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Extracellular vesicles (EVs), especially from stem/stromal cells (SCs), represent a cell-free alternative in regenerative medicine holding promises to promote tissue healing while providing safety and logistic advantages in comparison to cellular counterparts. Herein, we hypothesize that SC EVs, administered locally in a thermoresponsive gel, is a therapeutic strategy for managing post-surgical colo-cutaneous fistulas. This disease is a neglected and challenging condition associated to low remission rates and high refractoriness. Herein, EVs from a murine SC line were produced by a high-yield scalable method in bioreactors. The post-surgical intestinal fistula model was induced via a surgical cecostomy communicating the cecum and the skin in Wistar rats. Animals were treated just after cecostomy with PBS, thermoresponsive Pluronic F-127 hydrogel alone or containing SC EVs. A PET-monitored biodistribution investigation of SC EVs labelled with 89Zr was performed. Fistula external orifice and output assessment, probe-based confocal laser endomicroscopy, MRI and histology were carried out for therapy follow-up. The relevance of percutaneous EV administration embedded in the hydrogel vehicle was indicated by the PET-biodistribution study. Local administration of SC EVs in the hydrogel reduced colo-cutaneous fistula diameter, output, fibrosis and inflammation while increasing the density of neo-vessels when compared to the PBS and gel groups. This multi-modal investigation pointed-out the therapeutic potential of SC EVs administered locally and in a thermoresponsive hydrogel for the management of challenging post-surgical colon fistulas in a minimally-invasive cell-free strategy.

An early and persistent sign of Alzheimer’s disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Cannabidiol has demonstrated neuroprotective and anti-inflammatory properties but has not been evaluated by PET imaging in an AD model. Intracerebroventricular (icv) injection of streptozotocin (STZ) is a validated model for hypometabolism observed in AD. This proof-of-concept study evaluated the effect of cannabidiol treatment in the brain glucose metabolism of an icv-STZ AD model by PET imaging. Wistar male rats received 3 mg/kg of STZ and [18F]FDG PET images were acquired before and 7 days after STZ injection. Animals were treated with intraperitoneal cannabidiol (20 mg/kg—STZ–cannabidiol) or saline (STZ–saline) for one week. Novel object recognition was performed to evaluate short-term and long-term memory. [18F]FDG uptake in the whole brain was significantly lower in the STZ–saline group. Voxel-based analysis revealed a hypometabolism cluster close to the lateral ventricle, which was smaller in STZ–cannabidiol animals. The brain regions with more evident hypometabolism were the striatum, motor cortex, hippocampus, and thalamus, which was not observed in STZ–cannabidiol animals. In addition, STZ–cannabidiol animals revealed no changes in memory index. Thus, this study suggests that cannabidiol could be an early treatment for the neurodegenerative process observed in AD.

Multiple sclerosis (MS) is a neuroinflammatory disease with expanding axonal and neuronal degeneration and demyelination in the central nervous system, leading to motor dysfunctions, psychical disability, and cognitive impairment during MS progression. Positron emission tomography (PET) is an imaging technique able to quantify in vivo cellular and molecular alterations. Radiotracers with affinity to intact myelin can be used for in vivo imaging of myelin content changes over time. It is possible to detect either an increase or decrease in myelin content, what means this imaging technique can detect demyelination and remyelination processes of the central nervous system. In this protocol we demonstrate how to use PET imaging to detect myelin changes in the lysolecithin rat model, which is a model of focal demyelination lesion (induced by stereotactic injection) (i.e., a model of multiple sclerosis disease).

Background Obesity, characterized by excessive expansion of white adipose tissue (WAT), is associated with numerous metabolic complications. Conversely, brown adipose tissue (BAT) and beige fat are thermogenic tissues that protect mice against obesity and related metabolic disorders. We recently reported that deletion of miR-22 enhances energy expenditure and attenuates WAT expansion in response to a high-fat diet (HFD). However, the molecular mechanisms involved in these effects mediated by miR-22 loss are unclear. Methods and Results Here, we show that miR-22 expression is induced during white, beige, and brown adipocyte differentiation in vitro. Deletion of miR-22 reduced white adipocyte differentiation in vitro. Loss of miR-22 prevented HFD-induced expression of adipogenic/lipogenic markers and adipocyte hypertrophy in murine WAT. In addition, deletion of miR-22 protected mice against HFD-induced mitochondrial dysfunction in WAT and BAT. Loss of miR-22 induced WAT browning. Gain- and loss-of-function studies revealed that miR-22 did not affect brown adipogenesis in vitro. Interestingly, miR-22 KO mice fed a HFD displayed increased expression of genes involved in thermogenesis and adrenergic signaling in BAT when compared to WT mice fed the same diet. Conclusions Collectively, our findings suggest that loss of miR-22 attenuates fat accumulation in response to a HFD by reducing white adipocyte differentiation and increasing BAT activity, reinforcing miR-22 as a potential therapeutic target for obesity-related disorders.

