胰高血糖素样肽-1类似物在非酒精性脂肪性肝病中的应用

非酒精性脂肪性肝病(NAFLD)被认为是代谢综合征在肝脏的一种表现。目前研究显示,NAFLD与肥胖、胰岛素抵抗有关。胰高血糖素样肽-1(GLP-1)是一种可以通过多种机制调节葡萄糖代谢的肽类激素,具有控制血糖水平、减轻体重以及避免低血糖等多种药理效应。初步研究发现,GLP-1类似物能影响NAFLD患者肝组织中的脂质代谢、改善胰岛素抵抗、抑制炎性反应,可成为治疗NAFLD极具潜力的一类药物。     

雌激素及其受体在非酒精性脂肪性肝病发生发展中的作用机制

非酒精性脂肪性肝病(NAFLD)的发病率剧增,目前仍然缺乏有效的药物治疗。虽然对NAFLD发病相关机制研究取得了巨大进展,但对NAFLD的性别差异的理解依然不够。雌激素作为重要的性激素,通过调节情绪及能量稳态、脂肪组织功能及分布、炎症反应、胰岛素抵抗、肝脂蓄积、肝脏免疫等影响NAFLD的发生及发展。充分认识雌激素及雌激素受体在NAFLD中的作用机制,为NAFLD的治疗提供新思路。     

脂毒性在非酒精性脂肪性肝病发生发展中的作用

非酒精性脂肪性肝病(NAFLD)目前是体检时肝脏生化学指标异常的首要原因,但其发生发展的机制仍不十分明确,尚缺乏有效的治疗方法。简述了脂毒性通过触发肝脏内质网应激、细胞死亡、炎症三种病理反应驱动NAFLD向非酒精性脂肪性肝炎、肝硬化的发生及转化,认为脂毒性是促进NAFLD向炎症、纤维化发展的重要因素,为NAFLD的防治提供一种新的途径。     

非酒精性脂肪性肝病在研新药的进展

非酒精性脂肪性肝病(NAFLD)是全世界最常见的肝脏疾病,与肥胖、胰岛素抵抗和其他代谢性疾病密切相关。目前尚无批准用于治疗的药物,常规的生活方式管理也难以对疾病产生积极的影响。对目前在研的代谢调节剂、抗炎抗氧化剂及抗纤维化剂等NAFLD治疗药物进行了综述,归纳总结了其临床研究结果,为NAFLD的临床治疗及药物研发提供新思路。     

非酒精性脂肪性肝炎治疗的潜在新靶点:核受体FXR

目前,非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)已经成为全球性的慢性肝脏疾病,其较高的发病率与肥胖症、糖尿病及代谢紊乱等密切相关.伴随促炎症反应和肝纤维化而发生的胰岛素耐受、脂质代谢紊乱是NAFLD进一步恶化的标志.核受体法尼酯衍生物X受体(farnesoid X receptor,F X R)对脂类的代谢和体内平衡过程具有重要的调节作用,对其功能特性的深入研究,可为非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)的病理生理学特征提供更深的认识,并阐明NAFLD/NASH潜在药物治疗靶点的机制.FXR的激活可以抑制肝脏脂肪的从头合成,增加胰岛素的敏感性以及避免胆汁酸诱导的细胞毒性.结合临床研究提示,FXR的激动剂或调节剂有望用来治疗NAFLD和NASH类肝脏疾病.本文着重对FXR在NASH中的重要调节作用作一综述.     

非酒精性脂肪性肝病的药物治疗

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD) 是世界范围内最普遍的慢性肝病，但目前尚无 治疗NAFLD 的特效药物。饮食及生活方式改变是NAFLD 的基础治疗，但药物治疗也必不可少，主要是针对代谢 综合征和肝脏损伤的药物。目前常用药物有保肝药、胰岛素增敏剂、调脂药物、抗氧化剂、减肥药和肠道益生菌制剂 等, 针对NAFLD 不同发病机制的各种新型靶向药物也相继进入临床试验。文章对近年来NAFLD 的药物治疗及研 究近况加以概述。     

虎杖活性成分治疗非酒精性脂肪性肝病的相关信号通路及相互作用

非酒精性脂肪性肝病(NAFLD)的发病机制尚不清楚，且目前尚无任何治疗NAFLD的有效药物获批。虎杖是药用历史悠久的天然中药，研究证实其在治疗NAFLD中可发挥重要作用。本文通过梳理近年来虎杖活性成分应用于NAFLD的相关研究成果，可见虎杖活性成分通过调控核因子E2相关因子2、腺苷酸活化蛋白激酶、NF-κB、沉默信息调节因子1和过氧化物酶体增殖物激活受体α等多条相关信号通路，发挥改善胰岛素抵抗、抗氧化应激、调节脂质代谢、改善内质网应激、减轻炎症浸润等作用，达到防治NAFLD的作用，以期为NAFLD治疗药物研发及机制探索提供依据和思路。     

