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1.
Front Pharmacol ; 15: 1352907, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38434705

RESUMO

In the current study, Neosetophomone B (NSP-B) was investigated for its anti-cancerous potential using network pharmacology, quantum polarized ligand docking, molecular simulation, and binding free energy calculation. Using SwissTarget prediction, and Superpred, the molecular targets for NSP-B were predicted while cancer-associated genes were obtained from DisGeNet. Among the total predicted proteins, only 25 were reported to overlap with the disease-associated genes. A protein-protein interaction network was constructed by using Cytoscape and STRING databases. MCODE was used to detect the densely connected subnetworks which revealed three sub-clusters. Cytohubba predicted four targets, i.e., fibroblast growth factor , FGF20, FGF22, and FGF23 as hub genes. Molecular docking of NSP-B based on a quantum-polarized docking approach with FGF6, FGF20, FGF22, and FGF23 revealed stronger interactions with the key hotspot residues. Moreover, molecular simulation revealed a stable dynamic behavior, good structural packing, and residues' flexibility of each complex. Hydrogen bonding in each complex was also observed to be above the minimum. In addition, the binding free energy was calculated using the MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) and MM/PBSA (Molecular Mechanics/Poisson-Boltzmann Surface Area) approaches. The total binding free energy calculated using the MM/GBSA approach revealed values of -36.85 kcal/mol for the FGF6-NSP-B complex, -43.87 kcal/mol for the FGF20-NSP-B complex, and -37.42 kcal/mol for the FGF22-NSP-B complex, and -41.91 kcal/mol for the FGF23-NSP-B complex. The total binding free energy calculated using the MM/PBSA approach showed values of -30.05 kcal/mol for the FGF6-NSP-B complex, -39.62 kcal/mol for the FGF20-NSP-B complex, -34.89 kcal/mol for the FGF22-NSP-B complex, and -37.18 kcal/mol for the FGF23-NSP-B complex. These findings underscore the promising potential of NSP-B against FGF6, FGF20, FGF22, and FGF23, which are reported to be essential for cancer signaling. These results significantly bolster the potential of NSP-B as a promising candidate for cancer therapy.

2.
J Biomol Struct Dyn ; : 1-17, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38486461

RESUMO

The presence of conditions like Alpha-1 antitrypsin deficiency, hemochromatosis, non-alcoholic fatty liver diseases and metabolic syndrome can elevate the susceptibility to hepatic cellular carcinoma (HCC). Utilizing network-based gene expression profiling via network analyst tools, presents a novel approach for drug target discovery. The significance level (p-score) obtained through Cytoscape in the intended center gene survival assessment confirms the identification of all target center genes, which play a fundamental role in disease formation and progression in HCC. A total of 1064 deferential expression genes were found. These include MCM2 with the highest degree, followed by 4917 MCM6 and MCM4 with a 3944-degree score. We investigated the regulatory kinases involved in establishing the protein-protein interactions network using X2K web tool. The docking approach yields a favorable binding affinity of -8.7 kcal/mol against the target MCM2 using Auto-Dock Vina. Interestingly after simulating the complex system via AMBER16 package, results showed that the root mean square deviation values remained within 4.74 Å for a protein and remains stable throughout the time intervals. Additionally, the ligand's fit to the protein exhibited fluctuations at some intervals but remains stable. Finally, Gibbs free energy was found to be at its lowest at 1 kcal/mol which presents the real time interactive binding of the atomic residues among inhibitor and protein. The displacement of the ligand was measured showing stable movement and displacement along the active site. These findings increased our understanding for potential biomarkers in hepatocellular carcinoma and an experimental approach will further enhance our outcomes in future.Communicated by Ramaswamy H. Sarma.

