Spatiotemporally resolved metabolomics and isotope tracing reveal CNS drug targets

Deconvolution of potential drug targets of the central nervous system (CNS) is particularly challenging because of the complicated structure and function of the brain. Here, a spatiotemporally resolved metabolomics and isotope tracing strategy was proposed and demonstrated to be powerful for deconvoluting and localizing potential targets of CNS drugs by using ambient mass spectrometry imaging. This strategy can map various substances including exogenous drugs, isotopically labeled metabolites, and various types of endogenous metabolites in the brain tissue sections to illustrate their microregional distribution pattern in the brain and locate drug action-related metabolic nodes and pathways. The strategy revealed that the sedative-hypnotic drug candidate YZG-331 was prominently distributed in the pineal gland and entered the thalamus and hypothalamus in relatively small amounts, and can increase glutamate decarboxylase activity to elevate γ-aminobutyric acid (GABA) levels in the hypothalamus, agonize organic cation transporter 3 to release extracellular histamine into peripheral circulation. These findings emphasize the promising capability of spatiotemporally resolved metabolomics and isotope tracing to help elucidate the multiple targets and the mechanisms of action of CNS drugs.

Role of Vascular Aging in the Pathogenesis of Abdominal Aortic Aneurysm and Potential Therapeutic Targets / 中国医学科学院学报

Abdominal aortic aneurysm(AAA)is a common aortic degenerative disease in the elderly,and its incidence is gradually increasing with the aging of the population.There are no specific drugs available to delay the expansion of AAA.Once the aneurysm ruptures,the mortality will exceed 90%,which seriously threatens the life of patients.Given the high incidence of AAA in the elderly,this review discusses the role of vascular aging in the pathogenesis of AAA,involving chronic inflammation,oxidative stress,mitochondrial dysfunction,protein homeostasis imbalance,increased apoptosis and necrosis,extracellular matrix remodeling,nutritional sensing disorders,epigenetic changes,and increased pro-aging factors.Meanwhile,several potential aging-related drug targets of AAA are listed.This review provides new ideas for basic and translational medical research of AAA.

Identification of Drug-resistance Core Genes and Drug Targets in Lung Adenocarcinoma Patients Harboring ALK Fusion Gene / 肿瘤防治研究

Objective To compare DEGs between primary and metastatic lesions in lung adenocarcinoma patients with positive ALK fusion gene, and to explore the mechanism of drug-resistance and the potential drug targets in metastatic lesions of lung adenocarcinoma patients. Methods GSE125864 was obtained from GEO database. According to the different sampling sites of tumor tissue, two groups were divided: primary tumor lesions group and metastatic tumor lesions group. The DEGs between the two groups were compared, and the differences in biological functions and enrichment signaling pathways of these DEGs were analyzed. The protein-protein interaction network was constructed and applied to screen hub genes. Based on TCGA and cancer treatment response portal database, the prognosis and drug target prediction of the 10 key cores were analyzed. Results In total, 227 DEGs were identified, with 134 upregulated DEGs and 93 downregulated DEGs in the metastatic tumor lesions group, compared with primary tumor lesions group. GO and KEGG enrichment analyses showed that the functions of these DEGs were mainly involved in complement and coagulation cascade, chemical carcinogenesis and retinol metabolism pathways. The top 10 hub genes with the highest degree were analyzed in the protein-protein interaction network. The expression of HRG and AHSG genes were associated with poor prognosis of lung adenocarcinoma patients, and SERPINC1, HRG, ApoA1, FGA and FGG genes were correlated with a variety of potential small molecule drugs. Conclusion The molecular functions and signaling pathways involved in DEGs may induce drug-resistance in metastatic ALK-positive lung adenocarcinoma patients.

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infection that may break the healthcare system of several countries. Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. Finally, we also discuss patent protection issues, cost effectiveness and scalability of synthetic routes for some of the most studied repurposing candidates since these are key aspects to meet global demand for COVID-19 treatment.

