Effect of neuropeptides on production of inflammatory cytokines by human monocytes

Two groups of mediators, the neuropeptides substance P and K and the monocyte-derived cytokines, interact in the neural regulation of immunological and inflammatory responses. Substance P, substance K, and the carboxyl-terminal peptide SP(4-11) induce the release of interleukin-1, tumor necrosis factor-alpha, and interleukin-6 from human blood monocytes. The neuropeptide effects occur at low doses, are specific as shown by inhibition studies with a substance P antagonist, and require de novo protein synthesis. Since monocyte-derived cytokines regulate multiple cellular functions in inflammation and immunity and since neuropeptides can be released from peripheral nerve endings into surrounding tissues, these findings identify a potent mechanism for nervous system regulation of host defense responses.     

海洋软体动物生殖调控相关神经肽的研究进展

阐述了海洋软体动物相关生殖调控类神经肽的研究并发现其在软体动物的性腺发育与成熟和繁殖功能的维持中起着重要作用。采用免疫组织化学、酶联免疫吸附测定以及高效液相色谱等方法在多种软体动物中检测到了多种神经肽的存在,主要分布于中枢神经以及周围神经系统。部分神经肽经过RT-PCR已克隆出其片段基因。该类神经肽在软体动物中具有广阔的研究空间,该研究将为软体动物生殖调控机理提供理论依据。     

Substance P and somatostatin regulate sympathetic noradrenergic function

Peptidergic-noradrenergic interactions were examined in explants of rat sympathetic superior cervical ganglia and in cultures of dissociated cells. The putative peptide transmitters substance P and somatostatin each increased the activity of the catecholamine-synthesizing enzyme tyrosine hydroxylase after 1 week of exposure in culture. Maximal increases occurred at 10(-7) molar for each peptide, and either increasing or decreasing the concentration reduced the effects. Similar increases in tyrosine hydroxylase were produced by a metabolically stable agonist of substance P, while a substance P antagonist prevented the effects of the agonist. The data suggest that the increased tyrosine hydroxylase activity was mediated by peptide interaction with specific substance P receptors and that peptides may modulate sympathetic catecholaminergic function.     

The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice

The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.     

Symmetrical erosive peripheral polyarthritis in the Late Archaic Period of Alabama

Rheumatoid arthritis was first described unambiguously in 1800, but its etiology and historical origins are still obscure. Definite rheumatoid arthritis has not been demonstrated in pre-19th century Old World skeletal remains. Six individuals who lived 3000 to 5000 years ago in northwestern Alabama and present erosive polyarthritis characteristic of rheumatoid arthritis are described. The diagnosis raises the possibility that rheumatoid arthritis can be associated with a New World pathogen or allergen.     

Inflammation and collagenase production in rats with adjuvant arthritis reduced with 13-cis-retinoic acid

Oral administration of 13-cis-retinoic acid (40 or 160 milligrams per kilogram of body weight daily) significantly reduced the inflammation associated with developing and established adjuvant arthritis, an experimentally induced arthritis in rats that resembles human rheumatoid arthritis. The amount of collagenase secreted in tissue culture by adherent cells isolated from the inflamed joints of adjuvant rats treated with 13-cis-retinoic acid also decreased as compared to the amount secreted by cells from vehicle-treated adjuvant rats. Collagenase is important in the joint destruction accompanying rheumatoid arthritis. The successful use of retinoids in the treatment of this proliferative but nonmalignant disorder demonstrates a new application of these compounds.     

黄芪虫藤饮对类风湿关节炎大鼠关节滑膜细胞生长增殖的影响

目的 探讨黄芪虫藤饮对类风湿关节炎大鼠关节滑膜细胞增殖的影响。方法 无菌条件下分离正常大鼠和类风湿关节炎（RA）模型大鼠关节滑膜组织,制成单个滑膜细胞,流式细胞术鉴定后,取培养第三代的关节滑膜细胞进行药物干预,用MTT法测定药物对细胞增殖抑制作用;用流式细胞术检测细胞凋亡率以及细胞周期。结果 正常组大鼠关节滑膜细胞增长率与RA空白组（0.00 mg/L）比较,差异有统计学意义（P<0.05）;不同浓度（100.0,50.0,25.0,12.5,6.25,0 mg/L）黄芪虫藤饮对RA大鼠关节滑膜细胞增殖均有明显的抑制作用,细胞凋亡率明显高于空白组（P<0.05）,并能诱导滑膜细胞G0/G1期的细胞生长停滞,且呈现典型的剂量依赖性。结论 黄芪虫藤饮能抑制RA关节滑膜细胞的活性,促进细胞凋亡,可以较好地应用于临床。     

