Abstract 5765: 3T MRI Molecular Imaging of Benfluorex Treatment of Metabolic Syndrome with α v β 3 -Integrin Targeted Nanoparticles

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kejia Cai ◽  
Wenjing Huang ◽  
Todd A Williams ◽  
Huiying Zhang ◽  
Shelton D Caruthers ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Molecular Imaging ◽  
Cross Sections ◽  
Therapeutic Efficacy ◽  
Aortic Wall ◽  
Spin Echo ◽  
Vascular Inflammation ◽  
Heart Association ◽  
Whole Body ◽  
Wall Signal

1.5T MRI with α v β 3 -integrin targeted gadolinium nanoparticle contrast agents (NP) can detect stage I atherosclerosis in experimental animals by localizing specifically to inflammatory plaque components within minutes after injection. We hypothesized that NP could serve as an early surrogate biomarker of therapeutic efficacy for benfluorex treatment of metabolic syndrome in diabetic JCR-LA:cp rats on a 3T clinical scanner. Six week old JCR-LA:cp rats (n=6) received benfluorex in their feed (0.069% wt/wt) for 16 weeks, while control animals (n=5) received regular diet. The abdominal aorta was imaged (T1w spin echo) in 4 cross-sections at baseline and 2-hour post-injection (IV, 1.0 ml/kg NP) every 4 wks with a 3.0 T whole-body clinical MRI scanner, and total aortic wall signal was computed across all sections. Treatment of diabetic JCR-LA:cp rats with benfluorex reduced food consumption and body weight (16.0%; p<0.05); and fasting plasma insulin, leptin and triglyceride were decreased by 52.6%, 18.2% and 36.2% in treated animals. Aortic wall signal for untreated animals rose progressively, whereas signal in treated animals progressively decreased, indicative of attenuation of angiogenesis and vascular inflammation (Figure , *p<0.05). These observations represent the first report of the use of molecular imaging with an MRI surrogate biomarker at clinical field strength for quantifying therapeutic efficacy in a model of metabolic syndrome. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

Abstract 2238: New Pharmacokinetic Models for Quantitative Molecular Imaging of Plaque Angiogenesis with Intergrin-targeted Nanoparticles

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hoon Sim ◽  
Anne Neubauer ◽  
Shelton Caruthers ◽  
Gregory Lanza ◽  
Samuel Wickline ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Early Detection ◽  
Cross Sections ◽  
Aortic Wall ◽  
Spin Echo ◽  
Vasa Vasorum ◽  
Pharmacokinetic Models ◽  
Descending Thoracic Aorta ◽  
Targeted Nanoparticles ◽  
Simultaneous Fitting

Cardiovascular molecular imaging with targeted nanoparticles has emerged as a promising method for early detection of atherosclerosis and vulnerable plaque. However, traditional pharmacokinetic models for diffusible drugs are inadequate to describe the efficacy of nanoparticle carriers of diagnostic and therapeutic cargos. To quantify blood and MRI tissue signals from gadolinium-loaded nanoparticles (Gd-NP) targeted to avb3 integrins expressed on angiogenic capillaries in the aortas of cholesterol-fed rabbit, a novel 4 compartment open PK model was developed that utilized a unique simultaneous fitting scheme. In 10 rabbits fed 0.25% cholesterol for 3 months, the concentration of nanoparticles was measured serially from blood samples after injection of 1 ml/kg of targeted or nontargeted Gd-NP. The MRI proton signatures emanating from nanoparticles bound to the expanded vasa vasorum of the descending thoracic aorta was computed for all aortic cross sections in 1.5T T1w fa-suppressed spin-echo images. Based on the PK analysis, the concentration of targeted nanoparticles in the aortic wall is double that of non-targeted nanoparticles. Notably, this signal enhancement is achieved with 20x less gadolinium (4.6x10 −3 mmol Gd/kg BW) as compared with the dose of conventional gadolinium agents (0.1 mmol/kg). Further, the PK analysis shows that the targeted nanoparticles are more than three times more effective at reaching the aortic wall. These results should facilitate development and use of nanotechnologies intended for early detection of atherosclerosis and provide enhanced understanding of the kinetics and mechanisms of active targeting of plaque angiogenesis.

