Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors

Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7–12 (series A), N,S-dimethyl-dihydropyrimidines 13–18 (series B), hydrazine derivatives of dihydropyrimidine 19–24 (series C), and tetrazolo dihydropyrimidine derivatives 25–30 (series D), were synthesized and evaluated for in vitro urease inhibitory activity. The series B–D were first time examined for urease inhibition. Series A and C were found to be significantly active with IC₅₀ values between 34.7–42.9 and 15.0–26.0 μM, respectively. The structure–activity relationship showed that the free S atom and hydrazine moiety are the key pharmacophores against urease enzyme. The kinetic studies of the active series A (7–12) and C (19–24) were carried out to determine their modes of inhibition and dissociation constants K_i. Compounds of series A (7–12) and series C (19–24) showed a mixed-type of inhibition with K_i values ranging between 15.76–25.66 and 14.63–29.42 μM, respectively. The molecular docking results showed that all the active compounds of both series have significant binding interactions with the active sites specially Ni-ion of the urease enzyme. Cytotoxicity of all series A–D was also evaluated against mammalian mouse fibroblast 3T3 cell lines, and no toxicity was observed in cellular model.     

牛蛙致病变形菌的鉴定及其敏感药物筛选

【目的】分离鉴定引起牛蛙(Rana catesbeiana)皮肤溃疡病症的致病菌,筛选抗菌药物。【方法】采用无菌解剖组织划线分离法分离致病菌,通过人工感染试验、菌体和菌落形态观察、API20E系统鉴定、16S r RNA基因序列分析,确定分离菌的致病性及分类地位,并对该菌进行药物敏感性试验。【结果】从患病濒死牛蛙体内分离细菌NWG20141026,通过形态特征观察、生理生化试验、API 20E系统鉴定和16S r RNA基因序列相似性分析,认为NWG20141026菌株为普通变形菌(Proteus vulgaris)。人工感染试验显示,NWG20141026菌株不仅可以通过皮肤伤口感染引起蛙体表溃疡溃烂病症,也可通过消化道感染引起蛙肠炎病。药敏实验结果表明,氟苯尼考、四环素、多西环素、萘啶酸、磺胺异噁唑、恩诺沙星、红霉素等7种药物对普通变形菌具有较好的抑杀菌作用。【结论】引起牛蛙(R.catesbeiana)皮肤溃疡病症的致病菌NWG20141026为普通变形菌(P.vulgaris),所患疾病命名为牛蛙变形菌病。普通变形菌对健康牛蛙具有较强致病性,氟苯尼考、四环素、多西环素、萘啶酸、磺胺异噁唑等5种药可作为防治牛蛙变形菌病的候选药物。     

尖吻蝮蛇凝血酶治疗消化性溃疡出血的有效性和安全性评价

目的:评价尖吻蝮蛇凝血酶治疗消化性溃疡出血的有效性和安全性。方法:选取2014年4月~2015年4月我院消化科收治的消化性溃疡出血患者100例为研究对象,根据病情程度分为轻度、中度和重度,将入选患者随机分为观察组和对照组,每组各50例。对照组在抑酸、消炎和保护胃黏膜等常规治疗基础上采用垂体后叶素止血,观察组在上述常规治疗基础上采用尖吻蝮蛇凝血酶止血,比较观察两组不同病情程度患者的临床疗效和有既往心脑血栓病史患者再次发生血栓的情况。结果:观察组中度、重度患者的疗效明显优于对照组中、重度患者,且差异有统计学意义(P0.05),观察组中有既往心脑血栓病史的患者无再次发生血栓。结论:尖吻蝮蛇凝血酶治疗消化性溃疡出血具有较好的疗效和安全性。     

