脂质纳米粒-mRNA递送系统及其在嵌合抗原受体T细胞治疗中的应用

尽管嵌合抗原受体（CAR）T细胞治疗在血液系统恶性肿瘤患者中取得了显著的临床疗效，但需要进一步优化。脂质纳米粒（LNP）-信使核糖核酸（mRNA）递送系统作为一种非病毒性基因载体运用于CAR-T细胞治疗研究中，一方面通过LNP将密封蛋白-6 mRNA靶向递送至抗原提呈细胞，从而实现抗原提呈细胞辅助性增强密封蛋白-6靶向的CAR-T细胞的功能，以进一步诱导对实体瘤的清除；另一方面，通过LNP将成纤维细胞激活蛋白（FAP）CARmRNA靶向递送至T细胞，实现体内FAP靶向的CAR-T细胞的制备，以通过阻断心脏纤维化过程达到治疗急性心肌损伤的目的。在CAR-T细胞研究和治疗中，LNP-mRNA递送系统具有不与细胞基因组整合、价格便宜、毒副作用小及可修饰等优点，亦存在蛋白瞬时表达导致调控细胞功能的持久性不足及制备等方面的技术局限性。本文综述了LNP-mRNA递送系统及其在CAR-T细胞治疗中的应用研究。     

Recent advances in lipid nanoparticles for delivery of nucleic acid,mRNA, and gene editing-based therapeutics

Lipid nanoparticles (LNPs) are becoming popular as a means of delivering therapeutics, including those based on nucleic acids and mRNA. The mRNA-based coronavirus disease 2019 vaccines are perfect examples to highlight the role played by drug delivery systems in advancing human health. The fundamentals of LNPs for the delivery of nucleic acid- and mRNA-based therapeutics, are well established. Thus, future research on LNPs will focus on addressing the following: expanding the scope of drug delivery to different constituents of the human body, expanding the number of diseases that can be targeted, and studying the change in the pharmacokinetics of LNPs under physiological and pathological conditions. This review article provides an overview of recent advances aimed at expanding the application of LNPs, focusing on the pharmacokinetics and advantages of LNPs. In addition, analytical techniques, library construction and screening, rational design, active targeting, and applicability to gene editing therapy have also been discussed.     

肥胖型PCOS患者的生物学特征和临床特征

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是一种内分泌代谢紊乱综合征,临床表现高度异质性。肥胖是PCOS异质性临床表现之一,超过50%的PCOS患者超重或肥胖。肥胖型PCOS主要表现为高雄激素血症、中心型肥胖和糖脂代谢紊乱,非肥胖型PCOS主要表现为黄体生成激素（luteinizing hormone,LH）水平异常升高。尽管肥胖型和非肥胖型PCOS均存在内分泌代谢异常,然而肥胖可加重PCOS糖脂代谢紊乱;肥胖型PCOS还表现脂肪代谢的异常。综述肥胖型PCOS患者的临床特征、性激素水平、糖脂代谢特征,旨在为肥胖型和非肥胖型PCOS患者新的分型诊治提供参考。     

Interactions of polar lipids with cholesteryl ester multilayers elucidate tear film lipid layer structure

PurposeThe tear film lipid layer (TFLL) covers the tear film, stabilizing it and providing a protective barrier against the environment. The TFLL is divided into polar and non-polar sublayers, but the interplay between lipid classes in these sublayers and the structure-function relationship of the TFLL remains poorly characterized. This study aims to provide insight into TFLL function by elucidating the interactions between polar and non-polar TFLL lipids at the molecular level.MethodsMixed films of polar O-acyl-ω-hydroxy fatty acids (OAHFA) or phospholipids and non-polar cholesteryl esters (CE) were used as a model of the TFLL. The organization of the films was studied by using a combination of Brewster angle and fluorescence microscopy in a Langmuir trough system. In addition, the evaporation resistance of the lipid films was evaluated.ResultsPhospholipids and OAHFAs induced the formation of a stable multilamellar CE film. The formation of this film was driven by the interdigitation of acyl chains between the monolayer of polar lipids and the CE multilayer lamellae. Surprisingly, the multilayer structure was destabilized by both low and high concentrations of polar lipids. In addition, the CE multilayer was no more effective in resisting the evaporation of water than a polar lipid monolayer.ConclusionsFormation of multilamellar films by major tear film lipids suggest that the TFLL may have a similar structure. Moreover, in contrast to the current understanding, polar TFLL lipids may not mainly act by stabilizing the non-polar TFLL sublayer, but through a direct evaporation resistant effect.     

