ORCID Profile
0000-0002-6486-9835
Current Organisation
Qassim University
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Publisher: Elsevier BV
Date: 08-2023
Publisher: Frontiers Media SA
Date: 28-06-2021
DOI: 10.3389/FMOLB.2021.692835
Abstract: Pirin ( PIR ) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, it has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level. Keeping in view the importance of PIR in many crucial cellular processes in humans, we used a variety of computational tools to identify non-synonymous single-nucleotide polymorphisms (SNPs) in the PIR gene that are highly deleterious for the structure and function of PIR protein. Out of 173 SNPs identified in the protein, 119 are non-synonymous, and by consensus, 24 mutations were confirmed to be deleterious in nature. Mutations such as V257A, I28T, and I264S were unveiled as highly destabilizing due to a significant stability fold change on the protein structure. This observation was further established through molecular dynamics (MD) simulation that demonstrated the role of the mutation in protein structure destability and affecting its internal dynamics. The findings of this study are believed to open doors to investigate the biological relevance of the mutations and drugability potential of the protein.
Publisher: MDPI AG
Date: 12-2022
Abstract: Artemisia annua (A. annua) has been used as a medicinal plant in the treatment of several infectious and non-infectious diseases in the forms of tea and press juice since ancient times. The aim of this study was to evaluate the aqueous extract of A. annua (AAE) as an antimicrobial agent in vitro and to evaluate its chemopreventive efficacy in vivo in a small-cell lung cancer (SCLC) animal model. The dried powder of AAE was prepared using the Soxhlet extraction system from the leaves of Artemisia annua. The in vitro activity of AAE was determined against Candida albicans (C. albicans), Enterococcus faecalis (E. faecalis), Klebsiella pneumoniae (K. pneumoniae), and methicillin-resistant Staphylococcus aureus (MRSA) using the agar well diffusion method and propidium iodide (PI)-stained microbial death under a confocal microscope. The pretreatment of mice with AAE was initiated two weeks before the first dose of benzo[a]pyrene and continued for 21 weeks. The chemopreventive potential of the extract was evaluated by flow cytometry and biochemical and histopathological analyses of the tissues and serum accordingly, after sacrificing the mice. The data revealed the antimicrobial potential of AAE against all the species investigated, as it showed growth-inhibitory activity by MIC, as well as confocal microscopy. The pretreatment of AAE exhibited significant protection in carcinogen-modulated, average body weight (ABW), and relative organ weight (ROW) cancer biomarkers in the serum and antioxidants in the lungs. The hematoxylin and eosin (H& E) staining of the tissues revealed that AAE prevented malignancy in the lungs. AAE also induced apoptosis and decreased intracellular reactive oxygen species (ROS) in the lung cells analyzed by flow cytometry. The current findings demonstrated the use of AAE as an alternative medicine in the treatment of infectious disease and the chemoprevention of lung cancer. To our knowledge, this is the first study that summarizes the chemopreventive potential of AAE in a lung cancer model in vivo. However, further investigations are suggested to understand the role of AAE to potentiate the therapeutic index of the commercially available drugs that show multiple drug resistance against microbial growth and high toxicity during cancer chemotherapy.
Publisher: MDPI AG
Date: 21-03-2021
Abstract: Hepatitis C virus (HCV) causes chronic and acute hepatitis infections. As there is extreme variability in the HCV genome, no approved HCV vaccine has been available so far. An effective polypeptide vaccine based on the functionally conserved epitopes will be greatly helpful in curing disease. For this purpose, an immuno-informatics study is performed based on the published HCV subtype-3a from Pakistan. First, the virus genome was translated to a polyprotein followed by a subsequent prediction of T-cell epitopes. Non-allergenic, IFN-γ producer, and antigenic epitopes were shortlisted, including 5 HTL epitopes and 4 CTL, which were linked to the final vaccine by GPGPG and AAY linkers, respectively. Beta defensin was included as an adjuvant through the EAAAK linker to improve the immunogenicity of the polypeptide. To ensure its safety and immunogenicity profile, antigenicity, allergenicity, and various physiochemical attributes of the polypeptide were evaluated. Molecular docking was conducted between TLR4 and vaccine to evaluate the binding affinity and molecular interactions. For stability assessment and binding of the vaccine-TLR4 docked complex, molecular dynamics (MD) simulation and MMGBSA binding free-energy analyses were conducted. Finally, the candidate vaccine was cloned in silico to ensure its effectiveness. The current vaccine requires future experimental confirmation to validate its effectiveness. The vaccine construct produced might be useful in providing immune protection against HCV-related infections.
Publisher: Informa UK Limited
Date: 21-09-2022
Publisher: Elsevier BV
Date: 08-2022
Publisher: MDPI AG
Date: 05-01-2022
Abstract: This study investigated the health-promoting activities of methanolic extracts of Ajwa date seed and fruit pulp extracts through in vitro studies. These studies confirmed potential antioxidant, anti-hemolytic, anti-proteolytic, and anti-bacterial activities associated with Ajwa dates. The EC50 values of fruit pulp and seed extracts in methanol were reported to be 1580.35 ± 0.37 and 1272.68 ± 0.27 µg/mL, respectively, in the DPPH test. The maximum percentage of hydrogen peroxide-reducing activity was 71.3 and 65.38% for both extracts at 600 µg/mL. Fruit pulp and seed extracts inhibited heat-induced BSA denaturation by 68.11 and 60.308%, heat-induced hemolysis by 63.84% and 58.10%, and hypersalinity-induced hemolysis by 61.71% and 57.27%, and showed the maximum anti-proteinase potential of 56.8 and 51.31% at 600 μg/mL, respectively. Seed and fruit pulp inhibited heat-induced egg albumin denaturation at the same concentration by 44.31 and 50.84%, respectively. Ajwa seed showed minimum browning intensity by 63.2%, percent aggregation index by 64.2%, and amyloid structure by 63.8% at 600 μg/mL. At 100 mg/mL, Ajwa seed extract exhibited good antibacterial activity. Molecular docking analysis showed that ten active constituents of Ajwa seeds bind with the critical antioxidant enzymes, catalase (1DGH) and superoxide dismutase (5YTU). The functional residues involved in such interactions include Arg72, Ala357, and Leu144 in 1DGH, and Gly37, Pro13, and Asp11 in 5YTU. Hence, Ajwa dates can be used to develop a suitable alternative therapy in various diseases, including diabetes and possibly COVID-19-associated complications.
Publisher: MDPI AG
Date: 19-01-2022
DOI: 10.3390/W14030296
Abstract: Groundwater constitutes a significant component of freshwater resources in India being vital for its economy and domestic water security. The quantity, quality and accessibility of water resources forms the basis of balanced socio-economic development and its optimum utilization cannot be sustained unless its quality is assessed. The current study tries to access the quality and suitability of groundwater for drinking purposes in western drier parts of India in the state of Rajasthan. Based on collected data, selected hydro-geochemical parameters, the quality of water has been determined and Water Quality Index (WQI) have been prepared using GIS applications. Applying the Inverse Distance Weighting method, WQI values for 89 villages in the area have been computed, which ranged between 71.23 and 447.39. While 68% of the region had “poor water quality”, only 32% is sustained as ‘good water’ for consumption. The fluoride content ranging between 1.66 and 8.60 mg/L and TDS 1000 mg/L with average pH levels 7 (8–9 pH) were found to be very high amongst all the 12 water quality parameters taken for the study. The northeastern region with a WQI value of had the worst water quality. Furthermore, the existing water quality is also examined for influencing two water borne diseases, i.e., gastroenteritis and fluorosis in the region. The study thus establishes that the majority of groundwater in the region is beyond the permissible safer consumption limits, and a large population of the region, which is directly dependent on groundwater sources, is prone to water borne health hazards. A significantly high correlation was observed between Specific Water Quality Parameters in the region and prevalence of gastroenteritis (and fluorosis diseases with R2 = 0.530 and R2 = 0.813, respectively).
Publisher: Georg Thieme Verlag KG
Date: 06-07-2020
Abstract: Despite the establishment of successful surgical techniques and rehabilitation protocols for anterior cruciate ligament (ACL) reconstruction, published return to sport rates are less than satisfactory. This has led orthopaedic surgeons and researchers to develop more robust patient selection methods, and investigate prognostic patient characteristics. No previous studies have integrated baseline characteristics and responses to patient-reported outcome measures (PROMs) of patients with ACL rupture presenting for surgical review. Patients electing to undergo ACL reconstruction under the care of a single orthopaedic surgeon at a metropolitan public hospital were enrolled in a clinical quality registry. Patients completed Veterans RAND 12-item Health Survey (VR-12) Physical Component Summary and Mental Component Summary scores, Tegner activity scale, and International Knee Documentation Committee (IKDC) questionnaires at presentation. Total scores were extracted from the electronic registry, and a machine learning approach (k-means) was used to identify subgroups based on similarity of questionnaire responses. The average scores in each cluster were compared using analysis of variance (ANOVA Kruskal–Wallis) and nominal logistic regression was performed to determine relationships between cluster membership and patient age, gender, body mass index (BMI), and injury-to-examination delay. A s le of 107 patients with primary ACL rupture were extracted, with 97 (91%) available for analysis with complete datasets. Four clusters were identified with distinct patterns of PROMs responses. These ranged from lowest (Cluster 1) to highest scores for VR-12 and IKDC (Cluster 4). In particular, Cluster 4 returned median scores within 6 points of the patient acceptable symptom state for the IKDC score for ACL reconstruction (70.1, interquartile range: 59–78). Significant (p 0.05) differences in PROMs between clusters were observed using ANOVA, with variance explained ranging from 40 to 69%. However, cluster membership was not significantly associated with patient age, gender, BMI, or injury-to-examination delay. Patients electing to undergo ACL reconstruction do not conform to a homogenous group but represent a spectrum of knee function, general physical and mental health, and preinjury activity levels, which may not lend itself to uniform treatment and rehabilitation protocols. The factors driving these distinct responses to PROMs remain unknown but are unrelated to common demographic variables.
Publisher: MDPI AG
Date: 19-10-2021
Abstract: 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.
Publisher: Elsevier BV
Date: 12-2020
Publisher: MDPI AG
Date: 17-06-2029
DOI: 10.3390/ANTIBIOTICS10050477
Abstract: Giardiasis is an intestinal protozoal disease caused by Giardia lamblia. The disease became a global health issue due to development of resistance to commonly used drugs. Since many plant-derived products have been used to treat many parasitic infestations, we aimed to assess the therapeutic utility of Artemisia annua (A. annua) for giardiasis. We showed that NO production was significantly reduced whereas serum levels of IL-6, IFN-γ, and TNF-α were elevated in infected hamsters compared to uninfected ones. Additionally, infection resulted in increased numbers of intraepithelial lymphocytes and reduced villi heights, goblet cell numbers, and muscularis externa thickness. We also showed that inducible NO synthase (iNOS) and caspase-3 were elevated in the intestine of infected animals. However, treatment with A. annua significantly reduced the intestinal trophozoite counts and IEL numbers, serum IL-6, IFN-γ, and TNF-α, while increasing NO and restoring villi heights, GC numbers, and ME thickness. Moreover, A. annua treatment resulted in lower levels of caspase-3, which indicates a protective effect from apoptotic cell death. Interestingly, A. annua therapeutic effects are comparable to metronidazole. In conclusion, our results show that A. annua extract is effective in alleviating infection-induced intestinal inflammation and pathological effects, which implies its potential therapeutic utility in controlling giardiasis.
Publisher: MDPI AG
Date: 09-07-2022
Abstract: Porphyromonas gingivalis is a Gram-negative anaerobic bacterium, mainly present in the oral cavity and causes periodontal infections. Currently, no licensed vaccine is available against P. gingivalis and other oral bacterial pathogens. To develop a vaccine against P. gingivalis, herein, we applied a bacterial pan-genome analysis (BPGA) on the bacterial genomes that retrieved a total number of 4908 core proteins, which were further utilized for the identification of good vaccine candidates. After several vaccine candidacy analyses, three proteins, namely lytic transglycosylase domain-containing protein, FKBP-type peptidyl-propyl cis-trans isomerase and superoxide dismutase, were shortlisted for epitopes prediction. In the epitopes prediction phase, different types of B and T-cell epitopes were predicted and only those with an antigenic, immunogenic, non-allergenic, and non-toxic profile were selected. Moreover, all the predicted epitopes were joined with each other to make a multi-epitopes vaccine construct, which was linked further to the cholera toxin B-subunit to enhance the antigenicity of the vaccine. For downward analysis, a three dimensional structure of the designed vaccine was modeled. The modeled structure was checked for binding potency with major histocompatibility complex I (MHC-I), major histocompatibility complex II (MHC-II), and Toll-like receptor 4 (TLR-4) immune cell receptors which revealed that the designed vaccine performed proper binding with respect to immune cell receptors. Additionally, the binding efficacy of the vaccine was validated through a molecular dynamic simulation that interpreted strong intermolecular vaccine–receptor binding and confirmed the exposed situation of vaccine epitopes to the host immune system. In conclusion, the study suggested that the model vaccine construct has the potency to generate protective host immune responses and that it might be a good vaccine candidate for experimental in vivo and in vitro studies.