胃大部切除术后消化性溃疡患者残胃癌危险因素分析及其干预措施

目的:探究消化性溃疡患者胃大部切除术后发生残胃癌的危险因素,并提出相应干预措施。方法:选取我院收治的行胃大部切除术治疗后的消化性溃疡患者180例作为研究对象,将其随机分为两组,每组90例。对照组给予常规干预,观察组给予综合干预,观察两组的干预效果,同时将发生残胃癌患者与未发生残胃癌患者各项资料进行对比,分析影响残胃癌发生的危险因素。结果:观察组中没有患者发生残胃癌,对照组中有10例患者发生残胃癌,发生率为11.11%,显著高于观察组(P0.05);两组患者在首次手术年龄、性别、HP感染上进行对比差异无统计学意义(P0.05);两组患者在首次手术吻合方式、首次手术溃疡位置上对比具有统计学意义(P0.05),残胃癌组组采用毕Ⅰ式2例,毕Ⅱ式7例,Roux-Y式1例;未发生残胃癌组采用毕Ⅰ式82例,毕Ⅱ式74例,Roux-Y式14例,残胃癌组首次手术溃疡位置以十二指肠球部为主,未发生残胃癌组以十二指肠球部、胃体部为主;Logistics回归分析结果证实首次手术吻合方式、首次手术溃疡位置属于残胃癌发生的主要危险因素。结论:术后残胃癌发生危险因素包括首次手术吻合方式、首次手术溃疡位置,同时相关并发症的发生同样会增加术后残胃癌发生风险,应加强引流管干预、并发症干预,并将此作为基础制定综合干预方案。     

奥美拉唑不同给药方式治疗新生儿应激性溃疡的效果分析

目的:探讨奥美拉唑不同给药方式治疗新生儿应激性溃疡的临床效果及安全性。方法:选取2014年1月～2018年6月我院收治的应激性溃疡新生儿61例,根据随机数字表法分为两组,对照组患儿给予奥美拉唑0.6 mg/kg胃管注入治疗,观察组患儿给予奥美拉唑2 mg/kg持续24 h微泵静脉滴注。比较两组患儿的临床治疗效果、临床症状缓解时间、止血时间、胃肠喂养开始时间、p H值和不良反应的发生情况。结果:治疗后,两组患儿的临床总有效率比较无统计学差异(P0.05);观察组患儿临床症状消失时间和止血时间均显著短于对照组(P0.05),喂养开始时间≤24 h的患儿比例高于对照组,喂养开始时间≥72 h的患儿比例显著低于对照组(P0.05),pH值显著高于对照组(P0.05)。两组患儿治疗期间均未发生恶心、呕吐、便秘、皮疹等不良反应,且肝肾功能未受明显影响。结论:2 mg/kg奥美拉唑持续24 h微泵静脉滴注与0.6 mg/kg胃管注入治疗的临床总有效率相当,但微泵静脉滴注可显著提高患儿的pH值,缩短临床症状恢复时间、止血时间和胃肠喂养开始时间,且安全性高。     

埃索美拉唑为基础的四联疗法对消化性溃疡患者幽门螺杆菌根除率、炎性因子及生活质量的影响

目的:探讨埃索美拉唑为基础的四联疗法对消化性溃疡(PU)患者幽门螺杆菌(Hp)根除率、炎性因子及生活质量的影响。方法:选取2016年3月～2018年11月间我院接收的117例PU患者,根据数表法将患者随机分为对照组(n=58)和研究组(n=59),对照组给予以奥美拉唑为基础的四联疗法治疗,研究组给予以埃索美拉唑为基础的四联疗法治疗,比较两组患者临床疗效、Hp根除率、炎性因子、生活质量及不良反应。结果:研究组治疗后总有效率为74.58%(44/59),高于对照组患者的53.45%(31/58)(P0.05)。两组患者治疗后白介素-6(IL-6)、超敏C反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α)较治疗前降低,且研究组低于对照组(P0.05)。研究组的HP根除率高于对照组(P0.05)。两组患者治疗后临床症状、心理情感、社交及任务完成评分均较治疗前升高,且研究组高于对照组(P0.05)。两组不良反应发生率比较无统计学差异(P0.05)。结论:埃索美拉唑为基础的四联疗法治疗PU,可有效改善炎性因子水平、Hp根除率和生活质量,疗效确切,安全性好,临床应用价值较高。     

Human α defensins promote the expression of the inflammatory cytokine interleukin‐8 under high‐glucose conditions: Novel insights into the poor healing of diabetic foot ulcers

Sustained infection and chronic inflammation are the most common features and complex mechanisms of diabetic foot disease. In this study, we examined the expression and functional roles of human endogenous α defensins in diabetic foot ulcer. The expression levels of human α defensins HNP1, HNP3, and HNP4 were significantly higher in the wound center than the edge of diabetic foot ulcers. And the inflammatory cytokine interleukin IL‐8 (IL‐8) was also highly expressed in wound exudates. In human foreskin fibroblasts, these human α defensins were found only slightly to affect IL‐8 expression directly. hemoglobin A1C (HbA1c) is the main clinical indicator of diabetic foot disease. Advanced glycation end products of bovine serum albumin (AGE‐BSA), as HbA1c analogue, was found to promote IL‐8 expression. Human α defensins, in the presence of AGE‐BSA, further significantly promoted IL‐8 expression. These findings showed that human α defensins aggravated the inflammatory response in diabetic foot ulcers patients, providing new insights in to the poor healing of diabetic foot ulcers.     

