糖尿乐胶囊联合地特胰岛素治疗2型糖尿病的临床研究

目的探讨糖尿乐胶囊联合地特胰岛素注射液治疗2型糖尿病的临床疗效。方法选取2018年5月-2019年5月在大连市第五人民医院治疗的2型糖尿病患者86例,根据用药的差别分为对照组(43例)和治疗组(43例)。对照组皮下注射地特胰岛素注射液,0.1~0.2 U/kg/次,1次/d;治疗组在对照组基础上口服糖尿乐胶囊,1.2 g/次,3次/d。两组患者均治疗4周。观察两组患者临床疗效,同时比较治疗前后两组患者血糖相关指标、血清学指标、血糖波动情况和氧化应激指标。结果治疗后,对照组和治疗组临床有效率分别为81.40%和97.67%,两组比较差异有统计学意义(P<0.05)。经治疗,两组患者空腹血糖(FBG)、糖化血红蛋白(Hb A1c)、餐后2 h血糖(2 h PG)、胰岛素(FINS)、超敏C反应蛋白(hs-CRP)、γ-谷氨酰转移酶(γ-GT)、人颗粒蛋白前体(PGRN)、瘦素(LP)、血糖标准差(SDBG)、平均血糖波动幅度(MAGE)、24 h血糖波动次数(NGE)、24h血糖平均绝对差(MODD)和丙二醛(MDA)水平均显著下降(P<0.05),而脂联素(APN)、分泌型卷曲相关蛋白5(SFRP5)、谷胱甘肽过氧化物酶(GSH-PX)和超氧化物歧化酶(SOD)水平均显著升高(P<0.05),且治疗组这些指标较对照组改善更明显(P<0.05)。结论地特胰岛素注射液联合糖尿乐胶囊治疗2型糖尿病能够明显效控制血糖,促进机体氧化应激状态的改善。     

Progranulin as a therapeutic target for dementia

Introduction: Progranulin (PGRN) is an acrosomal glycoprotein that is synthesized during spermatogenesis. It is overexpressed in tumors and has anti-inflammatory properties. The protein may be cleaved into granulins which display pro-inflammatory properties. In 2006, mutations in progranulin gene (GRN) that cause haploinsufficiency were found in familial cases of frontotemporal dementia (FTD). Patients with null mutations in GRN display very low-plasma PGRN levels; this analysis is useful for identifying mutation carriers, independent of the clinical presentation, and in those before the appearance of symptoms.

Areas covered: Here, we review the current knowledge of PGRN physiological functions and GRN mutations associated with FTD; we also summarize state of the art clinical trials and those compounds able to replace PGRN loss in preclinical models.

Expert opinion: PGRN represents a promising therapeutic target for FTD. Cohorts suitable for treatment, ideally at the preclinical stage, where pathogenic mechanisms ongoing in the brain are targeted, are available. However, PGRN may have side effects, such as the risk of tumorigenesis, and the risk/benefit ratio of any intervention cannot be predicted. Furthermore, at present, the situation is complicated by the absence of adequate outcome measures.     

Progranulin null mutations in both sporadic and familial frontotemporal dementia

Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.     

单核细胞趋化蛋白1、颗粒蛋白前体、胶质细胞源性神经营养因子水平与阿尔茨海默病认知功能、日常生活能力相关性分析

目的 分析血清单核细胞趋化蛋白1(MCP-1)、颗粒蛋白前体(PGRN)、胶质细胞源性神经营养因子(GDNF)水平与阿尔茨海默病(AD)病人认知功能及日常生活能力的相关性,探讨其在AD中的诊断价值。方法 选取2019年7月至2021年6月入住苏州大学附属广济医院治疗的41例AD病人作为观察组,采用随机数字表法选取苏州大学附属广济医院同期经评估符合入组的41例健康志愿者作为对照组,运用酶联免疫吸附测定(ELISA)检测两组研究对象血清MCP-1、PGRN、GDNF水平;采用简易智力状态检查表(MMSE)及日常生活量表(ADL)评估其认知功能及日常生活能力。分析观察组病人血清MCP-1、PGRN、GDNF水平与MMSE、ADL评分的相关性;并通过受试者操作特征曲线(ROC曲线)分析MCP-1、PGRN、GDNF在AD中的诊断价值。结果 观察组MCP-1(321.7±51.1)ng/L、PGRN(42.6±8.5)μg/L水平较对照组MCP-1(242.6±35.2)ng/L、PGRN(26.5±6.1)μg/L显著增高,观察组GDNF(357.8±112.3)ng/L水平较对照组GDNF(...     

Progranulin locus deletion in frontotemporal dementia

Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.     

