Discovery of a highly specific 18F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination

As a member of cyclic nucleotide phosphodiesterase (PDE) enzyme family, PDE10A is in charge of the degradation of cyclic adenosine (cAMP) and guanosine monophosphates (cGMP). While PDE10A is primarily expressed in the medium spiny neurons of the striatum, it has been implicated in a variety of neurological disorders. Indeed, inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system (CNS) pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component. A PDE10A-targeted positron emission tomography (PET) radioligand would enable a better assessment of the pathophysiologic role of PDE10A, as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate, thus accelerating the development of effective PDE10A inhibitors. In this study, we designed and synthesized a novel ¹⁸F-aryl PDE10A PET radioligand, codenamed [¹⁸F]P10A-1910 ([¹⁸F]9), in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination. [¹⁸F]9 possessed good in vitro binding affinity (IC₅₀ = 2.1 nmol/L) and selectivity towards PDE10A. Further, [¹⁸F]9 exhibited reasonable lipophilicity (logD = 3.50) and brain permeability (P_app > 10 × 10⁻⁶ cm/s in MDCK-MDR1 cells). PET imaging studies of [¹⁸F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics. Preclinical studies in rodents revealed an improved plasma and brain stability of [¹⁸F]9 when compared to the current reference standard for PDE10A-targeted PET, [¹⁸F]MNI659. Further, dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of [¹⁸F]9 for evaluating target occupancy in vivo in higher species. In conclusion, our results indicated that [¹⁸F]9 is a promising PDE10A PET radioligand for clinical translation.KEY WORDS: Phosphodiesterase 10A, PET radioligand, ¹⁸F, Spirocyclic iodonium ylide, Nonhuman primate, Target occupancy     

Tei指数对高血压不同构型组心功能临床研究

目的评价心功能指标Tei指数在高血压患者各个不同构型组中的应用价值。方法对高血压组82例和正常对照组19例进行常规心脏超声、常规心脏收缩功能、心脏舒张功能指标及Tei指数测量。将原发性高血压划分为正常左室构型组Ⅰ、向心性重构组Ⅱ、向心性肥厚组Ⅲ、离心性肥厚组Ⅳ。结果(1)舒张功能:E/A值在Ⅰ、Ⅱ、Ⅲ组依次降低,Ⅳ组E/A反而增高,E/A>1。IVRT、EDT值高血压组各组间差异无显著意义。(2)收缩功能:EF、FS值在Ⅳ组才出现降低,SV和CO在Ⅰ和Ⅲ中无明显变化,Ⅱ减少,Ⅳ稍增加。(3)Tei指数高血压组较对照组皆增高,差异有显著意义。Ⅰ、Ⅱ、Ⅲ、Ⅳ组的Tei指数依次增高,除Ⅰ、Ⅱ组外,余各组之间差异有显著意义,Ⅳ组Tei值最高。结论Tei指数能早期发现反映整体功能的降低。这弥补了心脏舒张功能指标和收缩功能对高血压患者心功能评价的一些不足。     

Optimization of photo-biomodulation therapy for wound healing of diabetic foot ulcers in vitro and in vivo

Unclear optical parameters make photo-biomodulation (PBM) difficult to implement in diabetic foot ulcer (DFU) clinically. Here, 12 wavelengths (400–900 nm) were used to conduct PBM to heal DFU wounds in vitro and in vivo. PBM at 10 mW/cm² and 0.5–4 J/cm² with all 12 wavelengths promoted proliferation of diabetic wound cells. In a mimic DFU (mDFU) rat model, PBM (425, 630, 730, and 850 nm, and a combination light strategy) promoted mDFU healing. The positive cell proliferation, re-epithelialization, angiogenesis, collagen synthesis, and inflammation were possible mechanisms. The combination strategy had the best effect, which can be applied clinically.     

Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure

Programmed cell death(PCD),including apoptosis,apoptotic necrosis,and pyroptosis,is involved in various organ dysfunction syndromes.Recent studies have revealed that a substrate of caspase-3,gasdermin E(GSDME),functions as an effector for pyroptosis;however,few inhibitors have been reported to prevent pyroptosis mediated by GSDME.Here,we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD.Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity,exhibiting a lower IC50 than that of Z-DEVD-FMK.Functionally,Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3,preventing apoptotic and pyroptotic events in hepatocytes and macrophages.Furthermore,in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure,Ac-DMPD/DMLD-CMK significantly alleviated liver injury.Together,this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also,more importantly,shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD.     

姜黄素抗家兔慢性心力衰竭的机制研究

目的：观察姜黄素对家兔慢性心力衰竭的治疗作用并探讨其机制.方法：采用主动脉瓣返流联合腹主动脉缩窄制作慢性心力衰竭家兔模型,心衰和假手术动物均进一步分为姜黄素组和安慰剂组.10wk后行超声心动图测定心动能的指标,检测左室心肌肌浆网Ca^2＋-ATP酶的表达水平.结果：与假手术组相比,心衰组、心衰姜黄素组左室内径增大、室壁增厚,射血功能、心肌肌浆网Ca^2＋-ATP酶的表达水平降低（P〈0.05）;与心衰组相比,心衰姜黄素组左室内径、室壁厚度较小,射血分数、心肌肌浆网Ca^2＋-ATP酶的表达水平较高（P〈0.05）.结论：姜黄素可改善兔慢性心力衰竭模型的心功能,其机制可能与增加肌浆网Ca^2＋-ATP酶的表达有关.     

