Insights into dietary phytochemicals targeting Parkinson's disease key genes and pathways: A network pharmacology approach.

Parkinson's disease (PD) is a complex neurological disease associated with the degeneration of dopaminergic neurons. Oxidative stress is a key player in instigating apoptosis in dopaminergic neurons. To improve the survival of neurons many dietary phytochemicals have gathered significant attention recently. Thus, the present study implements a comprehensive network pharmacology approach to unravel the mechanisms of action of dietary phytochemicals that benefit disease management. A literature search was performed to identify ligands (i.e., comprising dietary phytochemicals and Food and Drug Administration pre-approved PD drugs) in the PubMed database. Targets associated with selected ligands were extracted from the search tool for interactions of chemicals (STITCH) database. Then, the construction of a gene-gene interaction (GGI) network, analysis of hub-gene, functional and pathway enrichment, associated transcription factors, miRNAs, ligand-target interaction network, docking were performed using various bioinformatics tools together with molecular dynamics (MD) simulations. The database search resulted in 69 ligands and 144 unique targets. GGI and subsequent topological measures indicate histone acetyltransferase p300 (EP300), mitogen-activated protein kinase 1 (MAPK1) or extracellular signal-regulated kinase (ERK)2, and CREB-binding protein (CREBBP) as hub genes. Neurodegeneration, MAPK signaling, apoptosis, and zinc binding are key pathways and gene ontology terms. hsa-miR-5692a and SCNA gene-associated transcription factors interact with all the 3 hub genes. Ligand-target interaction (LTI) network analysis suggest rasagiline and baicalein as candidate ligands targeting MAPK1. Rasagiline and baicalein form stable complexes with the Y205, K330, and V173 residues of MAPK1. Computational molecular insights suggest that baicalein and rasagiline are promising preclinical candidates for PD management.

Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19.

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.

Identifying potential drug targets and candidate drugs for COVID-19: biological networks and structural modeling approaches.

Background: Coronavirus (CoV) is an emerging human pathogen causing severe acute respiratory syndrome (SARS) around the world. Earlier identification of biomarkers for SARS can facilitate detection and reduce the mortality rate of the disease. Thus, by integrated network analysis and structural modeling approach, we aimed to explore the potential drug targets and the candidate drugs for coronavirus medicated SARS. Methods: Differentially expression (DE) analysis of CoV infected host genes (HGs) expression profiles was conducted by using the Limma. Highly integrated DE-CoV-HGs were selected to construct the protein-protein interaction (PPI) network.  Results: Using the Walktrap algorithm highly interconnected modules include module 1 (202 nodes); module 2 (126 nodes) and module 3 (121 nodes) modules were retrieved from the PPI network. MYC, HDAC9, NCOA3, CEBPB, VEGFA, BCL3, SMAD3, SMURF1, KLHL12, CBL, ERBB4, and CRKL were identified as potential drug targets (PDTs), which are highly expressed in the human respiratory system after CoV infection. Functional terms growth factor receptor binding, c-type lectin receptor signaling, interleukin-1 mediated signaling, TAP dependent antigen processing and presentation of peptide antigen via MHC class I, stimulatory T cell receptor signaling, and innate immune response signaling pathways, signal transduction and cytokine immune signaling pathways were enriched in the modules. Protein-protein docking results demonstrated the strong binding affinity (-314.57 kcal/mol) of the ERBB4-3cLpro complex which was selected as a drug target. In addition, molecular dynamics simulations indicated the structural stability and flexibility of the ERBB4-3cLpro complex. Further, Wortmannin was proposed as a candidate drug to ERBB4 to control SARS-CoV-2 pathogenesis through inhibit receptor tyrosine kinase-dependent macropinocytosis, MAPK signaling, and NF-kb singling pathways that regulate host cell entry, replication, and modulation of the host immune system. Conclusion: We conclude that CoV drug target "ERBB4" and candidate drug "Wortmannin" provide insights on the possible personalized therapeutics for emerging COVID-19.

Are the Allergic Reactions of COVID-19 Vaccines Caused by mRNA Constructs or Nanocarriers? Immunological Insights.

