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Introduction: This comprehensive study investigated the therapeutic potential of α-asarone in mitigating myocardial oxidative damage, primarily induced by hexavalent chromium (Cr(VI)) exposure in mice. Methods: In this experiment, 24 mice were divided into four groups to assess the cardioprotective role of α-asarone. The study focused on two treatment groups, receiving 25 mg and 50 mg of α-asarone, respectively. These groups were compared against a control group subjected to Cr(VI) without α-asarone treatment, and a normal control negative group. The key biochemical parameters evaluated included serum levels of Creatine Kinase-MB (CK-MB) and Troponin I, markers indicative of myocardial damage. Additionally, the levels of Malondialdehyde (MDA) were measured to assess lipid peroxidation, alongside the evaluation of key inflammatory biomarkers in cardiac tissue homogenates, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-1ß (IL-1ß). Results Remarkably, α-asarone treatment resulted in a significant reduction in these markers compared to the control group. The treatment also elevated the activity of cardinal antioxidant enzymes like catalase (CAT) and superoxide dismutase (SOD), and reduced the glutathione (GSH). Furthermore, a notable upregulation of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) in cardiac tissue homogenates was observed, highlighting a potential pathway through which α-asarone exerts its protective effects. Histopathological analysis of cardiac tissues revealed that α-asarone ameliorated the structural lesions induced by Cr(VI). The study thus provides substantial evidence that α-asarone ameliorates Cr(VI)-induced cardiotoxicity through a multifaceted approach. It enhances cardiac enzyme function, modulates free radical generation, improves antioxidant status, and mitigates histopathological damage in cardiac tissues. Given these findings, α-asarone emerges as a promising agent against Cr(VI)-induced myocardial injury. Purpose: This study paves the way for further research into the cardioprotective properties of α-asarone and its potential application in clinical settings by specifically exploring the protective efficacy of α-asarone against Cr(VI)-induced cardiotoxicity and delineating the underlying biochemical and molecular mechanisms involved.
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Derivados de Alilbenzenos , Anisóis , Cromo , Estresse Oxidativo , Animais , Derivados de Alilbenzenos/farmacologia , Anisóis/farmacologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Cardiotônicos/farmacologia , Antioxidantes/farmacologia , Relação Dose-Resposta a DrogaRESUMO
Uncontrolled or improperly managed wastewater is considered toxic and dangerous to plants, animals, and people, as well as negatively impacting the ecosystem. In this research, the use of we aimed to prepare polymer nanocomposites (guar gum/polyvinyl alcohol, and nano-montmorillonite clay) for eliminating heavy metals from water-based systems, especially Cu2+ and Cd2+ ions. The synthesis of nanocomposites was done by the green method with different ratios of guar gum to PVA (50/50), (60/40), and (80/20) wt%, in addition to glycerol that acts as a cross-linker. Fourier-transform infrared spectroscopy (FT-IR) analysis of the prepared (guar gum/PVA/MMT) polymeric nano-composites' structure and morphology revealed the presence of both guar gum and PVA's functional groups in the polymeric network matrix. Transmission electron microscopy (TEM) analysis was also performed, which verified the creation of a nanocomposite. Furthermore, theromgravimetric analysis (TGA) demonstrated the biocomposites' excellent thermal properties. For those metal ions, the extreme uptake was found at pH 6.0 in each instance. The Equilibrium uptake capacities of the three prepared nanocomposites were achieved within 240 min. The maximal capacities were found to be 95, 89 and 84 mg/g for Cu2+, and for Cd2+ were found to be 100, 91, 87 mg/g for guar gum (80/20, 60/40 and 50/50), respectively. The pseudo-2nd-order model with R2 > 0.98 was demonstrated to be followed by the adsorption reaction, according to the presented results. In less than 4 hours, the adsorption equilibrium was reached. Furthermore, a 1% EDTA solution could be used to revitalize the metal-ion-loaded nanocomposites for several cycles. The most promising nanocomposite with efficiency above 90% for the removal of Cu2+ and Cd2+ ions from wastewater was found to have a guar (80/20) weight percentage, according to the results obtained.
