维生素D与多囊卵巢患者胰岛素抵抗相关性及其机制研究

目的:探讨维生素D对多囊卵巢综合征(PCOS)患者胰岛素抵抗(IR)的影响及其机制研究.方法:选取自2013年2月～2014年2月在该院就诊的48例PCOS患者作为PCOS组,另选30例健康育龄期妇女作为对照组,测量研究者身高、体质量参数,计算体质指数(BMI),采用全自动生化分析仪葡萄糖氧化酶检测空腹血糖浓度(FBG)、化学发光法检测血清空腹胰岛素(FI)及胰岛素样生长因子-1(IGF-1)水平、ELISA方法测定血清25-(OH)D3浓度,计算稳态胰岛素评价指数(HOMA-IR)用于评价胰岛素抵抗性,量化胰岛素敏感指数(QUICKI)用于评价胰岛素敏感度,并分析FI、HOMA-IR、QUICKI及IGF-1与血清25-(OH)D3浓度的相关性.结果:PCOS组BMI及FBG与对照组相比,差异无统计学差异(P＞0.05),而FI、HOMA-IR、QUICKI、25-(OH) D3及IGF-1与对照组比较,差异均有统计学差异(P＜0.05);并且PCOS组FI和HOMA-IR与血清25-(OH)D3浓度呈显著负相关,差异有统计学意义(P＜0.05),QUICKI和IGF-1水平与血清25-(OH)D3浓度呈显著正相关,差异有统计学意义(P＜0.05).结论:PCOS患者IR可能与血清中维生素D缺乏有关,而IGF-1分泌减少又可能是导致PCOS患者维生素D缺乏的重要原因.     

苯扎贝特治疗儿童ApoE Tokyo(Arg25Cys)突变型脂蛋白肾病1例

脂蛋白肾病(Lipoprotein glomerulopathy,LPG),1989年首次由日本学者Saito报道,LPG主要累及肾脏,且以肾小球病变为主[1]。几乎所有患者均有不同程度的蛋白尿,多数表现为肾病综合征,少数表现为轻微蛋白尿和镜下血尿,部分患者伴有不同程度的贫血及高血压,血脂异常易被忽略为肾病综合征的低蛋白血症所致。载脂蛋白E(apolipoprotein E,ApoE)增高是LPG血脂改变的主要特点[2-3]。LPG为一种与脂质代谢紊乱密切相关的肾脏疾病,目前世界范围内有报道的病例不足200例,儿童报道仅10余例[2]。本病进展缓慢,临床常误诊为原发性肾病综合征[4]。因此,为增强对LPG的认识,提高诊治水平,现分析1例确诊的儿童LPG临床资料,总结LPG的临床特点、诊断、治疗及预后。     

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.     

Magnesium lithospermate B acts against dextran sodiumsulfate-induced ulcerative colitis by inhibiting activation of the NRLP3/ASC/Caspase-1 pathway

This study aimed to observe the therapeutic effects of magnesium lithospermate B on acute and chronic colitis induced by dextran sodiumsulfate (DSS) and the role of inflammasome complex (NOD-like receptor protein, NLRP; apoptosis-associated speck-like protein containing, ASC; caspase-1). Establishment of acute and chronic colitis models were by using 5% DSS oral administration in BALB/C male mice. Magnesium lithospermate B (240 mg/kg body weight) was given by subcutaneous injection. Samples were collected for biomarker assay, histological examination, immunohistochemical evaluation and western blot. There was obvious increase in TNF-α level and NLPR3, ASC, and caspase-1 expressions in acute and chronic colitis groups compared with the normal control. Significant decrease of the tumor necrosis factor-α level and the expressions of NLPR3, ASC, and caspase-1 were observed after treatment with magnesium lithospermate B. This study showed that magnesium lithospermate B could be used to treat acute and chronic colitis by inhibiting the activation of the NLRP3/ASC/Caspase-1 pathway.     

Curcumin ameliorates hepatic chronic inflammation induced by bile duct obstruction in mice through the activation of heme oxygenase-1

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AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9

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Association of genetic variants at MYP10 and MYP15 with high myopia in a Han Chinese population

Background: Previous genome-wide association study (GWAS) has revealed the association between MYP10 at 8p23 and MYP15 at 10q21.1 and high myopia (HM) in a French population. This study is managed to discover the connection between some single nucleotide polymorphism (located at MYP10 and MYP15) and Han Chinese HM.

