A newly synthetic chromium complex – chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance

AbstractLow-molecular-weight organic chromium complexes such as chromium picolinate are often used as dietary supplements to improve insulin sensitivity and to correct dyslipidemia. However, toxicity associated with such chromium compounds has compromised their therapeutic value. The aim of this study was to evaluate the impact of a newly synthesized complex of chromium with phenylalanine, Cr(pa)3 on insulin-signaling and glucose tolerance. Cr(pa)3 was synthesized by chelating chromium(III) with d-phenylalanine ligand in aqueous solution. In mouse 3T3-adipocytes, Cr(pa)3 augmented insulin-stimulated glucose-uptake as assessed by a radioactive-glucose uptake assay. At the molecular level, Cr(pa)3 enhanced insulin-stimulated phosphorylation of Akt in a time- and concentration-dependent manner without altering the phosphorylation of insulin receptor. Oral treatment with Cr(pa)3 (150μg/kg/d, for six weeks) in ob/ob(+/+) obese mice significantly alleviated glucose tolerance compared with untreated obese mice. Unlike chromium picolinate, Cr(pa)3 does not cleave DNA under physiological reducing conditions. Collectively, these data suggest that Cr(pa)3 may represent a novel, less-toxic chromium supplement with potential therapeutic value to improve insulin sensitivity and glycemic control in type II diabetes

Diagnostic and Prognostic Significance of Methionine Uptake and Methionine Positron Emission Tomography Imaging in Gliomas

The present most common image diagnostic tracer in clinical practice for glioma is 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for brain tumors diagnosis and prognosis. PET is a promising molecular imaging technique, which provides real-time information on the metabolic behavior of the tracer. The diffusive nature of glioblastoma (GBM) and heterogeneity often make the radiographic detection by FDG-PET inaccurate, and there is no gold standard. FDG-PET often leads to several controversies in making clinical decisions due to their uptake by normal surrounding tissues, and pose a challenge in delineating treatment-induced necrosis, edema, inflammation, and pseudoprogression. Thus, it is imperative to find new criteria independent of conventional morphological diagnosis to demarcate normal and tumor tissues. We have provided proof of concept studies for 11C methionine-PET (MET-PET) imaging of gliomas, along with prognostic and diagnostic significance. MET-PET is not widely used in the United States, though clinical trials from Japan and Germany suggesting the diagnostic ability of MET-PET imaging are superior to FDG-PET imaging for brain tumors. A major impediment is the availability of the onsite cyclotron and isotopic carbon chemistry facilities. In this article, we have provided the scientific rationale and advantages of the use of MET-PET as GBM tracers. We extend our discussion on the expected pitfalls of using MET-PET and ways to overcome them by incorporating a translational component of profiling gene status in the methionine metabolic pathway. This translational correlative component to the MET-PET clinical trials can lead to a better understanding of the existing controversies and can enhance our knowledge for future randomization of GBM patients based on their tumor gene signatures to achieve better prognosis and treatment outcome

miRNA-194-3p represses NF-κB in gliomas to attenuate iPSC genes and proneural to mesenchymal transition

Summary: Severe tumor heterogeneity drives the aggressive and treatment refractory nature of glioblastomas (GBMs). While limiting GBM heterogeneity offers promising therapeutic potential, the underlying mechanisms that regulate GBM plasticity remain poorly understood. We utilized 14 patient-derived and four commercially available cell lines to uncover miR-194-3p as a key epigenetic determinant of stemness and transcriptional subtype in GBM. We demonstrate that miR-194-3p degrades TAB2, an important mediator of NF-κB activity, decreasing NF-κB transcriptional activity. The loss in NF-κB activity following miR-194-3p overexpression or TAB2 silencing decreased expression of induced pluripotent stem cell (iPSC) genes, inhibited the oncogenic IL-6/STAT3 signaling axis, suppressed the mesenchymal transcriptional subtype in relation to the proneural subtype, and induced differentiation from the glioma stem cell (GSC) to monolayer (ML) phenotype. miR-194-3p/TAB2/NF-κB signaling axis acts as an epigenetic switch that regulates GBM plasticity and targeting this signaling axis represents a potential strategy to limit transcriptional heterogeneity in GBMs

