scholarly journals Pharmacokinetic and Toxicological Evaluation of a Zinc Gluconate-Based Chemical Sterilant Using In Vitro and In Silico Approaches

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Carlos F. Araujo-Lima ◽  
Rafael J. M. Nunes ◽  
Raphael M. Carpes ◽  
Claudia A. F. Aiub ◽  
Israel Felzenszwalb
Keyword(s):  
In Silico ◽  
Animal Health ◽  
Optimal Dose ◽  
Dependent Manner ◽  
Toxicological Evaluation ◽  
Mutagenic Potential ◽  
Zinc Gluconate ◽  
Sclerosing Agents ◽  
Toxicological Activity

Sclerosing agents as zinc gluconate-based chemical sterilants (Infertile®) are used for chemical castration. This solution is injected into the animal testis, but there are not enough evidences of its safety profiles for the receivers. The present work aimed to establish the pharmacokinetics and toxicological activity of Infertile, using in vitro and in silico approaches. The evaluation at the endpoint showed effects in a dose-dependent manner. Since necrosis is potentially carcinogenic, the possible cell death mechanism could be apoptosis. Our data suggested that Infertile at 60 mM presented risk for animal health. Even though Infertile is a licensed product by the Brazilian Ministry of Agriculture, Livestock and Supply, it presented a high mutagenic potential. We suggest that the optimal dose must be less than 6 mM, once, at this concentration, no mutagenicity or genotoxicity was observed.

scholarly journals Anti-Nosemosis Activity of Aster scaber and Artemisia dubia Aqueous Extracts

2018 ◽  
Vol 62 (1) ◽  
pp. 27-38
Author(s):  
Jae Kwon Lee ◽  
Jeong Hwa Kim ◽  
Mina Jo ◽  
Balamurugan Rangachari ◽  
Jin Kyu Park
Keyword(s):  
Optimal Dose ◽  
Dependent Manner ◽  
Aqueous Extracts ◽  
Active Components ◽  
Aqueous Fraction ◽  
Ethanol Extracts ◽  
Artemisia Dubia ◽  
Dose Dependent

Abstract In our previous study, we demonstrated that the ethanol extracts of Artemisia dubia (A. dubia) and Aster scaber (A. scaber) have anti-nosemosis activity. In our present study, we intend to establish the anti-nosemosis activity of aqueous, ethyl acetate (EA), and butanol (BuOH) extracts of A. dubia and A. scaber. In order to determine the optimal dose, we performed both in vitro and in vivo toxicity for all the extracts and also carried out anti-nosemosis experiments. Although all of the extracts (aqueous, EA, and BuOH) showed in vitro and in vivo anti-nosemosis activity in a dose-dependent manner, the aqueous extracts of A. dubia and A. scaber showed more potent anti-nosemosis activity than the EA and BuOH extracts. Moreover, an aqueous extract of A. dubia + A. scaber demonstrated stronger anti-nosemosis activity compared with the aqueous extracts of either A. dubia or A. scaber alone. Although the main ingredients in A. dubia and A. scaber remain unclear, our results suggest that the active components of A. dubia and A. scaber could dissolve in the aqueous fraction.

Deltamethrin-Induced Immunotoxicity and its Protection by Quercetin: An Experimental Study

2020 ◽  
Vol 20 (1) ◽  
pp. 67-76 ◽  
Author(s):  
Anoop Kumar ◽  
Meenakshi Gupta ◽  
Ruchika Sharma ◽  
Neelima Sharma
Keyword(s):  
In Silico ◽  
Immune Cell ◽  
Protective Role ◽  
B Cell Receptors ◽  
Dependent Manner ◽  
Cell Receptors ◽  
In Vitro Techniques

Background: Deltamethrin (DLM) is a type 2 pyrethroid insecticide used in agriculture and home to control pests. However, emerging reports have indicated the immunotoxicity of DLM. Objective: Thus, in the current investigation, we have checked the immune-protective role of quercetin in DLM-induced immunotoxicity by using in silico and in vitro techniques. Results: In silico results have shown good interaction of quercetin towards immune cell receptors (T & B cell receptors). The findings of in vitro studies indicated the decrease in oxidative stress which is elevated by DLM in concentration & time-dependent manner. The increased caspases-3 activity was decreased by treatment of quercetin. The apoptosis induced by DLM in thymus and spleen was suppressed only at higher concentration (50μg/ml) of quercetin. Finally, the phenotypic changes due to DLM were restored by quercetin. Conclusion: Quercetin has strong binding affinity towards CD4, CD8 and CD28, CD45 receptors and protects the thymocytes and splenocytes against DLM-induced apoptotic signaling pathways.