Methods and Results: This case-control association study contained 1673 samples, including 869 ophthalmic patients and 804 controls. Twelve tag SNPs have been selected from the MYP10 and MYP15 loci and genotyped by SNaPshot method. Among 12 SNPs, rs4840437 and rs6989782 in TNKS gene were found significant association with HM. Carriers of rs4840437G allele and rs4840437GG genotype created a low risk of high myopia (P = .036, OR = 0.81, 95%CI = 0.71–0.93; P = .016, OR = 0.73, 95%CI = 0.56–0.96; respectively). Carriers of rs6989782T allele and rs6989782TT+CT genotype also had a decreased risk of high myopia (P = .048, OR = 0.82, 95%CI = 0.71–0.94; P = .006, OR = 0.74, 95%CI = 0.59–0.92; respectively). Other 10 SNPs displaced nonsignificant association with HM. Additionally, the risk haplotype AC and the protective haplotype GT, generated by two SNPs in TNKS, were considerably more likely to be association with HM (for AC, P = .002 and OR = 1.26; for GT, P = .027 and OR = 0.84).

Conclusions: Our results demonstrated that some heritable variants in the TNKS gene are associated with HM in the Han population. The possible functions of TNKS in the development and pathogenesis of hereditary high myopia still require further researches to identify.     

补骨脂素抗增生性瘢痕作用机制研究

目的探讨补骨脂素抗增生性瘢痕的作用机制。方法体外培养成纤维细胞,按随机数字表法分为正常组(培养正常成纤维细胞)、瘢痕组(培养增生性瘢痕成纤维细胞)、TGF-β1组(10 ng/ml TGF-β1处理增生性瘢痕成纤维细胞5 min^12 h)、Smurf2 RNA干扰组[Smad泛素化调节因子2(Smad ubiquitin regulatory factor2,Smurf2)siRNA转染增生性瘢痕成纤维细胞72 h]、补骨脂素组(10μmol/L补骨脂素处理增生性瘢痕成纤维细胞继续培养72 h)、补骨脂素+TGF-β1组(增生性瘢痕成纤维细胞加入补骨脂素培养72 h后加入TGF-β1培养6 h)。采用Western blot法检测Smurf2、α-平滑肌肌动蛋白(α-actin SMA,α-SMA)蛋白表达;RT-PCR法检测Ⅰ型胶原蛋白mRNA表达;ELISA法检测TGF-β1蛋白分泌。结果与正常组比较,瘢痕组Smurf2蛋白[(0.83±0.08)比(0.38±0.07)]表达增加(P<0.05);与瘢痕组比较,Smurf2 RNA干扰组TGF-β1[(2.2±0.18)比(4.2±0.47)]表达降低(P<0.05);TGF-β1组Smurf2[(0.71±0.06)比(0.42±0.04)]、α-SMA[(1.42±0.12)比(0.91±0.09)]蛋白表达增加(P<0.05),Ⅰ型胶原蛋白mRNA[(0.72±0.09)比(0.41±0.07)]表达增加(P<0.05);补骨脂素组Smurf2[(0.05±0.01)比(0.42±0.04)]、α-SMA[(0.71±0.07)比(0.91±0.09)]蛋白表达降低(P<0.05),Ⅰ型胶原蛋白mRNA表达[(0.12±0.04)比(0.41±0.07)]降低(P<0.05)。结论补骨脂素可能通过TGF-β1/Smurf2信号通路抑制α-SMA蛋白表达,从而降低Ⅰ型胶原蛋白表达,起到抑制瘢痕形成的作用。     

Inactivated influenza vaccine formulated with single-stranded RNA-based adjuvant confers mucosal immunity and cross-protection against influenza virus infection

Influenza vaccination is considered the most valuable means to prevent and control seasonal influenza infections, which causes various clinical symptoms, ranging from mild cough and fever to even death. Among various influenza vaccine types, the inactivated subunit type is known to provide improved safety with reduced reactogenicity. However, there are some drawbacks associated with inactivated subunit type vaccines, with the main ones being its low immunogenicity and the induction of Th2-biased immune responses. In this study, we investigated the role of a single-stranded RNA (ssRNA) derived from the intergenic region in the internal ribosome entry site of the Cricket paralysis virus as an adjuvant rather than the universal vaccine for a seasonal inactivated subunit influenza vaccine. The ssRNA adjuvant stimulated not only well-balanced cellular (indicated by IgG2a, IFN-γ, IL-2, and TNF-α) and humoral (indicated by IgG1 and IL-4) immune responses but also a mucosal immune response (indicated by IgA), a key protector against respiratory virus infections. It also increases the HI titer, the surrogate marker of influenza vaccine efficacy. Furthermore, ssRNA adjuvant confers cross-protective immune responses against heterologous influenza virus infection while promoting enhanced viral clearance. Moreover, ssRNA adjuvant increases the number of memory CD4⁺ and CD8⁺ T cells, which can be expected to induce long-term immune responses. Therefore, this ssRNA-adjuvanted seasonal inactivated subunit influenza vaccine might be the best influenza vaccine generating robust humoral and cellular immune responses and conferring cross-protective and long-term immunity.