No abstract

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

Foodborne outbreaks associated with fresh fruits and vegetables are on the rise worldwide. Biofilm formation is one of the important traits of pathogens making them strongly attached to substrates as well as express virulence phenotypes. Present study investigates the biofilm forming ability of E. coli and Salmonella sp. isolated from fresh fruits and vegetables. A total of 53 strains, including 35 E. coli and 18 Salmonella sp. isolated from different fruit and vegetable samples were taken into account for the study. Initial screening for biofilm formation was done using Congo Red agar plate test. Results revealed that 22.8% E. coli and 22.2% Salmonella sp. were potential biofilm formers. However, the MTP (Micro-Titre Plate) assay suggested more isolates of both E. coli and Salmonella sp. were moderate to strong biofilm producers. Agar plate diffusion assay with Agrobacterium tumefaciens NTL-4 showed the production of quorum signaling molecules (AHLs) by three isolates of E. coli and one Salmonella sp. Two E. coli isolates showed a significant amount of EPS production indicating higher biofilm forming potential. The Presence of LUX R homologue gene (sdiA) in two of the Salmonella isolates were confirmed by PCR which demonstrated their potential pathogenicity. Results of the work underline the biofilm forming and potentially virulent capacities of isolates from the surface of fruits and vegetables.

Salmonella typhimurium (S. typhimurium) is one of the major food and waterborne bacteria that causes several health outbreaks in the world. Although there are few antibiotics against this bacterium, some of these drugs are challenged with resistance and toxicity. To mitigate this challenge, our group explored the ethnomedicinal/herbalism knowledge about a certain spice used in Northern Ghana in West Africa against bacterial and viral infection. This plant is Capsicum chinense (C. chinense). The plant is one of the commonest food spices consumed across the world. The seed of the plant contains both capsaicin and dihydrocapsaicin. Apart from capsaicin and dihydrocapsaicin, other major capsaicinoids in C. chinense include nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin. In this pilot work, we investigated the antibacterial activity of pure capsaicin and capsaicin extract obtained from C. chinense against S. typhimurium in vitro. Capsaicin extract showed potent inhibition of S. typhimurium growth at concentrations as low as 100 ng/mL, whereas pure capsaicin comparatively showed poorer inhibition of bacteria growth at such a concentration. Interestingly, both capsaicin extract and pure capsaicin were found to potently block a S. typhimurium invasion of the Vero cell in vitro. Taken together, we believed that capsaicin might work synergistically with dihydrocapsaicin or the other capsaicinoids to inhibit S. typhimurium growth, whereas individually, capsaicin or dihydrocapsaicin could potently block the bacteria entry and invasion of Vero cells.

No abstract

Neuroendocrine prostate cancer (NEPC) represents a highly aggressive form of prostate tumors. NEPC results from trans-differentiated castration-resistant prostate cancer (CRPC) with increasing evidence indicating that the incidence of NEPC often results from the adaptive response to androgen deprivation therapy. Recent studies have shown that a subset of NEPC exhibits overexpression of the MYCN oncogene along with the loss of tumor suppressing TP53 and RB1 activities. N-MYC is structurally disordered with no binding pockets available on its surface and so far, no clinically approved drug is available. We adopted a drug-repurposing strategy, screened ~1800 drug molecules, and identified fludarabine phosphate to preferentially inhibit the proliferation of N-MYC overexpressing NEPC cells by inducing reactive oxygen species (ROS). We also show that fludarabine phosphate affects N-MYC protein levels and N-MYC transcriptional targets in NEPC cells. Moreover, enhanced ROS production destabilizes N-MYC protein by inhibiting AKT signaling and is responsible for the reduced survival of NEPC cells and tumors. Our results indicate that increasing ROS production by the administration of fludarabine phosphate may represent an effective treatment option for patients with N-MYC overexpressing NEPC tumors.

As at 2021, the center for disease control (CDC) reported that Salmonella causes 1.2 million illness in the United States each year, with a mortality rate approaching 500 deaths per annum. Infants, the elderly, and persons with compromised immunity are the population with higher risk of mortality from this infection. At present there is no commercially available, safe and efficacious vaccine for the control and management of Salmonella typhimurium (S. typhimurium). More so, S. typhimurium has been shown to develop resistance against most antibiotics used for treatment of the infection. Capsaicin, a bioactive compound from Capsicum chinense (C. chinenses) is undoubtedly one of the most widely used spice in the world. This heat producing compound is not only been used as food additive but have been demonstrated to possess unique properties that have pharmacological, physiological, and antimicrobial applications. In this work, the antimicrobial property of pure capsaicin or capsaicin extract against S. typhimurium is tested to determine the compounds effectiveness in S. typhimurium inhibition. Capsaicin extract showed potent inhibition of S. typhimurium growth at concentrations as low as 100 ng/ml, whereas pure capsaicin comparatively showed poorer inhibition of the bacteria. Furthermore, both capsaicin extract and pure capsaicin potently blocked S. typhimurium invasion of an animal cell line in vitro. Taken together, this work revealed that capsaicin might work synergistically with dihydrocapsaicin or the other capsaicinoids to inhibit S. typhimurium growth, whereas individually, capsaicin or dihydrocapsaicin could potently block the bacteria entry and invasion of Vero cells.