Crop bioengineering via gene editing: reshaping the future of agriculture.

Genome-editing technologies have revolutionized research in plant biology, with major implications for agriculture and worldwide food security, particularly in the face of challenges such as climate change and increasing human populations. Among these technologies, clustered regularly interspaced short palindromic repeats [CRISPR]-CRISPR-associated protein [Cas] systems are now widely used for editing crop plant genomes. In this review, we provide an overview of CRISPR-Cas technology and its most significant applications for improving crop sustainability. We also review current and potential technological advances that will aid in the future breeding of crops to enhance food security worldwide. Finally, we discuss the obstacles and challenges that must be overcome to realize the maximum potential of genome-editing technologies for future crop and food production.

Argel's stemmoside C as a novel natural remedy for mice with alcohol-induced gastric ulcer based on its molecular mechanistic pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Solenostemma argel is widely distributed in Africa & Asia with traditional usage in alleviating abdominal colic, aches, & cramps. This plant is rich in phytochemicals, which must be explored for its pharmacological effects. PURPOSE: Peptic Ulcer Disease (PUD) is the digestion of the digestive tube. PUD not only interferes with food digestion & nutrient absorption, damages one of the largest defensive barriers against pathogenic micro-organisms, but also impedes drug absorption & bioavailability, rendering the oral route, the most convenient way, ineffective. Omeprazole, one of the indispensable cost-effective proton-pump inhibitors (PPIs) extensively prescribed to control PUD, is showing growing apprehensions toward multiple drug interactions & side effects. Hence, finding a natural alternative with Omeprazole-like activity & limited side effects is a medical concern. STUDY DESIGN: Therefore, we present Stemmoside C as a new gastroprotective phytochemical agent isolated from Solenostemma argel to be tested in upgrading doses against ethanol-induced gastric ulcers in mice compared to negative, positive, & reference Omeprazole groups. METHODS: We carried out in-depth pharmacological & histopathological studies to determine the possible mechanistic pathway. RESULTS: Our results showed that Stemmoside C protected the stomach against ethanol-induced gastric ulcers parallel to Omeprazole. Furthermore, the mechanistic studies revealed that Stemmoside C produced its effect using an orchestrated array of different mechanisms. Stemmoside C stimulates stomach defense by increasing COX-2, PGE-2, NO, & TFF-1 healing factors, IL-10 anti-inflammatory cytokine, & Nrf-2 & HO-1 anti-oxidant pathways. It also suppresses stomach ulceration by inhibiting leucocyte recruitment, especially neutrophils, leading to subsequent inhibition of NF-κBp65, TNF-α, IL-1ß, & iNOS pro-inflammatory cytokines & JAK-1/STAT-3 inflammation-induced carcinogenicity cascade in addition to MMP-9 responsible for tissue degradation. CONCLUSION: These findings cast light on Stemmoside C's clinical application against gastric ulcer progression, recurrence, & tumorigenicity & concurrently with chemotherapy.

Differential impacts of interactions between Serendipita indica, Chlorella vulgaris, Ulva lactuca and Padina pavonica on Basil (Ocimum basilicumL.).