Prioritisation of potential drug targets against Bartonella bacilliformis by an integrative in-silico approach

BACKGROUND Carrion's disease (CD) is a neglected biphasic illness caused by Bartonella bacilliformis, a Gram-negative bacteria found in the Andean valleys. The spread of resistant strains underlines the need for novel antimicrobials against B. bacilliformis and related bacterial pathogens. OBJECTIVE The main aim of this study was to integrate genomic-scale data to shortlist a set of proteins that could serve as attractive targets for new antimicrobial discovery to combat B. bacilliformis. METHODS We performed a multidimensional genomic scale analysis of potential and relevant targets which includes structural druggability, metabolic analysis and essentiality criteria to select proteins with attractive features for drug discovery. FINDINGS We shortlisted seventeen relevant proteins to develop new drugs against the causative agent of Carrion's disease. Particularly, the protein products of fabI, folA, aroA, trmFO, uppP and murE genes, meet an important number of desirable features that make them attractive targets for new drug development. This data compendium is freely available as a web server (http://target.sbg.qb.fcen.uba.ar/). MAIN CONCLUSION This work represents an effort to reduce the costs in the first phases of B. bacilliformis drug discovery.

Role of autophagy in islet β cells: A novel target for diabetes’ therapy / 中国临床药理学与治疗学

Autophagy is a catabolism process in which lysosomes degrade damaged organelles, protein aggregates and recover nutrients. Studies have shown that autophagy could protect the structure and function of islet β cell and maintaining normal secretion of insulin. In addition, autophagy plays important roles in the occurrence and development of diabetes mellitus by reducing oxidative stress, preventing apoptosis and removing ubiquitination protein aggregates. Therefore, autophagy may be a new target for the prevention and treatment of diabetes. At present, hypoglycemic drugs have been proved to play positive roles by regulating autophagy including thiazolidine dione and guanidine. Therefore, this paper will review autophagy definition, the role of autophagy in diabetes mellitus and autophagy-related hypoglycemic drugs, providing a new direction for clinical treatment of diabetes.

Molecular docking of various bioactive compounds from essential oil of Trachyaspermum ammi against the fungal enzyme Candidapepsin-1

The bioactive compounds from essential oil of Trachyaspermum ammi using gas chromatography–mass spectrometryand their inhibition potential against the enzyme Candidapepsin-1 were studied. The research work focuses on themolecular simulation of bioactive compounds against the enzyme that acts as a potential drug target and support thedrug discovery process. Candidapepsin-1 has been reported to be the cause for biofilm formation, superficial skininfections, and oral infections. Fifteen active compounds and their interactions with Candidapepsin-1 were studiedin this research work. The compounds satisfied Lipinski’s rule of five in order to be used as an oral drug. ADMETproperties of the compounds used to determine pharmacodynamic and pharmacokinetic properties which werereported in the study. The compounds were docked against the enzyme with the help of AutoDock 4.2.6 software.Ligustilide has the lowest free binding energy of −5.75 kcal/mol against the Candidapepsin-1 with three hydrogenbond interactions at Ile 223, Tyr 225, and Thr 222 at the active site of the enzyme followed by cedrane with −5.20kcal/mol. The hydrogen bond interactions, Vander Waals interactions, and two-dimensional and three-dimensionalinteractions were studied.

Dna Topoisomerases: A Review On Their Functionalaspects In Cell Division

DNA is double helical macromolecule which carries all the genetic information and it is usually found enveloped inside a nucleus. The DNA helix relaxes and supercoils itself frequently in order to derive information from the genes during processes like transcription, condensation, replication and recombination, which require mutable or immutable alterations to cause the separation of the two DNA strands. Due to problems caused by the helical structure of DNA, these topoisomerase enzymes perform the required DNA uncoiling. Their role in cell cycle is also significant as their mutation leads to failure of anaphase separation (1, 2). In the present review, the important roles of DNA topoisomerases and their inevitable role in cell growth and cell cycle are discussed viz. how they function in cell proliferation and what are the results when different inhibitors are added to the cells, affecting cell cycle at various checkpoints .

