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.     

基于系统药理学分析野生真菌硬皮马勃治疗肿瘤多层次作用机制＊

目的 鉴定当地民间应用普遍的野生药用真菌，并探讨其治疗肿瘤的作用机制。方法 采用形态学和分子生物学方法对一株采自定陶仿山野生药用真菌进行鉴定，确定为硬皮马勃。通过文献检索收集硬皮马勃化学成分，利用PubChem软件和TCMSP、GCS数据库得到化学成分结构信息及其药用动力学参数和相关靶点分析，通过SysDT和WES系统鉴定潜在化学成分靶点，利用CTD数据库获得靶点功能，将潜在化合物和肿瘤相关靶点导入Cytoscape3.8.0软件构建分子-靶标网络。应用DAVID数据库对肿瘤相关靶点进行GO和KEGG富集分析，揭示有关活性成分靶点所涉及的生物学过程和通路，将肿瘤相关靶点和通路导入Cytoscape3.8.0软件构建靶点-通路网络。结果 从文献中获得硬皮马勃的化学成分59个，通过ADME计算系统筛选出5个潜在活性的化合物即活性成分，预测到38个靶点，其中与肿瘤相关靶点16个。这些活性成分主要通过Toll-like receptor、PI3K-AKT、MAPK和NF-kappa B等通路参与免疫应答，抑制肿瘤细胞生长、增殖，促进其凋亡。结论 表明硬皮马勃治疗肿瘤具有多靶点、多途径协同作用的特点，并通过多层次效应达到治疗肿瘤的效果。本研究为更好理解硬皮马勃作用肿瘤的机制和肿瘤药物开发提供理论依据。     

Whose place? Lessons from a case study of a guardianship determination for an Australian Indigenous child

Whose values matter when considering which environment is healthier for a child whose guardianship is contested? The biological mother from a remote Australian Aboriginal community, who voluntarily relinquished her but has now requested her return? The foster mother who has cared for her in a metropolitan centre in another State of Australia, thousands of kilometres away? The welfare professionals who also live in that city? Or the child herself, who left her birth home and community five years earlier at the age of two? Drawing on a case study of a seven-year old Aboriginal girl, the authors argue that non-Indigenous values trumped Indigenous values without the realisation of key players who were empowered to make such determinations. The article uses Manuel DeLanda's neo-assemblage theory to consider the range of processes that exert themselves to shape place-values and social identity in colonised nations. It will also draw on Erik Erikson's and Lev Vygotsky's theories of psychosocial development to consider competing sets of values that raised feelings of dissonance within the child. Beliefs about what makes a place health-giving are revealed to be complex in colonised nations. Despite policy and legislative changes to better support Aboriginal people and their right to difference, non-Indigenous professionals can continue to be driven by an unrecognised systemic racism. While place-values are not, of course, the only (or perhaps even the most significant) consideration in guardianship determinations, this article will argue they can play a significant and covert role.     

Contemporary Epidemiology of and Risk Factors Associated with Removal of a Pathologically Normal Appendix in Children with Suspected Appendicitis

BackgroundThe goal of this study was to characterize contemporary performance benchmarks and risk factors associated with negative appendectomy (NA) in children with suspected appendicitis.MethodsA multicenter retrospective cohort analysis of children undergoing appendectomy for suspected appendicitis was performed using data from the 2016–2021 NSQIP-Pediatric Appendectomy Targeted Public Use Files. Multivariable regression was used to evaluate the influence of year, age, sex, and WBC count on NA rate, and to generate rate estimates for NA based on different combinations of demographic characteristics and WBC profiles.Results100,322 patients were included from 140 hospitals. The overall NA rate was 2.4%, and rates decreased significantly during the study period (2016: 3.1% vs. 2021: 2.3%, p < 0.001). In adjusted analyses, the highest risk for NA was associated with a normal WBC (<9000/mm³; OR 5.31 [95% CI: 4.87–5.80]), followed by female sex (OR 1.55 [95% CI: 1.42–1.68]) and age <5 years (OR 1.64 [95% CI 1.39, 1.94]). Model-estimated risk for NA varied significantly across demographic and WBC strata, with a 14.4-fold range in rates between subgroups with the lowest and highest predicted risk (males 13–17 years with elevated WBC [1.1%] vs. females 3–4 years with normal WBC [15.8%]).ConclusionsContemporary NA rates have decreased over time, however NA risk remains high in children without a leukocytosis, particularly for girls and children <5 years of age. These data provide contemporary performance benchmarks for NA in children with suspected appendicitis and identify high-risk populations where further efforts to mitigate NA risk should be targeted.Level of EvidenceIII.     

The Portuguese Osteopathic Practitioners Estimates and RAtes (OPERA): A cross-sectional survey

ObjectivesOsteopathy is regulated as an independent healthcare profession in Portugal. The Osteopathic Practitioners Estimates and RAtes (OPERA) project was developed as a survey to profile the osteopathic profession. This study aimed to describe the characteristics of Portuguese osteopathic practitioners.MethodsA voluntary online-based survey was distributed across Portugal between February and June 2020. The survey, composed of 52 questions and seven sections, was formally translated from English to Portuguese and adapted from the original version. Two pilot tests evaluated cultural adaptation and reproducibility. Adult, self-defined osteopaths working in Portugal were eligible. Recruitment of participants was performed through social media and an e-based campaign.ResultsA total of 222 osteopaths participated in the study, 143 were male (64%), aging between 30 and 39 years (42%), mainly working in Lisbon (30%). Most respondents had preliminary healthcare training (68%), mainly as massage therapists. The majority of respondents were self-employed (83%), owner of a clinic (55%) and working alone (59%). The median number of consultations per week was 21–25 and respondents scheduled 46–60 min for each consultation. The majority of patients seek care for lumbar (52%), cervical (38%) and upper spine (38%) complaints. Although most respondents experience a strong osteopathic identity, they do not advertise themselves exclusively as osteopaths.ConclusionsThis study represents the first nationwide document to determine osteopaths' characteristics in Portugal. The study results provide a basis for future surveys that will include cohorts with higher levels of education, as well as findings from other European countries.