Publisher: Elsevier BV
Date: 10-2021
Publisher: MDPI AG
Date: 02-06-2023
DOI: 10.3390/IJMS24119665
Abstract: Cancer is a major public health concern worldwide and main burden of the healthcare system. Regrettably, most of the currently used cancer treatment approaches such as targeted therapy, chemotherapy, radiotherapy and surgery usually cause adverse complications including hair loss, bone density loss, vomiting, anemia and other complications. However, to overcome these limitations, there is an urgent need to search for the alternative anticancer drugs with better efficacy as well as less adverse complications. Based on the scientific evidences, it is proven that naturally occurring antioxidants present in medicinal plants or their bioactive compounds might constitute a good therapeutic approach in diseases management including cancer. In this regard, myricetin, a polyhydroxy flavonol found in a several types of plants and its role in diseases management as anti-oxidant, anti-inflammatory and hepato-protective has been documented. Moreover, its role in cancer prevention has been noticed through modulation of angiogenesis, inflammation, cell cycle arrest and induction of apoptosis. Furthermore, myricetin plays a significant role in cancer prevention through the inhibition of inflammatory markers such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2). Moreover, myricetin increases the chemotherapeutic potential of other anticancer drugs through modulation of cell signaling molecules activity. This review elaborates the information of myricetin role in cancer management through modulating of various cell-signaling molecules based on in vivo and in vitro studies. In addition, synergistic effect with currently used anticancer drugs and approaches to improve bioavailability are described. The evidences collected in this review will help different researchers to comprehend the information about its safety aspects, effective dose for different cancers and implication in clinical trials. Moreover, different challenges need to be focused on engineering different nanoformulations of myricetin to overcome the poor bioavailability, loading capacity, targeted delivery and premature release of this compound. Furthermore, some more derivatives of myricetin need to be synthesized to check their anticancer potential.
Publisher: Wiley
Date: 22-10-2020
DOI: 10.1002/CA.23465
Abstract: The aims of this study were to (1) describe the three-dimensional characteristics and sources of anatomical variability in the geometry of the intercondylar fossa ("notch") in an anterior cruciate ligament (ACL)-injured s le and (2) assess the relationship between patient factors and anatomical variability of the fossa in the context of impingement risk. A retrospective analysis of preoperative magnetic resonance imaging (MRI) for 49 patients with ACL rupture was performed. Scans were examined in the axial plane using an online picture archiving and communication system (PACS) viewer and fossa width and angle assessed at multiple slices, as well as anteroposterior depth, fossa height, and calculated total volume. Principal component analysis was performed to prioritize the sources of variability. A multivariate linear regression was performed to assess relationships between different patient factors, controlling for imaging parameters and principal component loadings. Geometric properties were normally distributed for all but fossa volume, height, and distal angle. Three principal components (PCs) were identified explaining 80% of total variance, shape (PC1), size in the coronal plane (PC2), and size in the sagittal plane (PC3). Patient factors were significantly (P < 0.05) related to PC loadings however, a substantial amount of variance in each model remained unexplained. Intercondylar fossa characteristics vary considerably within ACL-injury patients with shape and size in coronal and axial planes, explaining most of the variance. Although patient factors are associated with anatomical characteristics, further work is required to identify the correct combination of factors accurately predicting geometry of the fossa for planning ACL reconstruction. Clin. Anat. 33:610-618, 2020. © 2019 Wiley Periodicals, Inc.
Publisher: MDPI AG
Date: 05-04-2021
DOI: 10.3390/MOLECULES26072082
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the bio erse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (Mpro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as Mpro inhibitors with ΔGbinding ≤ −40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 Mpro than lopinavir over 100 ns with ΔGbinding values of −51.9 vs. −33.6 kcal/mol, respectively. Protein–protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target–function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing.
Publisher: MDPI AG
Date: 19-10-2022
DOI: 10.3390/CIMB44100342
Abstract: (1) Background: SARS-CoV-2 Omicron BA.1 is the most common variation found in most countries and is responsible for 99% of cases in the United States. To overcome this challenge, there is an urgent need to discover effective inhibitors to prevent the emerging BA.1 variant. Natural products, particularly flavonoids, have had widespread success in reducing COVID-19 prevalence. (2) Methods: In the ongoing study, fifteen compounds were annotated from Echium angustifolium and peach (Prunus persica), which were computationally analyzed using various in silico techniques. Molecular docking calculations were performed for the identified phytochemicals to investigate their efficacy. Molecular dynamics (MD) simulations over 200 ns followed by molecular mechanics Poisson–Boltzmann surface area calculations (MM/PBSA) were performed to estimate the binding energy. Bioactivity was also calculated for the best components in terms of drug likeness and drug score. (3) Results: The data obtained from the molecular docking study demonstrated that five compounds exhibited remarkable potency, with docking scores greater than −9.0 kcal/mol. Among them, compounds 1, 2 and 4 showed higher stability within the active site of Omicron BA.1, with ΔGbinding values of −49.02, −48.07, and −67.47 KJ/mol, respectively. These findings imply that the discovered phytoconstituents are promising in the search for anti-Omicron BA.1 drugs and should be investigated in future in vitro and in vivo research.
Publisher: MDPI AG
Date: 12-01-2023
DOI: 10.3390/MOLECULES28020783
Abstract: The Bcl-2 protein has a vital function in controlling the programmed cell doom of mitochondria. If programmed cell death signals are obstructed, an imbalance between cell survival and death will occur, which is a significant reason for cancer. Therefore, the Bcl-2 protein was identified as a possible therapeutic target for carcinoma treatment. Herein, the Natural Products Atlas (NPAtlas) compounds were virtually screened, seeking potent inhibitors towards the Bcl-2 protein. The performance of AutoDock Vina software to predict the docking score and pose of the investigated compounds was first validated according to the available experimental data. Based on the validated AutoDock Vina parameters, the NPAtlas database was filtered against the Bcl-2 protein. The natural compounds with docking scores less than that of the venetoclax (calc. −10.6 kcal/mol) were submitted to MD simulations, followed by MM-GBSA binding energy calculations. According to MM-GBSA//200 ns MD simulations, saquayamycin F (NPA002200) demonstrated promising binding affinity with a ΔGbinding value of −53.9 kcal/mol towards the Bcl-2 protein when compared to venetoclax (ΔGbinding = −50.6 kcal/mol). The energetical and structural analyses showed a great constancy of the saquayamycin F inside the Bcl-2 protein active site. Moreover, the ADMET and drug-likeness features of the saquayamycin F were anticipated, indicating its good oral bioavailability. According to in silico computations, saquayamycin F is proposed to be used as a therapeutic agent against the wild-type Bcl-2 protein and warrants further experimental assays.
Publisher: Future Medicine Ltd
Date: 04-2023
Abstract: Aim: The aim of this study was to identify host factors that interact with the 5′ end of the MERS-CoV RNA genome. Materials & methods: RNA affinity chromatography followed by mass spectrometry analysis was used to identify the binding of host factors in Vero E6 cells. Results: A total of 59 host factors that bound the MERS-CoV RNA genome in non-infected Vero E6 cells were identified. Most of the identified cellular proteins were previously reported to interact with the genome of other RNA viruses. We validated our mass spectrometry results using western blotting. Conclusion: These data enhance our knowledge about the RNA–host interactions of coronaviruses, which could serve as targets for developing antiviral therapeutics against MERS-CoV.
Publisher: Bentham Science Publishers Ltd.
Date: 20-09-2021
DOI: 10.2174/1389201022666210218193445
Abstract: In the present study, we assessed the adjunct effect of vitamin D3 in combination with Fluconazole (FLZ) against Vulvovaginal Candidiasis (VVC) in mice. Prophylactic effect was assessed by pretreating mice with vitamin D3 before exposure of mice with 2 X 10 6 CFUs of Candida albicans followed by treatment with FLZ. To determine the combined therapeutic efficacy, C. albicans infected mice were treated with a combination of vitamin D3 (10 μg/kg) and FLZ (10 and 20 mg/kg). The efficacy of the treatment was assessed by analyzing the fungal load and blood cell count. Moreover, the levels of inflammatory cytokines, including IL- 1β, IL-17 and TNF-α, were analyzed in the vaginal tissues. The histological analysis of the vaginal tissue from the untreated and treated mice was performed to assess the efficacy of the treatment. Prophylactic treatment with vitamin D3 (10 and 20 μg/kg) significantly increased the therapeutic effect of FLZ against VVC. In a therapeutic experiment, mice in the infected control group showed the highest vaginal fungal load of 83627 ± 10058 CFUs. Treatment with FLZ at a dose of 10 mg/kg reduced fungal load to 55523 ± 14823 CFUs, whereas the mice treated with a combination of vitamin D3 and FLZ (10 mg/kg) had the fungal burden of 12156 ± 3219. Similarly, treatment with FLZ (20 mg/kg) reduced fungal load to 36394 ± 5648 CFUs, whereas the addition of vitamin D3 to FLZ (20 mg/kg) further reduced the fungal burden to 2179 ± 1188. The leukocyte numbers in the infected mice increased to 9802 ± 505 as compared to 5152 ± 778 in normal control mice. Whereas, a combination of vitamin D3 with FLZ (10 and 20 mg/kg) reduced leukocyte numbers to 7284 ± 607 and 5739 ± 1126. The histological analysis data revealed epithelial necrosis, shedding and ulceration in the vaginal wall. Treatment with FLZ or a combination of FLZ and vitamin D3 brought regenerative changes in the vaginal epithelium and lamina proparia. The results of the present work recommend that the addition of vitamin D3 may be considered to increase the efficacy of FLZ against VVC.
Publisher: Bentham Science Publishers Ltd.
Date: 17-07-2020
DOI: 10.2174/1871530320666191230141110
Abstract: Lactate dehydrogenase (LDH) is a group of oxidoreductase isoenzymes catalyzing the reversible reaction between pyruvate and lactate. The five isoforms of this enzyme, formed from two subunits, vary in isoelectric points and these isoforms have different substrate affinity, inhibition constants and electrophoretic mobility. These erse biochemical properties play a key role in its cellular, tissue and organ specificity. Though LDH is predominantly present in the cytoplasm, it has a multi-organellar location as well. The primary objective of this review article is to provide an update in parallel, the previous and recent biochemical views and its clinical significance in different diseases. With the help of certain inhibitors, its active site three-dimensional view, reactions mechanisms and metabolic pathways have been sorted out to a greater extent. Overexpression of LDH in different cancers plays a principal role in anaerobic cellular metabolism, hence several inhibitors have been designed to employ as novel anticancer agents. LDH performs a very important role in overall body metabolism and some signals can induce isoenzyme switching under certain circumstances, ensuring that the tissues consistently maintain adequate ATP supply. This enzyme also experiences some posttranslational modifications, to have ersified metabolic roles. Different toxicological and pathological complications damage various organs, which ultimately result in leakage of this enzyme in serum. Hence, unusual LDH isoform level in serum serves as a significant biomarker of different diseases. LDH is an important diagnostic biomarker for some common diseases like cancer, thyroid disorders, tuberculosis, etc. In general, LDH plays a key role in the clinical diagnosis of various common and rare diseases, as this enzyme has a prominent role in active metabolism.
Publisher: MDPI AG
Date: 16-11-2020
DOI: 10.3390/MOLECULES25225336
Abstract: A proper execution of basic cellular functions requires well-controlled homeostasis including correct protein folding. Endoplasmic reticulum (ER) implements such functions by protein reshaping and post-translational modifications. Different insults imposed on cells could lead to ER stress-mediated signaling pathways, collectively called the unfolded protein response (UPR). ER stress is also closely linked with oxidative stress, which is a common feature of diseases such as stroke, neurodegeneration, inflammation, metabolic diseases, and cancer. The level of ER stress is higher in cancer cells, indicating that such cells are already struggling to survive. Prolonged ER stress in cancer cells is like an Achilles’ heel, if aggravated by different agents including nanoparticles (NPs) may be exhausted off the pro-survival features and can be easily subjected to proapoptotic mode. Different types of NPs including silver, gold, silica, graphene, etc. have been used to augment the cytotoxicity by promoting ER stress-mediated cell death. The erse physico-chemical properties of NPs play a great role in their biomedical applications. Some special NPs have been effectively used to address different types of cancers as these particles can be used as both toxicological or therapeutic agents. Several types of NPs, and anticancer drug nano-formulations have been engineered to target tumor cells to enhance their ER stress to promote their death. Therefore, mitigating ER stress in cancer cells in favor of cell death by ER-specific NPs is extremely important in future therapeutics and understanding the underlying mechanism of how cancer cells can respond to NP induced ER stress is a good choice for the development of novel therapeutics. Thus, in depth focus on NP-mediated ER stress will be helpful to boost up developing novel pro-drug candidates for triggering pro-death pathways in different cancers.
Publisher: Informa UK Limited
Date: 04-2021
DOI: 10.2147/JIR.S300025
Publisher: MDPI AG
Date: 25-01-2022
Abstract: Antibiotic resistance (AR) is the resistance mechanism pattern in bacteria that evolves over some time, thus protecting the bacteria against antibiotics. AR is due to bacterial evolution to make itself fit to changing environmental conditions in a quest for survival of the fittest. AR has emerged due to the misuse and overuse of antimicrobial drugs, and few antibiotics are now left to deal with these superbug infections. To combat AR, vaccination is an effective method, used either therapeutically or prophylactically. In the current study, an in silico approach was applied for the design of multi-epitope-based vaccines against Providencia rettgeri, a major cause of traveler’s diarrhea. A total of six proteins: fimbrial protein, flagellar hook protein (FlgE), flagellar basal body L-ring protein (FlgH), flagellar hook-basal body complex protein (FliE), flagellar basal body P-ring formation protein (FlgA), and Gram-negative pili assembly chaperone domain proteins, were considered as vaccine targets and were utilized for B- and T-cell epitope prediction. The predicted epitopes were assessed for allergenicity, antigenicity, virulence, toxicity, and solubility. Moreover, filtered epitopes were utilized in multi-epitope vaccine construction. The predicted epitopes were joined with each other through specific GPGPG linkers and were joined with cholera toxin B subunit adjuvant via another EAAAK linker in order to enhance the efficacy of the designed vaccine. Docking studies of the designed vaccine construct were performed with MHC-I (PDB ID: 1I1Y), MHC-II (1KG0), and TLR-4 (4G8A). Findings of the docking study were validated through molecular dynamic simulations, which confirmed that the designed vaccine showed strong interactions with the immune receptors, and that the epitopes were exposed to the host immune system for proper recognition and processing. Additionally, binding free energies were estimated, which highlighted both electrostatic energy and van der Waals forces to make the complexes stable. Briefly, findings of the current study are promising and may help experimental vaccinologists to formulate a novel multi-epitope vaccine against P. rettgeri.