Cells isolated from residual intracranial tumors after treatment express iPSC genes and possess neural lineage differentiation plasticityResearch in context

Background: The goal of this study is to identify and characterize treatment resistant tumor initiating cells (TRTICs) using orthotopic xenografts. Methods: TRTICs were enriched from GBM cell lines using mouse xenografts treated with fractionated doses of radiation and temozolomide. TRTICs were characterized by neurosphere clonogenicity and self-renewal, serial xenotransplantation, differentiation potential, and mRNA & miRNA transcriptomic profiling. We use an unbiased approach to identify antigens encoding TRTIC and glioma stem cells (GSC) populations. Co-culture experiments of TRTIC and differentiated cells were conducted to evaluate the reliance of TRTIC differentiation on the secretome of differentiated cells. Findings: TRTICs acquire stem-like gene expression signatures and increased side population staining resulting from the activation of multi-drug resistance genes. Genetic and functional characterization of TRTICs shows a striking resemblance with GSCs. TRTICs can differentiate towards specific progeny in the neural stem cell lineage. TRTIC-derived tumors display all the histological hallmarks of glioblastoma (GBM) and exhibit a miRNA-transcript and mRNA-transcriptomic profile associated with aggressiveness. We report that CD24+/CD44+ antigens are expressed in TRTICs and patient-derived GSCs. Double positive CD24+/CD44+ exhibit treatment resistance and enhanced tumorigenicity. Interestingly, co-culture experiments with TRTICs and differentiated cells indicated that the regulation of TRTIC differentiation could rely on the secretome in the tumor niche. Interpretation: Radiation and temozolomide treatment enriches a population of cells that have increased iPSC gene expression. As few as 500 cells produced aggressive intracranial tumors resembling patient GBM. CD24+/CD44+ antigens are increased in TRTICs and patient-derived GSCs. The enrichment for TRTICs may result in part from the secretome of differentiated cells. Fund: NIH/NCI 1RC2CA148190, 1R01CA108633, 1R01CA188228, and The Ohio State University Comprehensive Cancer Center. Keywords: Treatment-resistance, Tumor-initiating, Glioma stem cell, CD24high/CD44high, Transcriptome, Neural lineag

Validation of differentiated microRNA expression profile by RT-qPCR method.

<p>RNA samples from fresh frozen (n = 8) and FFPE (n = 8) tissues were analyzed. Small nuclear RNA U6 was used as reference. MiR-21 and miR-19a had higher expression in fresh frozen samples than in FFPE samples, consistent with sequencing results.</p

Percentages of microRNA reads detected over the years of specimen collection.

<p>Percentages of microRNA reads detected over the years of specimen collection.</p

MicroRNA Pearson correlation coefficient distribution of eight matched fresh frozen and FFPE samples among the 250 microRNAs detected in all samples.

<p>MicroRNA Pearson correlation coefficient distribution of eight matched fresh frozen and FFPE samples among the 250 microRNAs detected in all samples.</p

Scatter plot of microRNAs variance (log10 transformed) versus Pearson correlation coefficients (Fisher transformed) from matched fresh frozen-FFPE samples.

<p>Scatter plot of microRNAs variance (log10 transformed) versus Pearson correlation coefficients (Fisher transformed) from matched fresh frozen-FFPE samples.</p

Percentage of microRNA reads among total reads.

<p>Percentage of microRNA reads among total reads.</p

41 microRNAs had correlation coefficients equal to or greater than 0.8 between FFPE and fresh frozen pairs.

<p>41 microRNAs had correlation coefficients equal to or greater than 0.8 between FFPE and fresh frozen pairs.</p