胰高血糖素样肽1受体激动剂对代谢相关脂肪性肝病作用机制的研究进展

非酒精性脂肪性肝病(NAFLD)(现已更名为代谢相关脂肪性肝病)是一种以肝实质内脂质过度沉积为特征,常与中心性肥胖、2型糖尿病、胰岛素抵抗、代谢综合征等疾病合并存在,被认为是代谢综合征的肝脏表现。非酒精性脂肪性肝炎(NASH)是一种可能导致肝硬化、肝细胞癌的进行性肝病。目前尚无批准用于治疗NAFLD/NASH的药物。近期研究表明胰高血糖素样肽1(GLP-1)受体激动剂作为降糖药,不仅通过肠促胰素作用改善代谢关键参数间接逆转NAFLD的进展,还直接影响肝细胞脂质代谢、炎症及氧化应激。文章对GLP-1受体激动剂在NAFLD/NASH中的作用及潜在机制进行综述。     

运动类型对代谢相关脂肪性肝病的影响

非酒精性脂肪性肝病(NAFLD)是从单纯的肝脏脂肪变性,到以脂肪变性加炎性反应为特征的非酒精性脂肪性肝炎(NASH),可以依次进展为肝脏纤维化、肝硬化和肝细胞癌的肝脏疾病谱。病理生理学机制包括脂肪酸、亚临床炎症、氧化应激和各种脂肪细胞因子。目前的治疗推荐包括饮食、运动、药物或手术治疗等各种减少体重的措施。着重于体重下降和身体活动的生活方式干预依然是NAFLD管理的基础,在NAFLD中有特殊的治疗作用。虽然运动的益处是显而易见的,但运动类型不同对NAFLD的作用也有所不同。此文针对NAFLD的发病机制,讨论在治疗和预防NAFLD中不同运动类型的可能作用。规律的运动可以改善胰岛素抵抗,减少脂肪沉积,抑制氧化应激,并减弱与NAFLD有关的炎性标志物。多模式运动作为NAFLD治疗的方法仍需要进一步的调查研究。     

肥胖症与非酒精性脂肪性肝病的关系及其治疗进展

非酒精性脂肪性肝病（NAFLD）是一种除外酒精和其他明确肝损因素的慢性肝脏疾病，其发病与肥胖、胰岛素抵抗等密切相关。肿瘤坏死因子（TNF）-α、脂联素等脂肪因子在NAFLD的发生、发展中起重要作用。在肝细胞脂肪变性的基础上发生氧化应激，引起炎症损伤的“二次打击”学说，是目前广泛认可的对NAFLD发病机制的解释。对肥胖患者行饮食、运动、行为、药物、手术治疗等可改善肥胖相关慢性炎症环境，是防治NAFLD重要而有效的手段。     

Three layer functional model and energy exchange concept of aging process

Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.     

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: Attempts to define mechanisms

Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm²) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.     

Melatonin and photoperiodic time measurement: Seasonal breeding in the sheep

Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Serological survey of HIV and syphilis in pregnant women in Madagascar

Objectives Peripartal transmission of human immunodeficiency virus (HIV) and Treponema pallidum, the causative agent of syphilis, leads to severe consequences for newborns. Preventive measures require awareness of the maternal infection. Although HIV and syphilis testing in Madagascar could be theoretically carried out within the framework of the national pregnancy follow‐up scheme, the required test kits are rarely available at peripheral health centres. In this study, we screened blood samples of pregnant Madagascan women for HIV and syphilis seroprevalence to estimate the demand for systemic screening in pregnancy. Methods Retrospective anonymous serological analysis for HIV and syphilis was performed in plasma samples from 1232 pregnant women that were taken between May and July 2010 in Ambositra, Ifanadiana, Manakara, Mananjary, Moramanga and Tsiroanomandidy (Madagascar) during pregnancy follow‐up. Screening was based on Treponema pallidum haemagglutination tests for syphilis and rapid tests for HIV, with confirmation of positive screening results on line assays. Results Out of 1232 pregnant women, none were seropositive for HIV and 37 (3%) were seropositive for Treponema pallidum. Conclusions Our findings are in line with previous studies that describe considerable syphilis prevalence in the rural Madagascan population. The results suggest a need for screening to prevent peripartal Treponema pallidum transmission, while HIV is still rare. If they are known, Treponema pallidum infections can be easily, safely and inexpensively treated even in pregnancy to reduce the risk of transmission.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Variabilité des concentrations plasmatiques de l’angiotensinogène et risque d’hypertension artérielle chez le rat transgénique

Aim

Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5 mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors.

Methods

Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n = 3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction).

Results

At baseline, transgenic rats had +18 mmHg higher bood pressure and –8% lower body weight compared to non-transgenic rats (P < 0.05) without significant changes for the vehicle groups throughout the study (P > 0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P < 0.05) in transgenic and +25%, +5.3% and +6.7% (P > 0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P > 0.05).

Conclusion

Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.