Stem cell (SC) therapy is a promising approach to improve post-myocardial infarction (MI) cardiac remodeling, but the proinflammatory microenvironment may lead to SC loss and, therefore, may have a negative impact on therapy. It appears that exercise training (ET) improves myocardial microenvironment for SC transplantation. Therefore, we tested the effect of ET on post-infarction retention of adipose-derived SCs (ADSCs) and its combined effects on the inflammatory microenvironment. Fischer-344 female rats were randomized to one of the following groups: Sham; sedentary coronary occlusion who did not receive ADSCs (sMI); sedentary coronary occlusion who received ADSCs; exercise coronary occlusion who received ADSCs. Rats were trained nine weeks prior to MI, followed by ADSCs transplantation. The MI led to left ventricle (LV) dilation and dysfunction, myocardial hypertrophy and fibrosis, and increased proinflammatory profile compared to Sham rats. Conversely, ADSCs transplanted rats exhibited, better morphological and functional LV parameters; inhibition of myocardial hypertrophy and fibrosis; and attenuation of proinflammatory cytokines (interleukins 1β and 10, tumor necrosis factor α, and transforming growth factor β) in the myocardium compared to sMI rats. Interestingly, ET enhanced the effect of ADSCs on interleukin 10 expression. There was a correlation between cytokine expression and myocardial ADSCs retention. The. ET enhanced the beneficial effects of ADSCs in infarcted myocardium, which was associated with higher ADSCs retention. These findings highlight the importance of ET in myocardial retention of ADSCs and attenuation of cardiac remodeling post-infarction. Cytokine analysis suggests improvement in ET-linked myocardial microenvironment based on its anti-inflammatory action.

Magnetic hyperthermia (MHT) has been shown as a promising alternative therapy for glioblastoma (GBM) treatment. This study consists of three parts: The first part evaluates the heating potential of aminosilane-coated superparamagnetic iron oxide nanoparticles (SPIONa). The second and third parts comprise the evaluation of MHT multiple applications in GBM model, either in vitro or in vivo. The obtained heating curves of SPIONa (100 nm, +20 mV) and their specific absorption rates (SAR) stablished the best therapeutic conditions for frequencies (309 kHz and 557 kHz) and magnetic field (300 Gauss), which were stablished based on three in vitro MHT application in C6 GBM cell line. The bioluminescence (BLI) signal decayed in all applications and parameters tested and 309 kHz with 300 Gauss have shown to provide the best therapeutic effect. These parameters were also established for three MHT applications in vivo, in which the decay of BLI signal correlates with reduced tumor and also with decreased tumor glucose uptake assessed by positron emission tomography (PET) images. The behavior assessment showed a slight improvement after each MHT therapy, but after three applications the motor function displayed a relevant and progressive improvement until the latest evaluation. Thus, MHT multiple applications allowed an almost total regression of the GBM tumor in vivo. However, futher evaluations after the therapy acute phase are necessary to follow the evolution or tumor total regression. BLI, positron emission tomography (PET), and spontaneous locomotion evaluation techniques were effective in longitudinally monitoring the therapeutic effects of the MHT technique.

Objective We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia. Methods We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats. Results Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to age-matched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity. Conclusions These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia., Highlights • Exercise training prolongs lifespan, reduces oxidative stress, and improves skeletal muscle function in tumor-bearing rats. • Muscle COP9 signalosome complex subunit 2 (COPS2) protein is downregulated in cancer cachexia. • Exercise training restores COPS2 protein expression to control levels. • Cancer-conditioned media decreased F-actin expression in myotubes, which is partially restored by COPS2 knockdown. • COPS2 overexpression decreases DR4 activity and COPS2 knockdown inhibits cancer-conditioned media effects on DR4 activity.

