Investigating MARK4 inhibitory potential of Bacopaside II: Targeting Alzheimer's disease.

Microtubule affinity regulating kinase 4 (MARK4) is known to hyperphosphorylate tau protein, which subsequently causes Alzheimer's disease (AD). MARK4 is a well-validated drug target for AD; thus, we employed its structural features to discover potential inhibitors. On the other hand, complementary and alternative medicines (CAMs) have been used for the treatment of numerous diseases with little side effects. In this regard, Bacopa monnieri extracts have been extensively used to treat neurological disorders because of their neuroprotective roles. The plant extract is used as a memory enhancer and a brain tonic. Bacopaside II is a major component of Bacopa monnieri; thus, we studied its inhibitory effects and binding affinity towards the MARK4. Bacopaside II show a considerable binding affinity for MARK4 (K = 107 M-1) and inhibited kinase activity with an IC50 value of 5.4 µM. To get atomistic insights into the binding mechanism, we performed Molecular dynamics (MD) simulation studies for 100 ns. Bacopaside II binds strongly to the active site pocket residues of MARK4 and a number of hydrogen bonds remain stable throughout the MD trajectory. Our findings provide the basis for the therapeutic implication of Bacopaside and its derivatives in MARK4-related neurodegenerative diseases, especially AD and neuroinflammation.

Myricetin inhibits breast and lung cancer cells proliferation via inhibiting MARK4.

Identifying novel molecules as potential kinase inhibitors are gaining significant attention globally. The present study suggests Myricetin as a potential inhibitor of microtubule-affinity regulating kinase (MARK4), adding another molecule to the existing list of anticancer therapeutics. MARK4 regulates initial cell division steps and is a potent druggable target for various cancers. Structure-based docking with 100 ns molecular dynamics simulation depicted activity of Myricetin in the active site pocket of MARK4 and the formation of a stable complex. The fluorescence-based assay showed excellent affinity of Myricetin to MARK4 guided by static and dynamic quenching. Moreover, the assessment of enthalpy change (∆H) and entropy change (∆S) delineated electrostatic interactions as a dominant force in the MARK4-myricetin interaction. Isothermal titration calorimetric measurements revealed spontaneous binding of Myricetin with MARK4. Further, the kinase assay depicted significant inhibition of MARK4 by Myricetin with IC50 = 3.11 µM. Additionally, cell proliferation studies established that Myricetin significantly inhibited the cancer cells (MCF-7 and A549) proliferation, and inducing apoptosis. This study provides a solid rationale for developing Myricetin as a promising anticancer molecule in the MARK4 mediated malignancies.

Growth behaviour and thermal inactivation of E. coli O157:H7 and Salmonella spp. in ground lean camel meat.

This study aimed to evaluate growth behaviour of Escherichia coli O157:H7, Salmonella spp., and background microbiota in ground lean camel meat during refrigerated storage for up to 7 d, and determine thermal inactivation parameters (D and z-values) of the pathogens in the meat. Fresh ground camel meat samples were individually inoculated with two isolates of each E. coli O157:H7 strains and Salmonella serovars. Inoculated and uninoculated samples were stored aerobically at 4 °C and abusive temperature (10 °C) for 1, 4 and 7 d. Inoculated samples were also heat-treated in a circulating water bath at 55-65 °C. Upon storage for 7 d at 4 °C, the population of E. coli O157:H7 and Salmonella cells decreased significantly in samples. In contrast, samples stored at 10 °C showed significant increases in microbial populations. With storage, the populations of mesophilic lactic acid bacteria, mesophilic total plate counts, yeasts and molds, Pseudomonas spp., as well as Enterobacteriaceae increased significantly. E. coli O157:H7 strains showed average D-values at 57.5 to 65 °C ranging from 1.8 to 0.067 min while Salmonella spp. at 55 to 62.5 °C showed D-values ranging from 2.2 to 0.057 min. The z-values of E. coli O157:H7 strains were 4.6 and 5.0 °C and were 5.1 and 5.5 °C for Salmonella spp. This study provides information to assist food industry and retail meat processors to enhance safety and storage quality of camel meat and facilitate validation of thermal processing of camel meat products.