Network pharmacology and experimental insights into STAT3 inhibition by novel isoxazole derivatives of piperic acid in triple negative breast cancer.

STAT3 is a crucial member within a family of seven essential transcription factors. Elevated STAT3 levels have been identified in various cancer types, notably in breast cancer (BC). Consequently, inhibiting STAT3 is recognized as a promising and effective strategy for therapeutic intervention against breast cancer. We herein synthesize a library of isoxazole (PAIs) from piperic acid [2E, 4E)-5-(2H-1,3-Benzodioxol-5-yl) penta-2,4-dienoic acid] on treatment with propargyl bromide followed by oxime under prescribed reaction conditions. Piperic acid was obtained by hydrolysis of piperine extracted from Piper nigrum. First, we checked the binding potential of isoxazole derivatives with breast cancer target proteins by network pharmacology, molecular docking, molecular dynamic (MD) simulation and cytotoxicity analysis as potential anti-breast cancer (BC) agents. The multi-source databases were used to identify possible targets for isoxazole derivatives. A network of protein-protein interactions (PPIs) was generated by obtaining 877 target genes that overlapped gene symbols associated with isoxazole derivatives and BC. Molecular docking and MD modelling demonstrated a strong affinity between isoxazole derivatives and essential target genes. Further, the cell viability studies of isoxazole derivatives on the human breast carcinoma cell lines showed toxicity in all breast cancer cell lines. In summary, our study indicated that the isoxazole derivative showed the significant anticancer activity. The results highlight the prospective utility of isoxazole derivatives as new drug candidates for anticancer chemotherapy, suggesting route for the continued exploration and development of drugs suitable for clinical applications.

Synthesis, biological profile and computational insights of new derivatives of benzo [B][1,4] diazepines as prospective anticancer agents for inhibiting the CDK-2 protein.

In the current work, a new series of benzo[b][1, 4] diazepines (A-1 to C-4) was synthesized and screened against three different human cancer cell lines, HepG2 (hepatocellular carcinoma), HeLa (cervical cancer) and MCF-7 (breast cancer), by employing MTT (MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The outcomes of in vitro screening revealed that all the compounds exhibited momentous anticancer activity, most notably against the MCF-7 cell line by B1-4 compounds. Further, network pharmacology, UALCAN analysis, molecular docking, molecular dynamics (MD) simulations and density functional theory calculations were conducted to explore expression analysis, pharmacokinetics, toxicity profiles and binding interactions of the B1-4 compounds. By UALCAN, we explored the expression analysis of CDK-2 in 19 cancers. Through UALCAN, Pan-cancer analysis revealed that the expression of CDK-2 in 19 cancers was statistically significant. Among the 19 cancers, the CDK-2 expression was significantly upregulated in breast cancer (BRCA), cervical cancer (CESC) and lung carcinoma (LUSC) than normal tissues. Enzyme-docking examination revealed that B1-4 compounds exhibited significant binding affinity against the CDK-2 (PDB ID: 5IEV) drug target protein. Furthermore, MD simulations supported the docking results, which confirmed that the ligand + protein complex was in a stable conformation throughout the simulation time of 100 nanoseconds. Therefore, the present study demonstrates the potential of these benzo [b][1,4] diazepines as promising drug candidates against cancer.Communicated by Ramaswamy H. Sarma.

A new series of benzodiazepine molecules were designed and synthesized as CDK-2 inhibitors.In vitro anticancer potential against HepG2, HeLa and MCF-7 cancer cells were assessed.Network pharmacology; expression analysis; in silico docking; molecular dynamics simulation; molecular mechanics­generalized Born and surface area; and absorption, distribution, metabolism, excretion and toxicity studies were carried out.This study overall revealed the anticancer activity of benzodiazepines by integrating network pharmacology, molecular modeling and in vitro experiments.

Design, synthesis, and unraveling the antibacterial and antibiofilm potential of 2-azidobenzothiazoles: insights from a comprehensive in vitro study.

