Association between hair dye use and cancer in women: a systematic review and meta-analysis of case-control studies.

Background: The use of hair dye for cosmetic purposes appears to be increasing worldwide. As 50-80% of women use hair dye throughout their lifetimes, the possible association between hair dye use and cancer is a public health concern. Method: This systematic review was performed by retrieving studies from PubMed, Scopus, WOS, and ProQuest databases. The inclusion criteria were case-control studies evaluating the association between hair dye use and cancer in women. Women with cancer who have used any hair dye were the focus of our study. Results: The present study combined 28 studies, to assess the association between hair dye use and cancer. The pooled odds ratio (OR) of hematopoietic system cancers among those who have generally ever used any type of hair dyes was 1.10 (95% CI:1.01-1.20) in 17 studies. In 11 studies investigating hair dye made before and after 1980 as a risk factor for cancer, the pooled OR for cancer was 1.31(95% CI:1.08-1.59). Likewise, in the 13 studies that evaluated the association of light and dark hair dye with cancer, the risk among those using dark hair dye increased by 9%, compared to non-users (OR=1.09; 95% CI:0.95-1.25). Conclusion: The present study suggests that, although the use of hair dye may increase the risk of cancer among users, a more detailed evaluation is required to assess the type of hair dye use in terms of guidelines and metrics.

Telmisartan anti-cancer activities mechanism through targeting N-cadherin by mimicking ADH-1 function.

This study aimed to investigate if Telmisartan as a novel N-cadherin antagonist, can overcome cell migration of cancer cells. We investigated the mechanism and influence of Docetaxel and Telmisartan (as an analogous to ADH-1, which is a well-known N-cadherin antagonist) on cancer cells. The effect of ADH-1 and Telmisartan on cell attachment in PC3, DU145, MDA-MB-468 cell lines using recombinant human N-cadherin was studied. Cell viability assay was performed to examine the anti-proliferative effects of Telmisartan, ADH-1 and Docetaxel. Migration was examined via wound healing assay, and apoptosis was determined by flow cytometry. The expression of AKT-1 as a downstream gene of N-cadherin signalling pathway was assayed by real-time PCR. Treatment of PC3, MDA-MB-468 and DU145 cells with Telmisartan (0.1 µM) and ADH-1 (40 µM) resulted in 50%, 58% and approximately 20% reduction in cell attachment to N-cadherin coated plate respectively. It shows reduction of cell attachment in PC3 and MDA-MB-468 cell lines appeared to be more sensitive than that of DU145 cells to the Telmisartan and ADH-1 treatments. Telmisartan (0.1 µM) and Docetaxel (0.01 nM) significantly reduced cell migration in PC3 and MDA-MB-468 cell lines compared with the control group. Using Real-time PCR, we found that Telmisartan, Docetaxel and ADH-1 had significant influence on the AKT-1 mRNA level. The results of the current study for the first time suggest that, Telmisartan, exerts anti-proliferation and anti-migration effects by targeting antagonistically N-cadherin. Also, these data suggest that Telmisartan as a less expensive alternative to ADH-1 could potentiate Docetaxel anticancer effects.

Designing a therapeutic and prophylactic candidate vaccine against human papillomavirus through vaccinomics approaches.

OBJECTIVE: Human papillomavirus (HPV) is the main cause of cervical cancer, the 4th prominent cause of death in women globally. Previous vaccine development projects have led to several approved prophylactic vaccines available commercially, all of which are made using major capsid-based (L1). Administration of minor capsid protein (L2) gave rise to the second generation investigational prophylactic HPV vaccines, none of which are approved yet due to low immunogenicity provided by the L2 capsid protein. On the other hand, post-translation proteins, E6 and E7, have been utilized to develop experimental therapeutic vaccines. Here, in silico designing of a therapeutic and prophylactic vaccine against HPV16 is performed. METHODS: In this study, several immunoinformatic and computational tools were administered to identify and design a vaccine construct with dual prophylactic and therapeutic applications consisting of several epitope regions on L2, E6, and E7 proteins of HPV16. RESULTS: Immunodominant epitope regions (aa 12-23 and 78-78 of L2 protein, aa 11-27 of E6 protein, and aa 70-89 of E7 protein) were employed, which offered adequate immunogenicity to induce immune responses. Resuscitation-promoting factors (RpfB and RpfE) of Mycobacterium tuberculosis were integrated in two separate constructs as TLR4 agonists to act as vaccine adjuvants. Following physiochemical and structural evaluations carried out by various bioinformatics tools, the designed constructs were modeled and validated, resulting in two 3D structures. Molecular docking and molecular dynamic simulations suggested stable ligand-receptor interactions between the designed construct and TLR4. CONCLUSION: Ultimately, this study led to suggest the designed construct as a potential vaccine candidate with both prophylactic and therapeutic applications against HPV by promoting Th1, Th2, CTL, and B cell immune responses, which should be further confirmed in experimental studies.

