Comprehensive transcriptomics and metabolomics analyses reveal that hyperhomocysteinemia is a high risk factor for coronary artery disease in a chinese obese population aged 40-65: a prospective cross-sectional study.

BACKGROUND: Clinical observations suggest a complex relationship between obesity and coronary artery disease (CAD). This study aimed to characterize the intermediate metabolism phenotypes among obese patients with CAD and without CAD. METHODS: Sixty-two participants who consecutively underwent coronary angiography were enrolled in the discovery cohort. Transcriptional and untargeted metabolomics analyses were carried out to screen for key molecular changes between obese patients with CAD (CAD obese), without CAD (Non-CAD obese), and Non-CAD leans. A targeted GC-MS metabolomics approach was used to further identify differentially expressed metabolites in the validation cohorts. Regression and receiver operator curve analysis were performed to validate the risk model. RESULTS: We found common aberrantly expressed pathways both at the transcriptional and metabolomics levels. These pathways included cysteine and methionine metabolism and arginine and proline metabolism. Untargeted metabolomics revealed that S-adenosylhomocysteine (SAH), 3-hydroxybenzoic acid, 2-hydroxyhippuric acid, nicotinuric acid, and 2-arachidonoyl glycerol were significantly elevated in the CAD obese group compared to the other two groups. In the validation study, targeted cysteine and methionine metabolomics analyses showed that homocysteine (Hcy), SAH, and choline were significantly increased in the CAD obese group compared with the Non-CAD obese group, while betaine, 5-methylpropanedioic acid, S-adenosylmethionine, 4-PA, and vitamin B2 (VB2) showed no significant differences. Multivariate analyses showed that Hcy was an independent predictor of obesity with CAD (hazard ratio 1.7; 95%CI 1.2-2.6). The area under the curve based on the Hcy metabolomic (HCY-Mtb) index was 0.819, and up to 0.877 for the HCY-Mtb.index plus clinical variables. CONCLUSION: This is the first study to propose that obesity with hyperhomocysteinemia is a useful intermediate metabolism phenotype that could be used to identify obese patients at high risk for developing CAD.

Monitoring of macrophage recruitment enhanced by Toll-like receptor 4 activation with MR imaging in nerve injury.

INTRODUCTION: Macrophage recruitment is critical for nerve regeneration after an injury. The aim of this study was to investigate whether ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle-based MRI could be used to monitor the enhanced macrophage recruitment by Toll-like receptor 4 (TLR4) activation in nerve injury. METHODS: Rats received intraperitoneal injections of either lipopolysaccharide (LPS) or phosphate buffered saline (PBS) or no injection (controls) after a sciatic nerve crush injury. After intravenous injection of the USPIOs (LPS and PBS groups) or PBS (control group), MRI was performed and correlated with histological findings. RESULTS: LPS group showed more remarkable hypointense signals on T2*-weighted imaging and lower T2 values in the crushed nerves than PBS group. The hypointense signal areas were associated with an enhanced recruitment of iron-loaded macrophages to the injured nerves. DISCUSSION: USPIO-enhanced MRI can be used to monitor the enhanced macrophage recruitment by means of TLR4 signal pathway activation in nerve injury. Muscle Nerve, 2018.

Assessment of the synergic effect of immunomodulation on nerve repair using multiparametric magnetic resonance imaging.

INTRODUCTION: The immune system plays a pivotal role in nerve injury. The aim of this study was to determine the role of multiparametric magnetic resonance imaging (MRI) in evaluation of the synergic effect of immunomodulation on nerve regeneration in neurotmesis. METHODS: Rats with sciatic nerve neurotmesis and surgical repair underwent serial multiparametric MR examinations over an 8-week period after subepineurial microinjection of lipopolysaccharide (LPS) and subsequent subcutaneous injection of FK506 or subepineurial microinjection of LPS or phosphate-buffered saline (PBS) alone. RESULTS: Nerves treated with immunomodulation showed more prominent regeneration than those treated with LPS or PBS alone and more rapid restoration toward normal T2, fractional anisotropy (FA), and radial diffusivity (RD) values than nerves injected with LPS or PBS. DISCUSSION: Nerves treated with immunomodulation exert synergic beneficial effects on nerve regeneration that can be predicted by T2 measurements and FA and RD values. Muscle Nerve 57: E38-E45, 2018.

Superparamagnetic Iron Oxide Nanoparticles-Complexed Cationic Amylose for In Vivo Magnetic Resonance Imaging Tracking of Transplanted Stem Cells in Stroke.

Cell-based therapy with mesenchymal stem cells (MSCs) is a promising strategy for acute ischemic stroke. In vivo tracking of therapeutic stem cells with magnetic resonance imaging (MRI) is imperative for better understanding cellular survival and migrational dynamics over time. In this study, we develop a novel biocompatible nanocomplex (ASP-SPIONs) based on cationic amylose, by introducing spermine and the image label, ultrasmall superparamagnetic iron oxide nanoparticles (SPIONs), to label MSCs. The capacity, efficiency, and cytotoxicity of the nanocomplex in transferring SPIONs into green fluorescence protein-modified MSCs were tested; and the performance of in vivo MRI tracking of the transplanted cells in acute ischemic stroke was determined. The results demonstrated that the new class of SPIONs-complexed nanoparticles based on biodegradable amylose can serve as a highly effective and safe carrier to transfer magnetic label into stem cells. A reliable tracking of transplanted stem cells in stroke was achieved by MRI up to 6 weeks, with the desirable therapeutic benefit of stem cells on stroke retained. With the advantages of a relatively low SPIONs concentration and a short labeling period, the biocompatible complex of cationic amylose with SPIONs is highly translatable for clinical application. It holds great promise in efficient, rapid, and safe labeling of stem cells for subsequent cellular MRI tracking in regenerative medicine.