Plant biostimulants (PBs) are used globally to increase crop yield and productivity. PBs such as (Serendipita indica) or algal extracts stimulate and accelerate plant physiological processes. The physiological, ecological, and biochemical effects of (Serendipita indica) or algal extracts individually and in combination on basil plant (Ocimum basilicum L.) were investigated. Macroalgae samples were collected from Abu Qir, Alexandria, Egypt. The growth parameters, chlorophyll index, and biochemical composition of basil were analyzed at 90th day. The (Chlorella vulgaris) + (Serendipita indica) (MI + F) treatment increased chlorophyll index by 61.7% (SPAD) compared to control. (Chlorella vulgaris) had the highest growth hormones, including GA3 at 158.2 ppb, GA4 at 149.1 ppb, GA7 at 142.6 ppb, IAA at 136.6 ppb, and TC at 130.9 ppb, while (Ulva lactuca) had the lowest. The MI + F treatment yielded the highest essential oil and antioxidant values. Treatment with (Chlorella vulgaris) increased S. indica colonization by 66%. In contrast, Ulva lactuca and (Padina Pavonica) inhibited S. indica colonization by 80% and 40%, respectively. (Ulva lactuca) and (Padina Pavonica) inhibited S. indica colonization by 80% and 40%, respectively. Combined treatments had a greater influence on basil performance than the individual treatments. The evidence of synergistic/additive benefits to plants performance due to the interactive effects of (Chlorella vulgaris) and (Serendipita indica) had been studied. Complementary modes of action between (Chlorella vulgaris) and (Serendipita indica), through their components newly emerging properties on basil, may explain observed synergistic effects. This study explores the potential of microbial-algal interactions, particularly (Chlorella vulgaris) and (Serendipita indica), as innovative plant biostimulants. These interactions demonstrate positive effects on basil growth, offering promise for more effective microbial-based formulations to enhance crop productivity and sustainability in agriculture. These novelties will help create a second generation of PBs with integrated and complementary actions.

Driving risk cognition of passengers in highly automated driving based on the prefrontal cortex activity via fNIRS.

For high-level automated vehicles, the human being acts as the passenger instead of the driver and does not need to operate vehicles, it makes the brain-computer interface system of high-level automated vehicles depend on the brain state of passengers rather than that of drivers. Particularly when confronting challenging driving situations, how to implement the mental states of passengers into safe driving is a vital choice in the future. Quantifying the cognition of the driving risk of the passenger is a basic step in achieving this goal. In this paper, the passengers' mental activities in low-risk episode and high-risk episode were compared, the influences on passengers' mental activities caused by driving scenario risk was first explored via fNIRS. The results showed that the mental activities of passengers caused by driving scenario risk in the Brodmann area 10 are very active, which was verified by examining the real-driving data collected in corresponding challenging experiments, and there is a positive correlation between the cerebral oxygen and the driving risk field. This initial finding provides a possible solution to design a human-centred intelligent system to promise safe driving for high-level automated vehicles using passengers' driving risk cognition.

Potential drug candidates as P-glycoprotein inhibitors to reverse multidrug resistance in cancer: an in silico drug discovery study.

The failure of chemotherapy in the treatment of carcinoma is mainly due to the development of multidrug resistance (MDR), which is largely caused by the overexpression of P-glycoprotein (P-gp/ABCB1/MDR1). Until recently, the 3D structure of the P-gp transporter has not been experimentally resolved, which restricted the discovery of prospective P-gp inhibitors utilizing in silico techniques. In this study, the binding energies of 512 drug candidates in clinical or investigational stages were assessed as potential P-gp inhibitors employing in silico methods. On the basis of the available experimental data, the performance of the AutoDock4.2.6 software to predict the drug-P-gp binding mode was initially validated. Molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy computations were subsequently conducted to screen the investigated drug candidates. Based on the current results, five promising drug candidates, namely valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus, showed promising binding energies against P-gp transporter with ΔGbinding values of -126.7, -112.1, -111.9, -102.9, and -101.4 kcal/mol, respectively. The post-MD analyses revealed the energetical and structural stabilities of the identified drug candidates in complex with the P-gp transporter. Furthermore, in order to mimic the physiological conditions, the potent drugs complexed with the P-gp were subjected to 100 ns MD simulations in an explicit membrane-water environment. The pharmacokinetic properties of the identified drugs were predicted and demonstrated good ADMET characteristics. Overall, these results indicated that valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus hold promise as prospective P-gp inhibitors and warrant further invitro/invivo investigations.

