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1.
J Ethnopharmacol ; 287: 114919, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34995693

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels has been extensively used in the ancient medical system of Pakistan, India, Bangladesh, and Sri Lanka to combat diabetes, inflammation, and renal disorders. These health-promoting aspects of S. cumini are related to bioactive metabolites such as phenolic acids, anthocyanins, tannins, and flavonoids. AIM OF THE STUDY: Earlier to this study, we have reported S. cumini extracts as potential sources of bioactive compounds bearing antioxidant and anti-inflammatory properties. However, prior further suggesting S. cumini fruit extracts for consumption against inflammatory disorders, it was mandatory to validate the claim and explore toxicity of the extracts. This study aims to determine the in vivo anti-nociceptive, anti-inflammatory, acute, and subacute toxicity properties of S. cumini crude extracts, followed by identifying and quantifying bioactive metabolites. MATERIAL AND METHODS: In the present study, the anti-nociceptive and anti-inflammatory potential of S. cumini sequential crude extracts were evaluated using formalin and glutamate-induced paw licking method in mice. The acute and sub-acute toxicity assessment of active extract was performed by oral administration in rats. An acute toxicity trial was performed with two different doses, i.e., 2000 mg/kg and 3000 mg/kg for consecutive 14 days, whereas a sub-acute toxicity study was conducted at doses of 750 mg/kg and 1500 mg/kg for the next 28 days. Identification of bioactive compounds was performed using HPLC, and at the end, in silico docking calculations of identified compounds were performed. RESULTS: The 100% methanolic extract (SCME) protected the mice from painful stimulation of formalin and glutamate in a dose-dependent manner with the maximum effect of 49% and 67% at 200 mg/kg, respectively, followed by moderate and non-influential effects of 50% methanolic extract and dichloromethane (DCM) extracts when compared to control, i.e., normal saline. The results of acute toxicity recorded LD50 of SCME over 3000 mg/kg, and no antagonistic effects were recorded during the subacute study when SCME dispensed at the rate of 750 mg/kg and 1500 mg/kg. SCME was found to induce no adverse effects to kidney, heart, liver, spleen, and paired lungs examined by hematological, serum biochemical, histological analysis. HPLC analysis of S. cumini 100% methanolic extracts revealed the presence of delphinidin 3-glucoside, peonidin-3,5-diglucoside, scopoletin, and umbelliferone at the concentration of 127.4, 2104, 31.3, 10.4 µg/g whereas in 50% methanolic extract, the quinic acid, catechin, and myricetin were present at the concentration of 54.9, 63.7, 12.3 µg/g, respectively. Umbelliferone and scopoletin are newly reported compounds in the present study. In silico docking calculations of these compounds indicated the potential of anti-nociceptive and anti-inflammatory activities. CONCLUSIONS: These findings validate that S. cumini fruit extracts are a rich source of bioactive compounds that needs to be considered to enhance biological activities with lesser side effects.

2.
Biol Trace Elem Res ; 200(1): 31-48, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33635516

RESUMO

Colorectal cancer (CRC) is currently one of the most frequent malignant neoplasms, ranking 3rd in incidence and 2nd in mortality both in the USA and across the world. The pathogenesis of CRC is a complex interaction between genetic susceptibility and environmental factors such as exposure to metals. Therefore, the present study was intended to assess the imbalances in the concentrations of selected essential/toxic elements (Pb, Cr, Fe, Zn, As, Cd, Cu, Se, Ni, and Hg) in the serum of newly diagnosed colorectal carcinoma patients (n = 165) in comparison with counterpart controls (n = 151) by atomic absorption spectrometry after wet-acid digestion method. Serum carcinoembryonic antigen (CEA) of the CRC patients was determined using immunoradiometric method. Body mass index (BMI) which is an established risk factor for CRC was also calculated for patients and healthy controls. Conversely, average Ni (2.721 µg/g), Cd (0.563 µg/g), As (0.539 µg/g), and Pb (1.273 µg/g) levels were significantly elevated in the serum of CRC patients compared to the healthy donors, while the average Se (7.052 µg/g), Fe (15.67 µg/g), Cu (2.033 µg/g), and Zn (8.059 µg/g) concentrations were elevated in controls. The correlation coefficients between the elements in the cancerous patients demonstrated significantly dissimilar communal relationships compared with the healthy subjects. Significant differences in the elemental levels were also showed for CRC types (primary colorectal lymphoma, gastrointestinal stromal tumor, and adenocarcinoma) and CRC stages (stage-I, stage-II, stage-III, and stage-IV) among the patients. Majority of the elements demonstrated perceptible disparities in their levels based on dietary, habitat, gender, and smoking habits of the malignant patients and healthy subjects. Multivariate methods revealed noticeably divergent apportionment among the toxic/essential elements in the cancerous patients than the healthy counterparts. Overall, the study showed significantly divergent distribution and associations of the essential and toxic elemental levels in the serum of the CRC patients in comparison with the healthy donors.