A systems pharmacology approach to identify the autophagy-inducing effects of Traditional Persian medicinal plants.

Aging is correlated with several complex diseases, including type 2 diabetes, neurodegeneration diseases, and cancer. Identifying the nature of this correlation and treatment of age-related diseases has been a major subject of both modern and traditional medicine. Traditional Persian Medicine (TPM) embodies many prescriptions for the treatment of ARDs. Given that autophagy plays a critical role in antiaging processes, the present study aimed to examine whether the documented effect of plants used in TPM might be relevant to the induction of autophagy? To this end, the TPM-based medicinal herbs used in the treatment of the ARDs were identified from modern and traditional references. The known phytochemicals of these plants were then examined against literature for evidence of having autophagy inducing effects. As a result, several plants were identified to have multiple active ingredients, which indeed regulate the autophagy or its upstream pathways. In addition, gene set enrichment analysis of the identified targets confirmed the collective contribution of the identified targets in autophagy regulating processes. Also, the protein-protein interaction (PPI) network of the targets was reconstructed. Network centrality analysis of the PPI network identified mTOR as the key network hub. Given the well-documented role of mTOR in inhibiting autophagy, our results hence support the hypothesis that the antiaging mechanism of TPM-based medicines might involve autophagy induction. Chemoinformatics study of the phytochemicals using docking and molecular dynamics simulation identified, among other compounds, the cyclo-trijuglone of Juglans regia L. as a potential ATP-competitive inhibitor of mTOR. Our results hence, provide a basis for the study of TPM-based prescriptions using modern tools in the quest for developing synergistic therapies for ARDs.

In Silico Elucidation of Deleterious Non-synonymous SNPs in SHANK3, the Autism Spectrum Disorder Gene.

SHANK3, a member of SH3 and multiple ankyrin repeat domains (SHANK) proteins, plays a crucial role in synaptic development and functions. Mutations in SHANK3 have been linked to a number of neuropsychiatric and neurodevelopmental disorders, including autism spectrum disorder. In this study, the functional and structural impacts of non-synonymous single-nucleotide polymorphisms (SNPs) on SHANK3 were predicted. Various databases were used to extract 16,894 non-redundant SNPs, out of which 1179 were annotated as missense variants. Missense variants were categorized as deleterious or non-deleterious. Twenty-nine missense variants were unanimously recognized as deleterious and subjected to structural and stability analyses. Mutations, including L47P, G54W, G172D, G250C/D, and G627E, which posed drastic effects on the secondary structure of SHANK3, were modeled. Stability analyses introduced L47P, G54W, and G250D as the most destabilizing mutations, thus they were subjected to molecular dynamics simulation. Simulation revealed significant changes in intramolecular interactions and high fluctuations in residues of 1-350 that significantly affect the ANK functional domain. G250C/D and G635R consensus deleterious mutations were found in the first and second binding domains of SHANK3, and none were found in the post-translational modification sites. This study suggests L47P, G54W, and G250C/D deleterious mutations as priorities for future studies on SHANK3.

Designing self-assembled peptide nanovaccine against Streptococcus pneumoniae: An in silico strategy.

