In-silico Results Research Articles

Design, Synthesis, and Molecular Docking of Quinazolines Bearing Caffeoyl Moiety for Targeting of PGK1/PKM2/STAT3 Signaling Pathway in the Human Breast Cancer.

PGK1 and PKM2 are glycolytic enzymes, and their expression is upregulated in cancer cells. STAT3 is a transcription factor implicated in breast cancer progression and chemoresistance. Researchers worldwide continue to explore how targeting genes might lead to more effective anti-breast cancer therapies. The present study aims to synthesize quinazolines containing caffeoyl moiety for developing innovative anticancer agents against the human breast cancer cell line (MCF-7). A new quinazoline 2 was synthesized by reacting caffeic acid with 5-amino-phenylpyrazole carboxylate 1 in the presence of PCl3. Compound 2 reacted with NH2NH2.H2O to produce compound 3 through cyclo-condensation. Apoptosis and necrosis as well as inhibition activity compounds 2 and 3 against PGK1, and PKM2 were evaluated. The effect of compounds 2 and 3 on the levels of GSH, GR, SOD, GPx, CAT, MDA, Bax, Bcl-2, caspase-3, P53 and VEGF levels as well as PGK1, PKM2 and STAT3 gene expression were estimated in MCF-7 tumor cells. The viability of MCF-7 cells was reduced to 22.42% and 45.86% after incubation with compounds 2 and 3 for 48 hours, respectively. The IC50 values for compounds 2 and 3 are 62.05 μg/mL and 16.73 μg/mL. Furthermore, compound 3 exhibited more significant apoptosis and necrosis than compound 2. IC50 values of compound 2 against PGK1, and PKM2 at interval concentration equals 1.04, and 0.32 μM/mL, respectively, after 210 minutes of incubation. Moreover, compound 3 were revealed strong inhibition of PGK1, and PKM2 with IC50 values equals 0.55 and 0.21 μg/mL, respectively after 210 minutes of incubation. Our results proved that the incubation of compounds 2 and 3 with MCF-7 cells increased the levels of apoptotic proteins, elevated MDA, Bax, caspase-3 and P53 levels, depleted GSH, GR, SOD, GPx, CAT, Bcl-2 levels and downregulated the levels of STAT3, PGK1, and PKM2 gene expression significantly. Our In-silico results proved that compound 2 showed a stronger estimated binding affinity with a ΔG of -7.2, -7.5, and - 7.9 kcal/mol., respectively towards PGK1, PKM2 and STAT3 proteins. Also, compound 3 exhibits a strong binding affinity with ΔG of -7.9, -8.5, and - 8.7 kcal/mol., towards PGK1, PKM2 and STAT3 proteins. The results show that compounds 2 and 3 induce apoptotic activity by blocking the PGK1- PKM2-STAT3 signaling pathway. The present investigation opens exciting possibilities for developing innovative new anticancer quinazolines bearing caffeoyl moiety.

In-silico evaluation of the T-cell based immune response against SARS-CoV-2 omicron variants

During of COVID-19 pandemic, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has continuously evolved, resulting in the emergence of several new variants of concerns (VOCs) with numerous mutations. These VOCs dominate in various regions due to increased transmissibility and antibody evasion, potentially reducing vaccine effectiveness. Nonetheless, it remains uncertain whether the recent SARS-CoV-2 VOCs have the ability to circumvent the T cell immunity elicited by either COVID-19 vaccination or natural infection. To address this, we conducted in-silico analysis to examine the impact of VOC-specific mutations at the epitope level and T cell cross-reactivity with the ancestral SARS-CoV-2. According to the in-silico investigation, T cell responses triggered by immunization or prior infections still recognize the variants in spite of mutations. These variants are expected to either maintain their dominant epitope HLA patterns or bind with new HLAs, unlike the epitopes of the ancestral strain. Our findings indicate that a significant proportion of immuno-dominant CD8 + and CD4 + epitopes are conserved across all the variants, implying that existing vaccines might maintain efficacy against new variations. However, further in-vitro and in-vivo studies are needed to validate the in-silico results and fully elucidate immune sensitivities to VOCs.