Assuntos
Neoplasias Colorretais , Oligoelementos , Humanos , Metais , Fumar , Espectrofotometria Atômica , Oligoelementos/análise
3.
Chemosphere ; : 133092, 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34856239

RESUMO

In order to enhance the photocatalytic performance and stability, the various proportions of the size controlled cerium oxide (CeO2) nanoparticles were dispersed at the pre-synthesized ZnO. Although, the expected dual absorption onsets, probably due to the diminutive difference between the bandgaps of CeO2 (∼2.9 eV) and ZnO (∼3.1 eV), were not observed however, a blue shift in the bandgap energy of ZnO was witnessed with the increasing surface density of CeO2 particles. The delayed excitons recombination process with the increasing concentration of CeO2 nanoparticles was verified by the PL spectra. The structural investigation by Raman and XRD analysis revealed the surface attachment of CeO2 particles without altering the rock-salt lattice of ZnO. The morphological and fine microstructural analysis established the uniform distribution of evenly sized CeO2 particles at the surface of ZnO with the discrete fringe patterns of both the entities whereas the XPS analysis confirmed the majority of Ce4+ in dispersed CeO2. In comparison to pure ZnO, cyclic voltammetric (CV) analysis, under illumination, exposed the supportive role of surface residing CeO2 particles in eradicating the photo-corrosion of ZnO whereas the chronopotentiometry (CP) predicted the prolonged life-span of the excitons. Compared to pure ZnO, an appreciably high activity was revealed for 10% CeO2 loading as compared to pure ZnO for the removal of mono and di-nitrophenol derivatives and their mixtures under natural sunlight exposure. The variations in the removal rates in the mixture as compared to individual nitrophenol exposed the structure-based priority of ROS for the respective phenol. The significantly enhanced photocatalytic activity of the composite catalysts revealed the incremental role of surface-mounted CeO2 entities in boosting the generation of ROS under sunlight irradiation. The experimental observations were correlated and compiled to establish the mechanism of the removal process.

4.
Vet Sci ; 8(12)2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34941839

RESUMO

This review highlights the diagnostic methods used, the control strategies adopted, and the global epidemiological status of canine cyclic thrombocytopenia and granulocytic anaplasmosis at the animal-human interface. Canine anaplasmosis is an important worldwide disease, mainly caused by Anaplasma platys and A. phagocytophilum with zoonotic implications. A. platys chiefly infects platelets in canids, while A. phagocytophilum is the most common zoonotic pathogen infecting neutrophils of various vertebrate hosts. Diagnosis is based on the identification of clinical signs, the recognition of intracellular inclusions observed by microscopic observation of stained blood smear, and/or methods detecting antibodies or nucleic acids, although DNA sequencing is usually required to confirm the pathogenic strain. Serological cross-reactivity is the main problem in serodiagnosis. Prevalence varies from area to area depending on tick exposure. Tetracyclines are significant drugs for human and animal anaplasmosis. No universal vaccine is yet available that protects against diverse geographic strains. The control of canine anaplasmosis therefore relies on the detection of vectors/reservoirs, control of tick vectors, and prevention of iatrogenic/mechanical transmission. The control strategies for human anaplasmosis include reducing high-risk tick contact activities (such as gardening and hiking), careful blood transfusion, by passing immunosuppression, recognizing, and control of reservoirs/vectors.

5.
Comput Biol Med ; 141: 105151, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34942394

RESUMO

Since its discovery, the Rift Valley Fever virus (RVFV) has been the source of numerous outbreaks in the Arab Peninsulas and Africa, wreaking havoc on humans and animals. The lack of therapeutics or licensed human vaccines limits the options for controlling RVFV outbreaks. Therefore, RVFV has been prioritized for rapid research and innovation of prevention strategies to control and prevent its outbreaks. The purpose of this study was to design a multi-epitope-based peptide vaccine (MEBPV) against RVFV. Bioinformatics approaches were used to design a potent MEBPV that can potentially activate both CD8+ and CD4+ T-cell immune responses, and several computational tools were employed to investigate its biological activities. Three antigenic proteins (Nucleocapsid (N), Glycoprotein C (GC), and Glycoprotein N (GN)) from the RVFV were chosen and potential immunogenic T- and B -cell epitopes were predicted from them. Based on in silico analysis, a MEBPV based on highly scored T and B-cell epitopes (6 CTL, 5 HTL, and 4 LBL) combined with linkers and adjuvants was developed. The finest predicted model was used for docking studies with Toll-like receptors (TLR3 and TLR8) and MHC molecules (MHC I and MHC II) after predicting and analyzing the tertiary structure of MEBPV. The designed MEBPV was then tested for stability with TLR3 and TLR8 receptors using molecular dynamics (MD) simulation and MMGBSA analysis. The MEBPV -TLR3, MEBPV -TLR8, MEBPV-MHC I and MEBPV -MHC II docked models were found stable during simulation time in MD and MMGBSA studies. In silico analysis revealed that the constructed vaccine could elicit both cell-mediated and humoral immune responses simultaneously. The proposed MEBPV could be a strong candidate against RVFV, but it will need to be tested in the laboratory to guarantee its safety and immunogenicity.

