RESUMEN
This study investigates the cardioprotective effects of Paeoniflorin (PF) on left ventricular remodeling following acute myocardial infarction (AMI) under conditions of hypobaric hypoxia. Left ventricular remodeling post-AMI plays a pivotal role in exacerbating heart failure, especially at high altitudes. Using a rat model of AMI, the study aimed to evaluate the cardioprotective potential of PF under hypobaric hypoxia. Ninety male rats were divided into four groups: sham-operated controls under normoxia/hypobaria, an AMI model group, and a PF treatment group. PF was administered for 4 weeks after AMI induction. Left ventricular function was assessed using cardiac magnetic resonance imaging. Biochemical assays of cuproptosis, oxidative stress, apoptosis, inflammation, and fibrosis were performed. Results demonstrated PF significantly improved left ventricular function and remodeling after AMI under hypobaric hypoxia. Mechanistically, PF decreased FDX1/DLAT expression and serum copper while increasing pyruvate. It also attenuated apoptosis, inflammation, and fibrosis by modulating Bcl-2, Bax, NLRP3, and oxidative stress markers. Thus, PF exhibits therapeutic potential for left ventricular remodeling post-AMI at high altitude by inhibiting cuproptosis, inflammation, apoptosis and fibrosis. Further studies are warranted to optimize dosage and duration and elucidate PF's mechanisms of action.
Asunto(s)
Glucósidos , Hipoxia , Monoterpenos , Infarto del Miocardio , Estrés Oxidativo , Ratas Sprague-Dawley , Remodelación Ventricular , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Remodelación Ventricular/efectos de los fármacos , Masculino , Ratas , Monoterpenos/farmacología , Monoterpenos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Hipoxia/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Vitamin D deficiency induced by diabetes mellitus is tightly associated with neurodegenerative diseases, but the mechanism is still unknown. Endoplasmic reticulum stress (ER stress) is involved in hippocampal lesion and promote diabetic neuropathy, so we focus on the effects of 1, 25-dihydroxy vitamin D3 on ER stress in hippocampus of diabetic rats. Streptozotocin (STZ)-induced diabetic rats were administrated with different doses of vitamin D and divided into 3 groups: high, low, and blank, compared to wild-type rats which were received the same treatment. At the end of 12 weeks of treatment, the brains of the rats were analyzed by proton magnetic resonance spectroscopy (1H-MRS). Rats were then weighed, tested for blood glucose, serum Ca, P, and vitamin D3, and sacrificed for histopathological analysis of the hippocampus. Neuronal nitric oxide synthase (nNOS) and vitamin D receptor (VDR) expression were measured, as well as ER stress markers, including glucose-regulated protein78 (GRP78), protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation, eukaryotic initiation factor 2α(eIF-2α) phosphorylation, and CCAAT enhancer-binding protein homologous protein (CHOP). Our study showed that treated with appropriate concentration of active vitamin D could decrease the number of pathological pyramidal neurons, improve hippocampal nerve metabolism, and reduce the over-expression of nNOS, along with the relieved activation of ER stress in hippocampus of diabetic rats. These results suggest that 1,25-dihydroxy vitamin D3 treatment can ameliorate hyperglycemia-induced damage on hippocampal metabolism, possibly through alleviating the aberrant activation of ER stress.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Suplementos Dietéticos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Vitamina D/farmacología , Animales , Hipocampo/lesiones , Masculino , Ratas , Ratas Sprague-Dawley , Vitamina D/administración & dosificaciónRESUMEN
The blood-brain barrier (BBB) protects the central nervous system from external insults by limiting substance diffusion through the endothelial interface. The presence of the BBB makes drug delivery in neurological disorders very challenging. Cisplatin has been shown to be cytotoxic to glioma cells, but substantial limitations exist in its clinical applications due to difficulties in penetration across the BBB. Here, we show that L-borneol, a messenger drug widely used in traditional Chinese medicine, can induce transient disruption of the BBB after 20 min of oral administration. The permeability of the BBB began to recover within 1 h of the administration of L-borneol. Different dosages of L-borneol (100, 150, 300, 600, and 900 mg/kg) could induce significant Evans blue leakage (P<0.05). Oral administration of L-borneol elevated cisplatin concentrations in peritumoral tissue (1.24±0.12 µg/g) and tumor loci (1.41±0.13 µg/g), compared with those in the paraffin control (0.88±0.10 and 0.92±0.15 µg/g, respectively) (P<0.05). Furthermore, we found that the median survival period of tumor-bearing mice was significantly higher in the cisplatin plus L-borneol group (24.0±4.9 days) than in the cisplatin plus vehicle group (19.3±3.9 days) (P<0.05). The neurological deficits were more severe in the vehicle and cisplatin plus vehicle groups at 14 and 21 days after implantation of intracranial glioma cells than in the cisplatin plus L-borneol group. In conclusion, our results indicate that the transient opening of the BBB induced by L-borneol could enhance cisplatin accumulation within the glioma tissue and improve the survival of tumor-bearing mice.
