Risk modification of colorectal cancer susceptibility by interleukin-8 -251T>A polymorphism in Malaysians

AIM: To investigate the allele and genotype frequencies and associated risk of interleukin (IL)-8 -251T>A polymorphism on colorectal cancer (CRC) susceptibility risk.METHODS: Peripheral blood samples of 255 normal controls and 255 clinically and histopathologically confirmed CRC patients were genotyped for IL-8 -251T>A polymorphism employing allele-specific polymerase chain reaction. The relative association of variant allele and genotypes with CRC susceptibility risk was determined by calculating the odds ratios (ORs). Corresponding χ² tests on the CRC patients and controls were carried out and 95% confidence intervals (CIs) were determined using Fisher’s exact test. The allele frequencies and its risk association were calculated using FAMHAP, haplotype association analysis software.RESULTS: On comparing the frequencies of genotypes of patients and controls, the homozygous variant AA was significantly higher in CRC patients (P = 0.002) compared to controls. Investigation on the association of the polymorphic genotypes with CRC susceptibility risk, showed that the homozygous variant IL-8 -251AA had a significantly increased risk with OR 3.600 (95% CI: 1.550-8.481, P = 0.001). In the case of allele frequencies, variant allele A of IL-8 -251 showed a significantly increased risk of CRC predisposition with OR 1.32 (95% CI: 1.03-1.69, P = 0.003).CONCLUSION: Variant allele and genotype of IL-8 (-251T>A) was significantly associated with CRC susceptibility risk and could be considered as a high-risk variant for CRC predisposition.     

Comprehensive in silico modeling of the rice plant PRR Xa21 and its interaction with RaxX21-sY and OsSERK2

The first layer of defense that plants deploy to ward off a microbial invasion comes in the form of pattern-triggered immunity (PTI), which is initiated when the pattern-recognition receptors (PRRs) bind with the pathogen-associated molecular patterns (PAMPs) and co-receptor proteins, and transmit a defense signal. Although several plant PRRs have been discovered, very few of them have been fully characterized, and their functional parameters assessed. In this study, the 3D-model prediction of an entire plant PRR protein, Xa21, was done by implementing multiple in silico modeling techniques. Subsequently, the PAMP RaxX21-sY (sulphated RaxX21) and leucine-rich repeat (LRR) domain of the co-receptor OsSERK2 were docked with the LRR domain of Xa21. The docked complex of these three proteins formed a heterodimer that closely resembles the other crystallographic PTI complexes available. Molecular dynamics simulations and MM/PBSA calculations were applied for an in-depth analysis of the interactions between Xa21 LRR, RaxX21-sY, and OsSERK2 LRR. Arg230 and Arg185 from Xa21 LRR, Val2 and Lys15 from RaxX21-sY and Lys164 from OsSERK2 LRR were found to be the prominent residues which might contribute significantly in the formation of a heterodimer during the PTI process mediated by Xa21. Additionally, RaxX21-sY interacted much more favorably with Xa21 LRR in the presence of OsSERK2 LRR in the complex, which substantiates the necessity of the co-receptor in Xa21 mediated PTI to recognize the PAMP RaxX21-sY. However, the free energy binding calculation reveals the favorability of a heterodimer formation of PRR Xa21 and co-receptor OsSERK2 without the presence of PAMP RaxX21-sY, which validate the previous lab result.

This study exhausts bioinformatics tools to acquire the entire multi-domain rice Xa21 protein structure and analyzes its interactions with its PAMP RaxX21-sY and co-receptor OsSERK2.     

Discovery of 4-(2-(dimethylamino)ethoxy)benzohydrazide derivatives as prospective microtubule affinity regulating kinase 4 inhibitors

Microtubule affinity regulating kinase 4 (MARK4) is a Ser/Thr kinase, considered as a potential drug target for cancer, diabetes and neurodegenerative diseases. Due to its significant role in the development and progression of cancer, different in-house libraries of synthesized small molecules were screened to identify potential MARK4 inhibitors. A small library of hydrazone compounds showed a considerable binding affinity to MARK4. The selected compounds were further scrutinized using an enzyme inhibition assay and finally two hydrazone derivatives (H4 and H19) were selected that show excellent inhibition (nM range). These compounds have a strong binding affinity for MARK4 and moderate binding with human serum albumin. Anticancer studies were performed on MCF-7 and A549 cells, suggesting H4 and H19 selectively inhibit the growth of cancer cells. The IC₅₀ value of compound H4 and H19 was found to be 27.39 μM and 34.37 μM for MCF-7 cells, while for A549 cells it was 45.24 μM and 61.50 μM, respectively. These compounds inhibited the colonogenic potential of cancer cells and induced apoptosis. Overall findings reflect that hydrazones/hydrazone derivatives could be exploited as potential lead molecules for developing effective anticancer therapies via targeting MARK4.

