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New aromatic O -alkyl pyridine derivatives were designed and synthesised as Proviral Integration Moloney (PIM)-1 kinase inhibitors. 4c and 4f showed potent in vitro anticancer activity against NFS-60, HepG-2, PC-3, and Caco-2 cell lines and low toxicity against normal human lung fibroblast Wi-38 cell line. Moreover, 4c and 4f induced apoptosis in the four tested cancer cell lines with high percentage. In addition, 4c and 4f significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 4c and 4f showed potent PIM-1 kinase inhibitory activity with IC 50  = 0.110, 0.095 µM, respectively. Kinetic studies indicated that 4c and 4f were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, in silico prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that 4c and 4f could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties.

Plant probiotics are live microbial cells or cultures that support plant growth and control plant pathogens through different mechanisms. They have various effects on plants, including plant growth promotion through the production of indole acetic acid (IAA), biological control activity (BCA), and production of cellulase enzymes, thus inducing systemic resistance and increasing the availability of mineral elements. The present work aimed to study the potential of Achromobacter marplatensis and Bacillus velezensis as plant probiotics for the field cultivation of potatoes. In vitro studies have demonstrated the ability of selected probiotics to produce IAA and cellulase, as well as antimicrobial activity against two plant pathogens that infect Solanum tuberosum as Fusarium oxysporum and Ralstonia solanacearum under different conditions at a broad range of different temperatures and pH values. In vivo study of the effects of the probiotics A. marplatensis and B. velezensis on S. tuberosum plants grown in sandy clay loamy soil was detected after cultivation for 90 days. Probiotic isolates A. marplatensis and B. velezensis were able to tolerate ultraviolet radiation (UV) exposure for up to two hours, the dose response curve exhibited that the D 10 values of A. marplatensis and B. velezensis were 28 and 16 respectively. In the case of loading both probiotics with broth, the shoot dry weight was increased significantly from 28 in the control to 50 g, shoot length increased from 24 to 45.7 cm, branches numbers increased from 40 to 70 branch, leaves number increased from 99 to 130 leaf, root dry weight increased from 9.3 to 12.9 g, root length increased from 24 to 35.7 cm, tuber weight increased from 15 to 37.0 g and tubers number increased from 9 to 24.4 tuber, the rot percentage was reduced to 0%. The addition of both probiotic isolates, either broth or wheat grains load separately has enhanced all the growth parameters; however, better results and increased production were in favor of adding probiotics with broth more than wheat. On the other hand, both probiotics showed a remarkable protective effect against potato pathogens separately and reduced the negative impact of the infection using them together., (© 2024. The Author(s).)

New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b , 5c , 6e, 13a , 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver-Burk double-reciprocal plot indicated that 5b , 5c , 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases.

This study aimed to investigate the effect of oral supplementation of rumen-protected L-arginine on semen quality, testes, and accessory genital glands biometry in rams. Ten apparently healthy and fertile rams were randomly divided into two equal groups; control, and rumen-protected L-arginine (20 mg/Kg body weight for 30 days) treated group. In all rams, ultrasonographic measurements of the testes and the accessory genital glands and blood sampling were performed at day (D)10, D20, and D30 (D0 is the start of supplementation). Semen ejaculates were collected twice/week and semen quantity, and quality was examined. Our results showed that, in the L-arginine treated group, there were significant increase in the ultrasound biometric measurement of right seminal vesicle (RSV) and right Cowper's gland (RCG) at D10, both testes, tail of the epididymis (TE), SV, and CG of both sides at D20, and of both testes, RTE, RSV, RCG, and LSV at D30. Semen quality and quantity parameters were significantly improved in L-arginine treated group. Moreover, testosterone level in the L-arginine treated group was significantly higher than that in the Control group. Serum thyroxine and glutathione peroxidase concentrations were significantly higher in the L-arginine treated group. The present study concluded that oral supplementation with rumen-protected L-arginine is beneficial in improvement of rams' fertility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hussein, Hassaneen, Ali, Sindi, Ashour, Fahmy, Swelum and Ahmed.)

