2-Thioxo-3,4-dihydropyrimidine and thiourea endowed with sulfonamide moieties as dual EGFRT790M and VEGFR-2 inhibitors: Design, synthesis, docking, and anticancer evaluations.

The effectiveness of a new series of thiopyrimidine and thiourea containing sulfonamides moieties was tested on HCT-116, MCF-7, HepG2, and A549. HepG2 cell line was the one that all the new derivatives affected the most. The greatest potent compounds against the four HepG2, HCT116, MCF-7, and A549 cell lines were 8f and 8g with IC50 = 4.13, 6.64, 5.74, 6.85 µM and 4.09, 4.36, 4.22, 7.25 µM correspondingly. Compound 8g exhibited higher activity than sorafenib against HCT116 and MCF-7 but exhibited lower activity against HepG2 and A549. Moreover, compounds 8f and 8g exhibited higher activities than erlotinib on HepG2, HCT116, and MCF-7 but demonstrated lower activity on A549. The most potent cytotoxic derivatives 6f, 6g, 8c, 8d, 8e, 8f, and 8g were examined on normal VERO cell lines. Our derivatives have low toxicity on VERO cells with IC50 values ranging from 32.05 to 53.15 µM. Additionally, all compounds were assessed for dual VEGFR-2 and EGFRT790M inhibition effects. Compounds 8f and 8g were the most potent derivatives inhibited VEGFR-2 at IC50 value of 0.88 and 0.90 µM, correspondingly. As well, derivatives 8f and 8g could inhibit EGFRT790M demonstrating strongest effects with IC50 = 0.32 and 0.33 µM sequentially. Additionally, the greatest active derivatives ADMET profile was evaluated in relationship with sorafenib and erlotinib as reference agents. The data attained from docking were greatly related to that achieved from the biological testing.

Ceiba pentandra ethyl acetate extract improves doxorubicin antitumor outcomes against chemically induced liver cancer in rat model: a study supported by UHPLC-Q-TOF-MS/MS identification of the bioactive phytomolecules.

Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide. Late-stage detection, ineffective treatments, and tumor recurrence contribute to the low survival rate of the HCC. Conventional chemotherapeutic drugs, like doxorubicin (DOX), are associated with severe side effects, limited effectiveness, and tumor resistance. To improve therapeutic outcomes and minimize these drawbacks, combination therapy with natural drugs is being researched. Herein, we assessed the antitumor efficacy of Ceiba pentandra ethyl acetate extract alone and in combination with DOX against diethylnitrosamine (DENA)-induced HCC in rats. Our in vivo study significantly revealed improvement in the liver-function biochemical markers (ALT, AST, GGT, and ALP), the tumor marker (AFP-L3), and the histopathological features of the treated groups. A UHPLC-Q-TOF-MS/MS analysis of the Ceiba pentandra ethyl acetate extract enabled the identification of fifty phytomolecules. Among these are the dietary flavonoids known to have anticancer, anti-inflammatory, and antioxidant qualities: protocatechuic acid, procyanidin B2, epicatechin, rutin, quercitrin, quercetin, kaempferol, naringenin, and apigenin. Our findings highlight C. pentandra as an affordable source of phytochemicals with possible chemosensitizing effects, which could be an intriguing candidate for the development of liver cancer therapy, particularly in combination with chemotherapeutic drugs.

Synthesis and Characterization of a New Class of Chromene-Azo Sulfonamide Hybrids as Promising Anticancer Candidates with the Exploration of Their EGFR, hCAII, and MMP-2 Inhibitors Based on Molecular Docking Assays.