6.
Nutrients ; 13(12)2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34960117

RESUMO

Globally grown and organoleptically appreciated Grewia species are known as sources of bioactive compounds that avert the risk of communicable and non-communicable diseases. Therefore, in recent years, the genus Grewia has attracted increasing scientific attention. This is the first systematic review which focusses primarily on the nutritional composition, phytochemical profile, pharmacological properties, and disease preventative role of Grewia species. The literature published from 1975 to 2021 was searched to retrieve relevant articles from databases such as Google Scholar, Scopus, PubMed, and Web of Science. Two independent reviewers carried out the screening, selection of articles, and data extraction. Of 815 references, 56 met our inclusion criteria. G. asiatica and G. optiva were the most frequently studied species. We found 167 chemical compounds from 12 Grewia species, allocated to 21 categories. Flavonoids represented 41.31% of the reported bioactive compounds, followed by protein and amino acids (10.7%), fats and fatty acids (9.58%), ash and minerals (6.58%), and non-flavonoid polyphenols (5.96%). Crude extracts, enriched with bioactive compounds, and isolated compounds from the Grewia species show antioxidant, anticancer, anti-inflammatory, antidiabetic, hepatoprotective/radioprotective, immunomodulatory, and sedative hypnotic potential. Moreover, antimicrobial properties, improvement in learning and memory deficits, and effectiveness against neurodegenerative ailments are also described within the reviewed article. Nowadays, the side effects of some synthetic drugs and therapies, and bottlenecks in the drug development pathway have directed the attention of researchers and pharmaceutical industries towards the development of new products that are safe, cost-effective, and readily available. However, the application of the Grewia species in pharmaceutical industries is still limited.


Assuntos
Grewia/química , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Etnofarmacologia/métodos , Flavonoides/análise , Flavonoides/farmacologia , Frutas/química , Humanos , Hipnóticos e Sedativos/farmacologia , Hipoglicemiantes/farmacologia , Camundongos , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Ratos , Sementes/química
7.
Vaccines (Basel) ; 9(11)2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34835141

RESUMO

Pegivirus, HPgV, earlier known as Gb virus and hepatitis G virus, is an enveloped, positive-stranded RNA and lymphotropic virus classified into the Flaviviridae family. The transmission routes primarily involve blood products, with infections worldwide, leading up to 25% of persistent infections. To date, no effective therapeutic means are available to resolve Pegivirus infections. Effective vaccine therapeutics are the best alternative to manage this disease and any associated potential pandemic. Thus, whole proteome-based mining of immunogenic peptides, i.e., CTL (cytotoxic T lymphocytes), HTL (helper T lymphocytes) and B cell epitopes were mapped to design a vaccine ensemble. Our investigation revealed that 29 different epitopes impart a critical role in immune response induction, which was also validated by exploring its physiochemical properties and experimental feasibility. In silico expression and host immune simulation using an agent-based modeling approach confirmed the induction of both primary and secondary immune factors such as IL, cytokines and antibodies. The current study warrants further lab experiments to demonstrate its efficacy and safety.