Impact of H5N8 duck and chicken viral isolates on the immunological profile of vaccinated specific pathogen free chickens

Nowadays, there is a global concern about outbreaks caused by the highly pathogenic avian influenza virus H5N8 clade 2.3.4.4 which caused devastating losses in the poultry industry sector. This clade was subdivided into two waves: clade 2.3.4.4A from 2014 to 2015 and clade 2.3.4.4b from 2016 until now. In this literature we aimed to evaluate the efficacy of recently used inactivated commercial avian influenza vaccines against two new Egyptian highly pathogenic avian influenza virus H5N8 isolates of clade 2.3.4.4b, A/chicken/Egypt/1526v/2020/H5N8 (H5N8-CH) and A/Duck/Egypt/Qalubia321/2021 (H5N8-D). Three-week-old specific pathogen free chickens were vaccinated with eight types of the most recently used inactivated avian influenza vaccines containing homologous and heterologous virus to the circulating H5N8 isolates. All specific pathogen free chicken groups were bled weekly post vaccination for antibody analysis using two H5N8 isolates of chicken and duck origin as antigen in hemagglutination inhibition test. Also, all vaccinated chicken groups were challenged 4 weeks post vaccination against the H5N8 duck isolate with a dose of 109 EID50/0.1 mL per chicken to measure the protection percentage of the commercial vaccines used. The results showed that vaccines with homologous and heterologous virus showed variable degrees of accepted protection percentage ranged from 90percent to 100percent, thus it was concluded that not only the genetic and antigenic match of the vaccine strains with the circulating highly pathogenic avian influenza viruses influences vaccine efficiency; other factors, such as manufacturing procedures, adjuvant, antigen content, vaccine dose and administration factors could affect vaccine efficacy, therefore, further vaccine development studies are needed to improve the percentage of protection and prevention of viral shedding against local highly pathogenic avian influenza H5 viruses in Egypt(AU)

En la actualidad, existe una preocupación mundial por los brotes causados por el virus de la gripe aviar altamente patógena H5N8 clado 2.3.4.4 que causó pérdidas devastadoras en el sector de la industria avícola. Este clado se subdividió en dos oleadas: clado 2.3.4.4A de 2014 a 2015 y clado 2.3.4.4b de 2016 hasta ahora. En el presente trabajo, dos aislamientos egipcios de la gripe aviar altamente patógena H5N8 del clado 2.3.4.4b, A/chicken/Egypt/1526v/2020/H5N8 (H5N8_CH) y A/Duck/Egypt/Qalubia321/2021 (H5N8_D), se utilizaron para evaluar la eficacia de vacunas comerciales inactivadas contra la gripe aviar de reciente utilización. Pollos libres de patógenos específicos de tres semanas de edad fueron vacunados con ocho vacunas inactivadas contra la influenza aviar, de uso reciente, que contenían virus homólogos y heterólogos a los aislamientos circulantes de H5N8. Todos los grupos de pollos libres de patógenos específicos fueron sangrados semanalmente tras la vacunación para el análisis de anticuerpos; dos virus H5N8 aislados de pollo y pato se utilizaron como antígeno en la prueba de inhibición de la hemaglutinación. Además, todos los grupos de pollos vacunados fueron retados 4 semanas después de la vacunación con el virus H5N8 aislado de pato, con una dosis de 109 EID50/0,1 mL por pollo, para medir el porcentaje de protección de las vacunas comerciales utilizadas. Los resultados mostraron que las vacunas con virus homólogos y heterólogos presentaron grados variables de aceptada protección, la que osciló entre el 90 por ciento y el 100 por ciento, por lo que se concluyó que no sólo la coincidencia genética y antigénica de las cepas vacunales con los virus circulantes de la influenza aviar altamente patógena influye en la eficacia de la vacuna; otros factores, como los procedimientos de fabricación, el adyuvante, el contenido en antígenos, la dosis de la vacuna y los factores de administración podrían afectar a la eficacia de la vacuna, por lo que es necesario seguir estudiando el desarrollo de vacunas para mejorar la protección y la prevención de la excreción viral contra los virus H5 de la influenza aviar altamente patógena locales en Egipto(AU)

A new cembranoid from the Red Sea soft coral Sarcophyton acutum.

