Modifiable lifestyle factors and cognitive reserve: A systematic review of current evidence

This systematic review aims to summarize cognitive reserve (CR) evaluation approaches and to examine the role of seven selected modifiable lifestyle factors (diet, smoking, alcohol consumption, physical activity, cognitive leisure activity, sleep, and meditation) in mitigating the impacts of age- or disease-related brain changes on cognition. Eighteen population-based English empirical studies were included. We summarize the study designs and identify three CR models that were broadly used in these studies, including a residual model assessing lifestyle factors in relation to unexplained variance in cognition after accounting for brain markers, a moderation model testing whether lifestyle factors moderate the relationship between brain status and cognition, and a controlling model examining the associations between lifestyle factors and cognition when controlling for brain measures. We also present the findings for the impact of each lifestyle factor. No studies examined diet, sleep, or meditation, and only two studies focused on smoking and alcohol consumption each. Overall, the studies suggest lifestyle activity factors (physical and cognitive leisure activities) may contribute to CR and attenuate the damaging impact of brain changes on cognition. Standardized measurements of lifestyle factors and CR are needed, and mechanisms underlying CR need to be further addressed as well.     

1例重型弥漫性轴索损伤伴肺挫裂伤患者的肺康复护理

总结1例重型弥漫性轴索损伤伴肺挫裂伤患者的肺康复护理经验。护理要点包括：组建多学科肺康复管理团队,实施个性化呼吸支持与降阶梯序贯氧疗护理,精准廓清呼吸道,开展一体化的早期肺功能康复锻炼。经过多学科团队合作,患者入院后第12天撤离呼吸机,第17天拔除气管插管,第20天下床活动,第37天顺利出院,随访6个月,患者恢复良好。     

我国弓形虫Chinese 1优势基因型感染对小鼠脑组织铁代谢影响

目的　探讨我国弓形虫Chinese 1优势基因型感染对宿主脑组织铁代谢及脑损伤的影响。方法　将20只C57BL/6（体质量15～17 g）小鼠随机分为对照组和感染组，每组10只。感染组每只小鼠腹腔注射4 000个弓形虫Chinese 1优势基因型TgCtwh3虫株速殖子，对照组小鼠注射等量无菌PBS，饲养6 d后处死小鼠并取其脑组织。采用电感耦合等离子体质谱法（inductively coupled plasma mass spectrometry, ICP⁃MS）检测小鼠脑组织铁元素水平；采用RNA芯片检测两组小鼠脑组织差异基因数目并对功能基因表达情况进行基因本体论（Gene Ontology, GO）功能富集；采用实时荧光定量PCR（fluorescent quantitative real⁃time PCR, qPCR）技术检测小鼠脑组织中弓形虫表面抗原1（Toxoplasma gondii surface antigen 1，TgSAG1）基因及部分锌铁调控蛋白（Zrt⁃ and Irt⁃like protein, ZIP）家族mRNA表达水平；采用光镜和电镜观察小鼠脑组织海马齿轮回（dentate gyrus, DG）超微结构；采用Western blotting检测谷胱甘肽过氧化物酶4（glutathione peroxidase 4, GPx4）蛋白表达水平；采用硫代巴比妥酸（TBA）法检测丙二醛（malondialdehyde, MDA）水平；采用免疫组化检测血管内皮生长因子（vascular endothelial growth factor, VEGF）蛋白表达光密度（optical density, OD）值。结果　光镜下可见感染组小鼠脑组织海马DG区细胞坏死，电镜下见感染组小鼠脑组织海马区出现胞质空泡化、核皱缩坏死、线粒体嵴断裂消融、自噬小体增加等超微结构变化。与对照组相比，感染组小鼠脑组织中铁元素水平上调[（32.92 ± 0.90） µg/g vs.（37.72 ± 1.10） µg/g；t = 3.397, P < 0.01]；RNA芯片检测感染组小鼠脑组织发现721个基因上调、276个基因下调，差异表达基因在金属离子结合能力上有明显富集。与对照组相比，感染组小鼠脑组织金属元素转运体ZIP2 mRNA表达水平上调（t = 8.659，P < 0.05）、GPx4表达下降[（1.046 ± 0.025） vs. （0.720 ± 0.101）；t = 3.129，P < 0.01]）、MDA水平升高[（4.37 ± 0.33） nmol/mgprot vs.（5.93 ± 0.54） nmol/mgprot；t = 2.451，P < 0.05）]、VEGF蛋白平均OD值上调[（0.348 3 ± 0.017 8） vs. （0.490 6 ± 0.010 5）；t = 6.641，P < 0.01]。结论　Chinese 1优势基因型弓形虫感染后，小鼠脑组织中铁元素蓄积、抗氧化能力下调、氧化应激水平升高，提示弓形虫感染可影响宿主脑组织铁代谢而导致脑损伤。     