Publisher: MDPI AG
Date: 06-2022
Abstract: Enterobacter cloacae (EC) is a significant emerging pathogen that is occasionally associated with lung infection, surgical site infection, urinary infection, sepsis, and outbreaks in neonatal intensive care units. In light of the fact that there is currently no approved vaccine or therapeutic option for the treatment of EC, the current study was developed to concentrate on applications based on modern computational approaches to design a multi-epitope-based E. cloacae peptide vaccine (MEBEPV) expressing the antigenic determinants prioritized from the EC genome. Integrated computational analyses identified two potential protein targets (phosphoporin protein-PhoE and putative outer-membrane porin protein) for further exploration on the basis of pangenome subtractive proteomics and immunoinformatic in-depth examination of the core proteomes. Then, a multi-epitope peptide vaccine was designed, which comprised shortlisted epitopes that were capable of eliciting both innate and adaptive immunity, as well as the cholera toxin’s B-subunit, which was used as an adjuvant in the vaccine formulation. To ensure maximum expression, the vaccine’s 3D structure was developed and the loop was refined, improving the stability by disulfide engineering, and the physicochemical characteristics of the recombinant vaccine sequence were found to be ideal for both in vitro and in vivo experimentation. Blind docking was then used for the prediction of the MEBEPV predominant blinding mode with MHCI, MHCII, and TLR3 innate immune receptors, with lowest global energy of −18.64 kJ/mol, −48.25 kJ/mol, and −5.20 kJ/mol for MHC-I, MHC-II, and TLR-4, respectively, with docked complexes considered for simulation. In MD and MMGBSA investigations, the docked models of MEBEPV-TLR3, MEBEPV-MHCI, and MEBEPV-MHCII were found to be stable during the course of the simulation. MM-GBSA analysis calculated −122.17 total net binding free energies for the TLR3-vaccine complex, −125.4 for the MHC I-vaccine complex, and −187.94 for the MHC II-vaccine complex. Next, MM-PBSA analysis calculated −115.63 binding free energy for the TLR3-vaccine complex, −118.19 for the MHC I-vaccine complex, and −184.61 for the MHC II-vaccine complex. When the vaccine was tested in silico, researchers discovered that it was capable of inducing both types of immune responses (cell mediated and humoral) at the same time. Even though the suggested MEBEPV has the potential to be a powerful contender against E. cloacae-associated illnesses, further testing in the laboratory will be required before it can be declared safe and immunogenic.
Publisher: Informa UK Limited
Date: 04-09-2023
Publisher: Bentham Science Publishers Ltd.
Date: 22-03-2019
DOI: 10.2174/1389201020666190119142331
Abstract: Numerous studies have been performed in understanding the development of cancer. Though, the mechanism of action of genes in the development of cancer remains to be explained. The current mode of treatment of cancer shows adverse effects on normal cells and also alter the cell signalling pathways. However, ginger and its active compound have fascinated research based on animal model and laboratories during the past decade due to its potentiality in killing cancer cells. Ginger is a mixture of various compounds including gingerol, paradol, zingiberene and shogaol and such compounds are the main players in diseases management. Most of the health-promoting effects of ginger and its active compound can be attributed due to its antioxidant and anti-tumour activity. Besides, the active compound of ginger has proven its role in cancer management through its modulatory effect on tumour suppressor genes, cell cycle, apoptosis, transcription factors, angiogenesis and growth factor. In this review, the role of ginger and its active compound in the inhibition of cancer growth through modulating cell signalling pathways will be reviewed and discussed.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2020
Publisher: Hindawi Limited
Date: 02-02-2021
DOI: 10.1155/2021/8833467
Abstract: Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance and impaired insulin secretion, which cannot be reversed with existing therapeutic strategies. Using mesenchymal stem cells (MSCs), cell-based therapy has been demonstrated in displaying therapeutic effects in T2DM for their self-renewable, differentiation potential, and immunosuppressive properties and higher levels of angiogenic factors. Stem cell therapies are complicated and have a serious adverse effect including tumor formation and immunogenicity, while using mesenchymal stem cell-conditioned media (MSC-CM) significantly reduces stem cell risk, maintaining efficacy and showing significantly higher levels of growth factors, cytokines, and angiogenic factors that stimulate angiogenesis and promote fracture healing in diabetes. In the present study, we investigated the therapeutic potential of the liver and adipose MSC-CM in diabetic endothelial dysfunction compared with standard insulin therapy. Fifty adult male Sprague Dawley rats were ided equally into 5 groups as follows: control, diabetic, diabetic+insulin, diabetic+liver MSC-CM, and diabetic+adipose MSC-CM all treatments continued for 4 weeks. Finally, we observed that liver MSC-CM therapy had the most apparent improvement in levels of blood glucose HbA1c AGEs lipid panel (cholesterol, TG, LDL, HDL, and total lipids) renal function (urea, uric acid, creatinine, and total protein) liver function (AST, ALT, ALP, bilirubin, and albumin) CPK C-peptide HO-1 inflammatory markers including IL-6, TNF-α, and CRP growth factors (liver and serum IGF-1) amylase histopathological changes pancreatic cell oxidative stress and antioxidant markers (MDA, GSH, ROS, CAT, SOD, HO-1, and XO) toward the normal levels compared with insulin and adipose MSCs-CM. Moreover, both the liver and adipose MSC-CM relieved the hyperglycemic status by improving pancreatic islet β cell regeneration, promoting the conversion of alpha cells to beta cells, reducing insulin resistance, and protecting pancreatic tissues against oxidative stress-induced injury as well as possessing the ability to modulate immunity and angiogenesis. These results indicated that MSC-CM infusion has therapeutic effects in T2DM rats and may be a promising novel therapeutic target.
Publisher: MDPI AG
Date: 11-2018
DOI: 10.3390/APP8112124
Abstract: Background: Squamous cell carcinoma (SCC) of the uterine cervix is a leading cause of morbidity and mortality among women. The alterations of Phosphatase and tensin homolog (PTEN), B-cell lymphoma 2 (Bcl2) and p53 expression seem to be significant in the development of various types of cancers. The altered expressions of PTEN, Bcl2 and p53 and their involvement in cancer of the uterine cervix are not well recognized. Aim: This study aimed at examining the expression patterns of PTEN, Bcl2 and p53 proteins and comparing them with the grade and stage of cervical cancer. Materials and Methods: Tissue blocks of SCC and ten cases of inflammatory lesions of the uterine cervix were examined immunohistochemically for the expression of PTEN, Bcl2 and p53 proteins. Results: Loss of PTEN expression was identified in 45.33% of cervical SCC and no expression was found in inflammatory lesions (p ≤ 0.05). PTEN expression was significantly associated with the clinical stage of SCC (61.36% and 45.16% in stages I–II and III–IV, respectively) (p 0.05), but not with the degree of differentiation of the SCC. The expression of Bcl2 was significantly high (60%) in cancer cases than in control cases (p 0.05). Bcl2 did not show any significant association with the histologic type and clinical stage of the SCC of the uterine cervix. The expression of p53 protein was significantly high (57.33%)) in cancer tissue, and no expression was noted in control cases (p 0.05). Moreover, the expression pattern of p53 protein in cervical cancer tissue s les was not linked with the patient age, grade and stage of the cervical SCC (p 0.05). Conclusion: The reduced expression of PETN and overexpressions of Bcl2 and p53 might play an indispensable role in carcinogenesis of cervical SCC. Moreover, a relationship was detected between PTEN expression and clinical stage of the cervical SCC.
Publisher: Informa UK Limited
Date: 10-2020
DOI: 10.2147/IDR.S266928
Publisher: Journal of Pure and Applied Microbiology
Date: 18-11-2020
Abstract: Door handles are being reported to harbor a erse group of microorganisms, mainly bacteria. Presence of pathogenic and antibiotic-resistant bacteria in the door handles carry risk to the health of the public. For this reason, a study was carried in the Qassim region of Saudi Arabia by isolating bacteria from the pharmacy door handles from four different areas. Total 100 s les were collected by wiping the door handles with a sterile cotton swab soaked in sterile water. Microorganisms were isolated using Blood agar and MacConkey agar and identified following standard microbiological procedure. Siemens MicroScan Walkaway system was used for determination of antibiotic susceptibility pattern. In total, 301 bacteria from 13 bacterial species were isolated and identified. The predominant bacterial species include Staphylococcus spp. 56.48% followed by Bacillus spp. 12.29% and Micrococcus spp. 10.30%. Gram-negative bacteria like Shigella sonnei and Salmonella paratyphiA were also isolated. Being the most predominant species, Antibiotic resistance pattern of 39 Staphylococcus spp. were determined. 38.46% of the Staphylococcus spp. were found to be resistant to Cefoxitin, and 30.76% were beta-lactamase producing. The results also indicated that about one -third of Staphylococcus spp. were methicillin resistant. The door handles of pharmacies in the Qassim region carry risk to the health of the public. Proper hygienic measures are recommended for the public health safety until doors are made automatic and touch-free.
Publisher: MDPI AG
Date: 08-05-2021
DOI: 10.3390/PHARMACEUTICS13050677
Abstract: In the present study, we investigated the activity of free thymoquinone (TQ) or liposomal thymoquinone (Lip-TQ) in comparison to standard antibiotic amoxicillin (AMX) against the drug-sensitive and drug-resistant Acinetobacter baumannii. A liposomal formulation of TQ was prepared and characterized and its toxicity was evaluated by analyzing the hematological, liver and kidney function parameters. TQ was effective against both drug-sensitive and drug-resistant A. baumannii as shown by the findings of drug susceptibility testing and time kill kinetics. Moreover, the therapeutic efficacy of TQ or Lip-TQ against A. baumannii was assessed by the survival rate and the bacterial load in the lung tissues of treated mice. The mice infected with drug-sensitive A. baumannii exhibited a 90% survival rate on day 30 post treatment with Lip-TQ at a dose of 10 mg/kg, whereas the mice treated with AMX (10 mg/kg) had a 100% survival rate. On the other hand, the mice infected with drug-resistant A. baumannii had a 70% survival rate in the group treated with Lip-TQ, whereas AMX was ineffective against drug-resistant A. baumannii and all the mice died within day 30 after the treatment. Moreover, Lip-TQ treatment effectively reduced the bacterial load in the lung tissues of the mice infected with the drug-sensitive and drug-resistant A. baumannii. Moreover, the blood of the mice treated with Lip-TQ had reduced levels of inflammation markers, leukocytes and neutrophils. The results of the present study suggest that Lip-TQ may prove to be an effective therapeutic formulation in the treatment of the drug-sensitive or drug-resistant A. baumannii infection as well.
Publisher: MDPI AG
Date: 15-07-2022
Abstract: Antimicrobial resistance has become a significant health issue because of the misuse of antibiotics in our daily lives, resulting in high rates of morbidity and mortality. Hafnia alvei is a rod-shaped, Gram-negative and facultative anaerobic bacteria. The medical community has emphasized H. alvei’s possible association with gastroenteritis. As of now, there is no licensed vaccine for H. alvei, and as such, computer aided vaccine design approaches could be an ideal approach to highlight the potential vaccine epitopes against this bacteria. By using bacterial pan-genome analysis (BPGA), we were able to study the entire proteomes of H. alvei with the aim of developing a vaccine. Based on the analysis, 20,370 proteins were identified as core proteins, which were further used in identifying potential vaccine targets based on several vaccine candidacy parameters. The prioritized vaccine targets against the bacteria are type 1 fimbrial protein, flagellar hook length control protein (FliK), flagellar hook associated protein (FlgK), curli production assembly/transport protein (CsgF), fimbria ilus outer membrane usher protein, fimbria ilus outer membrane usher protein, molecular chaperone, flagellar filament capping protein (FliD), TonB-dependent hemoglobin /transferrin/lactoferrin family receptor, Porin (OmpA), flagellar basal body rod protein (FlgF) and flagellar hook-basal body complex protein (FliE). During the epitope prediction phase, different antigenic, immunogenic, non-Allergenic, and non-Toxic epitopes were predicted for the above-mentioned proteins. The selected epitopes were combined to generate a multi-epitope vaccine construct and a cholera toxin B subunit (adjuvant) was added to enhance the vaccine’s antigenicity. Downward analyses of vaccines were performed using a vaccine three-dimensional model. Docking studies have confirmed that the vaccine strongly binds with MHC-I, MHC-II, and TLR-4 immune cell receptors. Additionally, molecular dynamics simulations confirmed that the vaccine epitopes were exposed to nature and to the host immune system and interpreted strong intermolecular binding between the vaccine and receptors. Based on the results of the study, the model vaccine construct seems to have the capacity to produce protective immune responses in the host, making it an attractive candidate for further in vitro and in vivo studies.