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BACKGROUND: Cervical cancer originates in the cervix, the lower part of the uterus, and results from the uncontrolled growth of abnormal cervical cells, forming malignant tumours. It poses a major global health challenge, calling for innovative drug design strategies to enhance treatment outcomes. METHOD: In this study, we have screened the FDA-approved drug library against four proteins, MCM10, MCM6, DNA polymerase epsilon subunit-2, and TBK1, which are essential for DNA replication, DNA repair, and cellular signalling pathways, which are dysregulated in cervical cancer cells, leading to uncontrolled growth. We have used the multisampling algorithms for screening using HTVS, SP, and XP docking; identified 6- oxidopamine HBr (C8H12BrNO3), which is used to create a model of Parkinson's disease in animals, and obtained the docking score ranging from -5.057 to -8.871 Kcal/mol. The poses were filtered with MM\GBSA score ranging from -21.67 to -27.63 Kcal/mol. We performed QM-based DFT and pharmacokinetics studies and compared them with the standard values, suggesting that the compound can be used in cervical cancer proteins. RESULT: The P-L complex's interaction fingerprints have resulted in the most interacting residues, 4THR, 4SER, and 4LYS, showing the compound's interaction pattern. CONCLUSION: Further, the stability of 6-oxidopamine HBr in complex with each protein was evaluated with 100ns MD simulation in the SPC water model in a neutralised state to analyse the deviation, fluctuations, and intermolecular interactions that have proven the compound to have a better inhibitory effect against each protein and that it can be used for cervical cancer; however, experimental validation is suggested before human use.
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Squamous cell carcinoma of the head and neck (HNSCC) is a globally prevalent form of cancer with significant morbidity and mortality rates. The present study examines the relationship of serum pro-inflammatory cytokines and leptin levels with the effectiveness of therapy in individuals with HNSCC and their potential role as biomarkers for treatment response and toxicity. Induction chemotherapy and concomitant chemoradiotherapy were evaluated for efficacy and safety in 52 individuals with HNSCC. Both response and toxicity were evaluated, and serum levels of pro-inflammatory cytokines Interlukin-1 beta (IL-1ß), Interlukin-2 (IL-2), Interlukin-6 (IL-6), and Tumor Necrosis Factor-Alpha (TNF-α) and leptin were measured using enzyme-linked immunoassay before and after treatment. Before treatment, these measurements were made in comparison with a control group with 50 healthy people. The results showed that serum cytokines and leptin levels varied depending on the response to treatment, with patients who had a complete or partial response (PR) showing significant decreases in IL-1 ß, IL-6, and TNF-α levels and significant increases in IL-2 and leptin levels after treatment, with an improvement in cachexia. These results imply that variations in serum pro-inflammatory cytokines and leptin levels are likely related to the therapeutic effectiveness in HNSCC and may act as biomarkers for treatment response.
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Breast cancer begins in the breast cells, mainly impacting women. It starts in the cells that line the milk ducts or lobules responsible for producing milk and can spread to nearby tissues and other body parts. In 2020, around 2.3 million women across the globe received a diagnosis, with an estimated 685,000 deaths. Additionally, 7.8 million women were living with breast cancer, making it the fifth leading cause of cancer-related deaths among women. The mutational changes, overexpression of drug efflux pumps, activation of alternative signalling pathways, tumour microenvironment, and cancer stem cells are causing higher levels of drug resistance, and one of the major solutions is to identify multitargeted drugs. In our research, we conducted a comprehensive screening using HTVS, SP, and XP, followed by an MM/GBSA computation of human-approved drugs targeting HER2/neu, BRCA1, PIK3CA, and ESR1. Our analysis pinpointed IRESSA (Gefitinib-DB00317) as a multitargeted inhibitor for these proteins, revealing docking scores ranging from -4.527 to -8.809 Kcal/mol and MM/GBSA scores between -49.09 and -61.74 Kcal/mol. We selected interacting residues as fingerprints, pinpointing 8LEU, 6VAL, 6LYS, 6ASN, 5ILE, and 5GLU as the most prevalent in interactions. Subsequently, we analysed the ADMET properties and compared them with the standard values of QikProp. We extended our study for DFT computations with Jaguar and plotted the electrostatic potential, HOMO and LUMO regions, and electron density, followed by a molecular dynamics simulation for 100 ns in water, showing an utterly stable performance, making it a suitable drug candidate. IRESSA is FDA-approved for lung cancer, which shares some pathways with breast cancers, clearing the hurdles of multitargeted drugs against breast and lung cancer. This has the potential to be groundbreaking; however, more studies are needed to concreate IRESSA's role.
