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.

Deciphering the chemical constituents and antimicrobial activity of Prangos pabularia Lindl. using LC-MS/MS in combination with experimental evaluation and computational studies.

This study meticulously explores the antimicrobial potential of Prangos pabularia Lindl.'s aerial parts through a comprehensive blend of in vitro and in silico analysis. Extracts with varying polarities underwent LC-MS/MS identification of active components, followed by in vitro and in silico assessments of antimicrobial efficacy against Escherichia coli, Bacillus cereus, Candida albicans, Candida glabrata, and Candida paropsilosis. The methanolic extract exhibited significant antimicrobial activity with a MIC value of 48 µg/mL against all tested strains. Molecular docking revealed the compound 9-(3-methylbut-2-enoxy)-furo-(3,2-g)-chromen-7-one's highest binding affinity against the penicillin-binding protein (PBP) bacterial drug target molecule. Other compounds also displayed substantial interactions with key antimicrobial drug target proteins. Further, Molecular dynamics simulations affirmed the stability of protein and ligand conformations. Collectively, these results underscore Prangos pabularia Lindl.'s aerial parts as a promising botanical resource in combating diverse microbial infections. This comprehensive approach not only validates it's in vitro antimicrobial properties but also provides molecular insights into interaction mechanisms, advancing our comprehension of the plant's therapeutic potential.

Comparative RNA-Seq analysis reveals insights in Salmonella disease resistance of chicken; and database development as resource for gene expression in poultry.

Salmonella, one of the major infectious diseases in poultry, causes considerable economic losses in terms of mortality and morbidity, especially in countries that lack effective vaccination programs. Besides being resistant to diseases, indigenous chicken breeds are also a potential source of animal protein in developing countries. For understanding the disease resistance, an indigenous chicken line Kashmir faverolla, and commercial broiler were selected. RNA-seq was performed after challenging the chicken with Salmonella Typhimurium. Comparative differential expression results showed that following infection, a total of 3153 genes and 1787 genes were differentially expressed in the liver and spleen, respectively. The genes that were differentially expressed included interleukins, cytokines, NOS2, Avß-defensins, toll-like receptors, and other immune-related gene families. Most of the genes and signaling pathways involved in the innate and adaptive immune responses against bacterial infection were significantly enriched in the Kashmir faverolla. Pathway analysis revealed that most of the enriched pathways were MAPK signaling pathway, NOD-like receptor signaling pathway, TLR signaling pathway, PPAR signaling pathway, endocytosis, etc. Surprisingly some immune-related genes like TLRs were upregulated in the susceptible chicken breed. On postmortem examination, the resistant birds showed small lesions in the liver compared to large necrotic lesions in susceptible birds. The pathological manifestations and RNA sequencing results suggest a balancing link between resistance and infection tolerance in Kashmir faverolla. Here we also developed an online Poultry Infection Database (https://skuastk.org/pif/index.html), the first publicly available gene expression resource for disease resistance in chickens. The available database not only shows the data for gene expression in chicken tissues but also provides quick search, visualization and download capacity.

Strategies Employed to Evade the Host Immune Response and the Mechanism of Drug Resistance in Mycobacterium tuberculosis: In Search of Finding New Targets.

The partial effectiveness of the host immune response to M. tuberculosis drives bacteria into a latent state, but it is difficult to eliminate the bacteria completely. Usually, this latent condition of M. tuberculosis is reversible, and reactivation of tuberculosis is the leading cause of the majority of transmission. A number of studies performed on animal models and humans have not yet provided a detailed understanding of the mechanisms or correlates of immunity of M. tuberculosis infection or why there is a significant immunity failure to remove the pathogen. Moreover, the mechanism of resistance involved in drug-resistant M. tuberculosis leads to the emergence of strains of bacteria that show significant resistance to the majority of anti-tuberculosis drugs. We have also provided the recent findings and trends regarding the development of new drug molecules to treat drug and multidrug-resistant tuberculosis and the advancements in immunotherapy in the treatment of drug-resistant tuberculosis. This article provides an in-depth and critical analysis of various strategies employed by the drug-resistant M. tuberculosis to escape the host immune response. This bacterium persists in the host for a longer period of time and leads to the development of tuberculosis infection. Furthermore, we also discussed the new targets for the effective treatment of drug-resistant tuberculosis.

Insights into decontamination of soils by phytoremediation: A detailed account on heavy metal toxicity and mitigation strategies.

In the current era of rapid industrialization, the foremost challenge is the management of industrial wastes. Activities such as mining and industrialization spill over a large quantity of toxic waste that pollutes soil, water, and air. This poses a major environmental and health challenge. The toxic heavy metals present in the soil and water are entering the food chain, which in turn causes severe health hazards. Environmental clean-up and reclamation of heavy metal contaminated soil and water are very important, and it necessitates efforts of environmentalists, industrialists, scientists, and policymakers. Phytoremediation is a plant-based approach to remediate heavy metal/organic pollutant contaminated soil and water in an eco-friendly, cost-effective, and permanent way. This review covers the effect of heavy metal toxicity on plant growth and physiological process, the concept of heavy metal accumulation, detoxification, and the mechanisms of tolerance in plants. Based on plants' ability to uptake heavy metals and metabolize them within tissues, phytoremediation techniques have been classified into six types: phytoextraction, phytoimmobilization, phytovolatilization, phytodegradation, rhizofiltration, and rhizodegradation. The development of research in this area led to the identification of metal hyper-accumulators, which could be utilized for reclamation of contaminated soil through phytomining. Concurrently, breeding and biotechnological approaches can enhance the remediation efficiency. Phytoremediation technology, combined with other reclamation technologies/practices, can provide clean soil and water to the ecosystem.

