FMS‐like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the ...design of new FLT3 inhibitors as potential hits for AML irradiation. Cell‐based screening was performed with 18 oxindole derivatives and 5a–c inhibited 68%–73% and 83%–91% of internal tandem duplication (ITD)‐mutated MV4‐11 cell growth for 48‐ and 72‐h treatments while only 0%–2% and 27%–39% in wild‐type THP‐1 cells. The most potent compound 5a inhibited MV4‐11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP‐1 cells, thus showing two‐fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High‐throughput protein profiling revealed low levels of the growth factors IGFBP‐2 and ‐4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF‐β. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.
A series of oxindole compounds (5a–c and 6a–o) carrying a vanillin functionality were designed and synthesized as FMS‐like tyrosine kinase 3 (FLT3) inhibitors for acute myeloid leukemia (AML). The oxindole compounds were more effective on MV4‐11 cells than on THP‐1 cells, demonstrating selective inhibition against the oncogenic internal tandem duplication (ITD) mutation. Compound 5a has the potential to become a specific therapeutic agent in ITD‐mutated AML.
Diabetes mellitus is a major challenge for global health, and
Willd. (
) is a widely used herbal remedy with diverse cultivars traditionally used for diabetes treatment. However, the comparative ...efficacy of these cultivars remains ambiguous. This study aimed to evaluate the D-pinitol content and DPPH radical-scavenging activity of methanolic leaves extracts of five
cultivars. Furthermore, the effects of these cultivars on various parameters, including blood glucose levels, oxidative stress markers, inflammatory cytokines, lipid profiles, liver enzymes, renal function markers, and histopathological changes, were assessed in STZ-induced diabetic rats after one month of oral daily treatment. All tested cultivars demonstrated significant improvements in the measured parameters, albeit to varying extents. Notably, the LOE cultivar, distinguished by its orange bracts, exhibited the highest efficacy, surpassing the effectiveness of glibenclamide, an antidiabetic medication, and displayed the highest concentration of D-pinitol. These findings underscore the importance of carefully selecting the appropriate
cultivar to maximize the antidiabetic efficacy, with a particular emphasis on the correlation between antidiabetic activity and D-pinitol concentrations.
A series of novel benzofuran-based compounds 7a-s were designed, synthesized, and investigated in vitro as acetylcholinesterase inhibitors (AChEIs). Compounds 7c and 7e displayed promising inhibitory ...activity with IC50 values of 0.058 and 0.086 μM in comparison to donepezil with an IC50 value of 0.049 μM.
The new molecules' antioxidant evaluation revealed that 7c, 7e, 7j, 7n, and 7q produced the strongest DPPH scavenging activity when compared to vitamin C. As it was the most promising AChEI, compound 7c was selected for further biological evaluation. Acute and chronic toxicity studies exhibited that 7c showed no signs of toxicity or adverse events, no significant differences in the blood profile, and an insignificant difference in hepatic enzymes, glucose, urea, creatinine, and albumin levels in the experimental rat group. Furthermore, 7c did not produce histopathological damage to normal liver, kidney, heart, and brain tissues, ameliorated tissue malonaldehyde (MDA) and glutathione (GSH) levels and reduced the expression levels of the APP and Tau genes in AD rats. Molecular docking results of compounds 7c and 7e showed good binding modes in the active site of the acetylcholinesterase enzyme, which are similar to the native ligand donepezil. 3D-QSAR analysis revealed the importance of the alkyl group in positions 2 and 3 of the phenyl moiety for the activity. Overall, these findings suggested that compound 7c could be deemed a promising candidate for the management of Alzheimer's disease.
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•Design and synthesis of novel benzofuran-based compounds 7a-s.•All compounds were evaluated as in vitro acetylcholinesterase inhibitors (AChEIs).•7c exhibited no histopathological damage to the normal and AD brain tissues.•7c ameliorated the levels of MDA, GSH, APP and Tau genes in AD-rats.•7c showed good binding in the active site of the acetylcholinesterase enzyme.
