病毒感染引起的内质网应激对不同生物学功能的影响研究进展

内质网(endoplasmic reticulum stress, ER)是蛋白质合成基地,也是蛋白质翻译后修饰、折叠和转运的重要场所。当细胞合成大量蛋白质、受到病毒感染、细胞缺氧、氧化应激等,都会致使未折叠/错误折叠蛋白在ER中大量积累,导致内质网应激(endoplasmic reticulum stress, ERS),激活未折叠蛋白反应(unfolded protein response, UPR)。近年来,研究人员对病毒感染引起的ERS及其对细胞自噬、凋亡、炎症等生物学功能的影响做了大量研究,取得了突破性的进展。本篇综述旨在对近年来关于病毒感染引起的ERS及其对多种生物学功能影响的研究现状进行总结归纳,从ERS视角为预防及治疗病毒感染性疾病提供新方向和干预措施。     

内质网应激与神经退行性疾病的关系

<正>内质网(ER)是真核细胞内蛋白质折叠组装、Ca~(2+)动态平衡的重要场所。遗传或环境等因素导致的内质网内稳态失衡将引起内质网应激(ERS),激活一系列应激反应如未折叠蛋白反应(UPR)。未折叠蛋白反应和早期的ERS,是一种自身代偿过程,对细胞起着调节与保护作用,而持续、强烈的ERS可诱导细     

内质网应激与肝细胞凋亡

内质网(endoplasmic reticulum,ER)是一种重要的真核细胞器,由于各种原因引起的内质网中出现错误折叠与未折叠蛋白在腔内聚集以及Ca~(2 )平衡紊乱的状态,称为内质网应激(ER stress,ERS).细胞凋亡(apoptosis),又称为程序性细胞死亡(programmed cell death,PCD),是受细胞外微环境和细胞内基因调控的一种细胞主动性死亡方式,他是机体用来去除衰老、有害、无用及异型细胞的一种重要机制,是确保机体正常发育、维持机体正常生理过程所必须的.肝细胞凋亡是造成肝脏损伤和肝脏疾病最基本的中心环节.既往研究认为肝细胞凋亡主要通过两条信号通路介导,即死亡受体通路和线粒体依赖性的细胞凋亡通路.但近来发现ERS亦介导肝细胞发生凋亡,本文主要讨论ERS途径所致肝细胞凋亡的机制.     

内质网应激与炎症性肠病

内质网（ER）是细胞内蛋白折叠修饰组装的场所,由于某种原因使错误折叠蛋白质或未折叠蛋白质在ER内聚集导致稳态失衡、生理功能发生紊乱称为内质网应激（ERS）.初期的ERS是一种代偿过程,能避免细胞损伤、恢复细胞功能,而ERS长时间持续或程度过强则会引起细胞凋亡,组织受损.近期研究发现,ERS在炎症性肠病的发生发展中起着重要作用.此文就近期ERS在炎症性肠病中作用的研究作一综述.     

内质网应激与炎症性肠病

内质网(ER)是细胞内蛋白折叠修饰组装的场所,由于某种原因使错误折叠蛋白质或未折叠蛋白质在ER内聚集导致稳态失衡、生理功能发生紊乱称为内质网应激(ERS)。初期的ERS是一种代偿过程,能避免细胞损伤、恢复细胞功能,而ERS长时间持续或程度过强则会引起细胞凋亡,组织受损。近期研究发现,ERS在炎症性肠病的发生发展中起着重要作用。此文就近期ERS在炎症性肠病中作用的研究作一综述。     

内质网应激与心血管疾病

内质网(endoplasmic reticulum,ER)是细胞内蛋白质折叠、Ca2+储存和脂质生物合成的重要部位。氧化应激、缺血、Ca2+稳态的失衡都可以引起ER内非折叠蛋白的聚集,通过ER内的分子伴侣激活非折叠蛋白反应（unfolded protein response,UPR)可促进细胞的生存,但是过度ER应激(endoplasmic reticulum stress,ERS)可以诱导凋亡信号起始,通过线粒体依赖或者非线粒体依赖途径导致细胞死亡。因此,近年来ER被认为是决定细胞生存与凋亡的重要器官。最近研究提示,ERS在多种心血管疾病的病生理机制中起着重要作用,包括心功能不全及缺血性心脏疾病等。对这些疾病分子机制的进一步认识,将有助于开发新的靶向药物并治疗疾病。本文将对ERS和其与心血管疾病的关系进行综述。     