In this study, novel selective antitumor compounds were synthesized based on their fundamental pharmacophoric prerequisites associated with EGFR inhibitors. A molecular hybridization approach was employed to design and prepare a range of 4H-chromene-3-carboxylates 7a-g, 8, and 11a-e derivatives, each incorporating a sulfonamide moiety. The structures of these hybrid molecules were verified using comprehensive analytical and spectroscopic techniques. During the assessment of the newly synthesized compounds for their anticancer properties against three tumor cell lines (HepG-2, MCF-7, and HCT-116), compounds 7f and 7g displayed remarkable antitumor activity against all tested cell lines, outperforming the reference drug Cisplatin in terms of efficacy. Consequently, these promising candidates were selected for further investigation of their anti-EGFR, hCAII, and MMP-2 potential, which exhibited remarkable effectiveness against EGFR and MMP2 when compared to Sorafenib. Additionally, docking investigations regarding the EGFR binding site were implemented for the targeted derivatives in order to attain better comprehension with respect to the pattern in which binding mechanics occur between the investigated molecules and the active site, which illustrated a higher binding efficacy in comparison with Sorafenib.

Discovery of 5-Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors.

SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors. Our efforts led to the discovery of the 5-azaquinoxaline as a new core for developing this class of compounds. Optimization of the potency and properties of this scaffold generated compound 30, that exhibited potent in vitro SHP2 inhibition and showed excellent in vivo efficacy and pharmacokinetic profile.

Cell Death Markers in Children with Immune Thrombocytopenic Purpura: A Preliminary Study.

Immune thrombocytopenic purpura (ITP) is an autoimmune disease with possible dysregulation of the apoptotic pathways. We aimed to evaluate the possible role of some apoptotic markers (caspase 3, caspase 8 and BCL2) in the pathogenesis and course of ITP. We investigated some apoptotic markers (caspase 3, caspase 8 and BCL2) using the flow cytometry in 60 children with newly diagnosed ITP, 20 children with chemotherapy-related thrombocytopenia (CRT) and 20 healthy children. We also assessed the effects of intravenous immunoglobulin (IVIG) and methyl prednisolone therapies on the platelet apoptosis in children with newly diagnosed ITP. We demonstrated significantly higher values of caspase 3 in the newly diagnosed ITP group than control and CRT groups, and non-significantly higher values of caspase 8 in the ITP group than the healthy group. After IVIG treatment, the platelet count increased in all patients, and there was a significant decrease in caspase 3 and caspase 8 levels while BCL2 level increased. Regarding methylprednisolone treatment, there was a significant decrease in BCL2 and caspase 8 levels while caspase 3 levels did not significantly decrease. There is a possible role of the caspase dependent cell death pathway of the platelets in the occurrence of newly diagnosed ITP. There is heterogeneity in the apoptotic changes of newly diagnosed ITP children who received IVIG versus those who received methylprednisolone.

Dentists' Utilization of Caries Risk Assessment and Individualized Caries Prevention Methods in Pediatric Patients in Saudi Arabia.

Introduction: The first step in any complete oral health care plan for a child is a thorough caries risk assessment (CRA). This study aimed to investigate whether the practice dentists in Saudi Arabia's Western province do CRA methods and offer Individualized Caries Prevention (ICP) to their pediatric patients. Material and Methods: Dentists in active clinical practice in the Western province of Saudi Arabia were the participants of this cross-sectional survey. The participants in this study were chosen using a simple random sampling technique. A self-administered, structured questionnaire was used to gather participants' responses. Results: A majority (88.2%) of the dentists agreed that it is very important to practice CRA on a regular basis among their pediatric patients. About 67% of dentists employed Individualized Caries Prevention methods. No statistically significant correlation was observed between ICP and CRA factors, indicating that interventions primarily focused on patients' financial affordability. Conclusion: Dentists should encourage parents/caregivers to establish a dental home concept at the earliest, which includes CRA, education, and anticipatory guidance on the prevention of oral diseases.

Proficiency of some synthetic alginate derivatives for sequestration of Iodine-131 from radioactive liquid waste.

