Papers by Juan Carlos Cutrin
Frontiers in Immunology, Nov 21, 2023
Molecular Imaging and Biology, Nov 21, 2012
This study aimed at demonstrating the in vivo potential of Gd(III)-loaded Glucan Particles (Gd-GP... more This study aimed at demonstrating the in vivo potential of Gd(III)-loaded Glucan Particles (Gd-GPs) as MRI positive agents for labeling and tracking phagocytic cells. Procedure: GPs were obtained from Saccharomyces cerevisae and loaded with the water-insoluble complex Gd-DOTAMA(C 18) 2. The uptake kinetics of Gd-GPs by murine macrophages was studied in vitro and the internalization mechanism was assessed by competition assays. In vivo performance of Gd-GPs was tested at 7.05 T on a mouse model of acute liver inflammation. Results: The minimum number of Gd-GPs-labeled J774.A1 macrophages detected in vitro by MRI was ca. 300 cells /μL of agar, which is the lowest number ever reported for cells labeled with a positive T 1 agent. Intravenous injection of macrophages labeled with Gd-GPs in a mouse model of liver inflammation enabled the MRI visualization of the cellular infiltration in the diseased area. Conclusions: Gd-GPs represent a promising platform for tracking macrophages by MRI as a T 1 alternative to the golden standard T 2-based iron oxide particles.
This work was performed to elucidate further the main cellular events underlying the protective e... more This work was performed to elucidate further the main cellular events underlying the protective effect of ischaemic preconditioning in an in vivo rat liver model of 90 min ischaemia followed by 30 min reperfusion. A significant attenuation of the various aspects of post-ischaemic injury, namely necrosis and the levels of hydrogen peroxide and 5-and 15-hydroperoxyeicosatetraenoic acids, was afforded by the prior application of a short cycle of ischaemia/reperfusion (10 þ 10 min) or when rats were previously treated with gadolinium chloride. However, when preconditioning was applied on Kupffer cell-depleted livers, no additional level of ischaemic tolerance was obtained. In terms of cellular pathology, this result could be suggestive of Kupffer cells as the target of the preconditioning phenomenon during the warm ischaemia/reperfusion injury. Accordingly, modulation of Kupffer cell activity was associated with a well-preserved hepatocyte integrity, together with low levels of pro-oxidant generation during reperfusion. As activated Kupffer cells can generate and release potentially toxic substances, their modulation by ischaemic preconditioning could help to provide new surgical and/or pharmacological strategies to protect the liver against reperfusion damage.
Biomedicines
Despite Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) -induced Oxidative Stress (O... more Despite Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) -induced Oxidative Stress (OxS) being well documented in different organs, the molecular pathways underlying placental OxS in late-pregnancy women with SARS-CoV-2 infection are poorly understood. Herein, we performed an observational study to determine whether placentae of women testing positive for SARS-CoV-2 during the third trimester of pregnancy showed redox-related alterations involving Catalase (CAT) and Superoxide Dismutase (SOD) antioxidant enzymes as well as placenta morphological anomalies relative to a cohort of healthy pregnant women. Next, we evaluated if placental redox-related alterations and mitochondria pathological changes were correlated with the presence of maternal symptoms. We observed ultrastructural alterations of placental mitochondria accompanied by increased levels of oxidative stress markers Thiobarbituric Acid Reactive Substances (TBARS) and Hypoxia Inducible Factor-1 α (HIF-1α) in SARS...