3.
Microb Pathog ; 189: 106572, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38354987

RESUMO

The JCV (John Cunningham Virus) is known to cause progressive multifocal leukoencephalopathy, a condition that results in the formation of tumors. Symptoms of this condition such as sensory defects, cognitive dysfunction, muscle weakness, homonosapobia, difficulties with coordination, and aphasia. To date, there is no specific and effective treatment to completely cure or prevent John Cunningham polyomavirus infections. Since the best way to control the disease is vaccination. In this study, the immunoinformatic tools were used to predict the high immunogenic and non-allergenic B cells, helper T cells (HTL), and cytotoxic T cells (CTL) epitopes from capsid, major capsid, and T antigen proteins of JC virus to design the highly efficient subunit vaccines. The specific immunogenic linkers were used to link together the predicted epitopes and subjected to 3D modeling by using the Robetta server. MD simulation was used to confirm that the newly constructed vaccines are stable and properly fold. Additionally, the molecular docking approach revealed that the vaccines have a strong binding affinity with human TLR-7. The codon adaptation index (CAI) and GC content values verified that the constructed vaccines would be highly expressed in E. coli pET28a (+) plasmid. The immune simulation analysis indicated that the human immune system would have a strong response to the vaccines, with a high titer of IgM and IgG antibodies being produced. In conclusion, this study will provide a pre-clinical concept to construct an effective, highly antigenic, non-allergenic, and thermostable vaccine to combat the infection of the John Cunningham virus.


Assuntos
Vírus JC , Vacinas , Humanos , Epitopos/genética , Simulação de Acoplamento Molecular , Escherichia coli , Vacinologia , Vacinas de Subunidades/genética , Epitopos de Linfócito T/genética , Biologia Computacional , Epitopos de Linfócito B , Simulação de Dinâmica Molecular
4.
Vaccine X ; 17: 100452, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38328274

RESUMO

Influenza virus has presented a considerable healthcare challenge during the past years, particularly in vulnerable groups with compromised immune systems. Therapeutics and vaccination have always been in research annals since the spread of influenza. Efforts have been going on to develop an antiviral therapeutic approach that could assist in better disease management and reduce the overall disease complexity, resistance development, and fatality rates. On the other hand, vaccination presents a chance for effective, long-term, cost-benefit, and preventive response against the morbidity and mortality associated with the influenza. However, the issues of resistance development, strain mutation, antigenic variability, and inability to cure wide-spectrum and large-scale strains of the virus by available vaccines remain there. The article gathers the updated data for the therapeutics and available influenza vaccines, their mechanism of action, shortcomings, and trials under clinical experimentation. A methodological approach has been adopted to identify the prospective therapeutics and available vaccines approved and within the clinical trials against the influenza virus. Review contains influenza therapeutics, including traditional and novel antiviral drugs and inhibitor therapies against influenza virus as well as research trials based on newer drug combinations and latest technologies such as nanotechnology and organic and plant-based natural products. Most recent development of influenza vaccine has been discussed including some updates on traditional vaccination protocols and discussion on next-generation and upgraded novel technologies. This review will help the readers to understand the righteous approach for dealing with influenza virus infection and for deducing futuristic approaches for novel therapeutic and vaccine trials against Influenza.

5.
J Biomol Struct Dyn ; : 1-12, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38174700

RESUMO

Understanding the pathogenesis mechanism of the Monkeypox virus (MPXV) is essential to guide therapeutic development against the Monkeypox virus. In the current study, we investigated the impact of the only two reported substitutions, S30L, D88N, and S30L-D88N on the G9R of the replication complex in 2022 with E4R using structural modeling, simulation, and free energy calculation methods. From the molecular docking and dissociation constant (KD) results, it was observed that the binding affinity did not increase in the mutants, but the interaction paradigm was altered by these substitutions. Molecular simulation data revealed that these mutations are responsible for destabilization, changes in protein packing, and internal residue fluctuations, which can cause functional variance. Additionally, hydrogen bonding analysis revealed that the estimated number of hydrogen bonds are almost equal among the wild-type G9R and each mutant. The total binding free energy for the wild-type G9R with E4R was -85.00 kcal/mol while for the mutants the TBE was -42.75 kcal/mol, -43.68 kcal/mol, and -48.65 kcal/mol respectively. This shows that there is no direct impact of these two reported mutations on the binding with E4R, or it may affect the whole replication complex or any other mechanism involved in pathogenesis. To explore these variations further, we conducted PCA and FEL analyses. Based on our findings, we speculate that within the context of interaction with E4R, the mutations in the G9R protein might be benign, potentially leading to functional diversity associated with other proteins.Communicated by Ramaswamy H. Sarma.