Asunto(s)
Antineoplásicos/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Canfanos/farmacología , Cisplatino/uso terapéutico , Glioma/tratamiento farmacológico , Animales , Barrera Hematoencefálica/fisiología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/diagnóstico por imagen , Canfanos/uso terapéutico , Permeabilidad Capilar/efectos de los fármacos , Claudina-5/metabolismo , Medios de Contraste/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glioma/complicaciones , Glioma/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/etiología , Ocludina/metabolismo , Platino (Metal)/farmacocinéticaRESUMEN
BACKGROUND: Primary brainstem hemorrhage (BSH) has the highest mortality and morbidity as a subtype of intracerebral hemorrhage. A major limitation of BSH research is the lack of a corresponding animal model. The purpose of this study was to establish a novel rat model of BSH and to characterize the resulting brain injury, especially focusing on white matter injury. METHODS: BSH was produced by stereotactically injecting autologous whole blood into the pons. Time course of hematoma resolution was observed by 7-T magnetic resonance imaging. White matter injury was evaluated in detail by multiple parameters including diffuse tensor imaging (DTI), demyelination, axonal injury, oligodendrocyte degeneration, and oligodendrocyte precursor cell proliferation. Brain water content and neurobehavior were also evaluated. RESULTS: Blood infusion (30 µL) led to a stable, reproducible hematoma in the right basotegmental pons. The hematoma absorption started, became obvious, and was nearly completed at 7, 14, and 30 days, respectively. Hematoma caused obvious brain edema at 3 days. White mater injury was observed pathologically, which was in line with decreased fractional anisotropy (FA) in DTI in the pons. FA reduction was also noticed in the cerebral peduncle and medulla. Behavioral abnormality persisted for at least 14 days and neurofunction was recovered within 1 month. CONCLUSIONS: This novel model can produce a stable hematoma resulting in brain edema, white matter injury, and neurofunctional deficits, which could be useful for future investigation of pathophysiological mechanisms and new treatment evaluation after BSH.
Asunto(s)
Conducta Animal , Transfusión de Sangre Autóloga , Edema Encefálico/etiología , Hematoma/etiología , Hemorragias Intracraneales/etiología , Leucoencefalopatías/etiología , Imagen por Resonancia Magnética , Puente/irrigación sanguínea , Sustancia Blanca/patología , Animales , Edema Encefálico/patología , Edema Encefálico/fisiopatología , Edema Encefálico/psicología , Imagen de Difusión Tensora , Modelos Animales de Enfermedad , Hematoma/patología , Hematoma/fisiopatología , Hematoma/psicología , Hemorragias Intracraneales/patología , Hemorragias Intracraneales/fisiopatología , Hemorragias Intracraneales/psicología , Leucoencefalopatías/patología , Leucoencefalopatías/fisiopatología , Leucoencefalopatías/psicología , Masculino , Puente/patología , Puente/fisiopatología , Ratas Sprague-Dawley , Factores de Tiempo , Sustancia Blanca/fisiopatologíaRESUMEN
Epidemiological studies have shown that an elevated uric acid (UA) level predicts the development of metabolic syndrome and diabetes; however, there is no direct evidence of this, and the underlying mechanism remains unclear. Here, we showed that a high-UA diet triggered the expression of pro-inflammatory cytokines, activated the NF-κB pathway, and increased gliosis in the hypothalamus. Intracerebroventricular injection of UA induced hypothalamic inflammation and reactive gliosis, whereas these effects were markedly ameliorated by the inhibition of NF-κB. Moreover, magnetic resonance imaging confirmed that hyperuricemia in rodents and humans was associated with gliosis in the mediobasal hypothalamus. Importantly, the rats administered UA exhibited dyslipidemia and glucose intolerance, which were probably mediated by hypothalamic inflammation and hypothalamic neuroendocrine alterations. These results suggest that UA can cause hypothalamic inflammation via NF-κB signaling. Our findings provide a potential therapeutic strategy for UA-induced metabolic disorders.