The Food and Drug Administration (FDA) has recently authorized the two messenger RNA (mRNA) vaccines BNT162b2 and mRNA-1273 for emergency use against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the COVID-19 coronavirus disease. BNT162b2 and mRNA-1273 vaccines were developed by Pfizer-BioNTech and Moderna, respectively, in 2020. The United Kingdom, Bahrain, Canada, Mexico, United States, Singapore, Oman, Saudi Arabia, Kuwait, and European Union began their vaccination programs with the BNT162b2 vaccine, while the United States and Canada also started the mRNA-1273 vaccination program in mid December 2020. On 28th December 2020, studies reported severe allergic reactions in people who received the BNT162b2, and few people who received the mRNA-1273 vaccine. Authors of the letter thus attempt to explore possible causes of anaphylaxis following COVID-19 vaccination.

Circulating miR-1246 Targeting UBE2C, TNNI3, TRAIP, UCHL1 Genes and Key Pathways as a Potential Biomarker for Lung Adenocarcinoma: Integrated Biological Network Analysis.

Analysis of circulating miRNAs (cmiRNAs) before surgical operation (BSO) and after the surgical operation (ASO) has been informative for lung adenocarcinoma (LUAD) diagnosis, progression, and outcomes of treatment. Thus, we performed a biological network analysis to identify the potential target genes (PTGs) of the overexpressed cmiRNA signatures from LUAD samples that had undergone surgical therapy. Differential expression (DE) analysis of microarray datasets, including cmiRNAs (GSE137140) and cmRNAs (GSE69732), was conducted using the Limma package. cmiR-1246 was predicted as a significantly upregulated cmiRNA of LUAD samples BSO and ASO. Then, 9802 miR-1246 target genes (TGs) were predicted using 12 TG prediction platforms (MiRWalk, miRDB, and TargetScan). Briefly, 425 highly expressed overlapping miRNA-1246 TGs were observed between the prediction platform and the cmiRNA dataset. ClueGO predicted cell projection morphogenesis, chemosensory behavior, and glycosaminoglycan binding, and the PI3K-Akt signaling pathways were enriched metabolic interactions regulating miRNA-1245 overlapping TGs in LUAD. Using 425 overlapping miR-1246 TGs, a protein-protein interaction network was constructed. Then, 12 PTGs of three different Walktrap modules were identified; among them, ubiquitin-conjugating enzyme E2C (UBE2C), troponin T1(TNNT1), T-cell receptor alpha locus interacting protein (TRAIP), and ubiquitin c-terminal hydrolase L1(UCHL1) were positively correlated with miR-1246, and the high expression of these genes was associated with better overall survival of LUAD. We conclude that PTGs of cmiRNA-1246 and key pathways, namely, ubiquitin-mediated proteolysis, glycosaminoglycan binding, the DNA metabolic process, and the PI3K-Akt-mTOR signaling pathway, the neurotrophin and cardiomyopathy signaling pathway, and the MAPK signaling pathway provide new insights on a noninvasive prognostic biomarker for LUAD.

Integrated PPI- and WGCNA-Retrieval of Hub Gene Signatures Shared Between Barrett's Esophagus and Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a deadly cancer with high mortality rate, especially in economically advanced countries, while Barrett's esophagus (BE) is reported to be a precursor that strongly increases the risk of EAC. Due to the complexity of these diseases, their molecular mechanisms have not been revealed clearly. This study aims to explore the gene signatures shared between BE and EAC based on integrated network analysis. We obtained EAC- and BE-associated microarray datasets GSE26886, GSE1420, GSE37200, and GSE37203 from the Gene Expression Omnibus and ArrayExpress using systematic meta-analysis. These data were accompanied by clinical data and RNAseq data from The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis were conducted to explore the relationship between gene sets and clinical traits as well as to discover the key relationships behind the co-expression modules. A differentially expressed gene-based protein-protein interaction (PPI) complex was used to extract hub genes through Cytoscape plugins. As a result, 403 DEGs were excavated, comprising 236 upregulated and 167 downregulated genes, which are involved in the cell cycle and replication pathways. Forty key genes were identified using modules of MCODE, CytoHubba, and CytoNCA with different algorithms. A dark-gray module with 207 genes was identified which having a high correlation with phenotype (gender) in the WGCNA. Furthermore, five shared hub gene signatures (SHGS), namely, pre-mRNA processing factor 4 (PRPF4), serine and arginine-rich splicing factor 1 (SRSF1), heterogeneous nuclear ribonucleoprotein M (HNRNPM), DExH-Box Helicase 9 (DHX9), and origin recognition complex subunit 2 (ORC2), were identified between BE and EAC. SHGS enrichment denotes that RNA metabolism and splicosomes play a key role in esophageal cancer development and progress. We conclude that the PPI complex and WGCNA co-expression network highlight the importance of phenotypic identifying hub gene signatures for BE and EAC.