8.
Front Mol Biosci ; 8: 716735, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765641

RESUMO

V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint and is a type I transmembrane protein. VISTA is linked to immunotherapy resistance, and it is a potential immune therapeutic target, especially for triple-negative breast cancer. It expresses at a high concentration in regulatory T cells and myeloid-derived suppressor cells, and its functional blockade is found to delay tumor growth. A useful medicinal plant database for drug designing (MPD3), which is a collection of phytochemicals from diverse plant families, was employed in virtual screening against VISTA to prioritize natural inhibitors against VISTA. Three compounds, Paratocarpin K (PubChem ID: 14187087), 3-(1H-Indol-3-yl)-2-(trimethylazaniumyl)propanoate (PubChem ID: 3861164), and 2-[(5-Benzyl-4-ethyl-1,2,4-triazol-3-yl)sulfanylmethyl]-5-methyl-1,3,4-oxadiazole (PubChem ID: 6494266), having binding energies stronger than -6 kcal/mol were found to have two common hydrogen bond interactions with VISTA active site residues: Arg54 and Arg127. The dynamics of the compound-VISTA complexes were further explored to infer binding stability of the systems. Results revealed that the compound 14187087 and 6494266 systems are highly stable with an average RMSD of 1.31 Å. Further affirmation on the results was achieved by running MM-GBSA on the MD simulation trajectories, which re-ranked 14187087 as the top-binder with a net binding energy value of -33.33 kcal/mol. In conclusion, the present study successfully predicted natural compounds that have the potential to block the function of VISTA and therefore can be utilized further in experimental studies to validate their real anti-VISTA activity.

9.
J Infect Dev Ctries ; 15(10): 1489-1496, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34780372

RESUMO

INTRODUCTION: The conventional interferon therapy of hepatitis C virus has been substituted substantially with sofosbuvir and daclatasvir due to constraints in efficacy and tolerability. This study aimed diagnostically to monitor the effectiveness and side effects of direct-acting antivirals in the management of HCV infections. METHODOLOGY: This prospective study was conducted on HCV-infected patients treated with sofosbuvir and daclatasvir. Different serological, biochemical, hematological, and molecular techniques were used for the assessment of patients. Only treatment-naive patients aged ≥ 18 to 75 years received 12 weeks of treatment. The primary endpoint was a sustained virologic response with undetectable HCV RNA in the patients' serum at the end of the treatment. RESULTS: We identified 229 cases of confirmed HCV infections by PCR, 94.3% of which had genotype 3. The study population comprised 66% females and 34% males with a median age of 42.2 ± 10.6 SD. Ninety-three percent of the patients accomplished SVR at week 12. The combined therapy of SOF/DAC achieved the highest efficacy rate (92.6%) among the different HCV genotype 3 patients. A statistically significant relationship was observed between low baseline viral load (p < 0.001; 95% CI = 1.2-3.1) and HCV genotype 3 with minor side effects, including lethargy, headache, nausea, insomnia, diarrhea, and fever. CONCLUSIONS: HCV-infected patients can be treated well with an interferon-free SOF/DAC regimen, tolerated with generally mild adverse effects with a higher SVR.

10.
Genome Biol ; 22(1): 304, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34736486

RESUMO

BACKGROUND: Coconut is an important tropical oil and fruit crop whose evolutionary position renders it a fantastic species for the investigation of the evolution of monocot chromosomes and the subsequent differentiation of ancient plants. RESULTS: Here, we report the assembly and annotation of reference-grade genomes of Cn. tall and Cn. dwarf, whose genome sizes are 2.40 Gb and 2.39 Gb, respectively. The comparative analysis reveals that the two coconut subspecies diverge about 2-8 Mya while the conserved Arecaceae-specific whole-genome duplication (ω WGD) occurs approximately 47-53 Mya. It additionally allows us to reconstruct the ancestral karyotypes of the ten ancient monocot chromosomes and the evolutionary trajectories of the 16 modern coconut chromosomes. Fiber synthesis genes in Cn. tall, related to lignin and cellulose synthesis, are found at a higher copy number and expression level than dwarf coconuts. Integrated multi-omics analysis reveals that the difference in coconut plant height is the result of altered gibberellin metabolism, with both the GA20ox copy number and a single-nucleotide change in the promoter together leading to the difference in plant height between Cn. tall and Cn. dwarf. CONCLUSION: We provide high-quality coconut genomes and reveal the genetic basis of trait differences between two coconuts through multi-omics analysis. We also reveal that the selection of plant height has been targeted for the same gene for millions of years, not only in natural selection of ancient plant as illustrated in coconut, but also for artificial selection in cultivated crops such as rice and maize.

