Background: Cathelicidins are a family of vertebrate antimicrobial peptides that play pivotal roles in host immune defense against microbial invasions. Results: A novel cathelicidin (Hc-CATH) with potent antimicrobial and anti-inflammatory activity and a special mechanism was identified from the sea snake Hydrophis cyanocinctus. Conclusion: Hc-CATH is a potent candidate for the development of peptide antibiotics. Significance: Hc-CATH is the first cathelicidin identified from sea snakes and possesses a special anti-inflammatory mechanism.
Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress–induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A–dependent (LDHA-dependent) metabolic rewiring. Chronic stress–induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The
SLUG
promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress–induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.
We report here the investigation of a novel description of specificity in protein-ligand binding based on energy landscape theory. We define a new term, intrinsic specificity ratio (ISR), which describes the level of discrimination in binding free energies of the native basin for a protein-ligand complex from the weaker binding states of the same ligand. We discuss the relationship between the intrinsic specificity we defined here and the conventional definition of specificity. In a docking study of molecules with the enzyme COX-2, we demonstrate a statistical correspondence between ISR value and geometrical shapes of the small molecules binding to COX-2. We further observe that the known selective (nonselective) inhibitors of COX-2 have higher (lower) ISR values. We suggest that intrinsic specificity ratio may be a useful new criterion and a complement to affinity in drug screening and in searching for potential drug lead compounds.
Data mining of available biomedical data and information has greatly boosted target discovery in the 'omics' era. Target discovery is the key step in the biomarker and drug discovery pipeline to diagnose and fight human diseases. In biomedical science, the 'target' is a broad concept ranging from molecular entities (such as genes, proteins and miRNAs) to biological phenomena (such as molecular functions, pathways and phenotypes). Within the context of biomedical science, data mining refers to a bioinformatics approach that combines biological concepts with computer tools or statistical methods that are mainly used to discover, select and prioritize targets. In response to the huge demand of data mining for target discovery in the 'omics' era, this review explicates various data mining approaches and their applications to target discovery with emphasis on text and microarray data analysis. Two emerging data mining approaches, chemogenomic data mining and proteomic data mining, are briefly introduced. Also discussed are the limitations of various data mining approaches found in the level of database integration, the quality of data annotation, sample heterogeneity and the performance of analytical and mining tools. Tentative strategies of integrating different data sources for target discovery, such as integrated text mining with high-throughput data analysis and integrated mining with pathway databases, are introduced.
Breast cancer that is accompanied by a high level of cyclin E expression usually exhibits poor prognosis and clinical outcome. Several factors are known to regulate the level of cyclin E during the cell cycle progression. The transcription factor DEC1 (also known as STRA13 and SHARP2) plays an important role in cell proliferation and apoptosis. Nevertheless, the mechanism of its role in cell proliferation is poorly understood. In this study, using the breast cancer cell lines MCF-7 and T47D, we showed that DEC1 could inhibit the cell cycle progression of breast cancer cells independently of its transcriptional activity. The cell cycle-dependent timing of DEC1 overexpression could affect the progression of the cell cycle through regulating the level of cyclin E protein. DEC1 stabilized cyclin E at the protein level by interacting with cyclin E. Overexpression of DEC1 repressed the interaction between cyclin E and its E3 ligase Fbw7α, consequently reducing the level of polyunbiquitinated cyclin E and increased the accumulation of non-ubiquitinated cyclin E. Furthermore, DEC1 also promoted the nuclear accumulation of Cdk2 and the formation of cyclin E/Cdk2 complex, as well as upregulating the activity of the cyclin E/Cdk2 complex, which inhibited the subsequent association of cyclin A with Cdk2. This had the effect of prolonging the S phase and suppressing the growth of breast cancers in a mouse xenograft model. These events probably constitute the essential steps in DEC1-regulated cell proliferation, thus opening up the possibility of a protein-based molecular strategy for eliminating cancer cells that manifest a high-level expression of cyclin E.
Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor-normal samples, we have identified a hotspot mutation (c.419T>C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-κB more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-κB, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-κB from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS.
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