The current effort in environmental remediation is aimed at removing iodine-131 radionuclide from radioactive liquid waste produced by an Egyptian nuclear power plant using some synthesised alginate derivatives. Two different copolymers, namely sodium alginate poly (acrylic acid) (P1) and sodium alginate poly (acrylic acid-methacrylic acid) (P2), are prepared using gamma radiation. The ability of these polymers to remove 131I radionuclide as sorbents has been investigated. The synthesised polymers exhibit excellent adsorption performance for 131I ions, and the adsorption equilibrium requires only 30 min, which reveals that the sorption process is kinetically faster than most of the other materials reported previously. The removal percents for 131I radionuclide at a pH of 3.0 at room temperature on P1 and P2 are 77.7% and 84.2%, respectively. The sorption capacities of the two polymers demonstrate that P2 > P1, with capacities of 67.9 and 58.5 mg/g, respectively. Four linear kinetic models are investigated: pseudo-first order, pseudo-second order, Elovich, and Weber-Morris models. Regarding their calculated parameters, these models indicate that the adsorption process of I-ions on both P1 and P2 is controlled by chemisorption. Four equilibrium isotherm models (Redlich-Peterson, Langmuir, Freundlich, and Harkin-Jura) are investigated, revealing that the adsorption process is a monolayer and multilayer process on a heterogeneous surface.

A new class of anti-proliferative activity and apoptotic inducer with molecular docking studies for a novel of 1,3-dithiolo[4,5-b]quinoxaline derivatives hybrid with a sulfonamide moiety.

A new series of 6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxaline-2-ylidines 10a-f, 12, 14, 16, and 18 were designed, synthesized, and evaluated for their in vitro anticancer activity. The structures of the novel compounds were systematically characterized by 1H NMR, 13C NMR, and elemental analysis. The synthesized derivatives were evaluated for their in vitro antiproliferative activity against three human cancer cell lines (HepG-2, HCT-116, and MCF-7) with more sensitivity to MCF-7. Moreover, three derivatives 10c, 10f, and 12 were the most promising candidates with sub-micromole values. These derivatives were further evaluated against MDA-MB-231, and the results displayed significant IC50 values ranging from 2.26 ± 0.1 to 10.46 ± 0.8 µM and showed low cellular cytotoxicity against WI-38. Surprisingly, the most active derivative 12 revealed sensitivity towards the breast cell lines MCF-7 (IC50 = 3.82 ± 0.2 µM) and MDA-MB-231 (IC50 = 2.26 ± 0.1 µM) compared with doxorubicin (IC50 = 4.17 ± 0.2 and 3.18 ± 0.1 M). Cell cycle analysis showed that compound 12 arrests and inhibits the growth of MCF-7 cells in the S phase with values of 48.16% compared with the untreated control 29.79% and exhibited a significantly higher apoptotic effect in MCF-7 with a value of 42.08% compared to control cell at 1.84%. Furthermore, compound 12 decreased Bcl-2 protein 0.368-fold and activation on pro-apoptotic genes Bax and P53 by 3.97 and 4.97 folds, respectively, in MCF-7 cells. Compound 12 exhibited higher inhibitory activity to EGFRWt, EGFRL858R, and VEGFR-2 with IC50 values (0.19 ± 0.009, 0.026 ± 0.001, and 0.42 ± 0.021 µM) compared with erlotinib (IC50 = 0.037 ± 0.002 and 0.026 ± 0.001 µM) and sorafenib (IC50 = 0.035 ± 0.002 µM). Finally, in silico ADMET prediction presented that 1,3-dithiolo[4,5-b]quinoxaline derivative 12 obeys the Lipinski rule of five and the Veber rule with no PAINs alarms and moderately soluble properties. Additionally, toxicity prediction revealed that compound 12 demonstrated inactivity to hepatotoxic carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Moreover, molecular docking studies showed good binding affinity with lower binding energy inside the active site of Bcl-2 (PDB: 4AQ3), EGFR (PDB: 1M17), and VEGFR (PDB: 4ASD).

Molecular Identification, Pathogenesis, and Life Cycle of Sarcocystis cruzi from Cattle (Bos taurus) in New Valley Governorate, Egypt.