Ligand modelling of Trachyspermum ammi phytocompounds for Aeromonas hydrophila cell wall synthesis enzyme in Labeo rohita

Aquaculture faces challenges from Aeromonas hydrophila, causing Motile Aeromonas Septicaemia, particularly affecting Labeo rohita (Rohu) in Pakistan. This study explores potential herbal antibacterials targeting A. hydrophila, molecular docking of Trachyspermum ammi (ajwain) phytocompounds against pathogen. The cell wall synthesis ligase, D-alanine–D-alanine ligase (PDB ID 6ll9) was processed in BIOVIA Discovery Studio and docked with 13 antibacterial phytocompounds found after QSAR analysis of T. ammi. Binding energies were calculated using PyRx to assess complex stability. ADME-TOX assessment for selected phytocompounds and parameterisation in CHARMM-GUI were performed. Docking the two best ligands with highest binding energies and ADME-TOX compliance, we found carvacrol and limonene formed most stable protein-ligand complexes, with raw and processed protein. Our findings suggest these herbal compounds can inhibit D-alanine–D-alanine ligase. These in-silico results support the potential of ‘ajwain’ in managing A. hydrophila, further in-vivo experiments are necessary to validate these inhibitory properties.

Optimizing the Extraction of Polyphenols from the Bark of Terminalia arjuna and an In-silico Investigation on its Activity in Colorectal Cancer.

The interconnection between different fields of research has gained interest due to its cutting-edge perspectives in solving scientific problems. Terminalia arjuna is indigenously used in India for curing several diseases, and its pharmacological activities are being revisited in recent drug-repurposing research. Efficient ultrasound-assisted extraction of phytochemicals from the bark of Terminalia arjuna is highlighted in this study. Following the optimization of the extraction process, the crude hydroethanolic extract is subjected to phytochemical profiling and an in-silico investigation of its anti-cancer properties. A three-level four-factor Box-Behnken design is exploited to optimize four operational parameters, namely extraction time, ultrasonic power, ethanol concentration (as the extracting solvent) and solute (in g): solvent (in mL) ratio. At the optimum parametric condition, the crude extract is obtained, and its GC-MS analysis is carried out. An analysis of network pharmacology (by constructing and visualizing biological networks using Cytoscape) combined with molecular docking reveals the potential antineoplastic targets of the crude extract. The ANOVA table exhibits the significance, adequacy and reliability of the proposed second-order polynomial model with the R² value of 0.917 and adjusted R² of 0.865. Experimental results portray the significant antioxidant potential of the prepared extract in its crude form. The GC-MS analysis of the crude extract predicts the extracted phytochemicals, while the constructed biological networks highlight its multi-targeted activity in colorectal cancer. The study identifies three phytochemicals viz. luteolin, β-sitosterol and arjunic acid as potent anti-cancer agents and can be extended with in-vitro and in-vivo experiments to validate the in-silico results, thus establishing lead phytochemicals in multi-targeted colorectal cancer therapies.

Multi-modal neuroprotection of Argemone mexicana L. against Alzheimer’s disease: In vitro and in silico study

Argemone mexicana L. is a medicinal plant, but its impact on Alzheimer's disease (AD) is right now undetermined. We intended to investigate the in-vitro anti-AD potential of leaves and flowers of A. mexicana methanol, ethanol, and ethyl extracts and to identify multi-modal anti-AD phytochemicals by computational approaches. Molecular docking of 196 phytochemicals identified three hit phytochemicals (protoberberine, protopine, and codeine) with higher binding affinity and multi-targeting ability toward AChE, BChE, BACE-1, and GSK-3β. Further MM-GBSA assays confirmed the integrity of these phytochemicals as the hit phytochemicals. However, these phytochemicals demonstrated favorable pharmacokinetics (PK) and drugable properties having no toxicity. Molecular dynamics simulations confirmed the binding strength of the hit phytoconstituents in the active pockets of AChE, BChE, BACE-1, and GSK-3β with multi-targeting inhibitory activities. All the extracts exhibited dose-dependent antioxidant and anti-cholinesterase activities supporting the insilico results in the context of oxidative stress and cholinergic pathways. Our results offer scientific validation of the anti-AD properties of Argemone mexicana L. and identified protoberberine, protopine, and codeine that could be used for the development of multi-modal inhibitors of AChE, BChE, BACE-1, and GSK-3β to combat AD. Additional in vivo validation is recommended to ensure a thorough assessment in the present research.

