Assessment of carcinogenic and non-carcinogenic risk of exposure to potentially toxic elements in tea infusions: Determination by ICP-OES and multivariate statistical data analysis.

BACKGROUND: The perennial evergreen tea (Camellia sinensis) plant is one of the most popular nonalcoholic drinks in the world. Fertilizers and industrial, agricultural, and municipal activities are the usual drivers of soil contamination, contaminating tea plants with potentially toxic elements (PTEs). These elements might potentially accumulate to larger amounts in the leaves of plants after being taken up from the soil. Thus, frequent monitoring of these elements is critically important. METHODS: The present study intended to determine PTEs (Al, Cr, Mn, Fe, Co, Ni, Cu, Zn, Cd, and Pb) in both tea leaves and infusions using ICP-OES. Various multivariate data analysis methods such as principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to elucidate the potential sources of PTEs contamination, whether from anthropogenic activities or natural origins. Additionally, Pearson's correlation coefficient (PCC) was calculated to assess the relationships between the variables under study. RESULTS: The mean contents (mg/L) of all studied elements in tea infusions decreased in order Mn (150.59 ±â€¯1.66) > Fe (11.39 ±â€¯0.99) > Zn (6.62 ±â€¯0.89) > Cu (5.86 ±â€¯0.62) > Co (3.25 ±â€¯0.64) > Ni (1.69 ±â€¯0.23) > Pb (1.08 ±â€¯0.16) > Cr (0.57 ±â€¯0.09) > Cd (0.46 ±â€¯0.09) > Al (0.05 ±â€¯0.008), indicating that Mn exhibits the highest abundance. The mean concentration trend in tea leaf samples mirrored that of infusions, albeit with higher concentrations of PTEs in the former. The tolerable dietary intake (TDI) value for Ni and provisional tolerable monthly intake (PTMI) value for Cd surpassed the standards set by the WHO and EFSA. Calculated hazard index (HI < 1) and cumulative cancer risk (CCR) values suggest negligible exposure risk. CONCLUSION: Elevated levels of PTEs in commonly consumed tea products concern the public and regulatory agencies.

Unveiling the Role of PAR 1: A Crucial Link with Inflammation in Diabetic Subjects with COVID-19.

Inflammation is a distinguished clinical manifestation of COVID-19 and type 2 diabetes mellitus (T2DM), often associated with inflammatory dysfunctions, insulin resistance, metabolic dysregulation, and other complications. The present study aims to test the hypothesis that serum concentrations of PAR-1 levels differ between COVID-19 diabetic patients (T2DM) and non-diabetic COVID-19 patients and determine their association with different biochemical parameters and inflammatory biomarkers. T2DM patients with COVID-19 (n = 50) with glycated hemoglobin (HbA1c) levels of (9.23 ± 1.66) and non-diabetic COVID-19 patients (n = 50) with HbA1c levels (4.39 ± 0.57) were recruited in this study. The serum PAR-1 levels (ELISA method) were determined in both groups and correlated with parameters such as age, BMI, inflammatory markers including CRP, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), D-dimer, homocysteine, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Demographic variables such as BMI (29.21 ± 3.52 vs. controls 21.30 ± 2.11) and HbA1c (9.23 ± 1.66 vs. controls 4.39 ± 0.57) were found to be statistically elevated in COVID-19 T2DM patients compared to non-diabetic COVID-19 patients. The concentrations of several inflammatory biomarkers and PAR-1 were remarkably increased in the COVID-19 T2DM group when compared with the non-diabetic COVID-19 group. The univariate analysis revealed that increased serum PAR-1 estimations were positively correlated with enhanced HbA1c, BMI, inflammatory cytokines, D-dimer, homocysteine, and NT-proBNP. The findings in the current study suggest that increased levels of serum PAR-1 in the bloodstream could potentially serve as an independent biomarker of inflammation in COVID-19 patients with T2DM.

Exploring Cassia mimosoïdes as a promising natural source of steroids with potent anti-cancer, urease inhibition, and antimicrobial properties.