Streptococcus pneumoniae is the main cause of diseases such as meningitis, pneumoniae and sepsis, especially in children and old people. Due to costly antibiotic treatment, and increasing resistance of pneumococcus, developing high-efficient protective vaccine against this pathogen is an urgent need. Although the pneumoniae polysaccharide vaccine (PPV) and pneumonia conjugate vaccines (PCV) are the efficient pneumococcal vaccine in children and adult groups, but the serotype replacement of S. pneumoniae strains causes the reduction in efficacy of such vaccines. For overcoming the aforesaid drawbacks epitope-based vaccines are introduced as the relevant alternative. In our previous research, the epitope vaccine was designed based on immunodominant epitopes from PspA, CbpA antigens as cellular stimulants and PhtD, PiuA as humoral stimulants. Because the low immunogenicity is the main disadvantage of epitope vaccine, in the current study, we applied coiled-coil self-assembled structures for developing our vaccine. Recently, self-assembled peptide nanoparticles (SAPNs) have gained much attention in the field of vaccine development due to their multivalency, self-adjuvanticity, biocompatibility, and size similarity to pathogen. In this regard, the final designed vaccine is comprised of cytotoxic T lymphocytes (CTL) epitopes from PspA and CbpA, helper T lymphocytes (HTL) epitopes from PhtD and PiuA, the pentamer and trimmer oligomeric domains form 5-stranded and 3-stranded coiled-coils as self-assembled scaffold, Diphtheria toxoids (DTD) as a universal T-helper, which fused to each other with appropriate linkers. The four different arrangements based on the order of above-mentioned compartments were constructed, and each of them were modeled, and validated to find the 3D structure. The structural, physicochemical, and immunoinformatics analyses of final vaccine construct represented that our vaccine could stimulate potent immune response against S. pneumoniae; however, the potency of that should be approved via various in vivo and in vitro immunological tests.

Selected application of peptide molecules as pharmaceutical agents and in cosmeceuticals.

Introduction: Peptide molecules are being vastly investigated as an emerging class of therapeutic molecules in recent years. Currently, 60 peptides have been approved by the US Food and Drug Administration (FDA), and more would enter the market in near future. Peptides have already opened their ways into cosmeceutical and food industries as well.Areas covered: Antibodies, vaccines, and antimicrobial agents are the major classes of therapeutic peptides. Additionally, peptides may be employed in drug development to support cell penetration or targeting. The interest in antimicrobial peptides is surging due to the increasing risk of antibiotic-resistant pathogens. Peptide vaccines with their significant advantages compared with traditional vaccines, are expected to find their place in coming years, especially for cancer, microbial and allergen-specific immunotherapy. The usage of peptides in cosmeceuticals is also growing rapidly.Expert opinion: Peptide synthesis has become accessible, and advances in peptide engineering, sequencing technologies, and structural bioinformatics have resulted in the rational designing of novel peptides. All these advancements would lead to the more prominent roles of peptides in the mentioned areas. In this review, we discuss applications of peptides in different fields including pharmaceuticals, cosmeceuticals, besides the critical factors in designing efficient peptide molecules.

Decreasing the immunogenicity of Erwinia chrysanthemi asparaginase via protein engineering: computational approach.

Immunogenicity of therapeutic proteins is one of the main challenges in disease treatment. L-Asparaginase is an important enzyme in cancer treatment which sometimes leads to undesirable side effects such as immunogenic or allergic responses. Here, to decrease Erwinase (Erwinia chrysanthemiL-Asparaginase) immunogenicity, which is the main drawback of the enzyme, firstly conformational B cell epitopes of Erwinase were predicted from three-dimensional structure by three different computational methods. A few residues were defined as candidates for reducing immunogenicity of the protein by point mutation. In addition to immunogenicity and hydrophobicity, stability and binding energy of mutants were also analyzed computationally. In order to evaluate the stability of the best mutant, molecular dynamics simulation was performed. Among mutants, H240A and Q239A presented significant reduction in immunogenicity. In contrast, the immunogenicity scores of D235A slightly decreased according to two servers. Binding affinity of substrate to the active site reduced significantly in K265A and E268A. The final results of molecular dynamics simulation indicated that H240A mutation has not changed the stability, flexibility, and the total structure of desired protein. Overall, point mutation can be used for reducing immunogenicity of therapeutic proteins, in this context, in silico approaches can be used to screen suitable mutants.

