SYNTHESIS, ANTITUMOR ACTIVITY, PHARMACOPHORE MODELING AND QSAR STUDIES OF NOVEL PYRAZOLES AND PYRAZOLO [1, 5-A] PYRIMIDINES AGAINST BREAST ADENOCARCINOMA MCF-7 CELL LINE

Objective: The present work aimed to synthesize New series of pyrazoles 3 and pyrazolo[1,5-a]pyrimidines 5, 7, 9 in order to evaluate their antiproliferative activity against human breast adenocarcinoma MCF-7cell line and study the cell cycle progression of the most active compounds. In addition, Pharmacophore modeling and QSAR Studies of these new compounds were done.Methods: The diazonium salt of 4-aminoacetophenone 1 was coupled with malononitrile in ethanol using sodium acetate affords 2-[(4-acetylphenyl)diazenyl] malononitrile Cycloaddition of hydrazine hydrate, in molar ratios 1:1 or 1:2, on compound 2, furnished 3,5-diaminopyrazolederivatives 3a and 3b respectively. Moreover, new pyrazolo[1,5-a]pyrimidine derivatives 5a-f were obtained upon cyclocondensation of 3a, b with different chalcones 4a-c in EtOH/piperidine,while compounds 7a-f were prepared via cycloaddition of 3a, b with various arylidene malononitriles 6a-c in the same reaction condition. Finally, treatment of 3a, b with ethyl 2-cyano-3-ethoxyacrylate 8a or 2-(ethoxymethylene)malononitrile 8b in EtOH/TEA yielded the novel pyrazolo[1,5-a]pyrimidine derivatives 9a, b respectively. These target compounds were screened for their cytotoxic activity against MCF-7 (human breast Cell Line) followed by study cell cycle of 7a. Finally, Pharmacophore modeling and QSAR Studies was carried out.Results: The pyrazolopyrimidine 7a was the most active compound (IC50 = 3.25 µM), whereas, some of the tested compounds exploited moderate growth inhibitory activity. Its effect was further studied on cell cycle progression; results showed that compound 7a induced cell cycle arrest at S-phase verifying this compound as a promising selective anticancer agent.Conclusion: Compound 7a was found to be the most active member against MCF-7 breast cancer (IC50= 3.25 μM), Further biological assessment of 7a using flow-cytometric analysis, revealed that it induced cell cycle arrest at S phase.Keywords: Pyrazole, Pyrazolo[1,5-a]pyrimidine, MCF-7 breast cancer cell line, Cell cycle profile, 3D pharmacophore,1 QSAR stud

Shear Performance of GFRP Reinforced Concrete Beams with Seawater and Chopped Fiber

This paper reports an experimental study on the behavior and shear strength of concrete beams reinforced with longitudinal GFRP bars mixed with sea water. In order to evaluate how much concrete contributes to shear resistance, seven beams were tested in bending. Similar in size and concrete strength, the beams were longitudinally reinforced with glass fiber-reinforced polymer bars; however, they did not even have shear reinforcement. The beams, which measured 3,100 mm in length, 400 mm in depth, and 200 mm in width, were conducted and tested up to failure. The test variables were longitudinal reinforcement ratios (1.0, 1.4, and 2.0%), chopped fiber content (0, 0.5, 2, and 3 kg/m3), and mixing water type (freshwater and seawater). The test findings showed that increasing the reinforcement ratio increased the neutral-axis depth and allowed the formation of more closely spaced fractures while decreasing the loss of flexural stiffness after cracking. By increasing the area of concrete in compression, this in turn enhances the contribution of aggregate interlock as well as the contribution of uncracked concrete. Furthermore, increasing the reinforcement ratio improves the dowel action, which reduces the tensile stresses that are created in the concrete around it. Doi: 10.28991/CEJ-2023-09-04-05 Full Text: PD

Influence of short- and long-term administration of Melengestrol acetate on estrus activity and reproductive performance of nulliparous Barki ewes

