杞菊胶囊对自发性高血压大鼠左室肥厚的防治

目的：观察杞菊胶囊对自发性高血压大鼠左室肥厚的防治作用,并从心肌细胞内钙离子浓度（[Ca^2＋]i）与钙调神经磷酸酶（CaN）角度探讨其作用机制.方法：以自发性高血压大鼠为左室肥厚模型,观察杞菊胶囊对左室重量、心肌[Ca^2＋]i与 CaN活性的影响.结果：杞菊胶囊可防治自发性高血压大鼠左室肥厚并降低心肌细胞内钙离子浓度与钙调神经磷酸酶活性.结论：杞菊胶囊可防治心肌肥厚,其机制与降低心肌钙浓度及钙调神经磷酸酶活性有关.     

环孢霉素A对缺血再灌注心肌的保护作用与CD4+T细胞的关系

目的 观察环孢霉素A对缺血再灌注心肌的影响,并探讨其与CD4+T细胞之间的关系.方法 将32只SD大鼠随机分为4组(n=8): 假手术组(Sham)、缺血再灌注(I/R)模型组、环孢霉素(CsA)组、CsA+5-羟基葵酸盐(5-HD)组.CsA、CsA+5-HD组给予CsA 15 mg/kg及1 mL生理盐水腹腔注射,...     

Increased ratio of calcineurin immunoreactive neurons in the caudate nucleus of patients with schizophrenia

Calcineurin (CaN) has been investigated extensively in numerous biochemical, behavioral, and genetic studies in schizophrenia because its function is closely related to dopamine-glutamate signal transduction, which is thought to be associated with pathophysiological changes in schizophrenia. Although evidence has suggested that dysfunction of CaN may be a risk factor for schizophrenia, there have been few reports focusing on the expression of CaN mRNA and CaN protein levels in the brains of schizophrenic patients. In addition, findings on CaN expression in postmortem brains from patients with schizophrenia have been inconsistent. Here, we conducted immunohistochemical examinations of several regions in postmortem brains, including the dorsolateral prefrontal cortex (DLPFC), hippocampus, caudate nucleus, and putamen, using specific antibodies, and compared the results from the brains of nine schizophrenic subjects to nine age- and sex-matched control subjects. There was no significant difference in the ratio of CaN immunoreactive (IR) neurons between schizophrenia and control groups in the DLPFC or hippocampus, and a significantly increased ratio of CaN-IR neurons was seen in the caudate nucleus in the brains from schizophrenia patients. As the striatum contains most of the brain dopamine, the results of the present study have critical implications and suggest that alterations in CaN signaling in the caudate contribute to the pathogenesis of schizophrenia. This is the first report of caudate CaN abnormalities in schizophrenia.     

Effect of Hypoxia on the Muscle Fiber Switching Signal Pathways CnA/NFATc1 and Myostatin in Mouse Myocytes

This study investigated the effects of a CoCl₂-simulated hypoxic environment on the muscle fiber switching signaling pathways calcineurin A/nuclear factor of activated T cells cytoplasmic 1 (CnA/NFATc1) and myostatin. In this study, C2C12 muscle cells were cultured in vitro under CoCl₂-simulated chemical hypoxic conditions, the expression levels of CnA and myostatin were detected through qRT-PCR and Western blot analyses, and a positioning study of NFATc1 was carried out by immunofluorescence labeling. Results showed that CoCl₂ treatment significantly increased the expression levels of CnA and myostatin. Moreover, the position of NFATc1 expression changed; actually, its expression in the nucleus considerably increased. Furthermore, CoCl₂-induced hypoxia inhibited the differentiation of C2C12 cells and reduced the expression levels of many slow- and fast-twitch muscles marker genes, but immunofluorescence staining results showed that the proportion of MyHC I type muscle fiber increased after CoCl₂ treatment. The hypoxic environment simulated by CoCl₂ can activate the signaling pathways CnA/NFATc1 and myostatin and increases the proportion of MyHC I type muscle fibers.     

Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

The structure and dynamics of dendritic spines reflect the strength of synapses, which are severely affected in different brain diseases. Therefore, understanding the ultra-structure, molecular signaling mechanism(s) regulating dendritic spine dynamics is crucial. Although, since last century, dynamics of spine have been explored by several investigators in different neurological diseases, but despite countless efforts, a comprehensive understanding of the fundamental etiology and molecular signaling pathways involved in spine pathology is lacking. The purpose of this review is to provide a contextual framework of our current understanding of the molecular mechanisms of dendritic spine signaling, as well as their potential impact on different neurodegenerative and psychiatric diseases, as a format for highlighting some commonalities in function, as well as providing a format for new insights and perspectives into this critical area of research. Additionally, the potential strategies to restore spine structure–function in different diseases are also pointed out. Overall, these informations should help researchers to design new drugs to restore the structure–function of dendritic spine, a “hot site” of synaptic plasticity.     