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Lung Cancer is the topmost death causing cancer and results from smoking, air pollution, cigar, exposure to asbestos or radon-like substances, and genetic factors. The cases of Lung Cancer in south Asian developing nations are being seen most due to heavy pollution and unbalanced lifestyle and putting a considerable burden on healthcare systems. The Food and Drug Administration of the USA has approved almost 100 drugs against SCLC and NSLC and a few drugs that are given to minimise the side effect of anticancer drugs. However, the drugs are shown to be resistant at significantly higher stages and non-affective on cancerous cells and have long-term side effects due to designing the drug by keeping one protein/gene target while designing or repurposing the drugs. In this study, we have taken five main lung cancer protein targets- Nerve growth factor protein (1SG1), Apoptosis inhibitor survivin (1XOX), Heat shock protein (3IUC), Protein tyrosine phosphate (3ZM3), Aldo-keto reductase (4XZL) and screened the complete prepared Drug Bank library of 155888 compounds and identified Variolin B (DB08694) as a multitargeted inhibitor against lung cancer using HTVS, SP and XP sampling algorithms followed by MM\GBSA calculation to sort the best pose. Variolin B is a natural marine antitumor and antiviral compound, so we analysed the ADMET properties and interaction patterns and then simulated all five P-L complexes for 100 ns in water using the NPT ensemble to check its selves against lung cancer. The docking results, ADMET and fingerprints have shown a good performance, and RMSD and RMSF results were with least deviation and fluctuations (<2Å) and produced a huge contact with other residues making the complex stable. The complexes initially fluctuated and deviated due to changes in the solute medium and sudden heat and stabilise after a few ns. However, extensive experimental validation is required before human use.Communicated by Ramaswamy H. Sarma.
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Neoplasias Pulmonares , Simulação de Dinâmica Molecular , Humanos , Simulação de Acoplamento Molecular , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Ligação Proteica , Detecção Precoce de CâncerRESUMO
Lung Cancer is the one that causes more fatalities in the world compared to other cancers, and its uniqueness is that it can be found in both males and females. However, recent data has shown that males are more affected due to lifestyle habits like smoking, tobacco consumption and inhaling polluted air. The World Health Organization has kept lung cancer on its priority list as it causes 1.8 million deaths worldwide each year, and the predictions show that the cases are going to increase year by year, and by 2050, there can be 3.8 million new cases and 3.2 million deaths, and the global health system is not prepared for it. Also, finding drug candidates that can help shrink cancerous cells and lead to their death is essential to reduce global mortality. The system needs drug compounds that can inhibit multiple paths together not to enter drug resistance quickly and to reduce costs. Our study identified a compound named Variolin B (DB08694) that belongs to the organic compounds class of pyrrolopyridines. The identified compound can inhibit multiple proteins, drastically reducing the global burden. Variolin B was identified as a potential candidate against lung cancer using the multisampling algorithm such as HTVS, SP, and XP, followed by MM\GBSA calculations showing the docking score of -9.245 Kcal/mol to -5.92 Kcal/mol. Also, we have validated it with ADMET predictions and molecular fingerprinting to analyse the interaction patterns. Further, the study was extended to molecular dynamics simulations for 100 ns to understand the complex stability and simulative interactions. The complex's overall molecular dynamics simulation helped us understand that the identified candidate is stable with the lowest deviation and fluctuations.Communicated by Ramaswamy H. Sarma.
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Compostos Aza , Neoplasias Pulmonares , Pirimidinas , Feminino , Masculino , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Background and objective Osteoarthritis (OA) is influenced by genetics and environmental factors, including vitamin D deficiency. This study aimed to investigate the association between vitamin D levels, growth/differentiation factor 5 (GDF-5) gene polymorphism, and serum GDF-5 in obese females with knee OA (KOA) in Saudi Arabia. Methodology The study enrolled 60 female patients with OA and 60 healthy females as controls. Blood samples were collected to evaluate the GDF-5 T>C (rs143383) polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The study also measured serum levels of vitamin D, GDF-5, calcium, uric acid, lipid profiles, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), and assessed the participants' BMI. Results The study demonstrated that KOA patients had reduced vitamin D levels in their bodies, along with GDF-5 and calcium. However, they had increased levels of uric acid, lipid profile, CRP, and ESR. Strong correlations were observed between vitamin D levels, lipid profile, CRP, ESR, BMI, GDF-5 gene polymorphisms, and GDF-5 protein. Genotype analysis showed KOA patients had TT (30%), TC (50%), and CC (20%) genotypes, while the control group showed TT (22%), TC (35%), and CC (43%) genotypes. Allele analysis revealed a noteworthy association between the T allele and KOA; the C allele was more common in the control group. Conclusions The study findings provide valuable insights into the association of vitamin D levels with GDF-5 T>C (rs143383) polymorphism, GDF-5 protein, and inflammatory markers in obese Saudi females with KOA. These findings suggest potential associations between these biomarkers and the pathogenesis or progression of KOA.
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Cathepsin L (CTSL) expression is dysregulated in a variety of cancers. Extensive empirical evidence indicates their direct participation in cancer growth, angiogenic processes, metastatic dissemination, and the development of treatment resistance. Currently, no natural CTSL inhibitors are approved for clinical use. Consequently, the development of novel CTSL inhibition strategies is an urgent necessity. In this study, a combined machine learning (ML) and structure-based virtual screening strategy was employed to identify potential natural CTSL inhibitors. The random forest ML model was trained on IC50 values. The accuracy of the trained model was over 90%. Furthermore, we used this ML model to screen the Biopurify and Targetmol natural compound libraries, yielding 149 hits with prediction scores >0.6. These hits were subsequently selected for virtual screening using a structure-based approach, yielding 13 hits with higher binding affinity compared to the positive control (AZ12878478). Two of these hits, ZINC4097985 and ZINC4098355, have been shown to strongly bind CTSL proteins. In addition to drug-like properties, both compounds demonstrated high affinity, ligand efficiency, and specificity for the CTSL binding pocket. Furthermore, in molecular dynamics simulations spanning 200 ns, these compounds formed stable protein-ligand complexes. ZINC4097985 and ZINC4098355 can be considered promising candidates for CTSL inhibition after experimental validation, with the potential to provide therapeutic benefits in cancer management.
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Simulação de Dinâmica Molecular , Neoplasias , Humanos , Catepsina L/metabolismo , Ligantes , Detecção Precoce de Câncer , Neoplasias/tratamento farmacológico , Simulação de Acoplamento MolecularRESUMO
BACKGROUND: Cardiovascular disease signifies a major cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). Serum uric acid (SUA) levels are elevated during the initial phases of impaired glucose metabolism. This work was designed to explore the association between SUA levels, serum oxido-inflammatory biomarkers, and the risk of coronary artery disease (CAD) in T2DM patients as the primary outcome. The secondary outcome was to assess the prognostic role of SUA in the prediction of the risk of CAD in T2DM patients. METHODS: In this case-control study, we enrolled 110 patients with T2DM who were further divided into patients with CAD and without CAD. In addition, 55 control participants were stringently matched to cases by age. RESULTS: Diabetic patients with CAD had significantly higher serum levels of the inflammatory biomarkers and the oxidative malondialdehyde but significantly lower levels of serum total antioxidant capacity (TAC) compared with the controls and diabetic patients without CAD. Significant positive correlations existed between SUA levels and serum levels of the inflammatory biomarkers and malondialdehyde, while a significant negative correlation existed between SUA levels and serum TAC. SUA demonstrated an accepted discrimination ability. SUA can differentiate between T2DM patients with CAD and patients without CAD, an area under the curve of 0.759. CONCLUSIONS: Elevated serum levels of SUA and oxido-inflammatory biomarkers are associated with an increased risk of CAD in T2DM. SUA levels reflect the body's inflammatory status and oxidant injury in T2DM. SUA could be utilized as a simple biomarker in the prediction of CAD risk in T2DM.
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Pseudomonas aeruginosa is notorious for its ability to develop a high level of resistance to antimicrobial agents. Resistance-nodulation-division (RND) efflux pumps could mediate drug resistance in P. aeruginosa. The present study aimed to evaluate the antibacterial and anti-efflux activities of cinnamon essential oil either alone or combined with ciprofloxacin against drug resistant P. aeruginosa originated from human and animal sources. The results revealed that 73.91% of the examined samples were positive for P. aeruginosa; among them, 77.78% were of human source and 72.73% were recovered from animal samples. According to the antimicrobial resistance profile, 48.73% of the isolates were multidrug-resistant (MDR), 9.2% were extensive drug-resistant (XDR), and 0.84% were pan drug-resistant (PDR). The antimicrobial potential of cinnamon oil against eleven XDR and one PDR P. aeruginosa isolates was assessed by the agar well diffusion assay and broth microdilution technique. The results showed strong antibacterial activity of cinnamon oil against all tested P. aeruginosa isolates with inhibition zones' diameters ranging from 34 to 50 mm. Moreover, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of cinnamon oil against P. aeruginosa isolates ranged from 0.0562-0.225 µg/mL and 0.1125-0.225 µg/mL, respectively. The cinnamon oil was further used to evaluate its anti-efflux activity against drug-resistant P. aeruginosa by phenotypic and genotypic assays. The cartwheel test revealed diminished efflux pump activity post cinnamon oil exposure by two-fold indicating its reasonable impact. Moreover, the real-time quantitative polymerase chain reaction (RT-qPCR) results demonstrated a significant (p < 0.05) decrease in the expression levels of MexA and MexB genes of P. aeruginosa isolates treated with cinnamon oil when compared to the non-treated ones (fold changes values ranged from 0.4204-0.7474 for MexA and 0.2793-0.4118 for MexB). In conclusion, we suggested the therapeutic use of cinnamon oil as a promising antibacterial and anti-efflux agent against drug-resistant P. aeruginosa.