Abstract 5760: Early Detection of Arteriopathy in Metabolic Syndrome by MR Molecular Imaging with Targeted Nanobeacons

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kejia Cai ◽  
Wenjing Huang ◽  
Todd A Williams ◽  
Shelton D Caruthers ◽  
Huiying Zhang ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Molecular Imaging ◽  
Heart Association ◽  
Inflammatory Cells ◽  
Black Blood ◽  
Mri Contrast ◽  
Fat Deposits ◽  
Black Blood Imaging ◽  
Obese Rats ◽  
Elevated Cholesterol

Metabolic syndrome elicits widespread inflammatory changes in vascular structures leading to early atherosclerosis that cannot be detected with classical imaging methods. Because pronounced early angiogenesis within the arterial wall typically accompanies activated inflammatory cells in standard models of atherosclerosis, we hypothesized that the expression of α v β 3 -integrins on neovascular endothelium would provide an abundant and sensitive biomarker of the metabolic vasculopathy. The mildly diabetic JCR:LA-cp rat was used as a model for MR molecular imaging of angiogenesis with α v β 3 -targeted gadolinium nanoparticles (NP). 5 month-old male JCR:LA-cp lean (control) and obese (affected) rats (n=5 each) were studied. The abdominal aorta was imaged with a 3.0 T clinical MRI scanner and a T1w, fat-suppressed, black-blood imaging sequence. Imaging was performed before (BSL) and 2 hours (2 HR) after NP injection (IV, 1.0 ml/kg). Fat suppressed imaging revealed large abdominal fat deposits in the obese rats but not in controls, concordant with elevated cholesterol levels (~2 times higher) in the obese rats (p<0.05). MRI contrast enhancement of angiogenesis in the aortic wall (Figure : top, arrow) in the obese rats was significantly higher than that in the lean rats (bottom, *p<0.05) indicating the widespread presence of neovasculature despite no apparent stenosis. MR molecular imaging of angiogenesis with integrin-targeted nanoparticles may represent a sensitive high-resolution surrogate signal for detecting early metabolic vasculopathy. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

459-P: Liver-Targeted Mitochondrial Uncoupling by CRMP Improves Whole-Body Insulin Sensitivity and Attenuates Atherosclerosis in A LDLR-/- Mouse Model of Metabolic Syndrome

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 459-P
Author(s):  
LEIGH GOEDEKE ◽  
NOEMI ROTLLAN ◽  
KESHIA TOUSSAINT ◽  
ALI NASIRI ◽  
XINBO ZHANG ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Mouse Model ◽  
Whole Body ◽  
Mitochondrial Uncoupling

scholarly journals Rind from Purple Mangosteen (Garcinia mangostana) Attenuates Diet-Induced Physiological and Metabolic Changes in Obese Rats

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 319
Author(s):  
Oliver D. John ◽  
Peter Mouatt ◽  
Sunil K. Panchal ◽  
Lindsay Brown
Keyword(s):  
Metabolic Syndrome ◽  
Inflammatory Cells ◽  
Left Ventricular ◽  
Metabolic Changes ◽  
Abdominal Circumference ◽  
Whole Body ◽  
Garcinia Mangostana ◽  
Tropical Fruit ◽  
Cardiovascular Parameters ◽  
Left Ventricular Stiffness

The pulp of the purple mangosteen, Garcinia mangostana, is a popular tropical fruit but the rind containing xanthones such as α-mangostin together with procyanidins and anthocyanidins is usually discarded as waste. However, this rind has been used in South-East Asia for diarrhoea, dysentery, skin infections and wounds. As xanthones have reported anti-inflammatory and antioxidant responses, this study has determined the bioactive compounds and evaluated the effects of G. mangostana rind on physiological, metabolic, liver and cardiovascular parameters in rats with diet-induced metabolic syndrome. Rats fed a diet with increased simple sugars and saturated fats developed obesity, hypertension, increased left ventricular stiffness, dyslipidaemia and fatty liver. Administration of G. mangostana rind as 5% of the food to rats with diet-induced metabolic syndrome gave a dose of 168 mg/kg/day α-mangostin, 355 mg/kg/day procyanidins, 3.9 mg/kg/day anthocyanins and 11.8 mg/kg/day hydroxycitric acid for 8 weeks which reduced body weight and attenuated physiological and metabolic changes in rats including decreased abdominal fat deposition, decreased abdominal circumference and whole-body fat mass, improved liver structure and function and improved cardiovascular parameters such as systolic blood pressure, left ventricular stiffness and endothelial function. These responses were associated with decreased infiltration of inflammatory cells, decreased deposition of collagen in both heart and liver and decreased mean adipocyte size in retroperitoneal adipose tissues. We conclude that, in rats with diet-induced metabolic syndrome, chronic intake of G. mangostana rind decreased infiltration of inflammatory cells which decreased physiological, metabolic, liver and cardiovascular symptoms.

scholarly journals Has molecular imaging delivered to drug development?

