The third-generation retinoid adapalene triggered DNA damage to induce S-phase arrest in HaCat cells

Epidermal proliferative diseases consisted of a series of common skin diseases, most of which were recurrent chronic skin diseases, and had greatly negative influence on the life quality of patient. Retinoids exhibited vital roles in the treatment of many skin diseases. Our recent study demonstrated that adapalene significantly inhibited the growth of HaCat cells, and the inhibitory activity was stronger than other retinoids, such as all-trans-retinoic acid, acitretin, isotretinoin, tazarotene, and bexarotene. Further study showed that adapalene suppressed the colony formation of HaCat cells, and it dramatically triggered S-phase arrest and apoptosis, rather than G1 phase arrest which was reported in other retinoids in several studies. Additionally, adapalene treatment greatly upregulated the protein expression of DNA damage marker γ-H2AX, which was in accord with the results of the elongation of tail moment by comet electrophoresis analysis. Moreover, DNA damage was triggered and DNA repair was suppressed synchronously with adapalene treatment, which accounted for the mechanism of S-phase arrest induced by adapalene. In summary, our recent work demonstrated that adapalene showed strong anti-proliferation activity in HaCat cells and could be an alternative agent for the epidermal proliferative disease.     

Increasing suction pressure during endotracheal suctioning increases the volume of suctioned secretions,but not procedure-related complications: A comparative study in open system endotracheal suctioning

ObjectivesTo compare the effect of three different suction pressures (80 mmHg, 150 mmHg, 250 mmHg) with the open system suction method in terms of the volume of secretions and complications development in intubated intensive care patients.Research methodology/designThis study was planned as a prospective, experimental, self-controlled design. The study sample included 47 patients. Data were collected using a data collection and patient follow-up form from patient records.SettingSingle adult intensive care unit in a university hospital.ResultsFifty five percent of the patients were male, 61.7% were older than 65 years and 38.32% had lung infection. The amount of suctioned secretions tended to increase significantly with increasing negative pressure and there was a significant difference between the pressures in terms of the median volume of suctioned secretions (p < 0.001). There was no significant difference between the suction pressures in terms of oxygen desaturation, hypertension rates (p > 0.05). Tachycardia, bradycardia, hypoxaemia, tracheal mucosal damage or mucosal bleeding were not observed during suctioning with three different suction pressures.ConclusionIt may be assumed that 250 mmHg suction pressure, via compliance with open system suction method related procedures, is being more effective and equally safe for secretion cleaning in comparison to the 80 and 150 mmHg suction pressures.     

联体尺动脉穿支皮瓣在多指毁损伤修复中的临床应用

目的探讨联体尺动脉穿支皮瓣修复多指毁损伤的临床效果。方法回顾性分析2011年3月至2017年10月东莞长安新安医院收治的12例多指毁损伤患者,男8例,女4例,年龄(32.6±4.3)岁,范围18~56岁。4指毁损伤2例,3指毁损伤4例,2指毁损伤6例。皮肤软组织损伤位置均为远掌横纹或指掌横纹以远,指骨为近节以远。皮肤总缺损面积(135.6±12.3)cm^2,范围6.0 cm×16.0 cm^6.0 cm×35.0 cm,应用皮瓣总面积(143.5±11.2)cm^2,范围5.0 cm×20.0 cm^3.2 cm×47.0 cm(双侧前臂)。双前臂尺动脉穿支皮瓣5例,单侧7例,所有皮瓣均为2条以上穿支蒂。皮瓣均设计为长条状,螺旋缠绕包裹于伤指骨,皮瓣穿支动脉与相应指固有动脉或掌背动脉吻合,伴行静脉与相应指掌侧静脉或掌背静脉吻合,皮瓣浅静脉与相应指背静脉或掌背静脉吻合,皮瓣神经与相应指固有神经或掌背相应感觉神经吻合。供区除1例植皮外,其余均直接缝合。术后随访观察疗效,包括感觉、外观、血液循环、骨吸收及手运动功能、日常生活、恢复工作情况等。评价标准为中华医学会手外科学会断指再植功能评定试用标准。结果所有皮瓣均成活,1例皮瓣末稍有约1.5 cm×1.5 cm坏死,二期缝合修复。所有病例均获6个月至6.5年随访,平均16.7个月,皮瓣质地良好,无色素沉着,外观无臃肿,指端无瘢痕或磨损,两点辨距觉6~10 mm,平均8.6 mm。术后半年骨吸收发生率59.4%(19/32),指短缩平均0.8 cm,其中5例6指取髂骨植骨。伤指拿捏及持物功能部分恢复,日常生活无明显影响;患手握力平均达到健侧的60.3%。参照断指再植功能评定试用标准:优2例,良5例,差4例,劣1例,优良率58.3%(7/12)。供区外观可。结论联体尺动脉穿支皮瓣为多指毁损或脱套伤患者的临床修复提供了一种有益的思路和有效的手术方案,效果良好。     