Computational approach to suggest a new multi-target-directed ligand as a potential medication for Alzheimer's disease.

Acetylcholinesterase (AChE) enzyme and myeloid differentiation 2 protein (MD2) are two critical proteins involved in Alzheimer's disease (AD). Since the nature of the active site of AChE and the binding pocket of MD2 are similar, some ligands can inhibit both of them appropriately. Oxidative stress has also been known as an important cause of AD. Designing an effective common inhibitor with antioxidant activity to inhibit AChE and MD2 proteins is the main goal of this work. In this regard, we used tacrine molecule with a high ligand efficiency (LE) and dehydrozingerone (DHZ) with anti-inflammatory, antioxidant and anti-Alzheimer activities. Some modifications on DHZ structure can increase its antioxidant activity. So, tacrine molecule was combined with modified DHZ to present a new multi-target-directed ligand (MTDL). The ability of the designed ligand to inhibit AChE and MD2 proteins was confirmed by molecular docking, molecular dynamics (MD) simulation, and binding-free energy calculations. Therefore, the designed ligand can target two proteins involved in AD. It can also act as a potent antioxidant. In general, three important causative agents of AD are targeted by the designed ligand. Moreover, the inhibition of MD2, as the main source of oxidative stress, significantly reduces the production of free radicals.

Evaluating the effect of BDNF Val66Met polymorphism on complex formation with HAP1 and Sortilin1 via structural modeling.

Brain derived neurotrophic factor (BDNF) has a critical role in the neurogenesis, differentiation, survival of the neurons, regulation of the appetite, and energy homeostasis. Two key proteins, Huntingtin associated protein-1 (HAP1) and sortilin1, regulate the intracellular trafficking and stabilization of the precursor proBDNF through interaction with its prodomain region and mark it for secretion. Evidence suggests that the most frequent single nucleotide polymorphism (SNP) of BDNF gene (rs6265) has been associated with different psychiatric, neurodegenerative and eating disorders. In this study, structural bioinformatics and molecular dynamics (MD) simulations were applied, in order to get precise insights into the impact of Val66Met polymorphism on the proBDNF structure and its interaction with HAP1 and Sortilin1. Homology modeling, structure validation, refinement and also protein-protein docking were performed using appropriate servers. The stability, the fluctuations and the compactness of protein complexes were measured by MD simulation parameters including root mean square deviation (RMSD), root mean square fluctuation (RMSF) and Radius of gyration (Rg), respectively. The mutant proBDNF complexes with HAP1 and Sortilin1 revealed higher RMSD and RMSF values and also variable Rg over time compared with wild-type proBDNF. These computational results indicated that, wild-type proBDNF possessed more stable structure in binding with HAP1 and Sortilin1 compared with its mutant form. Therefore, Val66Met SNP could be deleterious due to making structural changes. It may cause a decrease in proBDNF secretion, which could possibly lead to different psychiatric, neurodegenerative and eating disorders. Further experimental lab studies are required for a more accurate conclusion.

Vaccinomics approach for developing multi-epitope peptide pneumococcal vaccine.

Streptococcus pneumoniae is a leading cause of some diseases such as pneumonia, sepsis, and meningitis mostly in children less than 5 years of age. Presently, two types of pneumococcal vaccine are available on the market: polysaccharide vaccines (PPV) that are based on capsular polysaccharides of at least 92 different serotypes, and protein-conjugated polysaccharide vaccine (PCV). The PPVs such as PPV23 do not stimulate efficient protective immunity in children under 2 years old, while the PCVs such as PCV7, PCV10, and PCV13 that cover 7, 10, and 13 serotypes, respectively, highly protect newborns, but have some disadvantages such as complications in manufacturing, costly production, and also requires refrigeration and multiple injections. Epitope-based vaccines, including varied mixtures of conserved virulence proteins, are a promising alternative to the existing capsular antigen vaccines. In this study, it has been tried to design an efficient subunit vaccine in order to elicit both CTL and HTL responses. The immunodominant epitopes from highly protective antigens of S. pneumoniae (PspA, CbpA, PiuA, and PhtD) were selected from different databanks, such as IEDB, PROPRED, RANKPEP, and MHCPRED. The PspA and CbpA were chosen as CTL epitope stimulants, and PhtD and PiuA were defined as helper epitopes. Because of low immunogenicity of epitope vaccines, PorB protein as a TLR2 agonist was employed to increase the immunogenicity of the vaccine. All the peptide segments were fused to each other by proper linkers, and the physicochemical, structural, and immunological characteristics of the construct were also evaluated. To achieve a high-quality 3 D structure of the protein, modeling, refinement, and validation of the final construct were done. Docking and molecular dynamics analyses demonstrated an appropriate and stable interaction between the vaccine and TLR2 during the simulation period. The computational studies suggested the designed vaccine as a novel construct, capable to elicit efficient humoral and cellular immunities, which are crucial for protection against S. pneumoniae. Communicated by Ramaswamy H. Sarma.