Blood, 2021
The leukocyte surface antigen CD37 (TSPAN26), a member of the tetraspanin superfamily, is widely ... more The leukocyte surface antigen CD37 (TSPAN26), a member of the tetraspanin superfamily, is widely expressed on most malignant B cells, making it an actionable target for treatment of patients with chronic lymphocytic leukemia (CLL) and other B-cell non-Hodgkin lymphoma (NHL) indications. Accordingly, αCD37 antibodies have shown promising results in phase 1/2 clinical trials for CLL and NHL. Richter's syndrome (RS) is the transformation of CLL into an aggressive and rapidly fatal lymphoma, typically a diffuse large B cell lymphoma (DLBCL). RS is a challenging disease since very few effective treatment options exist for these patients and the available regimens, mainly based on R-CHOP scheme, show limited efficacy. We recently established patient-derived xenograft (PDX) models from RS patients and have shown that they can be used to test the efficacy of novel drugs and drug combinations 1,2. All available RS-PDX models were characterized by high-levels of CD37 expression, when asse...
BioMed Research International, 2017
Pyridoxamine, a structural analog of vitamin B6 that exerts antiglycative effects, has been propo... more Pyridoxamine, a structural analog of vitamin B6 that exerts antiglycative effects, has been proposed as supplementary approach in patients with initial diabetic nephropathy. However, the molecular mechanism(s) underlying its protective role has been so far slightly examined. C57Bl/6J mice were fed with a standard diet (SD) or a diet enriched in fat and fructose (HD) for 12 weeks. After 3 weeks, two subgroups of SD and HD mice started pyridoxamine supplementation (150 mg/kg/day) in the drinking water. HD fed mice showed increased body weight and impaired glucose tolerance, whereas pyridoxamine administration significantly improved insulin sensitivity, but not body weight, and reduced diet-induced increase in serum creatinine and urine albumin. Kidney morphology of HD fed mice showed strong vacuolar degeneration and loss of tubule brush border, associated with a drastic increase in both advanced glycation end products (AGEs) and AGEs receptor (RAGE). These effects were significantly c...
Neuro-Oncology, 2017
NEURO-ONCOLOGY • JUNE 2017 neutralizing antibody to IL-6 attenuated the microglia-stimulated medu... more NEURO-ONCOLOGY • JUNE 2017 neutralizing antibody to IL-6 attenuated the microglia-stimulated medulloblastoma invasion. This study reveals a mechanism by which medulloblastoma cells exploit microglia (M2-phenotype) for increased invasion. Specifically, medulloblastoma-derived CCL2 acts upon CCR2-bearing tumor associated microglias (TAMs), which produce IL-6 to stimulate medulloblastoma cells, in a CCL2/CCR2/IL-6 loop. We targeted this loop by combining radiation therapy with a 4-1BB (CD-137) monoclonal antibody (mAb), as CD-137 is involved in regulation of immune cell proliferation and survival. We re-educated microglia cells toward a cytotoxic M1-like phenotype and amplified effective anti-tumor immune responses in co-culture models. ELISA spot shows treatment with 50 ng of 4-1BB + 1Gy X-ray radiation converted the microglia from M2 to M1 phenotype via a decrease in CCR2. This treatment induces the M1 phenotype microglia to induce MP-1 cell death. Based on our results, the use of 4-1BB mAb plus radiation may prove to be beneficial for the treatment of medulloblastoma by targeting CCL2/CCR2/IL-6 loop.
Blood, Jan 2, 2015
We recently described morgana as an essential protein able to regulate centrosome duplication and... more We recently described morgana as an essential protein able to regulate centrosome duplication and genomic stability, by inhibiting ROCK. Here we show that morgana (+/-) mice spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome amplification, and cytogenetic abnormalities in the bone marrow (BM). Moreover, we found that morgana is underexpressed in the BM of patients affected by atypical CML, a disorder of poorly understood molecular basis, characterized by nonrecurrent cytogenetic abnormalities. Morgana is also underexpressed in the BM of a portion of patients affected by Philadelphia-positive CML (Ph(+) CML) caused by the BCR-ABL oncogene, and in this condition, morgana underexpression predicts a worse response to imatinib, the standard treatment for Ph(+) CML. Thus, morgana acts as an oncosuppressor with different modalities: (1) Morgana underexpression induces centrosome a...