The genus Cassia is a rich source of physiologically active secondary metabolites, including a novel compound named 21-methylene-24-ethylidene lophenol, alongside 15 known compounds. These compounds were characterized using different spectroscopic techniques. They exhibited promising antimicrobial activity, particularly against bacteria causing gastrointestinal infections. Compound 1 showed strong anti-bacterial activity against H. pylori and S. aur with MIC values of 0.28 and 0.12 µg mL-1 respectively. The study investigated their impact on H. pylori, a contributor to ulcer development, by inhibiting the urease enzyme. Inhibiting urease can reduce H. pylori's pathogenic potential, evident from the fact that the compounds evaluated toward urease enzyme showed higher inhibitory activity (1.024 ± 0.43 6.678±0.11 µM) compared to standard thiourea (IC50 = 18.61 ± 0.11 µM). Molecular docking studies confirmed their inhibitory action, with compound 7 notably outperforming thiourea in inhibiting urease (-6.95 kcal mol-1vs. -3.13 kcal mol-1). Additionally, these compounds showed positive effects on liver functioning, which H. pylori can impair. Compound 9 shows the best response against human HepG2 liver cancer cell lines i.e., % viability is 14.47% ± 0.69 and IC50 is 7.8 µM ± 0.21. These compounds hold potential as lead compounds for addressing gastrointestinal and liver disorders caused by H. pylori.

Computational Exploration of Fluorocyclopentenyl-purines and-pyrimidines Derivatives as Potential Inhibitors of Epidermal Growth Factor Receptor (EGFR) for the Treatment of Breast Cancer.

The Epidermal Growth Factor Receptor (EGFR) is an important therapeutic target for the treatment of a variety of epithelial malignancies, including breast cancer, in which EGFR is aberrantly expressed.The fluorocyclopentenyl-purine-pyrimidines derivatives, which have previously been described as powerful compounds against breast cancer, were selected to investigate their potential against EGFR using computational tools in an effort to obtain potent inhibitors with fewer adverse effects. The molecule's chemical reactivity and stability were assessed by determining the HOMO-LUMO energy gap using density functional theory (DFT) calculations. Among all the selected compounds, PU4 displayed a HOMO-LUMO gap of 0.191 eV. Additionally, molecular docking analysis was performed to assess the binding affinities of PU4 within the active pocket of EGFR-TK. The compound PU4 showed potent interactions with EGFR exhibiting -32.3 kJ/mol binding energy which was found best as compared to gefitinib i. e., -27.4 kJ/mol which was further validated by molecular dynamics simulations and ADMET analysis. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective EGFR inhibitor. Therefore, it is recommended to further investigate the inhibitory potential of these identified compounds using in vitro and in vivo approaches.

Exposure Assessment of Essential and Potentially Toxic Metals in Wheat-Based Sweets for Human Consumption: Multivariate Analysis and Risk Evaluation Studies.

In recent years, there has been a growing concern about the negative impact of unforeseen contaminants such as metals in commonly consumed food items, which pose a threat to human well-being. Therefore, it is of utmost importance to evaluate the levels of these contaminants to guarantee the safe consumption of these food items. The goal of the current research is to determine the levels of essential (EMs: Mg, Ca, Mn, Fe, Co, Cu, and Zn) and potentially toxic metals (PTMs: Al, Cr, Ni, As, Cd, and Pb) in various brands of wheat-based sweets. One hundred samples were collected and analysed via flame atomic absorption spectrometry (FAAS) and inductively coupled plasma-optical emission spectrometry (ICP-OES). Also, the current study was to investigate the distribution, correlation, and multivariate analysis of 13 metals (Mg, Ca, Mn, Fe, Co, Cu, Zn, Al, Cr, Ni, As, Cd, and Pb). Hierarchical cluster analysis (HCA) and principal component analysis (PCA) were used to interpret the metals' association. The concentration (mg/kg) ranges of EMs were, in order, Mg (12.70-65.67), Ca (24.02-209.12), Mn (1.32-9.61), Fe (4.55-111.23), Co (0.32-8.94), Cu (2.12-8.61), and Zn (2.60-19.36), while the concentration (mg/kg) ranges of PTMs were, in order, Al (0.32-0.87), Cr (0.17-5.74), Ni (0.36-1.54), Cd (0.16-0.56), and Pb (0.14-0.92), and As was not detected in any sample under investigation. The HCA data revealed that Co, Al, and Ni form clusters with other metals. Sweets are prepared at high temperatures, and the elevated temperatures can increase the likelihood of Ni and Al leaching from stainless steel. Tolerable dietary intake (TDI) values for Ni were higher than the values established by the European Food Safety Authority (EFSA). The CR value found for the Ni and Cr was at the threshold level of cancer risk, if an amount of 25 g were to be used over a lifetime. In a nutshell, this study highlights the monitoring of EM and PTM levels in wheat-based sweets, and from a food safety perspective, the study is important for consumers of wheat-based sweets.