Publisher: MDPI AG
Date: 20-01-2022
DOI: 10.3390/PHARMACEUTICS14020236
Abstract: Diallyl disulfide (DADS) is one of the main bioactive organosulfur compounds of garlic, and its potential against various cancer models has been demonstrated. The poor solubility of DADS in aqueous solutions limits its uses in clinical application. The present study aimed to develop a novel formulation of DADS to increase its bioavailability and therapeutic potential and evaluate its role in combination with oxaliplatin (OXA) in the colorectal cancer system. We prepared and characterized PEGylated, DADS (DCPDD), and OXA (DCPDO) liposomes. The anticancer potential of these formulations was then evaluated in HCT116 and RKO colon cancer cells by different cellular assays. Further, a molecular docking-based computational analysis was conducted to determine the probable binding interactions of DADS and OXA. The results revealed the size of the DCPDD and DCPDO to be 114.46 nm (95% EE) and 149.45 nm (54% EE), respectively. They increased the sensitivity of the cells and reduced the IC50 several folds, while the combinations of them showed a synergistic effect and induced apoptosis by 55% in the cells. The molecular docking data projected several possible targets of DADS and OXA that could be evaluated more precisely by these novel formulations in detail. This study will direct the usage of DCPDD to augment the therapeutic potential of DCPDO against colon cancer in clinical settings.
Publisher: Informa UK Limited
Date: 07-12-2022
Publisher: Informa UK Limited
Date: 05-2020
DOI: 10.2147/IJN.S249625
Publisher: Hindawi Limited
Date: 12-05-2021
DOI: 10.1155/2021/5575245
Abstract: Human bodies encompass very important symbiotic and mutualistic relationships with tiny creatures known as microbiota. Trillions of these tiny creatures including protozoa, viruses, bacteria, and fungi are present in and on our bodies. They play important roles in various physiological mechanisms of our bodies. In return, our bodies provide them with the habitat and food necessary for their survival. In this review, we comprehend the gut microbial species present in various regions of the gut. We can get benefits from microbiota only if they are present in appropriate concentrations, as if their concentration is altered, it will lead to dysbiosis of microbiota which further contributes to various health ailments. The composition, ersity, and functionality of gut microbiota do not remain static throughout life as they keep on changing over time. In this review, we also reviewed the various biotic and abiotic factors influencing the quantity and quality of these microbiota. These factors serve a significant role in shaping the gut microbiota population.
Publisher: Public Library of Science (PLoS)
Date: 15-07-2021
DOI: 10.1371/JOURNAL.PONE.0253036
Abstract: Although COVID-19 is an acute disease that usually resolves rapidly in most cases, the disease can be fatal and has a mortality rate of about 1% to 56%. Alveolar injury and respiratory failure are the main causes of death in patients with COVID 19. In addition, the effect of the disease on other organs is not fully understood. Renal system affection has been reported in patients with COVID 19 and is associated with a higher rate of erse outcomes, including mortality. Therefore, in the present work, we reported the clinical characteristics and laboratory data of hospitalized patients with COVID-19 and analyzed the manifestations that indicated renal system involvement and their impact on clinical outcomes. This was an observational retrospective study conducted at King Fahd Specialist Hospital, Buraydah, Saudi Arabia. All patients with COVID-19 who were admitted to this Hospital from April to December 2020 were included in the study. The patients’ findings at presentation were recorded. Demographic data and laboratory results (hematuria, proteinuria, urinary sediment cast and pus cell presence, and kidney function tests) were retrieved from electronic patient records. One hundred and ninety-three patients with confirmed COVID 19 were included in the study. Dipstick examinations of all urine s les showed proteinuria and hematuria in 53.9% and 22.3% of patients, respectively, whereas microscopic examination revealed the presence of pus and brown muddy granular casts in 33.7% and 12.4% of s les, respectively. Acute kidney injury was reported in 23.3% of patients. A multivariable analysis demonstrated that hematuria was associated with acute kidney injury (AKI) (OR, 2.4 95% CI, 1.2–4.9 P = 0.001), ICU admission (OR, 3.789 95% CI, 1.913–7.505 P = 0.003), and mortality (OR, 8.084 95% CI, 3.756–17.397 P = 0.002). Conversely, proteinuria was less significantly associated with the risk of AKI (OR, 1.56 95% CI, 1.91–7.50 P = 0.003), ICU admission (OR, 2.493 95% CI, 1.25–4.72 P = 0.001), and mortality (OR, 2.764 95% CI, 1.368–5.121 P = 0.003). Patients with AKI had a higher probability for mortality than did those without AKI (OR, 14.208 95% CI, 6.434–31.375 P = 0.003). The manifestations of the involvement of the renal system are not uncommon in COVID-19. These manifestations included proteinuria, hematuria, and AKI and were usually associated with a poor prognosis, including high incidences of both ICU admission and mortality.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Informa UK Limited
Date: 04-2022
DOI: 10.2147/JIR.S358632
Publisher: MDPI AG
Date: 15-06-2021
DOI: 10.3390/PHARMACEUTICS13060882
Abstract: Cryptococcus neoformans infections rose sharply due to rapid increase in the numbers of immunocompromised in iduals in recent years. Treatment of Cryptococcosis in immunocompromised persons is largely very challenging and hopeless. Hence, this study aimed to determine the activity of ellagic acid (EA) in the treatment of C. neoformans in cyclophosphamide injected leukopenic mice. A liposomal formulation of ellagic acid (Lip-EA) was prepared and characterized, and its antifungal activity was assessed in comparison to fluconazole (FLZ). The efficacy of the drug treatment was tested by assessing survival rate, fungal burden, and histological analysis in lung tissues. The safety of the drug formulations was tested by investigating hepatic, renal function, and antioxidant levels. The results of the present work demonstrated that Lip-EA, not FLZ, effectively eliminated C. neoformans infection in the leukopenic mice. Mice treated with Lip-EA (40 mg/kg) showed 70% survival rate and highly reduced fungal burden in their lung tissues, whereas the mice treated with FLZ (40 mg/kg) had 20% survival rate and greater fungal load in their lungs. Noteworthy, Lip-EA treatment alleviated cyclophosphamide-induced toxicity and restored hepatic and renal function parameters. Moreover, Lip-EA treatment restored the levels of superoxide dismutase and reduced glutathione and catalase in the lung tissues. The effect of FLZ or EA or Lip-EA against C. neoformans infection was assessed by the histological analysis of lung tissues. Lip-EA effectively reduced influx of inflammatory cells, thickening of alveolar walls, congestion, and hemorrhage. The findings of the present study suggest that Lip-EA may prove to be a promising therapeutic formulation against C. neoformans in immunocompromised persons.
Publisher: Elsevier BV
Date: 06-2021
Publisher: MDPI AG
Date: 30-03-2021
DOI: 10.3390/NANO11040884
Abstract: Burkholderia glumae and B. gladioli are seed-borne rice pathogens that cause bacterial panicle blight (BPB) disease, resulting in huge rice yield losses worldwide. However, the excessive use of chemical pesticides in agriculture has led to an increase in environmental toxicity. Microbe-mediated nanoparticles (NPs) have recently gained significant attention owing to their promising application in plant disease control. In the current study, we biologically synthesize zinc oxide nanoparticles (ZnONPs) from a native Bacillus cereus RNT6 strain, which was taxonomically identified using 16S rRNA gene analysis. The biosynthesis of ZnONPs in the reaction mixture was confirmed by using UV–Vis spectroscopy. Moreover, XRD, FTIR, SEM-EDS, and TEM analysis revealed the functional groups, crystalline nature, and spherical shape of ZnONPs with sizes ranging from 21 to 35 nm, respectively. Biogenic ZnONPs showed significant antibacterial activity at 50 µg mL−1 against B. glumae and B. gladioli with a 2.83 cm and 2.18 cm zone of inhibition, respectively, while cell numbers (measured by OD600) of the two pathogens in broth culture were reduced by 71.2% and 68.1%, respectively. The ultrastructure studies revealed the morphological damage in ZnONPs-treated B. glumae and B. gladioli cells as compared to the corresponding control. The results of this study revealed that ZnONPs could be considered as promising nanopesticides to control BPB disease in rice.
Publisher: MDPI AG
Date: 25-05-2022
DOI: 10.3390/PH15060659
Abstract: Rift valley fever virus (RVFV) is the causative agent of a viral zoonosis that causes a significant clinical burden in domestic and wild ruminants. Major outbreaks of the virus occur in livestock, and contaminated animal products or arthropod vectors can transmit the virus to humans. The viral RNA-dependent RNA polymerase (RdRp L protein) of the RVFV is responsible for viral replication and is thus an appealing drug target because no effective and specific vaccine against this virus is available. The current study reported the structural elucidation of the RVFV-L protein by in-depth homology modeling since no crystal structure is available yet. The inhibitory binding modes of known potent L protein inhibitors were analyzed. Based on the results, further molecular docking-based virtual screening of Selleckchem Nucleoside Analogue Library (156 compounds) was performed to find potential new inhibitors against the RVFV L protein. ADME (Absorption, Distribution, Metabolism, and Excretion) and toxicity analysis of these compounds was also performed. Besides, the binding mechanism and stability of identified compounds were confirmed by a 50 ns molecular dynamic (MD) simulation followed by MM/PBSA binding free energy calculations. Homology modeling determined a stable multi-domain structure of L protein. An analysis of known L protein inhibitors, including Monensin, Mycophenolic acid, and Ribavirin, provide insights into the binding mechanism and reveals key residues of the L protein binding pocket. The screening results revealed that the top three compounds, A-317491, Khasianine, and VER155008, exhibited a high affinity at the L protein binding pocket. ADME analysis revealed good pharmacodynamics and pharmacokinetic profiles of these compounds. Furthermore, MD simulation and binding free energy analysis endorsed the binding stability of potential compounds with L protein. In a nutshell, the present study determined potential compounds that may aid in the rational design of novel inhibitors of the RVFV L protein as anti-RVFV drugs.
Publisher: MDPI AG
Date: 09-01-2022
DOI: 10.3390/PHARMACEUTICS14010153
Abstract: Thymoquinone (TQ), which is one of the main bioactive constituents of Nigella sativa seeds, has demonstrated its potential against various cancer models. The poor solubility of TQ in aqueous solution limits its uses in clinical application. The present study aimed to develop a novel formulation of TQ to increase its bioavailability and therapeutic potential with minimal toxicity. Polyethylene glycol (PEG)-coated DSPC/cholesterol comprising TQ liposomes (PEG-Lip-TQ) were prepared and characterized on various aspects. A computational investigation using molecular docking was used to assess the possible binding interactions of TQ with 12 prospective anticancer drug targets. The in vitro anticancer activity was assessed in A549 and H460 lung cancer cells in a time- and dose-dependent manner, while the oral acute toxicity assay was evaluated in silico as well as in vivo in mice. TQ docked to the Hsp90 target had the lowest binding energy of −6.05 kcal/mol, whereas caspase 3 was recognized as the least likely target for TQ with a binding energy of −1.19 kcal/mol. The results showed 96% EE with 120 nm size, and −10.85 mv, ζ-potential of PEG-Lip-TQ, respectively. The cell cytotoxicity data demonstrated high sensitivity of PEG-Lip-TQ and a several fold decrease in the IC50 while comparing free TQ. The cell cycle analysis showed changes in the distribution of cells with doses. The in vivo data revealed an ~9-fold increase in the LD50 of PEG-Lip-TQ on free TQ as an estimated 775 and 89.5 mg/kg b.w, respectively. This study indicates that the pharmacological and efficacy profile of PEG-lip-TQ is superior to free TQ, which will pave the way for an exploration of the effect of TQ formulation in the treatment of lung cancer in clinical settings.
Publisher: Informa UK Limited
Date: 07-2021
Publisher: MDPI AG
Date: 13-07-2021
DOI: 10.3390/MD19070391
Abstract: The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding −33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of −43.8 and −34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340 biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.
Publisher: MDPI AG
Date: 26-03-2020
DOI: 10.3390/PR8040388
Abstract: Silver nanoparticle (AgNP) based approaches using plant materials have been accepted as biomedical applications. The current study aimed to test the antibacterial, antibiofilm, and anticancer activity of silver nanoparticles synthesized by seed extract of Nigella sativa (Ns) as stabilizing and reducing agents. Characterization was done through UV–visible spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electronic microscopy (SEM), and transmission electronic microscopy (TEM) analyses. UV-Vis spectroscopy showed a specific silver plasmon peak at 400 nm and a quick color change was observed in the bio-reaction medium. Electron microscopic images of Ns-AgNPs identified as spherical in shape with varied size ranged between 8 and 80 nm and zeta potential analysis evidenced the particles stability and polydisperity. Antibiofilm activity of Ns-AgNPs was evident as at 12.5 µg/mL Ns-AgNps restricted the biofilm formation by 88.42% for Enterococcus faecalis, 84.92% for E. coli, 81.86% for Klebsiella pneumonia, 82.84% for Staphylococcus aureus, and 49.9% for Pseudomonas aeruginosa, respectively. Furthermore, biologically synthesized AgNPs showed the significant bacteriostatic and bactericidal activity. Even the lowest concentration of Ns-AgNps restricted the highest rate of inhibition against S. aureus (6.5 and 15 µg/mL) and E. faecalis (6.5 and 15 µg/mL). Antimicrobial activity of S. aureus and E. fecalis was more prominent than E. coli (15 and 30 µg/mL), K. pneumonia (15 and 30 µg/mL) and P. aeruginosa (30 and 60 µg/mL) respectively. Moreover, Ns-AgNPs revealed significant cytotoxic ability and substantially killed human breast cancer cell (HCC-712) viability. The results of current study advocate that Ns-AgNps may be considered as a potential option in biomedical applications, alternative therapy, designing anti-biofilm agents, treating multi drug resistance bacterial infection, and anti-cancer therapy.
