Citromycin Isolated from the Antarctic Marine-Derived Fungi, Sporothrix sp., Inhibits Ovarian Cancer Cell Invasion via Suppression of ERK Signaling.

Recently, microorganisms and their metabolites in the Antarctic marine environment have attracted attention as useful sources for novel therapeutics, including anticancer drugs. Here, we investigated the effects of citromycin, isolated from the Antarctic marine-derived fungus, Sporothrix sp., on human ovarian cancer cells. Citromycin inhibited the migration and invasion of human ovarian cancer SKOV3 and A2780 cells, but had no cytotoxic activity against them. Additionally, it inhibited the expression of epithelial-mesenchymal transition (EMT) markers and the activation of matrix metalloproteinase (MMP)-2 and MMP9. Moreover, extracellular signal-regulated kinase (ERK)-1/2 signaling was inhibited after citromycin treatment, and the ectopic expression of ERK negated the anti-invasive activity of citromycin. Our findings suggest that citromycin inhibits the migration and invasion of human ovarian cancer cells by downregulating the expression levels of EMT markers and MMP-2/9 via inhibition of the ERK1/2 pathway.

CD8+ TILs in NSCLC differentiate into TEMRA via a bifurcated trajectory: deciphering immunogenicity of tumor antigens.

BACKGROUND: CD8+ tumor-infiltrating lymphocytes (TILs) comprise phenotypically and functionally heterogeneous subpopulations. Of these, effector memory CD45RA re-expressing CD8+ T cells (Temra) have been discovered and characterized as the most terminally differentiated subset. However, their exact ontogeny and physiological importance in association with tumor progression remain poorly understood. METHODS: We analyzed primary tumors and peripheral blood samples from 26 patients with non-small cell lung cancer and analyzed their phenotypes and functional characteristics using flow cytometry, RNA-sequencing, and bioinformatics. RESULTS: We found that tumor-infiltrating Temra (tilTemra) cells largely differ from peripheral blood Temra (pTemra), with distinct transcriptomes and functional properties. Notably, although majority of the pTemra was CD27-CD28- double-negative (DN), a large fraction of tilTemra population was CD27+CD28+ double-positive (DP), a characteristic of early-stage, less differentiated effector cells. Trajectory analysis revealed that CD8+ TILs undergo a divergent sequence of events for differentiation into either DP or DN tilTemra. Such a differentiation toward DP tilTemra relied on persistent expression of CD27 and CD28 and was associated with weak T cell receptor engagement. Thus, a higher proportion of DP Temra was correlated with lower immunogenicity of tumor antigens and consequently lower accumulation of CD8+ TILs. CONCLUSIONS: These data suggest a complex interplay between CD8+ T cells and tumors and define DP Temra as a unique subset of tumor-specific CD8+ TILs that are produced in patients with relatively low immunogenic cancer types, predicting immunogenicity of tumor antigens and CD8+ TIL counts, a reliable biomarker for successful cancer immunotherapy.

A Novel Cytotoxic Steroidal Saponin from the Roots of Asparagus cochinchinensis.

A new steroidal saponin, 26-O-ß-d-glucopyranosyl-(25R)-furost-5-ene-3ß,22α,26-triol 3-O-(1-4)-ß-d-glucopyranosyl-α-l-rhamnopyranosyl-(1-2)-[α-l-rhamnopyranosyl-(1-4)]-ß-d-glucopyranoside [asparacochioside A (1)] was isolated from a hot water extract of the roots of Asparagus cochinchinensis, together with the known steroidal saponins protodioscin (2), methyl protodioscin (3), aspacochioside A (4), aspacochioside C (5), 15-hydroxypseudoprotodioscin (6), and chamaedroside E (7). The structure of the new compound 1 was determined by interpretation of its spectroscopic data (1D- and 2D-NMR and HR-Q-TOF-MS) and sugar analysis. The isolated compounds 1-7 were tested for their in vitro cytotoxicity against human ovarian cancer cell lines (A2780 and SKOV3). Asparacochioside A (1) exhibited a significant cytotoxicity against both A2780 and SKOV3 cells with IC50 values of 5.25 ± 2.2 and 46.82 ± 9.43 µM, respectively. Furthermore, asparacochioside A (1) significantly increased the percentage of Annexin V-positive cells (apoptotic cells), suggesting that asparacochioside A induces ovarian cancer cell death via apoptosis.

