Estrogen Receptor Alpha Binders for Hormone-Dependent Forms of Breast Cancer: e-QSAR and Molecular Docking Supported by X-ray Resolved Structures.

Cancer, a life-disturbing and lethal disease with a high global impact, causes significant economic, social, and health challenges. Breast cancer refers to the abnormal growth of cells originating from breast tissues. Hormone-dependent forms of breast cancer, such as those influenced by estrogen, prompt the exploration of estrogen receptors as targets for potential therapeutic interventions. In this study, we conducted e-QSAR molecular docking and molecular dynamics analyses on a diverse set of inhibitors targeting estrogen receptor alpha (ER-α). The e-QSAR model is based on a genetic algorithm combined with multilinear regression analysis. The newly developed model possesses a balance between predictive accuracy and mechanistic insights adhering to the OECD guidelines. The e-QSAR model pointed out that sp2-hybridized carbon and nitrogen atoms are important atoms governing binding profiles. In addition, a specific combination of H-bond donors and acceptors with carbon, nitrogen, and ring sulfur atoms also plays a crucial role. The results are supported by molecular docking, MD simulations, and X-ray-resolved structures. The novel results could be useful for future drug development for ER-α.

In vitro efficacy of Boswellia carterii resin extracts formulated as an emulsifiable concentrate against Tetranychus urticae and phytopathogenic fungi.

Contemporary agriculture heavily relies on pesticides for pest eradication and disease management. Consequently, current study was carried out to assess the acaricidal/antifungal efficacy of emulsifiable concentrate (10 % EC) derived from Boswellia carterii (B. carterii) against adult females of Tetranychus urticae (T. urticae), and five fungal pathogens. The meticulous examination of the chemical constitution of the crude extracts derived from the resin of B. carterii was conducted through the employment of the venerable technique known as Gas-Liquid Chromatography (GLC). The formulated petroleum-ether extract (FPEE) and formulated ethyl-acetate extract (FEAE) of B. carterii at a concentration of 10 mg ml-1 exhibited notable antioxidant activity with rates of 62.0 % and 90.8 %, respectively. In vitro, the FEAE exhibited potent inhibition against all the tested phytopathogenic fungi at different concentrations, whereas FPEE showed comparatively less efficacy. Interestingly, at 4000 ppm concentration, FEAE completely ceased the mycelial growth compared with the control. Moreover, following a span of 72 h of intervention, FPEE exhibited a greater degree of toxicity towards mature females of the T. urticae. This was evidenced by the LC50 value of 422.52 parts per million (ppm) for FPEE, which surpassed the LC50 value of 539.50 ppm observed for FEAE. In summary, the present study indicates that B. carterii resin formulated as an emulsifiable concentrate (10 % EC) can offer a natural and effective alternative for integrated pest management, thereby reducing reliance on synthetic pesticides and offering a more environmentally sustainable strategy for pest control.

Evaluation of the Fungicidal Effect of Some Commercial Disinfectant and Sterilizer Agents Formulated as Soluble Liquid against Sclerotium rolfsii Infected Tomato Plant.

