氯胺酮在体内的分布与代谢

目前,氯胺酮(ketamine,俗称K粉)的滥用现象日益严重,并有愈演愈烈之势,特别流行于舞厅等娱乐场所,对社会治安和经济建设造成极大危害。滥用毒品倾向呈现年轻化、男女平均化且女性滥用者的比例上升和用药多元化的趋势,由滥用鸦片类药物发展到多种药物的滥用。调查发现,毒品滥用中K粉比例达20%以上,短期可使语言迷糊,引起幻觉,长期可使人记忆力衰退及认知能力障碍,导致心功能损害。因吸食氯胺酮或服用含有氯胺酮的摇头丸、迷奸药而中毒死亡的案件逐年上升。本文综述了对氯胺酮在体内各个部分的分布与代谢,更多、更快、更好的为氯胺酮相关案件的检材选取,分析检测及体内过程的评价提供科学依据。     

蝮蛇咬伤引起严重凝血功能障碍1例报告

蝮蛇毒为混合毒,被咬伤后多表现为明显的局部症状,如牙痕明显,少量渗血,患处肿胀,皮下瘀斑及压痛;全身症状,如头痛头晕、恶心呕吐、复视、胸闷气急、流涎等;很少表现为严重凝血功能障碍。我们于2006年7月14日收治1例蝮蛇咬伤引起严重凝血功能障碍患者,现报告如下。     

溴氰菊酯在鸡体内的排泄,分布和代谢

用三种不同部位~(14)C标记的溴氰菊酯喂食产卵母鸡,观察它在鸡体内的排泄、分布和代谢,结果表明鸡吞食溴氰萄酯后24小时大部分都由排泄物中排出,一星期内排出吞食量的90％左右。溴氰菊酯及其代谢产物在鸡体内的各组织中均有发现,其中以肝脏、肠及肌胃中较多,鸡蛋中也有发现。溴氰菊酯在鸡体内的代谢,其排泄物中除有未经代谢的溴氰菊酯外,还有包括二溴菊酸和3-苯氧基苯甲醛在内的23种代谢产物。     

脂肪因子与代谢综合征关系的研究进展

代谢综合症是一系列代谢和心血管功能失调的临床特征,包括中心性肥胖、高血压、血脂异常、高血糖及胰岛素抵抗等,其发病机制及如何预防及控制代谢综合症正日益成为目前的学术热点。目前已经公认,脂肪不仅是能量存储器官,也是一个重要的内分泌器官。脂肪组织分泌的生物活性分子被称为脂肪因子。近年来的研究表明,脂肪因子广泛参与肥胖、2型糖尿病、高血压病及心血管疾病等一系列代谢相关性疾病的病理生理过程。脂肪因子能通过介导一系列的信号转导通路,并广泛参与机体复杂的代谢平衡网络的调节。脂肪因子的失衡能导致机体发生对胰岛素敏感性改变等一系列的生物学反应,从而在肥胖和代谢综合症的病理过程中发挥重要的作用。本文综述了脂肪因子与代谢综合征的关系的研究进展。     

阴茎勃起及勃起功能障碍的研究进展

勃起功能障碍的基础研究须近十年来取得了较大进展,一氧化氮－cGMP(NO-cGMP)通路的发现使得阴茎平滑肌松驰的机制进一步阐明。一氧化氮合酶（NOS）、磷酸二酯酶（PDEs）的研究为勃起功能障碍的临床治疗提供了坚实的基础,进而促使了万艾可的问世。目前,勃起功能障碍的基因治疗停留在实验室阶段,但随着分子生物学的深入研究,转基因疗法可能成为临床上治疗勃起功能障碍的有效方法之一。     

NuMA 的分布和功能

核有丝分裂器蛋白(Nuclear Mitotic Apparatus Protein,NuMA)是一种在间期细胞核内有大量表达的大分子蛋白。NuMA是微管聚合因子,能使微管锚定于纺锤体极。在细胞有丝分裂,减数分裂过程中对纺锤体的形成和形态的维持发挥重要作用。     