Asunto(s)
Dislipidemias/etiología , Prueba de Tolerancia a la Glucosa , Hipotálamo/metabolismo , Inflamación/etiología , FN-kappa B/metabolismo , Ácido Úrico/metabolismo , Animales , Biomarcadores/metabolismo , Barrera Hematoencefálica , Dislipidemias/sangre , Gliosis/metabolismo , Humanos , Hipotálamo/patología , Imagen por Resonancia Magnética , Masculino , Ratas , Ratas Wistar , Ácido Úrico/sangreRESUMEN
Tea polyphenol serves as an environmentally friendly ligand-exchange molecule to synthesize multifunctional metal-doped superparamagnetic iron oxide nanoparticles via a catechol-metal coordination interaction. The resultant particles not only exhibit excellent hydrophilicity and protein adsorption resistance, but also are applicable as magnetic resonance/fluorescent dual-imaging probes due to their high T2 relaxivity, autofluorescence and large cellular uptake.
Asunto(s)
Tecnología Química Verde , Nanopartículas/química , Nanotecnología/métodos , Polifenoles/química , Té/química , Adsorción , Materiales Biocompatibles/química , Medios de Contraste/química , Compuestos Férricos/química , Células HeLa , Humanos , Ligandos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Nanopartículas del Metal/química , Metales/química , Microscopía Fluorescente , Óptica y Fotónica , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
PURPOSE: To use magnetic resonance (MR) imaging and positron emission tomography (PET) dual detection of cardiac-grafted embryonic stem cells (ESCs) to examine (a) survival and proliferation of ESCs in normal and infarcted myocardium, (b) host macrophage versus grafted ESC contribution to serial MR imaging signal over time, and (c) cardiac function associated with the formation of grafts and whether improvement in cardiac function is related to cardiac differentiation of ESCs. MATERIALS AND METHODS: All animal procedures were approved by the institutional animal care and use committee. Murine ESCs were stably transfected with a mutant version of herpes simplex virus type 1 thymidine kinase, HSV1-sr39tk, and also were labeled with superparamagnetic iron oxide (SPIO) particles. Cells were injected directly in the border zone of the infarcted heart or in corresponding regions of normal hearts in athymic rats. PET and MR imaging were performed longitudinally for 4 weeks in the same animals. RESULTS: ESCs survived and underwent proliferation in the infarcted and normal hearts, as demonstrated by serial increases in 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl) guanine PET signals. In parallel, the hypointense areas on MR images at the injection sites decreased over time. Double staining for host macrophages and SPIO particles revealed that the majority of SPIO-containing cells were macrophages at week 4 after injection. Left ventricular ejection fraction increased in the ESC-treated rats but decreased in culture media-treated rats, and border-zone function was preserved in ESC-treated animals; however, cardiac differentiation of ESCs was less than 0.5%. CONCLUSION: Dual-modality imaging permits complementary information in regard to cell survival and proliferation, graft formation, and effects on cardiac function. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/250/3/821/DC1.
Asunto(s)
Células Madre Embrionarias , Imagen por Resonancia Magnética/métodos , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/cirugía , Tomografía de Emisión de Positrones/métodos , Animales , Células Cultivadas , Células Madre Embrionarias/diagnóstico por imagen , Células Madre Embrionarias/patología , Células Madre Embrionarias/trasplante , Ratas , Ratas Desnudas , Técnica de Sustracción , Resultado del TratamientoRESUMEN
RATIONALE AND OBJECTIVES: We evaluated the potential of using intravascular magnetic resonance (MR)/radiofrequency (RF) to enhance vascular endothelial growth factor (VEGF) gene therapy of in-stent neointimal hyperplasia. MATERIALS AND METHODS: By using a catheter-based approach, VEGF/lentivirus was locally transferred into 10 (five paired) bilateral femoral-iliac arteries of five hypercholesterolemic pigs, whereas the right arteries were heated up to approximately 41 degrees C by using an intravascular MR/RF system. Then, identical stents were placed immediately into the bilateral VEGF-targeted arteries to create in-stent neointimal hyperplasia. At day 60 after gene/stent interventions, the targeted arteries were harvested for histological correlation. RESULTS: X-Ray angiography-detectable in-stent stenoses were found in three of the arteries treated with VEGF genes only, whereas there were no in-stent stenoses in arteries treated by using MR/RF-heated VEGF genes. Correlative histological examination confirmed a 138% reduction in average thickness of neointimal hyperplasia in VEGF/RF-treated arteries compared with VEGF-only-treated arteries (P < .01). CONCLUSION: We report a potential method of using an intravascular MR/RF heating technique to enhance gene therapy of in-stent restenosis.