眼部真菌感染菌种分布特征

目的分析眼部真菌感染的致病情况和菌种分布特征。方法统计山东省眼科研究所2000～2005年间所有真菌感染病例的培养结果,按照感染部位分类并分析不同菌种的致病情况。结果6年间共有970份真菌培养资料,阳性结果691份,阳性率为71.2%(691/970)。其中角膜溃疡阳性率为86.2%(669/776),镰刀菌占73.2%(490/669);眼内炎阳性率为10.4%(19/182),曲霉菌占68.4%(13/19);泪囊炎阳性率为25.0%(3/12),念珠菌占100.0%(3/3)。结论不同的感染部位常见的真菌菌种不同,镰刀菌是真菌性角膜溃疡的主要致病菌,曲霉菌是真菌性眼内炎的主要致病菌,而念珠菌则是泪囊炎的主要致病菌。     

胃康胶囊联合兰索拉唑肠溶胶囊对胃溃疡患者胃肠激素、炎症反应和T淋巴细胞亚群的影响

摘要 目的：观察胃康胶囊联合兰索拉唑肠溶胶囊治疗胃溃疡的疗效及对胃肠激素、炎症反应和T淋巴细胞亚群的影响。方法：选择2018年9月~2021年5月在中国人民解放军31694部队医院消化内科接受治疗的80例胃溃疡患者作为观察对象,根据信封抽签法分为对照组和观察组,各为40例。对照组患者接受兰索拉唑肠溶胶囊治疗,观察组患者接受胃康胶囊联合兰索拉唑肠溶胶囊治疗,连续治疗6周。对比两组临床疗效、幽门螺杆菌（Hp）根除率和溃疡愈合率,观察治疗期间不良反应发生情况,对比两组治疗前、治疗6周后的胃肠激素、血清炎症因子和T淋巴细胞亚群指标水平的变化。结果：观察组的临床总有效率较对照组高（P<0.05）。观察组的Hp根除率和溃疡愈合率均高于对照组（P<0.05）。治疗6周后,两组CD3⁺、CD4⁺、CD4⁺/CD8⁺较治疗前升高,CD8⁺ 较治疗前下降,且观察组的改善效果优于对照组（P<0.05）。治疗6周后,两组胃动素（MTL）水平较治疗前升高,胃泌素（GAS）水平较治疗前下降,且观察组的改善效果优于对照组（P<0.05）。治疗6周后,两组高迁移率族蛋白B1（HMGB1）、白介素-6（IL-6）、C反应蛋白（CRP）水平较治疗前下降,且观察组的改善效果优于对照组（P<0.05）。两组不良反应发生率对比无统计学差异（P>0.05）。结论：兰索拉唑肠溶胶囊联合胃康胶囊可提高胃溃疡患者的溃疡愈合率和Hp根除率,其作用机制可能与调节胃肠激素、炎症反应和T淋巴细胞亚群指标水平有关。     

Virtual screening of active compounds from Artemisia argyi and potential targets against gastric ulcer based on Network pharmacology

Artemisia argyi (AA) is one of the renowned herbs in China often used in the treatment of gastric ulcer (GU). Aiming to predict the active compounds and systematically investigate the mechanisms of Artemisia argyi for GU treatment, the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, respectively, in present study. A total of 13 predicted targets of the 103 compounds in Artemisia argyi were obtained. Sorted by pathogenic mechanisms of targets and structure types of compounds, it was revealed that flavonoids and sesquiterpenes had better performance than monoterpenes. The network analysis showed that Phospholipase a2 (PA21B), Sulfotransferase family cytosolic 2b member 1 (ST2B1), Nitric-oxide synthase, endothelial (NOS3), Gastrin (GAST), neutrophil collagenase (MMP-8), Leukotriene A-4 hydrolase (LKHA4), Urease maturation factor HypB (HYPB), and Periplasmic serine endoprotease DegP (HtrA) were the key targets with intensely interaction. The functional enrichment analysis indicated that AA probably produced the gastric mucosa protection effects by synergistically regulating many biological pathways, such as NF-κB signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, and Toll-like receptor signaling pathway, etc. In addition, C73 and C15 might be promising leading compounds with good molecular docking score. As a consequence, this study holistically illuminates the active constituents and mechanisms based on data analysis, which contributes to searching for leading compounds and the development of new drugs for gastric ulcer.