Risk Factors of Depression Screened by Two-Sample Mendelian Randomization Analysis: A Systematic Review / 生物医学与环境科学（英文）

OBJECTIVE@#This study explored the potentially modifiable factors for depression and major depressive disorder (MDD) from the MR-Base database and further evaluated the associations between drug targets with MDD.@*METHODS@#We analyzed two-sample of Mendelian randomization (2SMR) using genetic variant depression ( n = 113,154) and MDD ( n = 208,811) from Genome-Wide Association Studies (GWAS). Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes. The MR analysis was performed by screening drug targets with MDD in the DrugBank database to explore the therapeutic targets for MDD. Inverse variance weighted (IVW), fixed-effect inverse variance weighted (FE-IVW), MR-Egger, weighted median, and weighted mode were used for complementary calculation.@*RESULTS@#The potential causal relationship between modifiable risk factors and depression contained 459 results for depression and 424 for MDD. Also, the associations between drug targets and MDD showed that SLC6A4, GRIN2A, GRIN2C, SCN10A, and IL1B expression are associated with an increased risk of depression. In contrast, ADRB1, CHRNA3, HTR3A, GSTP1, and GABRG2 genes are candidate protective factors against depression.@*CONCLUSION@#This study identified the risk factors causally associated with depression and MDD, and estimated 10 drug targets with significant impact on MDD, providing essential information for formulating strategies to prevent and treat depression.

The Structure and Function of the Bunyavirus Nucleoprotein / 中国生物化学与分子生物学报

Bunyavirus is widely distributed, highly contagious, and has a high fatality rate. It is a negative- strand RNA virus that has a major impact on public health around the world. The development of vaccines and the search for drugs are the key to prevent bunyavirus infection. The nucleoprotein (NP) of viruses is necessary for the synthesis of viral RNA, which combines with viral RNA to form the nucleocapsid, participates in viral assembly and RNA transcription, and plays an important role in viral proliferation. In addition, NP also has B cell and T cell epitopes, which can induce cellular and humoral immunity, so NP is an ideal target for vaccine design and drug development. Given its abundance and specificity, NP is also commonly used in the detection of viral diseases. More and more bunyavirus NP structures and structures of NP-RNA complexes have been resolved. Researchers have discovered two important antiviral targets through these structures, the terminal arm and the RNA binding cleft. This paper reviews the function and three-dimensional structure of the bunyavirus NP and the research progress of NP as an antiviral target, in order to provide a theoretical basis for the prevention and treatment of the bunyavirus disease.

Mechanisms of Euphorbia fischeriana steud. alcohol extracts intreatment of HCC based on network pharmacology and experiment verification / 中国药理学通报

Aim To investigate the molecular mechanisms of alcohol extracts of Euphorbia fischeriana steud. against hepatocellular carcinoma (HCC) through a combination of network pharmacology analysis and experimental validation. Methods The active ingredients and targets of alcohol extracts of Euphorbia fischeriana steud. were determined through TCMSP, Swiss ADME, Swiss Target Prediction database and references. The databases DisGeNET and GeneCards were employed to screen potential HCC-related genes. Venny platform, STRING platform and Cytoscape software were applied to construct active ingredient-target-disease and protein-protein interaction (PPI) network maps. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed using the DAVID database. To assess the effects of Euphorbia fischeriana steud. alcohol extracts on BEL-7402 cells, the proliferation and apoptosis were detected by CCK-8, EdU and flow cytometry assays, and the related protein levels of JAK2/STAT3 pathway were analyzed by Western blot. Additionally, H22 hepatocellular carcinoma mouse model was used to evaluate the in vivo efficacy of Euphorbia fischeriana steud. alcohol extracts. Results A total of 916 HCC targeted genes, 30 active ingredients containing the related 567 potential targeted genes, and 115 intersection targets of disease and compounds were obtained. KEGG enrichment analysis identified JAK2/STAT3 signaling as a critical pathway. In vitro experiments showed the alcohol extracts of Euphorbia fischeriana steud. could inhibit proliferation, promote apoptosis and suppress JAK2/STAT3 signaling pathway in a dose-dependent manner in BEL-7402 cells. In addition, the alcohol extracts of Euphorbia fischeriana steud., either alone or in combination with sorafenib, dramatically blocked tumor growth in in vivo tests. Conclusions Euphorbia fischeriana steud. alcohol extracts have anti-cancer effects in HCC, and the molecular mechanisms may be connected to the regulation of JAK2/STAT3 signaling pathway.

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.

