颗粒蛋白前体衍生物 Atsttrin对骨关节炎的保护作用及对 CD+4T细胞的调节作用

目的 揭示颗粒蛋白前体衍生物Atsttrin对骨关节炎的保护作用及对CD+4 T细胞的调节作用.方法 本研究起止时间为2018年10月至2019年12月,60只5周龄SD雄性大鼠购自西安交通大学医学部实验动物中心.采用膝关节前交叉韧带横断法建立骨关节炎大鼠模型,通过关节内注射15μL Atsttrin(1μg/μL)对模型大鼠进行治疗,每周注射1次,连续注射4周.通过番红O固绿染色检测软骨损伤程度,采用OARSI评分系统评价软骨退化情况.ELISA法检测大鼠血清干扰素-γ(IFN-γ)、白细胞介素-4(IL-4)、白细胞介素-17(IL-17)和转化生长因子-β(TGF-β)水平.流式细胞仪分析血清Th1、Th2、Th17和Treg细胞比例.应用终浓度为10μg/L的肿瘤坏死因子-α(TNF-α)诱导滑膜细胞和软骨细胞48 h,并分别用终浓度为10μg/L、20μg/L、50μg/L的Atsttrin处理滑膜细胞和软骨细胞48 h.通过5-溴-2-脱氧尿苷(BrdU)细胞增殖测定试剂盒检测滑膜或软骨细胞的增殖.通过RT-PCR和Western blotting检测软骨细胞中解聚蛋白样金属蛋白酶-4(ADAMTS-4)、基质金属蛋白酶-13(MMP-13)、IFN-γ、IL-4、IL-17和TGF-β的信使核糖核酸(mRNA)和蛋白表达.结果 与模型组相比,Atsttrin组大鼠的膝关节软骨破坏情况明显减轻(P<0.05).与模型组相比,Atsttrin组大鼠国际骨关节炎研究学会(OARSI)评分显著降低[(2.56±0.21)比(1.08±0.11),P=0.001].Atsttrin组大鼠的血清IFN-γ和IL-17水平显著低于模型组,而IL-4和TGF-β水平显著高于模型组(P<0.05).Atsttrin组大鼠的血清Th1和Th17细胞比例显著低于模型组,而Th2和Treg细胞比例显著高于模型组(P<0.05).Atst?trin处理显著降低了TNF-α诱导的滑膜细胞的增殖能力,并提高了TNF-α诱导的软骨细胞的增殖能力(P<0.05).Atsttrin显著下调了TNF-α诱导的软骨细胞中ADAMTS-4、MMP-13、IFN-γ和IL-17的mRNA和蛋白表达水平,并上调了IL-4和TGF-β的表达水平(P<0.05).结论 Atsttrin可有效抑制骨关节炎大鼠模型的软骨病变并提高关节功能.Atsttrin可通过抑制滑膜细胞增殖、促进软骨细胞增殖、抑制软骨机制降解来维持关节内微环境的稳定.此外,Atsttrin的关节软骨保护作用与纠正Th1/Th2细胞以及Th17/Treg细胞的失衡有关.     

高通量血液透析对非糖尿病患者血清颗粒蛋白前体及胰岛素抵抗的影响

目的探讨高通量血液透析对非糖尿病维持性血液透析(MHD)患者血清颗粒蛋白前体(PGRN)及胰岛素抵抗的影响。方法入选非糖尿病MHD患者60例,随机分为高通量透析组(n=30)和普通透析组(n=30),同时选择年龄、性别相匹配的20例健康体检者作为对照组。两透析组随访6个月,使用稳态模型胰岛素抵抗指数(HOMA-IR)评估胰岛素抵抗,采用ELISA法测定治疗前后血PGRN、白细胞介素-6(IL-6)水平,并记录超敏C反应蛋白(hs-CRP)、血总钙、血磷、甲状旁腺素(PTH)、血脂、单室模型尿素清除指数(sp Kt/V)等指标的变化。结果与对照组相比,高通量透析组和普通透析组患者HOMA-IR均明显升高(P0.05)。治疗后高通量透析组的HOMAIR、PGRN、IL-6、hs-CRP、血磷、甘油三酯、总胆固醇较治疗前显著下降(P0.05),亦明显低于普通透析组(P0.05)。而普通透析组的HOMA-IR、PGRN、IL-6、hs-CRP、血磷、甘油三酯、总胆固醇等指标治疗前后差异无统计学意义(P0.05)。结论高通量透析能降低非糖尿病MHD患者血清PGRN水平,改善机体炎症状态及胰岛素抵抗。     

Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with α7 nicotinic acetylcholine receptor agonists

Mutations in the progranulin gene cause frontotemporal dementia (FTD), a debilitating neurodegenerative disease that involves atrophy of the frontal and temporal lobes and affects personality, behavior, and language. Progranulin-deficient mouse models of FTD exhibit deficits in compulsive and social behaviors reminiscent of patients with FTD, and develop excessive microgliosis and increased release of inflammatory cytokines. Activation of nicotinic acetylcholine receptors (nAChRs) by nicotine or specific α7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or α7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective α7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-κB in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNFα levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the α7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.     

The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments

The past year has seen a number of significant advances in our understanding of the neuropathological and molecular genetic basis of frontotemporal lobar degeneration (FTLD). Whereas, in the past, most attention focused on FTLD associated with tau-based pathology and microtubule associated protein tau gene (MAPT) mutations, there has recently been greater attention paid to non-tau FTLD. FTLD with tau-negative, ubiquitinated inclusions (FTLD-U) is now recognized as the most common pathology associated with clinical FTLD. Mutations in the progranulin gene (PGRN) have been identified as the cause of FTLD-U linked to chromosome 17. A rapidly growing number of PGRN mutations have been identified, and to date, all appear to cause FTLD by reducing the amount of functional PGRN protein (haploinsufficiency). The neuropathology associated with each of the known non-MAPT FTLD genes and loci (PGRN, valosin-containing protein gene, CHMP2B and 9p), has been shown to be a specific subtype of FTLD-U. The ubiquitinated pathological protein in FTLD-U has been identified as TAR deoxyribonucleic acid-binding protein with M _r 43 kDa (TDP-43). Immunohistochemical and biochemical studies of TDP-43 have helped to clarify the relationship between different sub-types of FTLD-U and related conditions. It is anticipated that these discoveries will facilitate the development of new diagnostic tests and therapeutics.     

Cerebrospinal fluid progranulin levels in patients with different multiple sclerosis subtypes

Progranulin has recently attracted attention due to the discovery of mutations in its encoding gene (GRN) in several cases of frontotemporal lobar degeneration, but also for a possible role in inflammatory processes. In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. Progranulin cerebrospinal fluid (CSF) levels were evaluated in 55 patients with multiple sclerosis (MS) as well as in 35 subjects with non-inflammatory neurological diseases (NIND), 7 individuals with other inflammatory neurological disease (OIND) and 8 controls (CON), matched for ethnic background, gender and age. No statistically significant differences were found in patients compared with either NIND, OIND or CON (P > 0.05), even stratifying according to disease subtype or gender. A positive correlation between progranulin CSF levels and age was observed in patients (ρ = 0.29, P = 0.03). According to these data, progranulin does not likely play a major role in the pathogenesis of MS.     

颗粒蛋白前体在呼吸系统疾病的研究进展

颗粒蛋白前体(PGRN)是多功能的生长因子,在正常组织的发生、增生、再生、宿主防御的动态调节中起重要作用.诸多研究表明PGRN参与传染病、伤口愈合、肿瘤发生、神经增殖和退化性疾病.目前研究发现PGRN在炎性疾病中发挥重要作用,此外,PGRN在COPD、ARDS、非小细胞肺癌、间质性肺病中也有研究,本文就PGRN在肺部疾病中的研究进展进行综述.     