Advances in pharmacological research of sanshool / 中国药理学通报

The pericarp of Zanthoxylum bungeanum Maxim. (Rutaceae) is a traditional Chinese herbal medicine with many therapeutic effects such as antipruritic, analgesic and insecticidal effects. In recent years, various studies have revealed sanshool as the main bioactive ingredient of Zanthoxylum bungeanum Maxim. It can bind to a variety of ion channels and receptors, exerting wide-ranging biological and pharmacological activities including analgesic effects, intestinal protection, hypoglycemic effects and other effects. The relevant pharmacokinetics, drug targets and pharmacological effects were reviewed in this paper to provide a reference for the systematic research of sanshool and the development of new drugs.

Pathological function of transient receptor potential canonical 6 channel in key central nervous system diseases:its prospects as drug targets / 中国药理学与毒理学杂志

Transient receptor potential canonical 6 (TRPC6) is a non-selective cation channel, which is involved in various physiological processes, including neuronal axonal growth cone guidance, promotion of dendritic growth and excitatory synaptic formation.Recent studies have shown that TRPC6 participates in many pathological process of central nervous system (CNS) diseases. Therefore, this review focuses on physiological roles of TRPC6,and its pathological roles in CNS,i.e.stroke,Alzheimer disease and epilepsy. We go on to discuss the research development of TRPC6 as drug targets.Finally,we overview and discuss the problems to be solved in further research, and the prospect of TRPC6 as a promising target for drug development.

Regulatory effects of GRK2 on GPCRs and possible use as a drug target / 中国药理学与毒理学杂志

G protein-coupled receptor kinase 2 (GRK2), as a key Ser/Thr protein kinase, belong to the member of the G protein-coupled receptor kinase (GRK) family. The C-terminus of GRK2 including a plekstrin homology domain and the N-terminus of GRK2 including the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors (GPCRs), G protein, phospholipase C, phosphatidylinositol 4,5-bisphosphate, extracellular signal-regulated kinase, protein kinase A and Gβγ, which can regulate the activity of GRK2. GRK2 can regulate GPCR desensitization and internalization by phosphorylating the GPCR, promoting the affinity of binding to arrestins, and uncoupling the receptors from G proteins, which play an important role in maintaining the balance between the receptors and signal transduction. Previous studies have indicated that cardiac GRK2 overexpression can promote the phosphorylation of β-adrenergic receptor (βAR) leading to βAR desen?sitization and internalization, which play a pivotal role in inducing heart failure (HF)-related dysfunction and myocyte death. GRK2, as a regulator of cell function, is overexpression in hypertension. Overex?pression GRK2 can inhibit Akt/eNOS signaling pathway and decreased the production and activation of eNOS leading to endothelial dysfunction. Collagen-induced arthritis induces the upregulation of GRK2 expression in fibroblast- like synoviocytes. In this review, we mainly discussed the evidence for the association between GRK2 overexpression and various diseases, which suggests that GRK2 may be an effective drug target for preventing and treating heart failure, hypertension and inflammatory disease.

Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases.

The bromodomains and extra-terminal domain (BET) family proteins recognize acetylated chromatin through their bromodomains (BDs) and help in regulating gene expression. BDs are chromatin ‘readers’: by interacting with acetylated lysines on the histone tails, they recruit chromatin-regulating proteins on the promoter region to regulate gene expression and repression. Extensive efforts have been employed by scientific communities worldwide to identify and develop potential inhibitors of BET family BDs to regulate protein expression by inhibiting acetylated histone (H3/H4) interactions. Several small molecule inhibitors have been reported, which not only have high affinity but also have high specificity to BET BDs. These developments make BET family proteins an important therapeutic targets for major diseases such as cancer, neurological disorders, obesity and inflammation. Here, we review and discuss the structural biology of BET family BDs and their applications in major diseases.