Fingolimod was the first oral drug approved for multiple sclerosis treatment. Its principal mechanism of action is blocking of lymphocyte trafficking. In addition, recent studies have shown its capability to diminish microglia activation. The effect of preventive and curative fingolimod treatment on the time-course of neuroinflammation was investigated in the experimental autoimmune encephalomyelitis rat model for multiple sclerosis. Neuroinflammatory progression was followed in Dark Agouti female rats after immunization. Positron-Emission tomography (PET) imaging with (R)-[11C]PK11195 was performed on day 11, 15, 19, 27, 29 and 34 during normal disease progression, preventive and curative treatments with fingolimod (1 mg/kg/day). Additionally, bodyweight and clinical symptoms were determined. Preventive treatment diminished bodyweight loss and inhibited the appearance of neurological symptoms. In non-treated rats, PET showed that neuroinflammation peaked in the brainstem at day 19, whereas the imaging signal was decreased in cortical regions. Both preventive and curative treatment reduced neuroinflammation in the brainstem at day 19. Eight days after treatment withdrawal, neuroinflammation had flared-up, especially in cortical regions. Preventive treatment with fingolimod suppressed clinical symptoms and neuroinflammation in the brainstem. After treatment withdrawal, clinical symptoms reappeared together with neuroinflammation in cortical regions, suggesting a different pathway of disease progression. Electronic supplementary material The online version of this article (doi:10.1007/s11481-017-9741-x) contains supplementary material, which is available to authorized users.

BACKGROUND: Hepatocellular carcinoma (HCC) can be the last step of non-alcoholic fatty liver disease (NAFLD) evolution. Experimental models are crucial to elucidate the pathogenesis of HCC secondary to NAFLD. The 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) plays an important role in evaluating HCC development and progression. OBJECTIVE: To standardize the imaging method of PET/CT with 18F-FDG as an evaluation tool of the experimental model of HCC secondary to NAFLD. METHODS: Ten male Sprague-Dawley rats were fed with choline-deficient high-fat diet and diethylnitrosamine (DEN) in the drinking water for 16 weeks and then received 1 mL of saline solution (0.9%) daily by gavage for three weeks. At the 16th and 19th weeks, abdominal ultrasonography (USG) was performed. 18F-FDG PET/CT images were obtained before the beginning of experiment (week 0) and at the end (week 19). Histological and immunohistochemically analysis were also performed. RESULTS: The USG results showed a homogeneous group at the 16th week with an average of 4.6±2.74 nodules per animal. At the 19th week, PET/CT findings demonstrated an average of 8.5±3.7 nodules per animal. The mean values of SUVmed and SUVmax were 2.186±0.1698 and 3.8±1.74, respectively. The average number of nodules per animal in the histological analysis was 5.5±1.5. From all nodules, 4.6% were classified as well-differentiated HCC and 81.8% were classified as poorly-differentiated HCC. CONCLUSION: 18F-FDG PET/CT was able to evaluate the development of HCC in an experimental model of NAFLD non-invasively. From the standardization of PET/CT in this model, it is possible to use this tool in future studies to monitor, in vivo and non-invasively, the progression of HCC. RESUMO BACKGROUND: O carcinoma hepatocelular (CHC) pode ser a última fase da doença hepática gordurosa não alcoólica (DHGNA). Modelos experimentais são cruciais para elucidação da patogênese do CHC secundário a DHGNA. A tomografia por emissão de pósitrons/tomografia computadorizada (PET/TC) com 2-desoxi-2-(18F)fluoro-D-glicose (18F-FDG) desempenha um importante papel na avaliação do desenvolvimento e progressão do CHC. OBJETIVO: Padronizar a metodologia de imagem por PET/TC com 18F-FDG como uma ferramenta de avaliação do modelo experimental de CHC secundário a DHGNA. MÉTODOS: Dez ratos Sprague-Dawley machos foram alimentados com dieta hiperlipídica deficiente em colina associada a dietilnitrosamina (DEN) na água de beber por 16 semanas e depois receberam 1 mL de solução salina (0,9%) por gavagem diariamente por três semanas. Nas 16ª e 19ª semanas, foi realizada a ultrassonografia abdominal. As imagens do PET/TC com 18F-FDG foram obtidas antes do início do experimento (semana 0) e no final (semana 19). Análises histológica e imunohistoquímica também foram realizadas. RESULTADOS: Os resultados da ultrassonografia demonstraram um grupo homogêneo na 16ª semana com uma média de 4,6±2,74 nódulos por animal. Na 19ª semana, os achados do PET/CT demonstraram uma média de 8,5±3,7 nódulos por animal. Os valores médios de SUVmed e SUVmáx foram 2,186±0,1698 e 3,8±1,74, respectivamente. A média do número de nódulos na análise histológica foi de 5,5±1,5. De todos os nódulos, 4,6% foram classificados como bem diferenciados e 81,8% foram classificados como CHC pouco diferenciado. CONCLUSÃO: O PET/TC com 18F-FDG foi capaz de avaliar o desenvolvimento do CHC secundário a DHGNA de forma não invasiva. A partir da padronização do PET/CT neste modelo, faz-se possível a utilização desta ferramenta em futuros estudos para monitorar, in vivo e de forma não invasiva, a progressão do CHC.