Progranulin promotes colorectal cancer proliferation and angiogenesis through TNFR2/Akt and ERK signaling pathways

Progranulin (PGRN) has been shown to be involved in the process of inflammation, wound healing, and cartilage development; and its role in the progression of breast and ovarian cancer is also well established. However, the expression status of PGRN in colorectal cancers (CRCs) and its molecular mechanisms responsible for tumorigenesis have not been addressed so far. Herein, we demonstrated that PGRN was highly expressed and had clinical relevance with CRCs since its overexpression was associated with advanced stages of CRCs, poorer patients’ prognosis, and increased expression of proliferation and angiogenesis markers. PGRN up-regulation significantly promoted the expression of Ki67 and vascular endothelial growth factor A (VEGF-A) as well as the growth rate in CRC cell lines, while PGRN down-regulation had the opposite effects. Strikingly, PGRN derived from CRCs could directly induce proliferation, migration, tubule formation, as well as VEGF-A expression in human umbilical vein endothelial cells (HUVECs). Furthermore, we provided mechanistic evidences that the regulation of Ki67 and VEGF-A expression by PGRN was mediated by tumor necrosis factor receptor 2 (TNFR2)/Akt and the ERK signaling pathways in both CRC cells and HUVECs. Taken together, these findings suggested that PGRN could promote proliferation and angiogenesis through TNFR2/Akt and ERK signaling pathways in CRCs, providing the new insight into the mechanism of PGRN in tumor proliferation and angiogenesis.     

颗粒蛋白前体在离体上皮性卵巢癌细胞恶性行为中的作用及意义

目的 研究颗粒蛋白前体(PGRN)在离体上皮性卵巢癌恶性行为中的作用及意义.方法 选择40例上皮性卵巢癌患者和40例卵巢良性肿瘤患者,采用免疫组织化学染色法比较肿瘤组织中PGRN的表达情况.采用慢病毒转染SKOV3细胞系,获得PGRN高表达(PGRN高表达组)和普通表达(对照组)的细胞系,传代培养比较两组细胞的增殖能力,通过Transwell小室建立转移和侵袭模型,比较两组细胞的侵袭和转移能力.结果 上皮性卵巢癌患者的PGRN免疫组化染色评分为(8.43±1.30)分,明显高于卵巢良性肿瘤患者的(3.08±1.25)分,差异有统计学意义(P﹤0.01);对照组和PGRN高表达组的细胞数量均随时间延长而明显增多(P﹤0.01),PGRN高表达组的细胞数量多于对照组(P﹤0.05).PGRN高表达组转移细胞数目为(170.73±8.13)/HP,明显多于对照组的(102.93±8.54)/HP(P﹤0.01);PGRN高表达组侵袭细胞数目为(109.33±7.37)/HP,明显多于对照组的(53.27±5.35)/HP(P﹤0.01).结论 PGRN在上皮性卵巢癌组织中高表达,并且可以促进癌细胞增殖、侵袭和转移等恶性行为.     

The CST3 B haplotype is associated with frontotemporal lobar degeneration

Background and purpose:  Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementia. Given the role of cystatin C in brain neurodegeneration and neuroregeneration, the aim of this study was to determine whether the cystatin C gene ( CST3 ) was genetically associated with FTLD.
Methods:  Hundred and eighty-six FTLD patients and 457 controls underwent CST3 analysis by PCR and KspI enzyme digestion.
Results:  In FTLD patients negative for the presence of PGRN mutations, we found an over-representation of the CST3 haplotype B [odds ratio (OR = 1.619, P  = 0.002)] and of AB/BB genotypes (OR = 1.704, P  =   0.008) in FTLD patients.
Conclusions:  The present study indicated the CST3 B haplotype as a putative risk factor for FTLD in PGRN mutations negative patients. The reduced level of cystatin C, previously associated with the B haplotype, might represent the molecular factor responsible for the increased risk. Long-term depletion of neurotrophic factors, such as cystatin C and progranulin proteins, seem to be a common theme in FTLD: boosting the expression of such proteins might be a promising therapeutic strategy for FTLD.     

Pharmacogenomics: Precision Medicine and Drug Response

Pharmacogenomics is the use of genomic and other “omic” information to individualize drug selection and drug use to avoid adverse drug reactions and to maximize drug efficacy. The science underlying pharmacogenomics has evolved rapidly over the 50 years since it was first suggested that genetics might influence drug response phenotypes. That process has occurred in parallel with advances in DNA sequencing and other molecular technologies, with striking increases in our understanding of the human genome. There are now many validated examples of the clinical utility of pharmacogenomics, and this type of clinical genomic information is increasingly being generated in clinical laboratories, incorporated into electronic health records, and used to “tailor” or individualize drug therapy. This review will survey the origins and development of pharmacogenomics; it will address some of the challenges associated with the clinical implementation of pharmacogenomics; and it will attempt to foresee future advances in this important genomic discipline, one that almost certainly will be among the earliest and most widely adopted aspects of clinical genomics.