2017 ◽  
Vol 375 (2107) ◽  
pp. 20170112 ◽  
Author(s):  
Philip S. Murphy ◽  
Neel Patel ◽  
Timothy J. McCarthy
Keyword(s):  
Molecular Imaging ◽  
Drug Development ◽  
Clinical Studies ◽  
Pharmaceutical Research ◽  
Whole Body ◽  
Drug Candidate ◽  
Clinical Drug Development ◽  
Target Binding ◽  
The Brain ◽  
Clinical Drug

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.

scholarly journals Personalized management of differentiated thyroid cancer in real life – practical guidance from a multidisciplinary panel of experts

Endocrine ◽  
2020 ◽  
Vol 70 (2) ◽  
pp. 280-291
Author(s):  
Alfredo Campennì ◽  
Daniele Barbaro ◽  
Marco Guzzo ◽  
Francesca Capoccetti ◽  
Luca Giovanella
Keyword(s):  
Nuclear Medicine ◽  
Thyroid Cancer ◽  
Clinical Practice ◽  
Molecular Imaging ◽  
Routine Clinical Practice ◽  
Whole Body ◽  
Neck Ultrasound ◽  
Long Term Follow Up

Abstract Purpose The standard of care for differentiated thyroid carcinoma (DTC) includes surgery, risk-adapted postoperative radioiodine therapy (RaIT), individualized thyroid hormone therapy, and follow-up for detection of patients with persistent or recurrent disease. In 2019, the nine Martinique Principles for managing thyroid cancer were developed by the American Thyroid Association, European Association of Nuclear Medicine, Society of Nuclear Medicine and Molecular Imaging, and European Thyroid Association. In this review, we present our clinical practice recommendations with regard to implementing these principles in the diagnosis, treatment, and long-term follow-up of patients with DTC. Methods A multidisciplinary panel of five thyroid cancer experts addressed the implementation of the Martinique Principles in routine clinical practice based on clinical experience and evidence from the literature. Results We provide a suggested approach for the assessment and diagnosis of DTC in routine clinical practice, including the use of neck ultrasound, measurement of serum thyroid-stimulating hormone and calcitonin, fine-needle aspiration, cytology, and molecular imaging. Recommendations for the use of surgery (lobectomy vs. total thyroidectomy) and postoperative RaIT are also provided. Long-term follow-up with neck ultrasound and measurement of serum anti-thyroglobulin antibody and basal/stimulated thyroglobulin is standard, with 123/131I radioiodine diagnostic whole-body scans and 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography suggested in selected patients. Management of metastatic DTC should involve a multidisciplinary team. Conclusions In routine clinical practice, the Martinique Principles should be implemented in order to optimize clinical management/outcomes of patients with DTC.

scholarly journals Whole Body Vibration Exercises and the Improvement of the Flexibility in Patient with Metabolic Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Danúbia da Cunha Sá-Caputo ◽  
Pedro Ronikeili-Costa ◽  
Rafaelle Pacheco Carvalho-Lima ◽  
Luciana Camargo Bernardo ◽  
Milena Oliveira Bravo-Monteiro ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Muscle Power ◽  
Whole Body Vibration ◽  
Whole Body ◽  
Mineral Density ◽  
Level Of Evidence ◽  
Body Vibration ◽  
Pubmed Database ◽  
Number Of Publications

Vibrations produced in oscillating/vibratory platform generate whole body vibration (WBV) exercises, which are important in sports, as well as in treating diseases, promoting rehabilitation, and improving the quality of life. WBV exercises relevantly increase the muscle strength, muscle power, and the bone mineral density, as well as improving the postural control, the balance, and the gait. An important number of publications are found in the PubMed database with the keyword “flexibility” and eight of the analyzed papers involving WBV and flexibility reached a level of evidence II. The biggest distance between the third finger of the hand to the floor (DBTFF) of a patient with metabolic syndrome (MS) was found before the first session and was considered to be 100%. The percentages to the other measurements in the different sessions were determined to be related to the 100%. It is possible to see an immediate improvement after each session with a decrease of the %DBTFF. As the presence of MS is associated with poorer physical performance, a simple and safe protocol using WBV exercises promoted an improvement of the flexibility in a patient with MS.

scholarly journals Hepatic Glucocorticoid Receptor Plays a Greater Role Than Adipose GR in Metabolic Syndrome Despite Renal Compensation