6.
PLoS One ; 19(1): e0296448, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38180980

RESUMO

BACKGROUND: The WHO has issued a call to action urging countries to accelerate the rollout of new WHO-recommended shorter all-oral treatment regimens for drug-resistant TB (DR-TB), which remains a public-health crisis. The all-oral, 6-month BPaL/M regimen comprises 3-4 drugs: pretomanid used in combination with bedaquiline and linezolid, with or without moxifloxacin. This regimen has been recommended by the WHO for use in DR-TB patients instead of ≥9-month (up to 24-month) regimens. This study aims to project this regimen's use, along with its components bedaquiline, pretomanid and linezolid, and other treatments for DR-TB globally through 2026. It is intended to guide global health stakeholders in planning and budgeting for DR-TB interventions. Projected usage could help estimate cost of the individual components of DR-TB regimens over time. METHODS: Semi-structured interviews were conducted with national TB programme participants in key countries to gather intelligence on established plans and targets for use of various DR-TB treatment regimens from 2023 to 2026. These data informed development of projections for the global use of regimens and drugs. RESULTS: Consistent global growth in the use of shorter regimens in DR-TB treatment was shown: BPaLM reaching 126,792 patients, BPaL reaching 43,716 patients, and the 9-11-month all-oral bedaquiline-based regimen reaching 13,119 patients by 2026. By 2026, the longer all-oral regimen is projected to be used by 19,262 patients, and individualised treatment regimens by 15,344 patients. CONCLUSION: The study shows BPaL/M will be used in majority of DR-TB patients by 2024, reaching 78% by 2026. However, national efforts to scale-up, case-finding, monitoring, drug-susceptibility testing, and implementation of new treatments will be essential for ensuring they are accessible to all eligible patients in the coming years and goals for ending TB are met. There is an urgent need to engage communities in capacity building and demand generation.


Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Linezolida , Protocolos Clínicos , Transporte Biológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
7.
J Trace Elem Med Biol ; 81: 127324, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37944220

RESUMO

BACKGROUND: Cadmium is widely reported to interfere with the proper functioning of cells by disrupting cellular redox balance, causing apoptosis, and leading to hepatocellular damage, neurotoxicity, pulmonary edema, cancer, and cardiac and neurodegenerative diseases. Treatment of Cd toxicity with drugs brings undesirable side effects, making it necessary to remove Cd from the body safely without harmful effects. OBJECTIVE: This study aimed to determine how Cd causing malfunctioning of cells could be treated with antioxidant-rich avocado and papaya fruit juices. This work fixated on elucidating and comparing the effects of avocado and papaya fruit juice on Cd-dependent impairment in memory and spatial learning. In addition, various markers of tissue damage, such as the concentration of biomarkers in liver and kidney tissue, the expression of antioxidant enzymes and Cd-induced lipid peroxidation, were analyzed. METHODOLOGY: in silico studies of the phytochemical constituents of avocado and papaya (ligands) were docked against antioxidant enzymes Catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) as macromolecules showed strong hydrogen binding with significant binding capacities. To develop the Cd in vivo model, rats were administered CdCl2 (200 ppm) in drinking water for 7 weeks. After induction of Cd toxicity, rats were post-treated with avocado and papaya (10% w/v each) in a standard diet. After post-treatment, memory and learning were assessed using the Morris water maze behavioural test. Biochemical tests for liver and kidney biomarkers were monitored. To determine the level of ROS, lipid peroxidation was determined by Malondialdehyde (MDA) assay. Gene expression of SOD, CAT and GPx were determined via qRT-PCR. RESULTS: This study demonstrated that Cd accumulation in the liver, kidney and hippocampal tissues was reduced after treatment with avocado and papaya. SOD, CAT and GPX gene expression were upregulated after avocado and papaya juice treatment. Moreover, a comparative analysis between avocado and papaya fruit juices clarified that papaya has more active potential for improving memory and learning, upregulating the expression of antioxidant enzymes, and reducing lipid peroxidation in the liver, kidney, and hippocampus. CONCLUSION: This study suggests that a diet containing papaya and avocado can help treat the lethal effects caused by Cd. Because their active constituents can improve health at the cellular and molecular levels.


