scholarly journals Targeting glioma-initiating cells via the tyrosine metabolic pathway

2020 ◽  
pp. 1-12 ◽  
Author(s):  
Daisuke Yamashita ◽  
Joshua D. Bernstock ◽  
Galal Elsayed ◽  
Hirokazu Sadahiro ◽  
Ahmed Mohyeldin ◽  
...  
Keyword(s):  
Metabolic Pathway ◽  
High Grade Glioma ◽  
Selective Inhibition ◽  
Tumor Metabolism ◽  
Tyrosine Aminotransferase ◽  
Data Set ◽  
Sphere Culture ◽  
Tyrosine Metabolism ◽  
Culture Models ◽  
Tumor Edge

OBJECTIVEDespite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism.METHODSComprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry.RESULTSMetabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core.CONCLUSIONSSelective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.

scholarly journals HOXA5 Is Recognized as a Prognostic-Related Biomarker and Promotes Glioma Progression Through Affecting Cell Cycle

2021 ◽  
Vol 11 ◽  
Author(s):  
Fengqin Ding ◽  
Ping Chen ◽  
Pengfei Bie ◽  
Wenhua Piao ◽  
Quan Cheng
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Glioma Cell ◽  
Molecular Subtype ◽  
High Grade Glioma ◽  
Surgical Removal ◽  
Data Set ◽  
M Phase ◽  
Glioma Cell Proliferation ◽  
Glioma Progression

Glioma is malignant tumor derives from glial cells in the central nervous system. High-grade glioma shows aggressive growth pattern, and conventional treatments, such as surgical removal and chemo-radiotherapy, archive limitation in the interference of this process. In this work, HOXA5, from the HOX family, was identified as a glioma cell proliferation-associated factor by investigating its feature in the TCGA and CGGA data set. High HOXA5 expression samples contain unfavorable clinical features of glioma, including IDH wild type, un-methylated MGMT status, non-codeletion 1p19q status, malignant molecular subtype. Survival analysis indicates that high HOXA5 expression samples are associated with worse clinical outcome. The CNVs and SNPs profile difference further confirmed the enrichment of glioma aggressive related biomarkers. In the meantime, the activation of DNA damage repair-related pathways and TP53-related pathways is also related to HOXA5 expression. In cell lines, U87MG and U251, by interfering HOXA5 expression significantly inhibit glioma progression and apoptosis, and cell cycle is arrested at the G2/M phase. Collectively, increased HOXA5 expression can promote glioma progression via affecting glioma cell proliferation.

scholarly journals Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis

PLoS Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. e3000796
Author(s):  
Marcos Sterkel ◽  
Lee R. Haines ◽  
Aitor Casas-Sánchez ◽  
Vincent Owino Adung’a ◽  
Raquel J. Vionette-Amaral ◽  
...  
Keyword(s):  
Degradation Pathway ◽  
Tyrosine Aminotransferase ◽  
Sub Saharan Africa ◽  
African Trypanosomiasis ◽  
Environment Friendly ◽  
Insect Pollinator ◽  
Pollinator Species ◽  
Tyrosine Metabolism ◽  
Neurotoxic Insecticides ◽  
Sub Saharan

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce populations of insect pollinator species. Here we present a promising, environment-friendly alternative to current insecticides that targets the insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded and eliminated. RNA interference (RNAi) of either the first two enzymes in the tyrosine degradation pathway (tyrosine aminotransferase (TAT) and 4-hydroxyphenylpyruvate dioxygenase (HPPD)) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, oral administration of NTBC to bumblebees did not affect their survival. Using a novel mathematical model, we show that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current disease elimination programmes.

scholarly journals Unveiling Prognostics Biomarkers of Tyrosine Metabolism Reprogramming in Liver Cancer by Cross-platform Gene Expression Analyses

2020 ◽  
Author(s):  
Tran Ngoc Nguyen ◽  
Ha Quy Nguyen ◽  
Duc-Hau Le
Keyword(s):  
Gene Expression ◽  
Normal Liver ◽  
Tyrosine Aminotransferase ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Enzymatic Reactions ◽  
Kaplan Meier ◽  
Catabolic Genes ◽  
Tyrosine Metabolism ◽  
Cross Platform

