Proteomic analysis of the effects of caffeine in a neonatal rat model of hypoxic‐ischemic white matter damage

AimWhite matter damage (WMD) is the main cause of cerebral palsy and cognitive impairment in premature infants. Although caffeine has been shown to possess neuroprotective effects in neonatal rats with hypoxic‐ischemic WMD, the mechanisms underlying these protective effects are unclear. Herein, proteins modulated by caffeine in neonatal rats with hypoxic‐ischemic WMD were evaluated.MethodsWe identified differential proteins and performed functional enrichment analyses between the Sham, hypoxic‐ischemic WMD (HI), and HI+caffeine‐treated WMD (Caffeine) groups. Confirmed the changes and effect of proteins in animal models and determined cognitive impairment via water maze experiments.ResultsIn paraventricular tissue, 47 differential proteins were identified between the Sham, HI, and Caffeine groups. Functional enrichment analyses showed that these proteins were related to myelination and axon formation. In particular, the myelin basic protein (MBP), proteolipid protein, myelin‐associated glycoprotein precursor, and sirtiun 2 (SIRT2) levels were reduced in the hypoxic‐ischemic WMD group, and this effect could be prevented by caffeine. Caffeine alleviated the hypoxic‐ischemic WMD‐induced cognitive impairment and improved MBP, synaptophysin, and postsynaptic density protein 95 protein levels after hypoxic‐ischemic WMD by preventing the HI‐induced downregulation of SIRT2; these effects were subsequently attenuated by the SIRT2 inhibitor AK‐7.ConclusionCaffeine may have clinical applications in the management of prophylactic hypoxic‐ischemic WMD; its effects may be mediated by proteins related to myelin development and synapse formation through SIRT2.     

Structural and functional biomarkers of the insula subregions predict sex differences in aggression subscales

Aggression is a common and complex social behavior that is associated with violence and mental diseases. Although sex differences were observed in aggression, the neural mechanism for the effect of sex on aggression behaviors remains unclear, especially in specific subscales of aggression. In this study, we investigated the effects of sex on aggression subscales, gray matter volume (GMV), and functional connectivity (FC) of each insula subregion as well as the correlation of aggression subscales with GMV and FC. This study found that sex significantly influenced (a) physical aggression, anger, and hostility; (b) the GMV of all insula subregions; and (c) the FC of the dorsal agranular insula (dIa), dorsal dysgranular insula (dId), and ventral dysgranular and granular insula (vId_vIg). Additionally, mediation analysis revealed that the GMV of bilateral dIa mediates the association between sex and physical aggression, and left dId–left medial orbital superior frontal gyrus FC mediates the relationship between sex and anger. These findings revealed the neural mechanism underlying the sex differences in aggression subscales and the important role of the insula in aggression differences between males and females. This finding could potentially explain sexual dimorphism in neuropsychiatric disorders and improve dysregulated aggressive behavior.     

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre

As the so-called “next frontier” in global economic terms, Africa’s disease burden continues to choke and cripple economic growth across the continent. The highest burden is attributable to malaria and tuberculosis (TB), which also remain among the deadliest infectious diseases affecting mankind the world over (Malaria, 627,000 deaths; TB, 1.5 million deaths, in 2020). In achieving self-determination with respect to the health needs of all who live on the continent, Africa must align with global north efforts and be a source of health innovation. This will in part require the creation of an ecosystem of innovative pharmaceutical R&D and expanding it across the continent by scaling up through sustained performance and excellence. To this end, the Holistic Drug Discovery and Development (H3D) Centre at University of Cape Town in South Africa has risen to this challenge. Here, we highlight the innovation experiences gained at H3D, covering the advances made in our quest to contribute to a global pipeline of therapeutic interventions against malaria and TB. We discuss selected chemical series starting from their identification, structure–activity relationships, mode of action, safety, proof-of-concept studies, and lessons learned.     