肥胖相关性高血压患者中心动脉压与靶器官损害相关性分析

【摘要】目的 探讨肥胖相关性高血压患者靶器管损害程度及中心动脉压（CBP）对靶器管损害的影响。方法 纳入徐州市中心医院2014年6月至2019年6月收住入院的高血压患者150例。根据高血压患者体质量指数，将样本分为正常体重高血压组（BMI<24Kg/m2）、超重高血压组(24 Kg/m2≤BMI<28 Kg/m2)、肥胖高血压组（BMI≥28 Kg/m2）。比较三组患者靶器管损害的差异及其与中心动脉压、24小时动态血压的相关性。结果 (1)与正常体重高血压组、超重高血压组比较，肥胖高血压组BMI、腰围、空腹血糖、同型半胱氨酸（HCY）、高密度脂蛋白（HDL-C）、低密度脂蛋白（LDL-c）、颈-股脉搏波传导速度(c-fPWV)、左心室质量（LVM）、左心室质量指数（LVMI）、尿微量白蛋白（mALB）较高（P<0.05）。(2)高血压患者c-fPWV与中心动脉脉压差（CPP）呈正相关（r=0.580，P=0.001）；LVMI与中心动脉收缩压（CSBP）呈正相关（r=0.279，P=0.004）；mALB与CSBP呈正相关（r=0.333，P=0.001）。结论 体重增加可进一步加重高血压患者靶器管损害，中心动脉压较24小时动态血压对高血压患者靶器管损害更为密切。     

探析新型冠状病毒肺炎的眼表损害及中西医治疗对策＊

新型冠状病毒肺炎（corona virus disease 2019，COVID-19）自2019年12月爆发以来，由于具有高传染性，迅速在世界各地蔓延，国内外疫情防治形势空前严峻。COVID-19不仅造成肺部、肠道、肾脏等多脏器损害，且部分患者以眼表损害为首发或伴发症状出现，临床上很容易被忽视。COVID-19的眼表损害归属于祖国医学“天行赤眼”范畴，本文结合国内外最新的文献报道，探讨新型冠状病毒（2019 novel corona virus，2019-nCoV）对眼表的损害，阐明其可能机制，并从中西医角度提出可行的治疗措施。     