Inhibitory effect of ginsenoside Rb1 on cardiac hypertrophy induced by monocrotaline in rat

Ginseng, the root of Panax ginseng, has been used as folk medicine in the treatment of various diseases for thousands of years in China. Ginsenoside Rb1 (Rb1), one of the effective components of ginseng, has been reported to release nitric oxide and decrease intracellular free Ca2+ in cardiac myocytes, both of which play important roles in antihypertrophic effect. This study was to investigate the potential effect of Rb1 on right ventricular hypertrophy (RVH) induced by monocrotaline (MCT) and its possible influence on calcineurin (CaN) signal trasnsduction pathway. MCT-treated animals were administered with Rb1 (10 and 40 mg /kg) from day 1 to day 14 (preventive administration) or from day 15 to day 28 (therapeutic administration), or with vehicle as corresponding controls. After 2 weeks, significantly hypertrophic reactions, including RVH index and the expressions of atrial natriuretic peptide mRNA, appeared in right ventricle of all MCT-treated animals (p < 0.05), which were significantly decreased with some improvements of myocardial pathomorphology in both Rb1 prevention- and therapy-groups (p < 0.05). Similarly, MCT-treatment caused the high expressions of mRNA and/or proteins of CaN, NFAT3 and GATA4 from cardiocytes (p < 0.05) and Rb1 could alleviate the expressions of these factors above (p < 0.05). These results suggest that Rb1 treatment can inhibit the RVH induced by MCT, which may be involved in its inhibitory effects on CaN signal transduction pathway.     

Disease relevance of T11TS-induced T-cell signal transduction through the CD2-mediated calcineurin–NFAT pathway: Perspectives in glioma immunotherapy

Malignant glioma is the most lethal of a wide array of CNS neoplasms. Its onset and progression are markedly associated with profound immunosupression and paralysis of T-cell survival and proliferation. Myriad immunotherapeutic strategies are presently used to target such T-cell anomalies in glioma. Our recent work has highlighted use of the novel glycopeptide, the CD2 ligand, T11 target structure (T11TS) as an immunotherapeutic agent against experimentally induced glioma in rats. We have shown that T11TS causes multi-target modulation of key components of the T-cell – antigen presenting cell (APC) immunological synapse. This consequently triggers T-cell activation so as to reverse glioma-induced changes to physiological levels. T11TS administration also causes CD2 upregulation. Earlier we also found T11TS to cause enhanced proliferation of both CD4+ and CD8+ T-cells in glioma conditions. These findings led us to believe that downstream CD2-stimulated “alternative pathway” of calcineurin–NFAT could be a possible target for modulation by T11TS. In the present paper we thus show that immunotherapy with T11TS induces a multi-targeted approach towards activation of this “alternative pathway” of T-cell signaling providing an immunotherapeutic advantage against glioma. We show here that T11TS immunotherapy causes positive modulations of the CD2 pathway-associated proteins, viz., p59fyn, protein kinase C-θ (PKC-θ), calcineurin and nuclear factor for activation of T-cells (NFAT) and hint that this may accord greater survival and proliferation advantage to T-cells of the glioma-bearing animals for augmented defence against glioma. These findings help open a molecular immunotherapeutic door – one which is directed towards clinical studies for glioma-immunotherapy using T11TS.     

黄芪甲苷衍生物ASId治疗慢性心力衰竭的机制研究

目的探讨黄芪甲苷衍生物ASId治疗慢性心力衰竭的作用机制。方法大鼠、犬提取心肌细胞膜检测酶活性;大鼠结扎冠脉引起心肌梗死后取左心室,利用免疫组织化学检测心肌肥厚信号转导通路的钙调神经磷酸酶（calcineurin,CaN）表达情况。结果 ASId对大鼠和犬心肌细胞膜Na＋/K＋-ATPase均有抑制作用,其IC50分别为（1.58±0.27）×106和（1.41±0.16）×107mol/L,在受试剂量下（108～105mol/L）对Ca2＋/Mg2＋-ATPase活性无明显抑制作用;免疫组化研究表明,ASId0.5、1.0mg/kg可显著降低CaN表达,与模型对照组比较,其表达分别下降73.1%（P〈0.01）、78.0%（P〈0.001）,提示ASId抗心肌肥厚机制与抑制心肌肥厚信号转导通路的重要关键因子CaN有关。结论 ASId治疗心衰机制与Na＋/K＋-ATPase抑制产生的即刻心肌收缩效应,以及抗心肌肥厚的远期效应有关。