NuMA的分布和功能

核有丝分裂器蛋白（Nuclear Mitotic Apparatus Protein,NuMA）是一种在间期细胞核内有大量表达的大分子蛋白。NuMA是微管聚合因子,能使微管锚定于纺锤体极。在细胞有丝分裂,减数分裂过程中对纺锤体的形成和形态的雏持发挥重要作用。     

具有脂肪代谢功能的果蝇细胞

果蝇与人类有很多共同基因,实践证明它们对了解几种人类疾病来说很有用,但它们的脂肪代谢机制一直是个谜,这限制了果蝇（及其很多遗传工具）在肝病和肥胖研究中的应用。所以关于果蝇体内也存在具有脂肪代谢功能的细胞、与人类肝脏中同样功能的细胞类似的发现,可以说是一项重要进展。这些细胞是绛细胞（oenocyte）,首次于140多年前发现于昆虫,但以前未发现其有某种特定功能。     

功能代谢组学技术在微生物研究中的应用

功能代谢组学是以代谢组学技术发现关键代谢物为基础,结合体内体外实验和分子生物学等技术手段,研究差异代谢物及相关蛋白、酶和基因的功能,从而揭示生物体内在的分子调控机制。功能代谢组学技术具有精准识别关键调控代谢物及其相关基因或酶的特性,近年来在微生物相关疾病的防控和工业化生产等方面受到了广泛的关注。本文介绍了功能代谢组学技术的分析流程、相关研究方法与平台及其在微生物研究方面的应用,其中重点阐述了真核、原核以及病毒微生物的代谢特性、调控靶点及相关防控策略等。最后,提出功能代谢组学研究在未来面临的问题与挑战,为后续功能代谢组学的研究与发展提供新的思路。     

SPATA4 improves aging‐induced metabolic dysfunction through promotion of preadipocyte differentiation and adipose tissue expansion

Spermatogenesis‐associated protein 4 (SPATA4) is conserved across multiple species. However, the function of this gene remains largely unknown. In this study, we generated Spata4 transgenic mice to explore tissue‐specific function of SPATA4. Spata4 overexpression mice displayed increased subcutaneous fat tissue compared with wild‐type littermates at an old age, while this difference was not observed in younger mice. Aging‐induced ectopic fat distribution, inflammation, and insulin resistance were also significantly attenuated by SPATA4. In vitro, SPATA4 promoted preadipocyte differentiation through activation of the ERK1/2 and C/EBPβ pathway and increased the expression of adipokines. These data suggest SPATA4 can regulate lipid accumulation in a tissue‐specific manner and improve aging‐induced dysmetabolic syndromes. Clarifying the mechanism of SPATA4 functioning in lipid metabolism might provide novel therapeutic targets for disease interventions.     

Mitochondrial Dysfunction in Age‐Related Metabolic Disorders

Aging is a natural biological process in living organisms characterized by receding bioenergetics. Mitochondria are crucial for cellular bioenergetics and thus an important contributor to age‐related energetics deterioration. In addition, mitochondria play a major role in calcium signaling, redox homeostasis, and thermogenesis making this organelle a major cellular component that dictates the fate of a cell. To maintain its quantity and quality, mitochondria undergo multiple processes such as fission, fusion, and mitophagy to eliminate or replace damaged mitochondria. While this bioenergetics machinery is properly protected, the functional decline associated with age and age‐related metabolic diseases is mostly a result of failure in such protective mechanisms. In addition, metabolic by‐products like reactive oxygen species also aid in this destructive pathway. Mitochondrial dysfunction has always been thought to be associated with diseases. Moreover, studies in recent years have pointed out that aging contributes to the decay of mitochondrial health by promoting imbalances in key mitochondrial‐regulated pathways. Hence, it is crucial to understand the nexus of mitochondrial dysfunction in age‐related diseases. This review focuses on various aspects of basic mitochondrial biology and its status in aging and age‐related metabolic diseases.     

