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1.
Magn Reson Med ; 2024 May 31.
Article in English | MEDLINE | ID: mdl-38818538

ABSTRACT

PURPOSE: To employ optimal control for the numerical design of Chemical Exchange Saturation Transfer (CEST) saturation pulses to maximize contrast and stability against B 0 $$ {\mathrm{B}}_0 $$ inhomogeneities. THEORY AND METHODS: We applied an optimal control framework for the design pulse shapes for CEST saturation pulse trains. The cost functional minimized both the pulse energy and the discrepancy between the corresponding CEST spectrum and the target spectrum based on a continuous radiofrequency (RF) pulse. The optimization is subject to hardware limitations. In measurements on a 7 T preclinical scanner, the optimal control pulses were compared to continuous-wave and Gaussian saturation methods. We conducted a comparison of the optimal control pulses with Gaussian, block pulse trains, and adiabatic spin-lock pulses. RESULTS: The optimal control pulse train demonstrated saturation levels comparable to continuous-wave saturation and surpassed Gaussian saturation by up to 50 % in phantom measurements. In phantom measurements at 3 T the optimized pulses not only showcased the highest CEST contrast, but also the highest stability against field inhomogeneities. In contrast, block pulse saturation resulted in severe artifacts. Dynamic Bloch-McConnell simulations were employed to identify the source of these artifacts, and underscore the B 0 $$ {\mathrm{B}}_0 $$ robustness of the optimized pulses. CONCLUSION: In this work, it was shown that a substantial improvement in pulsed saturation CEST imaging can be achieved by using Optimal Control design principles. It is possible to overcome the sensitivity of saturation to B0 inhomogeneities while achieving CEST contrast close to continuous wave saturation.

2.
NMR Biomed ; : e5151, 2024 Apr 07.
Article in English | MEDLINE | ID: mdl-38583871

ABSTRACT

Magnetization transfer spectroscopy relies heavily on the robust determination of T 1 $$ {T}_1 $$ relaxation times of nuclei participating in metabolic exchange. Challenges arise due to the use of surface RF coils for transmission (high B 1 + $$ {B}_1^{+} $$ variation) and the broad resonance band of most X nuclei. These challenges are particularly pronounced when fast T 1 $$ {T}_1 $$ mapping methods, such as the dual-angle method, are employed. Consequently, in this work, we develop resonance offset and B 1 + $$ {B}_1^{+} $$ robust excitation RF pulses for 31P magnetization transfer spectroscopy at 7T through ensemble-based time-optimal control. In our approach, we introduce a cost functional for designing robust pulses, incorporating the full Bloch equations as constraints, which are solved using symmetric operator splitting techniques. The optimal control design of the RF pulses developed demonstrates improved accuracy, desired phase properties, and reduced RF power when applied to dual-angle T 1 $$ {T}_1 $$ mapping, thereby improving the precision of exchange-rate measurements, as demonstrated in a preclinical in vivo study quantifying brain creatine kinase activity.

