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Abstract Background Interferon and nucleos(t)ide analogues are current therapeutic treatments for chronic Hepatitis B virus (HBV) infection with the limitations of a functional cure. Chrysin (5, 7-dihydroxyflavone) is a natural flavonoid, known for its antiviral and hepatoprotective activities. However, its anti-HBV activity is unexplored. Methods In the present study, the anti-hepatitis B activity of chrysin was investigated using the in vitro experimental cell culture model, HepG2 cells. In silico studies were performed where chrysin and lamivudine (used here as a positive control) were docked with high mobility group box 1 protein (HMGB1). For the in vitro studies, wild type HBV genome construct (pHBV 1.3X) was transiently transfected in HepG2. In culture supernatant samples, HBV surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) were measured by enzyme-linked immunosorbent assay (ELISA). Secreted HBV DNA and intracellular covalently closed circular DNA (cccDNA) were measured by SYBR green real-time PCR. The 3D crystal structure of HMGB1 (1AAB) protein was developed and docked with the chrysin and lamivudine. In silico drug-likeness, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties of finest ligands were performed by using SwissADME and admetSAR web servers. Results Data showed that chrysin significantly decreases HBeAg, HBsAg secretion, supernatant HBV DNA and cccDNA, in a dose dependent manner. The docking studies demonstrated HMGB1 as an important target for chrysin as compared to lamivudine. Chrysin revealed high binding affinity and formed a firm kissing complex with HMGB1 (∆G = − 5.7 kcal/mol), as compared to lamivudine (∆G = − 4.3 kcal/mol), which might be responsible for its antiviral activity. Conclusions The outcome of our study establishes chrysin as a new antiviral against HBV infection. However, using chrysin to treat chronic HBV disease needs further endorsement and optimization by in vivo studies in animal models. Graphical Abstract

Introduction: Sentrin-specific protease 1 (SENP1) is a protein whose main function is deSUMOylation. SENP1 inhibits apoptosis, and increases angiogenesis, estrogen and androgen receptor transcription and c-Jun transcription factor, proliferation, growth, cell migration, and invasion of cancer. The in vivo and in vitro studies also demonstrated which natural compounds, especially phytochemicals, minerals, and vitamins, prevent cancer. More than 3,000 plant species have been reported in modern medicine. Natural compounds have many anti-cancerous andanti-turmeric properties such as antioxidative, antiangiogenic, antiproliferative, and pro-apoptotic properties.Methods: In this study, we investigated the interaction of some natural compounds with SENP1 to inhibit its activity. We also screened the ZINC database including natural compounds. Molecular docking was performed, and toxicity of compounds was determined; then, molecular dynamics simulation (MDS) and essential dynamics (ED) were performed on natural compounds with higher free binding energies and minimal side effects. By searching in a large library, virtual screening of the ZINC database was performed using LibDock and CDOCKER, and the final top 20 compounds were allowed for docking against SENP1. According to the docking study, the top three leading molecules were selected and further analyzed by MDS and ED.Results: The results suggest that resveratrol (from the selected compounds) and ZINC33916875 (from the ZINC database) could be more promising SENP1 inhibitory ligands.Discussion: Because these compounds can inhibit SENP1 activity, then they can be novel candidates for cancer treatment. However, wet laboratory experiments are needed to validate their efficacy as SENP1 inhibitors.

Vitamins are important micronutrients and are often precursors of enzymes that living cells need to perform biochemical reactions. Because humans cannot biosynthesize most vitamins, therefore, they must be obtained exogenously. Although a variety of vitamins are found in most foods, many people's vitamin deficiencies still occur mainly due to malnutrition as a result of inadequate food consumption or poor eating habits. In this review article, the potential of lactic acid (LAB) and bifidobacteria probiotics is investigated as an inexpensive and terminating solution to this problem. Probiotics can produce important vitamins in the microbiome, including vitamin A, vitamin D, vitamin K, vitamin B12, and so on. Therefore, increasing the ratio of probiotics in the microbiome is one of the important ways to eliminate vitamin deficiency. The gut microbiome plays an important role in health and disease as personalized medicine. The results also showed that Lactobacillus reuteri and L. rhamnosus could be the best choices for producing a set of vitamins needed by a person in terms of diversity by producing B‐group vitamins, vitamin K2 and vitamin D.

