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A novel series of dihydropyrimidine/sulphonamide hybrids 3a–j with anti-inflammatory properties have been developed and tested as dual mPGES-1/5-LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound 3j was the most potent dual inhibitor with IC50 values of 0.92 µM and 1.98 µM, respectively. In vivo, anti-inflammatory studies demonstrated that compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-α, and IL-6) with gastrointestinal safety profiles. Molecular docking simulations explored the most potent derivatives’ binding affinities and interaction patterns within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation.

Abstract Nowadays, some relative warming temperatures related to climate change may be provided at the grafting time. Therefore, this study was conducted during two seasons (2018-2019) to study the effect of three callusing method (callusing room, callusing soil, callusing tunnel) and four grafting date (15 Jan., 1Feb., 15 Feb., 1 Mar.) for early (Flame seedless), medium (Thompson seedless) and late (Crimson seedless) grape varieties on grafted grape cuttings as short methods for transplant production. The results indicated that, the early grapes variety achieved higher grafting success on 1st Feb. grafting date as well as the late grape variety in callusing room and callusing soil methods. Also, Callusing soil achieved grafted success by 72.9%, 68.55% and 77.94% compared to callusing tunnel 37.3%, 45.9% and 55% for Flame seedless, Thompson seedless and Crimson seedless, respectively as mean of both seasons. High grafting success resulted from the high content of indole and sugars, along with low phenol content before callusing stage, as well as high indole and low sugars of grafts partner after callusing stage. while, higher phenols was accumulated in rootstock after callusing stage. There is no antagonistic effect between grafts partners. Callusing soil may be considered as an eco-friendly, sustainable and cheaper alternative tool for callusing of grafts cuttings.

Abstract Introduction One of the most robust global challenges and difficulties in the 21st century is cancer. Treating cancer is a goal which continues to motivate researchers to innovate in design and development of new treatments to help battle the disease. Objectives Our objective was developing new antiapoptotic hybrids based on biologically active heterocyclic motifs "benzimidazole?oxadiazole-chalcone hybrids'' that had shown promising ability to inhibit EGFR and induce apoptosis. We expected these scaffolds to display anticancer activity via inhibition of BRAF, EGFR, and Bcl-2 and induction of apoptosis through activation of caspases. Methods The new hybrids 7a-x were evaluated for their anti-proliferative, EGFR & BRAFV600E inhibitory, and apoptosis induction activities were detected. Docking study & dynamic stimulation into EGFR and BRAFV600E were studied. Results All hybrids exhibited remarkable cell growth inhibition on the four tested cell lines with IC50 ranging from 0.95 μM to 12.50 μM. which was comparable to Doxorubicin. Compounds 7k-m had the most potent EGFR inhibitory activity. While, compounds 7e, 7g, 7k and 7l showed good inhibitory activities against BRAFV600E. Furthermore, Compounds 7k, 7l, and 7m increased Caspases 3,8 & 9, Cytochrome C and Bax levels and decreased Bcl-2 protein levels. Compounds 7k-m received the best binding scores and showed binding modes that were almost identical to each other and comparable with that of the co-crystalized Erlotinib in EGFR and BRAF active sites. Conclusion Compounds 7k-m could be used as potential apoptotic anti-proliferative agents upon further optimization.

Introduction: The main objective of this study was to assess the cost of prostate cancer over a 1-year period from a societal perspective. Methods: We constructed a cost-of-illness model to assess the cost of different health states of prostate cancer, metastatic or nonmetastatic, among Egyptian men. Population data and clinical parameters were extracted from the published literature. We relied on different clinical trials to extract clinical data. We considered all direct medical costs, including the costs of treatment and required monitoring, in addition to the indirect costs. The unit costs were captured from Nasr City Cancer Center and Egyptian Authority for Unified Procurement, Medical Supply, and Management of Medical Technology, and resource utilization were collected from clinical trials and validated by the Expert Panel. One-way sensitivity analysis was conducted to ensure model robustness. Results: The number of targeted patients with nonmetastatic hormone-sensitive prostate cancer, hormone-sensitive prostate cancer, and metastatic castration-resistant prostate cancer was 215,207, 263,032, and 116,732, respectively. The total costs, in Egyptian pounds (EGP) and US dollars (USD), for the targeted patients, including drug costs and nondrug costs over a time horizon of 1 year, were EGP 41.44 billion (USD 9.010 billion) for localized prostate cancer; for metastatic prostate cancer, they doubled to EGP 85.14 billion (USD 18.510 billion), which reflects a huge burden on the Egyptian healthcare system. The drug costs for localized and metastatic prostate cancer are EGP 41,155,038,137 (USD 8.946 billion) and EGP 81,384,796,471 (USD 17.692 billion), respectively. A significant difference in nondrug costs between localized and metastatic prostate cancer was demonstrated. Nondrug costs were estimated at EGP 293,187,203 (USD 0.063 billion) for localized prostate cancer and EGP 3,762,286,092 (USD 0.817 billion) for metastatic prostate cancer. This significant difference in nondrug costs highlights the importance of early treatment due to the increased costs of progression and the burden of follow-up and productivity loss associated with metastatic prostate cancer. Conclusion: Metastatic prostate cancer has a huge economic burden on the Egyptian healthcare system compared with localized prostate cancer owing to the increased costs of progression, follow-up, and productivity loss. This highlights the necessity of early treatment of these patients to save costs and lighten the burden of the disease on the patient, society, and economy.