The present study reports the synthesis of 2-azidobenzothiazoles from substituted 2-aminobenzothiazoles using sodium nitrite and sodium azide under mild conditions. All the synthesized compounds were examined for their antibacterial activity against Gram (+) bacteria, Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 51299), Bacillus cereus (ATCC 10876) and Gram (-) bacteria, Escherichia coli (ATCC 10536), Pseudomonas aeruginosa (ATCC 10145), Klebsiella pneumonia (ATCC BAA-2146)and clinical isolates of Gram (+) Methicillin Resistant S. aureus (MRSA) and Multi Drug Resistant E. coli. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) values by broth dilution method revealed that compound 2d exhibited significant antibacterial potential against E. faecalis and S. aureus with MIC of 8 µg/mL, while other synthesized compounds had only moderate effects against all the tested species. The compound significantly inhibited the biofilm formation of the bacterial strains below its MIC. The selective cytotoxicity of Compound 2d towards bacterial cells was evidenced on extended exposure of Human Embryonic Kidney-293 cell line to higher concentrations of the compound. Hence, the present study confirmed that compound 2d can be a potential drug candidate for future development as an antibacterial drug.

Green synthesis of mono and bimetallic alloy nanoparticles of gold and silver using aqueous extract of Chlorella acidophile for potential applications in sensors.

Bimetallic or alloy nanoparticles (NPs) have improved properties compared to their monometallic forms. Microalgae being rich in biocompatible reductants and being ecofriendly are potential sources to synthesize fuctionalized NPs. In this study, biosynthesis of silver, gold, and bimetallic NPs was carried out via bioreduction using aqueous extract of algal isolate Chlorella acidophile, inhabitant of non-arable land. C. acidophile is known to contain highly bioactive functional moieties, which can serve as nanobiofactories for metallic NPs. Various characterization techniques viz, UV-visible spectrophotometer, X-ray diffraction analysis, X-ray photo-electron spectroscopy, and Raman spectroscopy were employed to determine their composition, structure, and crystal phase. The monometallic and bimetallic particles were found to be crystalline state and generally in a spherical shape. Their size ranged from 5 to 45 nm and the corresponding FTIR spectra indicated that the specific organic functional groups from algal extract were involved in the bio-reduction. Furthermore, the core-shell in the case of Au-Ag NPs was formed due to the simultaneous reduction of gold and silver ions. An enhanced and more pronounced Raman spectra of Au-Ag NP compared to individual Au NP indicated the improved properties of bimetallic NPs, the latter having been of immense potential to be used as sensors in industries.

Secondary Metabolites of Saussurea costus Leaf Extract Induce Apoptosis in Breast, Liver, and Colon Cancer Cells by Caspase-3-Dependent Intrinsic Pathway.

BACKGROUND: Apoptosis, a major form of programmed cell death, plays a vital role in regulating tissue development and maintenance of homeostasis in eukaryotes. Apoptosis can occur via a death receptor-dependent extrinsic or a mitochondrial-dependent intrinsic pathway and can be induced by various chemotherapeutic agents. In this study, the anticancer activity of Saussurea costus and its mode of intervention in human cancer cells of breast, colon, and liver were investigated. RESULTS: In this study, the bioactives of S. costus leaves were extensively extracted in five solvents of different polarity. The cytotoxicity and anticancer effect of the extracted secondary metabolites were investigated against breast (MCF-7), liver (HepG2), and colon (HCT116) cancer cell lines using a Sulphorhodamine B (SRB) assay. Secondary metabolites extracted using hexane, methanol, ethyl acetate, and chloroform had the highest cytotoxicity and thus the greatest anticancer effect on all the cancer cell lines tested (IC50; ranging from 0.25 to 2.5 µg/ml), while butanol was comparatively less active (IC50; ranging from 23.2 to 25.5 µg/ml). Further investigation using DNA flow cytometry and fluorescent microscopy revealed that the extract arrested the cells in the G1 phase of cell cycle and induced apoptosis. Furthermore, the elevated expression level of proapoptotic proteins and decreased expression level of antiapoptotic proteins confirmed that the intrinsic (mitochondrial) pathway was involved in mediating the apoptosis of cancer cells upon treatment with S. costus extract. These results altogether suggest that S. costus could be a potential anticancer agent. CONCLUSION: These results suggest that the S. costus extract is the potential source of the secondary metabolites that could be used as anticancer agent to treat diverse cancers of breast, colon, and liver.