Endocrinology ◽  
2016 ◽  
Vol 157 (12) ◽  
pp. 4943-4960 ◽  
Author(s):  
Sandip K. Bose ◽  
Irina Hutson ◽  
Charles A. Harris
Keyword(s):  
Metabolic Syndrome ◽  
Glucocorticoid Receptor ◽  
Mrna Expression ◽  
Kidney Tissue ◽  
Glycogen Metabolism ◽  
Whole Body ◽  
Pcr Analysis ◽  
Compensatory Mechanism ◽  
Key Genes ◽  
Specific Deletion

Exogenous glucocorticoid administration results in hyperglycemia, insulin resistance, hepatic dyslipidemia, and hypertension, a constellation of findings known as Cushing’s syndrome. These effects are mediated by the glucocorticoid receptor (GR). Because GR activation in liver and adipose has been implicated in metabolic syndrome (MS), we wanted to determine the role of GR in these tissues in the development of MS. Because GR knockout (KO) mice (whole-body KO) exhibit perinatal lethality due to respiratory failure, we generated tissue-specific (liver or adipose) GRKO mice using cre-lox technology. Real-time PCR analysis of liver mRNA from dexamethasone-treated wildtype (WT) and liver GRKO mice indicated that hepatic GR regulates the expression of key genes involved in gluconeogenesis and glycogen metabolism. Interestingly, we have observed that liver-specific deletion of GR resulted in a significant increase in mRNA expression of key genes involved in gluconeogenesis and glycogen metabolism in kidney tissue, indicating a compensatory mechanism to maintain glucose homeostasis. We have also observed that GR plays an important role in regulating the mRNA expression of key genes involved in lipid metabolism. Liver GRKO mice demonstrated decreased fat mass and liver glycogen content compared with WT mice administered dexamethasone for 2 weeks. Adipose-specific deletion of GR did not alter glucose tolerance or insulin sensitivity of adipose GRKO mice compared with WT mice administrated dexamethasone. This indicates that liver GR might be more important in development of MS in dexamethasone-treated mice, whereas adipose GR plays a little role in these paradigms.

Abstract 5509: Arginase Activity Mediates Vascular Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ruth B Caldwell ◽  
Wenbo Zhang ◽  
Babak Baban ◽  
Modesto Rojas ◽  
Suvika Virmani ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Leukocyte Adhesion ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Vascular Endothelial Cell ◽  
Heart Association ◽  
Arginase Activity ◽  
Vascular Endothelial ◽  
Oxide Synthase ◽  
Arginase I

We have shown before that activity of NOX2 NADPH oxidase has a critical role in causing vascular inflammation. We have also shown that diabetes-induced vascular endothelial cell (EC) dysfunction is mediated by increases in arginase activity which decreases availability of L-arginine to EC nitric oxide synthase (eNOS). While the specific role of arginase activity in vascular inflammation is not yet clear, increases in arginase I levels have been described in conditions of elevated oxidative stress and inflammation. We have now used a model of endotoxin-induced retinal inflammation to assess the hypothesis that increased arginase activity is involved in the development of vascular inflammation. Mice were injected with lipopolysaccharide (LPS, 4 mg/kg, ip, 3–16 hrs). Measurement of urea formation showed that retinal arginase activity was increased in the LPS-treated mice (1.9±0.3-fold, n=5). Quantitative PCR showed that arginase I (AI) mRNA was also increased with a peak at 12 hrs (2.2±0.1-fold, n=3). Expression of the AII isoform was unchanged. Western blotting, immunohistochemistry and flow cytometry confirmed an increase in AI protein expression, which was localized to vascular cells, glia and microglia. AI expression and arginase activity were also increased in LPS-treated glia and microglia. The LPS-induced increases in AI expression were correlated with increases in mRNA for MCP-1 (575.1±84.8-fold, n=5), TNF-alpha (55.6±10.3-fold, n=4) and iNOS (103.3±1.5-fold, n=3) and with increased leukocyte adhesion to the vessel wall (5.5±1.5 fold, n=3–5). Studies using knockout mice deficient in one copy of the AI gene and both copies of AII or mice treated with the selective arginase inhibitor ([S]-[2-boronoethyl]-L-cysteine-HCl, 20 mg/kg, iv) showed that LPS-induced increases in inflammatory gene expression and leukostasis were blocked by knocking down or inhibiting arginase. Furthermore, the LPS-induced increase in AI was abrogated by NOX2 deletion or apocynin treatment, indicating involvement of NADPH oxidase activity. In conclusion, LPS-induced vascular inflammation is mediated by NADPH oxidase-dependent increases in arginase activity. This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).

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