Publisher: SAGE Publications
Date: 2021
DOI: 10.1177/22808000211040304
Abstract: The implants are increasingly being a part of modern medicine in various surgical procedures for functional or cosmetic purposes. The progressive use of implants is associated with increased infectious complications and prevention of such infections always remains precedence in the clinical settings. The preventive approaches include the systemic administration of antimicrobial agents before and after the surgical procedures as well as the local application of antibiotics. The relevant literature and existing clinical practices have highlighted the role of antimicrobial coating approaches in the prevention of implants associated infections, although the applications of these strategies are not yet standardized, and the clinical efficacy is not much clear. The adequate data from the randomized control trials is challenging because of the unavailability of a large s le size although it is compulsory in this context to assess the clinical efficacy of preemptive practices. This review compares the efficacy of preventive approaches and the prospects of antimicrobial-coated implants in preventing implant-related infections.
Publisher: Informa UK Limited
Date: 05-05-2023
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.CCT.2014.11.007
Abstract: Home-based rehabilitation following total knee replacement surgery can be as effective as clinic-based or in-patient rehabilitation. The use of the Nintendo Wii has been postulated as a novel rehabilitation tool that adds an additional focus on balance and proprioception into the recovery protocol. The aim of the proposed clinical trial is to investigate the effectiveness of this novel rehabilitation tool, used at home for three months after total knee replacement surgery and to assess any lasting improvements in functional outcome at one year. This will be a randomised controlled trial of 128 patients undergoing primary total knee replacement. The participants will be recruited preoperatively from three surgeons at a single centre. There will be no change to the usual care provided until 6 weeks after the operation. Then participants will be randomised to either the Wii-Fit group or usual rehabilitative care group. Outcomes will be assessed preoperatively, a 6-week post surgery baseline and then at 18 weeks, 6 months and 1 year. The primary outcome is the change in self-reported WOMAC total score from week 6 to 18 weeks. Secondary outcomes include objective measures of strength, function and satisfaction scores. The results of this clinical trial will be directly relevant for implementation into clinical practice. If beneficial, this affordable technology could be used by many patients to rehabilitate at home. Not only could it optimize the outcomes from their total knee replacement surgery but decrease the need for clinic-based or outpatient therapy for the majority. (ACTRN12611000291987).
Publisher: Informa UK Limited
Date: 09-2023
DOI: 10.2147/IJN.S424872
Publisher: MDPI AG
Date: 03-10-2021
Abstract: 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.
Publisher: MDPI AG
Date: 11-04-2023
DOI: 10.3390/IJMS24087052
Abstract: The innovative advances in transforming clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) into different variants have taken the art of genome-editing specificity to new heights. Allosteric modulation of Cas9-targeting specificity by sgRNA sequence alterations and protospacer adjacent motif (PAM) modifications have been a good lesson to learn about specificity and activity scores in different Cas9 variants. Some of the high-fidelity Cas9 variants have been ranked as Sniper-Cas9, eSpCas9 (1.1), SpCas9-HF1, HypaCas9, xCas9, and evoCas9. However, the selection of an ideal Cas9 variant for a given target sequence remains a challenging task. A safe and efficient delivery system for the CRISPR/Cas9 complex at tumor target sites faces considerable challenges, and nanotechnology-based stimuli-responsive delivery approaches have significantly contributed to cancer management. Recent innovations in nanoformulation design, such as pH, glutathione (GSH), photo, thermal, and magnetic responsive systems, have modernized the art of CRISPR/Cas9 delivery approaches. These nanoformulations possess enhanced cellular internalization, endosomal membrane disruption/bypass, and controlled release. In this review, we aim to elaborate on different CRISPR/Cas9 variants and advances in stimuli-responsive nanoformulations for the specific delivery of this endonuclease system. Furthermore, the critical constraints of this endonuclease system on clinical translations towards the management of cancer and prospects are described.
Publisher: Bentham Science Publishers Ltd.
Date: 18-10-2019
DOI: 10.2174/1389201019666190722151126
Abstract: The present study was aimed to evaluate the effect of the aqueous extract of Tinospora cordifolia (AETC) against cyclophosphamide-induced immunosuppression and systemic Candida albicans infection in a murine model. The protective effect of AETC against cyclophosphamide-induced leukopenia was evaluated by quantitative and qualitative analysis of the leukocytes. The immune-stimulating potential of AETC on macrophages was assessed by determining the levels of secreted cytokines. To determine the direct antifungal activity, AETC or fluconazole was administered to C. albicans infected mice. The efficacy of treatment was assessed by determining the survival rate, kidney fungal burden, the organ index and liver inflammation parameters. Cyclophosphamide administration resulted in substantial depletion of leukocytes, whereas AETC treatment induced the recovery of leukocytes in cyclophosphamide-injected mice. Moreover, AETC treatment of macrophages resulted in enhanced secretion of IFN-γ, TNF-α and IL-1β. C. albicans infected mice treated with AETC at the doses of 50 and 100 mg/kg exhibited 40% and 60% survival rate, whereas the mice treated with fluconazole at a dose of 50 mg/kg showed 20% survival rate. Like survival data, the fungal load was found to be the lowest in the kidney tissues of mice treated with AETC at a dose of 100 mg/kg. Interestingly, mice infected with C. albicans demonstrated improvement in the organ indices and liver functioning after AETC treatment. These results suggest that AETC may potentially be used to rejuvenate the weakened immune system and eliminate systemic candidiasis in mice.
Publisher: MDPI AG
Date: 12-11-2022
DOI: 10.3390/MOLECULES27227790
Abstract: Due to the high propensity of drug resistance in
Publisher: Informa UK Limited
Date: 11-2021
DOI: 10.2147/JIR.S339092
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.COMPBIOMED.2021.105151
Abstract: 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
Publisher: MDPI AG
Date: 24-12-2021
Abstract: Elizabethkingia meningoseptica is a ubiquitous Gram-negative emerging pathogen that causes hospital-acquired infection in both immunocompromised and immunocompetent patients. It is a multi-drug-resistant bacterium therefore, an effective subunit immunogenic candidate is of great interest to encounter the pathogenesis of this pathogen. A protein-wide annotation of immunogenic targets was performed to fast-track the vaccine development against this pathogen, and structural-vaccinology-assisted epitopes were predicted. Among the total proteins, only three, A0A1T3FLU2, A0A1T3INK9, and A0A1V3U124, were shortlisted, which are the essential vaccine targets and were subjected to immune epitope mapping. The linkers EAAK, AAY, and GPGPG were used to link CTL, HTL, and B-cell epitopes and an adjuvant was also added at the N-terminal to design a multi-epitope immunogenic construct (MEIC). The computationally predicted physiochemical properties of the ensemble immunogen reported a highly antigenic nature and produced multiple interactions with immune receptors. In addition, the molecular dynamics simulation confirmed stable binding and good dynamic properties. Furthermore, the computationally modeled immune response proposed that the immunogen triggered a strong immune response after several doses at different intervals. Neutralization of the antigen was observed on the 3rd day of injection. Conclusively, the immunogenic construct produces protection against Elizabethkingia meningoseptica however, further immunological testing is needed to unveil its real efficacy.
Publisher: Informa UK Limited
Date: 06-2022
DOI: 10.2147/IDR.S377252
Publisher: MDPI AG
Date: 29-04-2022
DOI: 10.3390/APP12094537
Abstract: Green nanotechnology is the evolution of cost-effective and environmentally friendly processes for the production of metal-based nanoparticles due to medicinal importance and economic value. The aim of the present study was to biosynthesize and characterize silver nanoparticles (AgNPs) using the seed extract of Ajwa dates (Aw). The anti-bacteriostatic activity of biosynthesized Aw–AgNPs against Gram-positive and Gram-negative bacterial strains was evaluated. The anti-biofilm activity was examined by the tissue culture plate method. Lastly, the anti-cancer potential of Aw–AgNPs was investigated against the human breast cancer cell line HCC712. UV–visible absorption spectra exhibited the plasmon resonance peak at 430 nm, with the solution undergoing rapid color changes that verified the existence of biosynthesized silver nanoparticles in the solution. TEM and SEM images illustrated that the Aw–AgNPs were spherical and between 15 and 80 nm in diameter. The reduction and stabilization of Aw–AgNPs was due to the functional groups present in the biomolecules of the Ajwa seeds, as identified by FTIR. The Aw–AgNPs exhibited significant anti-bacterial activity against all the tested bacterial strains. Moreover, the Aw–AgNPs efficiently h ered the biofilm formation of the bacterial strains and exhibited cytotoxicity at various concentrations. Overall, these findings suggest that biosynthesized Aw–AgNPs may be used as a potential therapeutic formulation against bacterial infections and breast cancer.
Publisher: MDPI AG
Date: 23-09-2021
DOI: 10.3390/APP11198819
Abstract: Oxidative stress is linked with inflammation, diabetic complications, and advanced glycation end products formation. Intake of flavonoid-rich foods has been reported to have a beneficial effect on human health. The aim of this study was to verify the therapeutic potential of Phyllanthusemblica and Azadiractha indica against glycation and other oxidative stress-induced complications such as inflammation using in vitro study. Ethanol extracts of Phyllanthus emblica fruit pulp and dried leaf of Azadiractha indica were prepared to investigate in vitro anti-inflammatory and anti-glycating potentials. In a DPPH assay, the EC50 value of extract of P. emblica and A. indica was found to be 1532.36 ± 0.17 and 1380.61 ± 0.27 µg/mL, respectively. The FRAP value of P. emblica and A. indica extract was 86.6 and 32.12 µg ascorbic acid/100 mg dry weight of the extract. The maximum percentage of H2O2 scavenging activity was 71.30% and 67.38%, respectively. Extracts of P. emblica and A. indica showed maximum inhibition of heat-induced BSA denaturation by 62.42% and 53.00%, heat-induced denaturation of egg albumin, by 50.84%% and 44.31%, and heat-induced hemolysis by 54.44% and 50.21%. Both extracts (600 µg/mL) significantly reduced the browning, structural changes, aggregation, and AGEs formation. Our biophysical studies confirmed the AGEs formation was inhibiting the potential of extracts. Thus, our findings confirm that these extracts are a rich source of antioxidants and may be utilized to prevent the oxidative stress-induced destruction of biomolecules, glycation, and in the therapy of a variety of health problems, including inflammation. Further, a combination of extracts of P. emblica and A. indica may be extremely useful in preventing and treating health problems.
Publisher: Wiley
Date: 09-10-2022
DOI: 10.1002/CAC2.12366
Abstract: Clustered regularly interspaced short palindromic repeats‐associated protein (CRISPR/Cas9), an adaptive microbial immune system, has been exploited as a robust, accurate, efficient and programmable method for genome targeting and editing. This innovative and revolutionary technique can play a significant role in animal modeling, in vivo genome therapy, engineered cell therapy, cancer diagnosis and treatment. The CRISPR/Cas9 endonuclease system targets a specific genomic locus by single guide RNA (sgRNA), forming a heteroduplex with target DNA. The Streptococcus pyogenes Cas9/sgRNA:DNA complex reveals a bilobed architecture with target recognition and nuclease lobes. CRISPR/Cas9 assembly can be hijacked, and its nanoformulation can be engineered as a delivery system for different clinical utilizations. However, the efficient and safe delivery of the CRISPR/Cas9 system to target tissues and cancer cells is very challenging, limiting its clinical utilization. Viral delivery strategies of this system may have many advantages, but disadvantages such as immune system stimulation, tumor promotion risk and small insertion size outweigh these advantages. Thus, there is a desperate need to develop an efficient non‐viral physical delivery system based on simple nanoformulations. The delivery strategies of CRISPR/Cas9 by a nanoparticle‐based system have shown tremendous potential, such as easy and large‐scale production, combination therapy, large insertion size and efficient in vivo applications. This review aims to provide in‐depth updates on Streptococcus pyogenic CRISPR/Cas9 structure and its mechanistic understanding. In addition, the advances in its nanoformulation‐based delivery systems, including lipid‐based, polymeric structures and rigid NPs coupled to special ligands such as aptamers, TAT peptides and cell‐penetrating peptides, are discussed. Furthermore, the clinical applications in different cancers, clinical trials and future prospects of CRISPR/Cas9 delivery and genome targeting are also discussed.
Publisher: MDPI AG
Date: 08-2021
DOI: 10.3390/ANTIBIOTICS10080934
Abstract: Penicillin-binding proteins (PBPs) catalyze the final stages for peptidoglycan cell-wall bio-synthesis. Mutations in the PBP2a subunit can attenuate β-lactam antibiotic activity, resulting in unimpeded cell-wall formation and methicillin-resistant Staphylococcus aureus (MRSA). A double mutation in PBP2a (i.e., N146K and E150K) is resistant to β-lactam inhibitors however, (E)-3-(2-(4-cyanostyryl)-4-oxoquinazolin-3(4H)-yl) benzoic acid (QNZ), a heterocyclic antibiotic devoid of a β-lactam ring, interacts non-covalently with PBP2a allosteric site and inhibits PBP enzymatic activity. In the search for novel inhibitors that target this PBP2a allosteric site in acidic medium, an in silico screening was performed. Chemical databases including eMolecules, ChEMBL, and ChEBI were virtually screened for candidate inhibitors with a physicochemical similarity to QNZ. PBP2a binding affinities from the screening were calculated based on molecular docking with co-crystallized ligand QNZ serving as a reference. Molecular minimization calculations were performed for inhibitors with docking scores lower than QNZ (calc. −8.3 kcal/mol) followed by combined MD simulations and MM-GBSA binding energy calculations. Compounds eMol26313223 and eMol26314565 exhibited promising inhibitor activities based on binding affinities (ΔGbinding) that were twice that of QNZ (−38.5, −34.5, and −15.4 kcal/mol, respectively). Structural and energetic analyses over a 50 ns MD simulation revealed high stability for the inhibitors when complexed with the double mutated PBP2a. The pharmacokinetic properties of the two inhibitors were predicted using an in silico ADMET analysis. Calculated binding affinities hold promise for eMol26313223 and eMol26314565 as allosteric inhibitors of PBP2a in acidic medium and establish that further in vitro and in vivo inhibition experimentation is warranted.