scholarly journals Augmented Cell Signaling by Betanin insights Cancer Cell Remodeling: A Molecular Docking and Experimental Approach

2021 ◽  
Vol 12 (3) ◽  
pp. 3161-3172
Keyword(s):  
Cell Cycle ◽  
Molecular Docking ◽  
Cancer Cell ◽  
In Silico ◽  
Topoisomerase I ◽  
Caspase 3 ◽  
Dependent Manner ◽  
Dna Topoisomerase ◽  
Docking Analysis

Molecular docking analysis has shown to be an important tool for systematically harnessing natural pigment betanin's structural diversity. Natural betanin pigment was used to investigate its anticancer efficacy by in vitro cytotoxicity and cell cycle analysis in A549 lung cancer cell line. Furthermore, docking analysis was used to determine the promising molecular targets for the betanin using different receptor proteins and enzymes responsible for DNA replication (DNA topoisomerases I and II), cell cycle (CDK-6), and in silico apoptotic markers (Bcl-2 and caspase-3) using Glide Schrodinger. In vitro analysis revealed that betanin exerts cytotoxic effects in a cancer cell by inducing apoptosis in a dose-dependent manner with an IC50 value of 17 µM. Furthermore, the cell cycle arrest in response to betanin treatment was strongly observed in flow cytometry analysis. The in silico docking results revealed that betanin exhibited splendid interaction with high affinity against the CDK-6, Bcl-2, and caspase-3 with superior docking scores. Betanin was best docked with DNA topoisomerase II than DNA topoisomerase I. Overall, our report provides scientific evidence that betanin is a novel drug moiety with anticancer property attributes that might be developed and formulated as drug candidate/lead compounds for cancer chemotherapy.

Identification and Characterization of a Novel Jak2 Tyrosine Kinase Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3604-3604 ◽  
Author(s):  
Jacqueline Sayyah ◽  
David Ostrov ◽  
Peter Sayeski
Keyword(s):  
Growth Hormone ◽  
Tyrosine Kinase ◽  
In Silico ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Kinase Domain ◽  
Dependent Manner ◽  
Dose Dependent ◽  
Tyrosine Autophosphorylation

Abstract Jak2 is a cytoplasmic tyrosine kinase that has been linked to hematological malignancies. Recently, a somatic Jak2 mutation (Jak2-V617F) has been identified in several myeloproliferative disorders such as polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis. These myeloproliferative disorders are characterized by unregulated expansion of one or more cells in the blood. The presence of the Jak2-V617F mutation in cells results in uncontrolled cell division and resistance to the negative feedback mechanisms that govern normal cell growth. The availability of a Jak2 tyrosine kinase specific inhibitor would facilitate our understanding of these Jak2-related disorders and perhaps serve a clinical benefit for patients. However, the most widely used Jak2 inhibitor, AG490, suffers from a general lack of specificity. Here, we used a novel approach to identify Jak2-specific inhibitors. We used in silico homology modeling of the Jak2 kinase domain to identify solvent accessible exposed pockets on the surface of the Jak2 protein. We then used a high-throughput program called DOCK to predict the ability of 20,000 small molecules to interact with a structural pocket adjacent to the ATP binding site of murine Jak2. The predicted binding energies of interaction between each compound and the Jak2 kinase domain were calculated and the top six scoring compounds were tested for their ability to inhibit Jak2 tyrosine kinase function in vitro. One of these compounds, 2-methyl-1-phenyl-4-pyridin-2-yl-2-(2-pyridin-2-ylethyl)butan-1-one (Z3) effectively inhibited Jak2-V617F and Jak2-WT autophosphorylation. We were able to show that Z3 inhibits total Jak2 tyrosine phosphorylation as well as Jak2 phosphorylation at the critical tyrosine 1007 residue in both a dose-and time-dependent manner. Z3 is able to reduce growth hormone-dependent Jak2 activation and is a direct inhibitor of Jak2-WT and Jak2-V617F tyrosine kinase autophosphorylation as measured by an in vitro kinase assay. Moreover, we found that Z3 inhibits proliferation of human erythroleukemia (HEL) cells, which express the Jak2-V617F mutation. In summary, this work demonstrates proof-of-principle concept that in silico molecular modeling can be used as a means to identify specific tyrosine kinase inhibitors. Z3 Inhibits Jak2 Tyrosine Autophosphorylation in a Dose-Dependent Manner Z3 Inhibits Jak2 Tyrosine Autophosphorylation in a Dose-Dependent Manner Z3 Inhibits Growth Hormone Mediated Jak2 Phosphorylation at Tyrosine 1007 Z3 Inhibits Growth Hormone Mediated Jak2 Phosphorylation at Tyrosine 1007