A theoretical study of chemical bonding and topological and electrostatic properties of the anti-leprosy drug dapsone.

The theoretical charge density study for the gas phase of anti-leprosy drug Dapsone has been carried out in the light of the theory of atoms in molecules using density functional theory employing B3LYP(6-311G++(d, p) hybrid functional completed with dispersion corrections. The Hirshfeld surface analysis as well as fingerprint plots has been utilized to visualize and quantify the intermolecular contacts present in the molecule. The topological properties such as electron density and its Laplacian, delocalization index have been elucidated to throw light into the chemical bonding and atomic and molecular details. The electron localization function has been used to visualize and deduce information on the lone pair and the subshells of the Cl atom. The electrostatic potential visualizes the positive and negative electrostatic potential regions which are susceptible to nucleophilic and electrophilic attack. On the whole, this study provides an exact mechanism, interaction, and topological and electrostatic properties of the drug through theoretical insights which all will be a platform for our further investigation of the interaction between dapsone and dihydropteroate synthase (DHPS).

Ion Channels as Therapeutic Targets for Type 1 Diabetes Mellitus.

Ion channels are integral proteins expressed in almost all living cells and are involved in muscle contraction and nutrient transport. They play a critical role in the normal functioning of the excitable tissues of the nervous system and regulate the action potential and contraction events. Dysfunction of genes encodes ion channel proteins, which disrupt the channel function and lead to a number of diseases, among which is type 1 diabetes mellitus (T1DM). Therefore, understanding the complex mechanism of ion channel receptors is necessary to facilitate the diagnosis and management of treatment. In this review, we summarize the mechanism of important ion channels and their potential role in the regulation of insulin secretion along with the limitations of ion channels as therapeutic targets. Furthermore, we discuss the recent investigations of the mechanism regulating the ion channels in pancreatic beta cells, which suggest that ion channels are active participants in the regulation of insulin secretion.

Combining in silico and in vitro approaches to identification of potent inhibitor against phospholipase A2 (PLA2).

Phospholipase A2 (PLA2) is the main constituent of snake venom. PLA2 enzymes catalyze the Ca2+ dependent hydrolysis of 2-acyl ester bonds of 3-sn-phospholipids, releasing fatty acids and lysophospholipids. Inside the body of the victim, PLA2 from snake venom induces either direct or indirect pathophysiological effects, including anticoagulant, inflammatory, neurotoxic, cardiotoxic, edematogenic, and myotoxic activities. Therefore, there is a need to find the potential inhibitors against PLA2 responsible for snakebite. In this study, we employed in silico and in vitro methods to identify the potential inhibitor against PLA2. Virtual screening and molecular docking studies were performed to find potent inhibitor against PLA2 using Traditional Chinese Medicine Database (TCM). Based on these studies, Scutellarin (TCM3290) was selected and calculated by density functional theory calculation at B3LYP/6-31G**++ level to explore the stereo-electronic features of the molecule. Further, molecular docking and DFT of Minocycline was carried out. Quantum polarized ligand docking was performed to optimize the geometry of the protein-ligand complexes. The protein-ligand complexes were subjected to molecular dynamics simulation and binding free energy calculations. The residence time of a protein-ligand complex is a critical parameter affecting natural influences in vitro. It is nonetheless a challenging errand to expect, regardless of the accessibility of incredible PC assets and a large variety of computing procedures. In this metadynamics situation, we used the conformational flooding technique to deal with rank inhibitors constructions. The systematic free energy perturbation (FEP) protocol and calculate the energy of both complexes. Finally, the selected compound of TCM3290 was studied in vitro analysis such as inhibition of PLA2 activity, hyaluronidase activity and fibrinogenolytic activity. The TCM3290 had a more binding affinity compare to Minocycline, and interacted with the key residues of TYR63 and GLY31. DFT represented the highest HOMO and LUMO energy of 0.15146 eV. MD simulation with 100 ns proved that an inhibitor binding mode is more stable inside the binding site of PLA2. In vitro analysis shows that TCM3290 significantly neutralized by PLA2. The above observations confirmed that Scutellarin (TCM3290) had a potent snake venom neutralizing capacity and could hypothetically be used for therapeutic drives of snakebite envenomation.