Effects of baru almond oil (Dipteryx alata Vog.) supplementation on body composition,inflammation, oxidative stress,lipid profile,and plasma fatty acids of hemodialysis patients: A randomized,double-blind,placebo-controlled clinical trial

BackgroundThe consumption of nuts and edible seeds is associated with the improvement of the metabolic profile and reduction of cardiovascular diseases. However, the effects of its subproducts, such as oil, are still poorly studied. This study aimed to evaluate the effect of the baru almond oil supplementation on inflammation, oxidative stress, body composition, lipid profile, and plasma fatty acids of hemodialysis patients.MethodsIn a randomized, double-blind, 12-week placebo-controlled clinical study, hemodialysis patients were supplemented with 5 g of baru oil (BG, n = 17) or 5 g of mineral oil (placebo, BP, n = 12). Body composition, renal function, ultra-sensitive C-reactive protein (us-CRP), oxidative stress, plasma fatty acids, and lipid profile were analysed before and after the intervention.ResultsPatients were aged 50.5 ± 2.2 years and the average time of dialyses was 52,1 ± 42,6 months. The BG decreased us-CRP concentration compared to PG (-1.2 ± 0.2 vs. + 0.8 ± 0.2 mg / L,d = 0.88; p = 0.01). Baru almond oil supplementation was not effective in improving body composition, lipid profile, and oxidative stress.ConclusionBaru almond oil supplementation decreased us-CRP concentration in patients with chronic kidney disease under hemodialysis treatment.     

玉液汤对2型糖尿病肥胖患者肠道菌群及脂质代谢的影响

目的：探讨玉液汤对2型糖尿病肥胖患者肠道菌群及脂质代谢影响。方法：选取2017年2月至2019年2月广州市中医医院收治的2型糖尿病肥胖患者106例作为研究对象，按照就诊顺序分为对照组和观察组，每组53例。2组均给予基础治疗+药物治疗，观察组再加用玉液汤治疗。观察2组治疗前、完成治疗后肠道菌群、脂质代谢、中医症状积分、血糖相关指标、体质量、腰围、体质量指数(BMI)变化并比较。结果：2组治疗前各指标比较差异无统计学意义（P>0.05），完成治疗后观察组患者的中医症状积分、FINS、HOMA-IR、HbAlc、BMI、腰围、体质量、TC、TG、LDL-C、肠杆菌、酵母菌、肠球菌、畏寒肢冷、腰膝酸软、脘腹2组患者治疗后HDL-C、双岐杆菌、乳杆菌、拟杆菌均较治疗后明显上升，且观察组高于对照组（P<0.05）。结论：玉液汤能改善2型糖尿病肥胖患者脂质代谢和临床症状，降低血糖，能调节肠道菌群紊乱，从而提高疗效。     

The effects of carnitine supplementation on clinical characteristics of patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials

ObjectiveThe beneficial effects of carnitine supplementation on nonalcoholic fatty liver disease are unclear. We conducted a systematic review and meta-analysis to evaluate the effects of carnitine supplementation on liver function, lipid profile, body mass index, body weight, and homeostasis model assessment of insulin resistance in patients with nonalcoholic fatty liver disease.MethodsA comprehensive search of PubMed, Web of Science, Scopus, Cochrane Library, and Google Scholar databases were performed. Only randomized placebo-controlled human studies that examined the effects of carnitine supplementation on liver function, lipid profile, body mass index, body weight, and homeostasis model assessment of insulin resistance up to September 2019 were included. Fixed effects or random-effects models were applied to compute the pooled effect size. Heterogeneity assessments were performed using Cochran’s Q test and I-squared statistics. The quality of the studies was assessed using the Jaded scale.ResultsA total of 5 articles were selected, including 334 individuals (167 in control and 167 in intervention groups). The results demonstrated that carnitine supplementation significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) (WMD: −0.91; 95 % CI: −1.11, −0.72; p < 0.001, I² = 0.0 %) and the levels of aspartate aminotransferase (AST) (WMD: −16.62; 95 % CI: −28.11, −5.14; IU/l; p = 0.005, I² = 93.5 %), alanine aminotransferase (ALT) (WMD: -33.39; 95 % CI: −45.13, −21.66; IU/l; p < 0.001, I² = 93.4 %), and triglycerides (TG) (WMD: −22.13; 95 % CI: −38.91, −5.34; mg/dl; p = 0.01; I² = 0.0 %). However, the results of the pooled effect size did not show any significant effect of carnitine supplementation on body mass index (BMI) (WMD: 0.07; 95 % CI: −0.15, 0.29; p = 0.55; I² = 0.0 %), body weight (WMD: −0.28; 95 % CI: −2.23, 1.68; p = 0.78; I² = 45.7 %), the levels of gamma-glutamyl transferase (γGT) (WMD: −11.31; 95 % CI: −24.35, 1.73; IU/l; p = 0.09, I² = 61.1 %), cholesterol (WMD: −13.58; 95 % CI: −46.77, 19.60; mg/dl; p = 0.42; I² = 94.9 %), high-density lipoprotein-cholesterol (HDL-C) (WMD: 1.36; 95 % CI: −0.96, 3.68; mg/dl; p = 0.25; I² = 64.7 %), and low density lipoprotein-cholesterol (LDL-C) (WMD: −14.85; 95 % CI: −45.43, 15.73; mg/dl; p = 0.34; I² = 96.4 %).ConclusionsThis analysis shows that carnitine supplementation for patients with nonalcoholic fatty liver disease demonstrates a reduction in AST, ALT, TG levels and HOMA-IR. However, no significant effect of carnitine supplementation was observed on BMI, body weight, the levels of γGT, TC, HDL-cholesterol and LDL-cholesterol.     