In Silico and In Vitro Exploration of Poziotinib and Olmutinib Synergy in Lung Cancer: Role of hsa-miR-7-5p in Regulating Apoptotic Pathway Marker Genes.

Background and objectives: Non-small cell lung cancer (NSCLC) is often caused by EGFR mutations, leading to overactive cell growth pathways. Drug resistance is a significant challenge in lung cancer treatment, affecting therapy effectiveness and patient survival. However, combining drugs in research shows promise in addressing or delaying resistance, offering a more effective approach to cancer treatment. In this study, we investigated the potential alterations in the apoptotic pathway in A549 cells induced by a combined targeted therapy using tyrosine kinase inhibitors (TKIs) olmutinib and poziotinib, focusing on cell proliferation, differential gene expression, and in silico analysis of apoptotic markers. Methods: A combined targeted therapy involving olmutinib and poziotinib was investigated for its impact on the apoptotic pathway in A549 cells. Cell proliferation, quantitative differential gene expression, and in silico analysis of apoptotic markers were examined. A549 cells were treated with varying concentrations (1, 2.5, and 5 µM) of poziotinib, olmutinib, and their combination. Results: Treatment with poziotinib, olmutinib, and their combination significantly reduced cell proliferation, with the most pronounced effect at 2.5 µM (p < 0.005). A synergistic antiproliferative effect was observed with the combination of poziotinib and olmutinib (p < 0.0005). Quantitative differential gene expression showed synergistic action of the drug combination, impacting key apoptotic genes including STK-11, Bcl-2, Bax, and the Bax/Bcl-2 ratio. In silico analysis revealed direct interactions between EGFR and ERBB2 genes, accounting for 77.64% of their interactions, and 8% co-expression with downstream apoptotic genes. Molecular docking indicated strong binding of poziotinib and olmutinib to extrinsic and intrinsic apoptotic pathway markers, with binding energies of -9.4 kcal/mol and -8.5 kcal/mol, respectively, on interacting with STK-11. Conclusions: Combining poziotinib and olmutinib therapies may significantly improve drug tolerance and conquer drug resistance more effectively than using them individually in lung cancer patients, as suggested by this study's mechanisms.

Bioactivity-Guided Synthesis: In Silico and In Vitro Studies of ß-Glucosidase Inhibitors to Cope with Hepatic Cytotoxicity.

The major cause of hyperglycemia can generally be attributed to ß-glucosidase as per its involvement in non-alcoholic fatty liver disease. This clinical condition leads to liver carcinoma (HepG2 cancer). The phthalimides and phthalamic acid classes possess inhibitory potential against glucosidase, forming the basis for designing new phthalimide and phthalamic acid analogs to test their ability as potent inhibitors of ß-glucosidase. The study also covers in silico (molecular docking and MD simulations) and in vitro (ß-glucosidase and HepG2 cancer cell line assays) analyses. The phthalimide and phthalamic acid derivatives were synthesized, followed by spectroscopic characterization. The mechanistic complexities associated with ß-glucosidase inhibition were identified via the docking of the synthesized compounds inside the active site of the protein, and the results were analyzed in terms of the best binding energy and appropriate docking pose. The top-ranked compounds were subjected to extensive MD simulation studies to understand the mode of interaction of the synthesized compounds and binding energies, as well as the contribution of individual residues towards binding affinities. Lower RMSD/RMSF values were observed for 2c and 3c, respectively, in the active site, confirming more stabilized, ligand-bound complexes when compared to the free state. An anisotropic network model was used to unravel the role of loop fluctuation in the context of ligand binding and the dynamics that are distinct to the bound and free states, supported by a 3D surface plot. An in vitro study revealed that 1c (IC50 = 1.26 µM) is far better than standard acarbose (2.15 µM), confirming the potential of this compound against the target protein. Given the appreciable potential of the candidate compounds against ß-glucosidase, the synthesized compounds were further tested for their cytotoxic activity against hepatic carcinoma on HepG2 cancer cell lines. The cytotoxicity profile of the synthesized compounds was performed against HepG2 cancer cell lines. The resultant IC50 value (0.048 µM) for 3c is better than the standard (thalidomide: IC50 0.053 µM). The results promise the hypothesis that the synthesized compounds might become potential drug candidates, given the fact that the ß-glucosidase inhibition of 1c is 40% better than the standard, whereas compound 3c holds more anti-tumor activity (greater than 9%) against the HepG2 cell line than the known drug.

