A DEEP LEARNING MODEL FOR EDUCATION ANALYTICS – A SHORT REVIEW

Integrating deep learning with learning management systems can result in intelligent course material and high accuracy without any manual intervention. This paper reviews factors that influence deep learning in education, and hence this article aims to achieve deep learning on a large scale in the smart education system with a deep learning model to predict. The proposed model can reduce development and maintenance costs, reduce risks, and facilitate communication between stakeholders. HIGHLIGHTS: The current review focus on deep learning as an important tool for Indian teachers

Evaluation of Cytotoxic Effects and Underlying Mechanism of Phenolic Compounds on Breast Cancer Cell Lines

Breast cancer (BC) is the second most common cancer that causes higher mortality rates worldwide. It is a complex and heterogeneous disease with a median survival range of around three years. Breast cancer patients' overall survival has increased due to using chemotherapeutic medicines, namely anthracyclines and taxanes. However, drug resistance and subsequent progression of this disease were still observed in metastatic patients. Furthermore, the efficacy failure of even today's sophisticated chemotherapeutics negatively impacts breast cancer patients with side effects, highlighting the urgent need for the development of nontoxic medications, that have low side effects, and are patient-friendly. Tumor cell death has been associated with the activation of apoptotic signal transduction pathways in cancer cells, such as the intrinsic and/or extrinsic pathways. Thus, understanding the molecular mechanism of apoptosis opens the future perspective for drug development for breast cancer treatment. The present study focuses on the possibility of using newly synthesized indoline analogs as targeted therapy for breast cancer, which could selectively induce apoptosis in cancer cells. Advances in anticancer drug discovery using broad-spectrum drugs, such as substituted alkylamino phenolic rings or indoline rings, have emerged as promising molecules. Thus, investigating the effects of these compounds in inducing apoptosis would provide opportunities that directly evade the significant challenges in current breast cancer therapies. The present research work focuses on the in-vitro analysis of the anti-breast cancer activity of three novel indoline derivatives, 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol (THMPP), 2-((3,4-Dihydroquinolin-1(2H)-yl) (ptolyl)methyl)phenol)(THTMP) and N-(2-hydroxy-5-nitrophenyl (4’-methylphenyl)methyl) indoline (HNPMI). The present study’s findings have been published in four publications, each of which highlights the mechanism of action of each compound’s cytotoxic potential, its apoptotic induction potential, the regulation of the genes involved in the Epithelial Growth Factor Receptor (EGFR) signaling pathway, and the in-silico analysis to identify the compound’s interaction with the target receptor, EGFR. Absorption, distribution, metabolism, excretion, and toxicity (ADME/ T) analysis also confirms the drug likeliness of the compound to be used as a potent anticancer drug. The compounds' cytotoxicity was tested in breast cancer cells like MCF7 (ER+PR+/HER-), SkBr3 (ER-PR-/HER+), MDA MB-231, and non-tumorous cells like HEK293 and H9C2. The first compound we analyzed was 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol (THMPP). In human breast cancer cell lines MCF- 7 and SkBr3 and non-cancerous mouse myoblast cells, H9C2, it was evaluated for its potential cytotoxicity and method of action. THMPP induced cell death in MCF- 7 and SkBr3 cells at their IC50 concentration of 83.23 μM and 113.94 μM, respectively. The toxicity was 36.4% in MCF-7 cells and 18.86% in SkBr3 cells at 10μM concentrations. Interestingly, THMPP showed the lowest percentage of cytotoxicity to H9C2 cells (0.91%) than the other breast cancer cell line. The compound induced apoptosis through increased caspase three and caspase 9 with the fold level of 0.17-fold and 0.47-fold in MCF-7 cells and 0.07 and 0.25 in SkBr3 cells, respectively. THMPP also enhanced apoptosis of the breast cancer cells, causing inter-nucleosomal DNA fragmentation, thus leading to DNA strand breakage and cell death. FACS analysis has proved that THMPP improves breast cancer cells to enter various stages of apoptosis, especially in the late apoptotic stage. With a score of 5.79 kJ/mol, molecular docking validates THMPP's substantial interaction with EGFR, predicted to activate the downstream signaling pathway. The downregulation of PI3K and S6K1 genes involved in the Phosphatidylinositol 3-Kinase (PI3K)/AKT signaling pathway, which were considerably overexpressed in cancer cells, was validated by gene expression analysis. Quantitative Structure-Activity Relationship (QSAR) analysis confirmed the toxicity of THMPP against breast cancer cells. ADME/T analysis predicts the drug-likeliness of THMPP. The second important compound that was analyzed for its anti-breast cancer activity was 2-((3,4-Dihydroquinolin-1(2H)-yl) (p-tolyl) methyl) phenol) (THTMP), the derivative of THMPP. A methyl group replaced the 4-OMe substituent of the aryl ring in THMPP to synthesize THMPP. The compound exhibits a cytotoxic effect against MCF7 and SK-BR3 cells, with IC50 values of 87.92 μM and 172.51 μM, respectively. THTMP caused cell death in breast cancer cells by regulating critical apoptosis enzymes, caspase-3 and-9, with 33 percent of cells in the late apoptotic stage after 24 hours of treatment. The significant interaction of THTMP with EGFR inhibits PI3K/S6K1 gene expression, thus enhancing the apoptotic response of the breast cancer cells. Structural validation of QSAR also confirms the anticancer property of THTMP. ADME/T screening suggested the compound’s oral availability and better intestinal absorption with acceptable metabolism and toxicity parameters. Furthermore, seven N-substituted indoline derivatives have been assessed for their ability to interact with the EGFR protein. Among the seven compounds analyzed by molecular docking, it was confirmed that the N-(2-hydroxy-5-nitrophenyl (4’- methyl phenyl) methyl) indoline (HNPMI) possesses a stronger affinity with EGFR active sites. As a result, the EGFR signaling pathway was activated, which reduced the expression of PI3K and S6K1 to about 0.4-fold and 0.3-fold, respectively, thereby inducing cell death via inter-nucleosomal DNA fragmentation. The IC50 value of HNPMI was found to be 64.10 μM in MCF-7 cells and 119.99 μM in SkBr3 cells. Furthermore, HNPMI stimulated DNA fragmentation, which was validated by FACS analysis, resulting in caspase-mediated apoptosis. Structural elucidation also revealed the bi-molecular interaction of HNPMI-EGFR, relating its activity to the anti-proliferative and apoptotic activity. Finally, a combined computational analysis was performed to predict the compounds’ interaction with the tyrosine kinase receptor of EGFR. The study revealed that the HNPMI, THMPP, and THTMP interact with the active site region of the EGFR structure (PDB ID: 1M17). The interactions include hydrogen bonds, hydrophobic interactions, pi stacking, and salt bridges. HNPMI was found to have the lowest Glide docking score among the three compounds, reflecting that it can be a better inhibitor than the other two compounds. The investigation of the MMGB/ SA and QM/MM analysis also showed a coherent pattern. It was also found that the protein-ligand complex was stable when it was simulated for 100ns. The Molecular dynamics results also revealed that the ligand interacted with the protein for more than 30% of the simulation time. The compounds also possessed good pharmacokinetic properties, which were predicted by ADME/T analysis. Overall, the study demonstrates the effect of cytotoxicity and apoptotic induction of indoline derivatives THMPP, THTMP, and HNPMI. Furthermore, our results revealed the anti-breast cancer property of all three phenolic compounds with HNPMI as the lead molecule. HNPMI was also observed to be a potent EGFR pathway inhibitor, inhibiting the PI3K/ S6K1 signaling pathway and causing cell death in breast cancer cells. Thus, HNPMI can be subjected to further clinical testing and developed as a promising therapeutic medication for the treatment of breast cancer