葛根素减轻PM2.5对血管内皮细胞损伤的机制研究

探讨PM2.5对EA.hy926型人脐静脉内皮细胞损伤的影响及葛根素的保护作用及机制。采集大气PM2.5分别以0,20,200,400 mg·L~(-1)染毒EA.hy926细胞24 h,MTT法测细胞存活率,流式细胞术测细胞凋亡,Western blot法测p-ERK1/2,Bax,Bcl-2蛋白水平,ELISA法测肿瘤坏死因子-α(TNF-α)及白细胞介素-6(IL-6)含量,并测细胞丙二醛(MDA)含量、超氧化物歧化酶(SOD)及乳酸脱氢酶(LDH)活性;分别加入葛根素(10,50,100μmol·L~(-1))和ERK1/2通路特异性阻滞剂PD98059 20μmol·L~(-1)检测葛根素的干预作用及机制。检测发现与对照组比较,PM2.5染毒后呈剂量依赖性降低EA.hy926细胞存活率,上调p-ERK1/2蛋白水平及Bax/Bcl-2蛋白比率以促进细胞凋亡,诱导分泌TNF-α及IL-6含量增高,降低SOD活性,增加MDA含量及LDH活性(P0.05);葛根素呈剂量依赖性增加EA.hy926细胞的存活率,下调p-ERK1/2蛋白水平及Bax/Bcl-2蛋白比率以抑制细胞凋亡,降低TNF-α及IL-6含量,增加SOD活性,降低MDA含量及LDH活性(P0.05)。研究显示葛根素可能通过抑制ERK1/2通路减轻PM2.5对EA.hy926细胞的损伤。     

静脉注射剂中不溶性微粒的来源、危害及预防措施

综述了我国静脉注射剂中不溶性微粒的污染现状及控制措施的研究进展,对不溶性微粒的特性及测定方法进行总结,同时比较了美、英、日、中四国药典对不溶性微粒的检测方法及限度.针对各环节采取相应措施控制不溶性微粒的污染,提高静脉注射剂的质量.     

Associations of urban air particulate composition with inflammatory and cytotoxic responses in RAW 246.7 cell line

Epidemiological studies show heterogeneities in the particulate pollution-related exposure–effect relationships among cardiorespiratory patients, but the connection to chemical composition and toxic properties of the inhaled particles is largely unknown. To identify the chemical constituents and sources responsible for the diverse inflammatory and cytotoxic effects of urban air, fine (PM_2.5–0.2) and coarse (PM_10–2.5) particulate samples were collected during contrasting air pollution situations. We exposed mouse RAW 246.7 macrophages for 24?hrs to PM_2.5–0.2 and PM_10–2.5 samples from six European cities. The concentrations of proinflammatory cytokines (IL-6, TNFα), chemokine (MIP-2), and nitric oxide were measured from the cell culture medium, and the cytotoxicity was assayed. Spearman’s correlations between the chemical constituents and cellular responses were analyzed. In the PM_2.5–0.2 size range, the tracers of photo-oxidation of organics in the atmosphere (oxalate, succinate, malonate), some transition metals (Ni, V, Fe, Cu, Cr), and insoluble soil constituents (Ca, Al, Fe, Si) correlated positively with the response parameters. In contrast, the tracers of incomplete biomass (monosaccharide anhydrides) and coal (As) combustion, and polycyclic aromatic hydrocarbons (PAHs), had negative correlations with the inflammatory activity. The compositions of PM_10–2.5 samples were more uniform and there were only occasional high correlations between the chemical constituents, endotoxin, and the response parameters. The present results suggest that the local sources of incomplete combustion and resuspended road dust are important producers of harmful fine particulate constituents that may, however, operate via diverse toxicity mechanisms. The results agree well with our recent findings in the mouse lung.     

脑白质病变MRI视觉分级方法的比较

目的:比较7种常用的脑白质病变(WMLs)MRI视觉分级方法,评价各分级之间的相关性和一致性,并计算两两间相互转化的参数.方法:随机选取50例MRI T2-FLAIR显示有不同程度WMLs患者,由两名医师分别用7种分级方法对其WMLs进行评分. 视觉分级间的相关性评价采用Spearman 等级相关分析,不同评估者之间的一致性分析采用Kappa检验,通过回归分析计算各分级间相互转化的参数.结果:不同视觉分级在WMLs评分上均有较强的相关性(相关系数rs: 0.579～0.917, P＜0.05). 除Schelten(modilified)分级和Ylikoski分级外,其它分级在不同观察者间的一致性好(κ＞0.585). 除Aharon-Peretz J分级和De Groot JC分级外,通过回归分析得出了其它5个分级间相互转化的参数,其确定系数R2的范围为0.5856～0.8892.结论:7种不同白质病变的MRI视觉分级间有较好的相关性,而不同评估者间Aharon-Peretz J分级的一致性最好.     