11.
Molecules ; 26(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34641627

RESUMO

Peganum harmala (P. harmala) belongs to the family Zygophyllaceae, and is utilized in the traditional medicinal systems of Pakistan, China, Morocco, Algeria, and Spain to treat several chronic health disorders. The aim of the present study was to identify the chemical constituents and to evaluate the antioxidant, anti-inflammatory, and toxicity effects of P. harmala extracts both in vitro and in vivo. Sequential crude extracts including 100% dichloromethane, 100% methanol, and 70% aqueous methanol were obtained and their antioxidant and anti-inflammatory effects evaluated both in vitro and in vivo. The anti-inflammatory effect of the extract was investigated using the carrageenan-induced paw edema method in mice, whereas the toxicity of the most active extract was evaluated using an acute and subacute toxicity rat model. In addition, we have used the bioassay-guided approach to obtain potent fractions, using solvent-solvent partitioning and reversed phase high performance liquid chromatography from active crude extracts; identification and quantification of compounds from the active fractions was achieved using electrospray ionization mass spectrometry and high performance liquid chromatography techniques. Results revealed that the 100% methanol extract of P. harmala exhibits significant in vitro antioxidant activity in DPPH assay with an IC50 of 49 µg/mL as compared to the standard quercetin with an IC50 of 25.4 µg/mL. The same extract exhibited 63.0% inhibition against serum albumin denaturation as compared to 97% inhibition by the standard diclofenac sodium in an in vitro anti-inflammatory assay, and in vivo anti-inflammatory against carrageenan-induced paw edema (75.14% inhibition) as compared to 86.1% inhibition caused by the standard indomethacin. Furthermore, this extract was not toxic during a 14 day trial of acute toxicity when given at a dose of 3 g/kg, indicating that the lethal dose (LD50) of P. harmala methanol extract was greater than 3 g/kg. P. harmala methanolic fraction 2 obtained using bioassay-guided fractionation showed the presence of quinic acid, peganine, harmol, harmaline, and harmine, confirmed by electrospray ionization mass spectrometry and quantified using external standards on high performance liquid chromatography. Taken all together, the current investigation further confirms the antioxidant, anti-inflammatory, and safety aspects of P. harmala, which justifies its use in folk medicine.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Carragenina/efeitos adversos , Edema/tratamento farmacológico , Peganum/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Modelos Animais de Doenças , Edema/induzido quimicamente , Indometacina/farmacologia , Dose Letal Mediana , Camundongos , Extratos Vegetais/química , Quercetina/farmacologia , Ratos , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
12.
Infect Genet Evol ; 96: 105120, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34655808

RESUMO

Plasmodium vivax-induced malaria is among the leading causes of morbidity and mortality in sub-tropical and tropical regions and infect 2.85 billion people globally. The continual rise and propagation of resistance against anti-malarial drugs is a prerequisite to develop a potent vaccine candidate for Plasmodium vivax (P. vivax). Circumsporozoite protein (CSP) is an important immunogen of malaria parasite that has the conserved CSP structure as an immune dominant B-cell epitope. In current study, we focused on designing multi-epitope vaccines (MEVs) using various immunoinformatics tools against Pakistani based allelic variants VK210 and VK247 of P. vivax CSP (PvCSP) gene. Antigenicity, allergic potential and physicochemical parameters of both PvCSP variants were assessed for the designed MEVs and they were within acceptable range suitable for post experimental investigations. The three-dimensional structures of both MEVs have been predicted ab initio, optimized, and validated by using different online servers. The both MEVs candidates were stable and free from aggregation-prone regions. The stability of both MEVs had been improved by a disulfide engineering approach. To estimate the binding energy and stability of the MEVs, molecular docking simulation and binding free energy calculations with TLR-4 immune receptor have been conducted. The docking score of PvCSP210 and PvCSP247 for TLR-4 was -6.34 kJ/mol and - 2.3 kJ/mol, respectively. For PvCSP210-TLR4 system, mean RMSD was 4.96 Å while PvCSP247-TLR4 system, average RMSD was 4.49 Å. The binding free energy of PvCSP210-TLR4 complex and PvCSP247-TLR4 complex was -50.49/-117.15 kcal/mol (MMGBSA/MMPSA) and -52.94/-96.26 kcal/mol (MMGBSA/MMPSA), respectively. The expression of both MEVs produced in Escherichia coli K12 expression system by in silico cloning was significant. Immune simulation revealed that the proposed MEVs induce strong humoral and cellular immunological responses, in addition to significant production of interleukins and cytokines. In conclusions, we believed that the MEVs proposed in current research, using combine approach of immunoinformatics, structural biology and biophysical approaches, could induce protective and effective immune responses against P. vivax and the experimental validation of our findings could contribute to the development of potential malaria vaccine.