Aims: Sentrin-specific protease -2 (SENP2) is involved in deSUMOylation. Increased deSUMOylation in murine hearts by SENP2 upregulation resulted in cardiac dysfunction and congenital heart defects. Natural compounds via regulating cell proliferation and survival, induce cell cycle cessation, cell death, apoptosis, and producing reactive oxygen species and various enzyme systems cause disease prevention. Then, natural compounds can be suitable inhibitors and since SENP2 is a protein involved in heart disease, so our aim was inhibition of SENP2 by natural products for heart disease treatment. Material and methods: Molecular docking and molecular dynamics simulation of natural products i.e. Gallic acid (GA), Caffeic acid (CA), Thymoquinone (TQ), Betanin, Betanidin, Fisetin, and Ebselen were done to evaluate the SENP2 inhibitory effect of these natural products. The toxicity of compounds was also predicted. Results: The results showed that Betanin constituted a stable complex with SENP2 active site as it revealed low RMSD, high binding energy, and hydrogen bonds. Further, as compared to Ebselen, Betanin demonstrated low toxicity, formed a stable complex with SENP2 via four to seven hydrogen bonds, and constituted more stable MD plots. Therefore, depending upon the outcomes presented herein, Betanin significantly inhibited SENP2 and hence may be considered as a suitable natural compound for the treatment of heart failure. Further clinical trials must be conducted to validate its use as a potential SENP2 inhibitor.

Background & Objective: Leishmaniasis is taken into account as a parasitic disease caused by the Leishmania genus. A major challenge of the leishmaniasis is associated with the occurrence of treatment failure after drug treatment. Target identification is a significant factor to reach a drug development. Hence, protein kinases play an important role in drug designing (e.g, LmxMPK and CRK3). This study is developed to predict and assess the three-dimensional structure for E9BJT5 protein in Leishmania and its binding affinity for different calcium channel blockers. Materials & Methods: The three-dimensional structure was predicted and assessed for the protein by the I-TASSER and Procheck servers, respectively. In the molecular docking method, interactions between different calcium channel blockers and the predicted model of E9BJT5 were investigated using the Autodock vina in PyRx 0.8 software. Thereafter, the interaction results were analyzed by Chimera software, and thus the stronger potential interactions were identified. Results: Docking results showed that the lidoflazine and lercanidipine (the values were -8.3 and -7.6 kcal/mol, respectively) were obtained as the top-ranked drugs in the binding to the active site of the protein. Conclusion: In this study, using in silico approach, the E9BJT5 protein could be a viable target for designing the novel drugs against the Leishmania parasite. The docking results demonstrated that two drugs (i.e., lidoplasin and lercantipine) may be considered as anti-leishmanial drugs. Further studies are recommended to evaluate the interactions between these drugs and the target.

Sentrin specific-protease 1 (SENP1) is a protein involved in deSUMOylation that is almost overexpressed in cancer. SENP1 has a determinative role in the activation of transcription programs in the innate immune responses and the development B of and C lymphocytes. We found, SENP1 possibly plays a critical role in immune infiltration and acts as an expression marker in PAAD, ESCA, and THYM. CD4+ T cells, CD8+ T cells, and macrophages were more key-related immune cells, indicating that SENP1 might be introduced as a potential target for cancer immunotherapy. We further showed that dysregulation of SENP1 is powerfully associated with decreased patient survival and clinical stage. Total SENP1 protein also increases in cancer. SENP1 is also controlled by transcription factors (TFs) CREB1, KDM5A, REST, and YY1 that regulates apoptosis, cell cycle, cell proliferation, invasion, tumorigenesis, and metastasis. These TFs were in a positive correlation with SENP1. MiR-138–5p, miR-129-1-3p, and miR-129-2-3p also inhibit tumorigenesis through targeting of SENP1. The SENP1 expression level positively correlated with the expression levels of UBN1, SP3, SAP130, NUP98, NUP153 in 32 tumor types. SENP1 and correlated and binding genes: SAP130, NUP98, and NUP153 activated cell cycle. Consistent with this finding, drug analysis was indicated SENP1 is sensitive to cell cycle, apoptosis, and RTK signaling regulators. In the end, SENP1 and its expression-correlated and functional binding genes were enriched in cell cycle, apoptosis, cellular response to DNA damage stimulus. We found that the cell cycle is the main way for tumorigenesis by SENP1. SENP1 attenuates the effect of inhibitory drugs on the cell cycle. We also introduced effective FDA-Approved drugs that can inhibit SENP1. Therefore in the treatments in which these drugs are used, SENP1 inhibition is a suitable approach. This study supplies a wide analysis of the SENP1 across The Cancer Genome Atlas (CGA) cancer types. These results suggest the potential roles of SENP1 as a biomarker for cancer. Since these drugs and the drugs that cause to resistance are applied to cancer treatment, then these two class drugs can use to inhibition of SENP1.

