Effects of chronic apical periodontitis on the inflammatory response of the aorta in hyperlipemic rats

Clinical Oral Investigations - To study the effects of chronic apical periodontitis (CAP) on the inflammatory response and initial lesion of aorta in hyperlipemic rats. Sprague–Dawley (SD)...     

Regioselective O/C phosphorylation of α-chloroketones: a general method for the synthesis of enol phosphates and β-ketophosphonates via Perkow/Arbuzov reaction

A regioselective O/C phosphorylation of α-chloroketones with trialkyl phosphites was performed for the first time, which employed solvent-free Perkow reaction and NaI-assisted Arbuzov reaction under mild conditions respectively. Versatile enol phosphates were prepared in good to excellent yields as well as β-ketophosphinates.

A highly regioselective O/C phosphorylation of α-chloroketones with trialkyl phosphites was developed in the preparation of enol phosphates and β-ketophosphonates.     

扩张型心肌病患者左心室能量损耗及室壁剪应力的血流向量成像评价

目的应用血流向量成像（VFM）技术定量评估扩张型心肌病（DCM）患者的左心功能异常。 方法选取2019年1月至2019年4月于武汉亚洲心脏病医院确诊DCM的患者29例为DCM组,同期匹配健康志愿者32例为对照组。VFM模式下获取两组心尖四腔心、三腔心切面二维彩色多普勒血流动态图,脱机分析对比不同切面等容收缩期（P0）、快速射血期（P1）、等容舒张期（P2）、快速充盈期（P3）、心房收缩期（P4）能量损耗（EL）及各节段室壁剪应力（WSS）平均值的差异,评估DCM患者左心室血流动力学的改变。 结果与对照组相比,DCM组在P0、P1及P3期EL均减低［分别为（2.24±1.33）J/（s·m³）vs（1.39±0.49）J/（s·m³）、（6.14±3.58）J/（s·m³）vs（4.17±2.12）J/（s·m³）、（10.38±6.67）J/（s·m³）vs（4.92±2.73）J/（s·m³）,均P＜0.05］。DCM组左心室壁在P0期基底段［（0.45±0.30）N/m² vs（0.23±0.13）N/m²］,P1、P2期基底段和中间段［分别为（1.24±0.39）N/m² vs（0.93±0.40）N/m²、（0.55±0.30）N/m² vs（0.36±0.23）N/m²,（0.29±0.08）N/m² vs（0.12±0.05）N/m²、（0.14±0.08）N/m² vs（0.10±0.06）N/m²］,P3期各节段［分别为（0.60±0.24）N/m² vs（0.26±0.08）N/m²、（0.47±0.29）N/m² vs（0.14±0.04）N/m²、（0.13±0.06）N/m² vs（0.06±0.02）N/m²］以及P4期基底段［（0.40±0.15）N/m² vs（0.25±0.12）N/m²］的WSS较对照组均减低（均P＜0.05）。对照组WSS同一时相呈现基底段＞中间段＞心尖段,而DCM组P0、P2和P4期基底段与中间段WSS差异无统计学意义（均P＞0.05）。对照组WSS同一节段P0→P1→P2→P3→P4期表现为升高－减低－升高－减低改变（均P＜0.05）,而DCM组WSS仅基底段P0→P1→P2→P3期表现为升高－减低－升高趋势（均P＜0.05）,余节段WSS在各时相间变化差异均无统计学意义（均P＞0.05）。 结论VFM技术中的EL及WSS作为新的血流动力学量化参数,可评估DCM患者左心室功能异常。     

朱丹溪气郁用药规律研究

目的:探究朱丹溪气郁的用药规律及其对临床的指导意义.方法:以《朱丹溪医学全书》作为方剂的基本信息来源,收集书中所涉所有相关方剂,运用excel将书中所有涉及方药进行数据库录入,建立数据库,通过数据挖掘技术对药物类别、使用频次、归经、性味进行统计.结果:朱丹溪著作共涉及治气方剂914个,其中出现频数大于100的常用药物有16味,分别是炙甘草、人参、白术、茯苓、陈皮、生姜、当归、香附、白芍、半夏、川芎等;在药物类别上补虚药和理气药使用频次最高;按药性划分使用频率较高依次为温性药57.29％、平性药22.24％、寒性药占20.48％;按归经划分使用频次较高的依次为脾经26.63％、肺经15.68％、胃经13.36％、心经占12.07％;按药味划分使用频次较高依次为苦味药36.27％、辛味药30.03％、甘味药29.46％,酸味药4.23％.结论:朱丹溪在治疗气证时,擅长应用炙甘草,以四君子汤为主方,配以补虚药,补母益子;同时,朱丹溪治气还往往佐以治血、治痰,扶正祛邪.通过对统计结果进行比较发现,朱丹溪在治气药物归经偏于脾胃两经,重视中焦脾胃之气的升提作用.     