13.
Comput Biol Med ; 138: 104929, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34655900

RESUMO

Cholera is a severe small intestine bacterial disease caused by consumption of water and food contaminated with Vibrio cholera. The disease causes watery diarrhea leading to severe dehydration and even death if left untreated. In the past few decades, V. cholerae has emerged as multidrug-resistant enteric pathogen due to its rapid ability to adapt in detrimental environmental conditions. This research study aimed to design inhibitors of a master virulence gene expression regulator, HapR. HapR is critical in regulating the expression of several set of V. cholera virulence genes, quorum-sensing circuits and biofilm formation. A blind docking strategy was employed to infer the natural binding tendency of diverse phytochemicals extracted from medicinal plants by exposing the whole HapR structure to the screening library. Scoring function criteria was applied to prioritize molecules with strong binding affinity (binding energy < -11 kcal/mol) and as such two compounds: Strychnogucine A and Galluflavanone were filtered. Both the compounds were found favourably binding to the conserved dimerization interface of HapR. One rare binding conformation of Strychnogucine A was noticed docked at the elongated cavity formed by α1, α4 and α6 (binding energy of -12.5 kcal/mol). The binding stability of both top leads at dimer interface and elongated cavity was further estimated using long run of molecular dynamics simulations, followed by MMGB/PBSA binding free energy calculations to define the dominance of different binding energies. In a nutshell, this study presents computational evidence on antibacterial potential of phytochemicals capable of directly targeting bacterial virulence and highlight their great capacity to be utilized in the future experimental studies to stop the evolution of antibiotic resistance evolution.


Assuntos
Vibrio cholerae , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Compostos Fitoquímicos , Percepção de Quorum , Vibrio cholerae/genética , Vibrio cholerae/metabolismo
14.
Biology (Basel) ; 10(10)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34681096

RESUMO

Chlamydia trachomatis, a Gram-negative bacterium that infects the rectum, urethra, congenital sites, and columnar epithelium of the cervix. It is a major cause of preventable blindness, ectopic pregnancy, and bacterial sexually transmitted infections worldwide. There is currently no licensed multi-epitope vaccination available for this pathogen. This study used core proteomics, immuno-informatics, and subtractive proteomics approaches to identify the best antigenic candidates for the development of a multi-epitope-based vaccine (MEBV). These approaches resulted in six vaccine candidates: Type III secretion system translocon subunit CopD2, SctW family type III secretion system gatekeeper subunit CopN, SycD/LcrH family type III secretion system chaperone Scc2, CT847 family type III secretion system effector, hypothetical protein CTDEC_0668, and CHLPN 76kDa-like protein. A variety of immuno-informatics tools were used to predict B and T cell epitopes from vaccine candidate proteins. An in silico vaccine was developed using carefully selected epitopes (11 CTL, 2 HTL & 10 LBL) and then docked with the MHC molecules (MHC I & MHC II) and human TLR4. The vaccine was coupled with Cholera toxin subunit B (CTB) adjuvant to boost the immune response. Molecular dynamics (MD) simulations, molecular docking, and MMGBSA analysis were carried out to analyze the molecular interactions and binding affinity of MEBV with TLR4 and MHC molecules. To achieve the highest level of vaccine protein expression, the MEBV was cloned and reverse-translated in Escherichia coli. The highest level of expression was achieved, and a CAI score of 0.97 was reported. Further experimental validation of the MEBV is required to prove its efficacy. The vaccine developed will be useful in preventing infections caused by C. trachomatis.

15.
Artigo em Inglês | MEDLINE | ID: mdl-34682706

RESUMO

Morganella morganii is one of the main etiological agents of hospital-acquired infections and no licensed vaccine is available against the pathogen. Herein, we designed a multi-epitope-based vaccine against M. morganii. Predicted proteins from fully sequenced genomes of the pathogen were subjected to a core sequences analysis, followed by the prioritization of non-redundant, host non-homologous and extracellular, outer membrane and periplasmic membrane virulent proteins as vaccine targets. Five proteins (TonB-dependent siderophore receptor, serralysin family metalloprotease, type 1 fimbrial protein, flagellar hook protein (FlgE), and pilus periplasmic chaperone) were shortlisted for the epitope prediction. The predicted epitopes were checked for antigenicity, toxicity, solubility, and binding affinity with the DRB*0101 allele. The selected epitopes were linked with each other through GPGPG linkers and were joined with the cholera toxin B subunit (CTBS) to boost immune responses. The tertiary structure of the vaccine was modeled and blindly docked with MHC-I, MHC-II, and Toll-like receptors 4 (TLR4). Molecular dynamic simulations of 250 nanoseconds affirmed that the designed vaccine showed stable conformation with the receptors. Further, intermolecular binding free energies demonstrated the domination of both the van der Waals and electrostatic energies. Overall, the results of the current study might help experimentalists to develop a novel vaccine against M. morganii.