Globally, root rot disease of tomato plants caused by Sclerotium rolfsii is a severe disease leading to the death of infected plants. The effect of some commercial antiseptics and disinfectant agents, such as chloroxylenol (10%), phenic (10%) and formulated phenol (7%) on the control of root rot pathogen and its impact on growth and chemical constituents of tomato seedlings cv. Castle Rock were investigated in vitro and in vivo. The antifungal activity was measured in vitro following the poisoned food technique at different concentrations of 1000, 2000, 3000 and 4000 µL/L. Disinfectant agents and atrio (80%) were tested in vivo by soaking 20-day-old tomato seedlings in four concentrations of 125, 250, 500 and 1000 µL/100 mL water for 5 min and thereafter planting in soil infested by S. rolfsii. Fresh and dry weight, shoot and root length, and chemical constituents of tomato seedlings infected by S. rolfsii were investigated at 35 days after planting (DAP). Experimental results indicated that chloroxylenol (10%) was the most effective on fungus in vitro, recorded an effective concentration (EC50 = 1347.74 µL/L) followed by phenic (10%) (EC50 = 1370.52 µL/L) and formulated phenol (7%) (EC50 = 1553.59 µL/L). In vivo, atrio (80%) and disinfectant agents at different concentrations significantly (p ≤ 0.05) reduced disease incidence, increased shoot and root lengths and increased dry and fresh weight. Additionally, it significantly increased chlorophyll a, chlorophyll b, total carotenoids, total carbohydrates, total proteins, and total phenols. The highest reduction of root rot incidence and increase tomato growth parameters, as well as chemical compositions, were recorded on tomato seedlings treated with atrio (80%) as well as formulated phenol (7%) at different concentrations, followed by chloroxylenol (10%) at 125 and 250 µL/100 mL, whereas phenic (10%) was found to be the least effective treatment. Therefore, the application of formulated phenol (7%) could be commercially used to control tomato root rot diseases and increase the quality and quantity of tomato plants since it is promising against the pathogen, safe, and less expensive than fungicides.

Site-directed mutagenesis of Serine-72 reveals the location of the fructose 6-phosphate regulatory site of the Agrobacterium tumefaciens ADP-glucose pyrophosphorylase.

The allosteric regulation of ADP-glucose pyrophosphorylase is critical for the biosynthesis of glycogen in bacteria and starch in plants. The enzyme from Agrobacterium tumefaciens is activated by fructose 6-phosphate (Fru6P) and pyruvate (Pyr). The Pyr site has been recently found, but the site where Fru6P binds has remained unknown. We hypothesize that a sulfate ion previously found in the crystal structure reveals a part of the regulatory site mimicking the presence of the phosphoryl moiety of the activator Fru6P. Ser72 interacts with this sulfate ion and, if the hypothesis is correct, Ser72 would affect the interaction with Fru6P and activation of the enzyme. Here, we report structural, binding, and kinetic analysis of Ser72 mutants of the A. tumefaciens ADP-glucose pyrophosphorylase. By X-ray crystallography, we found that when Ser72 was replaced by Asp or Glu side chain carboxylates protruded into the sulfate-binding pocket. They would present a strong steric and electrostatic hindrance to the phosphoryl moiety of Fru6P, while being remote from the Pyr site. In agreement, we found that Fru6P could not activate or bind to S72E or S72D mutants, whereas Pyr was still an effective activator. These mutants also blocked the binding of the inhibitor AMP. This could potentially have biotechnological importance in obtaining enzyme forms insensitive to inhibition. Other mutations in this position (Ala, Cys, and Trp) confirmed the importance of Ser72 in regulation. We propose that the ADP-glucose pyrophosphorylase from A. tumefaciens have two distinct sites for Fru6P and Pyr working in tandem to regulate glycogen biosynthesis.

The ADP-glucose pyrophosphorylase from Melainabacteria: a comparative study between photosynthetic and non-photosynthetic bacterial sources.

Until recently, the cyanobacterial phylum only included oxygenic photosynthesizer members. The discovery of Melainabacteria as a group of supposed non-photosynthetic cyanobacteria asked to revisit such scenario. From metagenomic data, we were able to identify sequences encoding putative ADP-glucose pyrophosphorylases (ADP-GlcPPase) from free-living and intestinal Melainabacteria. The respective genes were de novo synthesized and over-expressed in Escherichia coli. The purified recombinant proteins from both Melainabacteria species were active as ADP-GlcPPases, exhibiting Vmax values of 2.3 (free-living) and 7.1 U/mg (intestinal). The enzymes showed similar S0.5 values (∼0.3 mM) for ATP, while the one from the intestinal source exhibited a 6-fold higher affinity toward glucose-1P. Both recombinant ADP-GlcPPases were sensitive to glucose-6P activation (A0.5 ∼0.3 mM) and Pi and ADP inhibition (I0.5 between 0.2 and 3 mM). Interestingly, the enzymes from Melainabacteria were insensitive to 3-phosphoglycerate, which is the principal activator of ADP-GlcPPases from photosynthetic cyanobacteria. As far as we know, this is the first biochemical characterization of an active enzyme from Melainabacteria. This work contributes to a better understanding of the evolution of allosteric regulation in the ADP-GlcPPase family, which is critical for synthesizing the main reserve polysaccharide in prokaryotes (glycogen) and plants (starch). In addition, our results offer further information to discussions regarding the phylogenetic position of Melainabacteria.

