Yuan-Cheng Wang

Bone Marrow Endothelial Progenitor Cell Transplantation After Ischemic Stroke: An Investigation Into Its Possible Mechanism.

We tested the hypothesis that endothelial progenitor cell (EPC)‐mediated functional recovery after stroke may be associated with the endothelial nitric oxide synthase (eNOS)/brain‐derived neurotrophic factor (BDNF) signaling pathway.

Salvaging brain ischemia by increasing neuroprotectant uptake via nanoagonist mediated blood brain barrier permeability enhancement.

Ischemic stroke is a leading cause of adult disability and cognitive impairment worldwide. Neuroprotective therapy aims to save neurons by impeding the deleterious ischemic insults. However, the low efficiency of the neuroprotectants crossing blood brain barrier (BBB) prevents their clinical translation. In this work, a nanoagonist (NA) was developed to enhance neuroprotectant uptake by specifically increasing BBB permeability in brain ischemia. This NA first targeted ischemic brain vasculatures, temporarily opened local BBB by activating adenosine 2A receptors, and up-regulated the neuroprotectant uptake in brain ischemia. This NA significantly increased the delivery of superoxide dismutase (SOD), a free radical scavenger, into mouse brain ischemia. The combined treatment of NA/SOD achieved a five-fold ischemic volume reduction rate compared to the animal models treated with SOD alone. Non-invasive magnetic resonance imaging (MRI) confirmed the ischemia targeted BBB opening, increased brain drug delivery efficiency and up-regulated therapeutic response during the combined NA/SOD treatment. Since the inefficient brain drug delivery is a general problem for the treatment of central nervous system (CNS) diseases, this work provides a novel strategy to deliver therapeutics by crossing BBB with high efficiency and targeting specificity.

Role of P38 MAPK on MMP Activity in Photothrombotic Stroke Mice as Measured using an Ultrafast MMP Activatable Probe.

Matrix metalloproteinases (MMPs) exert a dual effect in ischemic stroke and thus represent an ideal target for detection and therapy. However, to date, all clinical trials of MMP inhibitors have failed, and alternative drug candidates and therapeutic targets are urgently required. Nonetheless, further investigations are limited by the lack of non-invasive imaging techniques. Here, we report a novel, fast and ultrasensitive MMP activatable optical imaging probe for the dynamic visualization of MMP activity in photothrombotic stroke mice. This probe provides a significant signal enhancement in as little as 15 min, with the highest signal intensity occurring at 1 h post-injection, and shows high sensitivity in measuring MMP activity alterations, which makes it specifically suitable for the real-time visualization of MMP activity and drug discovery in preclinical research. Moreover, using this probe, we successfully demonstrate that the regulation of the p38 mitogen-activated protein kinase (MAPK) signal pathway is capable of modulating MMP activity after stroke, revealing a novel regulatory mechanism of postischemic brain damage and overcoming the limitations of traditional therapeutic strategies associated with MMP inhibitors by using a non-invasive molecular imaging method.

Significant perturbation in renal functional magnetic resonance imaging parameters and contrast retention for iodixanol compared with iopromide: an experimental study using blood-oxygen-level-dependent/diffusion-weighted magnetic resonance imaging and computed tomography in rats.

ObjectivesThe objective of this study was to investigate the renal changes after intravenous administration of a high dose of either iodixanol or iopromide using functional magnetic resonance imaging (MRI) and computed tomography (CT). Materials and MethodsThe study was approved by the institutional committee on animal research. Seventy-two male Sprague-Dawley rats were divided into 5 cohorts, comprising normal saline (NS), iopromide, iopromide + NS, iodixanol, and iodixanol + NS. Intravenous contrast was administrated at 8 g iodine/kg of body weight. Renal CT, quantitative functional MRI of blood-oxygen-level–dependent (BOLD) imaging and diffusion-weighted imaging (DWI), and histologic examinations were performed for 18 days after contrast administration. Statistical analysis was performed by using 1-way analysis of variance, Mann-Whitney test, and regression analysis. ResultsIn the renal cortex, BOLD showed persistent elevation of R2* and DWI showed persistent suppression of apparent diffusion coefficient after iodixanol administration for 18 days. Compared with iopromide, adjusted &Dgr;R2* (&Dgr;R2*adj) was significantly higher in the iodixanol group from 1 hour to 18 days (P < 0.04) after contrast; adjusted &Dgr;ADC (&Dgr;ADCadj) was significantly more pronounced at day 6 (P = 0.01) after contrast. The iodixanol cohort also exhibited persistently higher attenuation in the renal cortex on CT and more severe microscopic renal cortical vacuolization up to 18 days. Intravenous hydration decreased the magnetic resonance changes in both groups but more markedly with iodixanol. ConclusionsAt high doses, iodixanol induced greater changes in renal functional MRI (BOLD and DWI) relative to iopromide. Combined with longer contrast retention within the kidney, this suggests that iodixanol may produce more severe and longer-lasting contrast-induced renal damage.

