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1.
J Am Soc Nephrol ; 34(7): 1159-1165, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37094382

RESUMEN

BACKGROUND: In most CKDs, lysyl oxidase oxidation of collagen forms allysine side chains, which then form stable crosslinks. We hypothesized that MRI with the allysine-targeted probe Gd-oxyamine (OA) could be used to measure this process and noninvasively detect renal fibrosis. METHODS: Two mouse models were used: hereditary nephritis in Col4a3-deficient mice (Alport model) and a glomerulonephritis model, nephrotoxic nephritis (NTN). MRI measured the difference in kidney relaxation rate, ΔR1, after intravenous Gd-OA administration. Renal tissue was collected for biochemical and histological analysis. RESULTS: ΔR1 was increased in the renal cortex of NTN mice and in both the cortex and the medulla of Alport mice. Ex vivo tissue analyses showed increased collagen and Gd-OA levels in fibrotic renal tissues and a high correlation between tissue collagen and ΔR1. CONCLUSIONS: Magnetic resonance imaging using Gd-OA is potentially a valuable tool for detecting and staging renal fibrogenesis.


Asunto(s)
Riñón , Nefritis Hereditaria , Ratones , Animales , Riñón/diagnóstico por imagen , Riñón/patología , Nefritis Hereditaria/patología , Fibrosis , Imagen por Resonancia Magnética/métodos , Modelos Animales de Enfermedad
2.
JCI Insight ; 7(13)2022 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-35801591

RESUMEN

Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients, for which chemopreventive strategies are lacking. Recently, we developed a simple human cell-based system modeling a clinical prognostic liver signature (PLS) predicting liver disease progression and HCC risk. In a previous study, we applied our cell-based system for drug discovery and identified captopril, an approved angiotensin converting enzyme (ACE) inhibitor, as a candidate compound for HCC chemoprevention. Here, we explored ACE as a therapeutic target for HCC chemoprevention. Captopril reduced liver fibrosis and effectively prevented liver disease progression toward HCC development in a diethylnitrosamine (DEN) rat cirrhosis model and a diet-based rat model for nonalcoholic steatohepatitis-induced (NASH-induced) hepatocarcinogenesis. RNA-Seq analysis of cirrhotic rat liver tissues uncovered that captopril suppressed the expression of pathways mediating fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Mechanistic data in liver disease models uncovered a cross-activation of the EGFR pathway by angiotensin. Corroborating the clinical translatability of the approach, captopril significantly reversed the HCC high-risk status of the PLS in liver tissues of patients with advanced fibrosis. Captopril effectively prevents fibrotic liver disease progression toward HCC development in preclinical models and is a generic and safe candidate drug for HCC chemoprevention.


Asunto(s)
Captopril , Carcinoma Hepatocelular , Neoplasias Hepáticas , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Captopril/farmacología , Captopril/uso terapéutico , Carcinogénesis , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/prevención & control , Quimioprevención , Progresión de la Enfermedad , Receptores ErbB/metabolismo , Cirrosis Hepática/prevención & control , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/prevención & control , Peptidil-Dipeptidasa A/metabolismo , Ratas , Activación Transcripcional
3.
Gut ; 70(1): 157-169, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32217639

RESUMEN

OBJECTIVE: Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention. DESIGN: Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention. RESULTS: In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients. CONCLUSION: Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.


Asunto(s)
Carcinoma Hepatocelular/prevención & control , Epigénesis Genética , Hepatitis C Crónica/complicaciones , Neoplasias Hepáticas/prevención & control , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Animales , Carcinoma Hepatocelular/etiología , Modelos Animales de Enfermedad , Hepatitis C Crónica/genética , Hepatitis C Crónica/patología , Humanos , Neoplasias Hepáticas/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología
4.
Invest Radiol ; 56(4): 244-251, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33109919