Assuntos
Morganella morganii , Vacinas , Biologia Computacional , Epitopos de Linfócito T , Imunidade , Simulação de Acoplamento Molecular , Morganella morganii/genética
16.
PLoS One ; 16(9): e0257744, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34582469

RESUMO

Sepsis is a syndromic response to infections and is becoming an emerging threat to the public health sector, particularly in developing countries. Salmonella Typhi (S. Typhi), the cause of typhoid fever, is one primary cause of pediatric sepsis in typhoid endemic areas. Extensively drug-resistant (XDR) S. Typhi is more common among pediatric patients, which is responsible for over 90% of the reported XDR typhoid cases, but the majority of antibiotic resistance studies available have been carried out using S. Typhi isolates from adult patients. Here, we characterized antibiotic-resistance profiles of XDR S. Typhi isolates from a medium size cohort of pediatric typhoid patients (n = 45, 68.89% male and 31.11% female) and determined antibiotic-resistance-related gene signatures associated with common treatment options to typhoid fever patients of 18 XDR S. Typhi representing all 45 isolates. Their ages were 1-13 years old: toddlers aging 1-2 years old (n = 9, 20%), pre-schoolers aging 3-5 years old (n = 17, 37.78%), school-age children aging 6-12 years old (n = 17, 37.78%), and adolescents aging 13-18 years old (n = 2, 4.44%). Through analyzing blaTEM1, dhfR7, sul1, and catA1genes for multidrug-resistance, qnrS, gyrA, gyrB, parC, and parE for fluoroquinolone-resistance, blaCTX-M-15 for XDR, and macAB and acrAB efflux pump system-associated genes, we showed the phenotype of the XDR S. Typhi isolates matches with their genotypes featured by the acquisitions of the genes blaTEM1, dhfR7, sul1, catA1, qnrS, and blaCTX-M-15 and a point mutation on gyrA. This study informs the molecular basis of antibiotic-resistance among recent S. Typhi isolates from pediatric septicemia patients, therefore providing insights into the development of molecular detection methods and treatment strategies for XDR S. Typhi.


Assuntos
Proteínas de Bactérias/genética , Farmacorresistência Bacteriana Múltipla , Salmonella typhi/isolamento & purificação , Sepse/microbiologia , Febre Tifoide/diagnóstico , Adolescente , Antibacterianos/farmacologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mutação Puntual , Salmonella typhi/efeitos dos fármacos , Salmonella typhi/genética
17.
Colloids Surf B Biointerfaces ; 208: 112098, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34509085

RESUMO

Sorcin (SOluble Resistance-related Calcium bInding proteiN) is a calcium binding protein that plays a key role in multidrug resistance (MDR) in human cancers. This study aimed at understanding the binding mechanism and structural basis for the interaction of structurally and functionally unrelated chemotherapeutic agent, namely doxorubicin, etoposide, omacetaxine mepesuccinate and paclitaxel with Sorcin by utilizing docking and molecular dynamic simulation approaches. The docking evaluation of etoposide, omacetaxine mepesuccinate and paclitaxel have shown a high affinity binding with Sorcin at the Ca2+-binding C-terminal domain (SCBD) in a comparable mode and affinity of binding to doxorubicin. Moreover, all of the docked compounds were shown to interact both hydrophilically and hydrophobically with the same residues within the active pocket which is located at interface of the Sorcin and collectively formed by EF5 loop, G helix and EF4 loop. However, the MD simulations revealed that the dynamics of Sorcin structure is different in the presence of the compounds when compared and contrasted to the Apo Sorcin, particularly in the first 25 ns, after which each system gained considerable structure stability. The difference in dynamics might be the outcome of high N and C-terminal flexibility that seem not to disturb compounds binding conformation but more likely is affecting chemical interaction network by breaking and establishing old and new hydrogen bonds, respectively. This detailed mechanistic understanding of different chemotherapeutic agents binding to Sorcin might be useful to open windows for designing and developing new inhibitors that are potentially capable of reversing the MDR in human cancers.


Assuntos
Antineoplásicos , Simulação de Dinâmica Molecular , Antineoplásicos/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Doxorrubicina , Resistência a Múltiplos Medicamentos , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica
18.
Biomed Res Int ; 2021: 5561129, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589547