细胞内质网应激与糖脂代谢紊乱的机制关联

在真核细胞中,内质网是蛋白质合成、折叠、加工及其质量监控的重要场所。当内质网难以承担蛋白折叠的高负荷时则引发内质网应激(ER stress),激活细胞的未折叠蛋白响应(unfoldedprotein response,UPR)。细胞通过内质网跨膜蛋白ATF6、PERK和IRE1介导的三条极为关键的UPR信号通路,调控下游相关基因的表达,以增强内质网对蛋白折叠的处理能力。因此,UPR通路在细胞的稳态平衡中具有举足轻重的作用,而这一动态过程的调控对于维持机体的正常生理功能至关重要。近来大量研究表明,在哺乳动物中内质网应激与机体的营养感应和糖脂代谢的调控过程密切相关。在肝脏、脂肪、胰岛以及下丘脑等不同的组织器官中,内质网应激均影响代谢通路的调节机制,因此在糖脂代谢紊乱的发生发展中扮演重要的角色。综上所述,进一步深入了解内质网应激引发代谢异常的生理学机制,可以为肥胖、脂肪肝及2型糖尿病等相关代谢性疾病的防治提供新的潜在药物靶点和重要的理论线索。     

Human hormone-sensitive lipase (HSL): expression in white fat corrects the white adipose phenotype of HSL-deficient mice

In white adipose tissue (WAT), hormone-sensitive lipase (HSL) can mediate lipolysis, a central pathway in obesity and diabetes. Gene-targeted HSL-deficient (HSL-/-) mice with no detectable HSL peptide or activity (measured as cholesteryl esterase) have WAT abnormalities, including low mass, marked heterogeneity of cell diameter, increased diacylglycerol content, and low beta-adrenergic stimulation of adipocyte lipolysis. Three transgenic mouse strains preferentially expressing human HSL in WAT were bred to a HSL-/- background. One, HSL-/- N, expresses normal human HSL (41.3 +/- 9.1% of normal activity); two express a serine-to-alanine mutant (S554A) initially hypothesized to be constitutively active: HSL-/- ML, 50.3 +/- 12.3% of normal, and HSL-/- MH, 69.8 +/- 15.8% of normal. In WAT, HSL-/- N mice resembled HSL+/+ controls in WAT mass, histology, diacylglyceride content, and lipolytic response to beta-adrenergic agents. In contrast, HSL-/- ML and HSL-/- MH mice resembled nontransgenic HSL-/- mice, except that diacylglycerol content and perirenal and inguinal WAT masses approached normal in HSL-/- MH mice. Therefore, 1) WAT expression of normal human HSL markedly improves HSL-/- WAT biochemically, physiologically, and morphologically; 2) similar levels of S554A HSL have a low physiological effect despite being active in vitro; and 3) diacylglycerol accumulation is not essential for the development of the characteristic WAT pathology of HSL-/- mice.     

胰岛素对糖尿病大鼠代谢紊乱的调节作用

利用四氧嘧啶建立糖尿病大鼠模型,研究了胰岛素对糖尿病大鼠脂肪、蛋白质、自由基代谢紊乱的调节作用及对机体和肝脏氧化损伤的保护作用。结果表明,胰岛素0．5U/kg皮下注射8周,能明显抑制糖尿病引起大鼠体重的降低。皮下注射6周,显著提高了血清总蛋白、白蛋白、总胆固醇的水平,降低了血清甘油三酯的含量。胰岛素1U／kg皮下注射9d,能显著提高血清超氧化物歧化酶、谷肮甘肽过氧化物酶的活性,降低血清丙二醛的含量及促氧化酶黄嘌呤氧化酶的活性,提高肝线粒体谷胱甘肽过氧化物酶的活性,降低肝线粒体丙二醛的含量。从而调节糖尿病大鼠脂肪、蛋白质、自由基代谢紊乱,减轻机体的氧化损伤,改善肝功能。     

