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.     

孕烷X受体与炎症反应及中药干预机制研究进展

孕烷X受体(Pregnane X receptor,PXR)是核受体家族成员之一,可被多种内源性和外源性物质激活。PXR通过诱导药物代谢酶和转运体,在肝脏、肠道、皮肤和血管内皮中发挥重要的解毒作用。此外,PXR还具有调节糖脂代谢、胆固醇代谢、胆红素和胆汁酸代谢、免疫炎症反应等功能。研究证实,PXR已被公认为多种炎症性疾病的有效药物干预靶点,如炎性结肠炎、坏死性肠炎、肝炎、皮炎、糖尿病等。多种中药或其活性成分可以作为PXR受体激动剂通过核因子B(NF-κB)和尾部相关同源盒转录因子2(Cdx2)通路干扰炎症反应,如虎杖、木蝴蝶、黄芩、黄连、丹参、白芷、人参、香附、五味子、高良姜等。本文综述了近年来PXR调节炎症反应的最新研究成果以及中药激活PXR干预炎症反应的机制,以期为今后的研究提供参考。     

路径式营养管理在食管癌患者围术期的应用研究

目的 探讨路径式营养管理在食管癌围术期患者中的应用效果。方法 选取2018年1月至2018年7月在四川省肿瘤医院胸外科接受食管癌根治手术治疗的患者156例，随机分为干预组（n=78）和对照组（n=78），干预组采用路径式营养管理，对照组采用常规营养管理，比较两组患者在术后7d血红蛋白、前白蛋白、体质指数（BMI）、预后营养指数（PNI）等营养指标、术后并发症发生率及术后住院时间。结果 干预组患者术后7d血红蛋白（126.09±16.69）g/L、前白蛋白（208.74±38.51）mg/L、BMI（22.28±2.05）kg/m2、PNI（46.62±4.03）优于对照组，差异有统计学意义（P<0.05）；干预组患者胸腔积液发生率低于对照组，差异有统计学意义（t=4.02，P=0.04）；干预组患者住院时间短于对照组，差异有统计学意义（t=6.53，P=0.03）。结论 路径式营养管理能有效改善食管癌围术期患者营养状况、降低并发症发生率、缩短术后住院时间。     

Deciphering the roles of caveolin in neurodegenerative diseases: The good,the bad and the importance of context

Neurodegenerative diseases (NDDs), which contribute to progressive and irreversible impairments of both the structure and function of the nervous system, pose a substantial socioeconomic burden on society. Mitochondrial dysfunction, oxidative stress, membrane damage, DNA damage, and abnormal protein degradation pathways play pivotal roles in the etiology of NDDs. Recently, growing evidence has demonstrated that caveolins are important in the pathology of NDDs due to their cellular functions in signal transduction, endocytosis, transcytosis, cholesterol transport, and lipid homeostasis. Given the significance of caveolins, here we review the literature to clarify their molecular mechanisms and roles in NDDs. We first briefly introduce the general background on caveolins. Next, we focus on the various important functions of caveolins in the brain. Finally, we emphasize recent progress regarding caveolins, especially Cav-1, which exert both benefit and unfavorable effects in NDDs such as AD and PD. Collectively, the data presented here should advance the investigation of caveolins for the future development of innovative strategies for the treatment of NDDs.     

Intensidad de la señal en T1 en el núcleo dentado tras la administración del agente de contraste con gadolinio macrocíclico gadoterato de meglumina: un estudio observacional