Probiotic bacteria as potential detoxification tools: assessing their heavy metal binding isotherms

2006 ◽  
Vol 52 (9) ◽  
pp. 877-885 ◽  
Author(s):  
Fandi Ibrahim ◽  
Teemu Halttunen ◽  
Raija Tahvonen ◽  
Seppo Salminen
Keyword(s):  
Heavy Metal ◽  
Metal Binding ◽  
Animal Health ◽  
Lactobacillus Rhamnosus ◽  
Dietary Exposure ◽  
Probiotic Bacteria ◽  
Dependent Manner ◽  
Binding Isotherms ◽  
Cadmium And Lead

Dietary exposure to heavy metals may have detrimental effects on human and animal health, even at low concentrations. Specific probiotic bacteria may have properties that enable them to bind toxins from food and water. We assessed the interaction of probiotic bacteria with cadmium and lead in vitro as an initial screening step to identify strains for heavy metal decontamination in food and intestinal models. Binding isotherms for cadmium and lead were characterized for Lactobacillus rhamnosus LC-705, Propionibacterium freudenreichii subsp. shermanii JS and a mix of them used by the food industry. Differences among the strains and their combinations in binding performance at a range of concentrations between 0.1 and 100 mg·L–1 were evaluated with the Langmuir model for biosorption. The effects of pH, contact time, and viability on the binding capacities were also investigated. All strains and their combinations were found to bind cadmium and lead efficiently at low concentration ranges commonly observed in foods. However, the two strains and their combinations differed significantly in their maximum binding capacities and affinities represented by the Langmuir constants Qmax and b, respectively. The binding seemed to occur instantaneously and in a pH-dependent manner, which can be perfectly described by a segmented linear–plateau model.Key words: probiotics, cadmium, lead, binding, Langmuir.

scholarly journals IN VITRO ANTI-NEUROINFLAMMATORY EFFECT OF GENISTEIN (4',5,7-TRIHYDROXYISOFLAVONE) ON MICROGLIA HMC3 CELL LINE, AND IN SILICO EVALUATION OF ITS INTERACTION WITH ESTROGEN RECEPTOR-β

2021 ◽  
pp. 183-187
Author(s):  
BURHAN MA’ARIF ◽  
FAISAL A. MUSLIKH ◽  
WIRDA ANGGRAINI ◽  
MAXIMUS M. TAEK ◽  
HENING LASWATI ◽  
...  
Keyword(s):  
Cell Line ◽  
In Silico ◽  
In Silico Analysis ◽  
Physicochemical Characteristics ◽  
Dependent Manner ◽  
Discovery Studio ◽  
Mhc Ii ◽  
M1 Phenotype ◽  
Negative Controls

