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.

SGLT-2 inhibitors enhance the effect of metformin to ameliorate hormonal changes and inflammatory markers in a rat PCOS model.

Polycystic ovary syndrome (PCOS) is a common endocrine, reproductive, and metabolic disorder affecting females. The management of PCOS is challenging and current interventions are not enough to deal with all consequences of this syndrome. We explored the beneficial effect of combined sodium glucose co transporter-2 inhibitor (SGLT-2i); (empagliflozin) and metformin on hormonal and metabolic parameters in an animal model of PCOS and insulin resistance (IR). Forty adult female Wistar rats divided into five groups: control, PCOS-IR, PCOS-IR treated with metformin, PCOS-IR treated with empagliflozin, and PCOS-IR treated with combined metformin and empagliflozin. Single modality treatment with metformin or empagliflozin yielded significant improvement in body mass index, insulin resistance, lipid profile, sex hormones, inflammatory markers, and ovarian cystic follicles. Combined metformin with empagliflozin expressed further significant improvement in sex hormones, inflammatory markers with disappearance of ovarian cystic follicles. The superior significant improvement with combined treatment over the single modality was in line with significant improvement in the ovarian AMPKα-SIRT1 expression.

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.

Pattern of novel psychoactive substance use among patients presented to the poison control centre of Ain Shams University Hospitals, Egypt: A cross-sectional study.

Background: Novel psychoactive substances (NPSs) are relatively new substances in the illicit drug market, not previously listed in the United Nations Office on Drugs and Crime (UNDOC). Strox and Voodoo are considered some of the most popular blends of NPS in the Egyptian drug market. Objectives: The current study was conducted to assess NPS's use pattern: Voodoo and Strox among acutely intoxicated patients presented to the poison control center of Ain Shams University Hospitals (PCC- ASUH). Methods: A single center based cross-sectional study was carried out in the PCC-ASUH among acutely intoxicated patients presenting to the emergency department (ED) over four months (from January-April 2019. using a previously adopted and validated Fahmy and El-Sherbini socioeconomic scale (SES). Data were presented as mean, median and range as appropriate. Both smoking and crowding indexes were calculated and presented as previously reported. Results: Fifty-one patients were presented to the ED of PCC-ASUH during the study period. A total of 96.1% (n = 49) were males. The mean age was 25 ± 7.5 years. The most common NPS used was Strox: 54.9% (n = 28), followed by Voodoo: 27.4% (n = 14). Neurological and gastrointestinal (GI) symptoms were the most frequent presentations. The most common motive behind NPS use was the desire to give a trial of new psychoactive substances. The mean SES score was 35.1 ± 13.17. Most patients have the preparatory as the highest education 36.0% (n = 18). Conclusions: NPS use is common among young males in preparatory education from different social classes, starting it most commonly as a means to experiencing a new high. Neurological and GI manifestations are the most common presenting symptoms of NPS intoxication.

Voluntary testing for COVID-19: perceptions and utilization among the inhabitants of Saudi Arabia.

OBJECTIVES: Voluntary testing (VT) plays a crucial role in the prevention and control of infectious diseases. The present study investigated the perceptions and utilization of VT services for coronavirus disease 2019 (COVID-19) among the inhabitants of Saudi Arabia. METHODS: In total, 3,510 adult participants from all provinces of Saudi Arabia were recruited via a national online survey. RESULTS: Of the 3,510 participants, 88.9% were aware of the testing services available to them and of those, more than half (59.5%) had used the VT services and 96.1% were satisfied with the services. Contact with a positive COVID-19 case was the top reason for accessing VT, while a lack of awareness about the availability of VT services was the top perceived limiting factor. A history of chronic health conditions, anxiety and/or depression, and previous symptoms suggestive of COVID-19 were found to be predictors of the utilization of VT services (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.22-1.96; OR 1.48, 95% CI 1.16-1.88; and OR 3.31, 95% CI 2.77-3.95), respectively. CONCLUSION: The awareness of voluntary COVID-19 testing services was satisfactory among the Saudi Arabian population, but can be improved. Sociodemographic and health history predictors of the utilization of VT services were identified.

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.

Identification of 'Voodoo': an emerging substance of abuse in Egypt.

BACKGROUND: 'Voodoo' is a new substance of abuse that recently spread among youth in Egypt. It has numerous potentially dangerous effects on humans. However, to date the composition of the main constituents of this compound is unknown. PURPOSE: We sought to identify the active components of this unknown substance"voodoo". METHODS: Three samples were collected and analysed by high-performance liquid chromatography with photodiode array detector (HPLC-PAD), gas chromatography/mass spectrometry (GC/MS), and ultra-performance liquid chromatography/mass spectrometry (UPLC-MS/MS) using targeted multiple reaction monitoring (MRM). RESULTS: HPLC-PAD analysis showed that samples 1 and 2 had some common major peaks, the same retention time, and similar spectra, whereas sample 3 showed different peaks. GC/MS analysis revealed the presence of various putatively identified bioactive compounds, including quinazolines, morphinan alkaloid, cannabinoids, penitrem A, and the well-known synthetic cannabinoid FUB-AMB (methyl(2S)-2-{[1-[(4-fluorophenyl)methyl]indazole-3-carbonyl]amino}-3 methylbutanoate). UPLC-MS/MS analysis revealed the presence of common compounds such as tetrahydrocannabinol (THC), amphetamine, 3,4-methylenedioxyamphetamine, tramadol, and oxazepam. CONCLUSION: We concluded that Voodoo is a mixture of substances of abuse at varying concentrations.