Research in experimental medicine. Zeitschrift für die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie, 2000
Weanling rats fed a methyl-deficient diet develop acute renal failure, the morphological features... more Weanling rats fed a methyl-deficient diet develop acute renal failure, the morphological features of which vary from focal tubular necrosis to widespread cortical necrosis. We and others have shown that coconut oil, rich in saturated fatty acids, has a renal protective effect in this experimental model. In the experiment we are reporting now, we studied which fatty acid is involved in the protection afforded by coconut oil by feeding five groups of methyl-deficient rats a mixture of corn oil and hydrogenated vegetable oil, C6-C8-C10 fatty acids, C12 fatty acid, C14 fatty acid and C16-C18 fatty acids. Five groups of rats receiving the same diets supplemented with choline chloride were used as controls. The group of methyl-deficient rats fed C14 fatty acid (myristic acid) showed a greater percentage of surviving animals and lower renal damage than the other groups of methyl-deficient rats, indicating that the protective effect of coconut oil found in previous experiments is due to its...
Oxidative Medicine and Cellular Longevity, 2015
Edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, EDV) is a free-radical scavenger reduc... more Edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, EDV) is a free-radical scavenger reduces organ ischemic injury. Here we investigated whether the protective effects of EDV in renal ischemia/reperfusion (I/R) injury may be enhanced by an EDV derivative bearing a nitric oxide- (NO-) donor furoxan moiety (NO-EDV). Male Wistar rats were subjected to renal ischemia (45 minutes), followed by reperfusion (6 hours). Administration of either EDV (1.2–6–30 µmol/kg, i.v.) or NO-EDV (0.3–1.2–6 µmol/kg, i.v.) dose-dependently attenuated markers of renal dysfunction (serum urea and creatinine, creatinine clearance, urine flow, urinary N-acetyl-β-D-glucosaminidase, and neutrophil gelatinase-associated lipocalin/lipocalin-2). NO-EDV exerted protective effects in the dose-range 1.2–6 µmol/kg, while a higher dose (30 µmol/kg) was needed to obtain protection by EDV. Both EDV and NO-EDV modulated tissue markers of oxidative stress and lipid peroxidation. NO-EDV, but not EDV, activated endothe...
New Trends in Hepatology, 1996
Hepatic reperfusion injury in human orthotopic liver transplantation is associated with increased... more Hepatic reperfusion injury in human orthotopic liver transplantation is associated with increased steady state levels of reactive oxygen species. Different hematic parameters of tissue redox balance can be analyzed in adult patients at the beginning of liver transplantation and at different times after reperfusion. A significant increase of oxidative stress parameters, i.e. red cell malonaldehyde and plasma lipoperoxides, is evident soon after reperfusion with respect to basal time and is accompanied by a decrease of plasma vitamin E. This alteration of redox balance is paralelled by a significant increase of cytolysis evaluated in terms of alanine aminotransferase. The presence of a significant correlation between alterations of the redox status and irreversible cell damage after liver reperfusion supports the implication of oxidative reactions in the occurence of ischemia- reperfusion tissue injury following orthotopic liver transplantation.