Neurotransmitter plasticity at the molecular level

Contrary to long-held assumptions, recent work indicates that neurons may profoundly change transmitter status during development and maturity. For example, sympathetic neurons, classically regarded as exclusively noradrenergic or cholinergic, can also express putative peptide transmitters such as substance P. This neuronal plasticity is directly related to membrane depolarization and sodium ion influx. The same molecular mechanisms and plastic responses occur in mature as well as developing neurons. Further, contrary to traditional teaching, adult primary sensory neurons may express the catecholaminergic phenotype in vivo. Transmitter plasticity is not restricted to the peripheral nervous system: ongoing studies of the brain nucleus locus ceruleus in culture indicate that specific extracellular factors elicit marked transmitter changes. Consequently, neurotransmitter expression and metabolism are dynamic, changing processes, regulated by a variety of defined factors. Transmitter plasticity adds a newly recognized dimension of flexibility to nervous system function.     

A distinct endothelial cell recognition system that controls lymphocyte traffic into inflamed synovium

Lymphocytes are essential mediators of normal tissue inflammatory reactions and of pathologic tissue damage in, for example, rheumatoid arthritis and other autoimmune diseases. In a study of the mechanisms controlling lymphocyte entry into sites of inflammation from the blood, the function and specificity of lymphocyte-endothelial interactions were examined in inflamed joint tissue (synovium) from patients with rheumatoid arthritis. Synovial high endothelial venules (HEV) supported the binding of normal peripheral blood lymphocytes in vitro. The characteristics of this binding, which were similar to those of lymphocyte-HEV interactions controlling lymphocyte migration into organized lymphoid tissues, included a requirement for calcium ions, a dependence on metabolic activity, and a preferential adherence of circulating lymphocytes as opposed to immature thymocytes. However, the binding of lymphocytes to synovial HEV was not inhibited by a monoclonal antibody to lymphocyte receptors for lymph node HEV, and synovial HEV failed to bind either lymph node HEV-specific or mucosal HEV-specific B lymphoblastoid cells. The results suggest that a lymphocyte-endothelial cell recognition system that is distinct from such systems in organized lymphoid tissues directs the extravasation of normal lymphocytes as well as pathologically important effector cells into inflamed synovium.     

类风湿关节炎合并心血管疾病的研究进展

类风湿关节炎(RA)患者心血管疾病(CVD)的风险高于年龄和性别相匹配的一般人群的1.5～2.0倍。因全身慢性炎症导致的心血管风险增高是RA的特征之一。RA最优化心血管风险管理的挑战包括改进预测心血管风险的方法和确定目标危险因素以减少心血管风险。从RA研究中吸取经验教训,对于一般人群同样收益,因为炎症在动脉粥样硬化的发病机制中有着重要作用。     

A substance P antagonist, [D-Pro2, D-Trp7,9]SP, inhibits inflammatory responses in the rabbit eye

Neurogenic factors released by antidromic nerve stimulation are thought to be in part responsible for the vasodilation and breakdown of the blood-aqueous barrier that follows trauma to the eye. Substance P is one candidate for the mediation of the inflammatory response since it is thought to be a neurotransmitter in sensory afferents and since exogenous substance P is capable of eliciting a response characteristic of inflammation. In rabbits, intravitreal or topical application onto the eye of a specific substance P antagonist, [d-Pro2, D-Trp7,9]SP, inhibited not only the irritant effects of exogenous substance P but also the inflammatory response to a standardized trauma (infrared irradiation of the iris). These observations suggest that substance P, or a related peptide, is a neurogenic mediator of the inflammatory response in the eye.     