Fat tissue,aging, and cellular senescence

Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age‐related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro‐inflammatory, tissue‐remodeling, senescent‐like state. Other mesenchymal progenitors also can acquire a pro‐inflammatory, adipocyte‐like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, inflammatory cytokine and chemokine generation, and innate and adaptive immune response activation. These pro‐inflammatory processes may amplify each other and have systemic consequences. This model is consistent with recent concepts about cellular senescence as a stress‐responsive, adaptive phenotype that develops through multiple stages, including major metabolic and secretory readjustments, which can spread from cell to cell and can occur at any point during life. Senescence could be an alternative cell fate that develops in response to injury or metabolic dysfunction and might occur in nondividing as well as dividing cells. Consistent with this, a senescent‐like state can develop in preadipocytes and fat cells from young obese individuals. Senescent, pro‐inflammatory cells in fat could have profound clinical consequences because of the large size of the fat organ and its central metabolic role.     

Running Exercise Improves Metabolic Abnormalities and Fat Accumulation in Sucrose-Induced Insulin-Resistant Rats

NARA, MAKOTO, MASAKI TAKAHASHI, TSUGIYASU KANDA, YOUNOSUKE SHIMOMURA, ISAO KOBAYASHI. Running exercise improves metabolic abnormalities and fat accumulation in sucrose-induced insulin-resistant rats. Insulin resistance and hyperinsulinemia are observed in rats fed a high sucrose diet. Insulin resistance is thought to be related to abnormal fat distribution. We previously reported the metabolic characteristics and the fat distribution in rats with sucrose-induced insulin resistance. This study was designed to examine the effects of exercise in these rats. The rats were divided into three groups: those receiving a starch-based diet (control), those receiving a high-sucrose diet (sucrose fed), and those receiving a high-sucrose diet and wheel-running exercise (exercised). Animals were killed after 4 weeks or 12 weeks. After 4 weeks, the three groups did not differ with respect to gain in adipose tissues. The portal vein (PV) insulin concentration was significantly increased in the sucrose-fed and the exercised rats compared with the control rats. The inferior vena cava (IVC) glucose concentration and the PV free fatty acid (FFA) were significantly lower in the exercised rats than in the sucrose-fed rats. After 12 weeks, the exercised rats had significantly lower mesenteric fat (MS) and subcutaneous fat (SC) and a lower MS:SC ratio than the sucrose-fed rats. The glucose levels in IVC, PV, and FFA in PV were significantly reduced in the exercised rats as compared with the sucrose-fed rats. These findings suggest that long-term exercise improves insulin resistance by reducing the accumulation of MS as well as SC. It is also suggested that short-term exercise improves glucose metabolism without change of fat accumulation.     

高脂饮食对小鼠脂质代谢和leptin基因表达水平的影响

目的建立高脂饮食诱导小鼠肥胖模型,分析高脂饲料对小鼠脂质代谢和leptin基因表达水平的影响。方法用高脂饲料饲喂小鼠,每周定时称重和断尾采血一次,分别测定血清中血糖、胆固醇、甘油三酯、胰岛素和leptin的浓度;5周后,分离、称重小鼠体脂并提取腹部脂肪组织RNA,半定量RT-PCR分析leptin基因表达水平。结果从第2周开始,实验组小鼠体重明显高于对照组小鼠,4周后,体重差异显著（P〈0．05）;血清中血糖、胆固醇、甘油三酯、胰岛素和leptin的含量随体重增加明显增高,4周后,差异显著（P〈0．05）;实验组体脂含量明显高于对照组（P〈0．05）,半定量RT-PCR分析表明,肥胖小鼠脂肪组织leptin基因表达水平高于对照组（P〈0．05）。结论高脂饮食诱导可建立小鼠肥胖模型,并能够引起高胰岛素和高leptin血症,为进一步研究肥胖的发病机制奠定基础。     

