Metabonomic Investigation of Biological Effects of a New Vessel Target Protein tTF-pHLIP in a Mouse Model

Abstract

In recent years, tumor microenvironment has been recognized as potential targets for tumor treatment and tumor vascular system is one of such targets. Fusing truncated tissue factor (tTF) with a pH Low Insertion Peptides (pHLIP), tTF-pHLIP, can target tumor vessels owing to its acidic tumor microenvironment (TME) and cause tumor vessels occlusion by blood clotting and subsequently effectively inhibit tumor growth.To evaluate its bioeffects, we exposed the tTF-pHLIP to normal mice and mice xenograft with B16F10 tumor and analyzed the metabolic profiling of various tissues and biofluids including plasma and urine from mice treated with and without tTF-pHLIP. A combination of nuclear magnetic resonance (NMR) and gas chromatographymass spectrometry (GC-MS) and ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was employed in the study. We found that tTF-pHLIP treatment can effectively reduce tumor size and concurrently ameliorate tumor induced alterations in the TCA cycle metabolism and lipid metabolism. In addition, we found that toxicity of tTF-pHLIP to normal mice is minor and exposure of the tTF-pHLIP induced oxidative stress to the system. Hence, we concluded that tTF-pHLIP is of low toxicity and effective in reducing tumor size as well as rebalancing tumor induced metabolic derailment.

A Subset of Roux-en-Y Gastric Bypass Bacterial Consortium Colonizes the Gut of Nonsurgical Rats without Inducing Host-Microbe Metabolic Changes

“…Significantly altered peak intensities were calculated by univariate analysis with a P value of <0.05 after Benjamini-Hochberg correction. Metabolite identification was achieved by STOCSY ( 39 ), Chenomx Software (Alberta, Canada), and searching previous literature database ( 34 , 40 , 41 ).…”

Multiomics Integrative Analysis for Discovering the Potential Mechanism of Dioscin against Hyperuricemia Mice

“…PCA was used to visualize group clustering and visualize possible outliers, and OPLS-DA was used to classify different groups and identify potential biomarkers . Pareto scaling was used for data pretreatment; cross-validation with 200-time permutation tests and the CV-ANOVA method were used to identify the reliability of the OPLS-DA models . The quality of the models was evaluated by the values of R2X and Q2.…”

“…A loop for the T2 filter of 300 was used. Additionally, in order to facilitate the signal assignment and confirmation of metabolites, we carried out J -resolved spectroscopy ( J -RES), 1 H– 1 H COSY, TOCSY, HMBC, and HSQC experiments …”

“…15 Pareto scaling was used for data pretreatment; cross-validation with 200-time permutation tests and the CV-ANOVA method were used to identify the reliability of the OPLS-DA models. 16 The quality of the models was evaluated by the values of R2X and Q2. R2X indicates the goodness of fit, and Q2 indicates the predictive ability of the model.…”

The Evolution of Safe and Effective Coaguligands for Vascular Targeting and Precision Thrombosis of Solid Tumors and Vascular Malformations

“…Extracellular acidification, caused primarily by anaerobic metabolism and lactate secretion, allows conformational changes to the "pH (low) insertion peptide" (pHLIP) to form a transmembrane alpha-helix that can insert into the cell membrane within the acidic environment. This pH-responsive fusion protein was shown to selectively induce tumor infarction, delay growth in human breast xenografts [94], and, more recently, to induce growth reduction and tumor shrinkage in a mouse melanoma model with just 2.5-5 µg of tTF fusion protein [95].…”