Multimodal nanoprobes evaluating physiological pore size of brain vasculatures in ischemic stroke models.

Ischemic stroke accounts for 80% strokes and originates from a reduction of cerebral blood flow (CBF) after vascular occlusion. For treatment, the first action is to restore CBF by thrombolytic agent recombinant tissue-type plasminogen activator (rt-PA). Although rt-PA benefits clinical outcome, its application is limited by short therapeutic time window and risk of brain hemorrhage. Different to thrombolytic agents, neuroprotectants reduce neurological injuries by blocking ischemic cascade events such as excitotoxicity and oxidative stress. Nano-neuroprotectants demonstrate higher therapeutic effect than small molecular analogues due to their prolonged circulation lifetime and disrupted blood-brain barrier (BBB) in ischemic region. Even enhanced BBB permeability in ischemic territories is verified, the pore size of ischemic vasculatures determining how large and how efficient the therapeutics can pass is barely studied. In this work, nanoprobes (NPs) with different diameters are developed. In vivo multimodal imaging indicates that NP uptakes in ischemic region depended on their diameters and the pore size upper limit of ischemic vasculatures is determined as 10-11 nm. Additionally, penumbra defined as salvageable ischemic tissues performed a higher BBB permeability than infarct core. This work provides a guideline for developing nano-neuroprotectants by taking advantage of the locally enhanced BBB permeability in ischemic brain tissues.

Myocardial T1 rho mapping of patients with end-stage renal disease and its comparison with T1 mapping and T2 mapping: A feasibility and reproducibility study.

To evaluate the feasibility of T1rho mapping in myocardium at 3T and to determine whether T1rho mapping could better characterize myocardial injury in end‐stage renal disease (ESRD) patients compared to T1 and T2 mapping.

Renal fat fraction and diffusion tensor imaging in patients with early-stage diabetic nephropathy

ObjectiveTo investigate the renal fat fraction and water molecular diffusion features in patients with early-stage DN using Dixon imaging and diffusion tensor imaging (DTI).MethodsSixty-one type 2 diabetics (normoalbuminuria: n = 40; microalbuminuria: n = 21) and 34 non-diabetic volunteers were included. All participants received three-point Dixon imaging and DTI using a 3.0-T magnetic resonance imager. The fat fraction [FF] and DTI features [fractional anisotropy (FA), apparent diffusion coefficient (ADC), tract counts and length from DTI tractography] were collected. All image features were compared between cohorts using one-way ANOVA with Bonferroni post-hoc analysis.ResultsRenal FF in the microalbuminuric group was significantly higher than in the normoalbuminuric and control groups (5.6% ± 1.3%, 4.7% ± 1.1% and 4.3% ± 0.5%, respectively; p < 0.001). Medullary FA in the microalbuminuric group was the lowest (0.31 ± 0.06) in all cohorts. The tract counts and length in the renal medulla were significantly lower in the microalbuminuric group than in the other two groups.ConclusionsDixon imaging and DTI are able to detect renal lipid deposition and water molecule diffusion abnormalities in patients with early-stage DN. Both techniques have the potential to noninvasively evaluate early renal impairment in type 2 diabetes.Key points• Dixon imaging demonstrated renal fat deposition in early-stage DN;• Renal fractional anisotropy decreased in patients with early-stage DN;• Renal tractography demonstrated reduced track counts and length in early-stage DN.

