Mechanism of action of Orthosiphon stamineus against non-alcoholic fatty liver disease: Insights from systems pharmacology and molecular docking approaches

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of a metabolic syndrome caused by excessive accumulation of fat in the liver. Orthosiphon stamineus also known as Orthosiphon aristatus is a medicinal plant with possible potential beneficial effects on various metabolic disorders. This study aims to investigate the in vitro inhibitory effects of O. stamineus on hepatic fat accumulation and to further use the computational systems pharmacology approach to identify the pharmacokinetic properties of the bioactive compounds of O. stamineus and to predict their molecular mechanisms against NAFLD. Methods: The effects of an ethanolic extract of O. stamineus leaves on cytotoxicity, fat accumulation and antioxidant activity were assessed using HepG2 cells. The bioactive compounds of O. stamineus were identified using LC/MS and two bioinformatics databases, namely the Traditional Chinese Medicine Integrated Database (TCMID) and the Bioinformatics Analysis Tool for the Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Pathway enrichment analysis was performed on the predicted targets of the bioactive compounds to provide a systematic overview of the molecular mechanism of action, while molecular docking was used to validate the predicted targets. Results: A total of 27 bioactive compounds corresponding to 50 potential NAFLD-related targets were identified. O. stamineus exerts its anti-NAFLD effects by modulating a variety of cellular processes, including oxidative stress, mitochondrial β-oxidation, inflammatory signalling pathways, insulin signalling, and fatty acid homeostasis pathways. O. stamineus is significantly targeting many oxidative stress regulators, including JNK, mammalian target of rapamycin (mTOR), NFKB1, PPAR, and AKT1. Molecular docking analysis confirmed the expected high affinity for the potential targets, while the in vitro assay indicates the ability of O. stamineus to inhibit hepatic fat accumulation. Conclusion: Using the computational systems pharmacology approach, the potentially beneficial effect of O. stamineus in NAFLD was indicated through the combination of multiple compounds, multiple targets, and multicellular components.     

Performance of risk prediction models for post-operative mortality in patients undergoing liver resection

BackgroundLiver resection is commonly performed for hepatic tumors, however preoperative risk stratification remains challenging. We evaluated the performance of contemporary prediction models for short-term mortality after liver resection in patients with and without cirrhosis.MethodsThis retrospective cohort study examined National Surgical Quality Improvement Program data. We included patients who underwent liver resections from 2014 to 2019. VOCAL-Penn, MELD, MELD-Na, ALBI, and Mayo risk scores were evaluated in terms of model discrimination and calibration for 30-day post-operative mortality.ResultsA total 15,198 patients underwent liver resection, of whom 249 (1.6%) experienced 30-day post-operative mortality. The VOCAL-Penn score had the highest discrimination (area under the ROC curve [AUC] 0.74) compared to all other models. The VOCAL-Penn score similarly outperformed other models in patients with (AUC 0.70) and without (AUC 0.74) cirrhosis.ConclusionThe VOCAL-Penn score demonstrated superior predictive performance for 30-day post-operative mortality after liver resection as compared to existing clinical standards.     

Deepm5C: A deep-learning-based hybrid framework for identifying human RNA N5-methylcytosine sites using a stacking strategy

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Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 2. The biological variability of the murine Local Lymph Node Assay (LLNA) for skin sensitisation

The Local Lymph Node Assay (LLNA) is the most common in vivo regulatory toxicology test for skin sensitisation, quantifying potency as the EC3, the concentration of chemical giving a threefold increase in thymidine uptake in the local lymph node. Existing LLNA data can, along with clinical data, provide useful comparator information on the potency of sensitisers. Understanding of the biological variability of data from LLNA studies is important for those developing non-animal based risk assessment approaches for skin allergy. Here an existing set of 94 EC3 values for 12 chemicals, all tested at least three times in the same vehicle have been analysed by calculating standard deviations (SD) for logEC3 values. The SDs range from 0.08 to 0.22. The overall SD for the 94 logEC3 values is 0.147. Thus the 95% confidence limits (2xSD) for LLNA EC3 values are within a factor of 2, comparable to those for physico-chemical measurements such as partition coefficients and solubility. The residual SDs of Quantitative Mechanistic Models (QMMs) based on physical organic chemistry parameters are similar to the overall SD of the LLNA, indicating that QMMs of this type are unlikely to be bettered for predictive accuracy.     