Computational and theoretical chemistry of newly synthesized and characterized 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-acetamides.

Energetic heterocycles, including pyridines, triazoles, and tetrazoles, exhibit greater density, heats of formation, and oxygen balance compared to their carbocyclic counterparts, making them a promising approach for synthesizing novel bis-tetrazole acetamides. Synthesized compounds A-F, some of which feature a chlorine atom attached to the phenyl ring, serve as valuable synthons for aryl coupling reactions. Analysis via 1H-NMR and 13C-NMR spectroscopy, as well as density functional considerations through B3LYP functional correlation with 6-311 + + G(d) and 6-31G(d) basis set, revealed the observed LUMO/HOMO energies and charge transfer within the molecule. Additionally, the dipole moment, chemical hardness, softness, ionization potential, local reactivity potential via Fukui indices and thermodynamic properties (entropy, enthalpy, and Gibbs free energy) of the molecule were calculated through density functional theory studies. In addition, Molecular Docking studies were conducted to investigate the anti-cancer potential of synthesized heterocyclic compounds against caspase 3, NF-KAPPA-B and P53 protein. Molecular docking analysis demonstrated a potent interaction between 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-(2,4-dinitrophenyl) acetamides (6d) and TP53 and NF-KAPPA-B with binding energies of - 11.8 kJ/mol and - 10.9 kJ/mol for TP53 and NF-KAPPA-B, respectively. Similarly, 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-(2-chlorophenyl) acetamides (6f) exhibited a strong interaction with caspase-3 with binding energy of -10.0 kJ/mol, indicating their potential as therapeutic agents against these proteins. Furthermore, the findings of current study was further strengthen by 100 ns molecular dynamics (MD) simulations. Finally, theoretical studies of oxygen balance and nitrogen percentage suggest that these molecules can be utilized as energetic materials.

Evaluation of the Possible Pathways Involved in the Protective Effects of Quercetin, Naringenin, and Rutin at the Gene, Protein and miRNA Levels Using In-Silico Multidimensional Data Analysis.

Flavonoids are secondary metabolites that are non-essential for plant growth or survival, and they also provide numerous health benefits to humans. They are antioxidants that shield plants from the ill effects of ultraviolet light, pests, and diseases. They are beneficial to health for several reasons, including lowering inflammation, boosting cardiovascular health, and lowering cancer risk. This study looked into the physicochemical features of these substances to determine the potential pharmacological pathways involved in their protective actions. Potential targets responsible for the protective effects of quercetin, naringenin, and rutin were identified with SwissADME. The associated biological processes and protein-protein networks were analyzed by using the GeneMANIA, Metascape, and STRING servers. All the flavonoids were predicted to be orally bioavailable, with more than 90% targets as enzymes, including kinases and lyases, and with common targets such as NOS2, CASP3, CASP9, CAT, BCL2, TNF, and HMOX1. TNF was shown to be a major target in over 250 interactions. To extract the "biological meanings" from the MCODE networks' constituent parts, a GO enrichment analysis was performed on each one. The most important transcription factors in gene regulation were RELA, NFKB1, PPARG, and SP1. Treatment with quercetin, naringenin, or rutin increased the expression and interaction of the microRNAs' hsa-miR-34a-5p, hsa-miR-30b-5p, hsa-let-7a-5p, and hsa-miR-26a-1-3p. The anticancer effects of hsa-miR-34a-5p have been experimentally confirmed. It also plays a critical role in controlling other cancer-related processes such as cell proliferation, apoptosis, EMT, and metastasis. This study's findings might lead to a deeper comprehension of the mechanisms responsible for flavonoids' protective effects and could present new avenues for exploration.