Inhibition studies of MARK4 with selected hydrazone derivatives.     

Bi-doping improves the magnetic properties of zinc oxide nanowires

Room-temperature ferromagnetism in the large and direct bandgap diluted magnetic semiconductor zinc oxide (ZnO) is attributed to the intrinsic defects and p-orbital–p-orbital (p–p) coupling interaction. However, due to oxidation, the ferromagnetism induced by defects is unstable. In the present work, the solution process synthesis route was utilized to grow pristine and bismuth-doped, highly crystalline ZnO nanowire (ZnO NW)-based samples. The FE-SEM images showed that the grown ZnO NWs have a preferred orientation along the c-axis in the (001) direction due to the anisotropic crystal nature of ZnO. X-ray photoelectron spectroscopy (XPS) confirmed the presence of Bi, and at a higher doping content, the bismuth oxide phase appeared. The XRD patterns showed the wurtzite crystal structure, and the large intensity of the (002) peak suggests that most of the reflection was from the top hexagonal face of the NWs, and thus, the wires are predominantly aligned along the c-axis. The TEM analysis further confirmed the crystal growth direction along the (001) direction. The UV-Visible absorption and PL measurements also showed a decrease in the bandgap with an increase in doping concentration, which may be associated with the sp–d exchange interaction between the localized d-electrons and band electrons of the Bi ions. Bi-doping tended to increase the PL intensity in the visible region. The magnetic properties measured by SQUID at 4 and 300 K showed ferromagnetic behaviour for both the pristine and Bi-doped samples. However, the saturation magnetization for the Bi-doped samples was higher compared to that of the pristine ZnO samples until the threshold doping value. The obtained results demonstrated that Bi-doping can be used to tune both the optical and magnetic properties of ZnO NWs, hence paving the way for future spintronics and spin-polarized optoelectronics applications.

Room-temperature ferromagnetism in the large and direct bandgap diluted magnetic semiconductor zinc oxide (ZnO) is attributed to the intrinsic defects and p-orbital–p-orbital (p–p) coupling interaction.     

Correction: Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro

Correction for ‘Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 M^pro’ by Vishal M. Balaramnavar et al., RSC Adv., 2020, 10, 40264–40275, DOI: 10.1039/D0RA06038K.

The authors regret that the name of one of the authors (Talha Jawaid) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Multistage antiplasmodial activity of hydroxyethylamine compounds,in vitro and in vivo evaluations

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species. New therapeutics acting against the pathogenic asexual and sexual stages, including liver-stage malarial infection, have now attained more attention in achieving malaria eradication efforts. In this paper, two previously identified potent antiplasmodial hydroxyethylamine (HEA) compounds were investigated for their activity against the malaria parasite''s multiple life stages. The compounds exhibited notable activity against the artemisinin-resistant strain of P. falciparum blood-stage culture with 50% inhibitory concentrations (IC₅₀) in the low micromolar range. The compounds'' cytotoxicity on HEK293, HepG2 and Huh-7 cells exhibited selective killing activity with IC₅₀ values > 170 μM. The in vivo efficacy was studied in mice infected with P. berghei NK65, which showed a significant reduction in the blood parasite load. Notably, the compounds were active against liver-stage infection, mainly compound 1 with an IC₅₀ value of 1.89 μM. Mice infected with P. berghei sporozoites treated with compound 1 at 50 mg kg⁻¹ dose had markedly reduced liver stage infection. Moreover, both compounds prevented ookinete maturation and affected the developmental progression of gametocytes. Further, systematic in silico studies suggested both the compounds have a high affinity towards plasmepsin II with favorable pharmacological properties. Overall, the findings demonstrated that HEA and piperidine possessing compounds have immense potential in treating malarial infection by acting as multistage inhibitors.

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species.     

Parental Feeding Practices and Child-Related Factors are Associated with Overweight and Obesity in Children and Adolescents with Autism Spectrum Disorder

Journal of Autism and Developmental Disorders - Atypical eating behaviors displayed by children with autism spectrum disorder (ASD) predispose them to unhealthy weight gain. We determined the...