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The coronaviridae family has caused the most destruction among all the viral families in modern sciences. It is one of the recently discovered and added members of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has caused the global pandemic and significant destruction worldwide. However, scientists worldwide have developed vaccines, which are being given to humans. The mutated strain of the virus has caused various uncertainties about whether the discovered drug and vaccines affect it. Even after the World Health Organization's approval for the vaccines, their effectiveness and protection ratio are still a major concern. At the community level, to this date, there is no medicine available to cure the patients. In this study, we have screened the vast library from Drug Bank and identified N-(4-Aminobutanoyl)-S-(4-methoxybenzyl)-L-cysteinylglycine (NSL-CG) that can work against two major targets of SARS CoV-2, replication-transcription and RNA dependent polymerase. Further, we have performed the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and molecular dynamics simulation of the compound with both proteins individually, giving us enough evidence that the said drugs can work against the two targets together. Inhibiting the action of any of both proteins may lead to retaining the virus, and having a dual-targeted drug can be an extra precise measure for this process. The NSL-CG is an experimental drug belonging to the peptidomimetics class included in the small group of drugs with a docking score of -9.079 kcal/mol with replication-transcription -7.885 kcal/mol with RNA-dependent polymerase. Hence, through the complete flowed study, the NSL-CG can be further experimentally validated in in-vitro and in-vivo conditions before human utilisation.Communicated by Ramaswamy H. Sarma.
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Introduction: As a growing direction, nano-based therapy has become a successful paradigm used to address the phytogenic delivery-related problems in overcoming multivirulent vancomycin-resistant Staphylococcus aureus (VRSA) infection. Methods: Hence, our aim was to develop and assess a novel nanocarrier system (mesoporous silica nanoparticles, MPS-NPs) for free berberine (Free-BR) as an antimicrobial alkaloid against strong biofilm-producing and multi-virulent VRSA strains using in vitro and in vivo mouse model. Results and discussion: Our outcomes demonstrated vancomycin resistance in 13.7% of Staphylococcus aureus (S. aureus) strains categorized as VRSA. Notably, strong biofilm formation was observed in 69.2% of VRSA strains that were all positive for icaA gene. All strong biofilm-producing VRSA strains harbored a minimum of two virulence genes comprising clfA and icaA with 44.4% of them possessing all five virulence genes (icaA, tst, clfA, hla, and pvl), and 88.9% being multi-virulent. The study findings affirmed excellent in vitro antimicrobial and antibiofilm properties of BR-loaded MPS-NPs. Real-time quantitative reverse transcription PCR (qRT-PCR) assay displayed the downregulating role of BR-loaded MPS-NPs on strong biofilm-producing and multi-virulent VRSA strains virulence and agr genes in both in vitro and in vivo mice models. Additionally, BR-loaded MPS-NPs supplementation has a promising role in attenuating the upregulated expression of pro-inflammatory cytokines' genes in VRSA-infected mice with attenuation in pro-apoptotic genes expression resulting in reduced VRSA-induced apoptosis. In essence, the current study recommends the future scope of using BR-loaded MPS-NPs as auspicious alternatives for antimicrobials with tremendous antimicrobial, antibiofilm, anti-quorum sensing (QS), and anti-virulence effectiveness against problematic strong biofilm-producing and multi-virulent VRSA-associated infections.