Nano-Drug Delivery Systems: Possible End to the Rising Threats of Tuberculosis.

Tuberculosis (TB) is still one of the deadliest disease across the globe caused by Mycobacterium tuberculosis (Mtb). Mtb invades host macrophages and other immune cells, modifies their lysosome trafficking proteins, prevents phagolysosomes formation, and inhibits the TNF receptor-dependent apoptosis in macrophages and monocytes. Tuberculosis (TB) killed 1.4 million people worldwide in the year 2019. Despite the advancements in tuberculosis (TB) treatments, multidrugresistant tuberculosis (MDR-TB) remains a severe threat to human health. The complications are further compounded by the emergence of MDR/XDR strains and the failure of conventional drug regimens to eradicate the resistant bacterial strains. Thus, new therapeutic approaches aim to ensure cure without relapse, to prevent the occurrence of deaths and emergence of drug-resistant strains. In this context, this review article summarises the essential nanotechnology-related research outcomes in the treatment of tuberculosis (TB), including drug-susceptible and drug-resistant strains of Mtb. The novel anti-tuberculosis drug delivery systems are also being detailed. This article highlights recent advances in tuberculosis (TB) treatments, including the use of novel drug delivery technologies such as solid lipid nanoparticles, liposomes, polymeric micelles, nano-suspensions, nano-emulsion, niosomes, liposomes, polymeric nanoparticles and microparticles for the delivery of anti-TB drugs and hence eradication and control of both drug-susceptible as well as drug-resistant strains of Mtb.

Development of New Therapeutics to Meet the Current Challenge of Drug Resistant Tuberculosis.

Tuberculosis (TB) is a prominent infective disease and a major reason of mortality/ morbidity globally. Mycobacterium tuberculosis causes a long-lasting latent infection in a significant proportion of human population. The increasing burden of tuberculosis is mainly caused due to multi drug-resistance. The failure of conventional treatment has been observed in large number of cases. Drugs that are used to treat extensively drug-resistant tuberculosis are expensive, have limited efficacy, and have more side effects for a longer duration of time and are often associated with poor prognosis. To regulate the emergence of multidrug resistant tuberculosis, extensively drug-resistant tuberculosis and totally drug resistant tuberculosis, efforts are being made to understand the genetic/molecular basis of target drug delivery and mechanisms of drug resistance. Understanding the molecular approaches and pathology of Mycobacterium tuberculosis through whole genome sequencing may further help in the improvement of new therapeutics to meet the current challenge of global health. Understanding cellular mechanisms that trigger resistance to Mycobacterium tuberculosis infection may expose immune associates of protection, which could be an important way for vaccine development, diagnostics, and novel host-directed therapeutic strategies. The recent development of new drugs and combinational therapies for drug-resistant tuberculosis through major collaboration between industry, donors, and academia gives an improved hope to overcome the challenges in tuberculosis treatment. In this review article, an attempt was made to highlight the new developments of drug resistance to the conventional drugs and the recent progress in the development of new therapeutics for the treatment of drugresistant and non-resistant cases.

Comparative transcriptome analysis of mammary epithelial cells at different stages of lactation reveals wide differences in gene expression and pathways regulating milk synthesis between Jersey and Kashmiri cattle.

Jersey and Kashmiri cattle are important dairy breeds that contribute significantly to the total milk production of the Indian northern state of Jammu and Kashmir. The Kashmiri cattle germplasm has been extensively diluted through crossbreeding with Jersey cattle with the goal of enhancing its milk production ability. However, crossbred animals are prone to diseases resulting to unsustainable milk production. This study aimed to provide a comprehensive transcriptome profile of mammary gland epithelial cells at different stages of lactation and to find key differences in genes and pathways regulating milk traits between Jersey and Kashmiri cattle. Mammary epithelial cells (MEC) isolated from milk obtained from six lactating cows (three Jersey and three Kashmiri cattle) on day 15 (D15), D90 and D250 in milk, representing early, mid and late lactation, respectively were used. RNA isolated from MEC was subjected to next-generation RNA sequencing and bioinformatics processing. Casein and whey protein genes were found to be highly expressed throughout the lactation stages in both breeds. Largest differences in differentially expressed genes (DEG) were between D15 vs D90 (1,805 genes) in Kashmiri cattle and, D15 vs D250 (3,392 genes) in Jersey cattle. A total of 1,103, 1,356 and 1,397 genes were differentially expressed between Kashmiri and Jersey cattle on D15, D90 and D250, respectively. Antioxidant genes like RPLPO and RPS28 were highly expressed in Kashmiri cattle. Differentially expressed genes in both Kashmiri and Jersey were enriched for multicellular organismal process, receptor activity, catalytic activity, signal transducer activity, macromolecular complex and developmental process gene ontology terms. Whereas, biological regulation, endopeptidase activity and response to stimulus were enriched in Kashmiri cattle and, reproduction and immune system process were enriched in Jersey cattle. Most of the pathways responsible for regulation of milk production like JAK-STAT, p38 MAPK pathway, PI3 kinase pathway were enriched by DEG in Jersey cattle only. Although Kashmiri has poor milk production efficiency, the present study suggests possible physicochemical and antioxidant properties of Kashmiri cattle milk that needs to be further explored.