Overview of CF lung pathophysiology

Defects of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein affect the homeostasis of chloride, bicarbonate, sodium, and water in the airway surface liquid, influencing the mucus composition and viscosity, which induces a severe condition of infection and inflammation along the whole life of CF patients. The introduction of CFTR modulators, novel drugs directly intervening to rescue the function of CFTR protein, opens a new era of experimental research. The review summarizes the most recent advancements to understand the characteristics of the infective and inflammatory pathology of CF lungs.     

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.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

慢性眼移植物抗宿主病的临床特点及相关机制的新进展

异基因造血干细胞移植(allo-HSCT)可有效治疗多种血液病,目前随着移植技术的不断提高和经济水平的飞速发展,越来越多的血液病患者因接受了allo-HSCT治疗而得以长期存活。慢性眼移植物抗宿主病(coGVHD)是allo-HSCT术后最常见的眼部并发症,主要表现为难治性干眼,严重时可导致眼表稳态失衡、角膜缘干细胞缺乏而出现角膜穿孔、睑球粘连等威胁视功能和眼健康的一系列并发症,治疗十分棘手。目前,国际上对coGVHD的临床表现、诊断标准、治疗规范、致病机制的研究逐步深入,而国内的研究及临床规范的建立尚处于起步阶段。本文对coGVHD的临床特点和相关机制的研究进展进行综述,以期加深眼科医师尤其角膜眼表疾病专科医师对该病的认识,为今后的深入研究提供新的思路。     

全反式维甲酸对IL-22诱导HaCaT细胞中Cx43和GJIC功能影响研究

目的:探究全反式维甲酸(ATRA)对IL-22处理后HaCaT细胞Cx43蛋白表达水平和细胞间隙连接通讯(GJIC)功能的影响,以及该过程是否与JNK通路有关,进一步阐明ATRA对GJIC功能影响的分子作用机制。方法:筛选ATRA影响IL-22处理HaCaT细胞最适处理时间;划痕标记染料示踪试验观察GJIC功能影响;免疫荧光检测ATRA和/或IL-22处理组Cx43、p-JNK、JNK表达水平的变化。结果:ATRA使HaCaT细胞的GJIC功能呈处理时间依赖性上升。ATRA作用于IL-22诱导HaCaT细胞后, Cx43蛋白表达水平增加, GJIC功能上调,p-JNK表达无明显变化。结论:ATRA可抑制IL-22介导的Cx43表达减少和GJIC下调作用,这一过程与JNK通路无关。     

Protein Kinase CK2, a Potential Therapeutic Target in Carcinoma Management

The Protein kinase CK2 (formerly known as casein kinase 2) is a highly conserved serine/ threonine kinaseoverexpressed in various human carcinomas and its high expression often correlates with poor prognosis. CK2 proteinis localized in the nucleus of many tumor cells and correlates with clinical features in many cases. Increased expressionof CK2 in mice results in the development of various types of carcinomas (both solids and blood related tumors, suchas (breast carcinoma, lymphoma, etc), which reveals its carcinogenic properties. CK2 plays essential roles in many keybiological processes related to carcinoma, including cell apoptosis, DNA damage responses and cell cycle regulation.CK2 has become a potential anti-carcinoma target. Various CK2 inhibitors have been developed with anti-neoplasticproperties against a variety of carcinomas. Some CK2 inhibitors have showed good results in in vitro and pre-clinicalmodels, and have even entered in clinical trials. This article will review effects of CK2 and its inhibitors on commoncarcinomas in in vitro and pre-clinical studies.