Microglial activation can release free radicals and various pro-inflammatory cytokines, which implicates the progress of a neurodegenerative disease. Therefore suppression of microglial activation can be an appropriate strategy for combating neurodegenerative diseases. Betanin is a red food dye that acts as free radical scavenger and can be a promising candidate for this purpose. In this study, purification of betanin from red beetroots was carried out by normal phase colum chromatography, yielding 500 mg of betanin from 100 g of red beetroot. The purified betanin was evaluated by TLC, UV-visible, HPLC, ESI-MASS, FT-IR spectroscopy. Investigation on the inhibitory effect of betanin on activated microglia was performed using primary microglial culture. The results showed that betanin significantly inhibited lipopolysaccharide induced microglial function including the production of nitric oxide free radicals, reactive oxygen species, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β). Moreover, betanin modulated mitochondrial membrane potential, lysosomal membrane permeabilization and adenosine triphosphate. We further investigated the interaction of betanin with TNF-α, IL-6 and Nitric oxide synthase (iNOS or NOS2) using in silico molecular docking analysis. The docking results demonstrated that betanin have significant negative binding energy against active sites of TNF-α, IL-6 and iNOS.

Background: According to the World Allergy Organization (WAO), approximately 20% of the global population suffer from allergies. Allergic diseases are significant due to their high prevalence, and also due to the constant increase in their healthcare cost and their adverse effects on human life. Probiotics have been proposed as an intervention for the prevention and treatment of allergic diseases. Different mechanisms have been considered for the presence of probiotic properties, such as detecting related molecular patterns, including DNA motifs, through interaction with host immune systems by Toll-like receptors. Methods: We investigated the frequencies of Immunosuppressive motifs, which were extracted from earlier studies in the genome sequences of microbiota strains, and then the ratio was re-evaluated per million. Results: Lactobacillus ruminis, L. rhamnosus, L. casei, L. paracasei, and L. mucosae which are considered as probiotic species, have the highest frequency of immunosuppressive motifs among other probiotic species and pathogens. Conclusions: The effects of the immunomodulatory potential of probiotics and especially Lactobacillus spp. require validation for clinical application. Investigation of these immunosuppressive motifs and their anti-allergic effects related to the genomes of probiotics, can also be used for designing a package of probiotic bacteria to reduce allergenicity, and for implementing a new technique to ameliorate allergic disease. Keywords: Package of probiotic, Lactobacillus, Allergy, Immunosuppressive motif, Toll-like receptor-9

Gastric cancer is one of the most fatal cancers in the world. Many efforts in recent years have attempted to find effective proteins in gastric cancer. By using a comprehensive list of proteins involved in gastric cancer, scientists were able to retrieve interaction information. The study of protein-protein interaction networks through systems biology based analysis provides appropriate strategies to discover candidate proteins and key biological pathways.In this study, we investigated dominant functional themes and centrality parameters including betweenness as well as the degree of each topological clusters and expressionally active sub-networks in the resulted network. The results of functional analysis on gene sets showed that neurotrophin signaling pathway, cell cycle and nucleotide excision possess the strongest enrichment signals. According to the computed centrality parameters, HNF4A, TAF1 and TP53 manifested as the most significant nodes in the interaction network of the engaged proteins in gastric cancer. This study also demonstrates pathways and proteins that are applicable as diagnostic markers and therapeutic targets for future attempts to overcome gastric cancer. Keywords: Gastric cancer, Systems biology, Neurotrophin signaling pathway, HNF4A, TAF1, TP53

Allergens are proteins or glycoproteins which make widespread disorders that can lead to a systemic anaphylactic shock and even death within a short period of time. Understanding the protein features that are involved in allergenicity is important in developing future treatments as well as engineering proteins in genetic transformation projects. A big dataset of 1439 protein features from 761 plant allergens and 7815 non-allergen proteins was constructed. Thereafter, 10 different attribute weighting algorithms were utilized to find the key characteristics differentiating allergens and non-allergen proteins. The frequency of Leu, Arg and Gln selected by different attribute weighting algorithms with more than 50% confidence, including attribute weighting by Weight_Info Gain, Weight Chi Squared, Weight_Gini Index and Weight_Relief. High amount of Gln and low percentage of Leu and Arg discriminate plant allergens from non-allergens

