Should we listen to our clock to prevent type 2 diabetes mellitus?

The circadian clock drives a number of metabolic processes including energy intake, storage and utilization coupled with the sleep/wake cycles. Globally, the increasing prevalence of type 2 diabetes (T2DM) has become a significant international public health concern. In view of the heavy societal burden caused by diabetes, and further, to reduce its growing incidence, it is clearly essential to understand the causes of this disease and to devise more effective strategies for its treatment. Although many factors cause T2DM, this article centers on the role of circadian regulation of metabolism. The correlation between the increased occurrence of T2DM and the ubiquity of modern social pressures such as 24/7 lifestyles as well as nocturnal lighting conditions point strongly to the hypothesis that malfunctioning of circadian controls may be involved in the etiology of the illness. Nocturnal light exposure, unusual timing of food, irregular sleep/wake schedules and traveling between different time zones are some of the factors responsible for improper entrainment of the clock. Recent reports have proposed that strengthening of circadian clock functioning and proper timing of food intake could stabilize glucose homeostasis. This strategy thus represents a chronotherapeutic option for non-pharmaceutical intervention in treating T2DM patients.     

Melatonin and its atheroprotective effects: A review

Atherosclerosis is a chronic vascular disease in which oxidative stress and inflammation are commonly implicated as major causative factors. Identification of novel strategies that contribute to plaque stabilization or inhibition represents a continuing challenge for the medical community.     

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

Melatonin and its indoles derivatives are central in the synchronization of malaria parasites. In this research, we discovered that melatonin is unable to increase the parasitemia in the human malaria Plasmodium falciparum that lacks the kinase PfeIK1. The PfeIK1 knockout strain is a valuable tool in the screening of indol-related compound that blocks the melatonin effect in wild-type (WT) parasite development. The assays were performed by using flow cytometry with simultaneous labeling for mitochondria viability with MitoTracker Deep Red and nucleus staining with SYBR Green. We found that Melatotosil leads to an increase in parasitemia in P. falciparum and blocks melatonin effect in the WT parasite. Using microscopy imaging system, we found that Melatotosil at 500 nM is able to induce cytosolic calcium rise in transgenic PfGCaMP3 parasites. On the contrary, the compound Triptiofen blocks P. falciparum cell cycle with IC₅₀ 9.76 µM ± 0.6, inhibits melatonin action, and does not lead to a cytosolic calcium rise in PfGCaMP3 parasites. We also found that the synthetic indol-related compounds arrested parasite cycle for PfeIK1 knockout and (WT) P. falciparum (3D7) in 72 hours culture assays with the IC₅₀ values slighting lower for the WT strain. We concluded that the kinase PfeIK1 is central for melatonin downstream signaling pathways involved in parasite cell cycle progression. More importantly, the indol-related compounds block its cycle as an upstream essential mechanism for parasite survival. Our data clearly show that this class of compounds emerge as an alternative for the problem of resistance with the classical antimalarials.     

阿戈美拉汀的临床应用研究进展

阿戈美拉汀是一种新型的抗抑郁剂,它是神经褪黑色素受体激动剂和5-羟色胺2C受体拮抗剂,目前已经应用于临床实践,尤其适用于伴有睡眠障碍的抑郁症患者.现重点总结该药物的药理机制、临床治疗特点以及治疗的不良反应等方面,希望有利于临床医生更好地了解该药物,并且合理使用该药物.     

佐剂性关节炎大鼠外周血TNF-α、IL-1β、MIF与MLT的昼夜节律

目的：观察佐剂性关节炎（ AA）大鼠外周血肿瘤坏死因子-α（ TNF-α）、白介素-1β（ IL-1β）、巨噬细胞移动抑制因子（ MIF）和褪黑素（ MLT）水平的昼夜变化。方法采用Wistar大鼠复制AA模型,光、暗周期L∶ D=12∶12;于造模后第19天08：00、12：00、16：00、20：00、24：00、04：00共6个时间点采集尾静脉血,采用 ELISA 法检测TNF-α、IL-1β、MIF、MLT含量,余弦法分析其昼夜节律。造模前与造模后6个时间点采用容积测量仪检测大鼠双侧足爪容积。结果 AA大鼠足爪容积未发现明显昼夜变化（ P〉0．05）。昼夜不同时间点外周血细胞因子TNF-α、IL-1β、MIF、MLT水平的波动具有统计学意义（P〈0．05）;4种细胞因子昼夜节律特征相似,即峰值相位均位于夜间（暗期）,其中MIF的峰值出现时间较早,谷值相位均位于白天（明期）。结论 AA大鼠外周血TNF-α、IL-1β、MIF与MLT的表达存在昼夜节律,提示生物钟在类风湿关节炎的病理生理及治疗研究中具有重要意义。     