3.
J Biol Chem ; 299(6): 104788, 2023 06.
Article in English | MEDLINE | ID: mdl-37150323

ABSTRACT

Cardiac triacylglycerol accumulation is a common characteristic of obesity and type 2 diabetes and strongly correlates with heart morbidity and mortality. We have previously shown that cardiomyocyte-specific perilipin 5 overexpression (Plin5-Tg) provokes significant cardiac steatosis via lowering cardiac lipolysis and fatty acid (FA) oxidation. In strong contrast to cardiac steatosis and lethal heart dysfunction in adipose triglyceride lipase deficiency, Plin5-Tg mice do not develop heart dysfunction and show a normal life span on chow diet. This finding prompted us to study heart function and energy metabolism in Plin5-Tg mice fed high-fat diet (HFD). Plin5-Tg mice showed adverse cardiac remodeling on HFD with heart function only being compromised in one-year-old mice, likely due to reduced cardiac FA uptake, thereby delaying deleterious cardiac lipotoxicity. Notably, Plin5-Tg mice were less obese and protected from glucose intolerance on HFD. Changes in cardiac energy catabolism in Plin5-Tg mice increased ß-adrenergic signaling, lipolytic, and thermogenic protein expression in adipose tissue ultimately counteracting HFD-induced obesity. Acute cold exposure further augmented ß-adrenergic signaling in Plin5-Tg mice, whereas housing at thermoneutrality did not protect Plin5-Tg mice from HFD-induced obesity albeit blood glucose and insulin levels remained low in transgenic mice. Overall, our data suggest that the limited capacity for myocardial FA oxidation on HFD increases cardiac stress in Plin5-Tg mice, thereby stimulating adipose tissue ß-adrenergic signaling, triacylglycerol catabolism, and thermogenesis. However, long-term HFD-mediated metabolic stress causes contractile dysfunction in Plin5-Tg mice, which emphasizes the importance of a carefully controlled dietary regime in patients with cardiac steatosis and hypertrophy.


Subject(s)
Adipose Tissue , Heart Diseases , Lipolysis , Obesity , Receptors, Adrenergic , Ventricular Remodeling , Animals , Mice , Adipose Tissue/metabolism , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Mice, Transgenic , Myocytes, Cardiac/metabolism , Obesity/etiology , Obesity/metabolism , Triglycerides/metabolism , Perilipin-5/metabolism , Fatty Acids/metabolism , Heart Diseases/etiology , Heart Diseases/metabolism , Receptors, Adrenergic/metabolism
4.
J Cachexia Sarcopenia Muscle ; 14(1): 93-107, 2023 02.
Article in English | MEDLINE | ID: mdl-36351437

ABSTRACT

BACKGROUND: Cancer-associated cachexia (CAC) is a wasting syndrome drastically reducing efficacy of chemotherapy and life expectancy of patients. CAC affects up to 80% of cancer patients, yet the mechanisms underlying the disease are not well understood and no approved disease-specific medication exists. As a multiorgan disorder, CAC can only be studied on an organismal level. To cover the diverse aetiologies of CAC, researchers rely on the availability of a multifaceted pool of cancer models with varying degrees of cachexia symptoms. So far, no tumour model syngeneic to C57BL/6 mice exists that allows direct comparison between cachexigenic- and non-cachexigenic tumours. METHODS: MCA207 and CHX207 fibrosarcoma cells were intramuscularly implanted into male or female, 10-11-week-old C57BL/6J mice. Tumour tissues were subjected to magnetic resonance imaging, immunohistochemical-, and transcriptomic analysis. Mice were analysed for tumour growth, body weight and -composition, food- and water intake, locomotor activity, O2 consumption, CO2 production, circulating blood cells, metabolites, and tumourkines. Mice were sacrificed with same tumour weights in all groups. Adipose tissues were examined using high-resolution respirometry, lipolysis measurements in vitro and ex vivo, and radioactive tracer studies in vivo. Gene expression was determined in adipose- and muscle tissues by quantitative PCR and Western blotting analyses. Muscles and cultured myotubes were analysed histologically and by immunofluorescence microscopy for myofibre cross sectional area and myofibre diameter, respectively. Interleukin-6 (Il-6) was deleted from cancer cells using CRISPR/Cas9 mediated gene editing. RESULTS: CHX207, but not MCA207-tumour-bearing mice exhibited major clinical features of CAC, including systemic inflammation, increased plasma IL-6 concentrations (190 pg/mL, P ≤ 0.0001), increased energy expenditure (+28%, P ≤ 0.01), adipose tissue loss (-47%, P ≤ 0.0001), skeletal muscle wasting (-18%, P ≤ 0.001), and body weight reduction (-13%, P ≤ 0.01) 13 days after cancer cell inoculation. Adipose tissue loss resulted from reduced lipid uptake and -synthesis combined with increased lipolysis but was not associated with elevated beta-adrenergic signalling or adipose tissue browning. Muscle atrophy was evident by reduced myofibre cross sectional area (-21.8%, P ≤ 0.001), increased catabolic- and reduced anabolic signalling. Deletion of IL-6 from CHX207 cancer cells completely protected CHX207IL6KO -tumour-bearing mice from CAC. CONCLUSIONS: In this study, we present CHX207 fibrosarcoma cells as a novel tool to investigate the mediators and metabolic consequences of CAC in C57BL/6 mice in comparison to non-cachectic MCA207-tumour-bearing mice. IL-6 represents an essential trigger for CAC development in CHX207-tumour-bearing mice.