The Red Sea soft coral Sarcophyton acutum ethyl acetate extract has afforded one new cembranoid; sarcacutumolid A (1), along with six known metabolites have been isolated from S. acutum for the first time (2-7). Chemical structures were elucidated by employing several spectroscopic analyses. The cytotoxic potential of the isolated compounds was assessed against four human cancer cell lines; hepatocellular (HepG2), cervical (HeLa), breast (MCF-7) and colorectal cancer (Colo-205). Sarcacutumolid A (1) and gorgosterol (7) inhibited colorectal cancer cell proliferation in a concentration-dependent manner with IC50 values of 35.5 and 44.0 µM, respectively.

Reconfigurable Soft Robots by Building Blocks.

Soft robots are of increasing interest as they can cope with challenges that are poorly addressed by conventional rigid-body robots (e.g., limited flexibility). However, due to their flexible nature, the soft robots can be particularly prone to exploit modular designs for enhancing their reconfigurability, that is, a concept which, to date, has not been explored. Therefore, this paper presents a design of soft building blocks that can be disassembled and reconfigured to build different modular configurations of soft robots such as robotic fingers and continuum robots. First, a numerical model is developed for the constitutive building block allowing to understand their behavior versus design parameters, then a shape optimization algorithm is developed to permit the construction of different types of soft robots based on these soft building blocks. To validate the approach, 2D and 3D case studies of bio-inspired designs are demonstrated: first, soft fingers are introduced as a case study for grasping complex and delicate objects. Second, an elephant trunk is used for grasping a flower. Third, a walking legged robot. These case studies prove that the proposed modular building approach makes it easier to build and reconfigure different types of soft robots with multiple complex shapes.

Salt Priming as a Smart Approach to Mitigate Salt Stress in Faba Bean (Vicia faba L.).

The present investigation aims to highlight the role of salt priming in mitigating salt stress on faba bean. In the absence of priming, the results reflected an increase in H2O2 generation and lipid peroxidation in plants subjected to 200 mM salt shock for one week, accompanied by a decline in growth, photosynthetic pigments, and yield. As a defense, the shocked plants showed enhancements in ascorbate peroxidase (APX), catalase (CAT), glutathione reductase (GR), peroxidase (POX), and superoxide dismutase (SOD) activities. Additionally, the salt shock plants revealed a significant increase in phenolics and proline content, as well as an increase in the expression levels of glutathione (GSH) metabolism-related genes (the L-ascorbate peroxidase (L-APX) gene, the spermidine synthase (SPS) gene, the leucyl aminopeptidase (LAP) gene, the aminopeptidase N (AP-N) gene, and the ribonucleo-side-diphosphate reductase subunit M1 (RDS-M) gene). On the other hand, priming with increasing concentrations of NaCl (50-150 mM) exhibited little significant reduction in some growth- and yield-related traits. However, it maintained a permanent alert of plant defense that enhanced the expression of GSH-related genes, proline accumulation, and antioxidant enzymes, establishing a solid defensive front line ameliorating osmotic and oxidative consequences of salt shock and its injurious effect on growth and yield.

Anti-androgenic potential of the fruit extracts of certain Egyptian Sabal species and their genetic variability studies: a metabolomic-molecular modeling approach.

This work aimed to evaluate the anti-androgenic activity of S. blackburniana Glazebrook, S. causiarum (O. F. Cook) Becc, and S. palmetto (Walter) Lodd. Ex Schult fruit extracts in rats using Hershberger assay. Furthermore, to annotate secondary metabolites using LC-HRMS technique, to investigate underlying mechanisms responsible for 5-α-reductase inhibitory activity in silico and to compare cytotoxic effects in vitro against human prostatic stromal myofibroblast (WPMY-1) and human benign prostatic hyperplasia (BPH-1) cell lines using MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (spectrophotometrically). The results showed significant anti-androgenic implications with varying degrees, markedly decreased sex organ weights, reduction in testosterone and increase in LH and FSH serum levels. Genetic diversity study ensured the correct genotype and revealed outperformance of SCoT compared with CBDP markers to interpret polymorphism among selected species. S. blackburniana exhibited selective cytotoxic activity against BPH-1 compared to finasteride. Molecular docking of 59 dereplicated metabolites belonging to various chemical classes revealed that helasaoussazine, pinoresinol and tetra-O-caffeoylquinic acid are the top inhibitors of 5-α-reductase-2. Our study provides an insight into the anti-androgenic activity of selected species of Egyptian Sabal supported by docking study for the first time, demonstrates safety toward liver and kidney and highlights a new potential therapeutic candidate for anti-androgenic related disease such as benign prostatic hyperplasia.