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.

Acute Toxic Effects of the New Psychoactive Substance "Voodoo" among Patients presented to the Poison Control Center of Ain Shams University Hospitals (PCC-ASUH), Egypt, during 2017.

BACKGROUND: Voodoo is a heterogeneous mixture of psychoactive substances that has recently grown in popularity among youth in Egypt. Patients can present with a variety of manifestations that may lead to death in some cases. This study assessed the acute toxic effects of voodoo among patients presented to the Poison Control Center of Ain Shams University Hospitals (PCC-ASUH) during a one year period. METHODS: This is a retrospective study of all patients presented with voodoo intoxication at the PCC-ASUH from 1 January 2017 to 31 December 2017. Clinical data, routine laboratory findings, and ECG results as well as duration of hospitalization and outcome were compiled from hospital records. RESULTS: Seventy-one voodoo intoxication cases meeting the inclusion criteria were analyzed (mean age: 25.19 ± 9.54 years, range: 15-50 years, 97.2 % male). Pulse, blood pressure, and respiratory rate were normal in more than half of all patients. Neurological abnormalities including agitation, hallucinations, disturbance of consciousness were the most frequent manifestations. Respiratory acidosis was the most common laboratory finding (54.9 %), followed by increased serum urea (43.6 %), hypokalemia (33.8 %), hyperglycemia (28.1 %), and leukocytosis (26.7 %). The most common ECG finding was sinus tachycardia (31 %), followed by QT prolongation (15.4 %). More than half of the studied patients (53.5 %) co-administered other illicit substances, most frequently cannabis and tramadol. Most patients recovered fully and were discharged, but death occurred in two cases. CONCLUSIONS: Voodoo toxicity can manifest with many presentations, hampering timely diagnosis. Clinicians should consider possible voodoo poisoning in patients presenting with a history of drug use with neurological symptoms, and they should conduct follow-up arterial blood gases, electrolytes and ECG as voodoo may contain potentially fatal psychoactive substances.

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.

Caspases as prognostic markers and mortality predictors in acute organophosphorus poisoning.

BACKGROUND: Organophosphorus (OP) compounds have been widely available for decades in agriculture for crop protection and as cheap pest controllers, which increases the rate of exposure and poisoning cases. Using serum cholinesterase as prognostic markers for the acute OP toxicity is controversial; therefore, we aim to find out prognostic biomarkers that best correlate with mortality and outcomes of patients with acute OP toxicity. Levels of serum oxidative stress biomarkers (malondialdehyde (MDA) and total antioxidant capacity (TAC)) and activity of the apoptotic biomarkers (caspase 3 and caspase 9) and pseudo-cholinesterase (p.ChE) were performed. Also, we evaluated the apoptotic capacity through determining the genotoxic effects and chromosomal abnormalities among OP intoxicated patients. RESULTS: We found the activity of caspases and serum MDA and TAC were significantly increased after OP poisoning and decreased after the appropriate atropine and oxime treatment course. The ROC curve suggested caspases as mortality and outcome predictive markers for acute OP poisoning patients. However, OP poisoning cases before treatment showed significant DNA damage, and they did not show any chromosomal aberration. CONCLUSION: The mentioned results strongly suggest apoptotic-related markers (caspase 3, caspase 9) as prognostic markers for evaluation of the treatment, outcomes, and mortality rate in the acute OP toxicity patients.

Sequential intrathecal injection of fentanyl and hyperbaric bupivacaine at different rates: does it make a difference? A randomized controlled trial.

BACKGROUND: Previous studies have shown that sequential intrathecal injection of fentanyl and hyperbaric bupivacaine for cesarean section (CS) anesthesia provides a superior anesthetic effect than use of bupivacaine alone, and prolongs postoperative analgesia. Herein, we investigated whether rapid intrathecal injection of fentanyl followed by slow injection of hyperbaric bupivacaine affects the duration of postoperative analgesia, the effectiveness of anesthesia, and hemodynamic status. METHODS: Fifty-six parturients with American Society of Anesthesiologists physical status I or II, aged 18-40 years, and scheduled to undergo elective CS were randomly assigned to 2 groups of 28 patients each. The normal sequential group received sequential intrathecal injections of fentanyl and hyperbaric bupivacaine at the same rate, each with a 5 ml syringe. The rapid sequential group received a rapid intrathecal injection of fentanyl with an insulin syringe, followed by a slow injection of hyperbaric bupivacaine with a 5 ml syringe. The onset of sensory block, the timing of the first rescue analgesia, the doses of rescue analgesics, the degree of postoperative pain, the onset and duration of motor block, the incidence and duration of hypotension, and spinal anesthesia-related complications were recorded. RESULTS: While both approaches had comparable spinal anesthesia-related complications, incidence and duration of hypotension, and doses of ephedrine, the rapid sequential group exhibited a more rapid onset of sensory block, a higher sensory level, and more prolonged postoperative analgesia. CONCLUSIONS: Rapid sequential injection of fentanyl and hyperbaric bupivacaine produced superior anesthesia and more prolonged postoperative analgesia than sequential injections of both at the same rate.