Linn. (Tamarind, F. Fabaceae) is one of the most widely consumed fruits in the world. A crude extract and different fractions of
(using
-hexane, dichloromethane, ethyl acetate, and
-butanol) were ...evaluated
with respect to their DPPH scavenging and AchE inhibition activities. The results showed that the dichloromethane and ethyl acetate fractions showed the highest antioxidant activities, with 84.78 and 86.96% DPPH scavenging at 0.10 μg mL
. The
-hexane, dichloromethane, and ethyl acetate fractions inhibited AchE activity in a dose-dependent manner, and the
-hexane fraction showed the highest inhibition at 20 μg mL
. The results were confirmed by using
-hexane, dichloromethane, and ethyl acetate fractions
to regress the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model. Phytochemical investigations of those three fractions afforded two new diphenyl ether derivative compounds 1-2, along with five known ones (3-7). The structures of the isolated compounds were confirmed
1D and 2D NMR and HRESIMS analyses. The isolated compounds were subjected to extensive
-based investigations to putatively highlight the most probable compounds responsible for the anti-Alzheimer activity of
. Inverse docking studies followed by molecular dynamics simulation (MDS) and binding free energy (Δ
) investigations suggested that both compounds 1 and 2 could be promising AchE inhibitors. The results presented in this study may provide potential dietary supplements for the management of Alzheimer's disease.
AbstractThe aim of the present study was to assess the frequency of intestinal parasitic infection among patients with gastrointestinal tract disorders from the Greater Cairo region, Egypt. In ...addition, a comparison was made of the accuracy of direct thin and thick smear, formol-ether sedimentation (FEC), centrifugal flotation (CF), and mini-FLOTAC techniques in the diagnosis of infection. Out of 100 patients, the overall prevalence of parasitic infection was 51%. Only 6% had dual infection.
was the most common parasite (26%), followed by
(20%),
(8%), and
(3%). Except the statistically significant association between
infection and perianal itching and insomnia (
< 0.001), age, gender, and complaints of the examined individuals had no association with prevalence of parasitic infection. Both FEC and CF were equally the most accurate techniques (accuracy = 98.2%, confidence interval CI = 0.95-1.0, and κ index = 0.962), whereas the Kato-Katz method was the least accurate (accuracy = 67.5%, CI = 0.57-0.78, and κ index = 0.333). However, mini-FLOTAC-ZnSO
was the most accurate for diagnosis of helminthic infection, and FEC was more accurate for diagnosis of protozoal infection (accuracy = 100%, CI = 1.0-1.0, and κ index = 1).
More than 2.9 million people have died as a result of the global demographic impact of the coronavirus illness of 2019 (COVID-19). Numerous antiviral and anti-inflammatory medications have FDA ...approval to treat COVID-19 patients. For the simultaneous determination of COVID-19 utilized medications (Remdesivir, Moxifloxacin, Dexamethasone, Apixaban, and paracetamol) in their dosage forms, a sensitive technique has been developed and validated. The aforementioned medications were separated and quantified with the help of experimental design. The Box-Behnken design was used in the experiment to optimize the chromatographic method's analytical parameters. It employed RP-HPLC with a UV detector. An INERTSIL ODS-3 C
18
column (5 µm, 250 × 4.6 mm) with mobile phase composed of acetonitrile: 30 mmoL potassium dihydrogen phosphate buffer (pH = 7.5) (50:50, v/v), at room temperature was employed to separate the aforementioned drugs. Paracetamol was linear over the concentration range (1-50 µg/mL), Moxifloxacin (5-70 µg/mL), Apixaban (5-70 µg/mL), Dexamethasone (1-100 µg/mL), and Remdesivir (5-100 µg/mL). According to ICH guidelines, the new approach underwent thorough validation. Between the proposed method's results and those from the reference or reported methods, there was no significant difference. The technique is simple to use in research of the cited medications in their dosage forms for quality control aspects.
Expression of concern for 'The anti-Alzheimer potential of
: an
investigation supported by
and
approaches' by Abeer H. Elmaidomy
,
, 2022,
, 11769-11785, https://doi.org/10.1039/D2RA01340A.
Epidermal Growth Factor Receptor (EGFR), its wild type and mutations L858R/T790M, is overexpressed in non-small cell lung cancer (NSCLC) patients and is considered an inevitable oncology target. ...However, while the potential EGFR inhibitors have been represented in the literature, their cellular activity failed to establish broad potency against EGFR and its mutations. This study identifies a new series of EGFRL858R/T790M inhibitors bearing hydantoin acetanilides. Most compounds revealed strong antiproliferative activity in a range of NSCL cancer models (A549, H1975, and PC9), in which 5a and 5f were the most potent. Compounds 5a and 5f possessed potent anticancer activity on H1975 cells with IC50 values of 1.94 and 1.38 µM, respectively, compared to 9.70 µM for erlotinib. Favorably, 5a and 5f showed low activity on WI-38 normal cells. Western blotting and an EGFR kinase assay test proved the significant EGFR inhibitory activity of 5a. Besides, active hydantoin derivative 5a strongly arrested the cell cycle at the sub G1 and S phases and triggered apoptosis in A549 cells. These results imply that 5a could be considered a promising lead compound for additional development as a potential active agent for anticancer therapy.