分子伴侣氧调节蛋白150在内质网应激相关疾病中的研究进展

<正>多种因素可以影响内质网(ER)的功能,当未折叠蛋白或折叠错误的蛋白在ER腔中积聚时,可触发ER应激(ERS),进而导致ER未折叠蛋白反应(UPR)。氧调节蛋白(ORP)150是ERS重要的标志分子伴侣,且参与许多疾病的病理过程,但确切的作用机制尚不明确。本文综述ORP150在ERS相关疾病中的表达变化可能发挥的作用。1 ERS与ORP150ER是真核细胞内重要的细胞器,主要参与各种跨膜蛋白     

内质网应激与缺血性脑损伤

内质网应激是内质网内未折叠或错误折叠蛋白积聚所致。作为对内质网应激的响应,细胞形成了一条称为未折叠蛋白反应(UPR)的自我保护信号转导通路。然而,如果脑缺血诱导的内质网应激严重且持续时间长,UPR最终会启动细胞凋亡通路,导致神经元死亡。文章对脑缺血再灌注诱导内质网应激和UPR的研究进展做了综述。     

内质网应激相关机制及其在炎症性肠病中的作用

肠内稳态在维持胃肠正常功能方面发挥重要作用。肠内环境改变时,肠内稳态失衡,影响肠上皮细胞(intestinal epithelial cells,IECs)内质网腔内蛋白质折叠。当IECs内错误折叠蛋白过多或未折叠蛋白反应(unfolded protein response,UPR)功能受损时,引起内质网应激(endoplasmic reticulum stress,ERS),导致肠黏膜受损,介导炎症性肠病(inflammatory bowel disease,IBD)发生。固有免疫应答、自噬过程与ERS相互影响,共同促进IBD发展。本文就ERS相关机制及其在IBD发生中的作用作一概述。     

未折叠蛋白反应与肺部疾病关系的研究进展

正肺与外界直接接触,外界刺激如粉尘、气体、微生物容易导致肺内细胞产生大量错误合成蛋白,此时为保持细胞内蛋白平衡,内质网产生内质网应激(endoplasmic reticulum stress,ERS)促进错误蛋白进行正确折叠并降解无法折叠的蛋白,短暂的ERS有助于细胞恢复稳态,但是长期和高强度的ERS可以导致肺部许多疾病的发生。未折叠蛋白反应(unfold protein response,UPR)是ERS最主要的反应,主要分     

Panniculite mésentérique

Mesenteric panniculitis is a nonspecific inflammatory process affecting the fatty tissue at the root of the mesentery. This term is also used to describe the clinical and imaging findings in this disorder. Mesenteric panniculitis can be a misleading term: it is commonly misused to design an increased density of the mesentery without prejudice regarding the etiology. Pain is the main clinical symptom. Half of the patients are asymptomatic. There is a palpable mass in half of cases. Laboratory tests sometimes reveal an acute phase reaction of varying intensity. Mesenteric panniculitis is suspected when CT scan shows increased density of the mesenteric fat. Nevertheless, only histological examination could establish the diagnosis. Histologic examination may reveal various stages: lipodystrophy (the first stage when fat necrosis is predominant), mesenteric panniculitis (a majority of infiltrating lymphocytes), sclerosing mesenteritis (the end stage when fibrosis is predominant). Histopathologic differential diagnoses are lymphomas, lipomas, liposarcomas that can mimic mesenteric panniculitis on CT scan. Mesenteric panniculitis is associated with various diseases, especially with intra-abdominal inflammatory process. It also can be idiopathic. Rare complications can occur with vascular or digestive tract compressions. Empirical treatment is only useful in symptomatic patients. Colchicine, corticosteroids or immunosuppressive agents can be used. The only interest of surgery is the histological confirmation of the diagnosis. A better understanding of the pathophysiology of the immunoregulatory functions of adipose tissue will improve mesenteric panniculitis management.     

Further evidence for an argyrophilic fourth cell type in the pancreatic islet of the rat

Summary An argyrophilic fourth cell type in fetal and adult rat pancreatic islets can be identifed by using a modification of the Grimelius silver statin. This cell is much more abundant in the fetal pancreas than in the adult. By employing the modified silver technique followed by restaining with the indirect immunofluorescent procedure for somatostatin, the content of this argyrophilic fourth cell was studied further. Comparison of these histochemical studies demonstrated that somatostatin was not located in the fourth cell of either the adult or fetal rat pancreas. These results indicate that the D-cell and the fourth cell type are not the same cell. Thus far the only product associated with this argyrophilic cell is pancreatic polypeptide. As a result this cell probably represents the PP-cell of the Wiesbadan classification.     

Diabetes and the survival and recovery of the anoxic myocardium.