Background and Objective: Evaluation of the stage and severity of the chronic diabetic foot ulcer (CDFU) is vital to increase the healing rate and to select the suitable treatment. We aim to assess the influence of low-intensity laser irradiation (LILI) and hyperbaric oxygenation therapy (HBOT) to accelerate the CDFU healing thru the transcutaneous oxygen tension (TcPO2) measurements., Materials and Methods: Seventy-five diabetic patients (type 2) of both genders, their ages ranged from 40-65 years with CDFUs (duration of ulcer < 6 weeks). All patients were randomly assigned into LILI, HBOT, and the control group. Measurement of TcPO2 using transcutaneous oximetry was performed for all patients once in the baseline and consequently in the second, fourth, and sixth- weeks duration. LILI utilized by a 33-diode cluster contact applicator with output power 1440 mW, energy density (fluency) was adjusted for 4 J/Cm 2 at 10 kHz, and for 8 min per session, three times per week for a total of consecutive 6 weeks. HBOT was pressurized up to 2.5 ATA and patients delivered 100% oxygen for 60 min per session for 30 sessions. The Control group received conventional wound care only, twice daily, with saline and apply a new bandage after cleaning., Results: MANOVA revealed a statistically insignificant difference in the control group, while statistically significant improvement in both the LILI and HBOT groups. The intergroup comparisons showed an insignificant statistical difference in the pre-test, while highly statistically significant differences for the three post-measures in favor of HBOT and LILI groups. The percentage of improvement of the HBOT group was higher than LILI. Post-hoc test using the least significant difference (LSD) revealed statistically significant differences of HBOT in favor of the LILI group., Conclusion: Both LILI and HBOT may be used as adjunctive methods to improve TcPO2 that accelerate healing in CDFUs. HBOT may be favorable in the improvement of TcPO2 than LILI., Competing Interests: Conflicts of interest/Competing interestsThe authors stated and declare that No conflict or competing of interests., (© Springer Nature Switzerland AG 2021.)

STAT3 signaling is known to be associated with tumorigenesis and further cancer cell-intrinsic activation of STAT3 leads to altered regulation of several oncogenic processes. Given the importance of STAT3 in cancer development and progression particularly breast cancer, it is crucial to discover new chemical entities of STAT3 inhibitor to develop anti-breast cancer drug candidates. Herein, 4-benzyl-2-benzylthio-5-methyl-1H-imidazole (2a) and 4-benzyl-5-methyl-2-[(2,6-difluorobenzyl)thio]-1H-imidazole (2d) from a group of thirty imidazole-bearing compounds showed greater STAT3 inhibition than their lead compounds VS1 and the oxadiazole derivative MD77. Within all tested compounds, ten derivatives effectively inhibited the growth of the two tested breast cancer cells with IC 50 values ranging from 6.66 to 26.02 µM. In addition, the most potent derivatives 2a and 2d inhibited the oncogenic function of STAT3 as seen in the inhibition of colony formation and IL-6 production of breast cancer cell lines. Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the STAT3-SH2 domain. Collectively, our present study suggests 2-substituted-4-benzyl-5-methylimidazoles are a new class of anti-cancer drug candidates to inhibit oncogenic STAT3 function., (Copyright © 2021 Elsevier Inc. All rights reserved.)