Sarcocystis cruzi was identified by molecular methods from an intermediate host, cattle (Bos taurus), in El-Kharga, New Valley Governorate, Egypt, and its life cycle and pathogenicity were studied in the final host, dogs (Canis familiaris). 600 slaughtered cattle aged 6-8 years (480/120 males/females) were included. In addition, three laboratory-bred, coccidian-free puppies aged 2-3 months were fed infected bovine muscles to locate the definitive host and analyze sporogony. 18S rRNA-specific gene primers were used for DNA amplification from esophageal muscles. These polymerase chain reaction (PCR) amplicons were subjected to restriction fragment length polymorphism (RFLP) and molecular sequence analysis. Infection was detected in 78.8% (473/600; 95% CI, 75.56-82.11%). Histopathological examination of esophageal muscles showed oval- to spherical-shaped cysts, 96.7 µm wide by 326.9 µm long; cysts in cardiac muscles were ovoid and smaller. Infected puppies began shedding sporocysts in feces 7 days post-inoculation and showed distorted organ architecture, severe cellular damage, and inflammatory lesions in liver, kidney, esophagus, and stomach. Three oocysts with different shapes and sizes were identified. Partial 18S rRNA gene sequences of isolated New Valley sarcocysts were identical to S. cruzi isolated from different areas, verifying their genetic relatedness. Our analysis suggests that S. cruzi is the most prevalent in slaughtered cattle in New Valley Governorate, Egypt.

Virtual screening and molecular dynamics simulation study of abyssomicins as potential inhibitors of COVID-19 virus main protease and spike protein.

The lack of any effective cure for the infectious COVID-19 disease has created a sense of urgency and motivated the search for effective antiviral drugs. Abyssomicins are actinomyces-derived spirotetronates polyketides antibiotics known for their promising antibacterial, antitumor, and antiviral activities. In this study, computational approaches were used to investigate the binding mechanism and the inhibitory ability of 38 abyssomicins against the main protease (Mpro) and the spike protein receptor-binding domain (RBD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The results identified abyssomicins C, J, W, atrop-O-benzyl abyssomicin C, and atrop-O-benzyl desmethyl abyssomicin C as the most potential inhibitors of Mpro and RBD with binding energy ranges between -8.1 and -9.9 kcal mol-1; and between -6.9 and -8.2 kcal mol-1, respectively. Further analyses of physicochemical properties and drug-likeness suggested that all selected active abyssomicins, with the exception of abyssomicin J, obeyed Lipinski's rule of five. The stability of protein-ligand complexes was confirmed by performing molecular dynamics simulation for 100 ns and evaluating parameters such as such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), total number of contacts, and secondary structure. Prime/MM-GBSA (Molecular Mechanics-General Born Surface Area) and principal component analysis (PCA) analyses also confirmed the stable nature of protein-ligand complexes. Overall, the results showed that the studied abyssomicins have significant interactions with the selected protein targets; therefore, they were deemed viable candidates for further in vitro and in vivo evaluation.Communicated by Ramaswamy H. Sarma.

DFT and In-silico Investigations, along with In-vitro Antitumor and Antimicrobial Assessments of Pharmacological Molecules.

BACKGROUND: Molecules bearing an active methylene bridge are one of the most fruitful and remarkable precursors that have been incorporated into the synthetic strategy of an assortment of bioactive compounds. OBJECTIVE: The reactive methylene derivatives have been endowed with multiple reactions, which target biological and medicinal applications and result from their structural diversity and discrete reactivity. METHODS: The present report endeavors to synthesize, characterize, and in-vitro evaluate several novel propanoic acids, coumarin, and pyrazole derivatives as antimicrobial and antiproliferative agents. The in-silico molecular docking, physicochemical, pharmacokinetic/ADMET, bioactivity, and drug-likeness predictions were conducted for all the synthesized compounds. RESULTS: The highest docking score is -9.9 and -8.3 kcal/mol, respectively, for compound 9 (azocoumarin) and 13 (acrylic acid derivative) with the target proteins E. coli topoisomerase II, DNA gyrase subunit B and PI3K p110α domain, respectively. Moreover, this study predicts the synthesized molecules that may inhibit the novel COVID-19, obtained through virtual screenings only, where compounds 9, 13, 14, 17, and 19 came to the limelight with good docking scores i.e., more than -8 Kcal/mol. Safety profiling of the most potent compound 9 was utilized against normal cell lines and the hemolytic effect on RBCs. CONCLUSION: The in-silico ADMET studies of the synthesized compounds revealed moderate to good -likeness, high gastro intestinal (GI) absorption, and inhibiting the Cytochrome CYP2C19 and CYP2C9 and all the derivatives possess non-cancerous nature. The in-vitro screening demonstrated that several of the novel molecules are promising drug candidates. The density functional theory (DFT) theoretical calculations were performed to calculate the energy levels of the FMOs and their energy gaps, dipolemoment, andmolecular electrostatic potential. Such parameters, along with the physicochemical parameters, could be a good tool to confirm biological activity.

