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101.
Xu-Dong Kong Shuguang Yuan Lin Li She Chen Jian-He Xu Jiahai Zhou 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(44):15717-15722
Optically pure epoxides are essential chiral precursors for the production of (S)-propranolol, (S)-alprenolol, and other β-adrenergic receptor blocking drugs. Although the enzymatic production of these bulky epoxides has proven difficult, here we report a method to effectively improve the activity of BmEH, an epoxide hydrolase from Bacillus megaterium ECU1001 toward α-naphthyl glycidyl ether, the precursor of (S)-propranolol, by eliminating the steric hindrance near the potential product-release site. Using X-ray crystallography, mass spectrum, and molecular dynamics calculations, we have identified an active tunnel for substrate access and product release of this enzyme. The crystal structures revealed that there is an independent product-release site in BmEH that was not included in other reported epoxide hydrolase structures. By alanine scanning, two mutants, F128A and M145A, targeted to expand the potential product-release site displayed 42 and 25 times higher activities toward α-naphthyl glycidyl ether than the wild-type enzyme, respectively. These results show great promise for structure-based rational design in improving the catalytic efficiency of industrial enzymes for bulky substrates.Optically pure epoxides and the corresponding vicinal diols are valuable chiral building blocks for the production of pharmaceutically active compounds and other fine chemicals (1). Existing approaches for preparing enantiopure epoxides and diols include the asymmetric epoxidation or dihydroxylation of olefin substrates and the resolution of racemic epoxides. These reactions can be accomplished with either chemical catalysts such as chiral salen cobalt complexes and porphyrin manganese adducts or biocatalysts such as monooxygenases and epoxide hydrolases (EHs) (2–4). In the past two decades, EHs have received much attention because they are cofactor-independent enzymes that are “easy to use” for catalyzing the hydrolysis of racemic epoxides to yield highly enantiopure epoxides and vicinal diols (1, 5, 6). However, application of EHs in laboratory and industry was often hindered by their narrow substrate scope, low enantioselectivity, and regioselectivity, or product inhibition (7, 8).Many protein-engineering efforts have been made to overcome these drawbacks (9, 10). For example, directed evolution by error-prone PCR or DNA shuffling has been used to enhance the activity and enantioselectivity of EHs (11–13). Structure-guided mutagenesis also generated a few EH variants with improved catalytic performance (14–16). The strategy of iterative Combinatorial Active Site-Saturation Test (CAST) combines the rational approach and directed evolution to yield high-quality and small focused mutant libraries for screening EHs with better enantioselectivity (7, 17). By mutating residues at the substrate-binding site, the substrates of EHs have been expanded to include cyclic meso-epoxides, phenyl glycidyl ether (PGE) derivatives, and other styrene oxide-like analogs (18, 19). However, the catalytic efficiency of EH is still not satisfactory for bulky epoxide substrates including precursors of (S)-propranolol, (S)-alprenolol, and other β-adrenergic receptor blocking drugs (20, 21).In this work, we select BmEH, an EH cloned from Bacillus megaterium ECU1001, to expand its substrate scope for bulky pharmaco substrate α-naphthyl glycidyl ether (NGE). This enzyme is a potential industrial biocatalyst because it has unusual (R)-enantioselectivity and resolves ortho-substituted PGEs and para-nitrostyrene oxide with excellent enantiomeric ratios (E > 200) (22). We first identified the active tunnel of BmEH by solving its crystal structure complexed with a substrate analog phenoxyacetamide (POA) and analyzing the routes of substrate entry and product release by mass spectrum analysis. Alanine scanning experiments targeted to the potential product-release site of BmEH resulted in two variants, F128A and M145A, with efficient bioresolution abilities on NGE. Further kinetic measurements and structural analysis showed that M145A has much higher activity for the transition state intermediate formation, whereas both mutants exhibited expanded product-release site. The M145A BmEH variant has been successfully applied for the preparation of (S)-propranolol on a gram scale. The engineering of the potential product-release site described herein should have great promise for structure-based rational design of better industrial enzymes. 相似文献
102.
