Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice

Fatty acid amide hydrolase (FAAH) is the primary degradative enzyme of the endocannabinoid anandamide (N-arachidonoylethanolamine), which activates cannabinoid CB₁ and CB₂ receptors. FAAH disruption reduces nociception in a variety of acute rodent models of inflammatory pain. The present study investigated whether these actions extend to the chronic, collagen-induced arthritis (CIA) model. We investigated the anti-arthritic and anti-hyperalgesic effects of genetic deletion or pharmacological inhibition of FAAH in the CIA model. FAAH (−/−) mice, and FAAH-NS mice that express FAAH exclusively in nervous tissue, displayed decreased severity of CIA and associated hyperalgesia. These phenotypic anti-arthritic effects were prevented by repeated daily injections of the CB₂ receptor antagonist, SR144528, but not the CB₁ receptor antagonist rimonabant. Similarly, repeated administration of the FAAH inhibitor URB597 reduced CIA severity, and acute administration of rimonabant, but not SR144528, blocked the anti-hyperalgesic effects of prolonged FAAH inhibition, suggesting that prolonged CB₂ receptor activation reduces the severity of CIA, whereas acute CB₁ receptor activation reduces CIA-induced hyperalgesia. In contrast, acute administration of URB597 elicited a CB₁ receptor-dependent anti-hyperalgesic effect. The observed anti-arthritic and anti-hyperalgesic properties of FAAH inhibition, coupled with a lack of apparent behavioral alterations, suggest that endocannabinoid modulating enzymes offer a promising therapeutic target for the development of novel pharmacological approaches to treat rheumatoid arthritis and associated hyperalgesia.     

肺动脉血栓内膜剥脱术治疗慢性栓塞性肺动脉高压

目的:分析肺动脉血栓内膜剥脱术治疗慢性栓塞性肺动脉高压的疗效.方法:回顾性分析1994年3月～2005年6月,共进行134例肺动脉血栓内膜剥脱术,手术采用深低温间断停循环的方法进行.结果:总手术死亡率为9.7%,呈逐年下降(2004年为4.5%).主要死亡原因为气道出血、右心功能衰竭、败血症.再灌注肺水肿23例(17.2%),死亡1例.手术后平均肺动脉压力、平均动脉血氧分压、平均动脉血氧饱和度、平均肺血管阻力(PVR)、心脏指数(CI)均较术前改善,有显著统计学差异(P<0.01).92%的患者术后随访,最长10年.术后3月、1年、3年的生存率分别为(89.5±2.6)%,(87.8±2.9)%和(83.3±3.5)%.3年术后随访94%的患者心功能达到NYHA Ⅰ～Ⅱ级.结论:肺动脉血栓内膜剥脱术是治疗慢性栓塞性肺动脉高压有效治疗手段.合理的手术适应证、外科技术和围手术期处理是成功的关键.     

Epigalocatechin-3-gallate (EGCG) downregulates PEA15 and thereby augments TRAIL-mediated apoptosis in malignant glioma

EGCG is a flavonoid that exhibited therapeutic activity in cancer. In this study three glioblastoma cell lines (U87, A172 and U251) were treated with EGCG, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Treatment with subtoxic doses of EGCG in combination with TRAIL induces rapid apoptosis in TRAIL-resistant glioma cells, suggesting that this combined treatment may offer an attractive strategy for treating gliomas. EGCG treatment down-regulated phosphoprotein-enriched in astrocytes (PEA15) through an Akt (PKB)-dependent mechanism. In addition, over-expression of PEA15 attenuated cytotoxicity induced by the combination of EGCG and TRAIL. In summary, PEA15 is a key regulator in TRAIL-EGCG-mediated cell death in malignant glioma.     

免疫毒素抗膀胱癌的实验与初步临床应用

目的:探讨抗人膀胱癌单克隆抗体绿脓杆菌外毒素(BDI-1-PEA)对膀胱癌细胞的特异杀伤作用。方法:应用四甲基偶氮唑盐(MTT)法检测10-10～10^-7mol/L浓度下的BDI-1-PEA、抗人膀胱癌单克隆抗体(BDI-1)、BDI-1和绿脓杆菌外毒素(PEA)的混合物(PEA+BDI-1)对体外癌细胞的杀伤能力。接种于裸鼠背部皮下的癌细胞长至直径0.3cm大小实体瘤时,随机分三组,每组10只裸鼠,于尾静脉隔日分别注入100倍半致死剂量浓度(1×10^-7mol/L)的BDI-1-PEA100μl及相同剂量的BDI-1、正常小鼠IgG共6次,观察不同的药物对癌的抑制作用。24例膀胱移行细胞癌术后患者应用100倍半细胞致死剂量浓度(1×10^-7mol/L)50mlBDI-1-PEA进行了膀胱灌注治疗,每周2次,共8次。每3个月复查膀胱镜或B超。结果:BDI-1-PEA抗膀胱癌细胞系E-J的作用明显优于单抗及毒素与单抗的混合物(P<0.01),与对非靶细胞肾肿瘤细胞系786-0的细胞毒性作用相比较差异非常显著。24例膀胱移行细胞癌术后患者,用药后随访7～22个月,平均15个月,2例患者复发。结论:BDI-1-PEA对膀胱癌细胞具有特异杀伤作用,对预防膀胱癌术后复发有较好疗效。     

Levels of N-acylethanolamines in O,O,S-trimethylphosphorothioate (OOS-TMP)-treated C57BL/6J mice and potential anti-obesity, anti-diabetic effects of OOS-TMP in hyperphagia and hyperglycemia mouse models

O,O,S-Trimethylphosphorothioate (OOS-TMP) has been shown to induce hypophagia and hypopraxia. Recent studies suggest that OOS-TMP-induced anorexia is partly mediated by its effect on the central nervous system. In this study, we examined the profiles of N-acylethanolamines (NEAs), including five amide-linked compounds, in the gastrointestinal system in C57BL/6J (B6) mice. The present results shown an orexigenic profile of the levels of NEAs with downregulation of the anorectic lipid, N-stearoylethanolamine (SEA), upregulation of the orexigenic lipid, 2-arachidonoyl glycerol (2-AG), at 2 h and upregulation of 2-AG at 24 h albeit with significant anorexia. However, the data indicated that the high level of 2-AG may be responsible for the hypopraxia. We next explored whether OOS-TMP may affect two models of hyperphagia and hyperglycemia, ins2^+/Akita B6 (Akita) and B6-lepr^db/lepr^db mice (db/db). We identified potential anorexigenic effects in B6, Akita and db/db mice. Moreover, OOS-TMP was found to reduce blood glucose in Akita mice but not in db/db mice. Collectively, these findings suggest that N-acylethanolamines are not involved in the hypophagia but rather hypopraxia, and may play multiple physiological roles in this process. OOS-TMP might be a promising candidate for anti-obesity and anti-diabetic drug development.