New Eudesmane-Type Sesquiterpene Glycosides from the Leaves of Aster koraiensis.

Four new eudesmane-type sesquiterpenoids, (1R,5S,6R,7S,9S,10S)-1,6,9-trihydroxy-eudesm-3-ene-1,6-di-O-ß-d-glucopyranoside (1), (1R,5S,6S,7R,9S,10S)-1,6,9,11-tetrahydroxy-eudesm-3-ene-1,6-di-O-ß-d-glucopyranoside (3), (1R,5S,6R,7S,9S,10R)-9-O-(Z-p-coumaroyl)-1,6,9-trihydroxy-eudesm-3-ene-6-O-ß-d-glucopyranoside (6), and (1R,5S,6R,7S,9S,10R)-9-O-(E-feruloyl)-1,6,9-trihydroxy-eudesm-3-ene-6-O-ß-d-glucopyranoside (7), were isolated from a 95% EtOH extract of the leaves of Aster koraiensis by repeated chromatography. Moreover, three sesquiterpenoids (2, 4, and 5) and two caffeoylquinic acids (8 and 9) having previously known chemical structures were isolated during the isolation procedure. The four new compounds (1, 3, 6, and 7) were elucidated by spectroscopic data (1D- and 2D-NMR, MS, and ECD) interpretation and hydrolysis. Moreover, the absolute configurations of 2, 4, and 5 were determined for the first time in this study. The compounds isolated were tested for their viability on nitric oxide (NO) and prostaglandin E2 (PGE2) production on LPS-stimulated RAW 264.7 cells. Among them, only 7 presented weak inhibitory effects on both NO and PGE2 production.

Clinical response and pharmacokinetics of bendamustine as a component of salvage R-B(O)AD therapy for the treatment of primary central nervous system lymphoma (PCNSL).

BACKGROUND: A relatively high proportion of patients diagnosed with primary CNS lymphoma will experience recurrent disease, yet therapy options are limited in salvage therapy. This is the first study to evaluate a bendamustine-based combination regimen for the treatment of relapsed/refractory PCNSL and to characterize bendamustine pharmacokinetics in the human CSF. METHODS: Patients received bendamustine 75 mg/m2 for two days as part of R-B(O)AD administered intravenously every 4 weeks for up to 4 cycles. Response and adverse events of the regimen were assessed. A sparse sampling strategy and population based modeling approach was utilized for evaluation of plasma and CSF levels of bendamustine. RESULTS: Ten patients were enrolled into study of whom 70% were of refractory disease and with high IELSG prognostic risk scores. The ORR of R-BOAD was 50% (95% CI, 0.24 to 0.76) with one patient achieving CR and four PR. Primary toxicity of the regimen was reversible myelosuppression, mostly grade 3 or 4 neutropenia. The Cmax mean for plasma and CSF were 2669 ng/mL and 0.397 ng/mL, respectively, and patients with response at deep tumor sites displayed higher trends in peak exposure. Pharmacokinetic data was best described by a four-compartment model with first-order elimination of drug from central plasma and CSF compartments. CONCLUSIONS: R-BOAD is an effective salvage option for PCNSL, but with significant hematologic toxicity. Bendamustine CSF levels are minimal; however correspond to plasma exposure and response. TRIAL REGISTRATION: ClinicalTrials.gov NCT03392714 ; retrospectively registered January 8, 2018.

High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker.

Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes.