72 research outputs found

    Gene expression of multidrug-resistant ATP-binding cassette transporter (MDR1/ABCB1) in bovine mastitis

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    Purpose: To investigate the expression of multidrug-resistant ATP binding cassette transporter Pglycoprotein (MDR1/ABCB1/P-gp) in mastitis and its correlation with the expression of apoptosis regulation.Methods: Mastitic and normal mammary gland samples were collected after clinical examination and confirmed using field California mastitis test. Total RNA was extracted followed by cDNA synthesis and real-time PCR to detect the expression pattern of P-gp. Tissue sections were examined for pathological changes and immune reactivity to the apoptotic regulator, Bcl-2-associated X protein (BAX).Results: Stained sections from mastitic samples showed congestion, infiltration of inflammatory cells and hemorrhage. Using immunohistochemistry, it was shown that mastitis is associated with overexpression of the apoptosis regulator, Bcl-2-associated X protein (BAX). There was increased expression of the pro-apoptotic factor, Bax, in mastitic alveolar lining and lactic tubules compared with normal mammary gland tissues. Using real-time PCR, the expression level of MDR1/ABCB1 was determined to be 2.6-fold higher in mastitic tissues than in normal mammary tissues.Conclusion: Higher MDR1/P-gp level can modulate drug interventions by preventing intracellular accumulation of chemotherapeutics or anti-inflammatories via continuous efflux or export to extracellular fluids.Keywords: ABC transporter, P-glycoprotein, Drug exporters, Mastitis, Mammary glan

    Substructural dynamics of the phase-I drug metabolizing enzyme, carbonyl reductase 1, in response to various substrate and inhibitor configurations

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    Purpose: To investigate the substructure and molecular dynamics change in the phase-I drug metabolizing enzyme, carbonyl reductase 1 (CBR1), in response to different substrate and inhibitor configurations, using a molecular dynamics approach. Methods: CBR1 structure and drug ligands, including 2,3-butanedione, prostaglandin E2 (PGE2), oracine, mitoxantrone, menadione, rutoside, barbital, and biochanin A, were retrieved and 3D optimized. Docking runs were performed using template docking into CBR1 active binding site with GSH. Molecular dynamic (MD) simulation was implemented for 100 ns. Results: The docking scores were positively correlated with the detected ligand‚Äôs affinities. Molecular dynamics simulation indicated that lower affinity ligands or weaker inhibitors produced less stable CBR1 with higher root mean square deviations (RMSD) of CBR1 backbone őĪ-carbon atoms. Stronger inhibitors and substrates produced stable CBR1 structures with RMSD similar to or lower than CBR1- NADP complexes. Very low affinity ligands were unstable and were released from their sites within a few nanoseconds after commencing the simulation. Two flexible loops, LE92-PHE102 and VAL230- TYR251, were highly responsive to the nature of CBR1 ligands. Changes in the latter may be associated with lower CBR1 activity due to loss of stabilization of NADPH by the deviation of this loop‚Äôs residues. Conclusion: In this work, a model of CBR1 structural changes has been provided that can be used in the analysis of CBR1 future substrates and inhibitors. Docking followed by MD simulation and analysis of average backbone őĪ-carbon RMSD and changes in ILE92-PHE102 and VAL230-TYR251 loops can be used in the model analysis of unknown or new drug candidates to predict their binding efficiencies

    Anti-proliferative activity of leaves of Launaea capitata Asteraceae: Phytochemical, cytotoxicity and in silico studies

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    Purpose: To investigate the phytochemical contents of Launaea capitata (L. capitate) and its potential cytotoxic activity. Also, to examine its molecular modeling by docking of the isolated compounds.Methods: L. capitata was methanol-extracted and successively fractionated followed by determination of the total phenolic and flavonoid contents. Major constituents were isolated and purified. 3-(4, 5- Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cytotoxicity assays were conducted for all fractions. In silico studies were conducted using four anticancer target kinases, namely, protein kinase B (PKB/AKT), phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), and rapidly accelerated fibrosarcoma kinases (RAFK).Results: The results showed that total phenolic constituents ranged from 0.150 ¬Ī 0.004 to 60.229 ¬Ī 0.822 mg Gallic Acid Equivalent/g of dry extract, while the total flavonoid content varied from 0.004 ¬Ī 0.002 to 18.129 ¬Ī 1.599 mg quercetin equivalent/g of dry extract. Furthermore, the ethyl acetate fraction contained the highest amount of phenolic and flavonoid contents, which seemed to constitute the most effective anti-proliferative fraction. The plant‚Äôs major constituent was apigenin-7-O-glycoside and was isolated from the ethyl acetate fraction. The MTT cytotoxicity assay revealed the anti-proliferative activity of ethyl acetate and butanol fractions, and apigenin-7-O-glycoside with half-maximal concentration (IC50) comparable to that of doxorubicin. In silico studies revealed that apigenin-7-Oglycoside showed a better binding score and ligand efficiency when compared with standard ligands/inhibitors for AKT/PKB and PI3K, suggesting potential multiple targets for its anti-cancer activities.Conclusion: L. capitata contains considerable amounts of phenolic and flavonoid components. Its major constituent, apigenin-7-O-glycoside is a potential lead compound for developing new anticancer compounds. Keywords: Launaea capitata, Total phenolics, Total flavonoids, Docking, Cytotoxicit