Computational Analysis and Experimental Data Exploring the Role of Hesperetin in Ameliorating ADHD and SIRT1/Nrf2/Keap1/OH-1 Signaling.

Attention deficit hyperactivity disorder (ADHD) manifests as poor attention, hyperactivity, as well as impulsive behaviors. Hesperetin (HSP) is a citrus flavanone with strong antioxidant and anti-inflammatory activities. The present study aimed to test hesperetin efficacy in alleviating experimental ADHD in mice and its influence on hippocampal neuron integrity and sirtuin 1 (SIRT1) signaling. An in silico study was performed to test the related proteins. Groups of mice were assigned as control, ADHD model, ADHD/HSP (25 mg/kg), and ADHD/HSP (50 mg/kg). ADHD was induced by feeding with monosodium glutamate (0.4 g/kg, for 8 weeks) and assessed by measuring the motor and attentive behaviors (open filed test, Y-maze test, and marble burying test), histopathological examination of the whole brain tissues, and estimation of inflammatory markers. The in-silico results indicated the putative effects of hesperetin on ADHD by allowing the integration and analysis of large-scale genomic, transcriptomic, and proteomic data. The in vivo results showed that ADHD model mice displayed motor hyperactivity and poor attention in the behavioral tasks and shrank neurons at various hippocampal regions. Further, there was a decline in the mRNA expression and protein levels for SIRT1, the erythroid 2-related factor-2 (Nrf2), kelch like ECH associated protein 1 (Keap1) and hemeoxygenase-1 (OH-1) proteins. Treatment with HSP normalized the motor and attentive behaviors, prevented hippocampal neuron shrinkage, and upregulated SIRT1/Nrf2/Keap1/OH-1 proteins. Taken together, HSP mainly acts by its antioxidant potential. However, therapeutic interventions with hesperetin or a hesperetin-rich diet can be suggested as a complementary treatment in ADHD patients but cannot be suggested as an ADHD treatment per se as it is a heterogeneous and complex disease.

Resolution limits for radiation-induced acoustic imaging for in vivo radiation dosimetry

Objective. Radiation-induced acoustic (RA) computed tomographic (RACT) imaging is being thoroughly explored for radiation dosimetry. It is essential to understand how key machine parameters like beam pulse, size, and energy deposition affect image quality in RACT. We investigate the intricate interplay of these parameters and how these factors influence dose map resolution in RACT. Approach. We first conduct an analytical assessment of time-domain RA signals and their corresponding frequency spectra for certain testcases, and computationally validate these analyses. Subsequently, we simulated a series of x-ray-based RACT (XACT) experiments and compared the simulations with experimental measurements. In-silico reconstruction studies have also been conducted to demonstrate the resolution limits imposed by the temporal pulse profiles on RACT. XACT experiments were performed using clinical machines and the reconstructions were analyzed for resolution capabilities. Main results. Our paper establishes the theory for predicting the time- and frequency-domain behavior of RA signals. We illustrate that the frequency content of RA signal is not solely dependent on the spatial energy deposition characteristics but also on the temporal features of radiation. The same spatial energy deposition through a Gaussian pulse and a rectangular pulse of equal pulsewidths results in different frequency spectra of the RA signals. RA signals corresponding to the rectangular pulse exhibit more high-frequency content than their Gaussian pulse counterparts and hence provide better resolution in the reconstructions. XACT experiments with ∼3.2 us and ∼4 us rectangular radiation pulses were performed, and the reconstruction results were found to correlate well with the in-silico results. Significance. Here, we discuss the inherent resolution limits for RACT-based radiation dosimetric systems. While our study is relevant to the broader community engaged in research on photoacoustics, x-ray-acoustics, and proto/ionoacoustics, it holds particular significance for medical physics researchers aiming to set up RACT for dosimetry and radiography using clinical radiation machines.