During recent years, there has been exponential growth in biological information. With the emergence of large datasets in biology, life scientists are encountering bottlenecks in handling the biological data. This study presents an integrated geographic information system (GIS)-ontology application for handling microbial genome data. The application uses a linear referencing technique as one of the GIS functionalities to represent genes as linear events on the genome layer, where users can define/change the attributes of genes in an event table and interactively see the gene events on a genome layer. Our application adopted ontology to portray and store genomic data in a semantic framework, which facilitates data-sharing among biology domains, applications, and experts. The application was developed in two steps. In the first step, the genome annotated data were prepared and stored in a MySQL database. The second step involved the connection of the database to both ArcGIS and Protégé as the GIS engine and ontology platform, respectively. We have designed this application specifically to manage the genome-annotated data of rumen microbial populations. Such a GIS-ontology application offers powerful capabilities for visualizing, managing, reusing, sharing, and querying genome-related data.

Increasing evidence demonstrates that inflammation and endoplasmic reticulum (ER) stress is implicated in the development and progression of age-related macular degeneration (AMD), a multifactorial neurodegenerative disease. However the cross talk between these cellular mechanisms has not been clearly and fully understood. The present study investigates a possible intersection between ER stress and inflammation in AMD. In this study, we recruited two collections of involved protein markers to retrieve their interaction information from IMEx-curated databases, which are the most well- known protein-protein interaction collections, allowing us to design an intersection network for AMD that is unprecedented. In order to find expression activated subnetworks, we utilized AMD expression profiles in our network. In addition, we studied topological characteristics of the most expressed active subnetworks to identify the hubs. With regard to topological quantifications and expressional activity, we reported a list of the most pivotal hubs which are potentially applicable as probable therapeutic targets. Furthermore, we introduced MAPK signaling pathway as a significantly involved pathway in the association between ER stress and inflammation, leading to promising new directions in discovering AMD formation mechanisms and possible treatments.

Background: The ability of tumour suppressor protein p53 (P53) to regulate cell cycle processes can be modulated by hepatitis B virus (HBV). While preliminary evidences indicates the involvement of protein-x of HBV (HBx) in altering p53 DNA binding, no further data have been accumulated for the significance of serum p53 in chronic hepatitis B virus infected patients. Methods: 72 non-cirrhotic and 19 cirrhotic patients infected by HBV were enrolled for the analysis in this study. Enzyme linked immunosorbent assay (ELISA) was performed to study the concentrations of serum p53 protein. The tertiary structures of HBx and P53 were docked by Z-dock and Hex servers for in-silico protein-protein interaction analysis. Results: There was a significant association between the serum p53 and cirrhosis (OR=1.81 95% CI: 1.017-3.2, P=0.044). Cirrhotic patients had higher level of serum p53 compare with chronic infection of HBV (1.98±1.22 vs. 1.29±0.72 U/ml, P=0.05). No evidence of correlation was seen between the different variables such as age, gender, log viral load, serum alkaline phosphatase (ALP) and alanine aminotransferase (ALT) with serum p53. Tertiary model shows that the amino acid residues from Arg110 to Lys132 of the N-terminal of P53 which is critical for ubiquitination, are bonded to a region in N- terminal of HBx amino acid residues from Arg19 to Ser33. Conclusion: There is an increase in serum p53 in HBV-related cirrhosis patients. In this case, HBx might be responsible for such higher concentration of p53 through HBx-p53 protein-protein interaction, as is shown by molecular modeling approach.

