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.     

Phase 1/2 clinical trial of COVID-19 vaccine in Japanese participants: A report of interim findings

We initiated a randomized, placebo-controlled, phase 1/2 trial to evaluate the safety and immunogenicity of the S-268019-b recombinant protein vaccine, scheduled as 2 intramuscular injections given 21 days apart, in 60 randomized healthy Japanese adults. We evaluated 2 regimens of the S-910823 antigen (5 μg [n = 24] and 10 μg [n = 24]) with an oil-in-water emulsion formulation and compared against placebo (n = 12). Reactogenicity was mild in most participants. No serious adverse events were noted. For both regimens, vaccination resulted in robust IgG and neutralizing antibody production at days 36 and 50 and predominant T-helper 1-mediated immune reaction, as evident through antigen-specific polyfunctional CD4+ T-cell responses with IFN-γ, IL-2, and IL-4 production on spike protein peptides stimulation. Based on the interim analysis, the S-268019-b vaccine is safe, produces neutralizing antibodies titer comparable with that in convalescent serum from COVID-19-recovered patients. However, further evaluation of the vaccine in a large clinical trial is warranted.     

Orthogonally oriented scaffolds with aligned fibers for engineering intestinal smooth muscle

Controlling cellular alignment is critical in engineering intestines with desired structure and function. Although previous studies have examined the directional alignment of cells on the surface (x–y plane) of parallel fibers, quantitative analysis of the cellular alignment inside implanted scaffolds with oriented fibers has not been reported. This study examined the cellular alignment in the x–z and y–z planes of scaffolds made with two layers of orthogonally oriented fibers. The cellular orientation inside implanted scaffolds was evaluated with immunofluorescence. Quantitative analysis of coherency between cell orientation and fiber direction confirmed that cells aligned along the fibers not only on the surface (x–y plane) but also inside the scaffolds (x–z & y–z planes). Our study demonstrated that two layers of orthogonally aligned scaffolds can generate the histological organization of cells similar to that of intestinal circular and longitudinal smooth muscle.     

The effect of maternal antibodies on the cellular immune response after infant vaccination: A review

During the last few decades, maternal immunization as a strategy to protect young infants from infectious diseases has been increasingly recommended, yet some issues have emerged. Studies have shown that for several vaccines, such as live attenuated, toxoid and conjugated vaccines, high maternal antibody titers inhibit the infant’s humoral immune response after infant vaccination. However, it is not clear whether this decreased antibody titer has any clinical impact on the infant’s protection, as the cellular immune responses are often equally important in providing disease protection and may therefore compensate for diminished antibody levels. Reports describing the effect of maternal antibodies on the cellular immune response after infant vaccination are scarce, probably because such studies are expensive, labor intensive and utilize poorly standardized laboratory techniques. Therefore, this review aims to shed light on what is currently known about the cellular immune responses after infant vaccination in the presence of high (maternal) antibody titers both in animal and human studies. Overall, the findings suggest that maternally derived antibodies do not interfere with the cellular immune responses after infant vaccination. However, more research in humans is clearly needed, as most data originate from animal studies.     

Cellular immunotherapy in breast cancer: The quest for consistent biomarkers

Breast cancer is the most common malignancy in women worldwide, with a relatively high proportion of patients experiencing resistance to standard treatments. Cellular immunotherapy (CI), which is based on the extraction, modification, and re-infusion of the patient’s immune cells, is showing promising results in these patients. Among CI possible approaches, adoptive cell therapy (ACT) and dendritic cell (DC) vaccination are the most comprehensively explored in both primary/translational research studies and clinical trials. ACT may include the use of tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR)-, or chimeric antigen receptor (CAR)-engineered T-cells. There are indications suggesting that a biomarker-based approach might be beneficial in effectively selecting breast cancer patients for CI. Here, we sought to provide the current knowledge of CI in breast cancer, focusing on candidate biomarkers, ongoing clinical trials, limitations, and immediate future perspectives.     

Convergence and attractivity of memristor-based cellular neural networks with time delays

This paper presents theoretical results on the convergence and attractivity of memristor-based cellular neural networks (MCNNs) with time delays. Based on a realistic memristor model, an MCNN is modeled using a differential inclusion. The essential boundedness of its global solutions is proven. The state of MCNNs is further proven to be convergent to a critical-point set located in saturated region of the activation function, when the initial state locates in a saturated region. It is shown that the state convergence time period is finite and can be quantitatively estimated using given parameters. Furthermore, the positive invariance and attractivity of state in non-saturated regions are also proven. The simulation results of several numerical examples are provided to substantiate the results.     