Shiftwork and Metabolic Dysfunction

Many of the health problems that are more prevalent among shiftworkers are thought to be linked to their heightened susceptibility to metabolic syndrome, i.e., the association of even moderate degrees of visceral obesity, dyslipidemia, abnormal blood pressure, and serum glucose levels in the same individual. Although previous studies have identified associations between shiftwork and metabolic syndrome, there is relatively little evidence to date of how the risk of developing it varies as a function of exposure to shiftwork. The current study seeks to confirm earlier findings of an association between shiftwork exposure and metabolic dysfunction, and to examine the impact of exposure duration, while adjusting for a number of covariates in the analyses. The analyses were based on data from VISAT, a study involving the measurement of physiological, behavioral, and subjective outcomes from 1757 participants, 989 being current or former shiftworkers. The sample comprised employed and retired wage earners, male and female, who were 32, 42, 52, and 62 yrs old. The first analysis sought to confirm previous findings of an association between exposure to shiftwork and the risk of developing metabolic syndrome. It indicated that participants who were or who had previously been shiftworkers (i.e., working schedules that involved rotating shifts; not being able to go to bed before midnight; having to get up before 05:00?h; or being prevented from sleeping during the night) were more likely to exhibit symptoms of metabolic syndrome, after adjusting for age, sex, socioeconomic status, smoking, alcohol intake, perceived stress, and sleep difficulty (odds ratio [OR] 1.78; 95% confidence interval [CI] 1.03–3.08). The results suggest the association between shiftwork and metabolic syndrome cannot be fully accounted for by either higher levels of strain or increased sleep difficulty among shiftworkers, although it remains a possibility that either one or both of these factors may have played a contributing role. The second analysis addressed the issue of duration of exposure to shiftwork. Participants with >10 yrs' experience of working rotating shifts were more likely to exhibit symptoms of metabolic syndrome than participants without exposure to shiftwork, i.e., dayworkers, even after adjusting for age and sex (OR 1.96; 95% CI 1.03–3.75). Thus, the current study confirms the association between shiftwork exposure and metabolic syndrome. It also provides new information regarding the time course of the development of the illness as function of exposure duration, although this was only examined in relation to rotating shiftwork. It is concluded that those responsible for monitoring workers' health should pay particular attention to indices of metabolic dysfunction in workers who have been exposed to shiftwork for >10 yrs. (Author correspondence: p.t.tucker@swansea.ac.uk)     

Effect of High Sucrose Feeding on Fat Accumulation in the Male Wistar Rat

High sucrose intake is generally thought to be a risk factor for obesity and insulin resistance. We examined the effects of feeding sucrose on fat accumulation and insulin release in male rats. Six-week-old male Wistar rats were maintained on a high sucrose diet for 4 or 12 weeks. Control rats were fed a diet based on starch. No significant difference in daily caloric intake or weight gain existed between the two dietary groups. There was no difference between the two dietary groups in the gain of abdominal subcutaneous fat (SC) at 4-week. In contrast, rats fed the high sucrose diet had significantly more mesenteric fat (MES) than controls (p<0.01). At 12 weeks, rats fed the high sucrose diet had significantly more SC and MES than controls (SC:p<0.05, MES:p<0.01). Basal immunoreactive insulin (IRI) concentrations in the portal vein (PV) of rats fed the high sucrose diet was significantly higher compared to those of controls (4 wk: p<0.05, 12 wk: p<0.05). No difference between the two dietary groups in basal IRI concentrations in the inferior vena cava (TVC) existed at 4 weeks; whereas at 12 weeks, the basal IRI concentrations in the IV C in rats fed the high sucrose diet were significantly higher than in controls (p<0.05). The mesenteric and subcutaneous fat accumulations were closely related to hyperinsulinemia in the portal vein and inferior vena cava, respectively. Twelve weeks of high sucrose feeding caused accumulation of abdominal adipose tissue with marked hyperinsulinemia and hyperlipidemia. Our study is the first to demonstrate that abdominal fat induced by high sucrose intake in male rats is accompanied by an abnormal metabolic state similar to an insulin-resistant state.