Synthesis, Physicochemical Characterization, Biological Evaluation, In Silico and Molecular Docking Studies of Pd(II) Complexes with P, S-Donor Ligands.

One homoleptic (1) and three heteroleptic (2-4) palladium(II) complexes were synthesized and characterized by various physicochemical techniques, i.e., elemental analysis, FTIR, Raman spectroscopy, 1H, 13C, and 31P NMR. Compound 1 was also confirmed by single crystal XRD, showing a slightly distorted square planar geometry. The antibacterial results obtained via the agar-well diffusion method for compound 1 were maximum among the screen compounds. All the compounds have shown good to significant antibacterial results against the tested bacterial strains, Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus, except 2 against Klebsiella pneumonia. Similarly, the molecular docking study of compound 3 has shown the best affinity with binding energy scores of -8.6569, -6.5716, and -7.6966 kcal/mol against Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus, respectively. Compound 2 has exhibited the highest activity (3.67 µM), followed by compound 3 (4.57 µM), 1 (6.94 µM), and 4 (21.7 µM) against the DU145 human prostate cancer cell line using the sulforhodamine B (SRB) method as compared to cisplatin (>200 µM). The highest docking score was obtained for compounds 2 (-7.5148 kcal/mol) and 3 (-7.0343 kcal/mol). Compound 2 shows that the Cl atom of the compound acts as a chain side acceptor for the DR5 receptor residue Asp B218 and the pyridine ring is involved in interaction with the Tyr A50 residue via arene-H, while Compound 3 interacts with the Asp B218 residue via the Cl atom. The physicochemical parameters determined by the SwissADME webserver revealed that no blood-brain barrier (BBB) permeation is predicted for all four compounds, while gastrointestinal absorption is low for compound 1 and high for the rest of the compounds (2-4). As concluding remarks based on the obtained in vitro biological results, the evaluated compounds after in vivo studies might be a good choice for future antibiotics and anticancer agents.

Molecular Spectroscopy Evidence of 1,3,5-Tris(4-carboxyphenyl)benzene Binding to DNA: Anticancer Potential along with the Comparative Binding Profile of Intercalation via Modeling Studies.

One of medicinal chemistry's top priorities is the discovery of new molecules with anticancer potential. Compounds that interact with DNA are an intriguing family of chemotherapeutic medications used to treat cancer. Studies in this area have uncovered a plethora of potential anticancer medicines, such as groove binding, alkylating, and intercalator compounds. The anticancer activity of DNA intercalators (molecules that intercalate between DNA base pairs) has drawn special interest. The current study investigated the promising anticancer drug 1,3,5-Tris(4-carboxyphenyl)benzene (H3BTB) against breast and cervical cancer cell lines. In addition, 1,3,5-Tris(4-carboxyphenyl)benzene binds to DNA by groove binding. The binding of H3BTB to DNA was found to be significant which unwinds the DNA helix. Considerable electrostatic and non-electrostatic contributions were present in the binding's free energy. The cytotoxic potential of H3BTB is effectively demonstrated by the computational study outcomes, which include molecular docking and molecular dynamics (MD) simulations. The minor groove binding for the H3BTB-DNA complex is supported by molecular docking research. This study will promote empirical investigation into the synthesis of metallic and non-metallic H3BTB derivatives and their potential use as bioactive molecules for the treatment of cancer.

Anticancer Potential of Sulfonamide Moieties via In-Vitro and In-Silico Approaches: Comparative Investigations for Future Drug Development.