阿托伐他汀在缺血性卒中患者中的疗效研究

目的探讨阿托伐他汀对缺血性卒中患者的疗效。方法收集2012年6月~2014年2月来我院诊治的缺血性卒中患者311例为研究对象,依据其来诊的顺序随机分为实验组与对照组。两组均给予常规内科治疗,实验组加用阿托伐他汀治疗,治疗3个月后,观察两组的治疗效果。结果实验组的临床疗效明显高于对照组;治疗后实验组的总胆固醇、甘油三酯及低密度脂蛋白明显低于对照组,而高密度脂蛋白明显高于对照组。结论阿托伐他汀可以改善缺血性卒中患者血脂水平,提高缺血性卒中患者的治疗效果。     

中药相关性肝损害研究——从理论到临床

药源性肝损害是临床常见问题,在我国发生率为0.46%~1.08%,其中由中药引起的占30%左右。作者检索了公开发表的有关文献,梳理了中药相关性肝损害的基本情况,以期为中药的安全应用提供参考。易引发肝损害的单味中药主要有黄药子、雷公藤、铅丹等,复方中药主要有青黛丸、克银丸、消核片等,以及中药汤剂小柴胡汤等;造成肝损害的中药有毒成分主要包括生物碱类、萜类、内酯类及毒性植物蛋白类等;肝损害的主要表现为消化道症状、肝区不适、肝大、黄疸、转氨酶升高,损害程度与剂量及疗程密切相关。中药引起的肝损害多为可逆性,但严重者亦可致死。因此,中医临床医生应与时俱进,及时了解中药的现代药理研究,慎用、少用肝毒性中药,必要时定期监测患者肝功能的变化,以提高中药用药的安全性。     

Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies

Among the nine subtypes of human voltage-gated sodium (Na_v) channels, the brain and cardiac isoforms, Na_v1.1 and Na_v1.5, each carry more than 400 missense mutations respectively associated with epilepsy and cardiac disorders. High-resolution structures are required for structure–function relationship dissection of the disease variants. We report the cryo-EM structures of the full-length human Na_v1.1–β4 complex at 3.3 Å resolution here and the Na_v1.5-E1784K variant in the accompanying paper. Up to 341 and 261 disease-related missense mutations in Na_v1.1 and Na_v1.5, respectively, are resolved. Comparative structural analysis reveals several clusters of disease mutations that are common to both Na_v1.1 and Na_v1.5. Among these, the majority of mutations on the extracellular loops above the pore domain and the supporting segments for the selectivity filter may impair structural integrity, while those on the pore domain and the voltage-sensing domains mostly interfere with electromechanical coupling and fast inactivation. Our systematic structural delineation of these mutations provides important insight into their pathogenic mechanism, which will facilitate the development of precise therapeutic interventions against various sodium channelopathies.

The nine subtypes of human voltage-gated sodium (Na_v) channels are responsible for the initiation and transmission of electrical impulses in different tissues: Na_v1.1 to Na_v1.3 and Na_v1.6 mainly function in the central nervous system, Na_v1.7 to Na_v1.9 are mostly distributed in the peripheral nervous system, Na_v1.4 is specialized in skeletal muscle, and Na_v1.5 is the primary cardiac isoform (1–4). Abnormalities of these channels, hinging on their tissue specificity, are associated with a broad spectrum of channelopathies. To date, more than 1,000 disease mutations have been identified in the primary sequence of Na_v channels, among which Na_v1.1 and Na_v1.5 each host more than 400 missense mutations (5–8).Na_v1.1 is encoded by SCN1A, which may have the largest number of epilepsy-related mutations. Up to 900 SCN1A mutations, more than half of which result in truncations (9), have been identified in epilepsy syndromes with different severities. Nonsense and hundreds of missense mutations of SCN1A are found in 70 to 80% of patients with Dravet syndrome, which is also known as the severe myoclonic epilepsy of infancy (10–13) (SI Appendix, Table S1). Several dozen missense mutations are associated with generalized epilepsy with febrile seizures plus and intractable childhood epilepsy with generalized tonic-clonic seizures (10) (SI Appendix, Table S2). Although most of the Na_v1.1 disease mutations lead to loss of function to different degrees, some represent gain of function. In most cases, the pathogenic mechanism remains elusive.A brief summary of Na_v1.5 pathophysiology is presented in the companion paper (14). Mechanistic understanding of the sodium channelopathies entails high-resolution structures of human Na_v channels. In the past 4 y, we have reported the cryoelectron microscopy (cryo-EM) structures, at resolutions ranging between 2.6 and 4.0 Å, of Na_v channels from insect (Na_vPaS), electric eel (EeNa_v1.4), and finally human, including Na_v1.2, Na_v1.4, Na_v1.5, and Na_v1.7, in the presence of multiple modulators, such as β1 and β2 subunits, peptide toxins, and small-molecule toxins tetrodotoxin and saxitoxin (15–21). Structures of a truncated rat Na_v1.5 were recently reported (22). All structurally resolved eukaryotic Na_v channels except for Na_vPaS exhibit similar conformations of potentially inactivated state.Notwithstanding these advances, high-resolution structures of human Na_v1.1 and Na_v1.5 wild-type and representative disease variants are necessary to provide accurate templates to directly map the disease mutations and to facilitate drug discovery. Furthermore, as these two channels harbor 80% of all identified mutations related to sodium channelopathies, a comparative analysis of their structures may reveal potential mutational hotspots, offering invaluable insight into the function and disease mechanism of Na_v channels.Here we present the cryo-EM structure of human Na_v1.1 associated with a modulating auxiliary subunit β4. In the accompanying paper, we report the structure of human Na_v1.5 that carries a common disease variant E1784K. Comparative structural analyses have revealed several clusters of disease mutations that are common to both Na_v1.1 and Na_v1.5.     

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation

Activation of CD4⁺ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4⁺ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4⁺ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4⁺ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4⁺ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.