Deep analysis of N-cadherin/ADH-1 interaction: a computational survey.

Due to the considerable role of N-cadherin in cancer metastasis, tumor growth, and progression, inhibition of this protein has been highly regarded in recent years. Although ADH-1 has been known as an appropriate inhibitor of N-cadherin in clinical trials, its chemical nature and binding mode with N-cadherin have not been precisely specified yet. Accordingly, in this study, quantum mechanics calculations were used to investigate the chemical nature of ADH-1. These calculations clarify the molecular properties of ADH-1 and determine its reactive sites. Based on the results, the oxygen atoms are suitable for electrophilic reactivity, while the hydrogen atoms that are connected to nitrogen atoms are the favorite sites for nucleophilic reactivity. The higher electronegativity of the oxygen atoms makes them the most reactive portions in this molecule. Molecular docking and molecular dynamics (MD) simulation have also been applied to specify the binding mode of ADH-1 with N-cadherin and determine the important residues of N-cadherin involving in the interaction with ADH-1. Moreover, the verified model by MD simulation has been studied to extract the free energy value and find driving forces. These calculations and molecular electrostatic potential map of ADH-1 indicated that hydrophobic and electrostatic interactions are almost equally involved in the implantation of ADH-1 in the N-cadherin binding site. The presented results not only enable a closer examination of N-cadherin in complex with ADH-1 molecule, but also are very beneficial in designing new inhibitors for N-cadherin and can help to save time and cost in this field.

Immunoinformatics-aided design of a potential multi-epitope peptide vaccine against Leishmania infantum.

Visceral leishmaniasis (VL) or kala-azar, the most severe form of the disease, is endemic in more than eighty countries across the world. To date, there is no approved vaccine against VL in the market. Recent advances in reverse vaccinology could be promising approach in designing the efficient vaccine for VL treatment. In this study, an efficient multi-epitope vaccine against Leishmania infantum, the causative agent of VL, was designed using various computational vaccinology methods. Potential immunodominant epitopes were selected from four antigenic proteins, including histone H1, sterol 24-c-methyltransferase (SMT), Leishmania-specific hypothetical protein (LiHy), and Leishmania-specific antigenic protein (LSAP). To enhance vaccine immunogenicity, two resuscitation-promoting factor of Mycobacterium tuberculosis, RpfE and RpfB, were employed as adjuvants. All the aforesaid segments were joined using proper linkers. Homology modeling, followed by refinement and validation was performed to obtain a high-quality 3D structure of designed vaccine. Docking analyses and molecular dynamics (MD) studies indicated vaccine/TLR4 complex was in the stable form during simulation time. In sum, we expect our designed vaccine is able to induce humoral and cellular immune responses against L. infantum, and may be promising medication for VL, after in vitro and in vivo immunological assays.

Structural vaccinology considerations for in silico designing of a multi-epitope vaccine.