Plant cell cultures: An enzymatic tool for polyphenolic and flavonoid transformations.

BACKGROUND: In the pharmaceutical sector, tissue culture techniques for large-scale production of natural chemicals can be a less expensive alternative to large-scale synthesis. Although recent biotransformation research have used plant cell cultures to target a wide range of bioactive compounds, more compiled information and synopses are needed to better understand metabolic pathways and improve biotransformation efficiencies. PURPOSE: This report reviews the biochemical transformation of phenolic natural products by plant cell cultures in order to identify potential novel biotechnological approaches for ensuring more homogeneous and stable phenolic production year-round under controlled environmental conditions. METHODS: Articles on the use of plant cell culture for polyphenolic and flavonoid transformations (1988 - 2021) were retrieved from SciFinder, PubMed, Scopus, and Web of Science through electronic and manual search in English. Following that, the authors chose the required papers based on the criteria they defined. The following keywords were used for the online search: biotransformation, Plant cell cultures, flavonoids, phenolics, and pharmaceutical products. RESULTS: The initial search found a total of 96 articles. However, only 70 of them were selected as they met the inclusion criteria defined by the authors. The analysis of these studies revealed that plant tissue culture is applicable for the large-scale production of plant secondary metabolites including the phenolics, which have high therapeutic value. CONCLUSION: Plant tissue cultures could be employed as an efficient technique for producing secondary metabolites including phenolics. Phenolics possess a wide range of therapeutic benefits, as anti-oxidant, anti-cancer, and anti-inflammatory properties. Callus culture, suspension cultures, transformation, and other procedures have been used to improve the synthesis of phenolics. Their production on a large scale is now achievable. More breakthroughs will lead to newer insights and, without a doubt, to a new era of phenolics-based pharmacological agents for the treatment of a variety of infectious and degenerative disorders.

Nano-insecticides against the black cutworm Agrotis ipsilon (Lepidoptera: Noctuidae): Toxicity, development, enzyme activity, and DNA mutagenicity.

Frequent applications of synthetic insecticides might cause environmental pollution due to the high residue. In addition, increasing insecticide resistance in many insect pests requires novel pest control methods. Nanotechnology could be a promising field of modern agriculture, and is receiving considerable attention in the development of novel nano-agrochemicals, such as nanoinsectticides and nanofertilizers. This study assessed the effects of the lethal and sublethal concentrations of chlorantraniliprole, thiocyclam, and their nano-forms on the development, reproductive activity, oxidative stress enzyme activity, and DNA changes in the black cutworm, Agrotis ipsilon, at the molecular level. The results revealed that A. ipsilon larvae were more susceptible to the nano-forms than the regular forms of both nano chlorine and sulfur within the chlorantraniliprole and thiocyclam insecticides, respectively, with higher toxicities than the regular forms (ca. 3.86, and ca.2.06-fold, respectively). Significant differences in biological parameters, including developmental time and reproductive activity (fecundity and hatchability percent) were also observed. Correspondingly, increases in oxidative stress enzyme activities were observed, as were mutagenic effects on the genomic DNA of A. ipsilon after application of the LC50 of the nano-forms of both insecticides compared to the control. These promising results could represent a crucial step toward developing efficient nanoinsecticides for sustainable control of A. ipsilon.

Naturally occurring plant-based anticancerous candidates as prospective ABCG2 inhibitors: an in silico drug discovery study.

ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter related to the clinical multidrug resistance (MDR) phenomenon. Identifying ABCG2 inhibitors could help discover extraordinary curative strategies for carcinoma remediation. Hitherto, there is no medication drug inhibiting ABCG2 transporter, notwithstanding that a considerable number of drugs have been submitted to clinical-trial and investigational phases. In the search for unprecedented chemical compounds that could inhibit the ABCG2 transporter, an in silico screening was conducted on the Naturally Occurring Plant-based Anticancer Compound-Activity-Target (NPACT) database containing 1574 compounds. Inhibitor-ABCG2 binding affinities were estimated based on molecular docking and molecular minimization (MM) calculations and compared to a co-crystallized inhibitor (BWQ) acting as a reference inhibitor. Molecular dynamics (MD) simulations pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations were further executed for compounds with MM-GBSA//MM binding energies lower than BWQ (calc. - 60.5 kcal/mol). NPACT00968 and NPACT01545 demonstrated auspicious inhibitory activities according to binding affinities (ΔGbinding) over the 100 ns MD simulations that were nearly one and a half folds compared to BWQ (- 100.4, - 94.7, and - 62.9 kcal/mol, respectively). Throughout the 100 ns MD simulations, structural and energetical analyses unveiled outstanding stability of the ABCG2 transporter when bound with NPACT00968 and NPACT01545. In silico calculations hold a promise for those two inhibitors as drug candidates of ABCG2 transporter and emphasize that further in vitro and in vivo experiments are guaranteed.

Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study.

The main protease (Mpro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for Mpro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the Mpro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins-namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)-demonstrated higher binding affinities against SARS-CoV-2 Mpro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of -58.9, -55.9, -50.1, and -43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin-a venom of the Egyptian solitary wasp-holds promise as a potential Mpro inhibitor and warrants further in vitro/in vivo validation.

Development of rapid and precise approach for quantification of bacterial taxa correlated with soil health.

The structure and dynamic of soil bacterial community play a crucial role in soil health and plant productivity. However, there is a gap in studying the un-/or reclaimed soil bacteriome and its impact on future plant performance. The 16S metagenomic analysis is expensive and utilize sophisticated pipelines, making it unfavorable for researchers. Here, we aim to perform (1) in silico and in vitro validation of taxon-specific qPCR primer-panel in the detection of the beneficial soil bacterial community, to ensure its specificity and precision, and (2) multidimensional analysis of three soils/locations in Egypt ('Q', 'B', and 'G' soils) in terms of their physicochemical properties, bacteriome composition, and wheat productivity as a model crop. The in silico results disclosed that almost all tested primers showed high specificity and precision toward the target taxa. Among 17 measured soil properties, the electrical conductivity (EC) value (up to 5 dS/m) of 'Q' soil provided an efficient indicator for soil health among the tested soils. The 16S NGS analysis showed that the soil bacteriome significantly drives future plant performance, especially the abundance of Proteobacteria and Actinobacteria as key indicators. The functional prediction analysis results disclosed a high percentage of N-fixing bacterial taxa in 'Q' soil compared to other soils, which reflects their positive impact on wheat productivity. The taxon-specific qPCR primer-panel results revealed a precise quantification of the targeted taxa compared to the 16S NGS analysis. Moreover, 12 agro-morphological parameters were determined for grown wheat plants, and their results showed a high yield in the 'Q' soil compared to other soils; this could be attributed to the increased abundance of Proteobacteria and Actinobacteria, high enrichment in nutrients (N and K), or increased EC/nutrient availability. Ultimately, the potential use of a taxon-specific qPCR primer-panel as an alternative approach to NGS provides a cheaper, user-friendly setup with high accuracy.

In Silico Targeting Human Multidrug Transporter ABCG2 in Breast Cancer: Database Screening, Molecular Docking, and Molecular Dynamics Study.

