Scaffold Repurposing Reveals New Nanomolar Phosphodiesterase Type 5 (PDE5) Inhibitors Based on Pyridopyrazinone Scaffold: Investigation of In Vitro and In Silico Properties

Inhibition of PDE5 results in elevation of cGMP leading to vascular relaxation and reduction in the systemic blood pressure. Therefore, PDE5 inhibitors are used as antihypertensive and antianginal agents in addition to their major use as male erectile dysfunction treatments. Previously, we developed a novel series of 34 pyridopyrazinone derivatives as anticancer agents (series A–H). Herein, a multi-step in silico approach was preliminary conducted to evaluate the predicted PDE5 inhibitory activity, followed by an in vitro biological evaluation over the enzymatic level and a detailed SAR study. The designed 2D-QSAR model which was carried out to predict the IC50 of the tested compounds revealed series B, D, E and G with nanomolar range of IC50 values (6.00–81.56 nM). A further docking simulation model was performed to investigate the binding modes within the active site of PDE5. Interestingly, most of the tested compounds showed almost the same binding modes of that of reported PDE5 inhibitors. To validate the in silico results, an in vitro enzymatic assay over PDE5 enzyme was performed for a number of the promising candidates with different substitutions. Both series E and G exhibited a potent inhibitory activity (IC50 = 18.13–41.41 nM). Compound 11b (series G, oxadiazole-based derivatives with terminal 4-NO2 substituted phenyl ring and rigid linker) was the most potent analogue with IC50 value of 18.13 nM. Structure–activity relationship (SAR) data attained for various substitutions were rationalized. Furthermore, a molecular dynamic simulation gave insights into the inhibitory activity of the most active compound (11b). Accordingly, this report presents a successful scaffold repurposing approach that reveals compound 11b as a highly potent nanomolar PDE5 inhibitor worthy of further investigation

Anti-osteoporotic effect of medical herbs and calcium supplementation on ovariectomized rats

Estrogen deficiency and insufficient calcium in diet in postmenopause create serious problems with resultant osteoporosis and fractures. In the present study, forty adult albino rats weighting 200–220 g were used and divided into five groups. Group 1, control group included non-ovariectomized untreated rats. Group 2, ovariectomized)OVX) rats. Group 3, OVX rats daily received CaCO3 (27 mg/kg b.w.). Group 4, OVX rats daily received a mixture of herbs (sage, rosemary and thyme) (30 g/kg b.w.). Group 5, OVX rats daily received both herb mixture and CaCO3. The results showed significant decrease in serum calcium (Ca), inorganic phosphorus (P), total proteins (TP), calcitonin, bone mass density (BMD), reduced glutathione (GSH) and catalase (CAT) in OVX rats compared to the control group. While a significant increase in serum parathyroid hormone (PTH), osteocalcin, alkaline phosphatase (ALP) and acid phosphatase (ACP) were recorded. Also the recorded data showed increases in femur, tibia and vertebral lipid peroxidation (MAD) content and the activities of acid phosphatase and alkaline phosphatase in the ovariectomized rats. On the other hand, when OVX rats were fed on sage, rosemary and thyme supplemented diets or CaCO3 in a single or in combination, the data recorded a significant improvement in all the above mentioned parameters. Finally, the results of this study indicated that the combination of common herbs (sage, rosemary and thyme) with calcium carbonate, was more effective in reduction and prevention of osteoporosis in ovariectomized rats. So, it can be concluded that consumption of mixed herbs supplemented diets might be considered as a functional food for retarding risks of osteoporosis associated with estrogen deficiency in OVX states

Effect of conducting clinical nursing round training program for head nurses on their clinical round performance

Background: Clinical rounds are complex clinical activities, critical to providing high-quality, safe care for patients in a timely, relevant manner. It offers opportunities for effective communication, information sharing and joint learning through active participation of all members of the multidisciplinary team. Aim: The present study aimed to assess the effect of conducting clinical nursing round training program for head nurses on their clinical round performance. Design: A quasi-experimental pre-posttest design was used to achieve the aim of the present study. Sample: A convenient sample of all head nurses (n= 23), who are agreed to participate in the study was included in the . Setting: The study was conducted at departments of the new obstetric and midwifery hospital at Kaser El-Aini.Tool: one tool was used; clinical round performance checklist. result: the was a highly statistically significant difference between pre intervention and post intervention regarding to most items of nursing clinical round after attending the training program. Recommendation: Based on the study results the following were recommended applying training program for head nurses into wider scales