Publisher: Informa UK Limited
Date: 23-02-2023
Publisher: MDPI AG
Date: 04-05-2022
DOI: 10.3390/MOLECULES27092929
Abstract: (1) Background: Natural constituents are still a preferred route for counteracting the outbreak of COVID-19. Essentially, flavonoids have been found to be among the most promising molecules identified as coronavirus inhibitors. Recently, a new SARS-CoV-2 B.1.1.529 variant has spread in many countries, which has raised awareness of the role of natural constituents in attempts to contribute to therapeutic protocols. (2) Methods: Using various chromatographic techniques, triterpenes (1–7), phenolics (8–11), and flavonoids (12–17) were isolated from Euphorbia dendroides and computationally screened against the receptor-binding domain (RBD) of the SARS-CoV-2 Omicron variant. As a first step, molecular docking calculations were performed for all investigated compounds. Promising compounds were subjected to molecular dynamics simulations (MD) for 200 ns, in addition to molecular mechanics Poisson–Boltzmann surface area calculations (MM/PBSA) to determine binding energy. (3) Results: MM/PBSA binding energy calculations showed that compound 14 (quercetin-3-O-β-D-glucuronopyranoside) and compound 15 (quercetin-3-O-glucuronide 6″-O-methyl ester) exhibited strong inhibition of Omicron, with ΔGbinding of −41.0 and −32.4 kcal/mol, respectively. Finally, drug likeness evaluations based on Lipinski’s rule of five also showed that the discovered compounds exhibited good oral bioavailability. (4) Conclusions: It is foreseeable that these results provide a novel intellectual contribution in light of the decreasing prevalence of SARS-CoV-2 B.1.1.529 and could be a good addition to the therapeutic protocol.
Publisher: Informa UK Limited
Date: 08-2020
DOI: 10.2147/IJN.S256022
Publisher: Hindawi Limited
Date: 16-10-2020
DOI: 10.1155/2020/8836983
Abstract: Depression and anxiety are the most common disorders among all age groups. Several antidepressant drugs including benzodiazepine, antidepressant tricyclics, azapirone, noradrenaline reuptake inhibitors, serotonin selective reuptake inhibitors, serotonin, noradrenaline reuptake inhibitors, and monoamine oxidase inhibitors have been used to treat these psychiatric disorders. However, these antidepressants are generally synthetic agents and can cause a wide range of side effects. The potential efficacy of plant-derived alkaloids has been reviewed against various neurodegenerative diseases including Alzheimer’s disease, Huntington disease, Parkinson’s disease, schizophrenia, and epilepsy. However, data correlating the indole alkaloids and antidepressant activity are limited. Natural products, especially plants and the marine environment, are rich sources of potential new drugs. Plants possess a variety of indole alkaloids, and compounds that have an indole moiety are related to serotonin, which is a neurotransmitter that regulates brain function and cognition, which in turn alleviates anxiety, and ensures a good mood and happiness. The present review is a summary of the bioactive compounds from plants and marine sources that contain the indole moiety, which can serve as potent antidepressants. The prospects of naturally occurring as well as synthetic indole alkaloids for the amelioration of anxiety and depression-related disorders, structure-activity relationship, and their therapeutic prospects have been discussed.
Publisher: Journal of Pure and Applied Microbiology
Date: 09-2023
Publisher: MDPI AG
Date: 12-11-2021
DOI: 10.3390/BIOMEDICINES9111673
Abstract: Acinetobacter baumannii has recently been increasing as an aggressive pathogen in immunocompromised persons. In the present study, we determined the in vitro antibacterial and anti-biofilm activity of thymoquinone (TQ) against A. baumannii. A liposomal formulation of TQ (Lip-TQ) was prepared and its therapeutic potential was investigated in the treatment of A. baumannii infection in immunocompromised mice. Leukopenia was induced in mice by injecting cyclophosphamide (CYP) at a dose of 200 mg/kg and the leukopenic mice were infected with 1 × 106 CFUs of A. baumannii. The effectiveness of free TQ or Lip-TQ against A. baumannii infection was assessed by analyzing the survival rate and bacterial burden. Moreover, the efficacy of Lip-TQ was also studied by examining the systemic inflammatory markers and the histological changes in the lung tissues. The results showed that the mice in the group treated with Lip-TQ at a dose of 10 mg/kg exhibited a 60% survival rate on day 40 post-infection, whereas all the mice treated with free TQ at the same dose died within this duration. Likewise, the lowest bacterial burden was found in the lung tissue of mice treated with Lip-TQ (10 mg/kg). Besides, Lip-TQ treatment remarkably alleviated the infection-associated inflammation, oxidative stress, and histological changes in the lung tissues. Based on the findings of the present study, we recommend considering Lip-TQ as a valuable therapeutic formulation in the treatment of A. baumannii-associated pneumonia in immunocompromised subjects.
Publisher: MDPI AG
Date: 27-06-2022
DOI: 10.3390/PHARMACEUTICS14071357
Abstract: In recent years, the emergence of multidrug-resistant
Publisher: Elsevier BV
Date: 07-2023
Publisher: Elsevier BV
Date: 03-2017
Publisher: Informa UK Limited
Date: 12-2021
DOI: 10.2147/IJN.S338272
Publisher: Trans Tech Publications, Ltd.
Date: 05-2014
DOI: 10.4028/WWW.SCIENTIFIC.NET/AMM.553.305
Abstract: To investigate the importance of the meniscal non-linear behaviour on knee joint finite element analysis (FEA) study, the aim of this study was to compare linear elastic and nonlinear hyperelastic material models on the pressure distribution of meniscus. For this purpose, a 3D finite element (FE) knee model of a healthy living subject was constructed from magnetic resonance imaging (MRI) to simulate contact pressure under axial compressive loading. Differences in meniscal contact pressures were observed between linear elastic and nonlinear hyperelastic models. These findings emphasize the importance of accounting the nonlinear material behaviour of the menisci in knee joint FEA studies.
Publisher: MDPI AG
Date: 28-03-2022
DOI: 10.3390/MOLECULES27072192
Abstract: Garlic’s main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC10, IC25, and IC35 of DATSL with the IC10 of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC50 doses by more than 8- and 14-fold, respectively. However, the DATSL IC10, IC25, and IC35 showed escalating chemosensitivity, and treated the cells in combination with DOXL IC10. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of −4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.
Publisher: Informa UK Limited
Date: 11-2021
DOI: 10.2147/JIR.S337405
Publisher: Informa UK Limited
Date: 06-04-2023
Publisher: Elsevier BV
Date: 02-2021
Publisher: Informa UK Limited
Date: 08-2022
DOI: 10.2147/IJGM.S374090
Publisher: Hindawi Limited
Date: 15-06-2020
DOI: 10.1155/2020/3620192
Abstract: Asthma is characterized by the elevated level of Th2 immune responses, oxidative stress, and airway inflammation. Bilsaan, an exudate from the stem of Sambucus nigra , has been traditionally used in the treatment of various ailments in Saudi Arabia. Here, we investigated the therapeutic potential of Bilsaan against ovalbumin- (OVA-) induced allergic asthma in a mouse model. In order to induce allergic asthma, mice were intraperitoneally injected with alum-emulsified-OVA (20 μ g/mouse) on days 0, 14, and 21 that is followed by an intranasal OVA exposure from days 22 to 30. During this time, mice were orally administered with Bilsaan at the doses of 5, 10, and 25 mg/kg. The numbers of total and differential inflammatory cells and the levels of Th2 cytokines (IL-4, IL-5, and IL-13) and IgE were determined in bronchoalveolar lavage fluid (BALF). Moreover, the therapeutic effect of Bilsaan was also assessed to analyze the oxidative stress and inflammatory changes in the lung tissues. The results demonstrated that Bilsaan treatment significantly reduced the total and differential inflammatory cell count in the BALF. The BALF from the mice treated with Bilsaan showed significantly lower levels of IL-4, IL-5, IL-13, and IgE. Interestingly, a similar pattern was observed in IL-4, IL-5, and IL-13 secreted by OVA-sensitized splenocytes from the mice of various groups. Bilsaan treatment alleviated the status of oxidative stress by modulating malondialdehyde (MDA), superoxide dismutase (SOD), and catalase levels in the lung. Moreover, Bilsaan treatment reduced the infiltration of inflammatory cells, thickening of alveolar wall, and congestion in the lung tissues. The findings of the present study demonstrated an antiasthmatic effect of Bilsaan through the modulation of Th2 immune responses, inflammation, and the oxidative stress.
Publisher: MDPI AG
Date: 18-11-2022
DOI: 10.3390/MOLECULES27228023
Abstract: The roles of medicinal plants or their purified bioactive compounds have attracted attention in the field of health sciences due to their low toxicity and minimal side effects. Baicalein is an active polyphenolic compound, isolated from
Publisher: Informa UK Limited
Date: 06-2021
DOI: 10.2147/IJN.S303832
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.MEDENGPHY.2016.11.013
Abstract: Medial opening wedge high tibial osteotomy (MOWHTO) is a surgical procedure to treat knee osteoarthritis associated with varus deformity. However, the ideal final alignment of the Hip-Knee-Ankle (HKA) angle in the frontal plane, that maximizes procedural success and post-operative knee function, remains controversial. Therefore, the purpose of this study was to introduce a subject-specific modeling procedure in determining the biomechanical effects of MOWHTO alignment on tibiofemoral cartilage stress distribution. A 3D finite element knee model derived from magnetic resonance imaging of a healthy participant was manipulated in-silico to simulate a range of final HKA angles (i.e. 0.2°, 2.7°, 3.9° and 6.6° valgus). Loading and boundary conditions were assigned based on subject-specific kinematic and kinetic data from gait analysis. Multiobjective optimization was used to identify the final alignment that balanced compressive and shear forces between medial and lateral knee compartments. Peak stresses decreased in the medial and increased in the lateral compartment as the HKA was shifted into valgus, with balanced loading occurring at angles of 4.3° and 2.9° valgus for the femoral and tibial cartilage respectively. The concept introduced here provides a platform for non-invasive, patient-specific preoperative planning of the osteotomy for medial compartment knee osteoarthritis.
Publisher: MDPI AG
Date: 14-02-2022
DOI: 10.3390/MD20020139
Abstract: Gorgostane steroids are isolated from marine organisms and consist of 30 carbon atoms with a characteristic cyclopropane moiety. From the pioneering results to the end of 2021, isolation, biosynthesis, and structural elucidation using 13C-NMR will be used. Overall, 75 compounds are categorized into five major groups: gorgost-5-ene, 5,6-epoxygorgostane, 5,6-dihydroxygorgostane, 9,11-secogorgostane, and 23-demethylgorgostane, in addition to miscellaneous gorgostane. The structural ersity, selectivity for marine organisms, and biological effects of gorgostane steroids have generated considerable interest in the field of drug discovery research.
Publisher: MDPI AG
Date: 03-2021
DOI: 10.3390/MOLECULES26051315
Abstract: Polyphenolic flavonoids are considered natural, non-toxic chemopreventers, which are most commonly derived from plants, fruits, and vegetables. Most of these polyphenolics exhibit remarkable antioxidant, anti-inflammatory, and anticancer properties. Quercetin (Qu) is a chief representative of these polyphenolic compounds, which exhibits excellent antioxidant and anticancer potential, and has attracted the attention of researchers working in the area of cancer biology. Qu can regulate numerous tumor-related activities, such as oxidative stress, angiogenesis, cell cycle, tumor necrosis factor, proliferation, apoptosis, and metastasis. The anticancer properties of Qu mainly occur through the modulation of vascular endothelial growth factor (VEGF), apoptosis, phosphatidyl inositol-3-kinase (P13K)/Akt (proteinase-kinase B)/mTOR (mammalian target of rapamycin), MAPK (mitogen activated protein kinase)/ERK1/2 (extracellular signal-regulated kinase 1/2), and Wnt/β-catenin signaling pathways. The anticancer potential of Qu is documented in numerous in vivo and in vitro studies, involving several animal models and cell lines. Remarkably, this phytochemical possesses toxic activities against cancerous cells only, with limited toxic effects on normal cells. In this review, we present extensive research investigations aimed to discuss the therapeutic potential of Qu in the management of different types of cancers. The anticancer potential of Qu is specifically discussed by focusing its ability to target specific molecular signaling, such as p53, epidermal growth factor receptor (EGFR), VEGF, signal transducer and activator of transcription (STAT), PI3K/Akt, and nuclear factor kappa B (NF-κB) pathways. The anticancer potential of Qu has gained remarkable interest, but the exact mechanism of its action remains unclear. However, this natural compound has great pharmacological potential it is now believed to be a complementary—or alternative—medicine for the prevention and treatment of different cancers.