目的:分析我国已上市治疗用提取分离类和菌体制剂类产品存在的差距,明确努力方向。方法:基于我国已上市治疗用提取分离类和菌体制剂类产品批准数据进行统计分析和对比分析。结果:对我国已上市治疗用提取分离类产品中的血液制品和多组分生化药物以及菌体制剂类产品的批准数量、企业数量进行了梳理,并与FDA批准情况进行对比分析。结论:治疗用提取分离类和菌体制剂类产品都是早期的治疗用生物药物,血液制品目前仍发挥着重要的临床价值,但重复申报情况严重。多组分生化药物和菌体制剂重复申报情况很少,但在临床上应用很少。FDA批准的两类产品数量较少。 相似文献
103.
104.
105.
《The world journal of biological psychiatry》2013,14(2-2):231-238
When aripiprazole (ABILIFY®) received its approval in Germany for the treatment of schizophrenia, a hospital-based postmarketing surveillance study was initiated in order to gain further insights concerning safety and efficacy of the antipsychotic under real-life conditions. Efficacy was rated by using standard CGI, GAF, and SF-12 instruments, whereas safety was evaluated according to the reports on adverse effects. Data from 799 patients with schizophrenia from 122 psychiatric hospitals returned for evaluation. Eighty percent of the patients were treated for 4 weeks with 10–30 mg/day aripiprazole (mean modal dose 15 mg/day). Within the observation period significant improvements of CGI, GAF, and SF-12 ratings was observed. Aripiprazole was tolerated well by the patients. Most frequent adverse effects were insomnia, irritability, restlessness, nausea and vomiting, in general being moderate to mild and corresponding to the known tolerability profile of aripiprazole. The results demonstrate that the administration of aripiprazole can result in an improvement of the symptoms of schizophrenia within 4 weeks in a real-life hospital-based in- and outpatient setting. 相似文献
106.
Athanasios I. Zavras Gregory E. Rosenberg Jared D. Danielson Vassiliki M. Cartsos 《Journal of the American Dental Association (1939)》2013,144(9):1014-1021
BackgroundAccording to the U.S. Centers for Disease Control and Prevention, 48 percent of Americans (roughly 144 million people) used at least one prescribed medication in the preceding month; 11 percent used five or more. The authors describe the U.S. Food and Drug Administration's (FDA's) MedWatch program, the safety surveillance system for drugs and devices in the United States, and the dentist's role with regard to voluntary reporting of adverse effects (AEs). They also identify the most frequent AEs in the oral cavity as reported in the FDA Adverse Event Reporting System (FAERS).MethodsThe authors reviewed the literature regarding MedWatch, and they mined data in the FAERS public database for the 100 most commonly prescribed medications and their associated AEs.ResultsPharyngitis was the most common AE. Cough, dysgeusia and dysphagia also were common.ConclusionThe MedWatch program and its related databases contain useful information about AEs of pharmaceuticals and devices manifested in the oral cavity. Increased participation in the reporting of suspected adverse reactions will improve the national surveillance system and ultimately will protect patients' safety.Practical ImplicationsAs pharmaceutical consumption increases exponentially for a growing segment of the population, and as innovation in dental technology and devices flourishes, dentists have a distinct role in safeguarding patients' well-being. Promptly reporting AEs in the oral cavity improves quality of care and protects patients' well-being. 相似文献
107.