表没食子儿茶素-3-没食子酸酯对宫内生长受限大鼠肝脏脂代谢的影响和机制

目的 探讨表没食子儿茶素-3-没食子酸酯（EGCG）对宫内生长受限（IUGR）大鼠肝脏脂代谢的影响和机制。方法 采用母鼠孕期全程限食法建立IUGR大鼠模型，随机分为IUGR组和EGCG组，EGCG组大鼠在离乳后用含EGCG的饮用水喂养至10周，同时设立正常对照组，每组8只。13周龄时，测量各组大鼠体重后，采集大鼠血液及肝脏组织标本，检测各组大鼠血清空腹总胆固醇（TC）、甘油三酯（TG）、游离脂肪酸（FFA）、血糖（FPG）、胰岛素（FINS）和肝脏脂质水平，计算稳态模型评估胰岛素抵抗（HOMA-IR）和脂肪组织胰岛素抵抗（adipo-IR），观察肝脏组织病理切片，并采用实时荧光定量PCR法检测肝脏相关基因的相对表达水平。结果 13周龄时，各组大鼠体重比较差异无统计学意义（P=0.067）。各组间的FPG、FFA、FINS、HOMA-IR和adipo-IR水平比较差异均有统计学意义（P < 0.05）。各组间的血清TC和TG水平比较差异无统计学意义（P > 0.05），但在肝脏中IUGR组TC和TG水平均明显高于EGCG组（P < 0.05）。油红染色结果提示，IUGR大鼠的肝脏脂肪储积明显增加，而EGCG能够改善该现象。PCR结果显示，与对照组相比，IUGR组的Ampk mRNA及Adipor1 mRNA表达水平降低，Srebf1 mRNA表达水平增加（P < 0.05），EGCG能逆转IUGR大鼠Ampk mRNA及Srebf1 mRNA的表达水平，且与对照组比较差异无统计学意义（P > 0.05）。结论 早期EGCG干预可能通过Ampk/Srebf1通路下调脂肪酸的从头合成，并通过改善肝细胞的胰岛素抵抗，从而降低IUGR大鼠的肝脏脂肪积累。     

金水宝片联合依诺肝素对维持性血液透析患者血脂代谢的影响

目的：探究金水宝片联合依诺肝素对维持性血液透析患者血脂代谢的影响。方法：选取2018年12月至2019年3月马鞍山十七冶医院血液净化中心进行透析的患者154例作为研究对象，根据用药不同分为对照组和观察组,每组77例。对照组常规应用依诺肝素抗凝，观察组在对照组抗凝基础上加用金水宝片，各组均干预3个月，比较2组患者血脂变化及持续血液透析并发症发生情况。结果：治疗后，观察组患者三酰甘油、总胆固醇及低密度脂蛋白胆固醇水平下降，高密度脂蛋白胆固醇升高，与治疗前比较差异均有统计学意义（P<0.05），与对照组治疗后比较，差异有统计学意义（P<0.05）；观察组总并发症发生率明显低于对照组，2组比较差异有统计学意义（P<0.05）；2组患者维持性血液透析不良反应发生率均较低，组间比较差异无统计学意义（P>0.05）。结论：金水宝片联合依诺肝素有助于改善维持性血液透析患者血脂代谢水平，降低维持性血液透析相关并发症，值得临床推广应用。