Viewing the Emphasis on State-of-the-Art Magnetic Nanoparticles: Synthesis, Physical Properties, and Applications in Cancer Theranostics.

Cancer-related mortality is a leading cause of death among both men and women around the world. Target-specific therapeutic drugs, early diagnosis, and treatment are crucial to reducing the mortality rate. One of the recent trends in modern medicine is "Theranostics," a combination of therapeutics and diagnosis. Extensive interest in magnetic nanoparticles (MNPs) and ultrasmall superparamagnetic iron oxide nanoparticles (NPs) has been increasing due to their biocompatibility, superparamagnetism, less-toxicity, enhanced programmed cell death, and auto-phagocytosis on cancer cells. MNPs act as a multifunctional, noninvasive, ligand conjugated nano-imaging vehicle in targeted drug delivery and diagnosis. In this review, we primarily discuss the significance of the crystal structure, magnetic properties, and the most common method for synthesis of the smaller sized MNPs and their limitations. Next, the recent applications of MNPs in cancer therapy and theranostics are discussed, with certain preclinical and clinical experiments. The focus is on implementation and understanding of the mechanism of action of MNPs in cancer therapy through passive and active targeting drug delivery (magnetic drug targeting and targeting ligand conjugated MNPs). In addition, the theranostic application of MNPs with a dual and multimodal imaging system for early diagnosis and treatment of various cancer types including breast, cervical, glioblastoma, and lung cancer is reviewed. In the near future, the theranostic potential of MNPs with multimodality imaging techniques may enhance the acuity of personalized medicine in the diagnosis and treatment of individual patients.

Exploring the Papillomaviral Proteome to Identify Potential Candidates for a Chimeric Vaccine against Cervix Papilloma Using Immunomics and Computational Structural Vaccinology.

The human papillomavirus (HPV) 58 is considered to be the second most predominant genotype in cervical cancer incidents in China. HPV type-restriction, non-targeted delivery, and the highcost of existing vaccines necessitate continuing research on the HPV vaccine. We aimed to explore the papillomaviral proteome in order to identify potential candidates for a chimeric vaccine against cervix papilloma using computational immunology and structural vaccinology approaches. Two overlapped epitope segments (23⁻36) and (29⁻42) from the N-terminal region of the HPV58 minor capsid protein L2 are selected as capable of inducing both cellular and humoral immunity. In total, 318 amino acid lengths of the vaccine construct SGD58 contain adjuvants (Flagellin and RS09), two Th epitopes, and linkers. SGD58 is a stable protein that is soluble, antigenic, and non-allergenic. Homology modeling and the structural refinement of the best models of SGD58 and TLR5 found 96.8% and 93.9% favored regions in Rampage, respectively. The docking results demonstrated a HADDOCK score of -62.5 ± 7.6, the binding energy (-30 kcal/mol) and 44 interacting amino acid residues between SGD58-TLR5 complex. The docked complex are stable in 100 ns of simulation. The coding sequences of SGD58 also show elevated gene expression in Escherichia coli with 1.0 codon adaptation index and 59.92% glycine-cysteine content. We conclude that SGD58 may prompt the creation a vaccine against cervix papilloma.

Prognostic Impact of Tissue Inhibitor of Metalloproteinase-1 in Non- Small Cell Lung Cancer: Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) is a multifunctional natural matrixin inhibitor that is generally considered a negative regulator of cancer metastasis. Clinical studies reporting the prognostic value of TIMP-1 in Non-small Cell Lung Cancer (NSCLC) are inconsistent. Therefore, the present study aimed to determine the prognostic impact of TIMP-1 expression in NSCLC. METHODS: Appropriate studies with full-text articles were identified in searches of the China National Knowledge Infrastructure (CNKI), Cochrane Library, PubMed, and Web of Science databases up to March 7, 2018. The pooled Hazard Ratio (HR) of overall survival with a 95% confidence interval (95% CI) was employed to assess the relationship between the expression of TIMP-1 and NSCLC patient survival. RESULTS: The meta-analysis comprised 40 studies including 3,194 patients. Study outcomes indicated that high TIMP-1 expression is independently associated with poor overall survival (HR: 1.60; 95% CI: 1.50, 1.69; P < 0.00001) with 61% of heterogeneity. In addition, we analyzed subgroups, including ethnicities, histological types, percentage of TIMP-1 expression levels, specimens, and tumor stage. All results were statistically significant. The outcome of our meta-analysis indicates that high expression levels of TIMP-1 are correlated with poor prognosis in patients with NSCLC. CONCLUSION: Expression levels of TIMP-1 represent a potential prognostic biomarker in NSCLC patients in addition to being a possible therapeutic target.