AbstractTyrosine is mainly degraded in the liver by a series of enzymatic reactions. Abnormal expression of the tyrosine catabolic enzyme tyrosine aminotransferase (TAT) has been reported in patients with hepatocellular carcinoma (HCC). Despite this, aberration in tyrosine metabolism has not been investigated in cancer development. In this work, we conduct comprehensive cross-platform study to obtain foundation for discoveries of potential therapeutics and preventative biomarkers of HCC. We explore data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Gene Expression Profiling Interactive Analysis (GEPIA), Oncomine and Kaplan Meier plotter (KM plotter) and performed integrated analyses to evaluate the clinical significance and prognostic values of the tyrosine catabolic genes in HCC. We find that five tyrosine catabolic enzymes are downregulated in HCC compared to normal liver at mRNA and protein level. Moreover, low expression of these enzymes correlates with poorer survival in patients with HCC. Notably, we identify pathways and upstream regulators that might involve in tyrosine catabolic reprogramming and further drive HCC development. In total, our results underscore tyrosine metabolism alteration in HCC and lay foundation for incorporating these pathway components in therapeutics and preventative strategies.

scholarly journals BIMG-22. DEEP LEARNING SUPER-RESOLUTION MR SPECTROSCOPIC IMAGING TO MAP TUMOR METABOLISM IN MUTANT IDH GLIOMA PATIENTS

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i5-i6
Author(s):  
Xianqi Li ◽  
Ovidiu Andronesi ◽  
Bernhard Strasser ◽  
Kourosh Jafari-Khouzani ◽  
Daniel Cahill ◽  
...  
Keyword(s):  
Deep Learning ◽  
Similarity Index ◽  
Super Resolution ◽  
Spectroscopic Imaging ◽  
Tumor Metabolism ◽  
Metabolic Imaging ◽  
Data Set ◽  
Structural Details ◽  
Anatomical Mri ◽  
Mr Spectroscopic Imaging

Abstract Metabolic imaging can map spatially abnormal molecular pathways with higher specificity for cancer compared to anatomical imaging. However, acquiring high resolution metabolic maps similar to anatomical MRI is challenging due to low metabolite concentrations, and alternative approaches that increase resolution by post-acquisition image processing can mitigate this limitation. We developed deep learning super-resolution MR spectroscopic imaging (MRSI) to map tumor metabolism in patients with mutant IDH glioma. We used a generative adversarial network (GAN) architecture comprised of a UNet neural network as the generator network and a discriminator network for adversarial training. For training we simulated a large data set of 9600 images with realistic quality for acquired MRSI to effectively train the deep learning model to upsample by a factor of four. Two types of training were performed: 1) using only the MRSI data, and 2) using MRSI and prior information from anatomical MRI to further enhance structural details. The performance of super-resolution methods was evaluated by peak SNR (PSNR), structure similarity index (SSIM), and feature similarity index (FSIM). After training on simulations, GAN was evaluated on measured MRSI metabolic maps acquired with resolution 5.2×5.2 mm2 and upsampled to 1.3×1.3 mm2. The GAN trained only on MRSI achieved PSNR = 27.94, SSIM = 0.88, FSIM = 0.89. Using prior anatomical MRI improved GAN performance to PSNR = 30.75, SSIM = 0.90, FSIM = 0.92. In the patient measured data, GAN super-resolution metabolic images provided clearer tumor margins and made apparent the tumor metabolic heterogeneity. Compared to conventional image interpolation such as bicubic or total variation, deep learning methods provided sharper edges and less blurring of structural details. Our results indicate that the proposed deep learning method is effective in enhancing the spatial resolution of metabolite maps which may better guide treatment in mutant IDH glioma patients.

Nitric oxide synthase stimulates prostaglandin synthesis and barrier function inC. parvum-infected porcine ileum

2004 ◽  
Vol 287 (3) ◽  
pp. G571-G581 ◽  
Author(s):  
Jody L. Gookin ◽  
Laurel L. Duckett ◽  
Martha U. Armstrong ◽  
Stephen H. Stauffer ◽  
Colleen P. Finnegan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Barrier Function ◽  
Selective Inhibition ◽  
Prostaglandin Synthesis ◽  
Ileal Mucosa ◽  
Mucosal Permeability ◽  
Ussing Chambers ◽  
Nos Inhibitors ◽  
Culture Models ◽  
Nos Isoforms