Publisher: Informa UK Limited
Date: 05-2022
DOI: 10.2147/IDR.S360675
Publisher: MDPI AG
Date: 20-05-2022
DOI: 10.3390/MOLECULES27103297
Abstract: Honey is the principal premier product of beekeeping familiar to Homo for centuries. In every geological era and culture, evidence can be traced to the potential usefulness of honey in several ailments. With the advent of recent scientific approaches, honey has been proclaimed as a potent complementary and alternative medicine for the management and treatment of several maladies including various neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, etc. In the literature archive, oxidative stress and the deprivation of antioxidants are believed to be the paramount cause of many of these neuropathies. Since different types of honey are abundant with certain antioxidants, primarily in the form of erse polyphenols, honey is undoubtedly a strong pharmaceutic candidate against multiple neurological diseases. In this review, we have indexed and comprehended the involved mechanisms of various constituent polyphenols including different phenolic acids, flavonoids, and other phytochemicals that manifest multiple antioxidant effects in various neurological disorders. All these mechanistic interpretations of the nutritious components of honey explain and justify the potential recommendation of sweet nectar in ameliorating the burden of neurological disorders that have significantly increased across the world in the last few decades.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2021
DOI: 10.1038/S41598-021-89724-0
Abstract: As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, − 54.8 and − 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.
Publisher: Springer Science and Business Media LLC
Date: 10-03-2020
Publisher: MDPI AG
Date: 11-06-2021
DOI: 10.3390/ANTIBIOTICS10060705
Abstract: Giardiasis is a major diarrheal disease affecting approximately 2.5 million children annually in developing countries. Several studies have reported the resistance of Giardia lamblia (G. lamblia) to multiple drugs. Therefore, identifying an effective drug for giardiasis is a necessity. This study examined the antiparasitic effect of Punica granatum (pomegranate) and evaluated its therapeutic efficacy in rats infected with G. lamblia. In vitro study showed high efficacy of pomegranate peel ethanolic extract in killing G. lamblia cysts as demonstrated by eosin vital staining. We showed that treating infected rats with pomegranate extract resulted in a marked reduction in the mean number of G. lamblia cysts and trophozoites in feces and intestine respectively. Interestingly, the number of G. lamblia trophozoites and cysts were significantly lower in the pomegranate extract-treated group compared to the metronidazole-positive control group. Moreover, pomegranate extract treatment significantly induced nitric oxide (NO) and reduced serum IL-6 and TNF-α, compared to infected untreated rats. Histological and scanning electron microscopy (SEM) examination of the jejunum and duodenum of pomegranate extract-treated animals confirmed the antiparasitic effect of the extract, and demonstrated the restoration of villi structure with reduction of villi atrophy, decreased infiltration of lymphocytes, and protection of intestinal cells from apoptotic cell death. In conclusion, our data show that the pomegranate peel extract is effective in controlling G. lamblia infections, which suggests that it could be a viable treatment option for giardiasis.
Publisher: Informa UK Limited
Date: 04-2021
DOI: 10.2147/IDR.S305503
Publisher: MDPI AG
Date: 13-10-2020
Abstract: In the United States, prevalence of marijuana-use has doubled in the past 2 decades. The aim was to compare the periodontal conditions and whole-salivary IL-17A and IL-23 levels among young adult marijuana-smokers, heavy cigarette-smokers and non-smokers. Self-reported marijuana-smokers, heavy-cigarette-smokers, non-smokers with periodontitis and periodontally-healthy non-smokers were included. Demographic data was recorded and full-mouth plaque index (PI), bleeding on probing (BoP), probing depth (PD) and clinical attachment loss (AL), marginal bone loss (MBL) and missing teeth were recorded. Levels of IL-17A and IL-23 levels were measured in the whole saliva. p 0.01 was considered statistically significant. Fifteen-marijuana-smokers, 15 heavy-cigarette-smokers, 16 non-smokers-with-periodontitis and 15 periodontally-healthy-non-smokers) were included. The clinicoradiographic parameters were worse among marijuana-smokers (p 0.01), cigarette-smokers (p 0.01) and non-smokers-with-periodontitis (p 0.01) than periodontally-healthy-non-smokers. Marijuana- and cigarette-smokers had Stage-IV/Grade C and non-smokers with periodontitis had Stage-III/Grade-C. Salivary IL-17A and IL-23 levels were higher in marijuana-smokers than cigarette-smokers (p 0.01) and non-smokers-with-periodontitis (p 0.01). Whole salivary IL-17A and IL-23 levels were higher among cigarette-smokers than non-smokers with periodontitis (p 0.01) and periodontally-healthy-in iduals (p 0.01). Marijuana- and heavy cigarette-smokers have comparable clinicoradiographic periodontal statuses. This rejects hypothesis-1. However, whole salivary immunoinflammatory response may be moderately worse in marijuana-smokers compared with heavy cigarette-smokers and non-smoker with periodontitis thereby supporting hypothesis-2.
Publisher: American Geophysical Union (AGU)
Date: 2016
DOI: 10.1002/2015GB005239
Publisher: Informa UK Limited
Date: 07-2021
DOI: 10.2147/IJN.S321343
Publisher: MDPI AG
Date: 26-09-2021
Abstract: C. perfringens is a highly versatile bacteria of livestock and humans, causing enteritis (a common food-borne illness in humans), enterotoxaemia (in which toxins are formed in the intestine which damage and destroy organs, i.e., the brain), and gangrene (wound infection). There is no particular cure for the toxins of C. perfringens. Supportive care (medical control of pain, intravenous fluids) is the standard treatment. Therefore, a multiple-epitope vaccine (MEV) should be designed to battle against C. perfringens infection. Furthermore, the main objective of this in silico investigation is to design an MEV that targets C. perfringens. For this purpose, we selected the top three proteins that were highly antigenic using immuno-informatics approaches, including molecular docking. B-cells, IFN-gamma, and T cells for target proteins were predicted and the most conserved epitopes were selected for further investigation. For the development of the final MEV, epitopes of LBL5, CTL17, and HTL13 were linked to GPGPG, AAY, and KK linkers. The vaccine N-end was joined to an adjuvant through an EAAK linker to improve immunogenicity. After the attachment of linkers and adjuvants, the final construct was 415 amino acids. B-cell and IFN-gamma epitopes demonstrate that the model structure is enhanced for humoral and cellular immune responses. To validate the immunogenicity and safety of the final construct, various physicochemical properties, and other properties such as antigenicity and non-allergens, were evaluated. Furthermore, molecular docking was carried out for verification of vaccine compatibility with the receptor, evaluated in silico. Also, in silico cloning was employed for the verification of the proper expression and credibility of the construct.
Publisher: Emerald
Date: 21-09-2022
DOI: 10.1108/JRIM-05-2020-0111
Abstract: This study develops and validates a scale to measure social media influencers' intimate self-disclosure (SMIs' ISD), by accessing consumer perceptions of the intimacy levels of SMIs' self-disclosure. The authors further evaluate the extent to which SMIs' ISD fosters consumers' self-brand connections via consumer-SMI parasocial relationships. The scale was developed through item generation, purification, and validation. First, items were generated from existing scales and revised based on feedback provided by experts. The items were subjected to exploratory and confirmatory factor analyses using an online survey with 433 participants. Structural equation modeling (SEM) was used to examine the predictive power of SMIs' ISD on parasocial relationships and self-brand connections. The results suggest that the perceived SMIs' ISD is a unidimensional construct. As proposed, SMIs' ISD enhances consumer-brand connections through the underlying mechanism of consumers' sense of being in a parasocial relationship with an SMI. This study advances self-disclosure and influencer marketing literature by addressing the lack of measures on SMIs' ISD from a consumer perspective and the scarcity of empirical understanding of how brands can profit from SMIs' capabilities to make intimate self-disclosure. Based on the literature review, this study is the first to empirically consider factual, emotional, and cognitive intimacy to develop scale and demonstrate the importance of SMIs' ISD in developing consumers' self-brand connections.
Publisher: MDPI AG
Date: 27-09-2021
Abstract: Klebsiella is a genus of nosocomial bacterial pathogens and is placed in the most critical list of World Health Organization (WHO) for development of novel therapeutics. The pathogens of the genus are associated with high mortality and morbidity. Owing to their strong resistance profile against different classes of antibiotics and nonavailability of a licensed vaccine, urgent efforts are required to develop a novel vaccine candidate that can tackle all pathogenic species of the Klebsiella genus. The present study aims to design a broad-spectrum vaccine against all species of the Klebsiella genus with objectives to identify the core proteome of pathogen species, prioritize potential core vaccine proteins, analyze immunoinformatics of the vaccine proteins, construct a multi-epitopes vaccine, and provide its biophysical analysis. Herein, we investigated all reference species of the genus to reveal their core proteome. The core proteins were then subjected to multiple reverse vaccinology checks that are mandatory for the prioritization of potential vaccine candidates. Two proteins (TonB-dependent siderophore receptor and siderophore enterobactin receptor FepA) were found to fulfill all vaccine parameters. Both these proteins harbor several potent B-cell-derived T-cell epitopes that are antigenic, nonallergic, nontoxic, virulent, water soluble, IFN-γ producer, and efficient binder of DRB*0101 allele. The selected epitopes were modeled into a multi-epitope peptide comprising linkers and Cholera Toxin B adjuvant. For docking with innate immune and MHC receptors and afterward molecular dynamics simulations and binding free energy analysis, the vaccine structure was modeled for tertiary structure and refined for structural errors. To assess the binding affinity and presentation of the designed vaccine construct, binding mode and interactions analysis were performed using molecular docking and molecular dynamics simulation techniques. These biophysical approaches illustrated the vaccine as a good binder to the immune receptors and revealed robust interactions energies. The vaccine sequence was further translated to nucleotide sequence and cloned into an appropriate vector for expressing it at high rate in Escherichia coli K12 strain. In addition, the vaccine was illustrated to generate a good level of primary, secondary, and tertiary immune responses, proving good immunogenicity of the vaccine. Based on the reported results, the vaccine can be a good candidate to be evaluated for effectiveness in wet laboratory validation studies.
Publisher: MDPI AG
Date: 11-05-2023
DOI: 10.3390/IJMS24108630
Abstract: Cancer is the principal cause of death and its incidence is increasing continuously worldwide. Various treatment approaches are in practice to treat cancer, but these treatment strategies may be associated with severe side effects and also produce drug resistance. However, natural compounds have established their role in cancer management with minimal side effects. In this vista, kaempferol, a natural polyphenol, mainly found in vegetables and fruits, has been revealed to have many health-promoting effects. Besides its health-promoting potential, its anti-cancer potential has also been described in in vivo as well as in in vitro studies. The anti-cancer potential of kaempferol has been proven through modulation of cell signaling pathways in addition to the induction of apoptosis and cell cycle arrest in cancer cells. It leads to the activation of tumor suppressor genes, inhibition of angiogenesis, PI3K/AKT pathways, STAT3, transcription factor AP-1, Nrf2 and other cell signaling molecules. Poor bioavailability of this compound is one of the major limitations for its proper and effective disease management actions. Recently, some novel nanoparticle-based formulations have been used to overcome these limitations. The aim of this review is to provide a clear picture regarding the mechanism of action of kaempferol in different cancers through the modulation of cell signaling molecules. Besides this, strategies to improve the efficacy and synergistic effects of this compound have also been described. However, more studies are needed based on clinical trials to fully explore the therapeutic role of this compound, especially in cancer treatment.
Publisher: Springer Science and Business Media LLC
Date: 02-01-2021
Publisher: EManuscript Technologies
Date: 08-01-2021
Publisher: Informa UK Limited
Date: 2021
Publisher: MDPI AG
Date: 25-08-2021
DOI: 10.3390/JPM11090831
Abstract: Chronic kidney disease (CKD) is considered a major health problem, which poses a burden for health care systems worldwide. It has been estimated that 10% of the population worldwide have CKD however, most of the cases are undiagnosed. If left untreated, CKD could lead to kidney failure, which highlights the importance of early diagnosis and treatment. Pyuria has been reported in CKD patients, and could be the result of several comorbidities, such as diabetes, or urinary tract infections (UTIs). A few studies have shown that pyuria is associated with the late stages of CKD. However, there are limited data on the prevalence of non-UTI (sterile) and UTI–pyuria in different CKD patient populations, and its association with the decline in kidney function and progression of CKD. In this retrospective study, we report the prevalence of pyuria (sterile and UTI) in 754 CKD patients of King Fahd Specialist Hospital, Buraydah, Saudi Arabia. Our data showed that 164/754 CKD patients (21.8%) had pyuria, whereas 590 patients (78.2%) presented with no pyuria. There was a significantly higher percentage of late-stage (stage 4) CKD patients in the pyuric group compared to the non-pyuric group (36.6% vs. 11.9%). In line with the previous data, proteinuria was detected in a significantly higher percentage of pyuric patients, in addition to significantly higher levels of serum creatinine and urea, compared to non-pyuric patients. Furthermore, 13.4% of the pyuric CKD patients had UTI, whereas 86.6% presented with sterile pyuria. E. coli was indicated as the causative agent in 45.5% of UTI patients. Our patient data analysis showed that a significantly higher percentage of UTI–pyuric CKD patients, than sterile pyuric patients (63.6% vs. 19.7%), had higher numbers of urinary white blood cells ( /HPF, WBCs). The data also showed that a higher percentage of UTI–pyuric patients were late-stage CKD patients, compared to sterile pyuric patients (50% vs. 34.5%). Our findings indicate that a high level of pyuria could be considered as a marker for late-stage CKD, and that UTI is an important risk factor for the decline in kidney function and the progression to late-stage CKD. We believe that further studies are needed to correlate pyuria to kidney function, which could be helpful in monitoring the progression of CKD. Moreover, the management of comorbidities, such as diabetes and UTIs, which are risk factors for CKD and associated pyuria, could help to control the progression of CKD to the late stages.