硬膜外阻滞在中期妊娠引产镇痛时机选择的临床观察

目的：比较硬膜外阻滞在中期妊娠引产不同时点开始镇痛的临床效果。方法选取我院60例因计划外妊娠或有胎儿畸形等妊娠合并症要求终止妊娠者,随机分为两组实施硬膜外阻滞,A组为病房常规处理后产妇有疼痛感即开始实施麻醉,B组为病房常规处理后有规律宫缩开始实施麻醉,每组30例;记录镇痛开始前及镇痛后生命体征、各时点孕妇的VAS评分和运动神经阻滞分级、引产时间、出血量及不良反应情况。结果与B组比较,A组在镇痛后各时点VAS评分降低、引产时间延长,差异均有统计学意义（P＜0.05）;两组间孕妇引产期间生命体征平稳,出血量及不良反应差异无统计学意义（P＞0.05）。结论中期妊娠引产无须考虑胎儿因素,早期实施麻醉镇痛干预更为合理,在不增加出血量和不良反应的基础上引产时间略有延长。     

2型糖尿病伴非酒精性脂肪肝与胰岛素抵抗及血脂异常的研究

目的:探讨2型糖尿病(T2DM)伴非酒精性脂肪肝(NAFLD)与胰岛素抵抗(IR)及血脂异常的关系。方法:随机选取T2DM患者68例,按是否并发NAFLD分为脂肪肝组38例和非脂肪肝组30例,测定两组患者的甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、空腹血糖(FPG)、餐后2h血糖(2hPG)、糖化血红蛋白(HbA1c)、空腹胰岛素(FIns)及餐后2h血浆胰岛素(2hIns),计算并比较两组之间的体重指数(BMI)、腰臀比(WHR)以及胰岛素抵抗指数(HOMA-IR)。同时检测肝功能。结果:脂肪肝组TG、LDL-C、Fins、2hIns、BMI、WHR、HOMA-IR、ALT、AST的平均水平均显著高于非脂肪肝组,而HDL-C则显著低于非脂肪肝组。两组FPG、2hPG及HbA1c水平则无显著差异。结论:T2DM伴NAFLD患者存在着明显的胰岛素抵抗及脂质代谢异常。     

液基细胞学结合阴道镜检查在北京市社区妇女宫颈病变筛查中的意义

目的探讨宫颈液基细胞学及阴道镜检查在北京市社区妇女宫颈病变筛查中的临床意义。方法2006年6月至2007年6月对北京市展览路社区的795位20～54岁有性生活的妇女进行筛查。筛查对象接受妇科检查时,留取宫颈超柏氏薄层液基细胞学检测标本,并对宫颈细胞学异常者行阴道镜检查及活组织检查。结果宫颈细胞学阳性[≥ASC-US（不能明确意义的不典型鳞状细胞）]45例,占5．7％（45／795）。其中ASC-US33例,占73．3％（33／45）;低度鳞状上皮内病变8例;高度鳞状上皮内病变3例;不典型腺细胞1例。细胞学阴性750例,占94．3％（750／795）。宫颈细胞学阳性的45例中,5例拒绝行阴道镜检查,占11．1％（5／45）。在行阴道镜活组织病理检查的40例中,慢性宫颈炎11例（27．5％）;宫颈湿疣14例（35．0％）;宫颈上皮内瘤样病变（CIN）1为7例（17．5％）;CIN2为3例（7．5％）;CIN3为4例（10．0％）;早期浸润癌1例（2．5％）。细胞学阴性的750例中,宫颈湿疣2例（0．3％）;CIN1为5例（0．7％）;宫颈低级别腺上皮内病变1例（0．1％）。宫颈液基细胞学筛查CIN1及以上宫颈病变和宫颈癌的敏感度71．4％,特异度94．2％,阳性预测值37．5％,阴性预测值99．2％;筛查CIN2及以上宫颈病变和宫颈癌的敏感度100．0％,特异度96．0％,阳性预测值20．5％,阴性预测值100．0％。结论应重视并及时进行北京市社区人群宫颈病变的早期筛查,薄层液基细胞学结合阴道镜活组织检查及病理学检查,对提高早期宫颈癌筛查的准确性效果明显。     

手术前动脉介入化疗对胃癌患者外周血淋巴细胞化学发光的影响

目的 :研究手术前动脉介入化疗对胃癌患者外周血淋巴细胞化学发光的影响。　方法 :选择 70例胃癌患者 ,分别在术前动脉介入化疗前和化疗后 1、3、5、7天抽取患者外周静脉血 ,分离淋巴细胞进行化学发光 (Ly CL)和细胞周期动力学检测 ,观察其化疗前、后的变化。　结果 :胃癌患者化疗后 2 4hLy CL迅速降低 (P <0 .0 1) ,最低值一般出现在化疗后 3～ 5天 ,然后逐渐上升 ,第 7天时基本恢复至化疗前的水平 (P >0 .0 5 )。同时淋巴细胞增生指数也有相同的变化 ,与Ly CL呈明显的正相关 (r =0 .6 1,P <0 .0 1)。　结论 :测定Ly CL强度变化可反映胃癌患者在术前动脉介入化疗过程中淋巴细胞免疫功能的变化 ,可作为患者免疫功能改变的动态观察指标 ,指导诊断和治疗。