Time-Efficient Myocardial Contrast Partition Coefficient Measurement from Early Enhancement with Magnetic Resonance Imaging

Objective Our purpose was to validate an early enhancement time point for accurately measuring the myocardial contrast partition coefficient (lambda) using dynamic-equilibrium magnetic resonance imaging. Materials and Methods The pre- and post-contrast longitudinal relaxation rates (reciprocal of T1) of the interventricular septum (R1m) and blood pool (R1b) were obtained from fifteen healthy volunteers and three diabetic patients with hypertension using two optimized T1 mapping sequences (modified Look-Locker inversion recovery) on a 3-Tesla magnetic resonance scanner. Reference lambda values were calculated as the slope of the regression line of R1m versus R1b at dynamic equilibrium (multi-point regression method). The simplified pre-/post-enhancement two-acquisition method (two-point method) was used to calculate lambda by relating the change in R1m and R1b using different protocols according to the acquisition stage of the post-enhancement data point. The agreement with the referential method was tested by calculating Pearsons correlation coefficient and the intra-class correlation coefficient. Results The lambda values measured by the two-point method increased (from 0.479±0.041 to 0.534±0.043) over time from 6 to 45 minutes after contrast and exhibited good correlation with the reference at each time point (r≥0.875, p<0.05). The intra-class correlation coefficient on absolute agreement with the reference lambda was 0.946, 0.929 and 0.922 at the 6th, 7th and 8th minutes and dropped from 0.878 to 0.403 from the 9th minute on. Conclusions The time-efficient two-point method at 6–8 minutes after the Gd-DTPA bolus injection exhibited good agreement with the multi-point regression method and can be applied for accurate lambda measurement in normal myocardium.

Noninvasive Identification of Renal Hypoxia in Experimental Myocardial Infarctions of Different Sizes by Using BOLD MR Imaging in a Mouse Model

Purpose To test the feasibility of using blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging to measure alterations in renal oxygenation in a mouse model with experimental myocardial infarctions (MIs) of different sizes. Materials and Methods The study was approved by the local animal ethics committee. One hundred eighty-nine male C57BL/6 J mice were randomly subjected to MI surgery (with different locations of left anterior descending coronary artery occlusion) or sham surgery, defined as the exposure of the heart but no ligation. Mice with MI underwent late gadolinium enhancement imaging 1 day after occlusion to confirm infarct size. Mice were sorted into three groups: those with large MI (n = 48), those with small MI (n = 48), and those with sham operation (n = 36). Renal BOLD MR imaging was performed before and 1, 7, 14, 28, and 60 days after MI, and histologic analysis of renal hypoxia-inducible factor-1α (HIF-1α) and kidney injury molecule-1 (KIM-1) was performed to evaluate tissue hypoxia and kidney injury in subgroups imaged at each time point. The relationships between the BOLD R2* and HIF-1α expression and between HIF-1α and KIM-1 expression were assessed. Statistical analyses were performed with one-way analysis of variance or the Kruskal-Wallis test and Spearman correlation test. Results A significant elevation in R2* was detected in the MI groups compared with the sham group in the cortex (P < .001 for large MI vs sham group; P = .007 for small MI vs sham group) and medulla (P < .001 for large MI vs sham group; P = .003 for small MI vs sham group) on day 60, and R2* was higher in the large MI group than in the small MI group (P < .001). Renal HIF-1α expression was increased after MI and showed linear correlation with R2* in the cortex (R2 = 0.56) and medulla (R2 = 0.63). In addition, an increase in renal KIM-1 was observed in the MI groups compared with the sham group on day 60 (sham group, 53.9 × 103 arbitrary units [au] ± 35.2; large MI group, 389.3 × 103 au ± 99.8; and small MI group, 185.8 × 103 au ± 91.9; P < .001 for large MI group vs sham group; P = .037 for small MI group vs sham group), and renal KIM-1 showed a positive correlation with HIF-1α (R2 = 0.68). Conclusion The magnitude of renal hypoxia with MIs of different sizes can be noninvasively measured with BOLD MR imaging, and increased renal hypoxia is a potential risk factor for progressive tubulointerstitial injury in mouse kidneys.

Noninvasive assessment of age, gender, and exercise effects on skeletal muscle: Initial experience with T1 ρ MRI of calf muscle.

To prospectively investigate age‐ and gender‐related changes in the fast‐twitch (tibialis anterior, TA) and slow‐twitch (soleus, SOL) skeletal muscle of healthy rats and volunteers and to compare the exercise‐related difference in health volunteers with T1ρ magnetic resonance imaging (MRI).