    1,2,3-Triazolyl-tetrahydropyrimidine conjugates as potential Sterol Carrier Protein-2 Inhibitors: Larvicidal activity against the Malaria Vector Anopheles arabiensis and In Silico Molecular Docking Study

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    Alteration of insect growth regulators by the action of inhibitors is becoming an attractive strategy to combat disease-transmitting insects. In the present study, we investigated the larvicidal effect of 1,2,3-triazolyl-pyrimidinone derivatives against the larvae of the mosquito Anopheles arabiensis, a vector of malaria. All compounds demonstrated insecticidal activity against mosquito larvae in a dose-dependent fashion. A preliminary study of the structure‚Äďactivity relationship indicated that the electron-withdrawing substituent in the para position of the 4-phenyl-pyrimidinone moiety enhanced the molecules‚Äô potency. A docking study of these derivatives revealed favorable binding affinity for the sterol carrier protein-2 receptor, a protein present in the intestine of the mosquito larvae. Being effective insecticides against the malaria-transmitting Anopheles arabiensis, 1,2,3-triazole-based pyrimidinones represent a starting point to develop novel inhibitors of insect growth regulators.Fil: Venugopala, Katharigatta N.. Durban University Of Technology; Sud√°frica. King Faisal University; Arabia SauditaFil: Shinu, Pottathil. King Faisal University; Arabia SauditaFil: Tratrat, Christophe. King Faisal University; Arabia SauditaFil: Deb, Pran Kishore. Philadelphia University Jordan; JordaniaFil: Gleiser, Raquel M.. Universidad Nacional de C√≥rdoba; Argentina. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Centro Cient√≠fico Tecnol√≥gico C√≥rdoba. Instituto Multidisciplinar de Biolog√≠a Vegetal (P). Grupo Vinculado Centro de Relevamiento y Evaluaci√≥n de Recursos Agr√≠colas y Naturales; ArgentinaFil: Chandrashekharappa, Sandeep. National Institute Of Pharmaceutical Education And Research, Raebareli; IndiaFil: Chopra, Deepak. Indian Institute Of Science Education And Research Bhopal; IndiaFil: Attimarad, Mahesh. King Faisal University; Arabia SauditaFil: Nair, Anroop B.. King Faisal University; Arabia SauditaFil: Sreeharsha, Nagaraja. Vidya Siri College Of Pharmacy; India. King Faisal University; Arabia SauditaFil: Mahomoodally, Fawzi M.. University Of Mauritius; MauricioFil: Haroun, Michelyne. King Faisal University; Arabia SauditaFil: Kandeel, Mahmoud. Faculty Of Veteinary Medicine; Egipto. King Faisal University; Arabia SauditaFil: Asdaq, Syed Mohammed Basheeruddin. Almaarefa University; Arabia SauditaFil: Mohanlall, Viresh. Durban University Of Technology; Sud√°fricaFil: Al-Shari, Nizar A.. Jordan University Of Science And Technology; JordaniaFil: Morsy, Mohamed A.. King Faisal University; Arabia Saudita. Faculty Of Medicine; Egipt

    Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

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    Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

    Genome-Wide Identification of B3 DNA-Binding Superfamily Members (ABI, HIS, ARF, RVL, REM) and Their Involvement in Stress Responses and Development in Camelina sativa

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    The B3 DNA-binding superfamily is a group of gene families that contain a B3 domain in their proteins. Members of this superfamily are involved in responses to stresses including salt, drought, and cold stress. The B3 DNA-binding superfamily has not been fully studied in Camelina sativa. A total of eighty-seven members of this superfamily were identified in C. sativa. The identified genes were placed into five groups based on a phylogenetic analysis. All the proteins were predicted to be nuclear. The RAV and ARF gene family had the most conserved motifs, with nine out of ten motifs being preserved, while the REM gene family was discovered to have the fewest, with just one conserved motif being present. The RAV and REM gene families showed the least protein&ndash;protein interactions. The CsARF5 and CsARF7 genes showed the highest potent interaction score with multiple auxin-responsive proteins. A qPCR analysis was carried out on six genes that showed stress-induced expression changes. CsREM17, CsREM5, and CsRAVL5 were discovered to be considerably increased in response to drought stress, while CsARF10, CsARF4, and CsREM34 were found to be downregulated to a large extent. The B3 DNA-binding superfamily regulates abscisic acid signaling, which in turn influences plant growth and stress resistance
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