New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

New 1,3,4-trisubstituted pyrazole derivatives were synthesized and evaluated for their antiplasmodial activity. Compounds 4b, 4c, 7a and 7d were the most potent antiplasmodial agents against P. berghei with percent of suppression ranging from 90 to 100%. They were also screened for their in vitro antimalarial activity against the chloroquine resistant strain P. falciparum, (RKL9). Compound 4c displayed the highest in vitro antimalarial activity; 13-fold higher than standard chloroquine phosphate. Molecular docking of the most active compounds against the wildtype and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Furthermore, these compounds exhibited reasonable in silico drug-likeness and pharmacokinetic properties. Toxicity studies of the most active compounds revealed that all tested compounds were non-toxic and well-tolerated up to 150 mg/kg via oral route and 75 mg/kg via parentral route. According to RBC hemolysis assay, it was found that compound 7a was the most potent anti-inflammatory and least toxic derivative with IC 50 value 71-fold higher than IC 50 value related to the antimalarial activity. Moreover, cytotoxicity assessment revealed that compound 4c was the least toxic derivative with IC 50 value 70000-fold higher than IC 50 value related to the antimalarial activity., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Two new series of pyrazolo[3,4-d]pyrimidine bearing thiazolidinone moiety were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro (COX-1 and COX-2) inhibitory assay. Compounds that showed promising COX-2 selectivity were further subjected to in vivo anti-inflammatory screening applying formalin induced paw edema (acute model) and cotton-pellet induced granuloma (chronic model) assays using celecoxib and diclofenac sodium as reference drugs. The histopathological and ulcerogenic potential were also determined. In vivo anti-inflammatory data showed that compounds 2, 6, 7d displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, compounds 2, 3d, 3e, 7b and 7d displayed anti-inflammatory activity greater than or nearly equivalent to diclofenac sodium in the cotton pellet-induced granuloma assay. Moreover, most of the tested compounds revealed good gastrointestinal safety profile. Collectively, compounds 2 and 7d were considered as promising candidates in managing both acute and chronic inflammation with safe gastrointestinal margin., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: Novel open chain and cyclized derivatives containing pyrazole scaffold were designed, synthesized and evaluated as antileishmanial compounds. Methodology & results: In silico reverse docking experiment suggested Leishmania major pteridine reductase (Lm-PTR1) as a putative target for the synthesized compounds. In vitro antileishmanial screening against L. major promastigotes and amastigotes using miltefosine and amphotericin B as references showed that the majority of the compounds displayed activity higher than miltefosine. Compounds 3i and 5 showed the highest antileishmanial activity with IC 50 values of 1.45 ± 0.08 μM and 2.30 ± 0.09 μM, respectively, for the amastigote form. In silico drug-likeness and toxicity predictions showed acceptable profiles for most of the compounds, which were validated by experimental toxicity studies., Conclusion: This study offers promising entities for antileishmanial activity.

A series of pyridine and thieno[2,3-b]pyridine derivatives have been designed and synthesized as anticancer PIM-1 kinase inhibitors. Thirty-seven compounds were selected by NCI to be tested initially at a single dose (10 µM) in the full NCI 60 cell line panel. Compound 5b showed potent anticancer activity and was tested twice in the five-dose assay which confirmed its potent antitumor activity (GI 50 values 0.302-3.57 µM) against all tested tumor cell lines except six cell lines where they showed moderate sensitivity. This compound was sent to NCI biological evaluation committee and still under consideration for further testing. In addition, the most active anticancer compounds in each series, 5b, 8d, 10c, 13h, and 15e, were evaluated for their PIM-1 kinase inhibitory activity. Compound 8d was the most potent one with IC 50  = 0.019 µM followed by 5b, 15e, 10c and 13h with IC 50 values 0.044, 0.083, 0.128 and 0.479 µM respectively. Moreover, docking study of the most active compounds in PIM-1 kinase active site was consistent with the in vitro activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

New pyrazolo[3,4-d]pyrimidines substituted with various functionalities or attached to a substituted pyrazole ring through different linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity using in vitro COX-1/COX-2 inhibition assay and in vivo formalin induced paw edema and cotton pellet-induced granuloma assays. Results revealed that compounds 17b and 18 possessed COX-1/COX-2 selectivity indices higher than diclofenac sodium and celecoxib. However, compounds 16a,b exhibited selectivity indices higher than diclofenac sodium and nearly equivalent to celecoxib, whereas, 9b displayed selectivity index comparable to diclofenac sodium. In vivo anti-inflammatory data showed that compounds 9b, 16a, 18 displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, the pyrazolyl derivatives 9b, 16b and 17b displayed anti-inflammatory activity about 2-2.5-fold that of diclofenac sodium and nearly 8-10.5-fold that of celecoxib in the cotton pellet-induced granuloma assay. The ulcerogenic effect of the active compounds was also investigated and results revealed that compounds 16a, 17a,b and 18 showed good gastrointestinal safety profile. Based on this, compounds 16a and 18 were considered as safe and effective leads in managing acute inflammation, while, 17b was prominent in controlling chronic inflammation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