Objective: This study was aimed to evaluate the role of genistein or 4',5,7-trihydroxyisoflavone as a phytoestrogen in the treatment of estrogen deficiency-induced neuroinflammatory. The specific objectives of this study were to determine the anti-neuroinflammatory effect of genistein through measurement of MHC II and Arg1 expressions on microglia HMC3 cell line, as well as to prove that the effect occurs in an ER-dependent manner, through the measurement of free-ERβ expression. Methods: The cells were cultured in 24-well microplates, induced with 10 ng IFN-γ, and incubated for 24 h to activate the cell to M1 phenotype which has pro-inflammatory characteristics. Genistein with a concentration of 50 μM was added to the cells. The expression of MHC II, Arg1, and free-ERβ as markers was tested through an immunocytochemistry method and measured using the CLSM instrument. In silico approach was also conducted to determine the interaction between genistein and ERβ, compared to 17β-estradiol. Genistein structure was prepared with Avogadro 1.0.1, and molecular docking was done using PyRx 0.8 software. Biovia Discovery Studio Visualizer 2016 was used to visualize the structure of genistein against 3OLS protein. The physicochemical characteristics of genistein were analyzed using the SwissADME web tool. Results: Genistein can decrease MHC II expression and increase Arg1 expression in microglia HMC3 cells compared to negative controls (p<0.005), with expression value of 472.577±26.701 AU and 114.299±6.578 AU. But, genistein cannot decrease the free-ERβ expression in cells (p<0.005). The results of in silico analysis showed that genistein is an ERβ agonist. Conclusion: Genistein shows anti-neuroinflammatory effects by decreasing the MHC II expression and increasing Arg1 expression in the microglia HMC3 cell line. However, this effect does not occur through the binding of genistein to ERβ, but it is likely to occur through the binding of genistein with other types of ER.

scholarly journals Preclinical Techniques to Investigate Exercise Training in Vascular Pathophysiology

2021 ◽  
Author(s):  
Gurneet Singh Sangha ◽  
Craig J. Goergen ◽  
Sushant M. Ranadive ◽  
Steven J. Prior ◽  
Alisa M Clyne
Keyword(s):  
In Silico ◽  
Cardiovascular Health ◽  
Dependent Manner ◽  
Preclinical Research ◽  
High Intensity Training ◽  
In Silico Studies ◽  
Tissue Systems ◽  
Arterial Plaques

Atherosclerosis is a dynamic process starting with endothelial dysfunction and inflammation and eventually leading to life-threatening arterial plaques. Exercise generally improves endothelial function in a dose-dependent manner by altering hemodynamics, specifically by increased arterial pressure, pulsatility, and shear stress. However, athletes who regularly participate in high-intensity training can develop arterial plaques, suggesting alternative mechanisms through which excessive exercise promotes vascular disease. Understanding the mechanisms that drive atherosclerosis in sedentary versus exercise states may lead to novel rehabilitative methods aimed at improving exercise compliance and physical activity. Preclinical tools, including in vitro cell assays, in vivo animal models, and in silico computational methods, broaden our capabilities to study the mechanisms through which exercise impacts atherogenesis, from molecular maladaptation to vascular remodeling. Here, we describe how preclinical research tools have and can be used to study exercise effects on atherosclerosis. We then propose how advanced bioengineering techniques can be used to address gaps in our current understanding of vascular pathophysiology, including integrating in vitro, in vivo, and in silico studies across multiple tissue systems and size scales. Improving our understanding of the anti-atherogenic exercise effects will enable engaging, targeted, and individualized exercise recommendations to promote cardiovascular health rather than treating cardiovascular disease that results from a sedentary lifestyle.

scholarly journals Screening of Human CYP1A2 and CYP3A4 Inhibitors from Seaweed In Silico and In Vitro

Marine Drugs ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. 603
Author(s):  
Sung-Kun Yim ◽  
Kian Kim ◽  
SangHo Chun ◽  
TaeHawn Oh ◽  
WooHuk Jung ◽  
...  
Keyword(s):  
Phenolic Compounds ◽  
In Silico ◽  
Dependent Manner ◽  
Prosthetic Group ◽  
In Silico Modeling ◽  
Distal Surface ◽  
Ic50 Values ◽  
High Concentrations ◽  
Potential Inhibitors