RESUMEN

METHODS: Three groups of mice that develop either mild type 2 inflammation and fibrosis (wild type), severe fibrosis with exacerbated type 2 inflammation (Il10-/-Il12b-/-Il13ra2-/-), or minimal fibrosis with marked type 1 inflammation (Il4ra∂/∂) after infection with S. mansoni were imaged using both probes for determination of signal enhancement. Schistosoma mansoni-infected wild-type mice developed chronic liver fibrosis. RESULTS: The liver MR signal enhancement after either probe administration was significantly higher in S. mansoni-infected wild-type mice compared with naive animals. The S. mansoni-infected Il4ra∂/∂ mice presented with little liver signal enhancement after probe injection despite the presence of substantial inflammation. Schistosoma mansoni-infected Il10-/-Il12b-/-Il13ra2-/- mice presented with marked fibrosis, which correlated to increased signal enhancement after injection of either probe. CONCLUSIONS: Both MR probes, EP-3533 and Gd-Hyd, were specific for fibrosis in this model of chronic liver disease regardless of the presence or severity of the underlying inflammation. These results, in addition to previous findings, show the potential application of both molecular MR probes for detection and quantification of fibrosis from various etiologies.


Asunto(s)
Esquistosomiasis mansoni , Animales , Inflamación/diagnóstico por imagen , Hígado/diagnóstico por imagen , Hígado/patología , Cirrosis Hepática/diagnóstico por imagen , Imagen por Resonancia Magnética , Ratones , Schistosoma mansoni , Esquistosomiasis mansoni/diagnóstico por imagen , Esquistosomiasis mansoni/patología
5.
Clin Cancer Res ; 26(18): 5007-5018, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32611647

RESUMEN

PURPOSE: To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC. EXPERIMENTAL DESIGN: Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101. RESULTS: In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS P = 0.028, DFS P = 0.047). CPA increased the prognostic accuracy of a multivariable logistic regression model comprised of previously established PDAC risk factors [AUC CPA (-) = 0.76, AUC CPA (+) = 0.82]. In multiple murine orthotopic PDAC models, FOLFIRINOX therapy reduced tumor weight (P < 0.05) and increased tumor fibrosis by collagen staining (P < 0.05). CM-101 MR signal was significantly increased in fibrotic tumor regions. CM-101 signal retention was also increased in the more fibrotic FOLFIRINOX-treated tumors compared with untreated controls (P = 0.027), consistent with selective probe binding to collagen. No treatment-related differences were observed with Gd-DOTA imaging. CONCLUSIONS: In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.


Asunto(s)
Carcinoma Ductal Pancreático/terapia , Quimioradioterapia Adyuvante , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/epidemiología , Páncreas/patología , Neoplasias Pancreáticas/terapia , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Colágeno/análisis , Colágeno/metabolismo , Supervivencia sin Enfermedad , Femenino , Fibrosis , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Compuestos Heterocíclicos/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Persona de Mediana Edad , Imagen Molecular/métodos , Sondas Moleculares/administración & dosificación , Recurrencia Local de Neoplasia/prevención & control , Compuestos Organometálicos/administración & dosificación , Oxaliplatino/administración & dosificación , Páncreas/diagnóstico por imagen , Páncreas/cirugía , Pancreatectomía , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Radiology ; 296(1): 67-75, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32343209

