Colorectal cancer (CRC) has one of the highest mortality rates despite the advancement of treatment options. Aggressive CRC remains difficult to treat owing to the activation of oncogenic signaling pathways such as the Notch signaling pathway. The role of Notch receptors varies according to the difference in their structures; in particular, aberrant activation of Notch1 has been attributed to the severity of CRC. Notch1 activation in CRC is inhibited by small molecule inhibitors that target γ-secretase, an enzyme responsible for the third and last cleavage step of Notch receptors. γ-Secretase also produces the intracellular domain that finally carries out cellular functions by activating downstream effectors. However, most inhibitors block γ-secretase non-selectively and cause severe toxicity. Plant-source-derived small molecules, monoclonal antibodies, biological molecules (such as SiRNAs), and compounds targeting the Notch1 receptor itself or the downstream molecules such as HES1 are some of the options that are in advanced stages of clinical trials. The Negative Regulatory Region (NRR), which plays a central role in the transduction of Notch1 signaling in the event of ligand-dependent and ligand-independent Notch1 processing is also being targeted specifically by monoclonal antibodies (mAbs) to prevent aberrant Notch1 activation. In this review, we discuss the role of Notch1 in CRC, particularly its metastatic phenotype, and how mutations in Notch1, specifically in its NRR region, contribute to the aberrant activation of Notch1 signaling, which, in turn, contributes to CRC pathogenesis. We also discuss prevailing and emerging therapies that target the Notch1 receptor and the NRR region, and we highlight the potential of these therapies in abrogating Notch signaling and, thus, CRC development and progression.

Human feacal isolates were ascertain as genus Lactobacillus using specific primer LbLMA1/R16-1 and further identified as Lactobacillus plantarum with species specific primers Lpl-3/Lpl-2. 25 L. plantarum strains were further assessed for hydrophobicity following the microbial adhesion to hydrocarbons (MATH) method and colonization potentials based on their adherence to immobilized human collagen type-1. Surface proteins were isolated from selected L. plantarum 91(Lp91) strain. The purified collagen binding protein (Cbp) protein was assessed for its anti-adhesion activity against enteric Escherichia coli 0157:H7 pathogen on immobilized collagen. Four L. plantarum strains displayed high degree of hydrophobicity and significant adhesion to collagen. A 72 kDa protein was purified which reduced 59.71% adhesion of E. coli 0157:H7 on immobilized collagen as compared to control well during adhesion assay. Cbp protein is the major influencing factor in inhibition of E. coli 0157:H7 adhesion with extracellular matrix (ECM) components. Hydrophobicity and adhesion potential are closely linked attributes precipitating in better colonization potential of the lactobacillus strains. Cbp is substantiated as a crucial surface protein contributing in adhesion of lactobacillus strains. The study can very well be the platform for commercialization of indigenous probiotic strain once their functional attributes are clinically explored.

No abstract

The probiotic potential of lactic acid bacteria primarily point toward colonizing ability of Lactobacilli as the most important attribute for endowing all the known beneficial effects in a host. Lactobacillus species exert health-promoting function in the gastrointestinal tract through various mechanisms such as pathogen exclusion, maintenance of microbial balance, immunomodulation, and other crucial functions. It has been seen that many surface layer proteins are involved in host adhesion, and play significant role in the modification of some signaling pathways within the host cells. Interaction between different bacterial cell surface proteins and host receptor has been imperative for a better understanding of the mechanism through which Lactobacilli exert their health-promoting functions.

Epithelial to mesenchymal transition (EMT) in colorectal cancer (CRC) has been attributed to activation of AKT and Notch1 signaling pathways. As EMT corresponds to increased aggressiveness of CRC, approaches that prevent metastasis by targeting AKT/Notch1 pathways are at the forefront of current research paradigms. This study examined the anti-metastatic potential of Verrucarin J (VJ), a small molecule, in CRC cells overexpressing AKT and Notch1. VJ significantly inhibited AKT/HCT 116 cell growth by acting on the AKT/NFκB/Bcl-2 signaling axis and initiated apoptotic signaling as was evident from increased expression of pro-apoptotic markers such as cleaved PARP, cleaved caspase 3, and cleaved caspase 9. Also, VJ inhibited the cell growth in AKT/Notch1-overexpressing CRC cells and abrogated EMT. The down-regulation of AKT and Notch1 signaling was apparent in immunoblot analysis and corresponded with down-regulation of mesenchymal markers including Snail, and β-catenin. Intraperitoneal administration of VJ in control (pCMV/HCT 116) and AKT/HCT 116 mice significantly suppressed AKT-induced tumor growth in a xenograft model. In addition, down-regulation of prosurvival markers as well as AKT and Notch1 was observed in the immunohistochemical analysis of the xenografted tumors. In conclusion, our study substantiates the role of AKT and Notch1 in cell proliferation, angiogenesis, and EMT of CRC cells and demonstrates that VJ may be a viable therapeutic option to counter AKT-induced cell proliferation and tumor outgrowth in CRC.