Evidence suggests that exercise can modulate neuroinflammation and neuronal damage. We evaluated if such effects of exercise can be detected with positron emission tomography (PET) in a rat model of Parkinson’s disease (PD). Rats were unilaterally injected in the striatum with 6-hydroxydopamine (PD rats) or saline (controls) and either remained sedentary (SED) or were forced to exercise three times per week for 40 min (EX). Motor and cognitive functions were evaluated by the open field, novel object recognition, and cylinder tests. At baseline, day 10 and 30, glial activation and dopamine synthesis were assessed by [11C]PBR28 and [18F]FDOPA PET, respectively. PET data were confirmed by immunohistochemical analysis of microglial (Iba-1) / astrocyte (GFAP) activation and tyrosine hydroxylase (TH). [11C]PBR28 PET showed increased glial activation in striatum and hippocampus of PD rats at day 10, which had resolved at day 30. Exercise completely suppressed glial activation. Imaging results correlated well with post-mortem Iba-1 staining, but not with GFAP staining. [18F]FDOPA PET, TH staining and behavioral tests indicate that 6-OHDA caused damage to dopaminergic neurons, which was partially prevented by exercise. These results show that exercise can modulate toxin-induced glial activation and neuronal damage, which can be monitored noninvasively by PET.

Purpose S-[11C]-methyl-L-cysteine ([11C]MCYS) has been claimed to offer higher tumor selectivity than L-[methyl- 11C]methionine ([11C]MET). We examined this claim in animal models. Procedures Rats with implanted untreated (n = 10) or irradiated (n = 7, 1 × 25 Gy, on day 8) orthotopic gliomas were scanned after 6, 9, and 12 days, using positron emission tomography. Rats with striatal injections of saline (n = 9) or bacterial lipopolysaccharide (n = 9) were scanned after 3 days. Results Uptake of the two tracers in untreated gliomas was similar. [11C]MCYS was not accumulated in salivary glands, nasal epithelium, and healing wounds, in contrast to [11C]MET, but showed 40 % higher accumulation in the healthy brain. Both tracers showed a reduced tumor uptake 4 days after irradiation and minor accumulation in inflamed striatum. [11C]MCYS indicated higher lesion volumes than [11C]MET (untreated tumor + 47 %; irradiated tumor up to + 500 %; LPS-inflamed striatum + 240 %). Conclusions [11C]MCYS was less accumulated in some non-tumor tissues than [11C]MET, but showed lower tumor-to-brain contrast. Electronic supplementary material The online version of this article (10.1007/s11307-017-1137-z) contains supplementary material, which is available to authorized users.

PURPOSE: In this study, we compared the ability of [(11)C]CIC, [(11)C]MeDAS and [(11)C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake.METHODS: Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group).RESULTS: The kinetics of [(11)C]CIC, [(11)C]MeDAS and [(11)C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [(11)C]CIC make this tracer less suitable for in vivo PET imaging. [(11)C]PIB showed good uptake in the white matter in the cerebrum, but [(11)C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [(11)C]MeDAS distribution correlated well with myelin density in different brain regions.CONCLUSION: This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [(11)C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [(11)C]CIC and [(11)C]PIB.