Small extracellular vesicle-associated miR-6068 promotes aggressive phenotypes of prostate cancer through miR-6068/HIC2/SIRT1 axis.

Early diagnosis and treatment of patients with aggressive prostate cancer (PCa) remains a clinically unmet need. We aimed to determine the levels of small extracellular vesicle (sEV)-associated microRNAs (miRs); miR-4737, miR-6068, and miR-6076 in a large panel of PCa cells and delineate the biological significance of miR-6068 in promoting PCa cells. sEVs were isolated from the conditioned medium of PCa cells, followed by RNA extraction and quantitative Real-Time PCR analysis. Functional assays were performed, and the protein expression of hypermethylated in cancer 2 (HIC2), as a potential miR-6068 target gene, was evaluated in PCa tissues by immunohistochemistry. sEV-associated miR-6068, miR-4737, and miR-6076 levels displayed large and significant differences compared to normal cells. miR-6068 was explicitly upregulated in sEV of PC-3 and CWR-R1ca cells (P<0.010). Suppression of miR-6068 in CWR-R1ca cells decreased cell proliferation, colony formation, and cell migration. In contrast, upregulation of miR-6068 in RC77T/E cells decreased HIC2 levels and increased cell aggressive phenotypes. The overexpression of HIC2 in PCa tissues was primarily observed in the cytoplasm compared to benign prostatic hyperplasia (BPH) and normal tissues (P<0.0001). This study confirms the differential packaging of miR-4737, miR-6068, and miR-6076 in sEVs of PCa cells. MiR-6068 promotes PCa cells to acquire aggressive phenotypes by inhibiting the HIC2/Sirtuin 1 (SIRT1) axis.

Functionalized iron oxide nanoparticles: synthesis through ultrasonic-assisted co-precipitation and performance as hyperthermic agents for biomedical applications.

Dual-functional iron oxide nanoparticles (IONPs), displaying self-heating and antibacterial effects are highly desired for biomedical application. This study involved the synthesis of functionalized IONPs coated with 3-aminopropyltriethoxysilane and polyethylene glycol via ultrasonic-assisted co-precipitation technique. The synthesized IONPs were then characterized by using Fourier-transform infrared spectroscopy, X-ray diffraction, dynamic light scattering, scanning electron microscopy, zeta potential, vibrating sample magnetometer and thermogravimetric analysis techniques. In addition, the effect of the synthesized IONPs on bacterial growth (S. aureus and E. coli) was studied. The influence of magnetic field power, as well as the viscous carriers on the heating efficiency of the synthesized IONPs was investigated. The specific absorption rate values increased as the power increased and decreased with the increase in the carrier viscosity. These characteristics render the synthesized iron oxide nanoparticles synthesized in the present study suitable for biomedical application as hyperthermic agents.