A structural and biochemical approach to effect of temperature and pH on the Molten Globule phenomenon in a thermophilic protease: Molecular dynamics simulation, fluorescence spectroscopy and circular dichroism

Proteins in the molten globule (MG) stage have a reasonably stable secondary structure content, but changes in side-chain packing cause a noticeable decrease in the number of tertiary structures. Here, we investigated serine protease as a suitable model to study the folding route and characteristics of a protein in the MG state. Upon induction with IPTG, the protein exhibited a molecular weight of 42 kDa and achieved a final concentration of 1.7 mg/mL after the concentration process. Serine protease's intrinsic and extrinsic fluorescence was examined in the pH range of 1–12 using fluorescence spectroscopy with maximum intrinsic fluorescence in 335 nm and a blue shift in 510 nm for extrinsic fluorescence. It was suggested that the protein transitions probably to an MG state at pH 3. Evidences showed that serine protease's secondary structure using far-UV circular dichroism (CD) showed a little shift in the MG state intermediate, pH 3, relative to the original state, pH 8, which is typical for MG. Maximum decreases was observed in 228 to 300 nm for UV-near CD. Also revealed a notable alteration in the pH 3 of the enzyme compared to pH 8, which is the pH at which the protein takes on its natural structure. By using acrylamide to quench the fluorescence, the Stern-Volmer constant (KSV) was determined at pH values of 8 and 3, yielding values of 20 and 14 M−1, respectively. This is likely correlated with an increase in the enzyme's molecular volume in the MG state. Molecular dynamics (MD) simulation showed that although the thermal stability of this enzyme at 90° was confirmed in the Root-Mean-Square-Deviation (RMSD), Root-Mean-Square-Fluctuation (RMSF), Radius of gyration (Rg) as well as Solvent-Accessible-Surface-Area (SASA) graphs, but pH 3 may significantly disturb the tertiary structure and secondary structure. These in-silico results may also be analyzed in line with the occurrence of MG at pH 3.

Magnesium enhances aurintricarboxylic acid’s inhibitory action on the plasma membrane Ca2+-ATPase

Our research aimed to elucidate the mechanism by which aurintricarboxylic acid (ATA) inhibits plasma membrane Ca2+-ATPase (PMCA), a crucial enzyme responsible for calcium transport. Given the pivotal role of PMCA in cellular calcium homeostasis, understanding how it is inhibited by ATA holds significant implications for potentially regulating physiopathological cellular processes in which this pump is involved. Our experimental findings revealed that ATA employs multiple modes of action to inhibit PMCA activity, which are influenced by ATP but also by the presence of calcium and magnesium ions. Specifically, magnesium appears to enhance this inhibitory effect. Our experimental and in-silico results suggest that, unlike those reported in other proteins, ATA complexed with magnesium (ATA·Mg) is the molecule that inhibits PMCA. In summary, our study presents a novel perspective and establishes a solid foundation for future research efforts aimed at the development of new pharmacological molecules both for PMCA and other proteins.

Enantioselective synthesis, characterization, molecular docking simulation and ADMET profiling of α-alkylated carbonyl compounds as antimicrobial agents

All living organisms produce only one enantiomer, so we found that all natural compounds are presented in enantiomerically pure form. Asymmetric synthesis is highly spread in medicinal chemistry because enantiomerically pure drugs are highly applicable. This study initially demonstrated the feasibility of a good idea for the asymmetric synthesis of α-alkylated carbonyl compounds with high enantiomeric purity ranging from 91 to 94% using different quinazolinone derivatives. The structure of all compounds was confirmed via elemental analysis and different spectroscopic data and the enantioselectivity was determined via HPLC using silica gel column. The synthesized compounds’ mode of action was investigated using molecular docking against the outer membrane protein A (OMPA) and exo-1,3-beta-glucanase, with interpreting their pharmacokinetics aspects. The results of the antimicrobial effectiveness of these compounds revealed that compound 6a has a broad biocidal activity and this in-vitro study was in line with the in-silico results. Overall, the formulated compound 6a can be employed as antimicrobial agent without any toxicity with high bioavailability in medical applications.