Metabolism of non-steroidal anti-inflammatory drugs (NSAIDs) by Streptomyces griseolus CYP105A1 and its variants

In the field of drug development, technology for producing human metabolites at a low cost is required. In this study, we explored the possibility of using prokaryotic water-soluble cytochrome P450 (CYP) to produce human metabolites. Streptomyces griseolus CYP105A1 metabolizes various non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, meclofenamic acid, and ibuprofen. CYP105A1 showed 4′-hydroxylation activity towards diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, and meclofenamic acid. It should be noted that this reaction specificity was similar to that of human CYP2C9. In the case of mefenamic acid, another metabolite, 3′-hydroxymethyl mefenamic acid, was detected as a major metabolite. Substitution of Arg at position 73 with Ala in CYP105A1 dramatically reduced the hydroxylation activity toward diclofenac, flufenamic acid, and ibuprofen, indicating that Arg73 is essential for the hydroxylation of these substrates. In contrast, substitution of Arg84 with Ala remarkably increased the hydroxylation activity towards diclofenac, mefenamic acid, and flufenamic acid. Recombinant Rhodococcus erythrocyte cells expressing the CYP105A1 variant R84A/M239A showed complete conversion of diclofenac into 4′-hydroxydiclofenac. These results suggest the usefulness of recombinant R. erythropolis cells expressing actinomycete CYP, such as CYP105A1, for the production of human drug metabolites.     

ArgD of Mycobacterium tuberculosis is a functional N-acetylornithine aminotransferase with moonlighting function as an effective immune modulator

Mycobacterium tuberculosis (M. tuberculosis) encodes an essential enzyme acetyl ornithine aminotransferase ArgD (Rv1655) of arginine biosynthetic pathway which plays crucial role in M. tuberculosis growth and survival. ArgD catalyzes the reversible conversion of N-acetylornithine and 2 oxoglutarate into glutamate-5-semialdehyde and L-glutamate. It also possesses succinyl diaminopimelate aminotransferase activity and can thus carry out the corresponding step in lysine biosynthesis. These essential roles played by ArgD in amino acid biosynthetic pathways highlight it as an important metabolic chokepoint thus an important drug target. We showed that M. tuberculosis ArgD rescues the growth of ΔargD E. coli grown in minimal media validating its functional importance. Phylogenetic analysis of M. tuberculosis ArgD showed homology with proteins in gram positive bacteria, pathogenic and non-pathogenic mycobacteria suggesting the essentiality of this protein. ArgD is a secretory protein that could be utilized by M. tuberculosis to modulate host innate immunity as its moonlighting function. In-silico analysis predicted it to be a highly antigenic protein. The recombinant ArgD protein when exposed to macrophage cells induced enhanced production of pro-inflammatory cytokines TNF, IL6 and IL12 in a dose dependent manner. ArgD also induced the increased production of innate immune effector molecule NOS2 and NO in macrophages. We also demonstrated ArgD mediated activation of the canonical NFkB pathway. Notably, we also show that ArgD is a specific TLR4 agonist involved in the activation of pro-inflammatory signaling for sustained production of effector cytokines. Intriguingly, ArgD protein treatment activated macrophages to acquire the M1 phenotype through the increased surface expression of MHCII and costimulatory molecules CD80 and CD86. ArgD induced robust B-cell response in immunized mice, validating its antigenicity potential as predicted by the in-silico analysis. These properties of M. tuberculosis ArgD signify its functional plasticity that could be exploited as a possible drug target to combat tuberculosis.     

胶质淋巴系统——脑部疾病机制研究新方向

胶质淋巴系统是一个主要由星形胶质细胞水通道蛋白4介导的依靠动脉、静脉周围血管间隙的脑脊液-脑组织液交换流动的系统，是阿尔茨海默病、脑卒中、帕金森病、失眠、抑郁症等脑病的共同特征，是一条新的脑代谢途径，可以清除包括β-淀粉样蛋白、乳酸在内的代谢产物。本文综合分析了全球有关胶质淋巴系统在脑部疾病的研究，得出：胶质淋巴系统可能为神经退行性疾病等发病机制和诊治策略研究带来新视角；胶质淋巴系统有望为一些脑部疾病诊断提供新的有效证据；胶质淋巴系统可能是脑部疾病治疗给药方式的新途径。