Acacia senegal inhibits diabetic nephropathy ultrastructure alteration and renal biomarkers changes in rats / Acacia senegal inhibe la alteración de la ultraestructura de la nefropatía diabética y los cambios en los biomarcadores renales en rata

SUMMARY: Diabetic nephropathy (DN) is the most common complication of diabetes. Several studies have been done in a trial to protect against this problem at the ultrastructure level. This study investigates the protective effect of oral administration of Acacia senegal (AS) against the development of DN. Sixty male albino rats were randomly divided into six groups: control, Acacia senegal control, Diabetic untreated, diabetic insulin-treated, Diabetic AS treated, and Diabetic insulin and AS combined treated groups. Plasma glucose, HbA1c, serum Albumin, creatinine, urine creatinine was measured using specific kits. Determinations of creatinine clearance and blood pressure were done. The renal tissues of both kidneys were prepared to investigate under both light (LM) and electron microscope (EM). Ultrastructure examination of renal rats tissue of diabetic untreated rats showed the destruction of the glomerular basement membrane and endothelial cells together with hemorrhage in glomerular capsules (Bowman's capsules). On the other side, both LM and EM revealed improving the endothelial cells and the other glomerular capsules structures, especially with the combined treated group, which confirmed the improvement of the biochemical investigation in the study. In conclusion, from the present study, using the oral AS together with SC insulin could be protected against the development of DN.

RESUMEN: La nefropatía diabética (ND) es la complicación más común de la diabetes. Se han realizado varios estudios de ensayo para abordar esta dificultad a nivel de ultraestructura. Este estudio investiga el efecto protector de la administración oral de Acacia senegal (AS) contra el desarrollo de la ND. Se dividieron sesenta ratas albinas machos aleatoriamente en seis grupos: control, control de Acacia senegal, diabéticos no tratados, diabéticos tratados con insulina, diabéticos tratados con AS y grupos tratados con compuesto de insulina diabética + AS. Se midieron utilizando kits específicos, glucosa plasmática, HbA1c, albúmina sérica, creatinina en sangre y en orina. Se registraron la creatinina y la presión arterial. Los tejidos renales de ambos riñones se prepararon para investigar tanto con microscopio óptico (MO) como electrónico (ME). El examen de la ultraestructura del tejido renal de ratas diabéticas no tratadas mostró la destrucción de la membrana basal glomerular y las células endoteliales junto con hemorragia en las cápsulas glomerulares (cápsulas de Bowman). Por otro lado, tanto MO como ME revelaron una mejora de las células endoteliales y las estructuras capsulares glomerulares, en el grupo tratado con el compuesto, lo que confirmó la mejora de la investigación bioquímica. En conclusión, el uso de AS oral en combinación con insulina podría proteger contra el desarrollo de ND.

A novel spectrofluorimetric method based on a reaction with an azoisoxazoles-benzenesulfonamide derivative for determination of uranium (VI) ions in water samples.

Selective fluorometric detection and determination of uranium ions is provided here using a novel fluorescent reagent, namely (E)-4-([4-hydroxynaphthalen-1-yl]diazenyl)-N-(5-methyleisoxazol-3-yl) benzenesulfonamide (UVI reagent). The UVI reagent offers a selective fluorescence enhancement behaviour at emission wavelength = 557 nm. The parameters affecting fluorometric detection of uranium ions, such as the pH, solvent type, ligand concentration, interaction time, and interfering ions, were investigated and adjusted. The proposed UVI reagent can detect and determine uranium ions even at low concentrations, for which the obtained limit of detection was 0.1 ppm. Additionally, this proposed determination protocol was successfully used to detect, monitor, and determine uranium ions in actual water samples.

Chemical constituents from Carica papaya Linn. leaves as potential cytotoxic, EGFRwt and aromatase (CYP19A) inhibitors; a study supported by molecular docking.