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Alcaloides , Staphylococcus aureus Resistente à Meticilina , Nanopartículas , Infecções Estafilocócicas , Animais , Camundongos , Staphylococcus aureus , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Vancomicina , Porosidade , Antibacterianos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Biofilmes , Alcaloides/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
The prevalence of obesity has risen in the last decades, and it has caused massive health burdens on people's health, especially metabolic and cardiovascular issues. The risk of vitamin D insufficiency is increased by obesity, because adipose tissue alters both the requirements for and bioavailability of vitamin D. Exercise training is acknowledged as having a significant and long-term influence on body weight control; the favorable impact of exercise on obesity and obesity-related co-morbidities has been demonstrated via various mechanisms. The current work illustrated the effects of vitamin D supplementation and exercise on obesity induced by a high-fat diet (HFD) and hepatic steatosis in rats and explored how fatty acid transport protein-4 (FATP4) and Toll-like receptor-4 antibodies (TLR4) might be contributing factors to obesity and related hepatic steatosis. Thirty male albino rats were divided into five groups: group 1 was fed a normal-fat diet, group 2 was fed an HFD, group 3 was fed an HFD and given vitamin D supplementation, group 4 was fed an HFD and kept on exercise, and group 5 was fed an HFD, given vitamin D, and kept on exercise. The serum lipid profile adipokines, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were analyzed, and the pathological changes in adipose and liver tissues were examined. In addition, the messenger-ribonucleic acid (mRNA) expression of FATP4 and immunohistochemical expression of TLR4 in adipose and liver tissues were evaluated. Vitamin D supplementation and exercise improved HFD-induced weight gain and attenuated hepatic steatosis, along with improving the serum lipid profile, degree of inflammation, and serum adipokine levels. The expression of FATP4 and TLR4 in both adipose tissue and the liver was downregulated; it was noteworthy that the group that received vitamin D and was kept on exercise showed also improvement in the histopathological picture of this group. According to the findings of this research, the protective effect of vitamin D and exercise against obesity and HFD-induced hepatic steatosis is associated with the downregulation of FATP4 and TLR4, as well as a reduction in inflammation.
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Dieta Hiperlipídica , Fígado Gorduroso , Natação , Vitamina D , Masculino , Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inflamação/metabolismo , Lipídeos , Fígado , Obesidade/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Vitamina D/farmacologia , Vitamina D/uso terapêutico , Vitamina D/metabolismo , Vitaminas/metabolismo , RatosRESUMO
BACKGROUND/AIM: Type 2 diabetes (T2DM) is a metabolic condition associated with an increased risk of death, morbidity, and vascular problems. This study investigated the association of HIF-1α and dyslipidemia with the incidence of coronary artery disease in Saudi patients with T2DM. PATIENTS AND METHODS: This study included 100 Saudi patients aged 40-60 years who were attending King Abdulaziz Specialist Hospital in Taif, as well as 50 healthy controls. All were divided into three groups of 50 subjects each: control, patients with T2DM, and patients with T2DM with coronary complications. Serum levels of HIF-1α, fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c %), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were estimated. RESULTS: Serum HIF-1α, FBG, HbA1c %, TC, TG, and LDL-C levels were significantly increased in both groups of patients with diabetes (p<0.001) relative to the control group. Among patient groups, their levels were significantly increased in patients with coronary complications as compared to patients with diabetes (p<0.001). Serum HDL-C levels in both groups of patients with diabetes were significantly lower (p<0.001) than those in the control group. When HDL-C levels were compared between the two patient groups, its levels in patients with diabetes with coronary complications were significantly lower (p<0.001). Significant positive correlations were observed between serum HIF-1α and each of FBG, HbA1c %, TC, TG, and LDL-C levels, whereas negative correlations were observed with HDL-C in both groups of patients with diabetes. CONCLUSION: Increased serum HIF-1α levels are linked to dyslipidaemia in Saudi patients with T2DM, particularly those with coronary artery disease.