Subject(s)
Cachexia , Interleukin-6 , Neoplasms , Animals , Female , Male , Mice , Adipose Tissue/pathology , Cachexia/pathology , Fibrosarcoma/complications , Interleukin-6/metabolism , Mice, Inbred C57BL , Muscle Fibers, Skeletal/metabolism , Muscular Atrophy/pathology , Neoplasms/complications
5.
Biomed Pharmacother ; 154: 113640, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36081286

ABSTRACT

Atherosclerosis, the leading cause of cardiovascular disease responsible for the majority of deaths worldwide, cannot be sufficiently explained by established risk factors, including hypercholesterolemia. Elevated plasma homocysteine is an independent risk factor for atherosclerosis and is strongly linked to cardiovascular mortality. However, the role of homocysteine in atherosclerosis is still insufficiently understood. Previous research in this area has been also hampered by the lack of reproducible in vivo models of atherosclerosis that resemble the human situation. Here, we have developed and applied an automated system for vessel wall injury that leads to more homogenous damage and more pronounced atherosclerotic plaque development, even at low balloon pressure. Our automated system helped to glean vital details of cholesterol-independent changes in the aortic wall of balloon-injured rabbits. We show that deficiency of B vitamins, which are required for homocysteine degradation, leads to atherogenic transformation of the aorta resulting in accumulation of macrophages and lipids, impairment of its biomechanical properties and disorganization of aortic collagen/elastin in the absence of hypercholesterolemia. A combination of B vitamin deficiency and hypercholesterolemia leads to thickening of the aorta, decreased aortic water diffusion, increased LDL-cholesterol and impaired vascular reactivity compared to any single condition. Our findings suggest that deficiency of B vitamins leads to atherogenic transformation of the aorta even in the absence of hypercholesterolemia and aggravates atherosclerosis development in its presence.


Subject(s)
Atherosclerosis , Hypercholesterolemia , Hyperlipidemias , Vitamin B Complex , Animals , Aorta/metabolism , Atherosclerosis/metabolism , Cholesterol , Diet, Atherogenic , Homocysteine/metabolism , Humans , Hypercholesterolemia/metabolism , Hyperlipidemias/metabolism , Rabbits
6.
Cardiovasc Res ; 116(2): 339-352, 2020 02 01.
Article in English | MEDLINE | ID: mdl-31166588