AT rich interactive domain 1A (ARID1A) is one of the most commonly mutated genes in a broad variety of tumors. The mechanisms that involve ARID1A in ampullary cancer progression remains elusive. Here, we evaluated the frequency of ARID1A and KRAS mutations in ampullary adenomas and adenocarcinomas and in duodenal adenocarcinomas from two cohorts of patients from Singapore and Romania, correlated with clinical and pathological tumor features, and assessed the functional role of ARID1A . In the ampullary adenocarcinomas, the frequency of KRAS and ARID1A mutations was 34.7% and 8.2% respectively, with a loss or reduction of ARID1A protein in 17.2% of the cases. ARID1A mutational status was significantly correlated with ARID1A protein expression level (P=0.023). There was a significant difference in frequency of ARID1A mutation between Romania and Singapore (2.7% versus 25%, P=0.04), suggestive of different etiologies. One somatic mutation was detected in the ampullary adenoma group. In vitro studies indicated the tumor suppressive role of ARID1A . Our results warrant further investigation of this chromatin remodeller as a potential early biomarker of the disease, as well as identification of therapeutic targets in ARID1A mutated ampullary cancers.

The factors that contribute to musculoskeletal healthcare disparities may influence the results of studies regarding the long-term outcome of orthopaedic implants. Patient decisions regarding their healthcare and their subsequent outcomes are influenced by health literacy. Providing patients with the information that they need to consent to treatment must be provided in a culturally competent manner. The influence of the physician or healthcare provider on the treatment choice varies depending on the type of decision-making process: patient-based, physician-based, or shared decision making. Respecting the patient's autonomy while acknowledging the knowledge and experience of the physician, we advocate for shared decision making. This may require modification of existing regulations regarding informed consent. Furthermore, federal and state directives have been put into place to address healthcare disparities, especially with respect to culturally competent care and access to proper healthcare.

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., Methods: Seven hundred serum samples from vaccinated children and adults (aged 2-47 years) were used for quantitative and qualitative detection of HBsAb by ELISA. Three hundred and sixty serum samples representing undetectable or low or high HBsAb were screened for markers of active HBV infection (HBsAg, HBcAb (IgG) and HBeAb by ELISA, plus HBsAg by AxSYM) and HBV-DNA genotyping by nested multiplex PCR and by DNA sequencing., Results: It was found that 65% of children aged 2-4 years, and 20.5% aged 4-13 years, as well as 45% adults were good responders to HBV vaccination mounting protective level HBsAb. Poor responders were 28%, 59.5% and 34%, and non-responders were 7%, 20% and 21% respectively, in the three studied groups. Markers of asymptomatic HBV infections were HBsAg detected by ELISA in 2.5% vs 11.39% by AxSYM. Other markers were HBcAb (IgG) in 1.38%, HBeAb in 0.83%, and HBV-DNA in 7.8%. All had HBV genotype E infection., Conclusion: It is concluded that HBV vaccine is efficient in controlling HBV infection among children and adults. The vaccine breakthrough infection was by HBV genotype E. A booster dose of vaccine is recommended, probably four years after initial vaccination.