GC-MS analysis of Myrtus communis extract and its antibacterial activity against Gram-positive bacteria.

BACKGROUND: Myrtus communis is a typical plant of Mediterranean area. The different parts of this plant such as berries, branches, and leaves have been used worldwide as a traditional/folk medicine for the treatment of various ailments and diseases. METHODS: Ethanolic leaf extract of the plant was prepared by Soxhlet extraction method. Zone of inhibition, minimum inhibitory concentration and minimal bactericidal concentration were determined by well diffusion method and microplate alamar blue assay. GC-MS analysis was carried out to identify the compounds present in the extract. Microscopy and ImageJ software were used respectively for morphology and cell-length measurements. GraphPad Prism was used for statistical analysis. RESULTS: The ethanolic extract showed strong inhibitory effect against Gram-positive and acid-fast bacteria with significant inhibition-zone size (9-25 mm), MIC (4.87-78 µg/ml), as well as MBC (0.3-20 mg/ml). However, no effect was observed on the growth of Gram-negative bacteria. The growth inhibition was found to be associated with the damage of cell wall as the extract-treated cells were sensitive to cell wall-targeting antibiotics and displayed the cell wall damage-depicting morphological defects. GC-MS analysis confirmed the presence of novel compounds in addition to the most representative compounds of the essential oils/extracts of M. communis of other country origins. CONCLUSION: These results demonstrate that M. communis leaf extract could be the source of compounds to be used for the treatment of Gram-positive bacterial infections. This is the first report, which provides insights into the mechanism of action of the extract in inhibiting the growth of Gram-positive bacteria.

Posttransplant metabolic complications in living-related renal allograft recipients of Kashmir Valley.

OBJECTIVES: Renal transplant offers a definitive therapeutic modality for patients with end-stage renal disease; however, 50% to 70% of these patients have graft dysfunction after the transplant. Proactive prevention management of metabolic complications may reduce posttransplant morbidity and mortality in these patients. MATERIALS AND METHODS: A retrospective and prospective review of 120 kidney transplant recipients during 5 years' follow-up was performed to analyze the incidence and status of the various metabolic complications after a renal transplant. RESULTS: In our study, postrenal transplant diabetes mellitus was seen in 9 of 120 patients (7.5%). The incidence of posttransplant diabetes mellitus was 5% in tacrolimus-treated patients (n=6) compared with 2.5% in cyclosporine-treated patients (n=3). Dyslipidemia, as hypercholesterolemia and hyper-triglyceridemia, was seen in 31 recipients (25.83%). Significant posttransplant hyperlipidemia was documented (P < .05). Further, it was noted that 25 patients who developed hyperlipidemia (20.83%) were taking cyclosporine-based therapy, while 6 were treated with tacrolimus-based therapy (5%; P < .05). However, most subjects with hyperlipidemia had renal graft dysfunction. Posttransplant erythrocytosis affected 9 renal transplant recipients (7.5%) with a mean (±SD) hematocrit of 41.3%±6.7%. A statistically significant correlation was seen between prerenal and postrenal transplant hematocrit by 12 months. Hyperparathyroidism was observed in 1 renal transplant patient (1.25%). CONCLUSIONS: On the basis of this study, we conclude that posttransplant diabetes mellitus occurred in 7.5% patients, hypercholesteremia and hyper-triglyceridemia occurred in 25.83% patients, posttransplant erythrocytosis affected 7.5% patients, and hyperparathyroidism occurred in 1 renal transplant patient (1.25%). Moreover, dyslipidemia, contributed to progressive graft dysfunction.