Assuntos
Carica , Doença Hepática Induzida por Substâncias e Drogas , Persea , Ratos , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Cádmio/análise , Carica/metabolismo , Persea/metabolismo , Frutas/química , Frutas/metabolismo , Superóxido Dismutase/metabolismo , Biomarcadores/metabolismo , Estresse Oxidativo , Peroxidação de Lipídeos
8.
J Biomol Struct Dyn ; : 1-9, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38064307

RESUMO

The fibroblast growth factor receptor 3 (FGFR3) is warranted as a promising therapeutic target in bladder cancer as it is described in 75% of papillary bladder tumors. Considering this, the present study was conducted to use different approaches of computer-aided drug discovery (CADD) to identify the best binding compounds against the active pocket of FGFR3. Compared to control pyrimidine derivative, the study identified three promising lead structures; BDC_24037121, BDC_21200852, and BDC_21206757 with binding energy value of -14.80 kcal/mol, -12.22 kcal/mol, and -11.67 kcal/mol, respectively. The control molecule binding energy score was -9.85 kcal/mol. The compounds achieved deep pocket binding and produced balanced interactions of hydrogen bonds and van der Waals. The FGFR3 enzyme residues such as Leu478, Lys508, Glu556, Asn562, Asn622, and Asp635. The molecular dynamic (MD) simulation studies additionally validated the docked conformation stability with respect to FGFR3 with a mean root mean square deviation (RMSD) value of < 3 Å. The root mean square fluctuation (RMSF) complements the complexes structural stability and the residues showed less fluctuation in the presence of compounds. The Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods revalidated compounds better binding and highlighted van der Waals energy to dominate the overall net energy. The docked stability was additionally confirmed by WaterSwap and AMBER normal mode entropy energy analyses. In a nutshell, the compounds shortlisted in this study are promising in term of theoretical binding affinity for FGFR3 but experimental validation is needed.Communicated by Ramaswamy H. Sarma.

9.
PLoS One ; 18(12): e0294663, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38096182

RESUMO

Hepatitis E virus (HEV) is one of the leading acute liver infections triggered by viral hepatitis. Patients infected with HEV usually recover and the annual death rate is negligible. Currently, there is no HEV licensed vaccine available globally. This study was carried out to design a multi-epitope HEV peptide-based vaccine by retrieving already experimentally validated epitopes from ViPR database leading to epitope prioritization. Epitopes selected as potential vaccine candidates were non-allergen, immunogenic, soluble, non-toxic and IFN gamma positive. The epitopes were linked together by AAY linkers and the linker EAAAK was used to join adjuvant with epitopes. Toll-like receptor (TLR)-4 agonist was used as an adjuvant to boost efficacy of the vaccine. Furthermore, codon optimization followed by disulfide engineering was performed to analyse the designed vaccine's structural stability. Computational modeling of the immune simulation was done to examine the immune response against the vaccine. The designed vaccine construct was docked with TLR-3 receptor for their interactions and then subjected to molecular dynamic simulations. The vaccine model was examined computationally towards the capability of inducing immune responses which showed the induction of both humoral and cell mediated immunity. Taken together, our study suggests an In-silico designed HEV based multi-epitope peptide-based vaccine (MEPV) that needs to be examined in the wet lab-based data that can help to develop a potential vaccine against HEV.


Assuntos
Vírus da Hepatite E , Humanos , Epitopos de Linfócito T , Vacinas de Subunidades , Simulação de Dinâmica Molecular , Peptídeos , Biologia Computacional , Simulação de Acoplamento Molecular , Epitopos de Linfócito B
10.
Microorganisms ; 11(12)2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-38137971

RESUMO

The Hepatitis B virus (HBV) HBx and HBc proteins play a crucial role in associating with covalently closed circular DNA (cccDNA), the primary factor contributing to intrahepatic viral persistence and a major obstacle in achieving a cure for HBV. The cccDNA serves as a reservoir for viral persistence. Targeting the viral HBc and HBx proteins' interaction with cccDNA could potentially limit HBV replication. In this study, we present epitopes identified from global consensus sequences of HBx and HBc proteins that have the potential to serve as targets for the development of effective vaccine candidates. Furthermore, conserved residues identified through this analysis can be utilized in designing novel, site-specific anti-HBV agents capable of targeting all major genotypes of HBV. Our approach involved designing global consensus sequences for HBx and HBc proteins, enabling the analysis of variable regions and highly conserved motifs. These identified motifs and regions offer potent sites for the development of peptide vaccines, the design of site-specific RNA interference, and the creation of anti-HBV inhibitors. The epitopes derived from global consensus sequences of HBx and HBc proteins emerge as promising targets for the development of effective vaccine candidates. Additionally, the conserved residues identified provide valuable insights for the development of innovative, site-specific anti-HBV agents capable of targeting all major genotypes of HBV from A to J.

