Recent advancement in the discovery and development of COX-2 inhibitors: Insight into biological activities and SAR studies (2008–2019)

Cyclooxygenase-2 is a very important physiological enzyme playing key roles in various biological functions especially in the mechanism of pain and inflammation, among other roles, making it a molecule of high interest to the pharmaceutical community as a target. COX 2 enzyme is induced only during inflammatory processes or cancer and reflects no role in the guarding stomach lining. Thus, selective COX-2 inhibition can significantly reduce the adverse effects including GI tract damage and hepatotoxic effects of traditional NSAIDs like aspirin, ibuprofen, etc. Recent developments on COX-2 inhibitors is primarily focused on improving the selectivity index of the drug towards COX-2 along with enhancing the potency of the drug by modifying the scaffolds of Coxibs currently in the market like Celecoxib, Indomethacin, Oxaprozin, etc. We have reported the progress on new COX-2 inhibitors in the last decade (2008–2019) focussing on five heterocyclic rings- Pyrazole, Indole, Oxazole, Pyridine and Pyrrole. The addition of various moieties to these core rings and their structure-activity relationship along with their molecular modelling data have been explored in the article. This review aims to aid medicinal chemists in the design and discovery of better COX-2 inhibitors constructed on these five heterocyclic pharmacophores.     

Inhibition of BAP31 expression inhibits cervical cancer progression by suppressing metastasis and inducing intrinsic and extrinsic apoptosis

Cervical cancer is reported as one of the most lethal types of cancer among female. However, extensive studies of the molecular mechanisms that regulate the progression of cervical cancer are still required. B-cell associated protein (BAP)-31 is a 28-kDa integral membrane protein in the endoplasmic reticulum (ER), playing essential role in modulating various physiological processes. The present study indicated that BAP31 was a novel gene associated with cervical cancer development. Here, we demonstrated that BAP31 was significantly increased in human cervical cancer specimens, which was positively correlated to histological grade of the cancer. BAP31 knockdown suppressed cell proliferation, clonogenic ability and metastasis-associated traits in vitro, as well as carcinogenesis and pulmonary metastasis in vivo. Further studies indicated that the expression levels of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, MMP-9, Rho-associated protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA), Vimentin and N-cadherin were markedly reduced by BAP31 knockdown in cervical cancer cells. In addition, intrinsic and extrinsic apoptosis was significantly induced in BAP31 knockdown cells, as evidenced by the increased expression of cleaved Caspase-8/-9/-3 and poly (ADP-ribose) polymerases (PARP). Notably, suppressing the activities of Caspase-8/-9 and ?3 obviously diminished BAP31 silence-triggered apoptosis. Together, these findings highlighted an essential role for BAP31 in the modulation of tumorigenesis and metastatic potential of cervical cancer, and demonstrated a promising application of BAP31 in cancer prevention.     

Optimization of compressive loading parameters to mimic in vivo cervical spine kinematics in vitro

The human cervical spine supports substantial compressive load in vivo. However, the traditional in vitro testing methods rarely include compressive loads, especially in investigations of multi-segment cervical spine constructs. Previously, a systematic comparison was performed between the standard pure moment with no compressive loading and published compressive loading techniques (follower load – FL, axial load – AL, and combined load – CL). The systematic comparison was structured a priori using a statistical design of experiments and the desirability function approach, which was chosen based on the goal of determining the optimal compressive loading parameters necessary to mimic the segmental contribution patterns exhibited in vivo. The optimized set of compressive loading parameters resulted in in vitro segmental rotations that were within one standard deviation and 10% of average percent error of the in vivo mean throughout the entire motion path. As hypothesized, the values for the optimized independent variables of FL and AL varied dynamically throughout the motion path. FL was not necessary at the extremes of the flexion–extension (FE) motion path but peaked through the neutral position, whereas, a large negative value of AL was necessary in extension and increased linearly to a large positive value in flexion. Although further validation is required, the long-term goal is to develop a “physiologic” in vitro testing method, which will be valuable for evaluating adjacent segment effect following spinal fusion surgery, disc arthroplasty instrumentation testing and design, as well as mechanobiology experiments where correct kinematics and arthrokinematics are critical.     

