Dual activity of aminoarylthiazoles on the trafficking and gating defects of the cystic fibrosis transmembrane conductance regulator chloride channel caused by cystic fibrosis mutations

A large fraction of mutations causing cystic fibrosis impair the function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel by causing reduced channel activity (gating defect) and/or impaired exit from the endoplasmic reticulum (trafficking defect). Such defects need to be treated with separate pharmacological compounds termed potentiators and correctors, respectively. Here, we report the characterization of aminoarylthiazoles (AATs) as compounds having dual activity. Cells expressing mutant CFTR were studied with functional assays (fluorescence-based halide transport and short circuit current measurements) to assess the effect of acute and chronic treatment with compounds. We found that AATs are effective on F508del, the most frequent cystic fibrosis mutation, which is associated with both a gating and a trafficking defect. AATs are also effective on mutations like G1349D and G551D, which cause only a gating defect. Evaluation of a panel of AAT analogs identified EN277I as the most effective compound. Incubation of cells expressing mutant CFTR with EN277I caused a strong stimulation of channel activity as demonstrated by single channel recordings. Compounds with dual activity such as AATs may be useful for the development of effective drugs for the treatment of cystic fibrosis.     

药物依赖临床治疗的研究新进展

随着吸毒人员的剧增,药物依赖极大的危害着人类健康和社会稳定,已经成为目前严重的社会性问题。心瘾是患者复吸的重要原因,心瘾的戒断是治疗成瘾的关键。供临床医生选择的治疗方法有很多,但是根据成瘾者的病情合理的选择治疗措施是目前临床工作中面临的巨大挑战。本文综述了目前物质依赖的药物治疗的作用机制以及临床疗效、各种手术戒毒的效果以及不良反应、心理行为治疗的原因以及具体措施,药物治疗、手术治疗以及中西医联合治疗的最新进展。     

Redox regulation of pro-inflammatory cytokines and IkappaB-alpha/NF-kappaB nuclear translocation and activation

Reduction-oxidation (redox) state constitutes such a potential signaling mechanism for the regulation of an inflammatory signal associated with oxidative stress. Exposure of alveolar epithelial cells to ascending DeltapO(2) regimen+/-reactive oxygen species (ROS)-generating systems induced a dose-dependent release of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. Similarly, the Escherichia coli-derived lipopolysaccharide-endotoxin (LPS) up-regulated cytokine biosynthesis in a dose- and time-dependent manner. Irreversible inhibition of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), by L-buthionine-(S,R)-sulfoximine (BSO), induced the accumulation of ROS and augmented DeltapO(2) and LPS-mediated release of cytokines. Analysis of the molecular mechanism implicated revealed an inhibitory-kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF-kappaB)-independent pathway in mediating redox-dependent regulation of inflammatory cytokines. BSO stabilized cytosolic IkappaB-alpha and down-regulated its phosphorylation, thereby blockading NF-kappaB activation, yet it augmented cytokine secretion. Glutathione depletion is associated with the augmentation of oxidative stress-mediated inflammatory state in a ROS-dependent mechanism and the IkappaB-alpha/NF-kappaB pathway is redox-sensitive but differentially involved in regulating redox-dependent regulation of cytokines.     

乳杆菌阴道泡腾片与甲硝唑治疗细菌性阴道炎的疗效比较

目的观察乳杆菌阴道泡腾片治疗细菌性阴道炎的疗效。方法采用双盲、随机对照的方法,在4家医院的妇产科门诊将232例患者分成试验组(n=116)和对照组(n=116)。试验组用药为乳杆菌阴道泡腾片、对照组用药为甲硝唑阴道泡腾片,阴道放置,每晚1片,疗程7 d。治疗前后分别进行临床症状评分、测阴道分泌物pH、做线索细胞和胺试验检查,进行总有效率评定。结果经2种药物治疗后所有患者临床症状均明显减轻,治疗前后自身比较差异有显著性(P<0.01);80%以上的患者呈现线索细胞转(-)、胺试验转(-),超过一半的患者阴道分泌物pH低于4.5;临床治疗总有效率分别为74.78%和83.33%。2种药物组间比较治疗效果差异无显著性(P>0.05)。结论阴道补充乳杆菌与使用甲硝唑治疗产生了相似的效果,有可能成为新的治疗细菌性阴道炎的方法。     

SCN1AIVS5-91G>A polymorphism is associated with susceptibility to epilepsy but not with drug responsiveness

Sodium channel alpha subunit type 1 (SCN1A) is voltage gated ion channel which plays critical role in membrane excitability. A common SCN1A IVS5-91G>A (rs3812718) allele has been attributed to be a possible modifying factor for epilepsy susceptibility and therapeutic response. In the present study, we enrolled 485 epilepsy patients and 298 age-sex matched controls free of neurological deficits. Therapeutic response of carbamazepine/oxcarbamazepine (CBZ/OXC) and other antiepileptic drugs were observed in terms of drug responsiveness and drug resistance. Genotyping of SCN1A IVS5-91G>A is done by Taqman custom designed assay; in a real time7500HT System. We observe highly significant association [(P-values for GA (P = 6.58 × 10⁻⁵, OR = 2.13, 95% CI = 1.47–3.09) and AA (P = 4.11 × 10⁻⁹, OR = 3.59, 95% CI = 2.35–5.50)] at variant genotypes as well as A allele (P = 6.92 × 10⁻¹¹), OR = 1.99, 95%, CI = 1.62–2.45) in epilepsy patients versus control subjects. The relative risk for epilepsy susceptibility due to variant containing genotypes (GA + AA) was also significant (P = 1.64 × 10⁻⁵; OR = 2.56; 95% CI = 1.80–3.65) when compared with homozygous wild-type GG. The risk in recessive model (P = 1.34 × 10⁻⁵; OR = 2.12; 95% CI = 1.51–2.97) was also apparent when compared with GA + GG. In case-only analysis, we evaluated the effect of SCN1A IVS5-91G>A polymorphism with drug resistance of anti-epileptic drug therapies. However, we did not observe significant associations either with patients showing drug resistance to CBZ/OXC monotherapy or polytherapy. In conclusion, we report that SCN1AIVS5-91G>A polymorphism is associated with epilepsy susceptibility but not with drug responsiveness in epilepsy patients from North India.