The gene polymorphisms of drug targets in Pneumocystis jiroveci isolates / 中华传染病杂志

Objective To investigate gene polymorphisms of drug targets and mutations associated with drug resistance in Pneumocystis jiroveci (P.jiroveci) isolates.Methods Among 148 samples isolated from human immunodeficiency virus (HIV)infected patients with pneumonia in Guangdong,mitochondrid larg subunit rRNA (mtLSUrRNA) gene was amplified from 51 samples.Dihydropteroate synthase (DHPS),dihydrofolate reductase (DHFR) and Cytochrome b (CYB) genes of P.jiroveci were detected by gene sequencing,and compared with the reference sequences in GenBank to evaluate gene polymorphisms.Results P.jirovecii DHPS,DHFR and CYB genes were all successfully amplified from 51 samples.For DHPS gene,48 (94.1％) were wild-type and 3 (5.9％) had gene mutation associated with drug resistance.For DHFR gene,30 were wild-type,and 21 had a synonymous mutation at position 312,and 1 nonsynonymous mutation at position 188.There were no mutations associated with drug resistance.For CYB gene,polymorphisms of were detected at 5 sites,4 of which were synonymous mutations,1 was non-synonymous mutation.No mutation associated with drug resistance was found.Based on the gene polymorphism of CYB6,the strains can be classified into 6 genotypes,and 2 were first detected,including 25 CYB1,13 CYB2,2 CYB5,4 CYB8,as well as newly detected 4 CYB10 and 3 CYB11 strains.Conclusions The mutations associated with drug resistance in P.jiroveci isolates in Guangdong remain uncommon.CYB gene shows gene polymorphisms and can be selected as one of targeted genes for multilocus sequence typing.

Hepatitis B virus replication mechanisms and drug targets of chronic hepatitis B / 中国药理学通报

Hepatits B virus( HBV) infection is a global epidemic which seriously harms the public health. In spite of the great progress in hepatits B prevention and treatment, there is few ef-fective medicine. Research findings show that liver damage and degree of liver failure are sophisticatedly related to the interaction between HBV and the immune response of host. All these make it important to know the replication mechanism and the contrac-tion process, in order to lay a preliminary solid foundation for studying HBV drug targets and making a new ant-virus strategy. This article aims to summarize HBV viral replication process, while focusing on the latest research findings about drug targets, to find a new kind of anti-HBV drugs, and to explore the under-lying mechanism of effective drugs.

Research advances on regulatory effect of RhoA on myocardial ischemia reperfusion injury / 中国药理学通报

RhoA belongs to the small G binding proteins Rho subfamily, playing an important role in the various cellular func-tions, including migration, proliferation, adhesion and apopto-sis. Recent data indicate that RhoA/ROCK pathway causes myo-cardial damage by influencing the myocardial energy metabolism, inflammation, and endoplasmic reticulum stress. On the other hand, the activation of RhoA also has a positive role in MIRI. This article reviews the regulatory effect of RhoA on MIRI and its mechanisms, discusses the prospects of RhoA as a novel thera-peutic target for MIRI, and provides new therapeutic treatments and strategies for MIRI.

Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes

The worldwide prevalence of obesity is steadily increasing, nearly doubling between 1980 and 2008. Obesity is often associated with insulin resistance, a major risk factor for type 2 diabetes mellitus (T2DM): a costly chronic disease and serious public health problem. The underlying cause of T2DM is a failure of the beta cells of the pancreas to continue to produce enough insulin to counteract insulin resistance. Most current T2DM therapeutics do not prevent continued loss of insulin secretion capacity, and those that do have the potential to preserve beta cell mass and function are not effective in all patients. Therefore, developing new methods for preventing and treating obesity and T2DM is very timely and of great significance. There is now considerable literature demonstrating a link between inhibitory guanine nucleotide-binding protein (G protein) and G protein-coupled receptor (GPCR) signaling in insulin-responsive tissues and the pathogenesis of obesity and T2DM. These studies are suggesting new and emerging therapeutic targets for these conditions. In this review, we will discuss inhibitory G proteins and GPCRs that have primary actions in the beta cell and other peripheral sites as therapeutic targets for obesity and T2DM, improving satiety, insulin resistance and/or beta cell biology.