ABSTRACT

AIMS: Lipotoxic cardiomyopathy in diabetic and obese patients typically encompasses increased cardiac fatty acid (FA) uptake eventually surpassing the mitochondrial oxidative capacity. Lowering FA utilization via inhibition of lipolysis represents a strategy to counteract the development of lipotoxic heart dysfunction. However, defective cardiac triacylglycerol (TAG) catabolism and FA oxidation in humans (and mice) carrying mutated ATGL alleles provokes lipotoxic heart dysfunction questioning a therapeutic approach to decrease cardiac lipolysis. Interestingly, decreased lipolysis via cardiac overexpression of Perilipin 5 (Plin5), a binding partner of ATGL, is compatible with normal heart function and lifespan despite massive cardiac lipid accumulation. Herein, we decipher mechanisms that protect Plin5 transgenic mice from the development of heart dysfunction. METHODS AND RESULTS: We generated mice with cardiac-specific overexpression of Plin5 encoding a serine-155 to alanine exchange (Plin5-S155A) of the protein kinase A phosphorylation site, which has been suggested as a prerequisite to stimulate lipolysis and may play a crucial role in the preservation of heart function. Plin5-S155A mice showed a substantial increase in cardiac TAG and ceramide levels, which was comparable to mice overexpressing non-mutated Plin5. Lipid accumulation was compatible with normal heart function even under mild stress. Plin5-S155A mice showed reduced cardiac FA oxidation but normal ATP production and changes in the Plin5-S155A phosphoproteome compared to Plin5 transgenic mice. Interestingly, mitochondrial recruitment of dynamin-related protein 1 (Drp1) was markedly reduced in cardiac muscle of Plin5-S155A and Plin5 transgenic mice accompanied by decreased phosphorylation of mitochondrial fission factor, a mitochondrial receptor of Drp1. CONCLUSIONS: This study suggests that low cardiac lipolysis is associated with reduced mitochondrial fission and may represent a strategy to combat the development of lipotoxic heart dysfunction.


Subject(s)
Adipose Tissue/metabolism , Heart Diseases/prevention & control , Intracellular Signaling Peptides and Proteins/metabolism , Lipolysis , Mitochondria, Heart/metabolism , Mitochondrial Dynamics , Muscle Proteins/metabolism , Myocytes, Cardiac/metabolism , Adenosine Triphosphate/metabolism , Adipose Tissue/pathology , Animals , COS Cells , Ceramides/metabolism , Chlorocebus aethiops , Disease Models, Animal , Dynamins/metabolism , Fatty Acids/metabolism , Heart Diseases/genetics , Heart Diseases/metabolism , Heart Diseases/physiopathology , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/metabolism , Mice, Mutant Strains , Mitochondria, Heart/pathology , Mitochondrial Proteins/metabolism , Muscle Proteins/genetics , Mutation , Myocytes, Cardiac/pathology , Oxidation-Reduction , Phosphorylation , Rats , Signal Transduction , Triglycerides/metabolism
7.
Transl Oncol ; 12(2): 256-268, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30439626

ABSTRACT

BACKGROUND & AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termed Mallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: We analyzed livers of aged Krt18-/- mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18-/- mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18-/- mice with 26 human hepatoma cell lines and with data sets of >300 patients with HCC, where Krt18-/- gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC.

8.
Cell Metab ; 26(5): 753-763.e7, 2017 Nov 07.
Article in English | MEDLINE | ID: mdl-28988821

ABSTRACT

Fatty acids (FAs) activate and fuel UCP1-mediated non-shivering thermogenesis (NST) in brown adipose tissue (BAT). Release of FAs from intracellular fat stores by adipose triglyceride lipase (ATGL) is considered a key step in NST. Accordingly, the severe cold intolerance of global ATGL knockout (AKO) mice has been attributed to defective BAT lipolysis. Here we show that this conclusion is incorrect. We demonstrate that although the BAT-specific loss of ATGL impairs BAT lipolysis and alters BAT morphology, it does not compromise the ß3-adrenergic thermogenic response or cold-induced NST. Instead, NST depends on nutrient supply or lipolysis in white adipose tissue during fasting, suggesting that circulating energy substrates are sufficient to fuel NST. Cold intolerance in AKO mice is not caused by BAT dysfunction as previously suspected but by severe cardiomyopathy. We conclude that functional NST requires adequate substrate supply and cardiac function, but does not depend on ATGL-mediated lipolysis in BAT.