RESUMO

Diabetes mellitus termed as metabolic disorder is a collection of interlinked diseases and mainly body's inability to manage glucose level which leads to cardiovascular diseases, renal failure, neurological disorders, and many others. The drugs contemporarily used for diabetes have many inevitable side effects, and many of them have become less responsive to this multifactorial disorder. Momordica charantia commonly known as bitter gourd has many bioactive compounds with antidiabetic properties. The current study was designed to use computational methods to discover the best antidiabetic peptides devised from hypoglycemic polypeptide-P of M. charantia. The binding affinity and interaction patterns of peptides were evaluated against four receptor proteins (i.e., as agonists of insulin receptor and inhibitors of sodium-glucose cotransporter 1, dipeptidyl peptidase-IV, and glucose transporter 2) using molecular docking approach. A total of thirty-seven peptides were docked against these receptors. Out of which, top five peptides against each receptor were shortlisted based on their S-scores and binding affinities. Finally, the eight best ligands (i.e., LIVA, TSEP, EKAI, LKHA, EALF, VAEK, DFGAS, and EPGGGG) were selected as these ligands strictly followed Lipinski's rule of five and exhibited good ADMET profiling. One peptide EPGGGG showed activity towards insulin and SGLT1 receptor proteins. The top complex for both these targets was subjected to 50 ns of molecular dynamics simulations and MM-GBSA binding energy test that concluded both complexes as highly stable, and the intermolecular interactions were dominated by van der Waals and electrostatic energies. Overall, the selected ligands strongly fulfilled the drug-like evaluation criterion and proved to have good antidiabetic properties.

19.
Comput Biol Med ; 136: 104705, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34340127

RESUMO

Antimicrobial resistance (AMR) in bacterial pathogens is a major global distress. Due to the slow progress of antibiotics development and the fast pace of resistance acquisition, there is an urgent need for effective vaccines against such bacterial pathogens. In-silico approaches including pan-genomics, subtractive proteomics, reverse vaccinology, immunoinformatics, molecular docking, and dynamics simulation studies were applied in the current study to identify a universal potential vaccine candidate against the 18 multi-drug resistance (MDRs) bacterial pathogenic species from a WHO priority list. Ten non-redundant, non-homologous, virulent, and antigenic vaccine candidates were filtered against all targeted species. Nine B-cell-derived T-cell antigen epitopes which show a great affinity to the dominant HLA allele (DRB1*0101) in the human population were screened from selected vaccine candidates using immunoinformatics approaches. Screened epitopes were then used to design a multi-epitope peptide vaccine construct (MEPVC) along with ß-defensin adjuvant to improve the immunogenic properties of the proposed vaccine construct. Molecular docking and MD simulation were carried out to study the binding affinity and molecular interaction of MEPVC with human immune receptors (TLR2, TLR3, TLR4, and TLR6). The final MEPVC construct was reverse translated and in-silico cloned in the pET28a(+) vector to ensure its effectiveness. This in silico construct is expected to be helpful for vaccinologists to assess its immune protection effectiveness in vivo and in vitro to counter rising antibiotic resistance worldwide.


Assuntos
Biologia Computacional , Epitopos de Linfócito T , Resistência Microbiana a Medicamentos , Humanos , Simulação de Acoplamento Molecular , Vacinas de Subunidades , Organização Mundial da Saúde
20.
Sci Total Environ ; 790: 148221, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380261

RESUMO

Aim of this study is to quantify the impacts of climate change on phenology and yield of winter wheat in rainfed and irrigated regions of Pakistan by using integration of two well-known crop models including STICS and APSIM with CORDEX-SA regional climate models (RCMs). A number of different adaptation strategies based on early sowing (i.e. S1:10 and S2:20 days), irrigation (I1:15% and I2:30% additional water) and a combination of sowing and irrigation adaptations were examined to recover the potential losses that would occur due to climate change. The data for the wheat phenology, biomass (t/ha) at different stages and yield (t/ha) was obtained from several experiments at national research institutes in Pakistan under both rainfed and irrigated conditions. After calibration and validation of both crop models (STICS and APSIM), the current climate data were replaced with the CORDEX-SA RCM-projections for climate change impact analysis. A significant rising and declining trends were observed in temperature and precipitation patterns, respectively, for the selected study regions. Consequently, a substantial impact of climate change on wheat phenology (anthesis stage, maturity stage, growing length), biomass (t/ha) and yield (t/ha) was observed under scenario periods for RCP4.5 and RCP8.5. Additionally, the adaptation strategies on wheat for rainfed regions showed a substantial improvement in wheat biomass and yield simulated by STICS model particularly for sowing-2 under RCP4.5. Irrigated regions showed more improvement for irrigation-2 (I2) and combination of sowing-1 + irrigation-2 (S1 + I2) using the STICS model under both RCPs. Overall, it was observed that changes in crop phenology had a stronger impact in terms of crop yield for RCP8.5 as compare to RCP4.5. This study provides a valuable understanding and way forward for the better wheat management under changes in precipitation and temperature patterns. The study also discuss in detail, the adaptation strategies to cope with potential damage, over two different irrigation zones (rainfed and irrigated) in Pakistan.


Assuntos
Mudança Climática , Triticum , Agricultura , Paquistão , Estações do Ano
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