人胚胎下丘脑褪黑素受体鉴定及其生物学特性

目的为证实人胚胎下丘脑是否存在褪黑素受体（ＭＲ）,以及ＧＴＰγＳ和电解质对ＭＲ的影响,以阐明褪黑素（Ｍ）生物学特性及对内分泌系统作用的机制。方法应用放射配体结合法检测人胚胎下丘脑〔１２５Ｉ〕Ｍ特异结合。结果１．人胚胎下丘脑〔１２５Ｉ〕Ｍ特异结合的Ｓｃａｔｃｈａｒｄ分析：最大结合容量（Ｂｍａｘ）为（１．１５±０．３２）ｆｍｏｌ／ｍｇ蛋白质;平衡解离常数（Ｋｄ）为（３６±８）ｐｍｏｌ／Ｌ;２．动力学分析表明为可逆性结合;３．特异性分析表明对Ｍ高度特异性;４．１０μｍｏｌ／Ｌ和５０μｍｏｌ／ＬＧＴＰγＳ使〔１２５Ｉ〕Ｍ特异结合降低,且有剂量依赖性。结论实验结果表明人胚胎下丘脑存在〔１２５Ｉ〕Ｍ特异结合位点。ＧＴＰγＳ对〔１２５Ｉ〕Ｍ特异结合有明显抑制作用,提示ＭＲ属于Ｇ蛋白系统     

褪黑激素对心肌缺血再灌注损伤的保护作用

目的 :探讨褪黑激素增补于停搏液中对缺血再灌注离体鼠心的保护作用。方法 :将 2 4只Wistar大鼠随机分为褪黑激素组 ,对照组。离体鼠心在改良的Langendorff Neely灌注模型上 30min预灌注 ,12 0min停搏 ,30min再灌注。缺血前及再灌注期间测定血流动力学指标 ,心肌酶 (CPK ,LDH)、心肌超氧化物歧化酶(SOD)、过氧化脂质 (LPO)含量。电镜观察心肌超微结构。结果 :再灌注后 ,褪黑激素组心功能、心肌超微结构的改善明显优于对照组 ;CPK ,LDH ,LPO含量显著低于对照组 (P <0 .0 1) ;SOD含量显著高于对照组 (P <0 .0 1)。结论 :褪黑激素增补于停搏液中可显著减轻心肌缺血再灌注损伤 ,具有良好的心肌保护作用     

桥本甲状腺炎及正常甲状腺组织褪黑素受体亚型基因表达差异的研究

目的　研究成人桥本甲状腺炎及甲状腺腺瘤旁正常甲状腺组织褪黑素受体亚型基因表达的差异及意义。方法　取成人桥本甲状腺炎患者手术切除的甲状腺组织及甲状腺腺瘤瘤旁1. 0cm外正常甲状腺组织,抽提总RNA,合成mt1、MT2 受体引物,用逆转录多聚酶链反应半定量分析褪黑素受体亚型mRNA表达的改变。结果　成人桥本甲状腺炎、甲状腺腺瘤瘤旁正常甲状腺均存在mt1 受体表达,未检测到MT2 受体亚型。桥本甲状腺炎甲状腺组织mt1 受体表达量较正常甲状腺组织明显减少,统计学分析有显著性差异(P<0. 05)。结论　桥本甲状腺炎发病可能与mt1亚型受体抑制有关。褪黑素免疫调节作用可能通过mt1 受体介导。     

褪黑素对缺血再灌注心律失常的作用

目的:探讨外源性褪黑素(M LT)对在体大鼠心脏缺血再灌注心律失常的作用。方法:34只大鼠随机分为对照组、缺血再灌注(I/R)组及缺血再灌注 褪黑素(I/R M LT)组,I/R组及I/R M LT组在体大鼠心脏左冠状动脉前降支完全阻断10 m in,再灌15 m in,监测记录室性心动过速、室颤的发生情况,并测定局部再灌注心肌中M DA(丙二醛)的含量和SOD(超氧化物歧化酶)的活性。结果:室性心动过速、室颤的发生率I/R M LT组明显低于I/R组(P<0.05);I/R组M DA的含量明显高于对照组及I/R M LT组(P<0.01),SOD活性明显低于对照组及I/R M LT组(P<0.01),I/R M LT组M DA含量及SOD活性与对照组无明显差异(P>0.05)。结论:褪黑素可抑制在体大鼠心脏缺血再灌注心律失常的发生,其作用机制可能与其作为自由基清除剂抗氧化作用有关。