Several kinds of anticancer drugs are presently commercially accessible, but low efficacy, solubility, and toxicity have reduced the overall therapeutic indices. Thus, the search for promising anticancer drugs continues. The interactions of numerous essential anticancer drugs with DNA are crucial to their biological functions. Here, the anticancer effects of N-ethyl toluene-4-sulphonamide (8a) and 2,5-Dichlorothiophene-3-sulphonamide (8b) on cell lines from breast and cervical cancer were investigated. The study also compared how these substances interacted with the hearing sperm DNA. The most promising anticancer drug was identified as 2,5-Dichlorothiophene-3-sulfonamide (8b), which showed GI50 of 7.2 ± 1.12 µM, 4.62 ± 0.13 µM and 7.13 ± 0.13 µM against HeLa, MDA-MB231 and MCF-7 cells, respectively. Moreover, it also exhibited significant electrostatic and non-electrostatic contributions to the binding free energy. The work utilized computational techniques, such as molecular docking and molecular dynamic (MD) simulations, to demonstrate the strong cytotoxicity of 2,5-Dichlorothiophene-3-sulfamide (8b) in comparison to standard Doxorubicin and cisplatin, respectively. Molecular docking experiments provided additional support for a role for the minor groove in the binding of the 2,5-Dichlorothiophene-3-sulfamide (8b)-DNA complex. The molecular docking studies and MD simulation showed that both compounds revealed comparable inhibitory potential against standard Doxorubicin and cisplatin. This study has the potential to lead to the discovery of new bioactive compounds for use in cancer treatment, including metallic and non-metallic derivatives of 2,5-Dichlorothiophene-3-sulfonamide (8b). It also emphasizes the worth of computational approaches in the development of new drugs and lays the groundwork for future research.

Food Toxicity of Mycotoxin Citrinin and Molecular Mechanisms of Its Potential Toxicity Effects through the Implicated Targets Predicted by Computer-Aided Multidimensional Data Analysis.

The mycotoxin citrinin, which can contaminate food, is a major global concern. Citrinin is regarded as an inevitable pollutant in foods and feed since fungi are widely present in the environment. To identify contentious toxicity and lessen its severity by understanding the targets of citrinin in the human body and the impacted biosynthetic pathways, we analyzed the production of citrinin from Aspergillus flavus and Penicillium notatum and used a thorough bioinformatics analysis to characterize the toxicity and predict genes and protein targets for it. The predicted median fatal dosage (LD50) for citrinin was 105 mg/kg weight, and it belonged to toxicity class 3 (toxic if swallowed). Citrinin was found to be well absorbed by human intestinal epithelium and was a Pgp nonsubstrate (permeability glycoprotein), which means that once it is absorbed, it cannot be pumped out, hence leading to bioconcentration or biomagnification in the human body. The main targets of toxicity were casp3, TNF, IL10, IL1B, BAG3, CCNB1, CCNE1, and CDC25A, and the biological pathways implicated were signal transduction involved in DNA damage checkpoints, cellular and chemical responses to oxidative stress, DNA damage response signal transduction by P53, stress-activated protein kinase signaling cascade, netrin-UNC5B signaling, PTEN gene regulation, and immune response. Citrinin was linked to neutrophilia, squamous cell carcinoma, Fanconi anemia, leukemia, hepatoblastoma, and fatty liver diseases. The transcription factors E2F1, HSF1, SIRT1, RELA, NFKB, JUN, and MYC were found to be responsible. When data mining was performed on citrinin targets, the top five functional descriptions were a cell's response to an organic cyclic compound, the netrin-UNC5B signaling pathway, lipids and atherosclerosis, thyroid cancer, and controlling the transcription of the PTEN gene.

Toxicity Study and Binding Analysis of Newly Synthesized Antifungal N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide Derivative with Bovine Serum Albumin.

The presence of the p-aryl/cyclohexyl ring in the N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazine carbothioamide derivative (2C) is reported to enhance the antifungal properties when compared to those of itraconazole. Serum albumins present in plasma bind and transport ligands, including pharmaceuticals. This study explored 2C interactions with BSA using spectroscopic methods such as fluorescence and UV-visible spectroscopy. In order to acquire a deeper comprehension of how BSA interacts with binding pockets, a molecular docking study was carried out. The fluorescence of BSA was quenched by 2C via a static quenching mechanism since a decrease in quenching constants was observed from 1.27 × 105 to 1.14 × 105. Thermodynamic parameters indicated hydrogen and van der Waals forces responsible for the BSA-2C complex formation with binding constants ranging between 2.91 × 105 and 1.29 × 105, which suggest a strong binding interaction. Site marker studies displayed that 2C binds to BSA's subdomains IIA and IIIA. Molecular docking studies were conducted to further comprehend the molecular mechanism of the BSA-2C interaction. The toxicity of 2C was predicted by Derek Nexus software. Human and mammalian carcinogenicity and skin sensitivity predictions were associated with a reasoning level of equivocal, inferring 2C to be a potential drug candidate.