亚致死剂量吡虫啉对中华蜜蜂神经代谢基因表达的影响

【背景】新烟碱类杀虫剂的作用靶标是昆虫神经系统中的乙酰胆碱受体,由于其良好的内吸性及对人畜低毒性,使其在农业生产上获得了广泛应用,然而这也使得其在植物体内仍然具有较低的残留,而这种亚致死剂量残留仍可对访花昆虫如蜜蜂的行为和神经系统造成不利影响。【目的】明确亚致死剂量新烟碱类杀虫剂吡虫啉对中华蜜蜂（Apis cerana cerana,简称中蜂）神经生理和代谢系统的影响。【方法】首先以两个亚致死浓度梯度剂量5和10 μg·L^-1吡虫啉处理工蜂10 d（3个生物学重复）,提取总RNA后,以RNA-seq方法对所得文库进行高通量测序,利用生物信息学技术对序列进行从头组装、注释,并对亚致死剂量吡虫啉处理后的差异表达基因进行聚类和富集等分析,最后利用实时荧光定量PCR（RT-qPCR）技术对部分与中蜂神经和代谢系统相关的差异表达基因进行验证。【结果】从两个吡虫啉浓度梯度和对照组数据中共获得9个测序文库,测序有效数据比例超过94.45%,从获得的37 364个unigenes中鉴定出571个差异表达基因。经GO和KEGG富集分析发现这些差异表达基因主要与蛋白质翻译、氧化还原、氧化磷酸化和核糖体等多个通路有关,表明亚致死剂量的吡虫啉对中蜂多个生理过程和代谢通路造成影响。挑选了与昆虫神经信号传递和代谢功能有关的上调或下调差异表达基因,如神经肽F、神经肽SIFamide受体、3-磷酸肌醇依赖性蛋白激酶、激酶（PRKA）锚蛋白1、碳酸酐酶、超氧化物歧化酶、NADH脱氢酶亚基、表皮蛋白和气味结合蛋白17共9个差异表达基因进行了qPCR验证,其表达规律与转录组结果完全一致。【结论】亚致死剂量的吡虫啉能对中蜂神经信号转导、细胞呼吸、免疫反应、内环境稳态的维持和嗅觉感受等多方面造成影响。     

Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I

Human T cell leukemia virus type-I (HTLV-I) is the etiologic agent of adult T cell leukemia and has also been suggested to be involved in other diseases such as chronic arthritis or myelopathy. To elucidate pathological roles of the virus in disease, transgenic mice were produced that carry the HTLV-I genome. At 2 to 3 months of age, many of the mice developed chronic arthritis resembling rheumatoid arthritis. Synovial and periarticular inflammation with articular erosion caused by invasion of granulation tissues were marked. These observations suggest a possibility that HTLV-I is one of the etiologic agents of chronic arthritis in humans.     

类风湿关节炎患者关节液中IL-17的定量检测

目的探讨类风湿性关节炎（RA）患者关节液中IL-17的含量与关节炎症损伤的相关性,为研究RA的关节损伤机制提供科学依据.方法应用ELISA方法定量检测RA组40例和对照组40例关节液中IL-17的含量,应用t检验比较两组差异性.结果 RA组关节液中IL-17的含量显著高于对照组（P〈0.01）.结论 RA组关节液中具有较高的IL-17检测值,证实IL-17是RA患者关节滑膜损伤的重要因素之一.     

Glycosylation and the immune system

Almost all of the key molecules involved in the innate and adaptive immune response are glycoproteins. In the cellular immune system, specific glycoforms are involved in the folding, quality control, and assembly of peptide-loaded major histocompatibility complex (MHC) antigens and the T cell receptor complex. Although some glycopeptide antigens are presented by the MHC, the generation of peptide antigens from glycoproteins may require enzymatic removal of sugars before the protein can be cleaved. Oligosaccharides attached to glycoproteins in the junction between T cells and antigen-presenting cells help to orient binding faces, provide protease protection, and restrict nonspecific lateral protein-protein interactions. In the humoral immune system, all of the immunoglobulins and most of the complement components are glycosylated. Although a major function for sugars is to contribute to the stability of the proteins to which they are attached, specific glycoforms are involved in recognition events. For example, in rheumatoid arthritis, an autoimmune disease, agalactosylated glycoforms of aggregated immunoglobulin G may induce association with the mannose-binding lectin and contribute to the pathology.     