Subject(s)
Adipose Tissue, Brown/metabolism , Cold Temperature , Lipase/physiology , Lipolysis/physiology , Myocardium/metabolism , Thermogenesis/physiology , Adipose Tissue, White/metabolism , Animals , Eating , Electrocardiography , Fasting , Lipase/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Uncoupling Protein 1/genetics , Uncoupling Protein 1/metabolism
10.
MAGMA ; 30(5): 417-427, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28361185

ABSTRACT

OBJECTIVES: Bone bridge formation occurs after physeal lesions and can lead to growth arrest if not reversed. Previous investigations on the underlying mechanisms of this formation used histological methods. Therefore, this study aimed to apply a minimally invasive method using dynamic contrast-enhanced MRI (DCE-MRI). MATERIALS AND METHODS: Changes in functional parameters related to the microvessel system were assessed in a longitudinal study of a cohort of an animal model applying a reference region model. The development of morphology of the injured physis was investigated with 3D high-resolution MRI. To acquire complementary information for MRI-related findings qRT-PCR and immunohistochemical data were acquired for a second cohort of the animal model. RESULTS: The evaluation of the pharmacokinetic parameters showed a first rise of the transfer coefficient 7 days post-lesion and a maximum 42 days after operation. The analysis of the complementary data showed a connection of the first rise to microvessel proliferation while the maximum value was linked to bone remodeling. CONCLUSION: The pharmacokinetic analysis of DCE-MRI provides information on a proliferation of microvessels during the healing process as a sign for bone bridge formation. Thereby, DCE-MRI could identify details, which up to now required analyses of highly invasive methods.


Subject(s)
Growth Plate/blood supply , Growth Plate/diagnostic imaging , Magnetic Resonance Imaging/methods , Microvessels/diagnostic imaging , Microvessels/growth & development , Animals , Collagen Type IV/metabolism , Contrast Media , Gadolinium , Growth Plate/metabolism , Imaging, Three-Dimensional , Immunohistochemistry , Longitudinal Studies , Male , Microvessels/metabolism , Organometallic Compounds , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction
11.
Oncotarget ; 8(20): 33122-33136, 2017 May 16.
Article in English | MEDLINE | ID: mdl-28380440

ABSTRACT

Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (-/-) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)-/- mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.


Subject(s)
Apolipoproteins E/genetics , Asialoglycoproteins/genetics , Atherosclerosis/metabolism , Cholesterol/metabolism , Dyslipidemias/metabolism , Lectins, C-Type/genetics , Liver/metabolism , Membrane Proteins/genetics , Alcohol Oxidoreductases/metabolism , Animals , Arachidonic Acids/metabolism , Asialoglycoproteins/deficiency , Disease Models, Animal , Endocannabinoids/metabolism , Gene Knockout Techniques , Glycerides/metabolism , Intestinal Mucosa/metabolism , Lectins, C-Type/deficiency , Male , Membrane Proteins/deficiency , Mice
12.
Nat Commun ; 8: 14859, 2017 03 22.
Article in English | MEDLINE | ID: mdl-28327588

ABSTRACT

Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders.


Subject(s)
Adipose Tissue, White/enzymology , Fatty Liver/drug therapy , Fatty Liver/enzymology , Insulin Resistance , Lipase/antagonists & inhibitors , Animals , Body Weight/drug effects , Diet, High-Fat , Fatty Liver/blood , Fatty Liver/prevention & control , Feeding Behavior , Glucose/metabolism , Homeostasis/drug effects , Humans , Lipase/metabolism , Lipolysis/drug effects , Male , Mice, Inbred C57BL , Obesity/drug therapy , Obesity/enzymology , Obesity/pathology , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use
13.
PLoS One ; 11(11): e0164284, 2016.
Article in English | MEDLINE | ID: mdl-27832068

