Genome-wide bioinformatics analysis of FMN,SAM-I,glmS, TPP,lysine, purine,cobalamin, and SAH riboswitches for their applications as allosteric antibacterial drug targets in human pathogenic bacteria

Objectives: A constantly growing number of antibiotic-resistant strains of human pathogenic bacteria is an acute problem. Prolonged illnesses and increasing mortality worldwide mean that there is an urgent need to develop novel antibacterial drugs based on new targets and mechanisms of action. We present in silico analyses of bacterial riboswitches that may be suitable as antibacterial drug targets.

Methods: Most bacterial riboswitches are allosteric cis-acting gene control elements located in the 5?-untranslated region of messenger RNAs. Riboswitches sense specific metabolites and regulate the synthesis of some essential cellular metabolites in many pathogenic bacteria but are not found in humans. We present a complete and comprehensive genome-wide bioinformatics analyses of the suitability of eight riboswitches as antibacterial drug targets in various pathogenic bacteria.

Results: Based on our in silico analyses, we classify the riboswitches in four different groups based on their suitability to be used as antibacterial drug targets. We have estimated that FMN, SAM-I, glmS, TPP, and Lysine riboswitches are promising targets for antibacterial drug discovery.

Conclusion: This research enables us to focus antibacterial drug discovery research only on those riboswitches whose inhibition will result in suppression of the growth of certain pathogenic bacteria.     

Characterizing and optimizing human anticancer drug targets based on topological properties in the context of biological pathways

One of the challenging problems in drug discovery is to identify the novel targets for drugs. Most of the traditional methods for drug targets optimization focused on identifying the particular families of “druggable targets”, but ignored their topological properties based on the biological pathways. In this study, we characterized the topological properties of human anticancer drug targets (ADTs) in the context of biological pathways. We found that the ADTs tended to present the following seven topological properties: influence the number of the pathways related to cancer, be localized at the start or end of the pathways, interact with cancer related genes, exhibit higher connectivity, vulnerability, betweenness, and closeness than other genes. We first ranked ADTs based on their topological property values respectively, then fused them into one global-rank using the joint cumulative distribution of an N-dimensional order statistic to optimize human ADTs. We applied the optimization method to 13 anticancer drugs, respectively. Results demonstrated that over 70% of known ADTs were ranked in the top 20%. Furthermore, the performance for mercaptopurine was significant: 6 known targets (ADSL, GMPR2, GMPR, HPRT1, AMPD3, AMPD2) were ranked in the top 15 and other four out of the top 15 (MAT2A, CDKN1A, AREG, JUN) have the potentialities to become new targets for cancer therapy.     

Endoscopic ultrasound may be used to deliver gene expression signatures using digital mRNA detection methods to immunophenotype pancreatic ductal adenocarcinoma to facilitate personalized immunotherapy

Background & objectivesBiomarkers are increasingly required to molecularly characterize pancreatic ductal adenocarcinoma (PDAC) subgroup populations, to determine who may benefit from immune based targeted therapy. We evaluated the feasibility of gene expression signature detection and the respective landscape of specific tumor infiltrating lymphocytes (TILs), cancer/testis (CT) antigens, and immune checkpoints for possible future personalized immunotherapy eligibility.MethodsDedicated digital mRNA oncologic immune profiling of 770 genes using a Nanostring nCounter® PanCancer Immune Profiling Panel was performed using archived endoscopic ultrasound fine needle biopsy (EUS FNB) PDAC specimens as a case series in a tertiary care setting.ResultsThe spectrum of mRNA gene expression within the tumor specimens revealed that 44.8%, 10.0% and 50.7% of evaluated genes had a ≥ 2-fold increase, a ≤ 2-fold reduction or between <2 and >2 change of mRNA expression, when compared to normal controls. The corresponding landscape of TILs, CT antigens, and immune checkpoints highlighted several possibilities that could potentially be amenable to targeted personalized immunotherapy. This includes members of the Tumor Associated Macrophage family (CD68, CXCL5, and MARCO), members of the CT antigen family (PRAME, TTK and PBK) and the “second generation” checkpoints TIM3 and BTLA.ConclusionsOur study represents the ability to successfully perform digital mRNA expression profile analyses to immunophenotype PDAC EUS FNB specimens by evaluating the expression of >730 genes within the tumor immune microenvironment. This may facilitate the search for novel therapeutic targets, offering the opportunity to go beyond immune monotherapy, but perhaps to use combined immunomodulatory agents.     