ABCG2 is a substantial member of the ABC transporter superfamily that plays a significant role in multidrug resistance in cancer. Until recently, the 3D structure of ABCG2 has not been resolved, which resulted in the limitation of developing potential ABCG2 inhibitors using structure-based drug discovery. Herein, eMolecules, ChEMBL, and ChEBI databases, containing >25 million compounds, were virtually screened against the ABCG2 transporter in homodimer form. Performance of AutoDock4.2.6 software to predict inhibitor-ABCG2 binding mode and affinity were validated on the basis of available experimental data. The explored databases were filtered based on docking scores. The most potent hits with binding affinities higher than that of experimental bound ligand (MZ29) were then selected and subjected to molecular mechanics minimization, followed by binding energy calculation using molecular mechanics-generalized Born surface area (MM-GBSA) approach. Furthermore, molecular dynamics simulations for 50 ns, followed by MM-GBSA binding energy calculations, were performed for the promising compounds, unveiling eight potential inhibitors with binding affinities <-55.8 kcal/mol. Structural and energetic analyses demonstrated the stability of the eight identified inhibitors over the 50 ns MD simulation. This research sheds light on the potentiality of the identified ABCG2 inhibitors as a therapeutic approach to overcome multidrug resistance cancer therapy.

Roles of Exogenous α-Lipoic Acid and Cysteine in Mitigation of Drought Stress and Restoration of Grain Quality in Wheat.

Cysteine (Cys) and α-lipoic acid (ALA) are naturally occurring antioxidants (sulfur-containing compounds) that can protect plants against a wide spectrum of environmental stresses. However, up to now, there are no conclusive data on their integrative roles in mitigation of drought stress in wheat plants. Here, we studied the influence of ALA at 0.02 mM (grain dipping pre-cultivation treatment) and Cys (25 and 50 ppm as a foliar application) under well watered and deficit irrigation (100% and 70% of recommended dose). The results showed that deficit irrigation markedly caused obvious cellular oxidative damage as indicated by elevating the malondialdehyde (MDA) and hydrogen peroxide content (H2O2). Moreover, water stressed plants exhibited multiple changes in physiological metabolism, which affected the quantitative and qualitative variables of grain yield. The enzymatic antioxidants, including superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT) and peroxidase (POX) were improved by Cys application. SOD and APX had the same response when treated with ALA, but CAT and POX did not. Moreover, both studied molecules stimulated chlorophyll (Chl) and osmolytes' biosynthesis. In contrast, the Chl a/b ratio was decreased, while flavonoids were not affected by either of the examined molecules. Interestingly, all above-mentioned changes were associated with an improvement in the scavenging capacity of reactive oxygen species (ROS), leaf relative water content (RWC), grain number, total grain yield, weight of 1000 kernels, gluten index, falling number, and alveographic parameters (P, W, and P/L values). Furthermore, heatmap plot analysis revealed several significant correlations between different studied parameters, which may explore the importance of applied Cys and ALA as effective compounds in wheat cultivation under water deficit conditions.

PlantPathMarks (PPMdb): an interactive hub for pathways-based markers in plant genomes.

ABSTRACT: Over the past decade, the problem of finding an efficient gene-targeting marker set or signature for plant trait characterization has remained challenging. Many databases focusing on pathway mining have been released with one major deficiency, as they lack to develop marker sets that target only genes controlling a specific pathway or certain biological process. Herein, we present the PlantPathMarks database (PPMdb) as a comprehensive, web-based, user-friendly, and interactive hub for pathway-based markers in plant genomes. Based on our newly developed pathway gene set mining approach, two novel pathway-based marker systems called pathway gene-targeted markers (PGTMs) and pathway microsatellite-targeted markers (PMTMs) were developed as a novel class of annotation-based markers. In the PPMdb database, 2,690,742 pathway-based markers reflecting 9,894 marker panels were developed across 82 plant genomes. The markers include 691,555 PGTMs and 1,999,187 PMTMs. Across these genomes, 165,378 enzyme-coding genes were mapped against 126 KEGG reference pathway maps. PPMdb is furnished with three interactive visualization tools (Map Browse, JBrowse and Species Comparison) to visualize, map, and compare the developed markers over their KEGG reference pathway maps. All the stored marker panels can be freely downloaded. PPMdb promises to create a radical shift in the paradigm of the area of molecular marker research. The use of PPMdb as a mega-tool represents an impediment for non-bioinformatician plant scientists and breeders. PPMdb is freely available at http://ppmdb.easyomics.org .