RESUMEN

Background Liver biopsy is the reference standard to diagnose nonalcoholic steatohepatitis (NASH) but is invasive with potential complications. Purpose To evaluate molecular MRI with type 1 collagen-specific probe EP-3533 and allysine-targeted fibrogenesis probe Gd-Hyd, MR elastography, and native T1 to characterize fibrosis and to assess treatment response in a rat model of NASH. Materials and Methods MRI was performed prospectively (June-November 2018) in six groups of male Wistar rats (a) age- and (b) weight-matched animals received standard chow (n = 12 per group); (c) received choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) for 6 weeks or (d) 9 weeks (n = 8 per group); (e) were fed 6 weeks of CDAHFD and switched to standard chow for 3 weeks (n = 12); (f) were fed CDAHFD for 9 weeks with daily treatment of elafibranor beginning at week 6 (n = 14). Differences in imaging measurements and tissue analyses among groups were tested with one-way analysis of variance. The ability of each imaging measurement to stage fibrosis was quantified by using area under the receiver operating characteristic curve (AUC) with quantitative digital pathology (collagen proportionate area [CPA]) as reference standard. Optimal cutoff values for distinguishing advanced fibrosis were used to assess treatment response. Results AUC for distinguishing fibrotic (CPA >4.8%) from nonfibrotic (CPA ≤4.8%) livers was 0.95 (95% confidence interval [CI]: 0.91, 1.00) for EP-3533, followed by native T1, Gd-Hyd, and MR elastography with AUCs of 0.90 (95% CI: 0.83, 0.98), 0.84 (95% CI: 0.74, 0.95), and 0.65 (95% CI: 0.51, 0.79), respectively. AUCs for discriminating advanced fibrosis (CPA >10.3%) were 0.86 (95% CI: 0.76, 0.97), 0.96 (95% CI: 0.90, 1.01), 0.84 (95% CI: 0.70, 0.98), and 0.74 (95% CI: 0.63, 0.86) for EP-3533, Gd-Hyd, MR elastography, and native T1, respectively. Gd-Hyd MRI had the highest accuracy (24 of 26, 92%; 95% CI: 75%, 99%) in identifying responders and nonresponders in the treated groups compared with MR elastography (23 of 26, 88%; 95% CI: 70%, 98%), EP-3533 (20 of 26, 77%; 95% CI: 56%, 91%), and native T1 (14 of 26, 54%; 95% CI: 33%, 73%). Conclusion Collagen-targeted molecular MRI most accurately detected early onset of fibrosis, whereas the fibrogenesis probe Gd-Hyd proved most accurate for detecting treatment response. © RSNA, 2020 Online supplemental material is available for this article.


Asunto(s)
Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/terapia , Imagen por Resonancia Magnética/métodos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/terapia , Animales , Chalconas/uso terapéutico , Dieta/métodos , Modelos Animales de Enfermedad , Hígado/diagnóstico por imagen , Cirrosis Hepática/etiología , Masculino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Propionatos/uso terapéutico , Estudios Prospectivos , Ratas , Ratas Wistar
7.
FASEB J ; 33(6): 7103-7112, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30884252

RESUMEN

Farnesoid X receptor (FXR) is a nuclear receptor that has emerged as a key regulator in the maintenance of hepatic steatosis, inflammation, and fibrosis. However, the role of FXR in renal fibrosis remains to be established. Here, we investigate the effects of the FXR agonist EDP-305 in a mouse model of tubulointerstitial fibrosis via unilateral ureteral obstruction (UUO). Male C57Bl/6 mice received a UUO on their left kidney. On postoperative d 4, mice received daily treatment by oral gavage with either vehicle control (0.5% methylcellulose) or 10 or 30 mg/kg EDP-305. All animals were euthanized on postoperative d 12. EDP-305 dose-dependently decreased macrophage infiltration as measured by the F4/80 staining area and proinflammatory cytokine gene expression. EDP-305 also dose-dependently reduced interstitial fibrosis as assessed by morphometric quantification of the collagen proportional area and kidney hydroxyproline levels. Finally, yes-associated protein (YAP) activation, a major driver of fibrosis, increased after UUO injury and was diminished by EDP-305 treatment. Consistently, EDP-305 decreased TGF-ß1-induced YAP nuclear localization in human kidney 2 cells by increasing inhibitory YAP phosphorylation. YAP inhibition may be a novel antifibrotic mechanism of FXR agonism, and EDP-305 could be used to treat renal fibrosis.-Li, S., Ghoshal, S., Sojoodi, M., Arora, G., Masia, R., Erstad, D. J., Ferriera, D. S., Li, Y., Wang, G., Lanuti, M., Caravan, P., Or, Y. S., Jiang, L.-J., Tanabe, K. K., Fuchs, B. C. The farnesoid X receptor agonist EDP-305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction.