黄芪甲苷调节PI3K/Akt/FoxO1通路抑制糖尿病大鼠肝糖异生

目的:探讨黄芪甲苷对2型糖尿病(T2DM)大鼠肝损伤保护潜在机制及肝组织磷酯酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/叉头框转录因子1(FoxO1),磷酸烯醇式丙酮酸羧基酶(PEPCK)和葡萄糖6-磷酸酶(G6Pase)蛋白表达的影响。方法:6周高糖高脂饮食后,链脲佐菌素(STZ)一次性腹腔注射(0.035 g·kg^-1)建立T2DM大鼠模型,随机分为正常组、模型组、黄芪甲苷低、中、高剂量组及二甲双胍组。黄芪甲苷低、中、高剂量组灌胃黄芪甲苷0.02,0.04,0.08 g·kg^-1·d^-1,二甲双胍组灌胃二甲双胍0.2 g·kg^-1·d^-1;给药8周后,于末次灌胃24 h禁食不禁水后处死,测血清肝生化指标,肝脏指数等;采用苏木素-伊红(HE)染色观察肝脏组织病理形态学变化;马松(Masson)染色观察纤维化程度;过碘酸希夫(PAS)染色反应观察细胞内糖原等变化;免疫组化及蛋白免疫印迹法(Western blot)检测各组肝中PI3K/Akt/FoxO1信号蛋白及PEPCK,G6Pase蛋白表达水平。结果:与正常组比较,模型组肝脏指数显著升高(P<0.01),肝功能指标丙氨酸氨基转移酶(ALT),天门冬氨酸氨基转移酶(AST),总胆固醇(TC),甘油三酯(TG)的含量显著升高(P<0.01),高密度脂蛋白胆固醇(HDL-C)显著降低(P<0.01),大鼠体质量显著减轻(P<0.01),PI3K/Akt/Fox O1信号减弱(P<0.01),PEPCK,G6Pase蛋白表达水平显著增强(P<0.01);与模型组比较,黄芪甲苷中、高剂量组及二甲双胍组肝功能指标ALT,AST,TC,TG的含量明显降低(P<0.05,P<0.01),大鼠体质量明显增加(P<0.05,P<0.01),肝组织Fox O1,PEPCK及G6Pase蛋白水平明显降低(P<0.05,P<0.01),Fox O1的磷酸化水平明显增强(P<0.05,P<0.01)。结论:黄芪甲苷可能通过调节PI3K/Akt/Fox O1信号通路抑制高脂高糖加小剂量STZ诱导T2DM肝糖异生,从而起到延缓T2DM大鼠肝脏损伤作用。     

电离辐射致肠道急性损伤的中医病机探讨

电离辐射所致的肠道急性损伤在临床普遍存在,轻者出现纳差、食欲不振、消化不良;重者出现持续的腹痛腹泻,常伴黏液、脓血,肛门坠痛、里急后重,甚至出现梗阻、糜烂、溃疡、穿孔等症。结合电离辐射的中医病因学特点,电离辐射致肠道急性损伤的中医基本病机为:邪盛伤正,气血乏源,虚实夹杂;升降失常,泌别失职,传导失司;“热”“湿”“毒”“瘀”蕴结,损伤血络;屏障缺失,易于恶化。据证立法,方从法出,有的放矢,这不仅为电离辐射导致的肠道急性损伤寻找有效的中医药防治措施提供了理论依据,也进一步拓展了中医药理论的应用范围,因此具有重要的临床价值和实践意义。     

Genetic toxicity assessment using liver cell models: past,present, and future

ABSTRACT

Genotoxic compounds may be detoxified to non-genotoxic metabolites while many pro-carcinogens require metabolic activation to exert their genotoxicity in vivo. Standard genotoxicity assays were developed and utilized for risk assessment for over 40 years. Most of these assays are conducted in metabolically incompetent rodent or human cell lines. Deficient in normal metabolism and relying on exogenous metabolic activation systems, the current in vitro genotoxicity assays often have yielded high false positive rates, which trigger unnecessary and costly in vivo studies. Metabolically active cells such as hepatocytes have been recognized as a promising cell model in predicting genotoxicity of carcinogens in vivo. In recent years, significant advances in tissue culture and biological technologies provided new opportunities for using hepatocytes in genetic toxicology. This review encompasses published studies (both in vitro and in vivo) using hepatocytes for genotoxicity assessment. Findings from both standard and newly developed genotoxicity assays are summarized. Various liver cell models used for genotoxicity assessment are described, including the potential application of advanced liver cell models such as 3D spheroids, organoids, and engineered hepatocytes. An integrated strategy, that includes the use of human-based cells with enhanced biological relevance and throughput, and applying the quantitative analysis of data, may provide an approach for future genotoxicity risk assessment.     

Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G₁, G₁/S, G₂, and G₂/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.