Antiproliferative and antimicrobial compounds from Streptomyces levis: supported by in vitro and in silico molecular docking approach

The present work describes the investigation of secondary metabolites produced by rhizospheric soil isolate Streptomyces levis with respect to partial purification, bioactivity, structural elucidation, and docking study. MIC (Minimum Inhibitory Concentration) of the fraction was found to be 16 µg/mL, 32 µg/mL, and 8 µg/mL against S. aureus, E. coli, and C. albicans respectively. The fraction exhibited an IC50 of 90.48 μg/mL and 59.10 µg/mL against L929 and HeLa cell lines respectively. Spectroscopic analysis showed abundant of Isofucosterol 3-O-[6-O-(9-Octadecanoyl)-b-D-glucopyranoside], and Viniferal. These compounds were docked against receptor molecules E6, E7, Caspase-3, and Bcl2. The in-silico results suggested that all the secondary metabolites showed higher docking scores than the standard compound 5-Fluorouracil. Molecular docking study and published literature suggested that Isofucosterol 3-O-[6-O-(9-Octadecanoyl)-b-D-glucopyranoside] inactivated viral oncoprotein E7 and arrested the cell cycle from entering in S phase. Viniferal induced apoptosis by inactivation of Bcl2.

Targeting TNF-α-induced expression of TTR and RAGE in rheumatoid arthritis: Apigenin's mediated therapeutic approach

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease induced by TNF-α, which increases fibroblast-like synoviocytes inflammation, resulting in cartilage destruction. The current work sought to comprehend the pathophysiological importance of TNF-α stimulation on differential protein expression and their regulation by apigenin using in-vitro and in-vivo models of RA. MethodsThe human RA synovial fibroblast cells were stimulated with or without TNF-α (10 ng/ml) and treated with 40 μM apigenin. In-silico, in-vitro and in-vivo studies were performed to confirm the pathophysiological significance of apigenin on pro-inflammatory cytokines and on differential expression of TTR and RAGE proteins. ResultsTNF-α induced inflammatory response in synoviocytes revealed higher levels of IL-6, IL-1β, and TNF-α cytokines and upregulated differential expression of TTR and RAGE. In-silico results demonstrated that apigenin has a binding affinity towards TNF-α, indicating its potential effect in the inflammatory process. Both in-vitro and in-vivo results obtained by Western Blot analysis suggested that apigenin reduced the level of p65 (p = 0.005), TTR (p = 0.002), and RAGE (p = 0.020). ConclusionThe findings of this study suggested that TNF-α promotes the differential expression of pro-inflammatory cytokines, TTR, and RAGE via NF-kB pathways activation. Anti-inflammatory effect of apigenin impedes TNF-α mediated dysregulation or expression associated with RA pathogenesis.

Covalent organic framework aerogel for high-performance solid-phase extraction of tetracycline antibiotics: Experiment and simulated calculation on adsorption behavior

Three-dimensional sponge-architecture covalent organic frameworks (COFs)-aerogel was successfully designed and synthesized via a freeze-drying template approach, and utilized as an efficient sorbent in solid-phase extraction (SPE). A method for selective enrichment of pharmaceutical contaminants including tetracycline, chlortetracycline, methacycline and oxytetracycline in the environment and food samples was proposed by combining with high performance liquid chromatography (HPLC). To understand the adsorption mechanism, selectivity test and molecular dynamics (MD) simulated calculation were both carried out. The experimental and in-silico results demonstrated that the COFs-aerogel possessed high selectivity for contaminants with H bond acceptors/donors and good efficiency with maximum adsorption capacity up to 294.1 mg/g. The SPE-based HPLC method worked well in the range of 8–1000 ng/mL, with the need of little dose of adsorbent and sample volume while no need of spectrometer, outgoing the reported adsorbents. Under the optimized conditions, the intra-day and inter-day relative standard deviations (RSD) of repeatability were within 2.78–6.29 % and 2.44–8.42 % (n = 5). The results meet the current detection requirement for practical applications, and could be extended for further design of promising adsorbents.