子宫颈癌放疗的康复护理

目的：探讨子宫颈癌放射治疗的康复护理方法。方法：采用科普宣传、康复期指导、放射治疗前康复指导、并发症护理和出院后康复指导等方法对放射治疗的患者进行护理。结果：科学的康复护理使患者均能耐受高剂量放射治疗,提高了患者的生存质量,5年生存率明显提高。结论：科学护理是宫颈癌患者放射治疗期和康复期的重要手段。     

青藤碱抑制人宫颈癌的研究

目的：研究青藤碱（sinomenine,SIN）对宫颈癌Hela细胞增殖的影响及其机制,为SIN在宫颈癌的预防和治疗上提供实验依据。方法：不同浓度SIN分别处理体外培养的人宫颈癌细胞系Hela细胞后,采用噻唑蓝（Mar）法检测处理24h、48h、72h后Hela细胞的增殖活性,流式细胞仪测定细胞周期和细胞凋亡。结果：1．0．1、0．2、0．4、0．625、1．25、2．5mmml／L SIN处理Hela细胞24h、48h、72h后,细胞增殖明显受到抑制,呈时间和剂量依赖性特点;2．流式细胞仪细胞周期分析表明,SIN处理组G1期细胞比例明显增加,S期细胞比例明显减少,两组比较有统计学意义;3．细胞凋亡分析表明,SIN处理组细胞凋亡率较对照组升高,呈时间和剂量依赖性特点;结论：SIN在体外能有效抑制宫颈癌细胞生长,其机制可能与其阻滞细胞周期、诱导细胞凋亡有关,SIN有望应用于宫颈癌的辅助治疗。     

显微镜下减压联合前路Zero-P治疗颈椎病的早期临床疗效分析

目的:探讨前路颈椎显微镜辅助下精准减压联合前路椎间隙Zero-P融合器置入治疗颈椎病的早期临床疗效。方法:回顾性分析2016年6月至2018年1月我院收治的43例颈椎病患者,处理节段共73个;患者均行显微镜辅助颈椎前路减压、髓核切除、Zero-P置入融合内固定术。记录患者手术节段、手术时间,术中失血量及并发症。手术前,术后1个月、3个月、6个月、末次随访时的颈部及上肢疼痛视觉模拟评分(Visual Analogue Scale,VAS)、颈部日本骨科协会评分(Japanese Orthopedic Association,JOA)和颈椎残障功能指数(Neck Disability Index,NDI),并采用配对t检验对不同时间点的评分进行分析,评估临床疗效。并同期行颈椎X线、CT及MRI检查,测量和评估椎间隙高度、颈椎Cobb角的改变情况和邻近节段异位骨化形成(Adjacent Level Ossification Development,ALOD)。结果:所有患者术后均获得随访,随访时间12-18个月,平均(14.9±2.2)个月。平均手术时间(82.2±20.9)min,失血量(91.5±33.7) m L;未发生神经和血管损伤等严重并发症。与术前相比,患者术后1个月、3个月、6个月及末次随访时的VAS评分、JOA评分、NDI评分、椎间隙高度及Cobb角均明显改善,差异有统计学意义(P0.05)。但术后随访时间点比较,差异无统计学意义(P0.05)。术后出现轻度吞咽困难2例,中度和重度吞咽困难各1例。随访期间,所有患者均获椎间骨性融合,未发生Zero-P融合器松动、滑脱或断裂,椎体未出现继发性骨折。结论:显微镜辅助颈椎前路椎间盘切除、Zero-P融合器置入治疗颈椎病,能够精准的去除神经脊髓组织的压迫,术后短期和中期临床疗效良好,同时显微镜下止血、术中出血少;视野清晰、手术安全性高。     

早期子宫颈恶性肿瘤腹腔镜手术中两种示踪剂前哨淋巴结活检结果的对比分析

目的:通过在早期子宫颈恶性肿瘤患者中应用吲哚箐绿(ICG)及纳米炭混悬液为示踪剂行腹腔镜下前哨淋巴结(sentinel lymph node,SLN)切除术,对比两种示踪剂的示踪效果,寻找临床更适宜普遍使用的示踪剂。方法:选取仁济医院妇瘤科2016.8～2019.10期间诊断明确的122例早期子宫颈恶性肿瘤患者为研究对象。随机采用ICG或纳米炭为前哨示踪剂。对两种示踪剂的显影情况和SLN的示踪效果进行分析。结果:在122例子宫颈恶性肿瘤病例中,宫颈注射ICG64例,检出SLN385枚,平均每个患者检出6.02枚SLN,检出率100%(64/64),特异度96.77%,敏感度75%。宫颈注射纳米炭混悬液58例,检出SLN265枚,平均每个患者检出4.57枚SLN,检出率96.9%(56/58),特异度96.36%,敏感度66.67%。两种示踪剂都有较好的示踪效果(P=0.9356)。结论:早期子宫颈恶性肿瘤行宫颈注射ICG或纳米炭混悬液,腹腔镜下显影的SLN均具有较高的检出率与准确率,是一种较为可行的方法,可普遍开展,值得推广。     