Multiple Sclerosis (MS) is a neurodegenerative disease characterized by demyelinated lesions. PET imaging using specific myelin radioligands might solve the lack of a specific imaging tool for diagnosing and monitoring demyelination and remyelination in MS patients. In recent years, a few tracers have been developed for in vivo PET imaging of myelin, but they have not been fully evaluated yet. In this study, we compared [(11)C]CIC and [(11)C]MeDAS as PET tracers for monitoring demyelination and remyelination in cuprizone-fed mice. The ex vivo biodistribution of [(11)C]CIC showed decreased tracer uptake in mice fed with 0.2% cuprizone diet for 5 weeks, as compared to control mice. However, tracer uptake did not increase again after normal diet was restored for 5 weeks (remyelination). Surprisingly, in vivo PET imaging with [(11)C]CIC in cuprizone-fed mice revealed a significant reduction in whole brain tracer uptake after 5 weeks of remyelination. No correlation between ex vivo biodistribution and in vivo imaging data was found for [(11)C]CIC (r(2)=0.15, p=0.11). However, a strong correlation was found for [(11)C]MeDAS (r(2)=0.88, p

Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barre syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.

Gliomas are the most common type among all central nervous system tumors. The aggressiveness of gliomas is correlated with the level of angiogenesis and is often associated with prognosis. The aim of this study is to evaluate the novel GX1 peptide and the heterodimer RGD-GX1 radiolabeled with technetium-99m, for angiogenesis detection in glioma models. Radiolabeling and radiochemical controls were assessed for both radioconjugates. In vitro binding studies in glioma tumor cells were performed, as well as biodistribution in SCID mice bearing tumor cells, in order to evaluate the biological behavior and tumor uptake of the radiocomplexes. Blocking and imaging studies were also conducted. MicroSPECT/CT images were acquired in animals with experimentally implanted intracranial tumor. Open field activity was performed to evaluate behavior, as well as perfusion and histology analysis. The radiochemical purity of both radiotracers was greater than 96 %. In vitro binding studies revealed rather similar binding profi le for each molecule. The highest binding was for RGD-GX1 peptide at 120 min in U87MG cells (1.14 ± 0.35 %). Tumor uptake was also favorable for RGD-GX1 peptide in U87MG cells, reaching 2.96 ± 0.70 % at 1 h p.i. with 47 % of blocking. Imaging studies also indicated better visualization for RGD-GX1 peptide in U87MG cells. Behavior evaluation pointed brain damage and histology studies confirmed actual tumor in the uptake site. The results with the angiogenesis seeking molecule (99m)Tc-HYNIC-E-[c(RGDfk)-c(GX1)] were successful, and better than with (99m)Tc-HYNIC-PEG4-c(GX1). Future studies targeting angiogenesis in other glioma and nonglioma tumor models are recommended.

Circulating dipeptidyl peptidase IV (DPPIV) activity correlates with cardiac dysfunction in humans and experimental heart failure (HF) models. Similarly, inflammatory markers are associated with poorer outcomes in HF patients. However, the contributions of DPPIV to inflammation in HF remain elusive. Therefore, this study aimed to investigate whether the cardioprotective effects of DPPIV inhibition after myocardial injury are accompanied by reduced cardiac inflammation, whether circulating DPPIV activity correlates with the levels of systemic inflammatory markers in HF patients, and whether leukocytes and/or splenocytes may be one of the sources of circulating DPPIV in HF. Experimental HF was induced in male Wistar rats by left ventricular myocardial injury after radiofrequency catheter ablation. The rats were divided into three groups: sham, HF, and HF + DPPIV inhibitor (sitagliptin). Six weeks after surgery, cardiac function, perfusion and inflammatory status were evaluated. Sitagliptin treatment improved cardiac function and perfusion, reduced macrophage infiltration, and diminished the levels of inflammatory biomarkers including TNF-α, IL-1β, and CCL2. In HF patients, serum DPPIV activity correlated with CCL2, suggesting that leukocytes may be the source of circulating DPPIV in HF. Unexpectedly, DPPIV release was higher in splenocytes from HF rats and similar in HF circulating mononuclear cells compared with those from sham, suggesting an organ-specific modulation of DPPIV in HF. Collectively, our data provide new evidence that the cardioprotective effects of DPPIV inhibition in HF may be due to suppression of inflammatory cytokines. Moreover, they suggest that a vicious circle between DPPIV and inflammation may contribute to HF development and progression.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of human malignancies, including prostate cancer. Bombesin (BBN) is a 14 amino acids peptide that selectively binds to GRPR. In this study, we developed two novel Al(18)F-labeled lanthionine-stabilized BBN analogs, designated Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN, for positron emission tomography (PET) imaging of GRPR expression using xenograft prostate cancer models. (Methyl)lanthionine-stabilized 4,7-lanthionine-BBN and 2,6-lanthionine-BBN analogs were conjugated with a NOTA chelator and radiolabeled with Al(18)F using the aluminum fluoride strategy. Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN was labeled with Al(18)F with good radiochemical yield and specific activity>30 GBq/μmol for both radiotracers. The logD values measured for Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN were -2.14 ± 0.14 and -2.34 ± 0.15, respectively. In athymic nude PC-3 xenografts, at 120 min post injection (p.i.), the uptake of Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN in prostate cancer (PC-3) mouse models was 0.82 ± 0.23% ID/g and 1.40 ± 0.81% ID/g, respectively. An excess of unlabeled ɛ-aminocaproic acid-BBN(7-14) (300-fold) was co-injected to assess GRPR binding specificity. Tumor uptake of Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN in PC-3 tumors was evaluated by microPET (μPET) imaging at 30, 60 and 120 min p.i. Blocking studies showed decreased uptake in PC-3 bearing mice. Stabilized 4,7-lanthionine-BBN and 2,6-lanthionine-BBN peptides were rapidly and successfully labeled with (18)F. Both tracers may have potential for GRPR-positive tumor imaging.