Identification of potential DPP-4 inhibitors from Bryophyllum pinnatum by in-silico analysis

Background: An estimated 463 million people already live with diabetes and that figure is set to rise to over 700 million by 2045, as per the International Diabetes Federation (IDF). The current form of treatment for Type-2 DM can be done with sulfonylureas, meglitinides, metformin, thiazolidinediones, incretin mimetics: Glucagon-like peptide 1 (GLP-1), Glucose-dependent insulinotropic polypeptide (GIP), and amylin analogues (Pramlintide). Bryophyllum pinnatum (Lam.) Oken (B. pinnatum) belongs to the plant family crassulaceae used in traditional medicine in Asia. GLP-1 and Glucose-dependant Insulinotropic Polypeptide (GIP), both play a similar role in stimulating insulin secretion and are inactivated by dipeptidyl peptidase-4 (serine protease dipeptidyl peptidase-4) enzymes. Aims: To identify the potential anti-diabetic active compounds of Bryophyllum pinnatum against DPP-4 enzyme using in-silico methods. Methods and Material: The phytochemicals associated with Bryophyllum pinnatum were retrieved from ChEBI and canonical SMILES retrieved, followed by searching for its molecular properties and druglikeness using MolSoft LLC, toxicity test using ADVERPred, Swiss Target Prediction for predicting the DPP-4 inhibitors, molecular docking using Schrodinger software suite. Results: The in-silico study identified two phytochemicals from fourteen that have been predicted for DPP-4 inhibition potential against Type-2 DM. In CH2CL2 and CH3OH solvent compounds 3,5-dihydroxybenzoic acid (-5.623 kcal/mol) and 3,4-didehydro-N4-deethylbrinzolamide (-4.91 kcal/mol) displayed the highest docking scores against human DPP-4 (5Y7K). Conclusions: The above-mentioned compounds revealed no side effects. The in-silico results strongly favour the beneficial use of phytochemicals from Bryophyllum pinnatum as a probable herb that can be used for adjuvant therapy. Further in-vitro and in-vivo tests are needed for confirmation.

Structural design optimization through finite element analysis of additive manufactured bioresorbable polymeric stents

Coronary stents help to treat coronary artery disease. Polymeric-based stents are considered the next generation of these medical devices since the materials are more compatible with human cells. Developing a polymeric bioresorbable stent with a different and optimized design can improve the mechanical performance of polymeric additively manufactured coronary stents. In this study, two different polymers were processed by additive manufacturing, and their mechanical properties were analyzed: poly(lactic acid) (PLA) and poly(ε-caprolactone) (PCL). Five different designs (A, B, C, D, and E) were then conceptualized with three different thicknesses. Finite element analysis (FEA) of a stent implantation process, using the mechanical properties of the additively manufactured materials, was used to evaluate the influence of the design, after the stent expansion, on the radial recoil ratio (RRR) and foreshortening. The in-silico results demonstrated that reducing strut thickness originates more plastic deformation, which reduces the RRR and increases the absolute value of foreshortening. PLA-based stents presented less RRR but, simultaneously, more risk of fracture. In the case of PCL-based devices, only designs A, B, and C presented acceptable recoil ratios. Design A is the chosen design as it reduces the RRR for lower thicknesses without risk of fracture during the stent deployment.

Flavipin from fungi as a potential inhibitor of rheumatoid arthritis signaling molecules.