In Egypt, research focusing on estrous synchronization in small ruminants based on Melengestrol acetate (MGA) supplementation, particularly in nulliparous ewes, is still lacking. The present work aimed to evaluate effect of long-term and short-term administration of melengestrol acetate (MGA) treatments on estrus synchronization and reproductive performance of nulliparous Barki Ewes. This study was performed in Siwa Oasis Research Station (Tegzerty Experimental Farm for animal production), belonged to Desert Research Center, Egypt. Forty five nulliparous Barki ewes with age ranging from 15.5 to 16.5 months, and 38 ± 0.23 kg average live body weight were assigned to one of three groups: (1) control (C, n = 15); (2) long-term treatment with MGA (n = 15, 0.22 mg/ewe/d for 14 days) and (3) short-term treatment with MGA (n = 15, 0.22 mg/ewe/d for 7 days). At the end of MGA treatment (14 or 7 d) all treated ewes were injected by 600 IU PMSG intramuscularly. The results showed that, ewes treated with MGA exhibited highest (

Сравнение показателей соотношений тромбоциты / лимфоциты и нейтрофилы / лимфоциты в качестве предикторов исхода COVID-19

Clinical presentation is an undependable prognostic indicator of COVID-19 (COronaVIrus Disease 2019). So, a more objective predictor is needed to precisely evaluate and classify the prognosis. Immune dysregulation to lymphocytes, mainly T-lymphocytes, have been noticed between COVID-19 patients. The aim. This study was planned to determine the role of platelet-to-lymphocyte count ratio and neutrophil-to-lymphocyte ratio in assessment of COVID-19 prognosis. Methods. 70 hospitalized patients with confirmed COVID-19 were included in this study. All included patients underwent a consistent clinical, radiological and blood examination. Laboratory analysis was made by means of a commercially accessible kit. Blood cells ratios were computed by dividing their absolute counts. Results. Non-significant association was found between laboratory data and COVID-19 clinical severity. A significant association between CT classification and platelet-to-lymphocyte count ratio (higher value in L type; p = 0.001) was detected. Platelet-to-lymphocyte count ratio was significantly higher among intubated cases. However, Non-significant association was found between neutrophil-to-lymphocyte ratio and need of endotracheal intubation. Conclusion. Routine blood values are abnormal in patients with COVID-19. Platelet-to-lymphocyte count ratio ratios could be used as more meaningful biomarker than other values in predicting the prognosis of COVID-19. LMR helpful in COVID-19 severity.Клиническая картина является ненадежным показателем прогноза исхода новой коронавирусной инфекции (НКИ), поэтому для точной оценки и классификации прогноза необходим более объективный прогнозирующий фактор. У пациентов, перенесших НКИ, отмечается нарушение регуляции иммунного ответа со стороны лимфоцитов, в основном Т-лимфоцитов. Целью исследования явилось определение роли показателей соотношений тромбоциты / лимфоциты и нейтрофилы / лимфоциты при оценке прогноза COVID-19. Материалы и методы. В исследование были включены госпитализированные пациенты (n = 70) с подтвержденным COVID-19 (COronaVIrus Disease 2019). У всех пациентов проводились последовательное клиническое и рентгенологическое обследование и анализ крови. Лабораторные анализы выполнялись с помощью коммерческого набора. Соотношения показателей клеток крови рассчитывались путем деления их абсолютного количества. Результаты. Обнаружена незначимая связь между лабораторными показателями и степенью тяжести COVID-19. Выявлена значимая связь между степенью поражения легких по данным компьютерной томографии и показателем соотношения тромбоциты / лимфоциты (более высокое значение для L-типа; p = 0,001). У интубированных пациентов соотношение показателя тромбоциты / лимфоциты было значимо выше. Однако обнаружена незначимая связь между показателем соотношения нейтрофилы / лимфоциты и необходимостью интубации трахеи. Заключение. У пациентов с COVID-19 наблюдаются отклонения показателей рутинных анализов крови. Показатель соотношения тромбоциты / лимфоциты может служить биомаркером при прогнозировании течения COVID-19, а показатель соотношения лимфоциты / моноциты полезен при прогнозировании степени тяжести COVID-19