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Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Dislipidemias , HDL-Colesterol , LDL-Colesterol , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/complicações , Dislipidemias/epidemiologia , Hemoglobinas Glicadas , Humanos , Hipóxia , Arábia Saudita/epidemiologia , TriglicerídeosRESUMO
With more than 17 clinically approved Drugs and over 20 prodrugs under clinical investigations, marine bacteria are believed to have a potential supply of innovative therapeutic bioactive compounds. In the current study, Kocuria sp. strain AG5 isolated from the Red Sea was identified and characterized by biochemical and physiological analysis, and examination of a phylogenetic 16S rRNA sequences. Innovative exopolysaccharide (EPS) was separated from the AG5 isolate as a major fraction of EPS (EPSR5, 6.84 g/L-1). The analysis of EPSR5 revealed that EPSR5 has a molecular weight (Mw) of 4.9 × 104 g/mol and number average molecular weight (Mn) of 5.4 × 104 g/mol and contains sulfate (25.6%) and uronic acid (21.77%). Analysis of the monosaccharide composition indicated that the EPSR5 fraction composes of glucose, galacturonic acid, arabinose, and xylose in a molar ratio of 2.0:0.5:0.25:1.0, respectively. Assessment of the pharmacological potency of EPSR5 was explored by examining its cytotoxicity, anti-inflammatory, antioxidant, and anti-acetylcholine esterase influences. The antioxidant effect of EPSR5 was dose- and time-dependently increased and the maximum antioxidant activity (98%) was observed at 2000 µg/mL after 120 min. Further, EPSR5 displayed a significant repressive effect regarding the proliferation of HepG-2, A-549, HCT-116, MCF7, HEP2, and PC3 cells with IC50 453.46 ± 21.8 µg/mL, 873.74 ± 15.4 µg/mL, 788.2 ± 32.6 µg/mL, 1691 ± 44.2 µg/mL, 913.1 ± 38.8 µg/mL, and 876.4 ± 39.8 µg/mL, respectively. Evaluation of the inhibitory activity of the anti-inflammatory activity of EPSR5 indicated that EPSR5 has a significant inhibitory activity toward lipoxygenase (5-LOX) and cyclooxygenase (COX-2) activities (IC50 15.39 ± 0.82 µg/mL and 28.06 ± 1.1 µg/mL, respectively). Finally, ESPR5 presented a substantial hemolysis suppressive action with an IC50 of 65.13 ± 0.89 µg /mL, and a considerable inhibitory activity toward acetylcholine esterase activity (IC50 797.02 µg/mL). Together, this study reveals that secondary metabolites produced by Kocuria sp. strain AG5 marine bacteria serve as an important source of pharmacologically active compounds, and their impact on human health is expected to grow with additional global work and research.
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Surface-growing antibiotic-resistant pathogenic bacteria such as Escherichia coli and Staphylococcus aureus are emerging as a global health challenge due to dilemmas in clinical treatment. Furthermore, their pathogenesis, including increasingly serious antimicrobial resistance and biofilm formation, makes them challenging to treat by conventional therapy. Therefore, the development of novel antivirulence strategies will undoubtedly provide a path forward in combatting these resistant bacterial infections. In this regard, we developed novel biosurfactant-coated nanoparticles to combine the antiadhesive/antibiofilm properties of rhamnolipid (RHL)-coated Fe3O4 nanoparticles (NPs) with each of the p-coumaric acid (p-CoA) and gallic acid (GA) antimicrobial drugs by using the most available polymer common coatings (PVA) to expand the range of effective antibacterial drugs, as well as a mechanism for their synergistic effect via a simple method of preparation. Mechanistically, the average size of bare Fe3O4 NPs was ~15 nm, while RHL-coated Fe3O4@PVA@p-CoA/GA was about ~254 nm, with a drop in zeta potential from -18.7 mV to -34.3 mV, which helped increase stability. Our data show that RHL-Fe3O4@PVA@p-CoA/GA biosurfactant NPs can remarkably interfere with bacterial growth and significantly inhibited biofilm formation to more than 50% via downregulating IcaABCD and CsgBAC operons, which are responsible for slime layer formation and curli fimbriae production in S. aureus and E. coli, respectively. The novelty regarding the activity of RHL-Fe3O4@PVA@p-CoA/GA biosurfactant NPs reveals their potential effect as an alternative multitarget antivirulence candidate to minimize infection severity by inhibiting biofilm development. Therefore, they could be used in antibacterial coatings and wound dressings in the future. IMPORTANCE Antimicrobial resistance poses a great threat and challenge to humanity. Therefore, the search for alternative ways to target and eliminate microbes from plant, animal, and marine microorganisms is one of the world's concerns today. Furthermore, the extraordinary capacity of S. aureus and E. coli to resist standard antibacterial drugs is the dilemma of all currently used remedies. Methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) have become widespread, leading to no remedies being able to treat these threatening pathogens. The most widely recognized serotypes that cause severe foodborne illness are E. coli O157:H7, O26:H11, and O78:H10, and they display increasing antimicrobial resistance rates. Therefore, there is an urgent need for an effective therapy that has dual action to inhibit biofilm formation and decrease bacterial growth. In this study, the synthesized RHL-Fe3O4@PVA@p-CoA/GA biosurfactant NPs have interesting properties, making them excellent candidates for targeted drug delivery by inhibiting bacterial growth and downregulating biofilm-associated IcaABCD and CsgBAC gene loci.