Lepidium sativum Secondary Metabolites (Essential Oils): In Vitro and In Silico Studies on Human Hepatocellular Carcinoma Cell Lines.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the greatest cause of cancer-related death in the world. Garden cress (Lepidium sativum) seeds have been proven to possess extraordinary antioxidant, anti-inflammatory, hypothermic, and analgesic properties. In this study, in vitro cytotoxic efficiency evaluation of L. sativum fractions was performed against two hepatocellular carcinoma cell lines (HuH-7 and HEPG-2), and the expression of some apoptotic genes was explored. In addition, the chemical composition of a potent extract of L. sativum was analyzed using gas chromatography coupled with mass spectrometry. Then, molecular docking analysis was implemented to identify the potential targets of the L. sativum components' most potent extract. Overall, the n-hexane extract was the most potent against the two HCC cell lines. Moreover, these cytotoxicity levels were supported by the significant downregulation of EGFR and BCL2 gene expression levels and the upregulation of SMAD3, BAX, and P53 expression levels in both HuH-7 and HEPG2 cell lines. Regarding L. sativum's chemical composition, GC-MS analysis of the n-hexane extract led to the identification of thirty compounds, including, mainly, hydrocarbons and terpenoids, as well as other volatile compounds. Furthermore, the binding affinities and interactions of the n-hexane fraction's major metabolites were predicted against EGFR and BCL2 molecular targets using the molecular docking technique. These findings reveal the potential use of L. Sativum in the management of HCC.

Non-ß-Lactam Allosteric Inhibitors Target Methicillin-Resistant Staphylococcus aureus: An In Silico Drug Discovery Study.

Penicillin-binding proteins (PBPs) catalyze the final stages for peptidoglycan cell-wall bio-synthesis. Mutations in the PBP2a subunit can attenuate ß-lactam antibiotic activity, resulting in unimpeded cell-wall formation and methicillin-resistant Staphylococcus aureus (MRSA). A double mutation in PBP2a (i.e., N146K and E150K) is resistant to ß-lactam inhibitors; however, (E)-3-(2-(4-cyanostyryl)-4-oxoquinazolin-3(4H)-yl) benzoic acid (QNZ), a heterocyclic antibiotic devoid of a ß-lactam ring, interacts non-covalently with PBP2a allosteric site and inhibits PBP enzymatic activity. In the search for novel inhibitors that target this PBP2a allosteric site in acidic medium, an in silico screening was performed. Chemical databases including eMolecules, ChEMBL, and ChEBI were virtually screened for candidate inhibitors with a physicochemical similarity to QNZ. PBP2a binding affinities from the screening were calculated based on molecular docking with co-crystallized ligand QNZ serving as a reference. Molecular minimization calculations were performed for inhibitors with docking scores lower than QNZ (calc. -8.3 kcal/mol) followed by combined MD simulations and MM-GBSA binding energy calculations. Compounds eMol26313223 and eMol26314565 exhibited promising inhibitor activities based on binding affinities (ΔGbinding) that were twice that of QNZ (-38.5, -34.5, and -15.4 kcal/mol, respectively). Structural and energetic analyses over a 50 ns MD simulation revealed high stability for the inhibitors when complexed with the double mutated PBP2a. The pharmacokinetic properties of the two inhibitors were predicted using an in silico ADMET analysis. Calculated binding affinities hold promise for eMol26313223 and eMol26314565 as allosteric inhibitors of PBP2a in acidic medium and establish that further in vitro and in vivo inhibition experimentation is warranted.