Multi-epitope peptide vaccines, as a kind of fusion proteins, usually possess a string-of-beads structure, consisting of several peptidic epitopes, probably adjuvants and linkers. Very numerous options are possible in selecting the order of different segments and linkers. Such factors can affect the vaccine efficacy through impacting physicochemical characteristics and protein tertiary structure. To investigate such relations, eleven different constructs were designed and studied as a multi-epitope prophylaxis vaccine for human papilloma virus (HPV). The vaccine contained two epitopes from the minor protein of virus capsid (L2) of HPV16, two TLR agonists as adjuvants (flagellin and RS09, as TLR5 and TLR4 agonists, respectively), and two universal T-helper epitopes. Since the used TLR4 agonist was inserted in the middle of the construct, its appropriate interaction with the bulky TLR4 was a serious concern. Thus, beyond evaluating the physicochemical properties, secondary and tertiary structures, and conformational B-cell epitopes of the designed constructs, TLR4 agonist exposability was also studied. Besides, the interaction between TLR4 and its agonist was investigated through docking and MD studies. Consequently, one structure ("D") with proper physicochemical features, a high frequency of conformational B-cell epitopes, and appropriate interactions with TLR4 and TLR5 in docking and MD studies, was selected as a proper candidate. Accordingly, for in silico designing of multi-epitope vaccines, structural concerns should be considered, and the linkers and arrangement of epitopes and adjuvants should be optimized. Considering the diversity of the possible structures, devising computational tools for such investigations would be very valuable.

A novel HPV prophylactic peptide vaccine, designed by immunoinformatics and structural vaccinology approaches.

Human papillomavirus (HPV)-caused cervical cancer is the fourth common female cancer globally. Despite availability of three effective vaccines in market, development of HPV prophylactic vaccines is still pursued due to affordability issues and type-restricted protection of the marketed vaccines. Investigational second generation prophylactic HPV vaccines are mostly exploiting epitopes from the virus minor capsid protein (L2), which despite many advantages suffer from low immunogenicity, a common problem of epitope vaccines. Adjuvants such as TLR agonists may overcome this drawback. In this study, different immunoinformatics and computational tools were employed to design a novel peptide vaccine for protection against cervical cancer. Two immunodominant epitope domains (amino acids 10-36 and 65-89) from the L2 protein of HPV 16 with potential to promote Th1, Th2, CTL, B-cell, and INF-gamma responses were selected. Flagellin, as a TLR5 agonist, a short synthetic TLR4 agonist, and two universal T-helper agonists (PADRE and TpD) were added to ensure strong induction of immune responses. Different segments were joined by proper linkers, and the physicochemical, structural, and immunological characteristics of the resultant construct were evaluated. Modeling, refinement, and validation were done to achieve a high quality 3D structure of the vaccine protein. Docking and molecular dynamics (MD) studies demonstrated an appropriate and stable interaction between the vaccine and TLR5 during the simulation period. Totally, a potential vaccine candidate with proper immunological and physicochemical properties was designed for HPV prophylaxis. The designed vaccine is expected to be capable of generating humoral and cellular responses, which are vital for protection against HPV.

Designing an efficient multi-epitope oral vaccine against Helicobacter pylori using immunoinformatics and structural vaccinology approaches.

Helicobacter pylori is the cunning bacterium that can live in the stomachs of many people without any symptoms, but gradually can lead to gastric cancer. Due to various obstacles, which are related to anti-H. pylori antibiotic therapy, recently developing an anti-H. pylori vaccine has attracted more attention. In this study, different immunoinformatics and computational vaccinology approaches were employed to design an efficient multi-epitope oral vaccine against H. pylori. Our multi-epitope vaccine is composed of heat labile enterotoxin IIc B (LT-IIc) that is used as a mucosal adjuvant to enhance vaccine immunogenicity for oral immunization, cartilage oligomeric matrix protein (COMP) to increase vaccine stability in acidic pH of gut, one experimentally protective antigen, OipA, and two hypothetical protective antigens, HP0487 and HP0906, and "CTGKSC" peptide motif that target epithelial microfold cells (M cells) to enhance vaccine uptake from the gut barrier. All the aforesaid segments were joined to each other by proper linkers. The vaccine construct was modeled, validated, and refined by different programs to achieve a high-quality 3D structure. The resulting high-quality model was applied for conformational B-cell epitopes selection and docking analyses with a toll-like receptor 2 (TLR2). Moreover, molecular dynamics studies demonstrated that the protein-TLR2 docked model was stable during simulation time. We believe that our vaccine candidate can induce mucosal sIgA and IgG antibodies, and Th1/Th2/Th17-mediated protective immunity that are crucial for eradicating H. pylori infection. In sum, the computational results suggest that our newly designed vaccine could serve as a promising anti-H. pylori vaccine candidate.