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Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Animais , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Biofilmes , Escherichia coli , Glicolipídeos , Nanopartículas Magnéticas de Óxido de Ferro , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Sorogrupo , Staphylococcus aureusRESUMO
For the last few years, the world has been going through a difficult time, and the reason behind this is severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), one of the significant members of the Coronaviridae family. The major research groups have shifted their focus towards finding a vaccine and drugs against SARS-CoV-2 to reduce the infection rate and save the life of human beings. Even the WHO has permitted using certain vaccines for an emergency attempt to cut the infection curve down. However, the virus has a great sense of mutation, and the vaccine's effectiveness remains questionable. No natural medicine is available at the community level to cure the patients for now. In this study, we have screened the vast library of experimental drugs of Drug Bank with Schrodinger's maestro by using three algorithms: high-throughput virtual screening (HTVS), standard precision, and extra precise docking followed by Molecular Mechanics/Generalized Born Surface Area (MMGBSA). We have identified 3-(7-diaminomethyl-naphthalen-2-YL)-propionic acid ethyl ester and Thymidine-5'-thiophosphate as potent inhibitors against the SARS-CoV-2, and both drugs performed impeccably and showed stability during the 100 ns molecular dynamics simulation. Both of the drugs are among the category of small molecules and have an acceptable range of ADME properties. They can be used after their validation in in-vitro and in-vivo conditions.
Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologiaRESUMO
Foodborne infections and antibiotic resistance pose a serious threat to public health and must be addressed urgently. Pistacia lentiscus is a wild-growing shrub and has been utilized for medicinal applications as well as for culinary purposes. The antibacterial and antioxidant activities of P. lentiscus bark in vitro, as well as the phytochemical composition, are the focus of this inquiry. The bark extract of P. lentiscus showed significant antimicrobial activity in experiments on bacteria and yeast isolated from human and food sources. The exposure time for the complete inhibition of cell viability of P. aeruginosa in the extracts was found to be 5% at 15 min. Phytochemical inquiry of the methanol extract demonstrates the existence of carbohydrates, flavonoids, tannins, coumarins, triterpenes, and alkaloids. Deep phytochemical exploration led to the identification of methyl gallate, gallic acid, kaempferol, quercetin, kaempferol 3-O-α-rhamnoside, kaempferol 3-O-ß-glucoside, and Quercetin-3-O-ß-glucoside. When tested using the DPPH assay, the methanol extracts of P. lentiscus bark demonstrated a high free radical scavenging efficiency. Further, we have performed a molecular modelling study which revealed that the extract of P. lentiscus bark could be a beneficial source for novel flavonoid glycosides inhibitors against SARS-CoV-2 infection. Taken together, this study highlights the Pistacia lentiscus bark methanol extract as a promising antimicrobial and antiviral agent.
RESUMO
Lead (Pb) is a widespread and nondegradable environmental pollutant and affects several organs through oxidative mechanisms. This study was conducted to investigate the antioxidant protective effect of glycine betaine (GB) against Pb-induced renal and hepatic injury. Male albino rats (n = 45) were divided into three groups: G1 untreated control, G2 Pb-acetate (50 mg/kg/day), and G3 Pb-acetate (50 mg/kg/day) plus GB (250 mg/kg/day) administered for 6 weeks. For G3, Pb-acetate was administered first and followed by GB at least 4 h after. Pb-acetate treatment (G2) resulted in a significant decrease in renal function, including elevated creatinine and urea levels by 17.4% and 23.7%, respectively, and nonsignificant changes in serum uric acid levels. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphates (ALP) activities were significantly increased with Pb treatment by 37.6%, 59.3%, and 55.1%, respectively. Lipid peroxidation level was significantly increased by 7.8 times after 6 weeks of Pb-acetate treatment. The level of reduced glutathione (GSH-R) significantly declined after Pb-acetate treatment. Pb-acetate treatment also reduced the activities of superoxide dismutase (SOD), glutathione-S-transferase (GST), and glutathione peroxidase (GSH-PX) by 74.1%, 85.0%, and 40.8%, respectively. Treatment of Pb-intoxicated rats with GB resulted in a significant reduction in creatinine, urea, ALT, AST, and lipid peroxidation, as well as a significant increase in the level of GSH-R and in the activities of ALP, SOD, GST, and GSH-PX. The molecular interaction between GB and GSH-PX indicated that the activation of GSH-PX in Pb-intoxicated rats was not the result of GB binding to the catalytic site of GSH-PX. The affinity of GB to bind to the catalytic site of GSH-PX is lower than that of H2O2. Thus, GB significantly mitigates Pb-induced renal and liver injury through the activation of antioxidant enzymes and the prevention of Pb-induced oxidative damage in the kidney and liver.