Extracellular Vesicles from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients Deliver MiR-21 and Induce Methotrexate Resistance in Lung Cancer Cells.

Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued chemotherapy. Recent studies have shown that increased miRNA-21 (miR-21) expression in the CSF of patients with LM after intraventricular MTX-chemotherapy is associated with poor overall survival; however, the molecular mechanisms underlying this resistance are poorly understood.

Different Metabolomic and Proteomic Profiles of Cerebrospinal Fluid in Ventricular and Lumbar Compartments in Relation to Leptomeningeal Metastases.

The different molecular profiles of cerebrospinal fluid (CSF) between ventricular and lumbar compartments remain elusive, especially in the context of leptomeningeal metastasis (LM), which affects CSF flow. We evaluated CSF metabolomic and proteomic profiles based on the compartments and the diagnosis of spinal LM, proved by MRI from 20 paired ventricular and lumbar CSF samples of LM patients, including 12 spinal LM (+) samples. In metabolome analysis, 9512 low-mass ions (LMIs) were identified-7 LMIs were abundant in all lumbar versus paired ventricular CSF samples, and 3 LMIs were significantly abundant in all ventricular CSF.

Experimental Assessment of Leptomeningeal Metastasis Diagnosis in Medulloblastoma Using Cerebrospinal Fluid Metabolomic Profiles.

Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma LM assessment.

Exploratory Profiling of Extracellular MicroRNAs in Cerebrospinal Fluid Comparing Leptomeningeal Metastasis with Other Central Nervous System Tumor Statuses.

The diagnosis of leptomeningeal metastasis (LM) is often difficult due to the paucity of cancer cells in cerebrospinal fluid (CSF) and nonspecific findings on neuroimaging. Investigations of extracellular microRNAs (miRNAs) in CSF could be used for both the diagnosis and study of LM pathogenesis because they reflect the activity of disseminating cancer cells. We isolated CSF extracellular miRNAs from patients ( = 65) of different central nervous system tumor statuses, including cancer control, healthy control, LM, brain metastasis (BM), and primary brain tumor (BT) groups, and performed miRNA microarrays.

Enhanced Sensitivity of Nonsmall Cell Lung Cancer with Acquired Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors to Phenformin: The Roles of a Metabolic Shift to Oxidative Phosphorylation and Redox Balance.

Background: Although the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR- TKI) therapy has been proven in non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR-TKIs presents a serious clinical problem. Hence, the identification of new therapeutic strategy is needed to treat EGFR-TKI-resistant NSCLC.

Methods: Acquired EGFR-TKI-resistant lung cancer cell lines (HCC827, H1993, and H292 cells with acquired resistance to gefitinib or erlotinib) were used for cell-based studies.

Molecular Signature of Extracellular Vesicular Small Non-Coding RNAs Derived from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients: Functional Implication of miR-21 and Other Small RNAs in Cancer Malignancy.

Leptomeningeal metastasis (LM) is a fatal and rare complication of cancer in which the cancer spreads via the cerebrospinal fluid (CSF). At present, there is no definitive treatment or diagnosis for this deleterious disease. In this study, we systemically and quantitatively investigated biased expression of key small non-coding RNA (smRNA) subpopulations from LM CSF extracellular vesicles (EVs) via a unique smRNA sequencing method.

Nanoparticles in 472 Human Cerebrospinal Fluid: Changes in Extracellular Vesicle Concentration and miR-21 Expression as a Biomarker for Leptomeningeal Metastasis.

Leptomeningeal metastasis (LM) has a poor prognosis and is difficult to diagnose and predict the response of treatment. In this study, we suggested that the monitoring of changes in the concentration of extracellular vesicles in cerebrospinal fluid could help diagnose or predict outcomes for LM. We measured nanoparticles in 472 human cerebrospinal fluid (CSF) from patients including LM with both Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) after two-step centrifugations.

Comparative cerebrospinal fluid metabolites profiling in glioma patients to predict malignant transformation and leptomeningeal metastasis with a potential for preventive personalized medicine.

Glioma shows progression presenting as malignant transformation or leptomeningeal metastasis (LM). However, longitudinal biopsy of brain parenchyma is difficult due to its critical location, whereas cerebrospinal fluid (CSF) can be obtained serially with a little invasiveness of puncture. Thus, if we could find a biomarker for glioma progression, we could predict such event and determine therapeutic interventions as early as possible.

Dexamethasone Interferes with Autophagy and Affects Cell Survival in Irradiated Malignant Glioma Cells.

Objective: Radiation is known to induce autophagy in malignant glioma cells whether it is cytocidal or cytoprotective. Dexamethasone is frequently used to reduce tumor-associated brain edema, especially during radiation therapy. The purpose of the study was to determine whether and how dexamethasone affects autophagy in irradiated malignant glioma cells and to identify possible intervening molecular pathways.

Involvement of ER stress and reactive oxygen species generation in anti-cancer effect of CKD-516 for lung cancer.

Purpose: CKD-516 (Valecobulin), a vascular-disrupting agent, inhibits microtubule elongation. We evaluated the effect of CKD-516 on lung cancer cells and the underlying molecular mechanisms.

Methods: The effects of S516, an active metabolite of CKD-516, were evaluated in HUVECs and three lung cancer cell lines and by a microtubule polymerization assay.

Identification of interactions between multiple components in Socheongryong-tang using a plant profiling approach.

Traditional herbal medicine consists of multiple components. There are interactions among the components, which affect both potency and toxicity. The preparation of herbal medicines can be a cause of interactions between multicomponents in herbs.

GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy.

Background: Ligand-dependent activation of the G-protein coupled receptor 119 (GPR119) lowers blood glucose via glucose-dependent insulin secretion and intestinal glucagon-like peptide-1 production. However, the function of GPR119 in cancer cells has not been studied.

Methods: GPR119 expression was assessed by real-time qPCR and immunohistochemistry in human breast cancer cell lines and breast cancer tissues.

Essential Role of Polo-like Kinase 1 (Plk1) Oncogene in Tumor Growth and Metastasis of Tamoxifen-Resistant Breast Cancer.

The most common therapy for estrogen receptor-positive breast cancer is antihormone therapy, such as tamoxifen. However, acquisition of resistance to tamoxifen in one third of patients presents a serious clinical problem. Polo-like kinase 1 (Plk1) is a key oncogenic regulator of completion of G-M phase of the cell cycle.

Essential role of Notch4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer.

We previously demonstrated that tamoxifen (TAM)-resistant human breast cancer (TAMR-MCF-7) cells showed increased expression of mesenchymal marker proteins compared to the parent MCF-7 cells. Notch is functionally important in the promotion of epithelial-mesenchymal transition (EMT) during both development and tumor progression. Notch1 and Notch4 have been reported as prognostic markers in human breast cancer.

Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells.

We previously showed that S-adenosylmethionine-mediated hypermethylation of the PTEN promoter was important for the growth of tamoxifen-resistant MCF-7 (TAMR-MCF-7) cancer cells. Here, we found that the basal expression level of methionine adenosyltransferase 2A (MAT2A), a critical enzyme for the biosynthesis of S-adenosylmethionine, was up-regulated in TAMR-MCF-7 cells compared with control MCF-7 cells. Moreover, the basal expression level of MAT2A in T47D cells, a TAM-resistant estrogen receptor-positive cell line was higher compared to MCF-7 cells.

GPR119: a promising target for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is associated with metabolic syndrome and has the unique characteristic of excess lipid accumulation in liver. G-protein-coupled receptor 119 (GPR119) is a promising target for type 2 diabetes. However, the role of GPR119 activation in hepatic steatosis and its precise mechanism has not been investigated.

Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α.

Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct.

HepG2 cells as an in vitro model for evaluation of cytochrome P450 induction by xenobiotics.

Although various in vitro assays have been developed to evaluate the cytochrome P450 (CYP)-inducing potential of drug candidates, there is a continuing need for the development of a reliable model in drug discovery. The objective of the present study was to compare CYP induction by chemicals in HepG2 cells with Huh7, NKNT-3, and reverted NKNT-3 cells. HepG2 cells showed more similarity to human liver than the other cell lines in comparisons of the expression of cellular proteins.

Protective effect of nectandrin B, a potent AMPK activator on neointima formation: inhibition of Pin1 expression through AMPK activation.

Background And Purpose: Neointima is considered a critical event in the development of vascular occlusive disease. Nectandrin B from nutmeg functions as a potent AMP-activated protein kinase (AMPK) activators. The present study addressed whether nectandrin B inhibits intimal hyperplasia in guide wire-injured arteries and examined its molecular mechanism.

Inhibitory effect of Pleurotus eryngii extracts on the activities of allergic mediators in antigen-stimulated mast cells.

Pleurotus eryngii is an edible mushroom native to Europe, the Middle East, and North Africa, and is also grown in parts of Asia. The present study investigated the anti-allergy potential of P. eryngii extract (PEE) in antigen-stimulated RBL-2H3 mast cells.

Ethyl acetate extract of Psidium guajava inhibits IgE-mediated allergic responses by blocking FcεRI signaling.

Psidium guajava (P. guajava) is an important food crop and medicinal plant with antioxidant, anti-inflammatory, and anti-allergic activities, supporting its traditional uses. However, its precise effects remain unknown.

The role of cyclooxygenase-2-dependent signaling via cyclic AMP response element activation on aromatase up-regulation by o,p'-DDT in human breast cancer cells.

o,p'-Dichlorodiphenyltrichloroethane (o,p'-DDT) is a DDT isomer and xenoestrogen that can induce inflammation and cancer. However, the effect of o,p'-DDT on aromatase is unclear. Thus, we investigated the effects of o,p'-DDT on aromatase expression in human breast cancer cells.

Dihydro-N-caffeoyltyramine down-regulates cyclooxygenase-2 expression by inhibiting the activities of C/EBP and AP-1 transcription factors.

Dihydro-N-caffeoyltyramine (DHCT), a novel phenolic amide isolated from the root bark of Lycium chinense Miller, has potent antioxidative activity and anti-fungal effects. In the present study, we investigated the effects of DHCT on phorbol 12-myristate 13-acetate (PMA)-induced pro-inflammatory protein cyclooxygenase (COX-2) expression in macrophages. Treatment with DHCT suppressed PMA-mediated induction of COX-2 mRNA and protein.

Up-regulation of CYP1A1 by rutaecarpine is dependent on aryl hydrocarbon receptor and calcium.

Rutaecarpine is a quinazolinocarboline alkaloid isolated from a traditional Chinese medicinal fruit, Evodia rutaecarpa. In the present study, we investigated the effect of rutaecarpine on CYP1A1 expression mediated by [Ca(2+)] and the AhR pathway in mouse hepatoma Hepa-1c1c7 cells. Rutaecarpine also significantly increased CYP1A1 enzyme activity and mRNA and protein levels.