ABSTRACT

Quantitative magnetic resonance imaging (qMRI) offers several advantages in imaging and determination of soft tissue alterations when compared to qualitative imaging techniques. Although applications in brain and muscle tissues are well studied, its suitability to quantify relaxation times of intact and injured bone tissue, especially in children, is widely unknown. The objective observation of a fracture including its age determination can become of legal interest in cases of child abuse or maltreatment. Therefore, the aim of this study is the determination of time dependent changes in intact and corresponding injured bones in immature rats via qMRI, to provide the basis for an objective and radiation-free approach for fracture dating. Thirty-five MR scans of 7 Sprague-Dawley rats (male, 4 weeks old, 100 ± 5 g) were acquired on a 3T MRI scanner (TimTrio, Siemens AG, Erlangen, Germany) after the surgical infliction of an epiphyseal fracture in the tibia. The images were taken at days 1, 3, 7, 14, 28, 42 and 82 post-surgery. A proton density-weighted and a T1-weighted 3D FLASH sequence were acquired to calculate the longitudinal relaxation time T1 of the fractured region and the surrounding tissues. The calculation of T1 in intact and injured bone resulted in a quantitative observation of bone development in intact juvenile tibiae as well as the bone healing process in the injured tibiae. In both areas, T1 decreased over time. To evaluate the differences in T1 behaviour between the intact and injured bone, the relative T1 values (bone-fracture) were calculated, showing clear detectable alterations of T1 after fracture occurrence. These results indicate that qMRI has a high potential not only for clinically relevant applications to detect growth defects or developmental alterations in juvenile bones, but also for forensically relevant applications such as the dating of fractures in cases of child abuse or maltreatment.


Subject(s)
Fracture Healing , Fractures, Bone/diagnostic imaging , Magnetic Resonance Imaging/methods , Tibia/diagnostic imaging , Tibia/injuries , Animals , Male , Rats, Sprague-Dawley
14.
Diabetologia ; 59(8): 1743-52, 2016 08.
Article in English | MEDLINE | ID: mdl-27153842

ABSTRACT

AIMS/HYPOTHESIS: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s). METHODS: We studied metabolic adaptations in Lal (-/-) mice. RESULTS: Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice. In agreement, fasted Lal (-/-) mice exhibit reduced glucose and glycogen levels in skeletal muscle. We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice. Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes. However, treatment of Lal (-/-) mice with the PPARα agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal (-/-) mice. Depletion of hepatic nuclear factor 4α and forkhead box protein a2 in fasted Lal (-/-) mice might be responsible for reduced expression of microsomal TG transfer protein, defective VLDL synthesis and drastically reduced plasma TG levels. CONCLUSIONS/INTERPRETATION: Our findings indicate that neither activation nor inactivation of PPARα per se but rather the availability of hepatic acyl-CoA concentrations regulates VLDL synthesis and subsequent metabolic adaptations in Lal (-/-) mice. We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply.


Subject(s)
Cholesterol, VLDL/metabolism , Insulin Resistance/physiology , Sterol Esterase/metabolism , Animals , Cholesterol, VLDL/genetics , Female , Glucose/metabolism , Insulin Resistance/genetics , Lipolysis/genetics , Lipolysis/physiology , Liver/metabolism , Lysosomes/metabolism , Male , Mice , Sterol Esterase/deficiency , Sterol Esterase/genetics , Triglycerides/metabolism
15.
NMR Biomed ; 28(1): 79-88, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25379657

ABSTRACT

This article describes a new acquisition and reconstruction concept for positive contrast imaging of cells labeled with superparamagnetic iron oxides (SPIOs). Overcoming the limitations of a negative contrast representation as gained with gradient echo and fully balanced steady state (bSSFP), the proposed method delivers a spatially localized contrast with high cellular sensitivity not accomplished by other positive contrast methods. Employing a 3D radial bSSFP pulse sequence with half-echo sampling, positive cellular contrast is gained by adding artificial global frequency offsets to each half-echo before image reconstruction. The new contrast regime is highlighted with numerical intravoxel simulations including the point-spread function for 3D half-echo acquisitions. Furthermore, the new method is validated on the basis of in vitro cell phantom measurements on a clinical MRI platform, where the measured contrast-to-noise ratio (CNR) of the new approach exceeds even the negative contrast of bSSFP. Finally, an in vivo proof of principle study based on a mouse model with a clear depiction of labeled cells within a subcutaneous cell islet containing a cell density as low as 7 cells/mm(3) is presented. The resultant isotropic images show robustness to motion and a high CNR, in addition to an enhanced specificity due to the positive contrast of SPIO-labeled cells.