The phytochemical investigation of the hydromethanolic extract of Carica papaya Linn. leaves (Caricaceae) resulted in the isolation and characterization of ten compounds, namely; carpaine (1), methyl gallate (2), loliolide (3), rutin (4), clitorin (5), kaempferol-3-O-neohesperidoside (6), isoquercetin (7), nicotiflorin (8) and isorhamnetin-3-O-ß-d-glucopyranoside (9). The compounds 2, 3, 5-7 and 9 were isolated for the first time from the genus Carica. An in vitro breast cancer cytotoxicity study was evaluated with an MCF-7 cell line using the MTT assay. Methyl gallate and clitorin demonstrated the most potent cytotoxic activities with an IC50 of 1.11 ± 0.06 and 2.47 ± 0.14 µM, respectively. Moreover, methyl gallate and nicotiflorin exhibited potential EGFRwt kinase inhibition activities with an IC50 of 37.3 ± 1.9 and 41.08 ± 2.1 nM, respectively, compared with the positive control erlotinib (IC50 = 35.94 ± 1.8 nM). On the other hand, clitorin and nicotiflorin displayed the strongest aromatase kinase inhibition activities with an IC50 of 77.41 ± 4.53 and 92.84 ± 5.44 nM, respectively. Clitorin was comparable to the efficacy of the standard drug letrozole (IC50 = 77.72 ± 4.55). Additionally, molecular docking simulations of the isolated compounds to EGFR and human placental aromatase cytochrome P450 (CYP19A1) were evaluated. Methyl gallate linked with the EGFR receptor through hydrogen bonding with a pose score of -4.5287 kcal mol-1 and RMSD value of 1.69 Å. Clitorin showed the strongest interaction with aromatase (CYP19A1) for the breast cancer receptor with a posing score of -14.2074 and RMSD value of 1.56 Å. Compounds (1-3) possessed a good bioavailability score with a 0.55 value.

Role of fibrinogen in the attenuation of ischemia reperfusion and remote ischemic preconditioning / El papel del fibrinógeno en la atenuación de la isquemia-reperfusión y el preacondicionamiento isquémico remoto

Abstract Background: Ischemic reperfusion injury (IRI) is a common hazard involved in many human diseases, such as cerebral stroke, myocardial infarction, solid organ transplant dysfunction or failure, and vascular diseases. Understanding the molecular bases of this injury is essential for the prevention and control of these life-threatening conditions. Ischemic and remote ischemic preconditioning techniques (IPC and RIPC, respectively) have gained increasing importance in the clinical practice to protect against the IRI; however, the exact mechanisms of these techniques are not fully understood, which renders their clinical application query. Possible effectors: Nitric oxide (NO) has been reported by multiple studies to be an important mediator of the protective effects of those techniques. While the physiological concentrations of NO and fibrinogen (FB) are known to antagonize each other, the circulating levels of both effectors increase in response to RIPC. Hypothesis: While NO has potential anti-inflammatory effects, non-soluble fibrinogen (sFB) shows pro- inflammatory effects. However, the sFB may have the potential to act synergistically rather than antagonistically with NO toward the attenuation of the IRI. Conclusion: While increased FB is considered a risk factor for cardiovascular and inflammatory conditions that is also able to decrease the efflux of NO, and increase the NO oxidative metabolits and S- nitroglutathione, the increased sFB during the acute phase reaction might have other protective aspects that should be carefully investigated.

Resumen Antecedentes: La lesión por isquemia-reperfusión (LIR) es un riesgo común involucrado en muchas enfermedades humanas tales como derrame cerebral, infarto del miocardio, disfunción o falla de trasplante de órgano sólido, y enfermedades vasculares. Una comprensión de la base molecular de esta lesión es fundamental para la prevención y el control de estas enfermedades potencialmente mortales. Las técnicas de preacondicionamiento isquémico y preacondicionamiento isquémico remoto (PIR) han cobrado una creciente importancia en la práctica clínica para la protección contra la LIR, sin embargo, los mecanismos precisos de estas técnicas no se entienden plenamente, lo cual pone en duda su aplicación clínica. Posibles efectores: El óxido nítrico (ON) ha sido reportado por varios estudios como un importante mediador de los efectos protectores de estas técnicas. Si bien se sabe que las concentraciones fisiológicas del ON y fibrinógeno son antagónicas, los niveles circulantes de ambos efectores aumentan en respuesta al PIR. Hipótesis: Aunque el ON tiene posibles efectos anti-inflamatorios, el fibrinógeno insoluble muestra efectos proinflamatorios. Sin embargo, el fibrinógeno soluble puede tener el potencial de actuar de manera sinérgica en lugar de antagónica con el ON hacia la atenuación de la LIR. Conclusión: Aunque el fibrinógeno elevado se considera un factor de riesgo para las enfermedades cardiovasculares e inflamatorias, que también puede disminuir la descarga de ON y aumentar los niveles de metabolitos oxidantes del ON y de S-nitrosoglutatión, el aumento de fibrinógeno soluble durante la reacción de fase aguda puede tener otros aspectos protectores que deben ser cuidadosamente investigados.