胃癌侵袭性对患者血清E-钙粘附素浓度的影响

探讨E-钙粘附素(E-Cd)对人胃癌侵袭性的作用。方法:应用酶联免疫吸附方法测定29例胃癌患者血清可溶性E-Cd浓度。结果:胃癌组明显高于对照组(P<0.01),浸润组或有淋巴结转移组明显高于膨胀组或无淋巴结转移组(P<0.01～0.05),切除瘤体后上述各组的血清E-Cd浓度均明显下降(P<0.01～0.05)。结论:血清可溶性E-Cd浓度可能与人胃癌的生长方式和淋巴结转移密切相关。     

铜绿假单胞菌全细胞脂肪酸气相色谱分析及应用

本研究用计算机控制，可程序升温的毛细管柱气相色谱（ＧＣ）仪分析４８株铜绿假单胞菌标准株和临床株、部分常见假单胞菌、肠杆菌的细胞脂肪酸。结果表明：月桂烯酸（Ｃ１２：１），月桂酸（Ｃ１２：０）、十三碳烯酸（Ｃ１３：１）、十三碳酸（Ｃ１３：０）、肉豆劳动脑酸（Ｃ１４：１）、十七碳稀酸（Ｃ１７：１）、十七碳酸（Ｃ１７：０）、硬脂酸（Ｃ１８：０）和花生四烯酸（Ｃ２０：４）是铜绿包菌有鉴别意义的脂肪酸，组成与     

不育症患者精浆中细胞因子测定的临床研究

目的　 探讨精浆中白细胞介素 1β(IL 1β)、白细胞介素 2 (IL 2 )、白细胞介素 4 (IL 4 )、白细胞介素 6 (IL 6 )、白细胞介素 8(IL 8)、白细胞介素 10 (IL 10 )、肿瘤坏死因子 α(TNF α)等细胞因子浓度与不育症患者之间以及精子的各项功能指标之间的相互关系。方法　 应用放射免疫分析(RIA)技术对 12 6例不育男性精浆中IL 1β、IL 2、IL 4、IL 6、IL 8、IL 10、TNF α水平进行了检测。结果　 不育症组精浆IL 1β、IL 2、IL 6、IL 8、TNF α含量均高于生育组 ,两组间均存在显著性差异(P <0 .0 5或P <0 .0 1) ;精浆IL 4、IL 10含量均低于生育组 ,两组间均存在显著性差异 (P <0 .0 1)。不育症组精浆中IL 1β、IL 2、IL 4、IL 6、IL 8、IL 10、TNF α含量在WBC精液组与非WBC精液组、血清AsAb阳性组与血清AsAb阴性组之间均存在显著性差异 (P <0 .0 5或P <0 .0 1) ;精浆中IL 4、TNF α含量在精子活动力、活动率、精子穿透力、顶体完整率、尾部肿胀率正常组与不正常组之间均存在显著性差异 (P <0 .0 5或P <0 .0 1)。 结论　 精浆中IL 1β、IL 2、IL 4、IL 6、IL 8、IL 10、TNF α含量与男性不育症患者之间存在密切关系 ,检测精浆中IL 1β、IL 2、IL 4、IL 6、IL 8、IL 10、TNF α的含量可以反映男性     

The comparative evaluation of cellular localization of viral antigens with microscopic changes in the ileum of cattle infected with bovine viral diarrhea

The correlation between microscopic changes with cellular localization of viral antigens was studied in the ileum of 16 cases infected with bovine viral diarrhea virus (BVDV). Microscopic lesions in the ileum included multifocal erosive and ulcerative ileitis, severe congestion and hemorrhage, crypt dilation and mucus engorgement, epithelial debris and leukocytes, lymphoid depletion of Peyer’s patches, herniation of mucosal epithelium into depleted Peyer’s patches, and fibrinoid vasculitis of submucosal vessels. BVDV antigen was detected by immunohistochemistry in macrophages, dendritic cells, smooth muscle cells, endothelial cells, epithelial cells of crypts, and mucosal epithelium, together with other mononuclear cells including lymphocytes, plasma cells, fibroblasts, and intramural ganglial cells. No consistent correlation between the presence of BVDV antigen and vascular lesions in the ileum was identified. The intensity and distribution of the immunoperoxidase stain in the ileum was graded as highly positive (18.7%), moderately positive (56.3%), and mildly positive (25%). In conclusion, the pattern and density of distribution and localization of BVDV antigen in the ileum was not consistently correlated with the severity of microscopic lesions.