Fungal extracts are considered a promising source of bioactive compounds that represent the basic core of the drug industry.This study aimed at exploring the antimicrobial, antioxidant and larvicidal activities of three ethyl acetate extracts of three fungal isolates Fusarium oxysporum, Aspergillus fumigatus and Penicilluim griseofulvum. These fungi were isolated from sediment samples collected in water courses of three Egyptian governorates; Giza, Qalubeya and Gharbeya, during a year from January to December 2019, molecularly identified using 18Sr RNA technique and were grown on rice medium for 14 days and extracted with ethyl acetate. GC-MS/MS examination of extracts led to identification of 15, 29 and 24 compounds, respectively. Moreover, in Folin-Ciocalteu's assay, the tested fungal extracts showed noticeable total phenolic contents (TPCs) values of 115.84, 88.24 and 73.22, respectively for Aspergillus fumigatus, Penicillium griseofulvum and Fusarium oxysporum. Additionally, Aspergillus fumigatus extract exhibited strong total antioxidant capacity (TAC) value of 409.46 mg AAE/g dry extract, followed by Penicillium griseofulvum and Fusarium oxysporum extracts with TAC values of 299.28 and 281.31 mg AAE/g dry extract, respectively. All extracts exhibited antimicrobial activites against Staphylococcus aureus (G+ve bacterium), Escherichia coli (G-ve bacterium), Candida albicans (yeast) and Aspergillus niger (Fungus). Also, the extracts showed high larvicidal activity against miracidia and cercariae of Schistosoma mansoni. In conclusion, Fusarium oxysporum, Aspergillus fumigatus and Penicilluim griseofulvum are excellent sources of bioactive compounds which have multiple biological effects. [ J Adv Biotechnol Exp Ther 2022; 5(3.000): 456-472]

A new class of benzimidazole-based derivatives (4a–j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a–j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

Abstract Background Papilledema is optic disc pathology characterized by swelling of the optic disc occurring secondary to elevated intracranial pressure (ICP), and it was proposed that elevated ICP is transferred along the subarachnoid space to the optic nerve (ON) leading to metabolic process interruptions and MRI changes within ON head. This study aimed to rule out if DWI and ADC map can be used as a diagnostic tool for detection of papilledema and if ADC values can be helpful in papilledema grading. Result ADC value was significantly lower in papilledema cases group (A) in comparison with control group (B). Conclusion Diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) map can be utilized as a diagnostic tool for diagnosis of papilledema, and ADC values can be helpful in diagnosis of papilledema grade.

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAFV600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI50 values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI50 = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAFV600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAFV600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects.

New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a–j, 8a–j, 9a–c, and 10a–c. The oxime containing compounds 8a–j and 10a–c were more active as antiproliferative agents than their non-oxime congeners 7a–j and 9a–c. Compounds 8d, 8g, 8i, and 10c inhibited EGFR with IC50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d, 8g, 8i, and 10c exhibited binding free energies ranging from −12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from −9.16 to −12.00 kcal/mol at the JNK-2 binding site.

A series of novel 3-cyanopyridone/pyrazoline hybrids (21–30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.

Some new Bis-pyrazoline hybrids 8–17 with dual EGFR and BRAFV600E inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI50 values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAFV600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and BRAFV600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds 12, 15, and 17 have the potential to be dual EGFR/BRAFV600E inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.

Synthesis of thiazolidinone based on quinolone moiety was established starting from 4-hydroxyquinol-2-ones. The strategy started with the reaction of ethyl bromoacetate with 4-hydroxyquinoline to give the corresponding ethyl oxoquinolinyl acetates, which reacted with hydrazine hydrate to afford the hydrazide derivatives. Subsequently, hydrazides reacted with isothiocyanate derivatives to give the corresponding N,N-disubstituted thioureas. Finally, on subjecting the N,N-disubstituted thioureas with dialkyl acetylenedicarboxylates, cyclization occurred, and thiazolidinone derivatives were obtained in good yields. The two series based on quinolone moiety, one containing N,N-disubstituted thioureas and the other containing thiazolidinone functionalities, were screened for their in vitro urease inhibition properties using thiourea and acetohydroxamic acid as standard inhibitors. The inhibition values of the synthesized thioureas and thiazolidinones exhibited moderate to good inhibitory effects. The structure−activity relationship revealed that N-methyl quinolonyl moiety exhibited a superior effect, since it was proved to be the most potent inhibitor in the present series achieving (IC50 = 1.83 ± 0.79 µM). The previous compound exhibited relatively much greater activity, being approximately 12-fold more potent than thiourea and acetohydroxamic acid as references. Molecular docking analysis showed a good protein−ligand interaction profile against the urease target (PDBID: 4UBP), emphasizing the electronic and geometric effect of N,N-disubstituted thiourea.