An Insight into Wheat Germ Oil Nutrition, Identification of Its Bioactive Constituents and Computer-Aided Multidimensional Data Analysis of Its Potential Anti-Inflammatory Effect via Molecular Connections.

Wheat germ oil (WGO) is the richest source of unexplored antioxidants and anti-inflammatory compounds. In this study, we identified the constituents of WGO by gas chromatography-mass spectrometry (GC-MS). The physicochemical and pharmacokinetic behaviors were evaluated for the top 12 constituents with the common target FABP4. Three fatty acids with significant anti-inflammatory activity were evaluated for their interaction with FABP4 by molecular docking. The molecular mechanisms involved in anti-inflammatory responses were analyzed by various in-silico analytical tools and multidimensional data analysis. WGO showed anti-inflammatory activities via FABP4 interacting physically with target genes (77.84%) and by co-expressing with 8.01% genes. Primary targets for inflammatory pathways were PPARα, PPARγ, LPL, LEP, and ADIPOQ, as depicted by gene network enrichment analysis. The key pathways implicated were the metabolism of lipids, PPAR signaling, cellular response to alcohol, oxygen and nitrogen pathway, inflammatory response pathway, and regulation of the inflammatory pathway. The common transcription factors implicated were HNF1, AP2α, CEBP, FOX, STATS, MYC, Zic, etc. In this study, we found that WGO possesses anti-inflammatory potential via FABP4 binding to PPARα, PPARγ, LPL, LEP, and ADIPOQ gene expression by regulatory transcription factors HNF, AP2α, and CEPB.

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer.

Carbonic anhydrases (CA), having Zn2+ metal atoms, are responsible for the catalysis of CO2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (1H, 13C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of -6.12, -6.99, and -6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

Computational Investigation of 1, 3, 4 Oxadiazole Derivatives as Lead Inhibitors of VEGFR 2 in Comparison with EGFR: Density Functional Theory, Molecular Docking and Molecular Dynamics Simulation Studies.

Vascular endothelial growth factor (VEGF) is an angiogenic factor involved in tumor growth and metastasis. Gremlin has been proposed as a novel therapeutic pathway for the treatment of renal inflammatory diseases, acting via VEGFR 2 receptor. To date, most FDA-approved tyrosine kinase (TK) inhibitors have been reported as dual inhibitors of EGFR and VEGFR 2. The aim of the present study was to find the potent and selective inhibitor of VEGFR 2 specifically for the treatment of renal cancer. Fourteen previously identified anti-inflammatory compounds i.e., 1, 3, 4 oxadiazoles derivatives by our own group were selected for their anti-cancer potential, targeting the tyrosine kinase (TK) domain of VEGFR2 and EGFR. A detailed virtual screening-based study was designed viz density functional theory (DFT) study to find the compounds' stability and reactivity, molecular docking for estimating binding affinity, SeeSAR analysis and molecular dynamic simulations to confirm protein ligand complex stability and ADMET properties to find the pharmacokinetic profile of all compounds. The DFT results suggested that among all the derivatives, the 7g, 7j, and 7l were chemically reactive and stable derivatives. The optimized structures obtained from the DFTs were further selected for molecular docking, and the results suggested that 7g, 7j and 7l derivatives as the best inhibitors of VEGFR 2 with binding energy values -46.32, -48.89 and -45.01 kJ/mol. The Estimated inhibition constant (IC50) of hit compound 7j (0.009 µM) and simulation studies of its complexes confirms its high potency and best inhibitor of VEGFR2. All the derivatives were also docked with EGFR, where they showed weak binding energies and poor interactions, important compound 7g, 7j and 7i exhibited binding energy of -31.01, -33.23 and -34.19 kJ/mol respectively. Furthermore, the anticancer potential of the derivatives was confirmed by cell viability (MTT) assay using breast cancer and cervical cancer cell lines. At the end, the results of ADMET studies confirmed these derivatives as drug like candidates. Conclusively, the current study suggested substituted oxadiazoles as the potential anticancer compounds which exhibited more selectivity towards VEGFR2 in comparison to EGFR. Therefore, the identified lead molecules can be used for the synthesis of more potent derivatives of VEGFR2, along with extensive in vitro and in vivo experiments, that can be used to treat various cancers, especially renal cancers, and to prevent angiogenesis due to aberrant expression of VEGFR2.