Tomoyuki Kono Toshiho Ohtsuki Naohisa Hosomi Ikuko Takeda Shiro Aoki Yoshimasa Sueda Kayoko Ishihara Takeshi Nakamura Takemori Yamawaki Masayasu Matsumoto 《Geriatrics & Gerontology International》2012,12(3):468-474
Aim: Although several studies have reported various causes of ischemic stroke in patients with cancer, only a few have evaluated the clinical relevance of ischemic stroke pathogenesis to cancer. The aim of the present study was to elucidate the clinical characteristics of cancer‐associated ischemic stroke. Methods: We evaluated 154 ischemic stroke patients without cancer and 57 ischemic stroke patients with cancer who had either received continuous treatment for cancer within 5 years before to the onset of ischemic stroke, or who had been diagnosed with cancer within 1 year after the onset of ischemic stroke. Cancer patients were grouped into “cancer‐associated ischemic stroke,” the “conventional ischemic stroke,” or “other.” Results: A total of 15 patients (26%) were classified into the cancer‐associated ischemic stroke in cancer patients. In univariate analysis of the cancer‐associated ischemic stroke and the others, there were significant differences in the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d ‐dimer, fibrin degradation product and hemoglobin. With multivariate regression analysis of those factors, the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d ‐dimer and fibrin degradation product remained as statistically independent factors, which were associated with cancer‐associated ischemic stroke (n = 111, χ2 = 67.21, P < 0.0001). Conclusion: In acute ischemic stroke, the cancer‐associated ischemic stroke is associated with elevated d ‐dimer and fibrin degradation products, even after controlling hypertension, hyperlipidemia and advanced cancer (clinical stage IV). Geriatr Gerontol Int 2012; 12: 468–474. 相似文献
108.
PurposeTo characterize the entire rat corneal nerve architecture, the changes that occur with aging, and its sensory, sympathetic, and parasympathetic fiber distribution.MethodsSprague-Dawley rats (aged 1 day to 2 years old) of both sexes were euthanized, and the whole corneas were immunostained with protein gene product 9.5 (PGP9.5). The specimens were double-labeled with antibodies against calcitonin gene-related peptide (CGRP) and substance P (SP) as sensory nerve markers, vasoactive intestinal peptide (VIP) as a parasympathetic nerve marker, and neuropeptide Y (NPY) and tyrosine hydroxylase (TH) as markers of sympathetic fibers. Relative nerve density positive for each antibody was assessed by computer-assisted image analysis.ResultsThick nerve trunks enter the cornea in the middle of the stroma and run towards the anterior stroma, subsequently dividing into smaller branches that penetrate upwards into the epithelium to form the subbasal nerve bundles. There was no significant difference in corneal innervation between sexes. CGRP and SP were the major sensory neuropeptides with 47.6% ± 3.5% and 34.9% ± 5.1%, respectively, of the total nerves. VIP was 18.4% ± 5.7%, and NPY and TH positive fibers took up 6.92% ± 2.66% and 2.92% ± 1.52%, respectively. Epithelial nerve density increased with age, reached full development at 5 weeks, and decreased at 120 weeks.ConclusionThis study provides a complete nerve architecture and content of components of sensory, parasympathetic, and sympathetic nerves in the rat cornea. The normal innervation pattern described here will provide an essential baseline for investigators who use the rat model for assessing corneal pathologies that involve nerve alterations. 相似文献
109.
Aron Lindqvist 《Journal of plastic surgery and hand surgery》2013,47(5):246-252
We describe the types of hand injury sustained from powered wood splitters. Information about all patients with such injuries treated at the Department of Hand Surgery, University Hospital, Uppsala, during the period 1995–2001 was collected from their records, and from written questionnaires and telephone interviews. Fourteen of the 131 patients found were below the age of 15. There was no change in the annual injury rate for inpatients. Wedge splitters caused 82% and screw splitters 18% of all injuries. The part of the hand most often injured by screw splitters was the metacarpus and by wedge splitters the index finger. Screw splitters caused palmar perforation, avulsion of the thumb, and shredding injuries. Traumatic amputation and devascularising injuries were also common. Hand injury from powered wood splitters is an important and continuing problem. Most injuries are caused by wedge splitters, injuries caused by screw splitters differ from those caused by wedge splitters. Preventive measures are needed and should include keeping children away from splitters. Further research to facilitate prevention is warranted. 相似文献
110.
Takeshi Wada Satoshi Gando Asumi Mizugaki Yuichiro Yanagida Subrina Jesmin Hiroyuki Yokota Masahiro Ieko 《Thrombosis research》2013