宫颈癌患者新辅助化疗前后miR-138的表达及与化疗敏感性的关系研究

目的:研究宫颈癌患者新辅助化疗前后微小RNA-138(mi R-138)的表达及与化疗敏感性的关系。方法:选取2016年2月至2018年7月我院收治的宫颈癌患者18例为研究对象。所有患者均给予新辅助化疗,并根据治疗后的效果分为化疗有效组与化疗无效组。采用微阵列芯片技术分别检测两组患者化疗前后的mi R-138表达水平,同时采用Western blot技术检测mi R-138基因靶蛋白γH2AX的表达情况,分析患者化疗后mi R-138表达水平与临床病理特征的关系。结果:化疗有效组化疗后mi R-138△Ct值明显低于化疗前,且明显低于化疗无效组(P0.05),而化疗无效组化疗后mi R-138△Ct值与化疗前比较差异无统计学意义(P0.05)。化疗后两组靶蛋白γH2AX相对表达量均明显低于化疗前(P0.05),化疗有效组靶蛋白γH2AX相对表达量的差值显著低于化疗无效组(P0.05)。宫颈癌患者新辅助化疗后组织中mi R-138△Ct差值与肿瘤分化程度、浸润深度和淋巴结转移密切相关(P0.05),与年龄、FIGO临床分期无关(P0.05)。结论:新辅助化疗可以改变宫颈癌患者的mi R-138表达水平,且mi R-138的表达水平可能与化疗药物敏感性密切相关。     

加味二妙颗粒联合重组人干扰素a2b阴道泡腾胶囊治疗宫颈上皮内瘤变的疗效及对患者免疫功能的影响

目的:探讨加味二妙颗粒联合重组人干扰素a2b阴道泡腾胶囊治疗宫颈上皮内瘤变的疗效及对患者免疫功能的影响。方法:将西北妇女儿童医院妇科门诊自2018年1月至2019年1月收治的确诊为宫颈上皮内瘤变患者300例作为研究对象,将其随机的分为研究组和对照组,每组各150例。研究组患者给予加味二妙颗粒联合重组人干扰素a2b阴道泡腾胶囊进行治疗,对照组患者给予重组人干扰素a2b阴道泡腾胶囊进行治疗,比较两组患者治疗后的临床总有效率,治疗前后CD3~+、CD4~+、CD8~+、NK细胞水平和中医证候评分的变化及不良反应的发生情况。结果:治疗后,研究组临床总有效率为91.33%,明显高于对照组(74.67%,P0.05)。两组治疗后CD3~+、CD4~+、CD8~+、NK细胞水平均较治疗前明显升高,且研究组以上指标显著高于对照组(P0.05)。研究组治疗后中医证候评分降低程度明显优于对照组,其不良反应发生率为10.00%,明显低于对照组(28.67%,P0.05)。结论:与单用重组人干扰素a2b阴道泡腾胶囊治疗相比,加味二妙颗粒联合使用重组人干扰素a2b阴道泡腾胶囊治疗宫颈上皮内瘤变患者可显著提高患者的免疫功能,缓解症状,提高治疗效果,且安全性更高。     

加速康复外科理念在根治性子宫切除术患者中的应用研究

目的:探讨加速康复外科理念对行根治性子宫切除术的宫颈癌患者的围手术期应用价值。方法:选取2013年1月至2018年7月在我院行因宫颈癌行根治性子宫切除术的66例患者作为研究对象。将入院患者随机分为观察组及对照组,观察组接受加速康复外科理念治疗(30例),对照组为常规治疗组(36例)。比较两组患者的肠鸣音恢复时间、肛门排气时间、下床行走时间、术后住院时间以及术后并发症的发生情况。结果:观察组与对照组肠鸣音恢复时间分别为(35.9±3.4)h及(39.6±3.0)h,术后首次排气时间分别为(50.7±2.7)h及(54.8±3.2)h,下床行走时间分别为(49.9±2.6)h及(53.6±3.2)h。术后住院时间分别为(7.6±1.7)d及(9.2±1.8)d,观察组以上指标均显著短于对照组(P0.01)。观察组与对照组的术后并发症总发生率分别为10.11%及23.44%,观察组显著低于对照组(P0.05)。两组拔除尿管后尿潴留的发生情况比较差异无统计学意义(P0.05)。结论:加速康复外科理念用于宫颈癌根治术患者的围手术期可有效加速患者的康复,且安全性较高。