A total of 835 samples of leafy vegetables and some aromatic medicinal plants were collected from five different areas of Egypt during 1999. Ninety-seven per cent of the leafy vegetables were contaminated with heavy metals with 39% exceeding the maximum limits for each element. Cadmium was detected in 78 of 116 samples of leafy vegetable, although without any exceeding the maximum limits. However, lead was detected in 99 samples, of which 39 exceeded the maximum limits (0.3 mg kg(-1)) and 56 medicinal plant samples of 70 had lead levels above 0.5 mg kg(-1). Copper was detected in 69 medicinal plant samples, of which 58 samples contained levels higher than 10 mg kg(-1). However, cadmium was only found in 43% of samples with only two of 70 samples above the maximum limit. Seventy-three per cent of the samples of medicinal plants were contaminated with pesticide residues, of which 44% contained amounts that exceeded maximum residue limits. Malathion was the most frequently found pesticide residue, being detected in 203 of 391 (52%.) samples, followed by profenofos, which was detected in 131 of 391 (33%) samples.

Organophosphorus, dithiocarbamates, and some synthetic pyrethroids pesticides, which are commonly used in Egypt for pest control, were monitored, as well as persistent organochlorines, which had been prohibited from use several years ago. Fruit and vegetable samples (397) were collected from 8 local markets and examined for 52 pesticides. Of all analyzed samples, 42.8% contained detectable residues, of which 1.76% exceeded their maximum residue limits (MRLs). The rates of contamination with the different pesticides were 0-86%. However, violation rates among contaminated products were very low, ranging from 0 to 4.6%. In general, organochlorine pesticide residues were not detected in most samples. Dithiocarbamate residues were found in 70.4% of 98 samples analyzed for dithiocarbamates, but only one grape sample had residues exceeding the MRL established by the Codex Committee on Pesticide Residues.

Peel oils of lemon, grapefruit and navel orange were tested for insecticidal activities against larvae and adults of Culex pipiens and Musca domestica. Lemon peel oil was the most effective against larvae and adults of C. pipiens. Grapefruit peel oil was more toxic to adults of M. domestica while lemon oil, was more toxic Musca larvae. On the other hand, the orange peel oil was the least effective against larvae and adults of both species. The toxicity of oils applied to larval stages was extended to pupal and adult stages. C. pipiens adults appeared with paralyzed legs, while M domestica adults appeared normal. The weights of pupae treated as larvae were generally less than that of the control. All oils produced deleterious effects on fecundity of survivors of sublethal doses. The effect was obviously recorded in treated adults. Treatment of Culex & Musca with oils caused serious latent effect.

Pesticide residues in human milk and environmental samples from Kafr El-Zayat Governorate in Egypt were analyzed. This governorate is located near one of the biggest pesticide factories in Egypt. Organochlorine and organophosphorus pesticides were monitored, including those that have been prohibited from use in Egypt. Human milk samples (31 samples) from Kafr El-Zayat were compared with 11 samples collected from Cairo. Data were compared with results from studies performed in 1987 and 1990. The present study showed that aldrin and dieldrin, heptachlor and heptachlor epoxide, and endrin residues have been eliminated from human milk. Estimated daily intakes (EDIs) of DDT complex and gamma-HCH by breast-fed infants in Kafr El-Zayat were 85.96 and 3.1% of the respective acceptable daily intakes (ADIs). beta-HCH residues showed an increasing pattern, especially in human milk samples from Cairo. DDT complex and HCH isomers in orange, spinach, lettuce, potatoes, and clover samples ranged from undetectable to very low concentrations. Higher levels of DDT and HCH were detected, but aldrin, dieldrin, endrin, and the heptachlors were not detected in food of animal origin. Residues in fish samples were below maximum residue limits established by some developed countries. Those in animal milk samples approached the extraneous residue limits of the Codex Committee on Pesticide Residues. HCH residues in soil were negligible, but DDT residues in soil were somewhat higher. Among water samples, groundwater samples had the highest residues of HCHs and DDTs, followed by Nile River water and then tap water. However, the organochlorine pesticide residues were found at concentrations below the maximum allowable limits set by the World Health Organization for drinking water. Among 12 organophosphorus pesticides monitored as parent compounds, dimethoate, malathion, methamidophos, and chlorpyrifos residues were detected in low concentrations in soil samples from a pesticide factory. No organophosphorus pesticide residues were found in plant samples, except for very low residues of dimethoate in an orange sample. Water samples were devoid of organophosphorus residues as parent compounds.