Flavipin, a fungal lower molecular weight biomolecule (MW 196.16 g/mol), has not been yet extensively studied for beneficial preclinical and clinical applications. In recent years, various preclinical mouse models including adjuvant-induced arthritis (AIA) were employed to understand mechanisms associated with Rheumatoid arthritis (RA) and to develop new therapeutic drugs. In the current study, we studied the inhibitory effect of Flavipin on major signaling molecules involved in the inflammatory response during RA using both in-silico virtual interaction and in vivo mouse model of AIA. Our in-silico results clarified that Flavipin interacts with the tumor necrosis factor alpha (TNF-α) through conventional hydrogen binding (H-H) at one of TNF-α critical amino acids tyrosine residues, Tyr119, with binding energy (b.e.) -5.9. In addition, Flavipin binds to ATP-binging sites of the Jesus kinases, JAK1, JAK2 and JAK3, through H-H (b. e. between -5.8 and -6.1) and then it may inhibit JAKs, regulators of RA signaling molecules. Moreover, our molecular dynamics stimulation for the docked TNF-α/Flavipin complex confirmed the specificity and the stability of the interaction. In vitro, Flavipin is not toxic to normal cells at doses below 50 µM (its IC50 in normalfibroblast cell linewas above 100 µM). However, in vivo, the arthritis score and hind paw oedema parameters were modulated in Flavipin treated mice. Consistent with the in-silico results the levels of the TNF-α, the nuclear transcription factor kappaB (NF-κB) and the signal transduction and activator of transcription (STAT3, downstream of JAKs) were modulated at joint tissues of the hind-paw of Flavipin/AIA treatedmice. Our data suggest Flavipin as a potential therapeutic agent for arthritis can inhibit RA major signaling molecules.

Investigation of the effects of Terminalia chebula seed hydroalcoholic extract on Paraoxonase1 enzyme activity in rats

Background and aims: Paraoxonase 1 (PON1) is related to high-density lipoprotein (HDL) in serum and protects against low-density lipoprotein (LDL) oxidation. This study aimed to investigate the effects of Terminalia chebula on PON1 in hyperlipidemic rats and the molecular docking effects of some compounds of this medical plant on PON1 activity. Methods: Overall, 40 male rats (200–250 gr) were randomly divided into four groups, including the control group, the hyperlipid group, the hyperlipid group receiving 400 mg/kg of the hydroalcoholic extract of T. chebula seeds, and the hyperlipid group receiving 800 mg/kg of the hydroalcoholic extract of T. chebula seeds. The PON1 arylesterase activity in serum and the PON1 gene expression in the liver tissue underwent investigation. Then, the molecular docking effects of its compounds were studied on PON1 through in-silico studies using the AutoDock software (version 4.2.0). Results: T. chebula decreased (P<0.001) the serum triglycerides from 105.88±10.15 mg/dL in the hyperlipidemic group to 66.88±14.90 and 74.25±9.51 mg/dL in hyperlipidemic groups receiving 400 and 800 mg/kg of the hydroalcoholic extract of T. chebula seeds, respectively. In addition, the PON1 serum aryl esterase activity increased from 202.12±6058 in hyperlipidemic rats to 224.34±58.74 (P=0.83) and 235.80±37.05 (P=0.6) in hyperlipidemic groups receiving 400 mg/kg and 800 mg/kg of the hydroalcoholic extract of T. chebula seeds, respectively. It also demonstrated a significant effect on PON1 gene expression (P<0.001). In addition, the in-silico and docking results revealed that the main antioxidant compounds of T. chebula, such as catechin, kaempferol, and quercetin, could bind to the PON1 enzyme directly and influence the enzyme activity. Conclusion: T. chebula increased PON1 activity and PON1 gene expression. However, among the plant’s compounds, catechin, kaempferol, and quercetin played the most substantial role in the PON1 activity. It seems that these compounds can be useful as co-treatments in hyperlipidemia therapies.

EGFR Kinase Inhibiting Amino-enones for Breast Cancer; CADD Approach.