Cell culture models implicate increased nitric oxide (NO) synthesis as a cause of mucosal hyperpermeability in intestinal epithelial infection. NO may also mediate a multitude of subepithelial events, including activation of cyclooxygenases. We examined whether NO promotes barrier function via prostaglandin synthesis using Cryptosporidium parvum-infected ileal epithelium in residence with an intact submucosa. Expression of NO synthase (NOS) isoforms was examined by real-time RT-PCR of ileal mucosa from control and C. parvum-infected piglets. The isoforms mediating and mechanism of NO action on barrier function were assessed by measuring transepithelial resistance (TER) and eicosanoid synthesis by ileal mucosa mounted in Ussing chambers in the presence of selective and nonselective NOS inhibitors and after rescue with exogenous prostaglandins. C. parvum infection results in induction of mucosal inducible NOS (iNOS), increased synthesis of NO and PGE2, and increased mucosal permeability. Nonselective inhibition of NOS ( NG-nitro-l-arginine methyl ester) inhibited prostaglandin synthesis, resulting in further increases in paracellular permeability. Baseline permeability was restored in the absence of NO by exogenous PGE2. Selective inhibition of iNOS [l- N6-(1-iminoethyl)-l-lysine] accounted for ∼50% of NOS-dependent PGE2synthesis and TER. Using an entire intestinal mucosa, we have demonstrated for the first time that NO serves as a proximal mediator of PGE2synthesis and barrier function in C. parvum infection. Expression of iNOS by infected mucosa was without detriment to overall barrier function and may serve to promote clearance of infected enterocytes.

Discovery of metabolomic biomarkers for discriminating platinum-sensitive and platinum-resistant ovarian cancer by using GC-MS

2021 ◽  
pp. 146906672110579
Author(s):  
Evren C. Eroglu ◽  
Sule Tunug ◽  
Omer Faruk Geckil ◽  
Umran Kucukgoz Gulec ◽  
Mehmet Ali Vardar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Metabolic Pathway ◽  
Urine Samples ◽  
Serum Samples ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Tyrosine Metabolism ◽  
Acid Metabolites ◽  
Mannose Metabolism ◽  
Urine And Serum

This study aims to determine ovarian cancer (OC) patients with platinum resistance for alternative treatment protocols by using metabolomic methodologies. Urine and serum samples of platinum-resistant and platinum-sensitive OC were analyzed using GC-MS. After data processing of GC-MS raw data, multivariate analyses were performed to interpret complex data for biologically meaningful information and to identify the biomarkers that cause differences between two groups. The biomarkers were verified after univariate, multivariate, and ROC analysis. Finally, metabolomic pathways related to group separations were specified. The results of biomarker analysis showed that 3,4-dihydroxyphenylacetic acid, 4-hydroxybutyric acid, L-threonine, D- mannose, and sorbitol metabolites were potential biomarkers in urine samples. In serum samples, L-arginine, linoleic acid, L-glutamine, and hypoxanthine were identified as important biomarkers. R2Y, Q2, AUC, sensitivity and specificity values of platinum-resistant and sensitive OC patients’ urine and serum samples were 0.85, 0.545, 0.844, 91.30%, 81.08 and 0.570, 0.206, 0.743, 77.78%, 74.28%, respectively. In metabolic pathway analysis of urine samples, tyrosine metabolism and fructose and mannose metabolism were found to be statistically significant (p < 0.05) for the discrimination of the two groups. While 3,4-dihydroxyphenylacetic acid, L-tyrosine, and fumaric acid metabolites were effective in tyrosine metabolism. D-sorbitol and D-mannose metabolites were significantly important in fructose and mannose metabolism. However, seven metabolomic pathways were significant (p < 0.05) in serum samples. In terms of p-value, L-glutamine in the nitrogen metabolic pathway from the first three pathways; L-glutamine and pyroglutamic acid metabolites in D-glutamine and D-glutamate metabolism. In the arginine and proline metabolic pathway, L-arginine, L-proline, and L-ornithine metabolites differed significantly between the two groups.

Cell culture models of pediatric high-grade glioma are susceptible to parvovirus-1 induced cytotoxicity

2015 ◽  
Vol 227 (06/07) ◽  
Author(s):  
R Josupeit ◽  
S Bender ◽  
B Leuchs ◽  
C Herold-Mende ◽  
JR Schlehofer ◽  
...  
Keyword(s):  
Cell Culture ◽  
High Grade Glioma ◽  
High Grade ◽  
Culture Models ◽  
Cell Culture Models ◽  
Pediatric High Grade Glioma
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