Contemporary and future strategies in polycythemia vera

Polycythemia vera (PV) is characterized by clonal proliferation of a hematopoietic stem cell leading to erythrocytosis. Patients with PV have significantly higher morbidity and mortality compared to the general population due to increased risk of thrombosis, hemorrhage, and well-characterized microvascular and constitutional symptoms. There is also a propensity to transform to myelofibrosis and to an aggressive form of acute leukemia, further increasing morbidity and mortality. Current management is aimed at reducing the risk of thromboembolic events and improving symptom burden; however, none of the existing therapies have proven the ability to deplete the underlying malignant clone, or definitively reduce the risk of disease, progression leaving a large area of unmet need. In this review, we highlight the pathophysiology of PV, current management and limitations therein. We propose highly debated clinical practices that require further investigation. We conclude by discussing therapies in development and how these may fill unmet needs and be incorporated into the future PV treatment paradigm.     

Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases

Introduction: Mitochondrial-derived peptides (MDPs) are encoded within the mitochondrial genome. They signal within the cell or are released to act as autocrine/paracrine/endocrine cytoprotective factors playing a key role in the cellular stress response. The first reported and better characterized MDP is humanin (HN), which exerts robust protective effects against a myriad of cytotoxic stimuli in many cell types. These effects have led to the evaluation of HN and its analogs as therapeutic targets for several chronic diseases.

Areas covered: We describe the latest findings on the mechanism of action of HN and discuss the role of HN as therapeutic target for neurodegenerative and cardiovascular diseases, diabetes, male infertility, and cancer. Since HN can be detected in circulation, we also depict its value as a biomarker for these diseases.

Expert opinion: HN analogs and peptide mimetics have been developed over the last decade and show promising results in preclinical models of degenerative diseases. Local administration of gene therapy vectors that overexpress or silence endogenous HN could also hold therapeutic potential. Controversy on the role of HN in cancer progression and chemoresistance should be addressed before the translation of these therapeutic approaches.     

Toll‐like receptors as novel therapeutic targets for herpes simplex virus infection

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll‐like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV‐mediated molecular cues, in particular, NF‐κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR‐based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.     

基于网络药理学的康莱特注射液3种主要成分抗肿瘤机制研究

目的 利用网络药理学分析康莱特注射液3种主要成分的抗肿瘤作用机制。方法 以康莱特注射液中具有抗肿瘤作用的甘油三油酸酯、薏苡仁酯、薏苡素为研究对象，依托中药系统药理学数据库（TCMSP）、反向分子对接服务器（PharmMapper）、人类基因组注释数据库（GeneCards）、药物治疗靶标数据库（TTD）进行靶点预测和筛选，借助Cytoscape 3.5.1软件构建活性成分-靶点-疾病网络，借助STRING平台构建靶蛋白相互作用网络，通过DAVID平台对靶点基因本位生物过程和KEGG信号通路进行富集分析。结果 康莱特注射液活性成分作用于EGFR、PGR、PTGS2、AR、MAPK1等25个潜在抗肿瘤靶点，调控FoxO、前列腺癌、癌症、Rap1、TNF、Ras、MAPK信号通路，参与细胞增殖调控、蛋白激酶B信号调控、环氧合酶途径、细胞迁移调控等生物过程，可用于20多种癌症的治疗。结论 本研究为进一步深入研究康莱特注射液抗肿瘤机制提供了新的线索与思路。