Variants of the DEAD-Box Helicase 20 (DDX20), one of the microRNAs (miRNAs) machinery genes, can modulate miRNA/target gene expressions and, hence, influence cancer susceptibility and prognosis. ...Here, we aimed to unravel the association of DDX20 rs197412 T/C variant with colon cancer risk and/or prognosis in paired samples of 122 colon cancer and non-cancer tissue specimens by TaqMan allelic discrimination analysis. Structural/functional bioinformatic analyses were carried out, followed by a meta-analysis. We found that the T allele was more frequent in cancer tissues compared to control tissues (60.2% vs. 35.7%, p < 0.001). Furthermore, the T variant was highly frequent in primary tumors with evidence of recurrence (73% vs. 47.5%, p < 0.001). Genetic association models, adjusted by age and sex, revealed that the T allele was associated with a higher risk of developing colon cancer under heterozygote (T/C vs. C/C: OR = 2.35, 95%CI = 1.25−4.44, p < 0.001), homozygote (T/T vs. C/C: OR = 7.6, 95%CI = 3.5−16.8, p < 0.001), dominant (T/C-T/T vs. C/C: OR = 3.4, 95%CI = 1.87−8.5, p < 0.001), and recessive (T/T vs. C/C-T/C: OR = 4.42, 95%CI = 2.29−8.54, p = 0.001) models. Kaplan−Meier survival curves showed the shift in the C > T allele to be associated with poor disease-free survival. After adjusting covariates using a multivariate cox regression model, patients harboring C > T somatic mutation were 3.5 times more likely to develop a recurrence (p < 0.001). A meta-analysis of nine studies (including ours) showed a higher risk of CRC (81%) in subjects harboring the T/T genotype than in T/C + C/C genotypes, supporting the potential clinical utility of the specified study variant as a biomarker for risk stratification in CRC cases. However, results were not significant in non-colorectal cancers. In conclusion, the DDX20 rs197412 variant is associated with increased colon cancer risk and a higher likelihood of recurrence in the study population.
Emerging studies show that long intergenic non-protein coding RNA, regulator of reprogramming (
) is aberrantly expressed in several types of cancer, including colon cancer (CC).
intronic variant ...rs1942347 may impact gene regulation and disease phenotype. We aimed to explore the potential association of
(rs1942347) with the clinicopathological features and outcome of CC cases. Archived FFPE (n = 180) CC samples were enrolled. Taq-Man allelic discrimination PCR was used for genotyping in propensity-matched cohorts with/without positive staining for mutant BRAF protein after eliminating confounders bias. The rs1942347*A allele variant was associated with high pathological grade, larger tumor size, distant metastasis, and mortality. Multiple logistic regression analysis adjusted by sex and BRAF mutation showed A/A genotype carriers to have 3 times more risk of early onset of cancer (OR = 3.13, 95%CI = 1.28-7.69,
= 0.034) than T/T genotype carriers. Overall analysis showed that rs1942347*A allele carriers had higher risk of mortality under heterozygote (OR = 2.13, 95%CI = 1.08-4.35,
= 0.003), homozygote (OR = 5.0, 95%CI = 1.69-14.29,
= 0.003), dominant (OR = 3.33, 95%CI = 1.20-9.09,
= 0.003), and recessive (OR = 2.63, 95%CI = 1.37-5.0,
= 0.011) models compared to T/T allele carriers. Stratified analysis by BRAF status revealed that the ancestor T/T allele conferred protection in BRAF mutant CC patients and was associated with a 73-93% reduced risk of mortality under heterozygote/homozygote comparison models. Using Kaplan-Meier curves, carriers of the A/A genotype had shorter survival times than T/T cohorts. The univariate Cox regression model revealed that the A/A genotype was associated with a 3.5 times greater mortality risk than the T/T genotype. However, after adjustment by multiple Cox regression analysis, the risk was insignificant. In conclusion, this is the first study identifying the potential association of the
(rs1942347) variant with CC prognosis.
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