11.
Front Microbiol ; 14: 1270018, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38098671

RESUMO

The efficacy of antibiotics and other antimicrobial agents in combating bacterial infections faces a grave peril in the form of antimicrobial resistance (AMR), an exceedingly pressing global health issue. The emergence and dissemination of drug-resistant bacteria can be attributed to the rampant overuse and misuse of antibiotics, leading to dire consequences such as organ failure and sepsis. Beyond the realm of individual health, the pervasive specter of AMR casts its ominous shadow upon the economy and society at large, resulting in protracted hospital stays, elevated medical expenditures, and diminished productivity, with particularly dire consequences for vulnerable populations. It is abundantly clear that addressing this ominous threat necessitates a concerted international endeavor encompassing the optimization of antibiotic deployment, the pursuit of novel antimicrobial compounds and therapeutic strategies, the enhancement of surveillance and monitoring of resistant bacterial strains, and the assurance of universal access to efficacious treatments. In the ongoing struggle against this encroaching menace, phage-based therapies, strategically tailored to combat AMR, offer a formidable line of defense. Furthermore, an alluring pathway forward for the development of vaccines lies in the utilization of virus-like particles (VLPs), which have demonstrated their remarkable capacity to elicit a robust immune response against bacterial infections. VLP-based vaccinations, characterized by their absence of genetic material and non-infectious nature, present a markedly safer and more stable alternative to conventional immunization protocols. Encouragingly, preclinical investigations have yielded promising results in the development of VLP vaccines targeting pivotal bacteria implicated in the AMR crisis, including Salmonella, Escherichia coli, and Clostridium difficile. Notwithstanding the undeniable potential of VLP vaccines, formidable challenges persist, including the identification of suitable bacterial markers for vaccination and the formidable prospect of bacterial pathogens evolving mechanisms to thwart the immune response. Nonetheless, the prospect of VLP-based vaccines holds great promise in the relentless fight against AMR, underscoring the need for sustained research and development endeavors. In the quest to marshal more potent defenses against AMR and to pave the way for visionary innovations, cutting-edge techniques that incorporate RNA interference, nanomedicine, and the integration of artificial intelligence are currently under rigorous scrutiny.

12.
J Biomol Struct Dyn ; : 1-14, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37962871

RESUMO

Helicobacter pylori infects 50% of the world population and in 80% of cases, the infection progresses to the point where an ulcer develops leading to gastric cancer (GC). This study aimed to prevent GC by predicting Hub genes that are inducing GC. Furthermore, the study objective was to screen inhibitory molecules that block the function of predicted genes through several biophysical approaches. These proteins, such as Mucin 4 (MUC4) and Baculoviral IAP repeat containing 3 (BIRC3), had LogFC values of 2.28 and 3.39, respectively, and were found to be substantially expressed in those who had H. pylori infection. The MUC4 and BIRC3 inhibit apoptosis of infected cells and promote cancerous cell survival. The proteins were examined for their Physico-chemical characteristics, 3D structure and secondary structure analysis, solvent assessable surface area (SASA), active site identification, and network analysis. The MUC4 and BIRC3 expression was inhibited by docking eighty different compounds collected from the ZINC database. Fifty-seven compounds were successfully docked into the active site resulting in the lowest binding energy scores. The ZINC585267910 and ZINC585268691 compounds showed the lowest binding energy of -8.5 kcal/mol for MUC4 and -7.1 kcal/mol for BIRC3, respectively, and were considered best-docked solutions for molecular dynamics simulations. The mean root mean square deviation (RMSD) value for the ZINC585267910-MUC4 complex was 0.86 Å and the ZINC585268691-BIRC3 complex was 1.01 Å. The net MM/GBSA energy value of the ZINC585267910-MUC4 complex estimated was -46.84 kcal/mol and that of the ZINC585268691-BIRC3 complex was -44.84 kcal/mol. In a nutshell, the compounds might be investigated further as an inhibitor of the said proteins to stop the progress of GC induced by H. pylori.Communicated by Ramaswamy H. Sarma.