Publisher: MDPI AG
Date: 19-04-2022
Abstract: Due to the misuse of antibiotics in our daily lives, antimicrobial resistance (AMR) has become a major health problem. Penicillin, the first antibiotic, was used in the 1930s and led to the emergence of AMR. Due to alterations in the microbe’s genome and the evolution of new resistance mechanisms, antibiotics are losing efficacy against microbes. There are high rates of mortality and morbidity due to antibiotic resistance, so addressing this major health issue requires new approaches. Staphylococcus auricularis is a Gram-positive cocci and is capable of causing opportunistic infections and sepsis. S. auricularis is resistant to several antibiotics and does not currently have a licensed vaccine. In this study, we used bacterial pan-genome analysis (BPGA) to study S. auricularis pan-genome and applied a reverse immunology approach to prioritize vaccine targets against S. auricularis. A total of 15,444 core proteins were identified by BPGA analysis, which were then used to identify good vaccine candidates considering potential vaccine filters. Two vaccine candidates were evaluated for epitope prediction including the superoxide dismutase and gamma-glutamyl transferase protein. The epitope prediction phase involved the prediction of a variety of B-Cell and T-cell epitopes, and the epitopes that met certain criteria, such as antigenicity, immunogenicity, non-allergenicity, and non-toxicity were chosen. A multi-epitopes vaccine construct was then constructed from all the predicted epitopes, and a cholera toxin B-subunit adjuvant was also added to increase vaccine antigenicity. Three-dimensional models of the vaccine were used for downward analyses. Using the best-modeled structure, binding potency was tested with MHC-I, MHC-II and TLR-4 immune cells receptors, proving that the vaccine binds strongly with the receptors. Further, molecular dynamics simulations interpreted strong intermolecular binding between the vaccine and receptors and confirmed the vaccine epitopes exposed to the host immune system. The results support that the vaccine candidate may be capable of eliciting a protective immune response against S. auricularis and may be a promising candidate for experimental in vitro and in vivo studies.
Publisher: Journal of Infection in Developing Countries
Date: 30-04-2022
DOI: 10.3855/JIDC.14990
Abstract: Introduction: Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is one of the leading causes of death in the world. The resource constraints make it difficult to diagnose and monitor the cases of MDR-TB. GeneXpert is a recognized tool used to diagnose the patients of pulmonary tuberculosis in clinical settings across the globe. Methodology: The present one-year cross-sectional study was conducted to estimate the occurrence of MDR-TB in patients with pulmonary TB. A total of 1000 patients suspected of pulmonary tuberculosis were included in this study. A random convenient s ling technique was done to collect the sputum s les (twice) from the patients. S les were processed for the detection of Mycobacterium tuberculosis using conventional detection methods like the Ziehl Nelson staining method and fluorescent microscopy. Additionally, Cepheid GeneXpert was used for molecular detection of MDR-TB in smear-positive s les of pulmonary tuberculosis by lifying the rif icin resistance determining region (RRDR rpoB gene). All the tests were performed in the biosafety level III lab of District Headquarters Hospital Nankana Sahib. Results: It was observed that 103 (10.3%) in iduals were diagnosed as positive for tuberculosis among 1000 patients. Among these 103 TB positive cases, there were 11 (10.7%) patients diagnosed with rif icin resistance gene (RR-Gene) of Mycobacterium tuberculosis. Conclusions: Overall findings of the study showed that MDR-TB is prevalent in pulmonary TB patients and GeneXpert is the most sensitive technique for early diagnosis of the disease, which may be very helpful in the treatment and control of this public health menace in low and middle-income countries.
Publisher: MDPI AG
Date: 16-04-2020
DOI: 10.3390/PR8040468
Abstract: Protein glycation and oxidative stress lead to severe health complications in various diseases including diabetes mellitus. The intake of flavonoid-rich foods has been confirmed previously to have a positive effect on human health. Ginger is an important source of flavonoids and is one of the most widely used traditional medicines in many Asian countries. The aim of this study was to verify the therapeutic potential of methanolic extract from ginger against glycation and other oxidative stress-induced complications using in vitro study. In this study, quantitative estimations of antioxidant components such as total phenolic and flavonoids were determined by UV–visible spectrophotometry. The anti-inflammatory action of the ginger extract was checked by determining its protective action against the denaturation of proteins, anti-proteinase activity and its membrane stabilization effect. The anti-inflammatory action of ginger extract was found to be comparable with reference standard drugs. The antiglycating effect of ginger extract was investigated by placing bovine serum albumin (BSA) with glucose in the presence and absence of ginger extract for two weeks at 37 °C. The incubated s les were analyzed for the number of glycation products, secondary structural changes, aggregation and advanced glycation end products (AGEs) formation by checking browning intensity, determination of aggregation index and Congo red assays. Our findings demonstrated that ginger extract (600 µg/mL) significantly reduced the browning, secondary structural changes, aggregation and AGEs formation. Thus, it can be concluded from these results that ginger extract is a wealthy source of antioxidants and can be used to prevent the glycation and oxidative stress-induced damage of biomolecules in various health complications including inflammation.
Publisher: Hindawi Limited
Date: 17-03-2022
DOI: 10.1155/2022/2863023
Abstract: Patients treated with cyclophosphamide (CP) usually suffer from severe hemorrhagic cystitis (HC). Our previous study exhibited that mesna + celery cotherapy partially ameliorated HC. Therefore, there is a substantial need to seek alternative regimens to get complete protection against CP-induced HC. The current study investigated the effects of mesna + celery seed oil (MCSO) or mesna + manuka honey (MMH) cotherapy against CP-induced HC in adult male rabbits. The forty rabbits were ided into four equal groups and treated for three weeks. The control group (G1) received distilled water and the second group (G2) received CP (50 mg/kg/week). The third group (G3) received CP + MCSO (CPMCSO regimen), and the fourth group (G4) received CP + MMH (CPMMH regimen). The urinary bladder (UB) specimens were processed to evaluate UB changes through histopathological, immunohistochemical, ultrastructural, and biochemical investigations. In G2, CP provoked HC features (urothelial necrosis, ulceration, and sloughing), UB fibrosis, and TNF-α immunoexpression. Besides, CP reduced the activity of antioxidant enzymes (GPx1, SOD3, and CAT) and elevated the serum levels of NF-κB, TNF-α, IL-1B, and IL-6 cytokines in G2 rabbits. In contrast, the CPMMH regimen caused significant increments of UB protection against HC in G4 rabbits compared to the partial protection by the CPMCSO regimen in G3. Therefore, our study indicated for the first time that the novel CPMMH regimen resulted in complete UB protection against CP-induced HC via combined antioxidant, anti-inflammatory, and antifibrotic properties.
Publisher: Frontiers Media SA
Date: 05-05-2023
DOI: 10.3389/FMICB.2023.1175844
Abstract: Zoonotic virus spillover in human hosts including outbreaks of Hantavirus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) imposes a serious impact on the quality of life of patients. Recent studies provide a shred of evidence that patients with Hantavirus-caused hemorrhagic fever with renal syndrome (HFRS) are at risk of contracting SARS-CoV-2. Both RNA viruses shared a higher degree of clinical features similarity including dry cough, high fever, shortness of breath, and certain reported cases with multiple organ failure. However, there is currently no validated treatment option to tackle this global concern. This study is attributed to the identification of common genes and perturbed pathways by combining differential expression analysis with bioinformatics and machine learning approaches. Initially, the transcriptomic data of hantavirus-infected peripheral blood mononuclear cells (PBMCs) and SARS-CoV-2 infected PBMCs were analyzed through differential gene expression analysis for identification of common differentially expressed genes (DEGs). The functional annotation by enrichment analysis of common genes demonstrated immune and inflammatory response biological processes enriched by DEGs. The protein–protein interaction (PPI) network of DEGs was then constructed and six genes named RAD51, ALDH1A1, UBA52, CUL3, GADD45B, and CDKN1A were identified as the commonly dysregulated hub genes among HFRS and COVID-19. Later, the classification performance of these hub genes were evaluated using Random Forest (RF), Poisson Linear Discriminant Analysis (PLDA), Voom-based Nearest Shrunken Centroids (voomNSC), and Support Vector Machine (SVM) classifiers which demonstrated accuracy & %, suggesting the biomarker potential of the hub genes. To our knowledge, this is the first study that unveiled biological processes and pathways commonly dysregulated in HFRS and COVID-19, which could be in the next future used for the design of personalized treatment to prevent the linked attacks of COVID-19 and HFRS.
Publisher: Informa UK Limited
Date: 05-2021
DOI: 10.2147/NDT.S306585
Publisher: Scientific Foundation SPIROSKI
Date: 24-03-2019
Abstract: BACKGROUND: Tuberculosis is a chronic inflammatory disease with lymphadenopathy being the most common extra-pulmonary manifestation. The conventional Ziehl–Neelsen method plays an essential role in the diagnosis of tuberculosis however, it has a low sensitivity in detecting acid-fast bacilli. AIM: The present study emphasises the role of the microwave-heated method (modified Ziehl–Neelsen) over conventional Ziehl-Neelsen stain and to set at the best condition for irradiation. MATERIAL AND METHODS: The study included 90 patients with clinically suspected tuberculous lymphadenopathy who were referred to the Department of Pathology at Omdurman Military Hospital, Sudan. Demographic data such as age, sex, and site of swelling were documented for each patient. Specimens were stained with conventional Ziehl-Neelsen, fluoresce and the modified methods. RESULTS: Patient’s age ranged from 20 to 70 year. Of the total 90 cases with clinically suspected tuberculous lymphadenopathy, 18 cases were positive for AFB in conventional Ziehl-Neelsen method giving a sensitivity of 13.3%, while in microwave-heated method 82 cases of TB were detected positive for AFB yielded sensitivity and specificity of 97.6% and 85.7%, respectively, and positive and negative predictive values of 98.8% and 75.0% respectively compared to fluorescence methods. CONCLUSION: In the present study, the microwave-heated Ziehl-Neelsen method, was found to have sensitivity and specificity of 97.6% and 85.7%, respectively which matches the fluorescence technique. It has specificity in detecting lymph node tuberculosis that makes it superior over all other modified methods. However, the availability and cost-effectiveness might limit the use of fluorescence in routine practice. Furthermore, the study set the best staining temperature is provided at power 1 level (60 w) for 1.5 minutes.
Publisher: MDPI AG
Date: 17-12-2022
DOI: 10.3390/MOLECULES27249009
Abstract: Cancer is a main culprit and the second-leading cause of death worldwide. The current mode of treatment strategies including surgery with chemotherapy and radiation therapy may be effective, but cancer is still considered a major cause of death. Plant-derived products or their purified bioactive compounds have confirmed health-promoting effects as well as cancer-preventive effects. Among these products, flavonoids belong to polyphenols, chiefly found in fruits, vegetables and in various seeds/flowers. It has been considered to be an effective antioxidant, anti-inflammatory and to play a vital role in diseases management. Besides these activities, flavonoids have been revealed to possess anticancer potential through the modulation of various cell signaling molecules. In this regard, fisetin, a naturally occurring flavonoid, has a confirmed role in disease management through antioxidant, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential. As well, its cancer-preventive effects have been confirmed via modulating various cell signaling pathways including inflammation, apoptosis, angiogenesis, growth factor, transcription factor and other cell signaling pathways. This review presents an overview of the anti-cancer potential of fisetin in different types of cancer through the modulation of cell signaling pathways based on in vivo and in vitro studies. A synergistic effect with anticancer drugs and strategies to improve the bioavailability are described. More clinical trials need to be performed to explore the anti-cancer potential and mechanism-of-action of fisetin and its optimum therapeutic dose.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/925640
Abstract: Green tea is commonly used as a beverage worldwide, especially in China, Japan, Morocco, and Saudi Arabia. Green tea and its constituents have been considered very effective in the prevention and treatment of various diseases. It contains a variety of catechins, which show a pivotal role in the modulation of biological activities and also act as chemopreventive agents. Earlier studies have confirmed that green tea and its chief constituent epigallocatechin gallate (EGCG) have a potential role in the management of cancer through the modulation of cell signaling pathways. In this review, we focused on the beneficial effects of green tea and its constituents in the cancer prevention and treatment and its impact on modulation of molecular pathways.
Publisher: MDPI AG
Date: 08-02-2021
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a great threat to public health, being a causative pathogen of a deadly coronavirus disease (COVID-19). It has spread to more than 200 countries and infected millions of in iduals globally. Although SARS-CoV-2 has structural/genomic similarities with the previously reported SARS-CoV and MERS-CoV, the specific mutations in its genome make it a novel virus. Available therapeutic strategies failed to control this virus. Despite strict standard operating procedures (SOPs), SARS-CoV-2 has spread globally and it is mutating gradually as well. Diligent efforts, special care, and awareness are needed to reduce transmission among susceptible masses particularly elder people, children, and health care workers. In this review, we highlighted the basic genome organization and structure of SARS-CoV-2. Its transmission dynamics, symptoms, and associated risk factors are discussed. This review also presents the latest mutations identified in its genome, the potential therapeutic options being used, and a brief explanation of vaccine development efforts against COVID-19. The effort will not only help readers to understand the deadly SARS-CoV-2 virus but also provide updated information to researchers for their research work.
Publisher: Informa UK Limited
Date: 12-2020
DOI: 10.2147/JIR.S284279
Publisher: Elsevier BV
Date: 10-2022
No related grants have been discovered for Khaled Allemailem.