Cancer Immunoinformatics: A Promising Era in the Development of Peptide Vaccines for Human Papillomavirus-induced Cervical Cancer.

Cancer immunoinformatics have led to new directions towards vaccine design from predicted potential epitope candidates, which are able to stimulate the correct cellular or humoral immune responses. They were employed to accomplish an advanced vaccine design through reverse vaccinology by replacing the whole organisms. In this review, computational tools play an essential role in evaluating multiple proteomes to identify and select the potential targeted epitopes or combinations of distinct epitopes, so that candidates may afford a rationale design competent for obtaining suitable cytotoxic T lymphocytes (CTL) or B cell-mediated immune responses. This review is a complete collection of the most beneficial online and user-friendly immunological tools, servers, and databases for the design and development of the peptide vaccine. The mechanism of major histocompatability (MHC)-restricted peptide presentation and how these tools support the vaccine development are also presented. The human papillomavirus (HPV) is taken as a model microbial strain for peptide vaccine design and its sensitization against HPV-induced cervical cancer is discussed.

Designing of CD8+ and CD8+-overlapped CD4+ epitope vaccine by targeting late and early proteins of human papillomavirus.

BACKGROUND AND AIM: Human papillomavirus (HPV) is an oncogenic agent that causes over 90% of cases of cervical cancer in the world. Currently available prophylactic vaccines are type specific and have less therapeutic efficiency. Therefore, we aimed to predict the potential species-specific and therapeutic epitopes from the protein sequences of HPV45 by using different immunoinformatics tools. METHODS: Initially, we determined the antigenic potential of late (L1 and L2) and early (E1, E2, E4, E5, E6, and E7) proteins. Then, major histocompatibility complex class I-restricted CD8+ T-cell epitopes were selected based on their immunogenicity. In addition, epitope conservancy, population coverage (PC), and target receptor-binding affinity of the immunogenic epitopes were determined. Moreover, we predicted the possible CD8+, nested interferon gamma (IFN-γ)-producing CD4+, and linear B-cell epitopes. Further, antigenicity, allergenicity, immunogenicity, and system biology-based virtual pathway associated with cervical cancer were predicted to confirm the therapeutic efficiency of overlapped epitopes. RESULTS: Twenty-seven immunogenic epitopes were found to exhibit cross-protection (≥55%) against the 15 high-risk HPV strains (16, 18, 31, 33, 35, 39, 51, 52, 56, 58, 59, 68, 69, 73, and 82). The highest PC was observed in Europe (96.30%), North America (93.98%), West Indies (90.34%), North Africa (90.14%), and East Asia (89.47%). Binding affinities of 79 docked complexes observed as global energy ranged from -10.80 to -86.71 kcal/mol. In addition, CD8+ epitope-overlapped segments in CD4+ and B-cell epitopes demonstrated that immunogenicity and IFN-γ-producing efficiency ranged from 0.0483 to 0.5941 and 0.046 to 18, respectively. Further, time core simulation revealed the overlapped epitopes involved in pRb, p53, COX-2, NF-X1, and HPV45 infection signaling pathways. CONCLUSION: Even though the results of this study need to be confirmed by further experimental peptide sensitization studies, the findings on immunogenic and IFN-γ-producing CD8+ and overlapped epitopes provide new insights into HPV vaccine development.

Identification of target gene and prognostic evaluation for lung adenocarcinoma using gene expression meta-analysis, network analysis and neural network algorithms.