13.
J Formos Med Assoc ; 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37996327

RESUMO

Globally, more than 50 countries have been affected by Monkey pox virus after COVID-19 has subsided. WHO declared "public health emergency of international concern" in year 2022 because of virus affecting 60,000 people in just one month that belonged to clade-IIb. Previously, it had been transmitted by body fluids, lesions and touching items, but fresh transmission is via sexual activity among bisexuals and man to man sex (MSM). New outbreaks reported compromised health status of confirmed cases with rectal pain, bleeding, tenesmus, pus or blood in stool, vomiting, proctitis and abdominal pain, which became alarming for entire world because of complications leading to bacterial skin infections, sepsis, encephalitis, hemorrhagic disease, blindness and pneumonia eventually. This virus has been further deteriorating unstable and unsustainable economy that requires dire attention. Strict preventive measures in terms of personal hygiene, pet and livestock health care, hospital contaminant disposal, good surveillance record, pre and post exposure vaccination, waste and water management could be only possible strategies to eliminate devastatingly dangerous M-pox outbreaks in this epic.

14.
Dent J (Basel) ; 11(11)2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37999030

RESUMO

Dentistry is a branch of healthcare where nanobiotechnology is reverberating in multiple ways to produce beneficial outcomes. The purpose of this review is to bring into the awareness of the readers the various practical dimensions of the nano-dental complex (nanodentistry) in healthcare and how novelties linked with the field are revolutionizing dentistry. A methodological approach was adopted to collect the latest data on nanotechnology and dentistry from sources, including PubMed, Google Scholar, Scopus, and official websites like the WHO. Nanodentistry is an emerging field in dentistry that involves the use of nanomaterials, nanorobots, and nanotechnology to diagnose, treat, and prevent dental diseases. The results summarize the descriptive analyses of the uses of nanodentistry within orthodontics, preventive dentistry, prosthodontics, restorative dentistry, periodontics, dental surgeries, dental restoration technologies, and other areas of dentistry. The future directions of nano-industries and nano-healthcare have been included to link them with the oral healthcare sector, treatment plans, and improved medical services which could be explored in the future for advanced healthcare regulation. The major limitations to the use of dental nanoproducts are their cost-effectiveness and accessibility, especially in financially constrained countries. These data will help the readers to experience a detailed analysis and comprehensive covering of the diverse achievements of nanodentistry with past analyses, present scenarios, and future implications.

15.
Mol Biotechnol ; 2023 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-37934390

RESUMO

Proteus penneri (P. penneri) is a bacillus-shaped, gram-negative, facultative anaerobe bacterium that is primarily an invasive pathogen and the etiological agent of several hospital-associated infections. P. penneri strains are naturally resistant to macrolides, amoxicillin, oxacillin, penicillin G, and cephalosporins; in addition, no vaccines are available against these strains. This warrants efforts to propose a theoretical based multi-epitope vaccine construct to prevent pathogen infections. In this research, reverse vaccinology bioinformatics and immunoinformatics approaches were adopted for vaccine target identification and construction of a multi-epitope vaccine. In the first phase, a core proteome dataset of the targeted pathogen was obtained using the NCBI database and subjected to bacterial pan-genome analysis using bacterial pan-genome analysis (BPGA) to predict core protein sequences which were then used to find good vaccine target candidates. This identified two proteins, Hcp family type VI secretion system effector and superoxide dismutase family protein, as promising vaccine targets. Afterward using the IEDB database, different B-cell and T-cell epitopes were predicted. A set of four epitopes "KGSVNVQDRE, NTGKLTGTR, IIHSDSWNER, and KDGKPVPALK" were chosen for the development of a multi-epitope vaccine construct. A 183 amino acid long vaccine design was built along with "EAAAK" and "GPGPG" linkers and a cholera toxin B-subunit adjuvant. The designed vaccine model comprised immunodominant, non-toxic, non-allergenic, and physicochemical stable epitopes. The model vaccine was docked with MHC-I, MHC-II, and TLR-4 immune cell receptors using the Cluspro2.0 web server. The binding energy score of the vaccine was - 654.7 kcal/mol for MHC-I, - 738.4 kcal/mol for MHC-II, and - 695.0 kcal/mol for TLR-4. A molecular dynamic simulation was done using AMBER v20 package for dynamic behavior in nanoseconds. Additionally, MM-PBSA binding free energy analysis was done to test intermolecular binding interactions between docked molecules. The MM-GBSA net binding energy score was - 148.00 kcal/mol, - 118.00 kcal/mol, and - 127.00 kcal/mol for vaccine with TLR-4, MHC-I, and MHC-II, respectively. Overall, these in silico-based predictions indicated that the vaccine is highly promising in terms of developing protective immunity against P. penneri. However, additional experimental validation is required to unveil the real immune response to the designed vaccine.

