Marine-derived antimicrobial peptide piscidin-1 triggers extrinsic and intrinsic apoptosis in oral squamous cell carcinoma through reactive oxygen species production and inhibits angiogenesis.

Cancer of the head and neck encompasses a wide range of cancers, including oral and oropharyngeal cancers. Oral cancer is often diagnosed at advanced stages and has a dismal prognosis. Piscidin-1, a marine antimicrobial peptide (AMP) containing approximately 22 amino acids, also exhibits significant anticancer properties. We investigated the possible anti-oral cancer effects of piscidin-1 and clarified the mechanisms underlying these effects. We treated the oral squamous cell carcinoma cell lines OC2 and SCC4 with piscidin-1. Cell viability and the expression of different hallmark apoptotic molecules, including reactive oxygen species (ROS), were tested using the appropriate MTT assay, flow cytometry and western blotting assays, and human umbilical vein endothelial cell (HUVEC) wound healing, migration, and tube formation (angiogenesis) assays. Piscidin-1 increases cleaved caspase 3 levels to induce apoptosis. Piscidin-1 also increases ROS levels and intensifies oxidative stress in the endoplasmic reticulum and mitochondria, causing mitochondrial dysfunction. Additionally, it decreases the oxygen consumption rates and activity of mitochondrial complexes I-V. As expected, the antioxidants MitoTEMPOL and N-acetylcysteine reduce piscidin-1-induced ROS generation and intracellular calcium accumulation. Piscidin-1 also inhibits matrix metalloproteinase (MMP)-2/-9 expression in HUVECs, affecting migration and tube formation angiogenesis. We demonstrated that piscidin-1 can promote apoptosis via both intrinsic and extrinsic apoptotic pathways and findings indicate that piscidin-1 has anti-proliferative and anti-angiogenic properties in oral cancer treatment. Our study on piscidin-1 thus provides a basis for future translational anti-oral cancer drug research and a new theoretical approach for anti-oral cancer clinical research.

STAT3 phosphorylation inhibitor Bt354 exhibits anti-neoplastic activity in glioblastoma multiforme cells.

The high mortality rate of glioblastoma multiforme (GBM), a lethal primary brain tumor, is attributable to postsurgical recurrence. STAT3, an oncogenic protein, is a signal transducer and transcription activator encourages cancer cell migration and proliferation, which results in resistance to therapy. STAT3 inhibition reduces cancer metastasis and improves patient prognosis. Bt354, a small molecule STAT inhibitor, exhibits significant cytotoxic and anti-proliferative activities against certain cancer types. Here, we demonstrated that exposure of GBM cells (U87 MG) to Bt354 had a significant, concentration-dependent growth suppression. Bt354 also induced apoptosis and downregulated the expression of the epithelial-mesenchymal transition genes. Therefore, this study suggests the potential of Bt354 for treating GBM owing to its ability to induce cytotoxicity.

AhR Mediated Activation of Pro-Inflammatory Response of RAW 264.7 Cells Modulate the Epithelial-Mesenchymal Transition.

Pulmonary fibrosis, a chronic lung disease caused by progressive deterioration of lung tissue, is generated by several factors including genetic and environmental ones. In response to long-term exposure to environmental stimuli, aberrant tissue repair and epithelial cell-to- mesenchymal cell transition (EMT) trigger the subsequent progression of pulmonary fibrotic diseases. The Aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by ligands providing lung dysfunction when activated by environmental toxins, such as polycyclic aromatic hydrocarbons. Our previous study demonstrated that AhR mediates α-SMA expression by directly binding to the α-SMA (fibroblast differentiation marker) promoter, suggesting the role of AhR in mediating fibrogenic progression. Here we follow the hypothesis that macrophage infiltrated microenvironments may trigger inflammation and subsequent fibrosis. We studied the expression of cytokines in RAW 264.7 cells by AhR activation through an ELISA assay. To investigate molecular events, migration, western blotting and zymography assays were carried out. We found that AhR agonists such as TCDD, IP and FICZ, promote the migration and induce inflammatory mediators such as TNF-α and G-CSF, MIP-1α, MIP-1ß and MIP-2. These cytokines arbitrate EMT marker expression such as E-cadherin, fibronectin, and vimentin in pulmonary epithelial cells. Expression of proteins of MMPs in mouse macrophages was determined by zymography, showing the caseinolytic activity of MMP-1 and the gelatinolytic action of MMP-2 and MMP-9. Taken together, the present study showed that AhR activated macrophages create an inflammatory microenvironment which favours the fibrotic progression of pulmonary epithelial cells. Such production of inflammatory factors was accomplished by affecting the Wnt/ß-catenin signalling pathway, thereby creating a microenvironment which enhances the epithelial-mesenchymal transition, leading to fibrosis of the lung.

Outcome of improved care bundle in acute respiratory failure patients.

BACKGROUND: Prolonged physical immobilization has negative effects on patients on mechanical ventilation (MV). AIMS: To introduce a quality improvement programme with early mobilization on the outcomes of patients on MV in the intensive care unit (ICU). We particularly studied the impact of the ABCDE (daily Awakening, Breathing trial, drug Co-ordination, Delirium survey and treatment, and Early mobilization) bundle on the outcome of MV patients with acute respiratory failure in the ICU. DESIGN: This is a retrospective, observational, before-and-after outcome study. METHOD: Adult patients on MV (N = 173) admitted to a medical centre ICU with 19 beds in southern Taiwan were enrolled. A multidisciplinary team (critical care nurse, nursing assistant, respiratory therapist, physical therapist, patient's family) performed ABCDE with early mobilization within 72 hours of MV when patients became haemodynamically stable (twice daily [30 minutes each time], 5 days/week during family visits and in co-operation with family members). MAIN OUTCOME MEASURES: The main outcome measures were differences of MV duration, ICU and hospital length of stay, medical costs, and intra-hospital mortality before (phase 1) and after (phase 2) bundle care. RESULTS: Phases 1 and 2 revealed several differences, including Acute Physiology and Chronic Health Evaluation (APACHE) II and blood urea nitrogen and creatinine levels. The patients in phase 2 had a significantly lower mean ICU length of stay (8.0 vs 12.0 days) but a similar MV duration (170.2 vs 188.1 hours), hospital stays (21.1 vs 23.3 days) with reduced costs (22.1 vs 31.7 × 104 NT$), and intra-hospital mortality (8.3 vs. 36.6%). CONCLUSIONS: The ABCDE care bundle improved the outcome of acute renal failure patients with MV, especially shortening ICU stays and lowering medical costs and hospital mortality. RELEVANCE TO CLINICAL PRACTICE: An ABCDE care bundle with an inter-professional, evidence-based, multicomponent ICU early mobilization management strategy can reduce ICU stays, hospital expenditure, and mortality among acute respiratory failure patients with MV.