The American Journal of Gastroenterology, 2001
OBJECTIVE: Although possible implications of nitric oxide in the pathophysiology of liver cirrhos... more OBJECTIVE: Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have been extensively studied, until now few articles have addressed the assessment of nitric oxide production in primary biliary cirrhosis. This study was directed to evaluate circulating nitrosyl-hemoglobin levels as well as neutrophil elastase and soluble adhesion molecule concentrations in this condition, by assuming these parameters as possible markers of either inflammatory response or neutrophil activation. METHODS: Laboratory investigations were performed in 30 patients with primary biliary cirrhosis, in 13 patients with postviral and/or alcoholic cirrhosis, and in a group of eight subjects with chronic hepatitis. RESULTS: Although no difference was detected with respect to chronic hepatitis subjects, higher levels of nitrosyl-hemoglobin adducts were found in primary biliary cirrhosis patients than in postviral or alcoholic cirrhotics and in normal subjects (3.55 Ϯ 1.75 arbitrary units vs 1.95 Ϯ 0.57 and 0.84 Ϯ 0.34, p ϭ 0.0004 and p Ͻ 0.0001, respectively). Similarly, more elevated concentrations of neutrophil elastase (213.7 Ϯ 192.0 g/L vs 51.1 Ϯ 34.3 and 38.0 Ϯ 11.5, p Ͻ 0.0001 and p Ͻ 0.0001, respectively) as well as of soluble forms of intercellular adhesion molecule 1 and endothelial-leukocyte adhesion molecule 1 were shown in primary biliary cirrhosis patients than in subjects with cirrhosis of other etiologies and in controls. CONCLUSIONS: Highly enhanced nitric oxide production in primary biliary cirrhosis could be related to the development of strong inflammation and at least partially to neutrophil activation, thus suggesting a putative role of these cellular mediators in the development of liver damage owing to their ability to synthesize and release a wide variety of important factors, including elastase and nitric oxide.
Transplantation, 2002
Background. Preconditioning protects against both liver and lung damage after hepatic ischemia-re... more Background. Preconditioning protects against both liver and lung damage after hepatic ischemia-reperfusion (I/R). Xanthine and xanthine oxidase (XOD) may contribute to the development of hepatic I/R. Objective. To evaluate whether preconditioning could modulate the injurious effects of xanthine/XOD on the liver and lung after hepatic I/R. Methods. Hepatic I/R or preconditioning previous to I/R was induced in rats. Xanthine and xanthine dehydrogenase/xanthine oxidase (XDH/XOD) in liver and plasma were measured. Hepatic injury and inflammatory response in the lung was evaluated. Results. Preconditioning reduced xanthine accumulation and conversion of XDH to XOD in liver during sustained ischemia. This could reduce the generation of reactive oxygen species (ROS) from XOD, and therefore, attenuate hepatic I/R injury. Inhibition of XOD prevented postischemic ROS generation and hepatic injury. Administration of xanthine and XOD to preconditioned rats led to hepatic MDA and transaminase levels similar to those found after hepatic I/R. Preconditioning, resulting in low circulating levels of xanthine and XOD activity, reduced neutrophil accumulation, oxidative stress, and microvascular disorders seen in lung after hepatic I/R. Inhibition of XOD attenuated the inflammatory damage in lung after hepatic I/R. Administration of xanthine and XOD abolished the benefits of preconditioning on lung damage. Conclusions. Preconditioning, by blocking the xanthine/XOD pathway for ROS generation, would confer protection against the liver and lung injuries induced by hepatic I/R.
Neonatology, 1995
We have studied microsomal phospholipid, cholesterol and protein concentration in rat renal papil... more We have studied microsomal phospholipid, cholesterol and protein concentration in rat renal papilla, medulla and cortex during postnatal development, and the relationship between these membrane biochemical parameters and morphological changes. We also determined DNA concentration in each kidney zone. No changes were observed either in papillary microsomal phospholipids, proteins and cholesterol or in DNA concentration from 10- to 70-day-old rats. Medullary microsomal proteins and cholesterol did not change but a significant increase was observed in the microsomal phospholipid concentration during development; in this case, medullary DNA was significantly lower at 70 than at 10 days. In contrast, all biochemical parameters in renal cortex were significantly higher during development except for DNA concentration which suffered a great decrease. These biochemical findings agree with the morphological changes observed. Our results demonstrate that the developmental pattern is different ...
