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Characterization of four Latin American families confirms previous findings and reveals novel features of acid‐labile subunit deficiency 下载免费PDF全文
Paula A. Scaglia Ana C. Keselman Débora Braslavsky Lucía C. Martucci Liliana M. Karabatas Sabina Domené Mariana L. Gutiérrez María G. Ballerini María G. Ropelato Angela Spinola‐Castro Adriana A. Siviero‐Miachon Juliana Saito Tartuci María Sol Rodríguez Azrak Rodolfo A. Rey Héctor G. Jasper Ignacio Bergadá Horacio M. Domené 《Clinical endocrinology》2017,87(3):300-311
43.
Nahuel A. Ramella Isabel Andújar José L. Ríos Silvana A. Rosú M. Alejandra Tricerri Guillermo R. Schinella 《Pathophysiology》2018,25(4):397-404
The cascade of molecular events leading to Human apolipoprotein A–I (apoA–I) amyloidosis is not completely understood, not even the pathways that determine clinical manifestations associated to systemic protein deposition in organs such as liver, kidney and heart. About twenty natural variants of apoA–I were described as inducing amyloidosis, but the mechanisms driving their aggregation and deposition are still unclear. We previously identified that the mutant Gly26Arg but not Lys107-0 induced the release of cytokines and reactive oxygen species from cultured RAW 264.7 murine macrophages, suggesting that part of the pathogenic pathway could elicit of an inflammatory signal. In this work we gained deep insight into this mechanism and determined that Gly26Arg induced a specific pro-inflammatory cascade involving activation of NF-κB and its translocation into the nucleus. These findings suggest that some but not all apoA–I natural variants might promote a pro-oxidant microenvironment which could in turn result in oxidative processing of the variants into a misfolded conformation. 相似文献
44.
The vagus nerve is dominated by afferent fibers that convey sensory information from the viscera to the brain. Most vagal afferents are unmyelinated, slow-conducting C-fibers, while a smaller portion are myelinated, fast-conducting A-fibers. Vagal afferents terminate in the nucleus tractus solitarius (NTS) in the dorsal brainstem and regulate autonomic and respiratory reflexes, as well as ascending pathways throughout the brain. Vagal afferents form glutamatergic excitatory synapses with postsynaptic NTS neurons that are modulated by a variety of channels. The organization of vagal afferents with regard to fiber type and channels is not well understood. In the present study, we used tract tracing methods to identify distinct populations of vagal afferents to determine if key channels are selectively localized to specific groups of afferent fibers. Vagal afferents were labeled with isolectin B4 (IB4) or cholera toxin B (CTb) to detect unmyelinated and myelinated afferents, respectively. We find that TRPV1 channels are preferentially found in unmyelinated vagal afferents identified with IB4, with almost half of all IB4 fibers showing co-localization with TRPV1. These results agree with prior electrophysiological findings. In contrast, we found that the ATP-sensitive channel P2X3 is found in a subset of both myelinated and unmyelinated vagal afferent fibers. Specifically, 18% of IB4 and 23% of CTb afferents contained P2X3. The majority of CTb-ir vagal afferents contained neither channel. Since neither channel was found in all vagal afferents, there are likely further degrees of heterogeneity in the modulation of vagal afferent sensory input to the NTS beyond fiber type. 相似文献
45.
《Vaccine》2015,33(1):25-33
This review provides an outlook of the medical applications of immunomodulatory compounds taken from Pleurotus and proposes this fungus as a convenient host for the development of innovative vaccines. Although some fungal species, such as Saccharomyces and Pichia, occupy a relevant position in the biopharmaceutical field, these systems are essentially limited to the production of conventional expensive vaccines. Formulations made with minimally processed biomass constitute the ideal approach for developing low cost vaccines, which are urgently needed by low-income populations. The use of edible fungi has not been explored for the production and delivery of low cost vaccines, despite these organisms’ attractive features. These include the fact that edible biomass can be produced at low costs in a short period of time, its high biosynthetic capacity, its production of immunomodulatory compounds, and the availability of genetic transformation methods. Perspectives associated to this biotechnological application are identified and discussed. 相似文献
46.
Lauren M Reynolds Elif Engin Gabriella Tantillo Hew Mun Lau John W Muschamp William A Carlezon Jr Uwe Rudolph 《Neuropsychopharmacology》2012,37(11):2531-2540
Benzodiazepines such as diazepam are widely prescribed as anxiolytics and sleep aids. Continued use of benzodiazepines, however, can lead to addiction in vulnerable individuals. Here, we investigate the neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test, a procedure with which the reward-enhancing effects of these drugs can be measured. Benzodiazepines bind nonselectively to several different GABAA receptor subtypes. To elucidate the α subunit(s) responsible for the reward-enhancing effects of benzodiazepines, we examined mice carrying a histidine-to-arginine point mutation in the α1, α2, or α3 subunit, which renders the targeted subunit nonresponsive to diazepam, other benzodiazepines and zolpidem. In wild-type and α1-point-mutated mice, diazepam caused a dose-dependent reduction in ICSS thresholds (reflecting a reward-enhancing effect) that is comparable to the reduction observed following cocaine administration. This effect was abolished in α2- and α3-point-mutant mice, suggesting that these subunits are necessary for the reward-enhancing action of diazepam. α2 Subunits appear to be particularly important, since diazepam increased ICSS thresholds (reflecting an aversive-like effect) in α2-point-mutant animals. Zolpidem, an α1-preferring benzodiazepine-site agonist, had no reward-enhancing effects in any genotype. Our findings implicate α2 and α3 subunit containing GABAA receptors as key mediators of the reward-related effects of benzodiazepines. This finding has important implications for the development of new medications that retain the therapeutic effects of benzodiazepines but lack abuse liability. 相似文献
47.