BACKGROUND: Lung adenocarcinoma (LUAD) is a heterogeneous disease with poor survival in the advanced stage and a high incidence rate in the world. Novel drug targets are urgently required to improve patient treatment. Therefore, we aimed to identify therapeutic targets for LUAD based on protein-protein and protein-drug interaction network analysis with neural network algorithms using mRNA expression profiles. RESULTS: A comprehensive meta-analysis of selective non-small cell lung cancer (NSCLC) mRNA expression profile datasets from Gene Expression Omnibus were used to identify potential biomarkers and the molecular mechanisms related to the prognosis of NSCLC patients. Using the Network Analyst tool, based on combined effect size (ES) methods, we recognized 6566 differentially expressed genes (DEGs), which included 3036 downregulated and 3530 upregulated genes linked to NSCLC patient survival. ClueGO, a Cytoscape plugin, was exploited to complete the function and pathway enrichment analysis, which disclosed "regulated exocytosis", "purine nucleotide binding", "pathways in cancer", and "cell cycle" between exceptionally supplemented terms. Enrichr, a web tool examination, demonstrated "early growth response protein 1 (EGR-1)", "hepatocyte nuclear factor 4α (HNF4A)", "mitogen-activated protein kinase 14 (MAP3K14)", and "cyclin-dependent kinase 1 (CDK1)" to be among the most prevalent TFs and kinases associated with NSCLC. Our meta-analysis identified that MAPK1 and aurora kinase (AURKA) are the most obvious class of hub nodes. Furthermore, protein-drug interaction network and neural network algorithms identified candidate drugs such as phosphothreonine and 4-(4-methylpiperazin-1-yl)-n-[5-(2-thienylacetyl)-1,5-dihydropyrrolo[3,4-c]pyrazol-3-yl] benzamide and for the targets MAPK1 and AURKA, respectively. CONCLUSION: Our study has identified novel candidate biomarkers, pathways, transcription factors (TFs), and kinases associated with NSCLC prognosis, as well as drug candidates, which may assist treatment strategy for NSCLC patients.

Effect of Glycosin alkaloid from Rhizophora apiculata in non-insulin dependent diabetic rats and its mechanism of action: In vivo and in silico studies.

BACKGROUND AND AIM: Diabetes mellitus is a complex multifactorial disorder that remains a great challenging task in the clinical practice. Rhizophora apiculata from Indian medicinal mangrove is widely used to treat inflammation, wound healing and diabetes. Bioassay guided fractionation was followed to isolate Glycosin from the ethanolic extract of R. apiculata. The antidiabetic effect of Glycosin in diabetic rats was investigated and determined their possible mechanism of action. METHODS: Diabetes was induced in adult Wistar rats by a single intraperitoneal injection of streptozotocin and nicotinamide. Based on the oral glucose tolerance test, Glycosin (50mg/kg b.wt.) was orally administrated to diabetic rats for a period of 45 days. In different intervals, blood glucose and body weight were recorded. After 45 days, blood samples were collected to determine serum lipid profile, level of plasma insulin, hemoglobin, liver, and kidney functions using the appropriate tests. In addition the levels of carbohydrate metabolic enzymes in the liver homogenate were also measured. To determine the molecular mechanism of action, we followed the molecular docking of Glycosin in its possible targets, dipeptidyl peptidase-IV (DPP-IV), Peroxisome proliferator-activated receptor gamma (PPARγ), phosphorylated insulin receptor, and protein tyrosine phosphatase 1B (PTP-1B). RESULTS: Glycosin treatment significantly (p<0.01) reduced the blood-glucose level, increased the body weight, increase hemoglobin, high-density lipoprotein and insulin level, protein, in addition the activity of hexokinase when compared to untreated rats. Decreased activities of liver function enzymes as well as level of urea, and creatinine were observed in Glycosin treated rats. Docking simulation confirmed that Glycosin interacted with DPP-IV, Insulin receptor and PTP-1B and PPARγ with more affinity and binding energy. CONCLUSION: Glycosin acts as antihyperglycemic agent, associated with antihyperlipidemic and possibility function as a ligand for proteins that are targets for antidiabetes drugs.

Anti-nociceptive effect in mice of thillai flavonoid rutin.

We investigated the anti-nociceptive effect of Excoecaria agallocha (E.agallocha) against chemically and thermally induced nociception, Albino mice received a dose of 10, 15, 20, or 25 mg/kg of alkaline chloroform fraction (Alk-CF) of E.agallocha by oral administration. Compared with controls, Alk-CF decreased the writhing numbers (P<0.01) in a dose dependent manner. Further we determined that, Alk-CF contained, a potent compared to control, also potent anti-nociceptive agent that acted via opioid receptors and using HPLC, identified this compound as Rutin. Docking simulation demonstrated that Rutin interacted strongly with cyclooxygenase, forming a number of specific hydrogen bonds. In conclusion we have identified peripheral and central anti-nociceptive activities of E.agallocha that involve opioid receptor, and in which the active compound is Rutin.