Molecular Imaging and Biology, 2012
This study aimed at demonstrating the in vivo potential of Gd(III)-loaded Glucan Particles (Gd-GP... more This study aimed at demonstrating the in vivo potential of Gd(III)-loaded Glucan Particles (Gd-GPs) as MRI positive agents for labeling and tracking phagocytic cells. Procedure: GPs were obtained from Saccharomyces cerevisae and loaded with the water-insoluble complex Gd-DOTAMA(C 18) 2. The uptake kinetics of Gd-GPs by murine macrophages was studied in vitro and the internalization mechanism was assessed by competition assays. In vivo performance of Gd-GPs was tested at 7.05 T on a mouse model of acute liver inflammation. Results: The minimum number of Gd-GPs-labeled J774.A1 macrophages detected in vitro by MRI was ca. 300 cells /μL of agar, which is the lowest number ever reported for cells labeled with a positive T 1 agent. Intravenous injection of macrophages labeled with Gd-GPs in a mouse model of liver inflammation enabled the MRI visualization of the cellular infiltration in the diseased area. Conclusions: Gd-GPs represent a promising platform for tracking macrophages by MRI as a T 1 alternative to the golden standard T 2-based iron oxide particles.
Magnetic Resonance in Medicine, 2013
Purpose: A novel method based on the use of Yb-HPDO3A as MRI Para-CEST agent for in vivo pH mappi... more Purpose: A novel method based on the use of Yb-HPDO3A as MRI Para-CEST agent for in vivo pH mapping of the tumor region in a melanoma murine model is reported. This method does not require the knowledge of the concentration of the imaging agent. Methods: C57BL/6-mice were inoculated with B16-F10 cells. CEST-MR images of tumor and bladder were acquired upon the i.v. administration of Yb-HPDO3A (1.2 mmol/Kg). pH was assessed by the use of a ratiometric method. Results: Yb-HPDO3A distributes well in the extracellular space of the tumor allowing the detection of good levels of saturation transfer (ST). It is excreted throughout kidneys and accumulated in the bladder thus yielding a strong CEST signal from urine. By comparing the ST% obtained upon selective irradiation of the two AOH resonances belonging to the two isomeric forms of Yb-HPDO3A, it has been possible to measure the extracellular pH for each voxel (0.22 mm 3). The obtained pH-maps of tumors show a great heterogeneity. Marked differences are associated to tumor staging. Conclusion: The application of Yb-HPDO3A to measure extracellular tumor pH provides a good spatio-temporal resolution and it does not require the prior knowledge of the contrast agent concentration. The herein reported data support the potential clinical translation of Yb-HPDO3A. Magn Reson Med 71:326-332, 2014. V
Liver Transplantation, 2002
Ischemic preconditioning attenuates the oxidant-dependent mechanisms of reperfusion cell damage a... more Ischemic preconditioning attenuates the oxidant-dependent mechanisms of reperfusion cell damage and death in rat liver.
Kidney International, 2000
Contribution of ␥ glutamyl transpeptidase to oxidative damage fully understood. It is accepted th... more Contribution of ␥ glutamyl transpeptidase to oxidative damage fully understood. It is accepted that a loss of membraneof ischemic rat kidney. selective permeability and the collapse of the ionic gradi-Background. A variety of mechanisms have been considered ents through cell membrane, as well as the abnormal in the pathogenesis of the cell damage occurring in the kidney activation of phospholipases and proteases caused by that is undergoing transient ischemia. However, little informaimpaired calcium homeostasis induced by adenosine 5Јtion is available about the role of oxidative stress in building up the tissue injury in the hypoxic organ during short-term triphosphate (ATP) depletion, play the main roles in the ischemia. genesis of the biochemical and morphological alterations Methods. After a standard brief period (25 min) of unilateral observed in the proximal tubules during prolonged renal kidney ischemia in rats, pretreated or not with acivicin (60 ischemia [1-9]. However, because these changes do not mol/L/kg i.v.), tissue samples from both ischemic and not ischemic kidneys were obtained to measure malondialdehyde account for the whole cell damage, other pathogenetic (MDA) and glutathione (GSH) content, ␥ glutamyl transpeptiprocesses must contribute. Despite the very low oxygen dase (GGT) activity by spectrophotometry, localization and
International Journal of Cardiology, 1992
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Papers by Juan Carlos Cutrin