Keratitis is a global health issue that claims the eye sight of millions of people every year. Dry eye, contact lens wearing and refractive surgeries are among the most common causes. The resistance rate among fluoroquinolone antibiotics is >30%. This study aims at formulating a newly synthesized ciprofloxacin derivative (2b) niosomes and Solulan C24-, sodium cholate- and deoxycholate-modified niosomes. The prepared niosomal dispersions were characterized macroscopically and microscopically (SEM) and by percentage entrapment efficiency, in vitro release and drug release kinetics. While the inclusion of Solulan C24 produced something discoidal-shaped with a larger diameter, both cholate and deoxycholate were unsuccessful in forming niosomes dispersions. Conventional niosomes and discomes (Solulan C24-modified niosomes) were selected for further investigation. A corneal ulcer model inoculated with colonies of Pseudomonas aeruginosa in rabbits was developed to evaluate the effectiveness of keratitis treatment of the 2b-loaded niosomes and 2b-loaded discomes compared with Ciprocin® (ciprofloxacin) eye drops and control 2b suspension. The histological documentation and assessment of gene expression of the inflammatory markers (IL-6, IL1B, TNFα and NF-κB) indicated that both 2b niosomes and discomes were superior treatments and can be formulated at physiological pH 7.4 compatible with the ocular surface, compared to both 2b suspension and Ciprocin® eye drops.

In this study, the irrigation water infiltration rate (IR) is defined by input variables in linguistic terms using a fuzzy-logic approach. A fuzzy-logic model was developed using data collected from published data. The model was trained with three fuzzy membership functions: triangular (‘trimf’), trapezoid (trapmf), and pi (‘pimf’). The fuzzy system considered the number of irrigation events, applied water depth, polyacrylamide application rate, water application time, water electrical conductivity, soil surface slope, and soil texture components as input variables. The inputs were classified in terms of low, medium, and high levels. The output variable (i.e., IR) was rated in terms of five levels: very low, low, medium, high, and very high. Using statistical analysis, the values of IR resulting from the developed fuzzy-logic model were compared with the observations from the experiments. The results confirm that the agreement between the observations and predictive results was acceptable, except for fuzzy 'trimf'. The coefficient of determination provided the greatest value when using the 'trapmf' and 'pimf', with the value estimated for the 'pimf' slightly higher than that of 'trapmf'. Based on the results that were obtained, irrigation managers can use the fuzzy-logic approach to modify their field practices during the growing season to improve on-farm water management.

The aim of this study was to investigate the effects of Nigella sativa (NS) fixed oil in comparison to dexamethasone (Dex) on inducible nitric oxide synthase (iNOS), peripheral blood eosinophils (PBE), allergen specific serum IgG1 and interleukins and airway inflammation in a murine model of allergic asthma. Thirty-one mice were divided into four groups. Group I (n = 6) served as the control group. Group II (n = 10) mice were sensitized intraperitoneally and challenged intratracheally with cone albumin with no treatment. Group III(n = 6) mice were sensitized, challenged, and treated with Dex for 17 days starting at 24 hours after the first challenge. Group IV (n = 9) mice were sensitized, challenged, and treated with NS fixed oil for 17 days as well. For all groups, the following procedures were carried out: immunohistochemical study of iNOS in lung tissues, detection of PBE percentage, and histopathological examination of lung tissues for inflammatory cells. Lung tissue iNOS expression increased in sensitized, non-treated mice compared with controls, but this increase was not significant. NS fixed oil treatment significantly reduced PBE and lung inflammation but did not significantly reduce lung tissue iNOS expression compared with the control group. These effects were comparable to the effects of Dex. These results suggest that Nigella sativa exhibits immunomodulatory and anti-inflammatory effect which may be useful for treatment of allergic asthma.

Background: Histologically confirmed hepatocellular carcinomas (HCC) account for 90% of all hepatic malignancies and are notoriously fatal. Because of neovascularization, its blood supply is greater than that of the surrounding hepatic tissue. In order to diagnose HCC early and monitor its progress after surgery, a noninvasive technique called CTP, or computed tomography with perfusion imaging, measures the blood flow characteristics of the tumor and compares them to the surrounding tissue. Objective: To assess if CTP is a useful diagnostic method for identifying HCC for early surgical intervention and post-therapeutic assessment. Patients and Methods: Screening clinical trial study for patients who had HCC according to inclusion and exclusion criteria. 250 patients were included in the study. Results: Triphasic yields invisible results lesions were (20%) and visible lesions were (80%) of triphasic results. Regarding perfusion parameters, patients were (6%) negative and (94%) positive. CT perfusion was more sensitive and wa s 100% specific in the early detection of HCC lesions for early surgical intervention and also for follow-up after surgery to detect the recurrence if the positive predictive value was high, which means a high percent of true positive results and a small percent of false positive results. Conclusion: When it comes to evaluating surgical interventional techniques for HCC and making an early diagnosis, CTP is a specialized and secure imaging method. [ABSTRACT FROM AUTHOR]