48.
蛋白激酶A(PKA)是由1个调节亚基(R亚基)二聚体和两个催化亚基(C亚基)组成的四聚体,全酶无活性。R亚基有RⅠα、RⅠβ、RⅡα和RⅡβ4种亚型,分别具有不同的理化性质。RⅡβ亚基氨基端包含1个二聚化/对接结构域,PKA通过此结构域与腺苷酸激酶锚定蛋白结合锚定于细胞的特定位点。羧基端是两个串联的高度保守的环核苷酸结构域,与PKA全酶解聚以及激活有关。两个RC异二聚体通过RⅡβ亚基中的β4~β5环相锚定。细胞质中存在足够的Mg ATP时将导致RⅡβ亚基自身磷酸化。RⅡβ在特定组织表达,主要表达于内分泌腺、脑和脂肪组织。生物信息学分析表明,RⅡβ与其他R亚基的序列有很大差别,只有大约50%的序列相同,提示RⅡβ可能具有不同的生物学功能。因此,目前对PKA RⅡβ的功能及其作用机制的研究已逐渐成为热点。 相似文献
49.
Gonzalez-Gutierrez G Miranda-Laferte E Nothmann D Schmidt S Neely A Hidalgo P 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(37):14198-14203
Inactivation of voltage-gated calcium channels is crucial for the spatiotemporal coordination of calcium signals and prevention of toxic calcium buildup. Only one member of the highly conserved family of calcium channel β-subunits—CaVβ—inhibits inactivation. This unique property has been attributed to short variable regions of the protein; however, here we report that this inhibition actually is conferred by a conserved guanylate kinase (GK) domain and, moreover, that this domain alone recapitulates CaVβ-mediated modulation of channel activation. We expressed and refolded the GK domain of CaVβ2a, the unique variant that inhibits inactivation, and of CaVβ1b, an isoform that facilitates it. The refolded domains of both CaVβ variants were found to inhibit inactivation of CaV2.3 channels expressed in Xenopus laevis oocytes. These findings suggest that the GK domain endows calcium channels with a brake restraining voltage-dependent inactivation, and thus facilitation of inactivation by full-length CaVβ requires additional structural determinants to antagonize the GK effect. We found that CaVβ can switch the inactivation phenotype conferred to CaV2.3 from slow to fast after posttranslational modifications during channel biogenesis. Our findings provide a framework within which to understand the modulation of inactivation and a new functional map of CaVβ in which the GK domain regulates channel gating and the other conserved domain (Src homology 3) may couple calcium channels to other signaling pathways. 相似文献
50.
目的:应用基因沉默技术,观察下调20S蛋白酶体β5亚单位(PSMB5)对人骨髓间充质干细胞(hBMSCs)增殖能力的影响及其潜在机制,寻求调节干细胞活力的关键靶点。方法:构建PSMB5-shRNA慢病毒载体感染早期hBMSCs,根据感染条件不同将细胞分为绿色荧光蛋白(GFP)对照组和shRNA组。倒置荧光显微镜观察转染效率,RT-PCR和免疫印迹检测PSMB5沉默效率,荧光分光光度法检测蛋白酶体活性;BrdU掺入实验观察PSMB5基因沉默对早期hBMSCs增殖潜能的影响,流式细胞术检测细胞周期分布,免疫印迹检测细胞周期相关蛋白1(cyclin D1)及其激酶CDK4的表达变化。结果:慢病毒感染早期hBMSCs 72 h可见约95%以上细胞表达绿色荧光蛋白。shRNA组PSMB5 mRNA和蛋白表达水平较GFP对照组分别降低93.31%±0.59%和56.83%±13.31%,且蛋白酶体活性较对照组降低37.47%±0.41%。此外,shRNA组BrdU阳性率26.14%±8.13%较对照组49.53%±11.18%显著降低,G1期细胞较GFP对照组增多,而S期和G2/M期细胞却较对照组减少,Cyclin D1和CDK4的表达水平分别下降54.55%±7.76%和63.26%±15.76%。结论:PSMB5基因沉默能够下调Cyclin D1和CDK4的表达,导致细胞G1/S转换停滞,影响hBMSCs增殖潜能。 相似文献