Magnetic Cationic Amylose Nanoparticles Used to Deliver Survivin-Small Interfering RNA for Gene Therapy of Hepatocellular Carcinoma In Vitro.

Amylose is a promising nanocarrier for gene delivery in terms of its good biocompatibility and high transfection efficiency. Small interfering RNA against survivin (survivin-siRNA) can cause tumor apoptosis by silencing a hepatocellular carcinoma (HCC)-specific gene at the messenger RNA level. In this study, we developed a new class of folate-functionalized, superparamagnetic iron oxide (SPIO)-loaded cationic amylose nanoparticles to deliver survivin-siRNA to HCC cells. The cellular uptake of nanocomplexes, cytotoxicity, cell apoptosis, and gene suppression mediated by siRNA-complexed nanoparticles were tested. The results demonstrated that folate-functionalized, SPIO-loaded cationic amylose nanoparticles can mediate a specific and safe cellular uptake of survivin-siRNA with high transfection efficiency, resulting in a robust survivin gene downregulation in HCC cells. The biocompatible complex of cationic amylose could be used as an efficient, rapid, and safe gene delivery vector. Upon SPIO loading, it holds a great promise as a theranostic carrier for gene therapy of HCC.

Assessment of Nonalcoholic Fatty Liver Disease in Rats Using Quantitative Dynamic Contrast-Enhanced MRI.

PURPOSE: To evaluate the usefulness of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the assessment of nonalcoholic fatty liver disease (NAFLD) severity. MATERIALS AND METHODS: Liver DCE-MRI at 3.0T was performed in 36 adult Sprague-Dawley rats with methionine choline-deficient diet-induced NAFLD and 10 untreated control rats. Pharmacokinetic parameters of DCE-MRI including Ktrans , Kep , Ve , Vp , and hepatic portal index (HPoI) were measured using the dual-input extended Tofts model. Animals were categorized as normal (n = 10), simple steatosis (SS, n = 11), borderline nonalcoholic steatohepatitis (bNASH, n = 20), and NASH (n = 5) subgroups according to the NAFLD activity score system, and classified into F0 (n = 24), F1 (n = 11), F2 (n = 7), and F3 (n = 4) subgroups according to an established scoring system. DCE-MRI parameters were compared. Receiver operating characteristic analyses were performed to assess the diagnostic performance of various DCE-MRI parameters in grading NAFLD activity and staging liver fibrosis. RESULTS: Ktrans and HPoI were elevated with increasing severity of NAFLD activity and increased fibrosis stage. The areas under the receiver operating characteristic curve (AUROCs) of HPoI ranged from 0.895-0.951 for discriminating between different grades of NAFLD activity, and the AUROC was 0.852 for discriminating F0 stage from overall F1-F3 stages. The AUROC of Ktrans for discriminating non-NASH from bNASH and NASH groups was 0.968, and 0.898 for discriminating between normal and overall fibrosis groups. CONCLUSION: DCE-MRI may play a role in assessing NAFLD severity. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;45:1485-1493.

Diffusion tensor imaging of symptomatic nerve roots in patients with cervical disc herniation.

RATIONALE AND OBJECTIVES: Cervical disc degeneration can result in nerve root compression and severe symptoms that significantly impair the patient's quality of life. The purpose of this study is to investigate multiple diffusion metrics changes in the diffusion tensor imaging (DTI) of cervical nerve roots and their relationship with the clinical severity of patients with cervical disc herniation. MATERIALS AND METHODS: High directional DTI of the cervical nerve roots was performed in 18 symptomatic patients and 10 healthy volunteers with a 3.0-T magnetic resonance system after a routine cervical disc scanning. The fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated from the DTI data and compared between the affected and unaffected sides in the same patient and between healthy volunteers and symptomatic patients. The correlation between the side-to-side diffusion metric differences and the clinical International Standards for Neurological Classification of Spinal Cord Injury scores was analyzed. RESULTS: C5-C8 nerve roots were clearly delineated with DTI. The FA, MD, AD, and RD of compressed nerve roots were 0.31 ± 0.091, 2.06 ± 0.536, 2.69 ± 0.657, and 1.75 ± 0.510 mm(2)/s, respectively. Compared to the unaffected side or healthy volunteers, the nerve roots of the affected side showed decreased FA (P < .022) and increased MD (P < .035), AD (P < .047), and RD (P < .012). The clinical International Standards for Neurological Classification of Spinal Cord Injury scores of the patients were negatively correlated with MD (r = -0.57, P = .002), AD (r = -0.451, P = .021), and RD (r = -0.564, P = .003) but not with FA (r = 0.004, P = .984). CONCLUSIONS: DTI can potentially be used to assess microstructural abnormalities in the cervical nerve roots in patients with disc herniation.