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.

Genome-wide SNP discovery and genotyping delineates potential QTLs underlying major yield-attributing traits in buckwheat.

Buckwheat (Fagopyrum spp.) is an important nutritional and nutraceutical-rich pseudo-cereal crop. Despite its obvious potential as a functional food, buckwheat has not been fully harnessed due to its low yield, self-incompatibility, increased seed cracking, limited seed set, lodging, and frost susceptibility. The inadequate availability of genomics resources in buckwheat is one of the major reasons for this. In the present study, genome-wide association mapping (GWAS) was conducted to identify loci associated with various morphological and yield-related traits in buckwheat. High throughput genotyping by sequencing led to the identification of 34,978 single nucleotide polymorphisms that were distributed across eight chromosomes. Population structure analysis grouped the genotypes into three sub-populations. The genotypes were also characterized for various qualitative and quantitative traits at two diverse locations, the analysis of which revealed a significant difference in the mean values. The association analysis revealed a total of 71 significant marker-trait associations across eight chromosomes. The candidate genes were identified near 100 Kb of quantitative trait loci (QTLs), providing insights into several metabolic and biosynthetic pathways. The integration of phenology and GWAS in the present study is useful to uncover the consistent genomic regions, related markers associated with various yield-related traits, and potential candidate genes having implications for being utilized in molecular breeding for the improvement of economically important traits in buckwheat. Moreover, the identified QTLs will assist in tracking the desirable alleles of target genes within the buckwheat breeding populations/germplasm.

Metabolic-GWAS provides insights into genetic architecture of seed metabolome in buckwheat.

BACKGROUND: Buckwheat (Fagopyrum spp.), belonging to the Polygonaceae family, is an ancient pseudo-cereal with high nutritional and nutraceutical properties. Buckwheat proteins are gluten-free and show balanced amino acid and micronutrient profiles, with higher content of health-promoting bioactive flavonoids that make it a golden crop of the future. Plant metabolome is increasingly gaining importance as a crucial component to understand the connection between plant physiology and environment and as a potential link between the genome and phenome. However, the genetic architecture governing the metabolome and thus, the phenome is not well understood. Here, we aim to obtain a deeper insight into the genetic architecture of seed metabolome in buckwheat by integrating high throughput metabolomics and genotyping-by-sequencing applying an array of bioinformatics tools for data analysis. RESULTS: High throughput metabolomic analysis identified 24 metabolites in seed endosperm of 130 diverse buckwheat genotypes. The genotyping-by-sequencing (GBS) of these genotypes revealed 3,728,028 SNPs. The Genome Association and Prediction Integrated Tool (GAPIT) assisted in the identification of 27 SNPs/QTLs linked to 18 metabolites. Candidate genes were identified near 100 Kb of QTLs, providing insights into several metabolic and biosynthetic pathways. CONCLUSIONS: We established the metabolome inventory of 130 germplasm lines of buckwheat, identified QTLs through marker trait association and positions of potential candidate genes. This will pave the way for future dissection of complex economic traits in buckwheat.

Biochemical and proteomic insights revealed selenium priming induced phosphorus stress tolerance in common bean (Phaseolus vulgaris L.).

BACKGROUND: Mineral stress is one of the dominating abiotic stresses, which leads to decrease in crop production. Selenium (Se) seed priming is a recent approach to mitigate the plant's mineral deficiency stress. Although not an essential element, Se has beneficial effects on the plants in terms of growth, quality, yield and plant defense system thus, enhancing plant tolerance to mineral deficiency. METHODS AND RESULTS: The present research was accomplished to find out the effect of Se priming on common bean plant (SFB-1 variety) under phosphorus (P) stress. The seeds were grown invitro on four different MGRL media which are normal MGRL media as control with non-Se primed seeds (Se- P+), non -Se primed seeds grown on P deficient MGRL media (Se- P-), Se primed seeds grown on normal MGRL media (Se+P+) and Se primed seeds grown on P deficient MGRL media (Se+P -). The various morphological and biochemical parameters such as proline content, total sugar content, polyphenols and expression of proteins were analyzed under P stress. The results showed that Se priming has significantly (p ≤ 0.05) affected the morphological as well as biochemical parameters under normal and P stress conditions. The morphological parameters-length, weight, number of nodes and leaves of Se+P+, Se+P- root and shoot tissue showed significant increase as compared to Se-P+, Se-P-. Similarly various biochemical parameters such as total chlorophyll content, proline, total sugar content and polyphenols of Se+P+, Se+P- increased significantly as compared to Se-P+, Se-P-. The differential protein expression in both Se+P+, Se+P- and Se-P+, Se-P- plants were determined using MALDI-MS/MS. The differentially expressed proteins in Se+P+, Se+P- plants were identified as caffeic acid-3-O-methyltransferase (COMT) and SecA protein (a subunit of Protein Translocan transporter), and are found responsible for lignin synthesis in root cell walls and ATP dependent movement of thylakoid proteins across the membranes in shoot respectively. The differential expression of proteins in plant tissues, validated morphological and biochemical responses such as maintaining membrane integrity, enhanced modifications in cellular metabolism, improved polyphenol activities and expression of defensive proteins against mineral deficiency. CONCLUSIONS: The study provided an understanding of Se application as a potential approach increasing tolerance and yield in crop plants against mineral deficiency.