Phenolic compounds and carotenoids are potential inhibitors of cytochrome P450s. Sixteen known compounds, phenolic compounds and carotenoids from seaweed were examined for potential inhibitory capacity against CYP1A2 and CYP3A4 in silico and in vitro. Morin, quercetin, and fucoxanthin inhibited the enzyme activity of CYP1A2 and CYP3A4 in a dose-dependent manner. The IC50 values of morin, quercetin, and fucoxanthin were 41.8, 22.5, and 30.3 μM for CYP1A2 and 86.6, 16.1, and 24.4 μM for CYP3A4, respectively. Siphonaxanthin and hesperidin did not show any significant effect on CYP1A2, but they slightly inhibited CYP3A4 activity at high concentrations. In silico modeling of CYP’s binding site revealed that the potential inhibitors bound in the cavity located above the distal surface of the heme prosthetic group through the 2a or 2f channel of CYPs. This study presents an approach for quickly predicting CYP inhibitory activity and shows the potential interactions of compounds and CYPs through in silico modeling.

scholarly journals Cnicin as an Anti-SARS-CoV-2: An Integrated In Silico and In Vitro Approach for the Rapid Identification of Potential COVID-19 Therapeutics

Antibiotics ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 542
Author(s):  
Hani A. Alhadrami ◽  
Ahmed M. Sayed ◽  
Hossam M. Hassan ◽  
Khayrya A. Youssif ◽  
Yasser Gaber ◽  
...  
Keyword(s):  
Natural Products ◽  
In Silico ◽  
Structural Information ◽  
Chemical Constituents ◽  
Rapid Identification ◽  
Dependent Manner ◽  
Modeling Tools ◽  
Clinical Experiments

Since the emergence of the SARS-CoV-2 pandemic in 2019, it has remained a significant global threat, especially with the newly evolved variants. Despite the presence of different COVID-19 vaccines, the discovery of proper antiviral therapeutics is an urgent necessity. Nature is considered as a historical trove for drug discovery, especially in global crises. During our efforts to discover potential anti-SARS CoV-2 natural therapeutics, screening our in-house natural products and plant crude extracts library led to the identification of C. benedictus extract as a promising candidate. To find out the main chemical constituents responsible for the extract’s antiviral activity, we utilized recently reported SARS CoV-2 structural information in comprehensive in silico investigations (e.g., ensemble docking and physics-based molecular modeling). As a result, we constructed protein–protein and protein–compound interaction networks that suggest cnicin as the most promising anti-SARS CoV-2 hit that might inhibit viral multi-targets. The subsequent in vitro validation confirmed that cnicin could impede the viral replication of SARS CoV-2 in a dose-dependent manner, with an IC50 value of 1.18 µg/mL. Furthermore, drug-like property calculations strongly recommended cnicin for further in vivo and clinical experiments. The present investigation highlighted natural products as crucial and readily available sources for developing antiviral therapeutics. Additionally, it revealed the key contributions of bioinformatics and computer-aided modeling tools in accelerating the discovery rate of potential therapeutics, particularly in emergency times like the current COVID-19 pandemic.

scholarly journals Antiproliferative Efficacy of Kaempferol on Cultured Daudi Cells: An In Silico and In Vitro Study

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Felisa Parmar ◽  
Chirag Patel ◽  
Hyacinth Highland ◽  
Himanshu Pandya ◽  
Linz-Buoy George
Keyword(s):  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
In Silico ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Binding Interaction ◽  
Daudi Cells ◽  
Lead Inhibitors ◽  
Cell Growth And Proliferation

There is always a constant need to develop alternative or synergistic anticancer drugs with minimal side effects. One important strategy to develop effective anticancer agents is to investigate potent derived compounds from natural sources. The present study was designed to determine antiproliferative activity of Kaempferol using in silico as well as in vitro study. Docking was performed using human GCN5 (hGCN5) protein involved with cell cycle, apoptosis, and glucose metabolism. Cell viability and cytotoxicity on Daudi cells were evaluated by trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays in a dose and time dependent manner, respectively. The compound inhibited the proliferation and growth of the Daudi cells, through induced cell death. The pure compound proved lead inhibitors of cell proliferation, thus manifesting significant antiproliferative activity. The docking results revealed that Kaempferol exhibited binding interaction to hGCN5 protein. Further, molecular dynamics using the dock pose of hGCN5-Kaempferol complex were performed to understand the basic structural unit which lead to inefficiency in binding and, therefore, pronounced instability and its possible consequences of reduced binding affinity. The data obtained in this study indicates that Kaempferol is a promising compound leading to inhibition of Daudi cell growth and proliferation.

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