Hexosomal Dispersion: A Nano-Based Approach to Boost the Antifungal Potential of Citrus Essential Oils against Plant Fungal Pathogens.

The demand for natural fungicides to replace synthetic ones has surged since toxic residues persist in soils, causing environmental contamination and posing a serious threat to worldwide public health. In the context of crop protection and enhancing the efficiency and safety of fungicides, nanotechnology is an eco-friendly strategy in managing fungal pathogens. In the present study, essential oils were isolated from the peels of four citrus fruits (Citrus lemon, Citrus aurantifolia, Citrus maxima, and Citrus sinensis) and were investigated using gas chromatography-mass spectrometric analysis. Monoterpene hydrocarbon was the most predominant group and limonene was the most abundant in the four oils. The antifungal potential of the oils was investigated, and the most active oil (Citrus lemon) was loaded into hexosomal dispersion, and its antifungal potential was retested against the same fungi. The structurally unique nano-based formulation showed great potency for fungal control. To the best of our knowledge, it is the first time the oil of Citrus lemon in nano-hexosomes has been formulated and its fungicidal activity examined. The data collected suggest that citrus essential oils (CEOs), especially when nano-formulated, could be successfully used in integrated fungus management programs.

Chemical composition and potentiation of insecticidal and fungicidal activities of Citrus trifoliata L. fruits essential oil against Spodoptera littoralis, Fusarium oxysporum and Fusarium solani via nano-cubosomes.

Development of natural nano-based plant-protection formulations represents an emerging phenomenon that has been widely improved for crops protection and for enhancing the efficiency and safety of pesticides. In the present study we isolated the essential oil from the fruits of Citrus trifoliata L. and investigated it using gas chromatography-mass spectrometry analysis. Limonene (78.46%) was the major component followed by ß-Myrcene (7.94%) and Caryophyllene (4.20%). Citrus trifoliata essential oil (CTEO) loaded nano-cubosomes were successfully prepared by the emulsification technique. The insecticidal and fungicidal activities of formulated CTEO nano-cubosomes and unformulated CTEO were tested. While both of them exhibited substantial activities, CTEO nano-cubosomes were more effective than unformulated oil. It is the first time to formulate CTEO in nano-cubosomes and examine their insecticidal and fungicidal activities. In light of the current study, CTEO as it is or as nano-cubosomes is recommended as a promising candidate for pest and fungal pathogens control.Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1675063.

Red Blood Cells and Lipoproteins: Important Reservoirs and Transporters of Polyphenols and Their Metabolites.

Dietary polyphenols are protective for chronic diseases. Their blood transport has not been well investigated. This work examines multiple classes of polyphenols and their interactions with albumin, lipoproteins, and red blood cell (RBC) compartments using four models and determines the % polyphenol in each compartment studied. The RBC alone model showed a dose-response polyphenol association with RBCs. A blood model with flavanones determined the % polyphenol that was inside RBCs and bound to the surface using a new albumin washing procedure. It was shown that RBCs can methylate flavanones. The whole blood model separated the polyphenol into four compartments with the aid of affinity chromatography. More polyphenols were found with albumin and lipoproteins (high-density lipoproteins and low-density lipoproteins) than with RBCs. In the plasma model, the polyphenols associated almost equally between lipoproteins and albumin. RBCs and lipoproteins are shown to be important reservoirs and transporters of polyphenols in blood.