Morphological, Biochemical, and Proteomic Studies Revealed Impact of Fe and P Crosstalk on Root Development in Phaseolus vulgaris L.

Mineral stress is one of the major abiotic stresses faced by crop plants. The present study was undertaken to investigate the impact of mineral stress (iron (Fe) and phosphorus (P)) on various morphological and biochemical responses of the shoot and root tissues and root architecture of common bean (Phaseolus vulgaris L.). This study also leads us to the identification of P stress responsive proteins. The study was conducted under in vitro conditions, in which seeds of Shalimar French Bean-1 (SFB-1) variety were cultured on four different MGRL medium (control (P1Fe1), iron deficient (P1Fe0), phosphorus deficient (P0Fe1), and phosphorus and iron deficient (P0Fe0)). Chlorophyll content of leaves, Fe/P content of root tissues, total sugars, proline, length, and weight of shoot and root tissues were assessed and compared within and between the treatments. The analyzed data revealed significant difference between control and other three treatments. Chlorophyll content of shoots was found significantly decreased under mineral stress treatments P0Fe1, P1Fe0, and P0Fe0 than control. Length and weight of shoot and root were also observed significantly decreased under P0Fe1, P1Fe0, and P0Fe0 as compared to control. Total sugar was significantly higher in P0Fe1 of roots in comparison to control. Proline content was significantly higher in both tissues of shoots and roots of plants grown under P1Fe0, P0Fe1, and P0Fe0 than control condition. Furthermore, we unexpectedly observed the recovery of roots (mainly primary roots) under P0Fe0 as compared to P1Fe0 and P0Fe1. Interestingly higher concentration of Fe was also observed in P0Fe1 compared to other treatments and also higher concentration of P was observed in P1Fe1. These findings suggested that there is a crosstalk between Fe and P and also revealed that there is a disruption in the ability of PR (primary root) to sense local P deficiency in the absence of Fe. Furthermore, proteomics analysis (SDS-PAGE followed by MALDI MS) helped in identification of defensive proteins in P stress condition compared to control.

Exploring the new dimensions of selenium research to understand the underlying mechanism of its uptake, translocation, and accumulation.

Selenium (Se) is a vital mineral for both plants and animals. It is widely distributed on the earth's crust and is taken up by the plants as selenite or selenate. Plants substantially vary in their physiological response to Se. The amount of Se in edible plants is genetically controlled. Its availability can be determined by measuring its phytoavailability in soil. The low concentration of Se in plants can help them in combating stress, whereas higher concentrations can be detrimental to plant health and in most cases it is toxic. Thus, solving the double-edged sword problem of nutritional Se deficiency and its elevated concentrations in environment requires a better understanding of Se uptake and metabolism in plants. The studies on Se uptake and metabolism can help in genetic biofortification of Se in plants and also assist in phytoremediation. Moreover, Se uptake and transport, especially biochemical pathways of assimilation and incorporation into proteins, offers striking mechanisms of toxicity and tolerance. These developments have led to a revival of Se research in higher plants with significant break throughs being made in the previous years. This review explores the new dimensions of Se research with major emphasis on key research events related to Se undertaken in last few years. Further, we also discussed future possibilities in Se research for crop improvement.