16.
J Transl Int Med ; 11(3): 216-225, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37662888

RESUMO

Ebola virus (EBOV) related health complications have presented a great threat to the healthcare system in the endemic regions. The outbreaks of 2013-2016 and 2018-2020 brought along a huge healthcare burden for the afected communities. Knowing the seriousness of the matter, a series of research experiments have been actively carried out to devise efective therapeutics, drugs, and vaccination protocols against the Ebola virus disease (EVD) in the past decade. The purpose of this piece of literature is to shed light on vaccination protocols being clinically evaluated for EVD. A methodological approach has been adopted to gather relevant data from the latest publications. The compiled data include the molecular mechanistic insights into Ebola infection and a brief overview of diferent vaccination strategies: inactivated and DNA vaccines, virus-like particles and replicons, reverse genetic and recombinant approaches, entry, ion, and gene expression inhibitors, and some repurposed drugs. This data will help the scientific community to get a comprehensive overview of therapeutic interventions against Ebola that could be related to modifying EBOV vaccines and designing other antiviral vaccinations. Having said that, further work in modern therapeutic design is pertinent to tackle and lessen the healthcare burden expected from such outbreaks in the future.

17.
Saudi Pharm J ; 31(10): 101775, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37719892

RESUMO

The growing concerns and cases of COVID-19 with the appearance of novel variants i.e., BA.2.75. BA.5 and XBB have prompted demand for more effective treatment options that could overcome the risk of immune evasion. For this purpose, discovering novel small molecules to inhibit druggable proteins such as PLpro required for viral pathogenesis, replication, survival, and spread is the best choice. Compounds from the Dark chemical matter (DCM) database is consistently active in various screening tests and offer intriguing possibilities for finding drugs that are extremely selective or active against uncommon targets. Considering the essential role of PLpro, the current study uses DCMdatabase for the identification of potential hits using in silico virtual molecular screening and simulation approaches to inhibit the current and emerging variants of SARS-CoV-2. Our results revealed the 10 best compounds with docking scores between -7.99 to -7.03 kcal/mol better than the control drug (GRL0617) among which DC 5977-0726, DC 6623-2024, DC C879-0379 and DC D135-0154 were observed as the best hits. Structural-dynamics properties such as dynamic stability, protein packing, and residue flexibility demonstrated the pharmacologically favorable properties of these top hits in contrast to GRL0617. The hydrogen bonding half-life revealed that Asp164, Arg166, Tyr264, and Tyr268 have major contributions to the hydrogen bonding during the simulation. However, some of the important hydrogen bonds were missing in the control drug (GRL0617). Finally, the total binding free energy was reported to be -34.41 kcal/mol for GRL0617 (control), -41.03 kcal/mol for the DC5977-0726-PLpro, for the DC6623-2024-Plpro complex the TBE was -48.87 kcal/mol, for the for DCC879-0379-Plpro complex the TBE was -45.66 kcal/mol while for the DCD135-0154-PLpro complex the TBE was calculated to be -40.09 kcal/mol respectively, which shows the stronger potency of these compounds against PLpro and further in in vivo and in vitro test are required for the possible usage as potential drug against SARS-CoV-2.