Background: Injection of lysolecithin in the central nervous system results in demyelination accompanied by local activation of microglia and recruitment of monocytes. Positron-emission tomography (PET) imaging, using specific tracers, may be an adequate technique to monitor these events in vivo and therefore may become a tool for monitoring disease progression in multiple sclerosis (MS) patients. Objectives: The objective of this paper is to evaluate the potential of PET imaging in monitoring local lesions, using [11C]MeDAS, [11C]PK11195 and [18F]FDG as PET tracers for myelin density, microglia activation and glucose metabolism, respectively. Methods: Sprague-Dawley rats were stereotactically injected with either 1% lysolecithin or saline in the corpus callosum and striatum of the right brain hemisphere. PET imaging was performed three days, one week and four weeks after injection. Animals were terminated after PET imaging and the brains were explanted for (immuno)histochemical analysis. Results: PET imaging was able to detect local demyelination induced by lysolecithin in the corpus callosum and striatum with [11C]MeDAS and concomitant microglia activation and monocyte recruitment with [11C]PK11195. [18F]FDG imaging demonstrated that glucose metabolism was maintained in the demyelinated lesions. Conclusion: PET imaging with multiple tracers allows simultaneous in vivo monitoring of myelin density, neuroinflammation and brain metabolism in small MS-like lesions, indicating its potential to monitor disease progression in MS patients.

The experimental autoimmune encephalomyelitis model is a model of multiple sclerosis that closely mimics the disease characteristics in humans. The main hallmarks of multiple sclerosis are neuroinflammation (microglia activation, monocyte invasion, and T-cell infiltration) and demyelination. PET imaging may be a useful noninvasive technique for monitoring disease progression and drug treatment efficacy in vivo. Methods: Experimental autoimmune encephalomyelitis was induced by myelin-oligodendrocyte glycoprotein immunization in female Dark Agouti rats. Experimental autoimmune encephalomyelitis rats were imaged at baseline and at days 6, 11, 15, and 19 after immunization to monitor monocyte and microglia activation (11C-PK11195) and demyelination ( 11C-MeDAS) during normal disease progression and during treatment with dexamethasone. Results: 11C-PK11195 PET detected activation of microglia and monocytes in the brain stem and spinal cord during disease progression. The uptake of 11C-PK11195 was elevated in dexamethasone-treated animals that had shown mild clinical symptoms that had resolved at the time of imaging. Demyelination was not detected by 11C-MeDAS PET, probably because of the small size of the lesions (average, 0.13 mm). Conclusion: PET imaging of neuroinflammation can be used to monitor disease progression and the consequences of treatment in the experimental autoimmune encephalomyelitis rat model. PET imaging was more sensitive than clinical symptoms for detecting inflammatory changes in the central nervous system. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.Chemicals/CAS: dexamethasone acetate, 1177-87-3