Analysis of projects funded by National Natural Science Foundation of China (NSFC) in field of pharmacology during 2004~2013 / 中国药理学通报

Pharmacology can be defined as the study of sub-stances that interact with living systems through chemical proces-ses. Pharmacology plays an important role to bridge the transla-tional gap between the basic medicine and clinical medicine. In this article, the projects in pharmacology funded by NSFC during 2004~2013 were reviewed. The new features and new problems in the projects of pharmacology were briefly analyzed.

Studies on cell death and survival regulatory protein c-FLIP as a target for cancer treatment / 中国药理学通报

Many tumor cells are resistant to cell apoptosis through the expression of antiapoptotic proteins. c-FLIP is a ma-jor resistance protein of antiapoptosis. In human cells, there are three types of c-FLIP, c-FLIPL , c-FLIPS and c-FLIPR . The c-FLIP binds to FADD to prevent the formation of procaspase-8-DISC and the subsequent activation of caspase cascade. Further-more, c-FLIPL and c-FLIPS have multifunctional roles in various cellular signaling pathways, as well as up-regulating several cyto-protective signaling. Studies show that upregulation of c-FLIP has been found in various tumors, and its downregulation has been shown to restore apoptosis triggered by various chemothera-peutic agents, like the transcriptional regulating agents, trichos-tatin-A, camptothecin, cisplatin, doxorubicin, etc. or other new biotechnologies, such as the specific siRNA. Therefore, c-FLIPS are important targets of cancer therapy. This review summarizes the results on the role of c-FLIP in cancer chemotherapy of tradi-tional antitumor agents and siRNA, and to provide new ideas and rationales of searching for the antiapoptosis effective compounds that can specifically antagonize c-FLIP.

Role of macrophage polarization in atherosclerosis and its drug target / 中国药理学通报

Atherosclerosis is a complex metabolic cardiovascular disease. such inflammatory phenomena as the invasion of lipid into the arterial intima and accumulation, the increase of foam cells, the exacerbation of inflammatory lesions, plaque necrosis and disintegration, ulcer bleeding and thrombosis, fibrosis and calcification, etc, are basic pathological characteristics of ather-osclerosis. In this process, macrophages and T lymphocytes play an important role. In recent years,atherosclerosis pathology re-search mainly focuses on the role of macrophage polarization. Basically,macrophage can be divided into two subtypes: classi-cal activation macrophage M1 and alternative activation macro-phage M2. Therefore to paper reviews the meaning of M1 and M2 macrophage polarization during atherosclerosis, regulatory pathways and drug targets research status to provide new direc-tion for innovative drugs and disease treatment.

Protease inhibitors in potential drug development for leishmaniasis.

Leishmaniasis is a deadly protozoan parasitic disease affecting millions of people worldwide. The treatment strategy of Leishmania infection depends exclusively on chemotherapy till date. But the treatment of the disease is greatly hampered due to high cost, toxicity of the available drugs and more importantly emergence of drug resistance. Hence the potential new drugs are highly needed to combat this disease. The first and foremost step of the drug discovery process is to search and select the putative target in a specific biological pathway in the parasite that should be either unambiguously absent in the host or considerably different from the host homolog. Importantly, Leishmania genome sequences enrich our knowledge about Leishmania and simultaneously reinforce us to identify the ideal drug targets that distinctly exist in the parasite as well as to develop the effective drugs for leishmaniasis. Though the leishmanial research has significantly progressed during the past two decades, the identification of suitable drug targets or development of effective drugs to combat leishmaniasis is far from satisfactory. Enzymatic systems of Leishmania metabolic and biochemical pathways are essential for their survival and infection. Concurrently, it is noteworthy that Leishmania proteases, especially the cysteine proteases, metalloproteases and serine proteases have been extensively investigated and found to be indispensable for the survival of the parasites and disease pathogenesis. Herein, we have discussed the importance of few enzymes, particularly the Leishmania proteases and their inhibitors as promising candidates for potential development of anti-leishmanial drugs.