Every year, more than 250,000 invasive candidiasis infections are reported with 50,000 deaths worldwide. The limited number of antifungal agents necessitates the need for alternative antifungals with potential novel targets. The 2-benzylidenebenzofuran-3-(2H)-ones have become an attractive scaffold for antifungal drug design. This study aimed to determine the antifungal activity of a synthetic aurone compound and characterize its mode of action. Using the broth microdilution method, aurone SH1009 exhibited inhibition against C. albicans, including resistant isolates, as well as C. glabrata, and C. tropicalis with IC50 values of 4–29 μM. Cytotoxicity assays using human THP-1, HepG2, and A549 human cell lines showed selective toxicity toward fungal cells. The mode of action for SH1009 was characterized using chemical-genetic interaction via haploinsufficiency (HIP) and homozygous (HOP) profiling of a uniquely barcoded Saccharomyces cerevisiae mutant collection. Approximately 5300 mutants were competitively treated with SH1009 followed by DNA extraction, amplification of unique barcodes, and quantification of each mutant using multiplexed next-generation sequencing. Barcode post-sequencing analysis revealed 238 sensitive and resistant mutants that significantly (FDR P values ≤ 0.05) responded to aurone SH1009. The enrichment analysis of KEGG pathways and gene ontology demonstrated the cell cycle pathway as the most significantly enriched pathway along with DNA replication, cell division, actin cytoskeleton organization, and endocytosis. Phenotypic studies of these significantly enriched responses were validated in C. albicans. Flow cytometric analysis of SH1009-treated C. albicans revealed a significant accumulation of cells in G1 phase, indicating cell cycle arrest. Fluorescence microscopy detected abnormally interrupted actin dynamics, resulting in enlarged, unbudded cells. RT-qPCR confirmed the effects of SH1009 in differentially expressed cell cycle, actin polymerization, and signal transduction genes. These findings indicate the target of SH1009 as a cell cycle-dependent organization of the actin cytoskeleton, suggesting a novel mode of action of the aurone compound as an antifungal inhibitor.
Salinity stress (SS) is major abiotic stress that is seriously limiting crop production across the globe. The application of organic amendments (OA) mitigate the effects of salinity and improves soil health and crop production on a sustainable basis. However, limited studies are conducted to determine the impact of farmyard manure (FYM) and press mud (PM) on the performance of rice crop. Therefore, we performed this study to determine the impacts of FYM and PM on the growth, physiological and biochemical attributes, yield, and grain bio-fortification of rice crop under SS. The experiment was comprised of SS levels; control, 6 and 12 dS m−1 SS and OA; control, FYM: 5%, press mud 5% and combination of FYM (5%) + PM (5%). Soil salinity imposed deleterious impacts on the growth, yield, and grain quality of rice, however, OA appreciably offset the deleterious impacts of SS and improved the growth, yield, and grain bio-fortification of rice crop. The combined application of FYM + PM improved the growth and yield of rice through an increase in chlorophyll contents, leaf water contents, anti-oxidant activities (ascorbate peroxidise: APX; catalase: CAT, peroxidise: POD and ascorbic acid: AsA), K+ accumulation and decrease in Na+/K+ ratio, electrolyte leakage, malondialdehyde (MDA), hydrogen peroxide (H2O2), Na+ accumulation. Moreover, the combined application of FYM + PM significantly improved the grain protein (5.84% and 12.90%), grain iron (40.95% and 42.37%), and grain zinc contents (36.81% and 50.93%) at 6 and 12 dS m−1 SS. Therefore, this study suggested that the application of FYM and PM augmented the growth, yield, physiology, biochemistry, and grain bio-fortification of rice and proved to be a good practice for better rice production in salt-affected soils.
Candida albicans is the major fungal cause of healthcare-associated bloodstream infections worldwide with a 40% mortality rate. The scarcity of antifungal treatments due to the eukaryotic origin of fungal cells has challenged the development of selectively antifungal drugs. In an attempt to identify novel antifungal agents, aurones SH1009 and SH9051, as synthetically bioactive compounds, have been recently documented as anti-Candida agents. Since the molecular mechanisms behind the inhibitory activities of these aurones in C. albicans are unclear, this study aimed to determine the comprehensive cellular processes affected by these aurones and their molecular targets. Genome-wide transcriptional analysis of SH1009- and SH9051-treated C. albicans revealed uniquely repressed expression in different metabolic pathways, particularly trehalose and sulfur amino acid metabolic processes for SH1009 and SH9051, respectively. In contrast, the most commonly enriched process for both aurones was the up-regulation of RNA processing and ribosomal cleavages as an indicator of high oxidative stress, suggesting that a common aspect in the chemical structure of both aurones led to pro-oxidative properties. Additionally, uniquely induced responses (iron ion homeostasis for SH1009 and arginine biosynthesis for SH9051) garnered attention on key roles for the aurone functional groups. Deletion of the transcription factor for the trehalose biosynthesis pathway, Tye7p, resulted in an SH1009-resistant mutant, which also exhibited low trehalose content, validating the primary molecular target of SH1009. Aurone SH9051 uniquely simulated an exogenous supply of methionine or cysteine, leading to sulfur amino acid catabolism as evidenced by quantifying an overproduction of sulfite. Phenyl aurone, the common structure of aurones, contributed proportionally in the pro-oxidative activity through ferric ion reduction effects leading to high ROS levels. Our results determined selective and novel molecular mechanisms for aurone SH1009 and also elucidated the diverse cellular effects of different aurones based on functional groups.
Drought stress is an inevitable factor that disturbs the production of plants by altering morphological, physiological, biochemical, and molecular functions. Breeding for drought tolerance requires a complete understanding of the molecular factors controlling stress-responsive pathways. The plant responds to drought stress by adopting four mechanisms: avoidance, escape, tolerance, and recovery. Traditional plant-breeding tools have been employed to increase tolerance in cotton, but the complexity of drought tolerance has limited the use of these breeding methods. The plant adopts several key strategies against drought stress, such as activating the signaling network and activating molecular factors. Cotton breeders have been engaged in elucidating the molecular mechanisms of drought tolerance in cotton using significant molecular tools such as quantitative trait loci (QTL) mapping, transcription factor (TFs) analysis, transcriptome analysis, genome-wide association studies (GWAS), genetic engineering, and CRISPR/Cas9. Breeders have studied the functional description of genes and the interacting pathways accountable for controlling drought tolerance in cotton. Hundreds of genes/QTL have been identified, and many have been cloned for drought tolerance in cotton; however, a complete understanding of these traits still needs more study. This review presents a detailed overview of molecular tools, their application for improving drought tolerance in cotton, and their prospects. This review will help future researchers to conduct further studies to develop drought-tolerant cotton genotypes that can thrive under conditions of water scarcity.
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