Anticancer activity of THMPP: Downregulation of PI3K/ S6K1 in breast cancer cell line.

Breast cancer is the most common cancer that majorly affects female. The present study is focused on exploring the potential anticancer activity of 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol (THMPP), against human breast cancer. The mechanism of action, activation of specific signaling pathways, structural activity relationship and drug-likeness properties of THMPP remains elusive. Cell proliferation and viability assay, caspase enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR, QSAR and ADME analysis were executed to understand the mode of action of the drug. The effect of THMPP on multiple breast cancer cell lines (MCF-7 and SkBr3), and non-tumorigenic cell line (H9C2) was assessed by MTT assay. THMPP at I

Benzenesulfonamide Analogs : Synthesis, Anti-GBM Activity and Pharmacoprofiling

The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives were synthesized, and their inhibitory activities in TrkA overexpressing cells, U87 and MEF cells were investigated. The cytotoxic effect of benzenesulfonamide derivatives and cisplatin was determined using trypan blue exclusion assays. The mode of interaction of benzenesulfonamides with TrkA was predicted by docking and structural analysis. ADMET profiling was also performed for all compounds to calculate the drug likeness property. Appropriate QSAR models were developed for studying structure–activity relationships. Compound 4-[2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfon-amide (AL106) and 4-[2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (AL107) showed acceptable binding energies with the active sites for human nerve growth factor receptor, TrkA. Here, AL106 was identified as a potential anti-GBM compound, with an IC50 value of 58.6 µM with a less toxic effect in non-cancerous cells than the known chemotherapeutic agent, cisplatin. In silico analysis indicated that AL106 formed prominent stabilizing hydrophobic interactions with Tyr359, Ser371, Ile374 and charged interactions with Gln369 of TrkA. Furthermore, in silico analysis of all benzenesulfonamide derivatives revealed that AL106 has good pharmacokinetics properties, drug likeness and toxicity profiles, suggesting the compound may be suitable for clinical trial. Thus, benzenesulfonamide analog, AL106 could potentially induce GBM cell death through its interaction with TrkA and might be an attractive strategy for developing a drug targeted therapy to treat glioblastoma.Peer reviewe

Anticancer activity of THMPP : Downregulation of PI3K/ S6K1 in breast cancer cell line