Neuromuscular transmitter substance in insect visceral muscle

Stimulation of the nerves innervating the proctodeum (hindgut) of the cockroach Periplaneta americana (L.) causes a slow-type, graded contraction of the longitudinal muscles. An unidentified substance, or substances, present in the foregut and hindgut, the specific activity of which is highest in the nerves innervating these organs, effects a similar contraction. This "gut-factor" is depleted from the hindgut after surgical section of the proctodeal nerves. None of Factors P(1) and P(2), 5-hydroxytryptamine, acetylcholine, adrenaline, noradrenaline, alpha-ami-nobutyric acid or glutamate duplicates the pharmacological behavior of this substance. The active factor is associated with subcellular particles that require centrifugal forces of approximately 1,000,000 g-min for sedimentation. The substance is inactivated in homogenates of gut tissue in the absence of suitable precautions. It is proposed that the "gut-factor" functions as an excitatory neuromuscular transmitter substance in insect visceral muscle.     

Blood sugar level following intravenous glucose in rheumatoid arthritis

Since the majority of patients with rheumatoid arthritis show a slower fall in the blood sugar level after the intravenous injection of glucose than do the normal controls, the alteration cannot be explained on the basis of gastrointestinal dysfunction. Differences in the renal threshold of glucose do not explain the altered glucose tolerance, since approximately the same amount of glucose is lost in the urine in both groups. Blood samples taken at 3 and 5 minutes following the injection of the glucose showed the height of the blood sugar level to be approximately the same in the patients with rheumatoid arthritis and in normals. The slower fall in the blood sugar level of the former is therefore not a simple function of a greater rise following the intravenous administration of the glucose. Although the patients with severe poliomyelitis had as much or more atrophy than the rheumatoid arthritic patients, there was no delay in rate of fall of the blood sugar level after the intravenous administration of glucose. In view of the fact that the hepatic homeostatic control regulates the blood sugar level, faulty utilization of glucose by extrahepatic tissues cannot be considered the primary factor responsible for the alteration of the glucose tolerance. The altered glucose tolerance in rheumatoid arthritis is explainable on the basis of an altered threshold of the hepatic homeostatic control of the blood sugar. Additional studies must be done to determine whether this derangement emanates directly from extrahepatic influences.     

Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme

The hallmark of rheumatoid arthritis (RA) is specific destruction of the synovial joints. In a mouse line that spontaneously develops a disorder with many of the features of human RA, disease is initiated by T cell recognition of a ubiquitously expressed self-antigen; once initiated, pathology is driven almost entirely by immunoglobulins. In this study, the target of both the initiating T cells and pathogenic immunoglobulins was identified as glucose-6-phosphate isomerase, a glycolytic enzyme. Thus, some forms of RA or related arthritides may develop by a mechanism fundamentally different from the currently popular paradigm of a joint-specific T cell response.     

Delta 9 -tetrahydrocannabinol and ethanol: differential effects on sympathetic activity in differing environmental setting

Serum dopamine beta-hydroxylase activity, a useful biochemical index of peripheral sympathetic nervous activity, was measured in rats treated with Delta(9)-tetrahydrocannabinol or ethanol or both substances. After 7 days of treatment with either substance, serum dopamine beta-hydroxylase activity decreased significantly. Combined treatment with both agents enhanced the effects of each given alone. In rats subjected to immobilization stress, treatment with Delta(9)- tetrahydrocannabinol appeared to potentiate the stress-induced increase in serum enzyme activity. Treatment with ethanol, with or without Delta(9)-tetrahydrocannabinol, effectively blocked this increase in enzyme activity. These results show that both substances have significant effects on the sympathetic nervous system which are critically influenced by environmental setting.     

Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia

The endogenous neuropeptide cholecystokinin, when administered systemically or perispinally, potently antagonizes opiate analgesia produced by foot shock and morphine. Nonopiate foot-shock analgesia is not reduced by this neuropeptide. The spinal cord appears to be a critical site of cholecystokinin action. These experiments suggest a physiological role for cholecystokinin as a specific opiate antagonist in analgesia-mediating systems. A similar mode of action may explain other behavioral effects of cholecystokinin, such as suppression of food intake.