Acetophenone-Based 3,4-Dihydropyrimidine-2(1H)-Thione as Potential Inhibitor of Tyrosinase and Ribonucleotide Reductase: Facile Synthesis, Crystal Structure, In-Vitro and In-Silico Investigations.

The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one (1), 4-acetyl aniline (2) and potassium thiocyanate. The spectroscopic analysis including: FTIR, 1H-NMR, and single crystal analysis proved the structure of synthesized compound (4), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N-H ⋯ S and C-H ⋯ O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R22 (8) and R22 (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H ⋯ H (59.5%), H ⋯ S/S ⋯ H (16.1%), and H ⋯ C/C ⋯ H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density functional theory (DFT) studies using B3LYP functional and 6-31G* as a basis set. The compound 4 displayed the high chemical reactivity with chemical softness of 2.48. In comparison to the already reported known tyrosinase inhibitor, the newly synthesized derivatives exhibited almost seven-fold better inhibition of tyrosinase (IC50 = 1.97 µM), which was further supported by molecular docking studies. The compound 4 inside the active pocket of ribonucleotide reductase (RNR) exhibited a binding energy of -19.68 kJ/mol, and with mammalian deoxy ribonucleic acid (DNA) it acts as an effective DNA groove binder with a binding energy of -21.32 kJ/mol. The results suggested further exploration of this compound at molecular level to synthesize more potential leads for the treatment of cancer.

Determination of anticancer potential of a novel pharmacologically active thiosemicarbazone derivative against colorectal cancer cell lines.

Thiosemicarbazones have received noteworthy attention due to their numerous pharmacological activities. Various thiosemicarbazone derivatives have been reported to play a key role as potential chemotherapeutic agents for the management of cancer. Herein, we aimed to establish the anticancer efficacy of novel thiosemicarbazone derivative C4 against colon cancer in vitro. The MTT viability assay identified C4 as a promising anticancer compound in a panel of cancer cell lines with the most potent activity against colon cancer cells. Further, anticancer potential of C4 was evaluated against HT-29 and SW620 colon cancer cell lines considering the factors like cell adhesion and migration, oxidative stress, cell cycle arrest, and apoptosis. Our results showed that C4 significantly inhibited the migration and adhesion of colon cancer cells. C4 significantly increased the intracellular reactive oxygen species (ROS) and induced apoptotic cell death. Cell cycle analysis revealed that C4 interfered in the cell cycle distribution and arrested the cells at the G2/M phase of the cell cycle. Consistent with these results C4 also down-regulated the Bcl-XL and Bcl-2 and up-regulated the caspase-3 expression. These findings introduced C4 as the potential anticancer agent against colon cancer.

Glutathione improves low temperature stress tolerance in pusa sheetal cultivar of Solanum lycopersicum.

To investigate the impact of Glutathione (GSH) in mitigating low-temperature stress in Pusa Sheetal cv. of Solanum lycopersicum and imparting low-temperature tolerance by evaluating the different physiological responses. The plant under research was also being studied for its growth and stress tolerance. Low temperatures (LT) stress was applied to seedlings with or without GSH application 12 h before LT stress (prophylactic dose), after 12 h-LT (preemptive dose), and post 12-h recovery (curative dose). Different concentrations of GSH [0, G1 (0.5 mM), G2 (1 mM) and G3 (2 mM)] against LT stress were used. Antioxidant activities, photosynthesis, growth, and stress tolerance indices were quantified. LT stress caused an oxidative burst in S. lycopersicum seedlings of the Pusa Sheetal cv. as indicated by increased peroxidation of lipids and H2O2 concentration. Glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) activities were enhanced. The best concentration was G2 (1 mM), which resulted in a rise in antioxidant activity. Moreover, a decline in lipid peroxidation and H2O2 levels was also seen. The purpose of this study is to identify the role of GSH in reducing LT stress and to find the best dose concentration. This is the first report to assess the GSH-mediated LT stress tolerance in S. lycopersicum (Pusa Sheetal cv.). Therefore, exogenous GSH application of optimal concentration of GSH to LT stressed S. lycopersicum can be an effective approach for augmenting the plant detoxification system and promoting its growth and development.