The Computer-Aided Drug Discovery (CADD) approach was used to develop a few Epidermal Growth Factor Receptor (EGFR) kinase inhibitors. EGFR kinase expression is highly associated with genomic instability, higher proliferation, lower hormone receptor levels, and HER2 over-expression. It is more common in breast cancer. Thus, EGFR Kinase is one of the main targets in discovering new cancer medicine. To computationally validate some amides substituted β-amino enones as EGFR inhibitors and to carry out associated in vitro anticancer agents. We used tools such as molecular docking, MD simulations, DFT calculations, and ADMET predictions in silico to establish a preliminary SAR. In vitro, we used BT474 (ER+HER2+) and MCF-7 (ER-HER2) cell lines along with normal breast cell epithelial cells (MFC-10a) for anticancer studies and EGFR kinase inhibition assay studies. As the Reactive Oxygen Species (ROS) plays the main role in cancer development, we also analyzed the antioxidant potentials of these compounds. Among the family of eleven amides substituted (Z)-β-amino enones (5a-k), compounds 5b, 5c, 5g, and 5h showed valuable in silico and in vitro bio-activity. Remarkably, the in-silico results almost coincided with in vitro study results. We recommend compounds 5b, 5c, 5g, and 5h for pre-clinical and clinical evaluation to establish them as future cancer therapeutics.

Genotoxic effects and mitosis aberrations of chromium (VI) on root cells of Vicia faba and its molecular docking analysis

Like other heavy metals, Cr (VI) is a powerful carcinogen and mutagen agent. Its toxic effects on plants are well considered. In order to elucidate its adverse effects, the present work aims to study the mitosis aberrations of Cr (VI) on the Vicia faba root-cells and its molecular docking analysis to understand the genotoxicity mechanisms. In-vivo, Vicia faba plants were exposed to 50 and 100 μM Cr (VI) for 48 h. In-silico, molecular docking and molecular dynamics simulation were used to study the interactions between dichromate and tubulin tyrosine ligase T2R-TTL (PDBID: 5XIW) with reference to Colchicine (microtubule inhibitor). According to our results, Cr (VI) affects growth and cell division and also induces many mitosis aberrations such as chromosome sticking, anaphase/telophase bridges, lagging chromosomes and fragmentation during all phases of mitosis. On the one hand, Cr (VI) reduces mitotic index and promotes micronuclei induction. The in-silico results showed that dichromate establishes very strong bonds at the binding site of the tubulin tyrosine ligase T2R-TTL, with a binding affinity of −5.17 Kcal/Mol and an inhibition constant of 163.59 μM. These interactions are similar to those of colchicine with this protein, so dichromate could be a very potent inhibitor of this protein's activity. TTL plays a fundamental role in the tyrosination/detyrosination of tubulin, which is crucial to the regulation of the microtubule cytoskeleton. Its inhibition leads to the appearance of many morphogenic abnormalities such as mitosis aberrations. In conclusion, our data confirm the highest genotoxicity effects of Cr (VI) on Vicia faba root-cells.

Double closed-loop feedback control strategy for enhanced external counterpulsation to regulate hemodynamic response of human common carotid artery

Enhanced external counterpulsation (EECP) is a mechanical therapy for the clinical management of ischemic cardio-cerebrovascular diseases. Applying different EECP modes to different patients would be based on the experience of physicians. Existing hemodynamic models could describe the quantitative relationship between different EECP modes and hemodynamic parameters of specific parts of human blood circulatory system. However, currently there is no closed-loop control system available for precisely, personally, and intelligently performing the EECP. Therefore, to significantly improve the clinical benefits of rehabilitation treatment of ischemic cardio-cerebrovascular diseases with the EECP, this study developed a double closed-loop physiological control algorithm for the EECP device. Firstly, a detailed lumped parameter model describing the hemodynamics of human blood circulatory system was updated based on the available models; then the EECP device was coupled to it and the updated model was tested with the clinical data; finally, a double closed-loop feedback control strategy for precise regulation of the carotid hemodynamic response by the EECP was proposed. The control objectives were to maintain the mean arterial pressure and EECP pressure amplitude of patients with two gain-scheduled proportional-integral (PI) controllers. In-silico results showed that the clinical data can prove the accuracy of the updated model, and the appropriate EECP pressure amplitude could provide patients with the best benefits. The proposed control system could generate satisfied hemodynamic effects even with noise, demonstrating its feasibility and robustness. It is also easy to apply with high accuracy, and may be the effective solutions for developing intelligent and personalized EECP devices.