cells against MPP(+) but not salsolinol induced cellular ATP depletion and cytotoxicity. These results suggest that cell death induced by salsolinol is due to impairment of cellular energy supply, caused in particular by inhibition of mitochondrial complex II (succinate-Q reductase), but not complex I.     

Modulation of dihydroxyphenylacetaldehyde extracellular levels in vivo in the rat striatum after different kinds of pharmacological treatment

We recently identified the direct product of dopamine (DA) by monoamine-oxidase (MAO) activity, dihydroxyphenylacetaldehyde (DOPALD) in the trans-striatal dialysate. Based on these findings, in this work, we directly measured the variations in DOPALD levels after various kinds of pharmacological treatment in rat striatal extracellular fluid. Using both reversible and irreversible MAO inhibitors, we found that MAO-A inhibition suppressed, whereas MAO-B inhibition did not modify DOPALD levels in the dialysate. The vesicular DA uptake blocker Ro 4-1284 led to an increase in extracellular DA and DOPALD, whereas the increase in extracellular DA obtained after administration of the plasma membrane DA uptake blocker GBR-12909 occurred without concomitant changes in DOPALD extracellular levels. Microinfusions of DA through the dialysis probe or systemic administration of L-DOPA increased striatal DOPALD to a greater extent compared with other DA metabolites, both in intact and in 6-hydroxydopamine (6-OHDA)-lesioned striatum. This study indicates that the direct product of MAO activity within the rat striatum derives from the activity of the isoenzyme MAO-A. The assay of DOPALD, together with DOPAC, represents a reliable tool to measure directly, in freely moving animals, DA oxidative metabolism. As recent studies have shown that microinfusions of exogenous DOPALD might induce cell death, pharmacological modulation of DOPALD levels might also be relevant for an understanding of the mechanisms involved in DA neurotoxicity.     

Long-term effects on feeding and body weight after stimulation of forebrain or hindbrain CRH receptors with urocortin

Research on the contribution of CRH receptor stimulation to energy homeostasis has focused on forebrain substrates. In this study, we explored the effects of caudal brainstem administration of the CRH receptor agonist, urocortin, on food intake and body weight, and on plasma glucose and corticosterone (CORT) in non-deprived rats. Urocortin (0, 0.3, 1, 3 microg) delivered, respectively, to the fourth and lateral ventricles yielded substantial suppression of food intake measured 2, 4 and 24 h later. A significant but more modest anorexia was observed between 24 and 48 h after injection. Intake responses did not differ between the injection sites, but body weight loss measured 24 h after lateral-i.c.v. injection was substantially greater than that after fourth-i.c.v. injection. Fourth-i.c.v. urocortin administration (3 microg) produced substantial elevations in plasma glucose and CORT that were not distinguishable in magnitude and duration from responses to lateral-i.c.v. delivery. Unilateral microinjection of urocortin into the dorsal vagal complex significantly reduced 24-h food intake at a dose (0.1 microg) that was subthreshold for the response to ventricular administration, suggesting that fourth-i.c.v. effects are mediated in part by stimulation of CRH receptors in this region of the caudal brainstem. The results indicate that similar effects can be obtained from stimulation of anatomically disparate populations of CRH receptors, and that interactions between forebrain and hindbrain structures should be considered in the evaluation of CRH contributions to food intake and body weight control.