In studies with the isolated perfused working hearts from rats with experimentally induced diabetes, the ability of the hearts to survive during, and recovery from, 30 min of anoxia has been studied. In contrast with hearts obtained from normal rats, which gave good and sustained recoveries, the hearts from diabetic animals after an initial period of recovery (approx. 2 min), exhibited cardiac failure for periods of up to 4 min. After this period the hearts entered a second phase of recovery but did not recover to the same extent as the hearts from normal animals. Hearts of diabetic animals therefore appear to be more vulnerable to anoxic damage than do those from normal rats.Using metabolic inhibitors the biochemical basis of this transient post-anoxic failure in diabetic hearts was investigated. It was discovered that the immediate post-anoxic recovery of the hearts was supported in part by endogenous supplies of pre-formed high energy phosphates and in part from energy derived from the glycolysis of endogenous glycogen. During the initial recovery period of approx. 2 min there was little dependence upon the oxidative metabolism of either endogenous or exogenous substrates. In normal hearts the role of major energy provider was rapidly assumed by oxidative processes utilizing exogenous substrate. In the insulin deficient diabetic hearts the impaired transport of glucose into the cell and consequent energy shortage led to the transient cardiac failure and accounted for the delayed secondary recovery. This condition could be completely overcome either by the provision of exogenous insulin or by the provision of substrates such as pyruvate, acetate, citrate or hydroxybutyrate, whose efficient utilization was not impaired by an insulin deficiency.The relevance of these findings in the diabetic rat heart is discussed in relation to the known insulin deficiency occurring in the human during heart failure and the proposed importance of glucose metabolism in the support of the failing myocardium. In addition, these findings are considered in relation to the possible role of insulin both in the genesis and the treatment of heart failure with particular reference to heart failure in humans with diabetes mellitus.     

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.     

Colon carcinoid tumors

PURPOSE: The aim of our investigation was to evaluate the clinical presentation of patients with carcinoid tumors of the colon and to estimate the survival and potential prognostic factors of this tumor type. METHODS: A population-based study was performed using data from the Alberta Cancer Registry between 1964 and 1988 (inclusive). The clinical records and the pathologic material of eligible patients were reviewed. Survival was estimated both as crude survival and with the Kaplan-Meier method. RESULTS: During the 25-year study period (1964–1988), 36 true carcinoid tumors of the colon were diagnosed in Alberta. Carcinoids of the ileocecal region and of the rectum were excluded from the study. The average age at time of diagnosis was 68.4 years; there were 20 males and 16 females. Symptoms (abdominal pain, diarrhea, weakness, anorexia) occurred late in the course of the disease: 64 percent of the lesions were in Dukes D stage and 22 percent were Dukes C at diagnosis. Only one patient presented with a malignant carcinoid syndrome. Lesions occurred most frequently in the cecum (39 percent), followed by transverse and sigmoid colon. Most of the patients were managed surgically. The perioperative mortality rate was with 22 percent, which is quite high. The average size of the lesions was 5.8 (range, 2–10) cm, and most tumors (31/36) had invaded the pericolic fat. The most common immunohistochemical pattern was argentaffin/argyrophil negative and neuron-specific enolase positive. Two-year and five-year actuarial (Kaplan-Meier) survival was 34 percent and 26 percent, respectively. Survival for carcinoids of the colon was significantly lower compared with carcinoids of the rectum or appendix, and with colon adenocarcinomas. Size of the tumor and tumor invasion into the muscularis propria—the two major histopathologic prognostic factors for carcinoids of the gastrointestinal tract—were not found to influence survival significantly. Rather, tumor stage, histologic pattern, tumor differentiation, nuclear grade, and mitotic rate were found to significantly influence the survival rate. CONCLUSION: Carcinoid tumors of the colon are extremely rare tumors, diagnosed late in the course of the disease, and they carry a bad prognosis. Prognostic factors are tumor stage, histologic pattern, differentiation, nuclear grade, and mitotic rate of the tumor.Presented in part at the meetings of the International Society of University Colon and Rectal Surgeons, Crete, Greece, October 25 to 29, 1992, and the Royal College of Physicians and Surgeons, Quebec, Quebec, Canada, September 19 to 23, 1991.     