Introduction and aimsContradictory results have been reported about hyperintensity of the globus pallidus and/or dentate nucleus on unenhanced T1-weighted magnetic resonance (MR) images after exposure to various gadolinium-based contrast agents. This change in signal intensity varies with different gadolinium-based contrast agents. We aimed to determine whether signal intensity in the dentate nucleus is increased in unenhanced T1-weighted images in patients who have undergone multiple studies with the macrocyclic gadolinium-based contrast agent gadoterate meglumine. We thoroughly reviewed the literature to corroborate our results.Materials and methodsWe included patients who had undergone more than 10 MR studies with gadoterate meglumine. We quantitatively analyzed the signal intensity in unenhanced T1-weighted MR images measured in regions of interest placed in the dentate nucleus and the pons, and we calculated the dentate nucleus-to-pons signal intensity ratios and the differences between the ratio in the first MR study and the last MR study. We used t-tests to evaluate whether the differences between the signal intensity ratios were different from 0. We also analyzed the subgroups of patients who had been administered < 15 and ≥15 doses of gadoterate meglumine. We used Pearson correlation to determine the relationships between the differences in the signal intensity ratios and the number of doses of gadoterate meglumine administered.ResultsThe 54 patients (26 men) had received a mean of 13.8 ± 3.47 doses (range, 10-23 doses). The difference in the dentate nucleus-pons signal intensity ratio between the first and last MR study was -0.0275 ± 0.1917 (not significantly different from 0; p = 0.2968) in the entire group, -0.0357 ± 0.2204 (not significantly different from 0; p = 0.351 in the patients who had received < 15 doses (n = 34), and -0.0135 ± 0.1332 (not significantly different from 0; p = 0.655) in those who had received ≥15 doses (n = 20). Differences in signal intensity ratios did not correlate significantly with the accumulated dose of gadoterate meglumine (P = 0.9064; ρ = -0.0164 [95%]).ConclusionsReceiving more than 10 doses of gadoterate meglumine was not associated with increased signal intensity in the dentate nucleus.     

The effect of interleukin 6 deficiency on myocardial signal transduction pathways activation induced by bacterial lipopolysaccharide in young and old mice

PurposeExaggerated release of proinflammatory mediators during sepsis contributes to inadequate vasodilatation and depressed myocardial contractility, which lead to development of shock and circulatory collapse. The aim of the study was to evaluate the effect of IL-6 and aging on activation of intracellular signaling pathways in the myocardium induced by bacterial lipopolysaccharide (LPS) administration.Material/methodsLPS was injected intraperitoneally to male 3- and 24-month old mice with systemic IL-6 gene knock-out (IL-6KO) and the reference strain (WT). LPS was given intraperitoneally in single low (0.1 mg/kg) or high (10 mg/kg) dose, or in two doses (0.1 + 10 mg/kg) with 24-h delay. The expression and phosphorylation of STAT3, ERK1/2, Akt1/2/3 proteins in the left ventricular myocardium was evaluated after 24 h using Western blotting.ResultsLow LPS dose induced higher STAT3 phosphorylation only in old IL-6KO mice, not affecting ERK1/2 and Akt1/2/3 phosphorylation in any group. High LPS dose upregulated STAT3 phosphorylation similarly in all groups, reduced ERK1/2 expression in young WT mice and upregulated Akt1/2/3 expression and phosphorylation in young IL-6KO mice. Pretreatment with low LPS dose attenuated phosphorylation of STAT3 in both old groups and phosphorylation of Akt1/2/3 in young IL-6KO group. Two-dose approach also significantly potentiated ERK1/2 phosphorylation in both old groups.ConclusionsObtained results show that IL-6 deficiency alters the activity of intracellular signaling pathways: JAK/STAT in old and Akt in young LPS-treated mice. This may indicate that lack of IL-6 attenuates Akt-related cytoprotective effect of pretreatment with low LPS dose in young but not in aged animals.     

Membrane-associated mucins of the ocular surface: New genes,new protein functions and new biological roles in human and mouse

The mucosal glycocalyx of the ocular surface constitutes the point of interaction between the tear film and the apical epithelial cells. Membrane-associated mucins (MAMs) are the defining molecules of the glycocalyx in all mucosal epithelia. Long recognized for their biophysical properties of hydration, lubrication, anti-adhesion and repulsion, MAMs maintain the wet ocular surface, lubricate the blink, stabilize the tear film and create a physical barrier to the outside world. However, it is increasingly appreciated that MAMs also function as cell surface receptors that transduce information from the outside to the inside of the cell. A number of excellent review articles have provided perspective on the field as it has progressed since 1987, when molecular cloning of the first MAM was reported. The current article provides an update for the ocular surface, placing it into the broad context of findings made in other organ systems, and including new genes, new protein functions and new biological roles. We discuss the epithelial tissue-equivalent with mucosal differentiation, the key model system making these advances possible. In addition, we make the first systematic comparison of MAMs in human and mouse, establishing the basis for using knockout mice for investigations with the complexity of an in vivo system. Lastly, we discuss findings from human genetics/genomics, which are providing clues to new MAM roles previously unimagined. Taken together, this information allows us to generate hypotheses for the next stage of investigation to expand our knowledge of MAM function in intracellular signaling and roles unique to the ocular surface.