Polymeric Nanocomposites for Environmental and Industrial Applications.

Polymeric nanocomposites (PNC) have an outstanding potential for various applications as the integrated structure of the PNCs exhibits properties that none of its component materials individually possess. Moreover, it is possible to fabricate PNCs into desired shapes and sizes, which would enable controlling their properties, such as their surface area, magnetic behavior, optical properties, and catalytic activity. The low cost and light weight of PNCs have further contributed to their potential in various environmental and industrial applications. Stimuli-responsive nanocomposites are a subgroup of PNCs having a minimum of one promising chemical and physical property that may be controlled by or follow a stimulus response. Such outstanding properties and behaviors have extended the scope of application of these nanocomposites. The present review discusses the various methods of preparation available for PNCs, including in situ synthesis, solution mixing, melt blending, and electrospinning. In addition, various environmental and industrial applications of PNCs, including those in the fields of water treatment, electromagnetic shielding in aerospace applications, sensor devices, and food packaging, are outlined.

Latency reversal plus natural killer cells diminish HIV reservoir in vivo.

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1. Utilizing genetically barcoded virus technology, we show these natural killer cells efficiently reduced viral clones rebounding from latency. Moreover, a kick and kill strategy comprised of the protein kinase C modulator and latency reversing agent SUW133 and allogeneic human peripheral blood natural killer cells during anti-retroviral therapy eliminated the viral reservoir in a subset of mice. Therefore, combinations utilizing latency reversal agents with targeted cellular killing agents may be an effective approach to eradicating the viral reservoir.

Kaempferol prevents cadmium chloride-induced liver damage by upregulating Nrf2 and suppressing NF-κB and keap1.

This study evaluated the protective effect of kaempferol, a natural flavonoid, against cadmium chloride (CdCl2)-induced liver damage and examined the possible anti-inflammatory and antioxidant mechanisms of protection. Adult male rats were divided into 4 groups (each of 8 rats) as control, kaempferol (50 mg/kg/day orally), CdCl2 (15 ppm/day), and CdCl2 (15 ppm/day) + kaempferol (50 mg/kg/day). All treatments were given for 30 days. With no effect on attenuating the reduced food intake, kaempferol significantly increased body weight and lowered serum levels of liver injury markers including bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase 1 (γ-GTT1) in the CdCl2-treated rats. It also restored normal liver architectures, prevented hepatocyte, loss, and swelling and reduced inflammatory cell infiltration. These effects were associated with a reduction in mitochondrial permeability transition pore, as well as in the expression of cytochrome-c and cleaved caspase-3, markers of mitochondrial damage, and intrinsic cell death. In both the control positive and CdCl2-treated rats, kaempferol significantly lowered the hepatic levels of reactive oxygen species, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), Interleukine-6 (IL-6), and the nuclear activity and localization of NF-κB p65. Besides, kaempferol significantly increased the hepatic total and nuclear levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1, as well as levels of superoxide dismutase (SOD) and reduced glutathione (GSH) but reduced the cytoplasmic protein levels of keap1. In conclusion, the protective effect of kaempferol against CdCl2-induced hepatic damage is mediated by antioxidant and anti-inflammatory effects driven by upregulating Nrf2/HO-1 axis and suppressing the NF-κB p65 and keap1.