Subject(s)
Contrast Media , Dextrans/metabolism , Imaging, Three-Dimensional , Magnetic Resonance Imaging/methods , Staining and Labeling , Animals , Computer Simulation , Humans , Injections, Subcutaneous , Magnetite Nanoparticles , Mice , Phantoms, Imaging , Signal Processing, Computer-Assisted
17.
Chem Commun (Camb) ; 48(93): 11398-400, 2012 Dec 04.
Article in English | MEDLINE | ID: mdl-23066527

ABSTRACT

Core-shell hydrophilic superparamagnetic iron oxide (SPIO) nanoparticles, surface functionalized with either terephthalic acid or 2-amino terephthalic acid, showed large negative MRI contrast ability, validating the advantage of using low molecular weight and π-conjugated canopies for engineering functional nanostructures with superior performances.


Subject(s)
Contrast Media/chemistry , Drug Design , Ferric Compounds/chemistry , Magnetic Resonance Imaging/methods , Magnets/chemistry , Animals , Contrast Media/toxicity , Ferric Compounds/toxicity , Magnets/toxicity , Mice , NIH 3T3 Cells , Surface Properties
18.
Int J Nanomedicine ; 7: 2349-59, 2012.
Article in English | MEDLINE | ID: mdl-22661890

ABSTRACT

BACKGROUND: Magnetic liposomes (MLs) are phospholipid vesicles that encapsulate magnetic and/or paramagnetic nanoparticles. They are applied as contrast agents for magnetic resonance imaging (MRI). MLs have an advantage over free magnetic nanocores, in that various functional groups can be attached to the surface of liposomes for ligand-specific targeting. We have synthesized PEG-coated sterically-stabilized magnetic liposomes (sMLs) containing ultrasmall superparamagnetic iron oxides (USPIOs) with the aim of generating stable liposomal carriers equipped with a high payload of USPIOs for enhanced MRI contrast. METHODS: Regarding iron oxide nanoparticles, we have applied two different commercially available surface-coated USPIOs; sMLs synthesized and loaded with USPIOs were compared in terms of magnetization and colloidal stability. The average diameter size, morphology, phospholipid membrane fluidity, and the iron content of the sMLs were determined by dynamic light scattering (DLS), transmission electron microscopy (TEM), fluorescence polarization, and absorption spectroscopy, respectively. A colorimetric assay using potassium thiocyanate (KSCN) was performed to evaluate the encapsulation efficiency (EE%) to express the amount of iron enclosed into a liposome. Subsequently, MRI measurements were carried out in vitro in agarose gel phantoms to evaluate the signal enhancement on T1- and T2-weighted sequences of sMLs. To monitor the biodistribution and the clearance of the particles over time in vivo, sMLs were injected in wild type mice. RESULTS: DLS revealed a mean particle diameter of sMLs in the range between 100 and 200 nm, as confirmed by TEM. An effective iron oxide loading was achieved just for one type of USPIO, with an EE% between 74% and 92%, depending on the initial Fe concentration (being higher for lower amounts of Fe). MRI measurements demonstrated the applicability of these nanostructures as MRI probes. CONCLUSION: Our results show that the development of sMLs is strictly dependent on the physicochemical characteristics of the nanocores. Once established, sMLs can be further modified to enable noninvasive targeted molecular imaging.