18.
J Infect Public Health ; 16(11): 1761-1768, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37738692

RESUMO

BACKGROUND: Dengue fever is a zoonotic viral infection that raises a global alarm in the tropics and subtropics, with the potentially escalating into newer geographical regions. Severe dengue may be associated with fatal complications such as myocarditis. There is a paucity of available data on the prevalence of dengue-associated myocarditis. The objective of this systematic review and meta-analysis was to estimate the global prevalence of dengue-associated myocarditis. METHODS: A systematic search was conducted utilizing the Cochrane library, PubMed, Scopus, ProQuest, Web of Science, and Preprint servers such as arXiv, medRxiv, bioRxiv, BioRN, ChiRN, ChiRxiv, and SSRN as of November 25, 2022. All primary studies (case series, cross-sectional, retrospective, and prospective) that reported confirmed cases of dengue myocarditis were included. The I2 statistic test assessed the heterogenic characteristics and publication bias was evaluated using Doi plot and Egger regression tests. RESULTS: A total of 12 studies conducted between 2007 and 2022 with 2795 laboratory-confirmed dengue patients were included. Of the included cases, 502 were positive for myocarditis, with a prevalence of 2.4-78%. The pooled prevalence of dengue-induced myocarditis in the studied population was 21.0% (95% CI, 9 - 38%). The prediction interval was estimated to be 0.00 - 0.81. CONCLUSION: Myocarditis in dengue patients is a significant and understudied complication in many aspects. To prevent dengue-associated myocarditis, appropriate measures such as early detection of cases and signs, symptoms-based diagnosis via electrocardiography and echocardiography, as well as relevant vector control policies must be implemented.

19.
Molecules ; 28(18)2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37764400

RESUMO

Knowing the beneficial aspects of nanomedicine, scientists are trying to harness the applications of nanotechnology in diagnosis, treatment, and prevention of diseases. There are also potential uses in designing medical tools and processes for the new generation of medical scientists. The main objective for conducting this research review is to gather the widespread aspects of nanomedicine under one heading and to highlight standard research practices in the medical field. Comprehensive research has been conducted to incorporate the latest data related to nanotechnology in medicine and therapeutics derived from acknowledged scientific platforms. Nanotechnology is used to conduct sensitive medical procedures. Nanotechnology is showing successful and beneficial uses in the fields of diagnostics, disease treatment, regenerative medicine, gene therapy, dentistry, oncology, aesthetics industry, drug delivery, and therapeutics. A thorough association of and cooperation between physicians, clinicians, researchers, and technologies will bring forward a future where there is a more calculated, outlined, and technically programed field of nanomedicine. Advances are being made to overcome challenges associated with the application of nanotechnology in the medical field due to the pathophysiological basis of diseases. This review highlights the multipronged aspects of nanomedicine and how nanotechnology is proving beneficial for the health industry. There is a need to minimize the health, environmental, and ethical concerns linked to nanotechnology.

20.
Vaccines (Basel) ; 11(8)2023 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-37631896

RESUMO

BACKGROUND: Nearly half of the world is at risk of developing dengue infection. Dengue virus is the causative agent behind this public healthcare concern. Millions of dengue cases are reported every year, leading to thousands of deaths. The scientific community is working to develop effective therapeutic strategies in the form of vaccines and antiviral drugs against dengue. METHODS: In this review, a methodological approach has been used to gather data from the past five years to include the latest developments against the dengue virus. RESULTS: Different therapeutics and antiviral targets against the dengue virus are at different stages of development, but none have been approved by the FDA. Moreover, various vaccination strategies have also been discussed, including attenuated virus vaccines, recombinant subunit vaccines, viral vector vaccines, DNA vaccines, nanotechnology, and plant-based vaccines, which are used to develop effective vaccines for the dengue virus. Many dengue vaccines pass the initial phases of evaluation, but only two vaccines have been approved for public use. DENGVAXIA is the only FDA-approved vaccine against all four stereotypes of the dengue virus, but it is licensed for use only in individuals 6-16 years of age with laboratory-confirmed previous dengue infection and living in endemic countries. Takeda is the second vaccine approved for use in the European Union, the United Kingdom, Brazil, Argentina, Indonesia, and Thailand. It produced sustained antibody responses against all four serotypes of dengue virus, regardless of previous exposure and dosing schedule. Other dengue vaccine candidates at different stages of development are TV-003/005, TDENV PIV, V180, and some DNA vaccines. CONCLUSION: There is a need to put more effort into developing effective vaccines and therapeutics for dengue, as already approved vaccines and therapeutics have limitations. DENGVAXIA is approved for use in children and teenagers who are 6-16 years of age and have confirmed dengue infection, while Takeda is approved for use in certain countries, and it has withdrawn its application for FDA approval.

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