Immunoinformatics analysis and in silico designing of a novel multi-epitope peptide vaccine against Staphylococcus aureus.

Staphylococcus aureus is a pathogen that causes a variety of infections in humans. Methicillin-resistant S. aureus, which is an antibiotic-resistant form, is responsible for nosocomial staphylococcal infections, whose frequency is increasing in healthy people. Thereby, the development of novel techniques is required to overcome this bacterial infection. In this context, the use of vaccines to control infections is an appropriate alternative. In this study, immunoinformatics analysis is used on three antigenic determinants as vaccine candidates, and a novel multi-epitope vaccine is designed to induce cellular, humoral, and innate immune responses against S. aureus. Alpha-enolase, clumping factor A, and iron surface determinant B were selected as the protective antigens; and phenol-soluble modulin alpha 4was applied as the adjuvant. Epitopes identification was done for each antigen using various immunoinformatics servers. Moreover, the tertiary structure of our protein vaccine was predicted and validated. Subsequently, the best-modeled protein structure was used for the refinement process. There fined model was then applied for docking studies with Toll-like receptor 2 (TLR2).In the next step, molecular dynamics (MD) simulation was used to evaluate the stability of vaccine molecule and TLR2-vaccine complex. The high ranked epitopes were selected from the mentioned antigens. The selected epitopes and the adjuvant were fused together by proper linkers. Then, the modeled protein structure was selected and validated. Validation results indicated that the initial model needs refinement. After a refinement process, the final model was generated. Finally, the best-docked model of vaccine and TLR2 complex was selected. In this research, we attempted to design an efficient subunit vaccine, which could stimulate humoral and cellular immune responses. Therefore, we expect that our designed vaccine could defeat antibiotic-resistant staphylococcal infections.

Designing an efficient multi-epitope peptide vaccine against Vibrio cholerae via combined immunoinformatics and protein interaction based approaches.

Cholera continues to be a major global health concern. Among different Vibrio cholerae strains, only O1 and O139 cause acute diarrheal diseases that are related to epidemic and pandemic outbreaks. The currently available cholera vaccines are mainly lived and attenuated vaccines consisting of V. cholerae virulence factors such as toxin-coregulated pili (TCP), outer membrane proteins (Omps), and nontoxic cholera toxin B subunit (CTB). Nowadays, there is a great interest in designing an efficient epitope vaccine against cholera. Epitope vaccines consisting of immunodominant epitopes and adjuvant molecules enhance the possibility of inciting potent protective immunity. In this study, V. cholerae protective antigens (OmpW, OmpU, TcpA and TcpF) and the CTB, which is broadly used as an immunostimulatory adjuvant, were analyzed using different bioinformatics and immunoinformatics tools. The common regions between promiscuous epitopes, binding to various HLA-II supertype alleles, and B-cell epitopes were defined based upon the aforementioned protective antigens. The ultimately selected epitopes and CTB adjuvant were fused together using proper GPGPG linkers to enhance vaccine immunogenicity. A three-dimensional model of the thus constructed vaccine was generated using I-TASSER. The model was structurally validated using the ProSA-web error-detection software and the Ramachandran plot. The validation results indicated that the initial 3D model needed refinement. Subsequently, a high-quality model obtained after various refinement cycles was used for defining conformational B-cell epitopes. Several linear and conformational B-cell epitopes were determined within the epitope vaccine, suggesting likely antibody triggering features of our designed vaccine. Next, molecular docking was performed between the 3D vaccine model and the tertiary structure of the toll like receptor 2 (TLR2). To gain further insight into the interaction between vaccine and TLR2, molecular dynamics simulation was performed, corroborating stable vaccine-TLR2 binding. In sum, the results suggest that our designed epitope vaccine could incite robust long-term protective immunity against V. cholera.