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.     

不同时间电针对直肠癌开腹手术患者围术期应激反应和免疫功能的影响

目的观察不同时点电针对直肠癌开腹手术患者围术期应激反应及免疫功能的影响。方法240例择期行直肠癌根治性开腹手术而住院的患者,随机分为A组、B组、C组、D组,每组60例。A组设为空白对照组,B组于手术前1 d、C组于手术前1 d和麻醉诱导前30 min、D组分别于手术前1 d、麻醉诱导前30 min及手术后1 d行电针。分别于手术前1 d电针前(T1)、麻醉诱导前电针前(T2)、术毕(T3)和手术后1 d电针后(T4)4个时间采集患者空腹外周静脉血,用Sysmex血细胞分析仪对白细胞与中性粒细胞进行计数;ELISA检测急性期C反应蛋白(CRP)与热反应蛋白70(HSP70)以及细胞因子白介素6(IL-6)、干扰素(IFN-g)、白介素4(IL-4)水平,并计算IFN-g与IL-4比值;采用流式细胞仪测定CD4、CD8的细胞含量并计算两者比值。结果HSP70与CRP水平、白细胞数与中性粒细胞数、IL-4与IL-6水平变化趋势均一致,4组T1、T2时间比较,差异无统计学意义(P>0.05);A组与B组T3和T4时间比较,差异无统计学意义(P>0.05);C组、D组T3和T4时间显著低于A组与B组(P<0.05);D组T4时间显著低于C组(P<0.05);4组T2时间与T1时间比较差异无统计学意义(P>0.05),T3时间高于T2时间(P<0.05),T4时间低于T3时间(P<0.05)。IFN-g变化不显著(P>0.05),IFN-g/IL-4、CD4/CD8变化趋势与以上相反。结论电针术前使用对直肠癌患者无显著疗效,但能够减轻术后应激反应和免疫抑制,并且随着电针次数的合理增加疗效更加显著。     

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。     

急性高容量性血液稀释对妇科肿瘤患者围术期T淋巴细胞亚群的影响

目的探讨急性高容量性血液稀释(AHH)对妇科肿瘤患者围手术期T淋巴细胞亚群的影响.方法40例ASAⅠ～Ⅱ级的妇科肿瘤手术病人随机分成两组:高容量性血液稀释组(A组)在切皮前30分钟内输入6%羟乙基淀粉液1000ml;对照组(C组)常规输液,不实施血液稀释.分别与麻醉诱导前、手术结束后、术后24小时抽取静脉血,用流式细胞仪测定T淋巴细胞亚群CD3 、CD4 、CD8 及CD4 /CD8 细胞百分率.结果两组病人手术结束后(T1)、手术后第1天(T2)与麻醉诱导前(T0)比较:T淋巴细胞亚群CD3 、CD4 及CD4 CD8 均明显降低(P＜0.01或P＜0.05),CD8 无显著性变化;但A组手术结束后和手术后第1天CD3 、CD4 及CD4 /CD8 明显高于C组(P＜0.05).结论术前采用急性高容量性血液稀释(AHH),可显著改善妇科肿瘤患者T淋巴细胞的免疫功能.