مقدمه: ناشنوایی یک اختلال شایع می‌باشد که به طور معمول، هتروژنی ژنتیکی را در جمعیت‌های انسانی نشان می‌دهد. بروز ناشنوایی مادرزادی به میزان 1 در هر 500 تولد محاسبه شده است که حدود 70 درصد این موارد به عوامل ژنتیکی نسبت داده می‌شوند. نقص ژنتیکی ناشنوایی به دو نوع سندرمیک و غیر سندرمیک دسته‌بندی می‌شود و در میان ناشنوایی‌های غیر سندرمیک نوع اتوزومال مغلوب (ARNSHL یا Autosomal, recessive, non-syndromic hearing loss) برای حدود 80-75 درصد موارد محاسبه می‌شود. این نوع از ناشنوایی بسیار هتروژن می‌باشد و بیش از 100 لوکوس را شامل می‌شود. برای ناشنوایی مغلوب، شایع‌ترین ژن‌های مورد بررسی در سراسر جهان شامل 2GJB ، 4A26SLC، A15MYO، OTOF و 23CDH می‌باشند. بنابراین هدف این مطالعه، تعیین نقش موتاسیون‌های ژن A15MYO (3DFNB) در خانواده‌های ایرانی به وسیله‌ی آنالیز پیوستگی می‌باشد. روش‌ها: در این مطالعه، برای بررسی فراوانی لوکوس 3DFNB در ناشنوایی، آنالیز پیوستگی در 30 خانواده‌ی ایرانی با بیش از سه فرد ناشنوا و منفی برای ژن 2GJB انجام شد. شجره‌های با موتاسیون منفی برای ژن 2GJB برای پیوستگی به لوکوس 3DFNB با استفاده از نشانگرهای STR (Short tandem repeat) مورد بررسی قرار گرفتند. یافته‌ها: موتاسیون delG35 در 5 خانواده از 30 خانواده‌ی مورد بررسی به وسیله‌ی تعیین توالی ناحیه‌ی کد کننده‌ی ژن 2GJB شناسایی شد. در میان بقیه‌ی خانواده‌ها، یک خانواده به لوکوس 3DFNB پیوستگی نشان داد. نتیجه‌گیری: بر اساس نتایج این مطالعه و سایر مطالعات، لوکوس 3DFNB در جمعیت ایرانی سومین عامل ناشنوایی بعد از 1DFNB (2GJB) و 4DFNB (4A26SLC) می‌باشد.

BACKGROUND: T-cells play an important role in the immune response and are activated in response to the presentation of antigens bound to major histocompatibility complex (MHC) molecules participating with the T-cell receptor (TCR). T-cell receptor complexes also contain four CD3 (cluster of differentiation 3) subunits. The TCR-CD3 complex is vital for T-cell development and plays an important role in intervening cell recognition events. Since microRNAs (miRNAs) are highly stable in blood serum, some of which may target CD3 molecules, they could serve as good biomarkers for early cancer detection. The aim of this study was to see whether there is a relationship between cancers and the amount of miRNAs -targeted CD3 molecules. METHODS: Bioinformatics tools were used in order to predict the miRNA targets for these genes. Subsequently, these highly conserved miRNAs were evaluated to see if they are implicated in various kinds of cancers. Consequently, human disease databases were used. According to the latest research, this study attempted to investigate the possible down- or upregulation of miRNAs cancer patients. RESULTS: We identified miRNAs which target genes producing CD3 subunit molecules. The most conserved miRNAs were identified for the CD3G gene, while CD247 and CD3EAP genes had the least number and there were no conserved miRNA associated with the CD3D gene. Some of these miRNAs were found to be responsible for different cancers, following a certain pattern. CONCLUSIONS: It is highly likely that miRNAs affect the CD3 molecules, impairing the immune system, recognizing and destroying cancer tumor; hence, they can be used as suitable biomarkers in distinguishing cancer in the very early stages of its development.

Background: There is a novel hypothesis in that antibodies may have specificity for two distinct antigens that have been named "dual specificity." This hypothesis was evaluated for some defined therapeutic monoclonal antibodies (mAbs) such as Trastuzumab, Pertuzumab, Bevacizumab, and Cetuximab. In silico design and construction of expression vectors for trastuzumab monoclonal antibody also in this work were performed. Materials and Methods: First, in bioinformatics studies the 3D structures of concerned mAbs were obtained from the Protein Data Bank (PDB). Three-dimensional structural alignments were performed with SIM and MUSTANG softwares. AutoDock4.2 software also was used for the docking analysis. Second, the suitable genes for trastuzumab heavy and light chains were designed, synthesized, and cloned in the prokaryotic vector. These fragments individually were PCR amplified and cloned into pcDNA™ 3.3-TOPO® and pOptiVEC™ TOPO® shuttle vectors, using standard methods. Results: First, many bioinformatics tools and softwares were applied but we did not meet any new dual specificity in the selected antibodies. In the following step, the suitable expression cascade for the heavy and light chains of Trastuzumab therapeutic mAb were designed and constructed. Gene cloning was successfully performed and created constructs were confirmed using gene mapping and sequencing. Conclusions: This study was based on a recently developed technology for mAb expression in mammalian cells. The obtained constructs could be successfully used for biosimilar recombinant mAb production in CHO DG44 dihydrofolate reductase (DHFR) gene deficient cell line in the suspension culture medium.