SULPHATED POLYSACCHARIDES (SPS) FROM THE GREEN ALGA ULVA FASCIATA EXTRACT MODULATES LIVER AND KIDNEY FUNCTION IN HIGH FAT DIET-INDUCED HYPERCHOLESTEROLEMIC RATS

Objective: Hypercholesterolemia (HC) was frequently associated with oxidative stress, and release of inflammatory cytokines is to determine the hypolipidemic effects of sulphated polysaccharides from seaweed Ulva fasciata algal extracts through measuring the activities of some parameters related to liver and kidney functions in the serum of hypercholesterolemic rats as compared to normal one.Methods: Different groups of rats were administered a high cholesterol diet. Liver and kidney functions, inflammatory cytokines (TNF-α, CRP, MPO and IL-10), oxidative stress (GSH, MDA and NO), in addition to cell adhesion molecules (ICAM-1 and VCAM-1) were assessed before and after treatment with the algal polysaccharides. In addition, histological examination of liver and kidney were performed to confirm the biochemical findings.Results: The obtained results showed that oxidative stress and inflammatory markers associated with hypercholesterolemia were significantly increased in HC-rats. The histopathological examination of liver and kidney demonstrated severe degeneration with diffuse vacuolar degeneration, necrosis and the presence of fatty droplets. In addition; nephron-histological examination revealed, mild glomerular injury with mild vascular and inflammatory changes. Treatment with the algal sulphated polysaccharides effectively improved these disorders and diminished the formation of fatty liver, as well as renal dysfunction more than the reference drug; fluvastatin. Conclusion: It could be concluded that the consumption of UFP (Ulva fasciata polysaccharides), may be associated with attenuation of inflammatory markers, amelioration of fatty liver and improvement of renal dysfunction, that in turn lead to counteract hypercholesterolemia and its related disorders; such as obesity, and heart disease.Keywords: Non-alcoholic fatty liver disease, Seaweed, Ulva fasciata, Hypercholesterolemia, Hypolipidemic activity, Sulphated polysaccharides (SPs

Concurrent use of nivolumab and radiotherapy for patients with metastatic non‑small cell lung cancer and renal cell carcinoma with oligometastatic disease progression on nivolumab

Checkpoint inhibitors (CPIs), such as nivolumab, have transformed the treatment paradigm for patients with metastatic non‑small cell lung cancer (mNSCLC) and metastatic renal cell carcinoma (mRCC). The combination of CPIs and radiotherapy (RT) constitutes a multimodal treatment approach that may work synergistically and facilitate augmented systemic responses. The aim of the present retrospective study was to assess the efficacy and safety of continuation of nivolumab treatment with the addition of RT in patients with mNSCLC and mRCC who develop oligometastatic disease progression on single‑agent nivolumab. All patients with mNSCLC and mRCC who received nivolumab at the Department of Oncology, Prince Sultan Military Medical City (Riyadh, Saudi Arabia) between November 2016 and April 2018 were identified. The records of patients who developed oligometastatic disease progression during nivolumab treatment and were subsequently treated with RT, with nivolumab continued beyond disease progression, were retrospectively reviewed. Details of RT, clinical outcomes and toxicity data were collected. Of the 96 patients who received nivolumab, 22 received multiple courses of RT. A total of 39 sites were irradiated: Bone (n=15), lung (n=9), brain (n=8), adrenal gland (n=2), renal bed (n=2), skin (n=1), ethmoid sinus (n=1) and scalp (n=1). Partial response and complete response were noted at 25 (64%) and 3 (8%) sites, respectively. Stable disease was noted at 6 sites (15%) and disease progression was noted at 5 sites (13%). The median time on nivolumab from the date of the first fraction of RT was 4.5 months (range, 1.5‑29 months) for patients with mNSCLC and 5 months (range, 1‑38.5 months) for patients with mRCC. No patients developed grade 3‑4 toxicities. Grade 2 pneumonitis was noted in 3 patients receiving lung RT. The addition of RT appeared to initiate a response and prolong the duration of nivolumab treatment. Therefore, the combination of nivolumab and RT was found to be well tolerated, with response rates exceeding those in published studies of nivolumab monotherapy