Sodium Channel NaV1. 7 and Neuropathic Pain / 中国生物化学与分子生物学报

Sodium channel Nav1. 7 is one of the subtypes of voltage-gated sodium channel. Most of it is expressed on the nociceptors of small C fibers in dorsal root ganglion (DRG). It has the characteristics of slow opening and slow closing of inactivation. It can produce a large amount of ramp current, reduce the threshold of action potential in sensory neurons, and amplify the external small and slow depolarization ramp current. Thus, it can increase the excitability of neurons and play a key role in the generation, transmission and regulation of pain. With the deepening of genetic research, Nav1. 7 channel has become a particularly attractive drug target in new analgesic therapy due to its function acquired mutation and function deletion mutation. However, the study found that Nav1. 7 channel improves neuronal excitability and participates in neuropathic pain through different ways in neuropathic pain caused by different factors, which has brought great obstacles to the research and development of Nav1. 7 selective inhibitors. Although the existing Nav1. 7 selective inhibitors have effective analgesic effects without obvious side effects or addiction problems, it is extremely difficult to find Nav1. 7 selective ligands. In addition, the existing Nav1. 7 selective inhibitors also differ in inhibitory efficacy, targeting, safety and feasibility due to different types of neuropathic pain. It is suggested that finding the general mechanism of Nav1. 7 channel acting on different neuropathic pain or the specific receptor binding site of Nav1. 7 channel may be the main direction of the research and development of Nav1. 7 selective inhibitors in the future. This paper briefly reviews the main role of Nav1. 7 channel in neuropathic pain caused by different factors.

Research progress of potential anti-tumor and anti-inflammatory target PARP14 / 中国药理学通报

PARP14 is an intracellular single AI)P-ribose transferase member of the superfamily of polyADP-ribose polymerases.PARP14 is associated with a wide range of biochemical transfor-mations in vivo through poly( ADP-ribosylation, PAKs) modifi- cation of target proteins.For example, it plays an important part in eellular transcriptional regulation, stress response, DNA re-pair, RNA splieing, mitoehondrial function, division, and nu- cleosome formation.PAR PI 4 is elosely related to the development and progression of cancers (such as hepatoeellular carcino- ma, multiple myeloma and pancreatic cancer) , metabolie diseases, and inflammatory diseases, making it a potential dnig dis- eovery target.This research reviews the structure and biological functions of PARP14, and summarizes the role of PARP14 in disease, as well as the existing PARP14 small molecule inhibitors and decompressors.It provides a brief update to the research and development of PARP14 inhibitors and decompressors to assist in the development of selective PARP14 inhibitors and decompressors.It provides reference for the research and development of drugs or chemical sensitizers targeting PARP14.

Biochemical characterization of the recombinant schistosome tegumental protein SmALDH_312 produced in E. coli and baculovirus expression vector system

BACKGROUND The heterologous expression of parasitic proteins is challenging because the sequence composition often differs significantly from host preferences. However, the production of such proteins is important because they are potential drug targets and can be screened for interactions with new lead compounds. Here we compared two expression systems for the production of an active recombinant aldehyde dehydrogenase (SmALDH_312) from Schistosoma mansoni, which causes the neglected tropical disease schistosomiasis. RESULTS We produced SmALDH_312 successfully in the bacterium Escherichia coli and in the baculovirus expression vector system (BEVS). Both versions of the recombinant protein were found to be active in vitro, but the BEVS-derived enzyme showed 3.7-fold higher specific activity and was selected for further characterization. We investigated the influence of Mg2+, Ca2+ and Mn2+, and found out that the specific activity of the enzyme increased 1.5-fold in the presence of 0.5 mM Mg2+. Finally, we characterized the kinetic properties of the enzyme using a design-of-experiment approach, revealing optimal activity at pH 7.6 and 41C. CONCLUSIONS Although, E. coli has many advantages, such as rapid expression, high yields and low costs, this system was outperformed by BEVS for the production of a schistosome ALDH. BEVS therefore rovides an opportunity for the expression and subsequent evaluation of schistosome enzymes as drug targets

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.

Neutrophil extracellular traps and its role in gouty diseases / 中国临床药理学与治疗学

Neutrophil extracellular traps (NETs) are an important part of the innate immunity. They are mainly involved in the occurrence of gout disease through NADPH oxidase 2-dependent pathways and it is related to the spontaneous remission of gouty arthritis and the formation of tophi. These pathological features can be analyzed by methods such as electron microscopy and immunohistochemical staining. In order to further explore the molecular mechanism of NETs and discover potential drug targets for gouty arthritis, this article summarizes its role in gouty diseases and related detection techniques.

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.

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.