基于控墒补灌的春小麦滴灌制度研究

为优化北疆绿洲区滴灌春小麦的灌溉制度,采用控墒补灌法研究了不同灌水量对滴灌春小麦光合特征、干物质分配及水分利用效率的影响。结果表明,拔节～开花期小麦株高、干物质积累量和叶面积指数均随着灌水量的增加显著（P<0.05）升高。小麦旗叶各时期净光合（Pn）、气孔导度（Gs）和蒸腾速率（Tr）增加显著（P<0.05）升高,而胞间CO₂浓度（Ci）变化趋势相反;过量灌溉T5各时期Gs均有所降低,Pn和Tr成熟期下降显著（P<0.05）;亏缺灌溉（T1）Pn峰值提前至孕穗期,各时期WUE均最低、LS最高。干物质向籽粒的分配、花前同化物转运率和对籽粒的贡献率随墒度随灌水量增加显著（P<0.05）降低。二次曲线拟合表明,灌水量为371 mm时可取得7 450 kg·hm^-2的高产,灌溉频率约每7 d灌1次是本地区春小麦的最佳灌溉方案。     

新疆伊贝母有效成分含量与土壤、气候和遗传因子相关性分析

目的 通过对新疆伊贝母有效成分含量与土壤、气候和遗传因子相关性研究,筛选影响其质量的主导因子,为保证伊贝母药材质量及其临床用药的有效性,提高伊贝母的合理利用提供理论依据,为揭示伊贝母适宜生长机制奠定科学基础。方法 应用系统相关分析法、灰色关联度分析和逐步回归分析进行综合分析。结果 对主成分分析、相关分析、灰色关联度分析和逐步回归分析的结果进行综合考虑,年均相对湿度和速效钾对伊贝母总生物碱含量的影响最大,多态性位点(P)、多态性位点百分率(PPB)和速效氮对伊贝母水溶性成分含量的影响最大。结论 综合分析伊贝母有效成分与土壤、气候和遗传因子主导因子的相关性表明,在众多影响因子中,多态性位点(P)、多态性位点百分率(PPB) 、年均相对湿度、速效钾和速效氮是影响伊贝母质量的主导因子,对伊贝母有效成分含量的积累具有重要意义。     

大鼠中脑中央灰质与前脑结构的联系——HRP逆、顺行追踪研究

在22只体重140g左右的SD大鼠,用HRP逆行和顺行追踪方法(TMB-ST法成色),研究了中脑中央灰质(CG)与前脑结构的联系。按照泳注中心位置,将实验材料分作背侧区(CGD)、内侧区(CGM)和外侧区(CGL)三组。三组逆行标记细胞分布没有明显差别。在大脑皮质(以扣带前、压后和额叶皮质为著)、终纹床核、视前区、广泛的下丘脑结构(以下丘脑前区、背侧区、灰结节区、外侧区以及下丘脑腹内侧核、背侧乳头体前核为著,下丘脑室旁核亦见标记细胞)以及未定带、缰外侧核等结构察见标记细胞,均以同侧为主。值得注意的CGL组在终板血管器观察到相当丰富的标记细胞,CGM组在邻近弓状核的室管膜内见相当典型的标记细胞。顺行标记纤维主要循同侧背侧纵束、室周纤维系统和内侧前脑束上行,部分向背颅侧或外颅侧方向穿中脑顶盖或网状结构行进。CGD组达束旁核、丘脑室旁核、外侧和内侧缰核、下丘脑脑后区、未定带、乳头体上核、背侧下丘脑区、下丘脑前区、丘脑后核和顶盖前区。CGM和CGL组延伸较远,除至以上部位外,还可抵达未定带下核、Forel区、背侧乳头体前核、下丘脑室旁核、内侧和外侧视前区、斜角带、终纹床核丘脑中线区和内髓板区等部位。