Introducing deinked old newsprint as a new resource of electrical purposes paper

Finding new uses for recycled paper (a cellulose rich raw material), and increasing the rate of recycling is beneficial to the environmental efficiency of the whole paper industry. The present work introduces, for the first time, deinked recycled old newsprint as a new resource of electrical purposes paper. Impregnation of recycled deinked old newsprint paper, by linseed oil, enhances the breaking length of paper and remarkably improves its electrical properties i.e., the dielectric constant increases greatly and the a.c. conductivity decreases significantly due to impregnation. It was found that the electrical properties of deinked recycled old newsprint paper and its linseed oil impregnated counterpart, are close to the electrical properties of paper made from the more expensive virgin wood pulps and their linseed oil impregnated counterparts. In a series of research articles, the authors and others threw light for the first time on the electrical properties of paper made from agricultural residues pulps, and their linseed oil impregnated counterparts. Some, of the investigated agricultural residues papers, showed electrical properties close to wood papers, or even superior to it. This motivated the authors to expand the studies, on electrical properties of paper, to other cheap and abundant raw materials. Recycled old newsprint is an abundant raw material that is cheaper than virgin wood pulps. Therefore, recycled deinked old newsprint paper was chosen as a new raw material to study its electrical properties in this work. The effect of elevated temperatures on the electrical properties of paper is, also, studied. It is shown that improvement in electrical properties, due to impregnation, is sustained at elevated temperatures. Impregnated deinked recycled old newsprint paper produced in this work finds its use as specialty electrical purposes paper

Biological Validation of Novel Polysubstituted Pyrazole Candidates with in Vitro Anticancer Activities

With the aim of developing novel antitumor scaffolds, a novel series of polysubstituted pyrazole derivatives linked to different nitrogenous heterocyclic ring systems at the C-4 position were synthesized through different chemical reactions and characterized by means of spectral and elemental analyses and their antiproliferative activity against 60 different human tumor cell lines was validated by the U.S. National Cancer Institute using a two stage process. The in vitro anticancer evaluation revealed that compound 9 showed increased potency toward most human tumor cell lines with GI50MG-MID = 3.59 µM, as compared to the standard drug sorafenib (GI50 MG-MID = 1.90 µM). At the same time, compounds 6a and 7 were selective against the HOP-92 cell line of non-small cell lung cancer with GI50 1.65 and 1.61 µM, respectively

HBV vaccine efficacy and detection and genotyping of vaccineé asymptomatic breakthrough HBV infection in Egypt

AIM: To evaluate the impact of mass vaccination against the hepatitis B virus (HBV) in Egypt, and to search for vaccinee asymptomatic breakthrough HBV infection and its genotype

Curcumin Mitigates Malathion-Induced Renal Injury: Suppression of Apoptosis and Modulation of NF-κβ/TNF-α and Nrf2, and HO-1 Signaling

Malathion is one of the most used organophosphorus pesticides that is used for many reasons such as agriculture and industry. Human exposure to malathion may occur through various means, such as eating food that has been treated with it. Malathion not only increases oxidative stress but also decreases the antioxidant capacity. Curcumin is a powerful antioxidant with many pharmacological actions. Curcumin can act as a free radical scavenger and inhibit the activation and nuclear translocation of NF-κB. Curcumin could combat the lipid peroxidation and antioxidant depletion that trigger the apoptotic pathways. This study aims to examine the antioxidant, anti-inflammatory, and antiapoptotic effects of curcumin. Twenty-four Sprague Dawley rats were divided into four groups (six rats each): control, curcumin, malathion, and malathion + curcumin groups. At the assigned time, blood samples were used for the assessment of serum creatinine, and the kidneys were excised and washed; parts of them were used for the assessment of total oxidant status (TOS), oxidative stress index (OSI), the oxidative stress marker malondialdehyde (MDA), total antioxidant capacity (TAC), and glutathione (GSH) activity, other parts were fixed in formalin for further staining. Histopathological evaluation was performed for the fixed specimens after staining with H&E, sirus red, and the immunohistochemical staining for NF-κβ, TNF-α, Caspase-3, Nrf2, and HO-1. Curcumin significantly decreases the serum creatinine after malathion exposure and significantly restores the oxidant/antioxidant balance by increasing TAC and GSH and decreasing TOS, OSI, and MDA. Curcumin exerts its reno-protective effect and restores the histological architecture of the kidney by downregulating the immune expression of NF-κβ, TNF-α, and Caspase-3 and upregulating the expression of Nrf2 and HO-1. This study concluded that curcumin protects against nephrotoxicity caused by malathion by exerting its antioxidant, anti-inflammatory, and anti-apoptotic capabilities