Human ovarian follicular development: From activation of resting follicles to preovulatory maturation

By integrating morphometrical and endocrinological data, as well as biological effects of various molecules synthesized by the human follicle, we propose a dynamic view of the follicle growth within the human ovary. Folliculogenesis starts with entry of resting follicles into the growth phase, a process where the kit system plays a key role. Several months are required for a new growing follicle to reach the preantral stage (0.15 mm), then 70 additional days to reach the size of 2 mm. Early growing follicle growth is regulated by subtle interactions between follicle-stimulating hormone (FSH) and local factors produced by theca and granulosa cells (GCs), as well as the oocyte. From the time they enter the selectable stage during the late luteal phase, follicles become sensitive to cyclic changes of FSH in terms of granulosa cell proliferation. During the early follicular phase, the early selected follicle grows very quickly and estradiol is present in the follicular fluid. However, the total steroid production remains moderate. From the mid-follicular phase, the preovulatory follicle synthesizes high quantities of estradiol, then after the mid-cycle gonadotropin surge, very large amounts of progesterone. At this stage of development, the responsiveness of the follicle to gonadotropins is maximum, especially to luteinizing hormone (LH) that triggers granulosa wall dissociation and cumulus expansion as well as oocyte nuclear maturation. Thus, as the follicle develops, its responsiveness to gonadotropins progressively increases under the control of local factors acting in an autocrine/paracrine fashion.     

Immunohistochemical study of the colonic muscle and innervation in idiopathic chronic constipation

PURPOSE: This study was designed to investigate neural and muscular features of the colonic wall in patients with severe idiopathic constipation. METHODS: By using quantitative immunohistochemistry, resected specimens from 14 patients with idiopathic chronic constipation and 17 nonobstructed cancer controls were studied. RESULTS: Routine histology revealed no significant histologic abnormality throughout the colon apart from four cases of melanosis coli. Ratio of the thickness of circular to longitudinal muscle was significantly lower in the left colon in constipated subjects. The myenteric plexus appeared morphologically normal in all subjects. S-100 protein, which stains neuronal supporting tissues, demonstrated an increase in the proportion of neural tissue in the myenteric plexus. There was an increased number of PGP-9.5 immunoreactive nerve fibers in the muscularis propria in constipated patients, and this was significantly higher in the ascending and descending colon. CONCLUSION: Intractably constipated patients have alterations in the neural composition of the colonic myenteric plexus and innervation of the circular muscle.Supported by a grant from Yonsei University Research Foundation, Seoul, Korea. Dr. Talbot is supported in part by the Imperial Cancer Research Fund.     

Three-dimensional computer model of the entire human heart for simulation of reentry and tachycardia: Gap phenomenon and Wolff-Parkinson-White syndrome

Summary A computer model of the entire human heart has been developed for simulation of the excitation and repolarization process. Spatial distribution of refractory periods and conduction velocities in the different cardiac tissues, the anisotropy of conduction in the ventricles, and the cycle length dependence of refractory periods and conduction velocities are taken into account. The algorithm calculating the activation process is based on a modified version of Huygen's principle for constructing wavefronts. This study presents simulations concerning the gap phenomenon of the conduction system and the initiation of tachycardias in a heart with Wolff-Parkinson-White syndrome. Results are compared for different basic cycle lengths and for normal and prolonged refractory periods in the His-Purkinje system. The gap phenomenon was found to be present only when using the prolonged refractory periods in the His-Purkinje-system at a cycle length of 700 ms. Induction of tachycardia by a single extrastimulus in the high right atrium in a heart with a bidirectionally conducting accessory pathway is possible by properly timed extrastimuli. The coupling interval of the stimulus for initiating a reentrant tachycardia depends on the cycle length, the conduction velocities and the set of refractory periods used. The same parameters determine whether or not a gap phenomenon in atrioventricular conduction occurs. The model may be useful for investigating similar questions concerning the reentry phenomena of tachycardia.     

Apple tree flowering is mediated by low level of melatonin under the regulation of seasonal light signal

Melatonin regulates the seasonal reproduction in photoperiodic sensitive animals. Its function in plants reproduction has not been extensively studied. In the current study, the effects of melatonin on the apple tree flowering have been systematically investigated. For consecutive 2‐year monitoring, it was found that the flowering was always associated with the drop of melatonin level in apple tree. Melatonin application before flowering postponed apple tree flowering with a dose‐dependent manner. The increased melatonin levels at a suitable range also resulted in more flowering. The data indicated that similar to the animals, the melatonin also serves as the signal of the environmental light to regulate the plant reproduction. It was mainly the blue and far‐red light to regulate the gene expression of melatonin synthetic enzymes and melatonin production in plants. The seasonal alterations of the blue and far‐red lights coordinated well with the changes of the melatonin levels and led to decreased melatonin level before flowering. The mechanism studies showed that melatonin per se inhibits all the four flowering pathways in apple. The results not only provide the basic knowledge for melatonin research, but also uncover melatonin as a chemical message of light signal to mediate plant reproduction. This information can be potentially used to control flowering period and prolong the harvest time, helpfully to open a new avenue for increasing crop yield by melatonin application.