Asunto(s)
Terapia Genética/métodos , Oclusión de Injerto Vascular/prevención & control , Magnetismo/uso terapéutico , Terapia por Radiofrecuencia , Stents/efectos adversos , Transfección/métodos , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Animales , Oclusión de Injerto Vascular/etiología , Porcinos , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
PURPOSE: To evaluate the feasibility of radiofrequency (RF)-enhanced vascular gene transduction and expression by using a magnetic resonance (MR) imaging-heating guidewire as an intravascular heating vehicle during MR imaging-guided therapy. MATERIALS AND METHODS: The institutional committee for animal care and use approved the experimental protocol. The study included in vitro evaluation of the use of RF energy to enhance gene transduction and expression in vascular cells, as well as in vivo validation of the feasibility of intravascular MR imaging-guided RF-enhanced vascular gene transduction and expression in pig arteries. For in vitro experiments, approximately 10(4) vascular smooth muscle cells were seeded in each of four chambers of a cell culture plate. Next, 1 mL of a green fluorescent protein gene (gfp)-bearing lentivirus was added to each chamber. Chamber 4 was heated at approximately 41 degrees C for 15 minutes by using an MR imaging-heating guidewire connected to a custom RF generator. At day 6 after transduction, the four chambers were examined and compared at confocal microscopy to determine the efficiency of gfp transduction and expression. For the in vivo experiments, a lentivirus vector bearing a therapeutic gene, vascular endothelial growth factor 165 (VEGF-165), was transferred by using a gene delivery balloon catheter in 18 femoral-iliac arteries (nine artery pairs) in domestic pigs and Yucatan pigs with atherosclerosis. During gene infusion, one femoral-iliac artery in each pig was heated to approximately 41 degrees C with RF energy transferred via the intravascular MR imaging-heating guidewire, while the contralateral artery was not heated (control condition). At day 6, the 18 arteries were harvested for quantitative Western blot analysis to compare VEGF-165 transduction and expression efficiency between RF-heated and nonheated arterial groups. RESULTS: Confocal microscopy showed gfp expression in chamber 4 that was 293% the level of expression in chamber 1 (49.6% +/- 25.8 vs 16.8% +/- 8.0). Results of Western blot analysis showed VEGF-165 expression for normal arteries in the RF-heated group that was 300% the level of expression in the nonheated group (70.4 arbitrary units [au] +/- 107.1 vs 23.5 au +/- 29.8), and, for atherosclerotic arteries in the RF-heated group, 986% the level in the nonheated group (129.2 au +/- 100.3 vs 13.1 au +/- 4.9). CONCLUSION: Simultaneous monitoring and enhancement of vascular gene delivery and expression is feasible with the MR imaging-heating guidewire.
Asunto(s)
Cateterismo/métodos , Terapia Genética , Hipertermia Inducida/métodos , Imagen por Resonancia Magnética , Terapia por Radiofrecuencia , Enfermedades Vasculares/terapia , Animales , Western Blotting , Estudios de Factibilidad , Vectores Genéticos , Proteínas Fluorescentes Verdes , Lentivirus/genética , Músculo Liso Vascular/citología , PorcinosRESUMEN
Previous studies have confirmed the possibility of using an intravascular MR imaging guidewire (MRIG) as a heating source to enhance vascular gene transfection/expression. This motivated us to develop a new intravascular system that can perform MR imaging, radiofrequncy (RF) heating, and MR temperature monitoring simultaneously in an MR scanner. To validate this concept, a series of mathematical simulations of RF power loss along a 0.032-inch MRIG and RF energy spatial distribution were performed to determine the optimum RF heating frequency. Then, an RF generator/amplifier and a filter box were built. The possibility for simultaneous RF heating and MR thermal mapping of the system was confirmed in vitro using a phantom, and the obtained thermal mapping profile was compared with the simulated RF power distribution. Subsequently, the feasibility of simultaneous RF heating and temperature monitoring was successfully validated in vivo in the aorta of living rabbits. This MR imaging/RF heating system offers a potential tool for intravascular MR-mediated, RF-enhanced vascular gene therapy.