颗粒蛋白前体与糖尿病及肥胖的关系

颗粒蛋白前体是一种分泌性蛋白,广泛表达于各种组织,尤其是快速增殖的细胞中,参与胚胎发育、损伤修复、细胞周期等病理生理过程.炎性反应与2型糖尿病及肥胖相关,并且是胰岛素抵抗形成的重要机制之一.最新研究发现,颗粒蛋白前体在2型糖尿病及肥胖患者的体内表达明显升高,并通过白细胞介素-6炎性反应信号通路参与慢性炎性反应状态及胰岛素抵抗的形成,提示颗粒蛋白前体可能与2型糖尿病及肥胖的发病密切相关.     

颗粒蛋白前体在免疫和感染及炎症中的研究进展

颗粒蛋白前体(PGRN)是一个多功能生长因子,其对调节和维护机体正常组织的发展、增殖、再生及防御稳态发挥重要作用。PGRN与感染、免疫、炎症这三个紧密相关的病理生理过程密切相关。最近,PGRN对免疫信号转导通路,特别是肿瘤坏死因子受体的影响倍受瞩目。预期PGRN对临床上种类繁多的炎症性疾病具有巨大的治疗潜力。     

Novel progranulin variants do not disrupt progranulin secretion and cleavage

A subset of frontotemporal dementia cases are neuropathologically defined by tau-negative, TAR DNA-binding protein-43, and ubiquitin-positive inclusions in the brain and are associated with mutations in the progranulin gene (GRN). Deep sequencing of families exhibiting late-onset dementia revealed several novel variants in GRN. Because of the small size of these families and limited availability of samples, it was not possible to determine whether the variants segregated with the disease. Furthermore, none of these families had autopsy confirmation of diagnosis. We sought to determine if these novel GRN variants alter progranulin (PGRN) protein stability, PGRN secretion, and PGRN cleavage in cultured cells. All the novel GRN variants behave like PGRN wild-type protein, suggesting that these variants represent rare polymorphisms. However, it remains possible that these variants affect other aspects of PGRN function or represent risk factors for dementia when combined with other modifying genes.     

短暂性脑缺血再灌注对大鼠脑PGRN表达的影响

目的检测短暂性脑缺血再灌注早期,大鼠的额颞叶皮质、海马及纹状体中颗粒蛋白前体(progranulin,PGRN)的表达变化,为进一步探讨PGRN对脑缺血的治疗提供实验基础。方法 SPF级成年SD大鼠随机分为2组,假手术组(shamoperation group)和实验组(MCAO group)。用线栓法制作右侧大脑中动脉阻塞(MCAO)1 h,然后再灌注30 min、2 h、12 h、24 h模型,以缺血侧为实验组(ipsilateral group),其对侧为对照组(contralateral group)。假手术组为处理对照。用TTC染色法观察缺血梗死体积。用免疫荧光组织化学法和Western-blot分别检测PGRN的细胞定位及其表达变化。结果 TTC染色表明,脑缺血区域呈现白色,而对照无缺血区为红色。免疫组织化学结果提示,PGRN在神经元中大量表达,在小胶质细胞中有少量表达,而在星形胶质细胞中几乎无表达。Western blot结果提示,与对照组相比,缺血再灌注后2 h大鼠脑额颞叶皮质的缺血侧与非缺血侧PGRN含量均显著上调。在海马区缺血再灌注能瞬间降低PGRN水平,随着时间延长PGRN表达水平在24 h逐步恢复到正常水平。与皮质和海马相比,纹状体在短时间再灌注后PGRN具有较高的表达,特别是在缺血再灌注24 h后。结论短暂性脑缺血再灌注能显著影响PGRN在大鼠脑缺血区及半暗带区的水平,提示PGRN可能参与缺血后脑的调节。