Breast cancer is the most common cancer that majorly affects female. The present study is focused on exploring the potential anticancer activity of 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol (THMPP), against human breast cancer. The mechanism of action, activation of specific signaling pathways, structural activity relationship and drug-likeness properties of THMPP remains elusive. Cell proliferation and viability assay, caspase enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR, QSAR and ADME analysis were executed to understand the mode of action of the drug. The effect of THMPP on multiple breast cancer cell lines (MCF-7 and SkBr3), and non-tumorigenic cell line (H9C2) was assessed by MTT assay. THMPP at IC50 concentration of 83.23 μM and 113.94 μM, induced cell death in MCF-7 and SkBr3 cells, respectively. Increased level of caspase-3 and -9, fragmentation of DNA, translocation of phosphatidylserine membrane and morphological changes in the cells confirmed the effect of THMPP in inducing the apoptosis. Gene expression analysis has shown that THMPP was able to downregulate the expression of PI3K/S6K1 genes, possibly via EGFR signaling pathway in both the cell lines, MCF-7 and SkBr3. Further, molecular docking also confirms the potential binding of THMPP with EGFR. QSAR and ADME analysis proved THMPP as an effective anti-breast cancer drug, exhibiting important pharmacological properties. Overall, the results suggest that THMPP induced cell death might be regulated by EGFR signaling pathway which augments THMPP being developed as a potential candidate for treating breast cancer.publishedVersionPeer reviewe

Identification of novel GPR17-agonists by structural bioinformatics and signaling activation.

G Protein-coupled Receptor 17 (GPR17) is phylogenetically related to the purinergic receptors emerged as a potential drug target for multiple sclerosis, Parkinson disease, Alzheimer disease and cancer. Unfortunately, the crystal structure of GPR17 is unresolved. With the interest in structure-based ligand discovery, we modeled the structure of GPR17. The model allowed us to identify two novel agonists, AC1MLNKK and T0510.3657 that selectively activate GPR17 which exhibit better interaction properties than previously known ligand, MDL29951. We report detailed protein-ligand interactions and the dynamics of GPR17-ligand interaction by molecular docking and molecular dynamics experiments. Ex vivo validation of GPR17-ligand interaction provides evidence that ligand T0510-3657 and AC1MLNKK inhibit the cAMP levels in GPR17-HEK293T cells, with a pE

Synthesis and pharmacological evaluation of some benzylidene-4-nitroanilines

A number of nine benzylidene-4-nitroanilines were synthesized by condensation method. The formation of the substituted (E)-N-benzylidene-4-nitrobenzenamines has been confirmed from their physical and Ultra-Violet, Infra-Red, NMR spectral data. The evaluation of antimicrobial screening of substituted (E)-N-benzylidene-4-nitrobenzenamines was conducted by using standard Bauer-Kirby method. Three gram-positive microbes namely Bacillus subtilis, Micrococcus luteus and Staphylococcus aureus, and two gram-negative microbes, Escherichia coli and Pseudomonas aeruginosa, were used for the antibacterial evaluation. The antifungal activities against Aspergillus niger and Penicilium scup fungal species were also performed. A good antibacterial effect has been possessed by some of the substituted (E)-N-benzylidene-4-nitrobenzenamines on the microorganisms utilized in the present stud

Antiproliferative and apoptotic effects of indole derivative, N-(2-hydroxy-5-nitrophenyl (4\u27-methylphenyl) methyl) indoline in breast cancer cells.

Indoline derivatives functions as an inhibitors of epidermal growth factor receptor (EGFR) with the anticancer potential against various cancers. We aim to investigate anti-breast cancer effects and mechanism of action of novel indoline derivatives. Molecular docking of seven indoline derivates with EGFR revealed, N-(2-hydroxy-5-nitrophenyl (4\u27-methylphenyl) methyl) indoline (HNPMI) as the top lead compound. RT-PCR analysis showed the downregulation of PI3K/S6K1 genes in breast cancer cells through the activation of EGFR with HNPMI. This compound found to have higher cytotoxicity than Cyclophosphamide, with the 50 of 64.10 μM in MCF-7 and 119.99 μM in SkBr3 cells. HNPMI significantly reduced the cell proliferation of MCF-7 and SkBr3 cells, without affecting non-cancerous cells, H9C2. Induction of apoptosis was analyzed by Caspase-3 and -9, DNA fragmentation, AO/EtBr staining and flow cytometry assays. A fold change of 0.218- and 0.098- for caspase-3 and 0.478- and 0.269- for caspase-9 in MCF7 and SkBr3 cells was observed, respectively. Caspase mediated apoptosis caused DNA fragmentation in breast cancer cells upon HNPMI treatment. The structural elucidation of HNPMI by QSAR model and ADME-Tox suggests, a bi-molecular interaction of HNPMI-EGFR which is related to antiproliferative and apoptotic activity. The data concludes that, HNPMI-induced the apoptosis via EGFR signaling pathway in breast cancer cells. Thus, HNPMI might serve as a scaffold for developing a potential anti-breast cancer therapeutic agent