Asunto(s)
Fibrosis/etiología , Fibrosis/prevención & control , Enfermedades Renales/etiología , Enfermedades Renales/prevención & control , Receptores Citoplasmáticos y Nucleares/agonistas , Esteroides/farmacología , Obstrucción Ureteral/complicaciones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Esteroides/uso terapéutico , Proteínas Señalizadoras YAP
8.
J Gastrointest Surg ; 23(1): 101-111, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30367397

RESUMEN

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide due to the lack of effective treatments. Chemoprevention in high-risk patients is a promising, alternative strategy. In this study, pioglitazone was investigated for its ability to prevent hepatocarcinogenesis in two rodent models of cirrhosis. METHODS: In the first model, male Wistar rats were given repeated, low-dose injections of diethylnitrosamine (DEN) to accurately recapitulate the progression of fibrosis to cirrhosis and HCC. In the second model, a single dose of DEN was administered to male C57Bl/6 pups at day fifteen followed by administration of a choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) at week six for 24 weeks. Pioglitazone treatment started at the first signs of fibrosis in both models. RESULTS: Pioglitazone effectively reduced fibrosis progression and HCC development in both models. Gross tumor nodules were significantly reduced after pioglitazone treatment (7.4 ± 1.6 vs. 16.6 ± 2.6 in the rat DEN model and 5.86 ± 1.82 vs. 13.2 ± 1.25 in the mouse DEN+CDAHFD model). In both models, pioglitazone reduced the activation of mitogen-activated protein kinase (MAPK) and upregulated the hepato-protective AMP-activated protein kinase (AMPK) pathway via increasing circulating adiponectin production. CONCLUSION: Pioglitazone is an effective agent for chemoprevention in rodents and could be repurposed as a multi-targeted drug for delaying liver fibrosis and hepatocarcinogenesis.


Asunto(s)
Carcinoma Hepatocelular/prevención & control , Hipoglucemiantes/uso terapéutico , Neoplasias Hepáticas/prevención & control , Pioglitazona/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/sangre , Animales , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Colina/administración & dosificación , Dieta Alta en Grasa , Dietilnitrosamina , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos
9.
Radiology ; 287(2): 581-589, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29156148

RESUMEN

Purpose To evaluate the biodistribution, metabolism, and pharmacokinetics of a new type I collagen-targeted magnetic resonance (MR) probe, CM-101, and to assess its ability to help quantify liver fibrosis in animal models. Materials and Methods Biodistribution, pharmacokinetics, and stability of CM-101 in rats were measured with mass spectrometry. Bile duct-ligated (BDL) and sham-treated rats were imaged 19 days after the procedure by using a 1.5-T clinical MR imaging unit. Mice were treated with carbon tetrachloride (CCl4) or with vehicle two times a week for 10 weeks and were imaged with a 7.0-T preclinical MR imaging unit at baseline and 1 week after the last CCl4 treatment. Animals were imaged before and after injection of 10 µmol/kg CM-101. Change in contrast-to-noise ratio (ΔCNR) between liver and muscle tissue after CM-101 injection was used to quantify liver fibrosis. Liver tissue was analyzed for Sirius Red staining and hydroxyproline content. The institutional subcommittee for research animal care approved all in vivo procedures. Results CM-101 demonstrated rapid blood clearance (half-life = 6.8 minutes ± 2.4) and predominately renal elimination in rats. Biodistribution showed low tissue gadolinium levels at 24 hours (<3.9% injected dose [ID]/g ± 0.6) and 10-fold lower levels at 14 days (<0.33% ID/g ± 12) after CM-101 injection with negligible accumulation in bone (0.07% ID/g ± 0.02 and 0.010% ID/g ± 0.004 at 1 and 14 days, respectively). ΔCNR was significantly (P < .001) higher in BDL rats (13.6 ± 3.2) than in sham-treated rats (5.7 ± 4.2) and in the CCl4-treated mice (18.3 ± 6.5) compared with baseline values (5.2 ± 1.0). Conclusion CM-101 demonstrated fast blood clearance and whole-body elimination, negligible accumulation of gadolinium in bone or tissue, and robust detection of fibrosis in rat BDL and mouse CCl4 models of liver fibrosis. © RSNA, 2017 Online supplemental material is available for this article.


Asunto(s)
Fibrosis/patología , Gadolinio/farmacocinética , Cirrosis Hepática/diagnóstico por imagen , Hígado/patología , Imagen por Resonancia Magnética , Polisacáridos Bacterianos/farmacocinética , Animales , Tetracloruro de Carbono/farmacocinética , Modelos Animales de Enfermedad , Fibrosis/diagnóstico por imagen , Semivida , Hígado/diagnóstico por imagen , Espectrometría de Masas , Ratones , Ratas , Distribución Tisular
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