Chemical Profile of Cyperus laevigatus and Its Protective Effects against Thioacetamide-Induced Hepatorenal Toxicity in Rats

Cyperus species represent a group of cosmopolitan plants used in folk medicine to treat several diseases. In the current study, the phytochemical profile of Cyperus laevigatus ethanolic extract (CLEE) was assessed using UPLC-QTOF–MS/MS. The protective effect of CLEE at 50 and 100 mg /kg body weight (b.w.) was evaluated on hepatorenal injuries induced by thioacetamide (100 mg/kg) via investigation of the extract’s effects on oxidative stress, inflammatory markers and histopathological changes in the liver and kidney. UPLC-QTOF–MS/MS analysis of CLEE resulted in the identification of 94 compounds, including organic and phenolic acids, flavones, aurones, and fatty acids. CLEE improved the antioxidant status in the liver and kidney, as manifested by enhancement of reduced glutathione (GSH) and coenzyme Q10 (CoQ10), in addition to the reduction in malondialdehyde (MDA), nitric oxide (NO), and 8-hydroxy-2′-deoxyguanosine (8OHdG). Moreover, CLEE positively affected oxidative stress parameters in plasma and thwarted the depletion of hepatorenal ATP content by thioacetamide (TAA). Furthermore, treatment of rats with CLEE alleviated the significant increase in plasma liver enzymes, kidney function parameters, and inflammatory markers. The protective effect of CLEE was confirmed by a histopathological study of the liver and kidney. Our results proposed that CLEE may reduce TAA-hepatorenal toxicity via its antioxidant and anti-inflammatory properties suppressing oxidative stress

Osteogenic Differentiation Potential of Human Bone Marrow and Amniotic Fluid-Derived Mesenchymal Stem Cells in Vitro & in Vivo

BACKGROUND: Cell therapies offer a promising potential in promoting bone regeneration. Stem cell therapy presents attractive care modality in treating degenerative conditions or tissue injuries. The rationale behind this is both the expansion potential of stem cells into a large cell population size and its differentiation abilities into a wide variety of tissue types, when given the proper stimuli. A progenitor stem cell is a promising source of cell therapy in regenerative medicine and bone tissue engineering. AIM: This study aimed to compare the osteogenic differentiation and regenerative potentials of human mesenchymal stem cells derived from human bone marrow (hBM-MSCs) or amniotic fluid (hAF-MSCs), both in vitro and in vivo studies. SUBJECTS AND METHODS: Human MSCs, used in this study, were successfully isolated from two human sources; the bone marrow (BM) and amniotic fluid (AF) collected at the gestational ages of second or third trimesters. RESULTS: The stem cells derived from amniotic fluid seemed to be the most promising type of progenitor cells for clinical applications. In a pre-clinical experiment, attempting to explore the therapeutic application of MSCs in bone regeneration, Rat lumbar spines defects were surgically created and treated with undifferentiated and osteogenically differentiated MSCs, derived from BM and second trimester AF. Cells were loaded on gel-foam scaffolds, inserted and fixed in the area of the surgical defect. X-Ray radiography follows up, and histopathological analysis was done three-four months post- operation. The transplantation of AF-MSCs or BM-MSCs into induced bony defects showed promising results. The AF-MSCs are offering a better healing effect increasing the likelihood of achieving successful spinal fusion. Some bone changes were observed in rats transplanted with osteoblasts differentiated cells but not in rats transplanted with undifferentiated MSCs. Longer observational periods are required to evaluate a true bone formation. The findings of this study suggested that the different sources; hBM-MSCs or hAF-MSCs exhibited remarkably different signature regarding the cell morphology, proliferation capacity and osteogenic differentiation potential CONCLUSIONS: AF-MSCs have a better performance in vivo bone healing than that of BM-MSCs. Hence, AF derived MSCs is highly recommended as an alternative source to BM-MSCs in bone regeneration and spine fusion surgeries. Moreover, the usage of gel-foam as a scaffold proved as an efficient cell carrier that showed bio-compatibility with cells, bio-degradability and osteoinductivity in vivo