Gynecologic Malignancy-Associated Venous Thromboembolism and Predictive Tool at Thammasat University Hospital

Objectives: Aims were to investigate the prevalence and risk factors of venous thromboembolism (VTE) in gynecologic malignancy cases. Value of screening tool (Caprini) for prediction of VTE was also assessed. Study design: A retrospective study of gynecologic malignancy subjects who underwent major gynecological operation via exploratory laparotomy at Thammasat University Hospital, Pathum Thani, Thailand from January 2015 to December 2020. Participants were categorized into VTE and non-VTE groups. Caprini score, associated laboratory and clinical factors of both groups were evaluated. Results: A total of 392 subjects were recruited into the study. Prevalence of VTE was 7.4 (29/392) percent. VTE was diagnosed in subjects with endometrial, ovarian and cervical cancer at percentage of 7.8 (15/192), 7.9 (11/138) and 5.7 (3/53), respectively. Demographic characters of both groups were comparable. VTE group had significant more Caprini score, platelets count and platelet lymphocyte ratio (PLR) than non-VTE group. Modified Caprini score (2 multiply Caprini score plus 1 multiply PLR) was generated for better VTE prediction. Sensitivity and specificity of Caprini (≥5.5) and modified Caprini scores (≥22.8) were 72.4 vs 39.4, and 79.3 vs 52.1 percent, respectively. Conclusion: Prevalence of VTE among gynecologic malignancy cases was 7.4 percent. The modified Caprini score was an alternative VTE predictive tool. Cut-off point of modified Caprini score at equal or more than 22.8 was proposed.     

电针复合TCI靶控输注在单肺通气食管癌开胸手术麻醉中的应用与安全性＊

目的 探讨电针复合靶控输注（Target Controlled Infusion， TCI）在单肺通气食管癌开胸手术麻醉中的应用价值。方法 选取于我院拟行单肺通气食管癌开胸切除手术患者60例作为研究对象。随机将其分为试验组与对照组，对照组30例采取气管插管全麻及TCI靶控输注维持麻醉深度，试验组30例则在对照组方案基础上辅助电针麻醉，记录两组患者手术麻醉时间、药物用量、苏醒时间、并发症；以及术前（T_Ⅰ）、插管前即刻（T_Ⅱ）、插管后1 min（T_Ⅲ）、切皮即刻（T_Ⅳ）、去骨时（T_Ⅴ）、拔管即刻（T_Ⅵ）时平均动脉压（MAP）、平均心率（HR）、BIS值；术前、术后1天、术后3天简易智能精神状态检查量表（MMSE）；并于麻醉诱导前（T₀）、手术开始2 h（T₁）、术后1天（T₂）、术后3天（T₃）时抽取患者外周静脉血检测IL-1β、IL-6、IL-10、TNF-α浓度。结果 试验组手术用时、麻醉时间略低于对照组，但差异无统计学意义（P>0.05），试验组异丙酚、舒芬太尼用量以及苏醒时间均明显低于对照组（P<0.05）；T_Ⅱ时两组平均动脉压（Mean Arterial Pressure， MAP）、心率（Heartrate， HR）较术前明显降低，且试验组MAP明显低于对照组（P<0.05），但两组T_Ⅱ时HR比较无显著差异（P>0.05）；T_Ⅲ、T_Ⅵ时对照组MAP、HR明显高于T_Ⅰ时，而试验组MAP、HR与T_Ⅰ比较无显著差异（P>0.05）。术后1天、3天试验组简易智能精神状态检查量表（Mini-Mental State Examination， MMSE）评分低于对照组，有显著性差异（P<0.05）。T₁、T₂、T₃时试验组白介素-1β（IL-1β）、白介素-6（IL-6）、肿瘤坏死因子（Tumor Necrosis Factor-α， TNF-α）水平明显低于对照组（P<0.05），白介素-10（IL-10）水平明显高于对照组（P<0.05）。结论 采用电针复合TCI靶控输注麻醉方案可有效提升单肺通气食管癌开胸手术麻醉效果，能够降低患者术后认知功能障碍发生风险。