Subject(s)
Contrast Media/chemistry , Liposomes/chemistry , Magnetic Resonance Imaging/instrumentation , Magnetite Nanoparticles/chemistry , Animals , Colorimetry , Contrast Media/pharmacokinetics , Female , Fluorescence Polarization , Liposomes/pharmacokinetics , Magnetic Resonance Imaging/methods , Magnetite Nanoparticles/analysis , Male , Mice , Particle Size , Phantoms, Imaging , Tissue Distribution
19.
Science ; 333(6039): 233-8, 2011 Jul 08.
Article in English | MEDLINE | ID: mdl-21680814

ABSTRACT

Cachexia is a multifactorial wasting syndrome most common in patients with cancer that is characterized by the uncontrolled loss of adipose and muscle mass. We show that the inhibition of lipolysis through genetic ablation of adipose triglyceride lipase (Atgl) or hormone-sensitive lipase (Hsl) ameliorates certain features of cancer-associated cachexia (CAC). In wild-type C57BL/6 mice, the injection of Lewis lung carcinoma or B16 melanoma cells causes tumor growth, loss of white adipose tissue (WAT), and a marked reduction of gastrocnemius muscle. In contrast, Atgl-deficient mice with tumors resisted increased WAT lipolysis, myocyte apoptosis, and proteasomal muscle degradation and maintained normal adipose and gastrocnemius muscle mass. Hsl-deficient mice with tumors were also protected although to a lesser degree. Thus, functional lipolysis is essential in the pathogenesis of CAC. Pharmacological inhibition of metabolic lipases may help prevent cachexia.


Subject(s)
Adipose Tissue, White/enzymology , Cachexia/enzymology , Lipase/metabolism , Lipolysis , Neoplasms, Experimental/enzymology , Neoplasms/enzymology , Sterol Esterase/metabolism , Adipose Tissue, White/pathology , Animals , Blood Glucose/metabolism , Body Mass Index , Body Weight , Cachexia/etiology , Cachexia/pathology , Cytokines/blood , Fatty Acids/blood , Glycerol/metabolism , Humans , Lipase/deficiency , Lipase/genetics , Melanoma, Experimental , Mice , Mice, Inbred C57BL , Muscle, Skeletal/pathology , Myocardium/pathology , Neoplasms/complications , Neoplasms/pathology , Neoplasms, Experimental/complications , Neoplasms, Experimental/pathology , Peptides/metabolism , Sterol Esterase/deficiency , Sterol Esterase/genetics , Triglycerides/blood , Weight Loss
20.
MAGMA ; 24(1): 43-50, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21213016

ABSTRACT

OBJECTIVE: Variable density random sampling patterns have recently become increasingly popular for accelerated imaging strategies, as they lead to incoherent aliasing artifacts. However, the design of these sampling patterns is still an open problem. Current strategies use model assumptions like polynomials of different order to generate a probability density function that is then used to generate the sampling pattern. This approach relies on the optimization of design parameters which is very time consuming and therefore impractical for daily clinical use. MATERIALS AND METHODS: This work presents a new approach that generates sampling patterns by making use of power spectra of existing reference data sets and hence requires neither parameter tuning nor an a priori mathematical model of the density of sampling points. RESULTS: The approach is validated with downsampling experiments, as well as with accelerated in vivo measurements. The proposed approach is compared with established sampling patterns, and the generalization potential is tested by using a range of reference images. Quantitative evaluation is performed for the downsampling experiments using RMS differences to the original, fully sampled data set. CONCLUSION: Our results demonstrate that the image quality of the method presented in this paper is comparable to that of an established model-based strategy when optimization of the model parameter is carried out and yields superior results to non-optimized model parameters. However, no random sampling pattern showed superior performance when compared to conventional Cartesian subsampling for the considered reconstruction strategy.


Subject(s)
Image Interpretation, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Pattern Recognition, Automated/methods , Data Interpretation, Statistical , Humans , Magnetic Resonance Imaging/instrumentation , Probability , Reference Values , Reproducibility of Results , Sensitivity and Specificity
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