RESUMEN
The aggregation and accumulation of amyloid beta (Aß) peptide is believed to be the primary cause of Alzheimer's disease (AD) pathogenesis. Vitamin D-binding protein (DBP) can attenuate Aß aggregation and accumulation. A biocompatible polymer poly (D,L-lactic acid-co-glycolic acid) (PLGA) can be loaded with therapeutic agents and control the rate of their release. In the present study, a PLGA-based drug delivery system was used to examine the therapeutic effects of DBP-PLGA nanoparticles in Aß-overexpressing (5XFAD) mice. DBP was loaded into PLGA nanoparticles and the characteristics of the DBP-PLGA nanoparticles were analyzed. Using a thioflavin-T assay, we observed that DBP-PLGA nanoparticles significantly inhibited Aß aggregation in vitro. In addition, we found that intravenous injection of DBP-PLGA nanoparticles significantly attenuated the Aß accumulation, neuroinflammation, neuronal loss and cognitive dysfunction in the 5XFAD mice. Collectively, our results suggest that DBP-PLGA nanoparticles could be a promising therapeutic candidate for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Portadores de Fármacos/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Proteína de Unión a Vitamina D/administración & dosificación , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Masculino , Ratones , Ratones Transgénicos , Nanopartículas/química , Agregación Patológica de Proteínas/tratamiento farmacológico , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Proteína de Unión a Vitamina D/uso terapéuticoRESUMEN
Regulated autophagy is involved in the repair of renal ischemia-reperfusion injury (IRI). Fat-1 transgenic mice produce ω3-Polyunsaturated fatty acids (ω3-PUFAs) from ω6-Polyunsaturated fatty acids (ω6-PUFAs) without a dietary ω3-PUFAs supplement, leading to a high accumulation of omega-3 in various tissues. ω3-PUFAs show protective effects against various renal injuries and it has recently been reported that ω3-PUFAs regulate autophagy. We assessed whether ω3-PUFAs attenuated IR-induced acute kidney injury (AKI) and evaluated its associated mechanisms. C57Bl/6 background fat-1 mice and wild-type mice (wt) were divided into four groups: wt sham (n = 10), fat-1 sham (n = 10), wt IRI (reperfusion 35 min after clamping both the renal artery and vein; n = 15), and fat-1 IRI (n = 15). Kidneys and blood were harvested 24 h after IRI and renal histological and molecular data were collected. The kidneys of fat-1 mice showed better renal cell survival, renal function, and pathological damage than those of wt mice after IRI. In addition, fat-1 mice showed less oxidative stress and autophagy impairment; greater amounts of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, Beclin-1, and Atg7; lower amounts of p62; and, higher levels of renal cathepsin D and ATP6E than wt kidneys. They also showed more adenosine monophosphate-activated protein kinase (AMPK) activation, which resulted in the inhibition of phosphorylation of the mammalian target of rapamycin (mTOR). Collectively, ω3-PUFAs in fat-1 mice contributed to AMPK mediated autophagy activation, leading to a renoprotective response.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Lesión Renal Aguda/metabolismo , Autofagia , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Ácido Graso Desaturasas/genética , Ácidos Grasos Omega-3/metabolismo , Ratones Transgénicos/genética , Daño por Reperfusión/metabolismo , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Animales , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Ácido Graso Desaturasas/metabolismo , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos/metabolismo , Estrés Oxidativo , Daño por Reperfusión/complicaciones , Daño por Reperfusión/genética , Daño por Reperfusión/patologíaRESUMEN
Omega-3 polyunsaturated fatty acids (PUFA) are critical for optimal brain health and are involved in psychiatric and neurological ailments. Here, we report the effects of higher endogenous omega-3 PUFA on memory impairment in the hippocampus by studying mice with transgenic expression of the fat-1 gene that converts omega-6 to omega-3 PUFA. We performed Y-maze and passive avoidance tests to evaluate the memory function of fat-1 mice treated with scopolamine. Fat-1 mice showed induced alternation in the Y-maze test and increased latency in the passive avoidance test. The effects of scopolamine on hippocampal neurogenesis were confirmed by increases in the number of Ki-67- and DCX-positive cells in the fat-1 mice. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein levels, and lower scopolamine-induced apoptosis based on the cleaved-caspase 3 protein level in fat-1 mice. These findings suggest that higher endogenous omega-3 PUFA prevented granular cell loss, increased BDNF signaling, and decreased apoptosis signaling in scopolamine-treated fat-1 mice. These processes may underlie granular cell survival and suggest potential therapeutic targets for memory impairment.
Asunto(s)
Amnesia/metabolismo , Cadherinas/metabolismo , Ácidos Grasos Omega-3/farmacología , Hipocampo/efectos de los fármacos , Memoria/efectos de los fármacos , Escopolamina/efectos adversos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína Doblecortina , Ácidos Grasos Omega-3/administración & dosificación , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacologíaRESUMEN
Temozolomide (TMZ) is an alkylating agent commonly used as a firstline treatment for highgrade glioblastoma. However, TMZ has short halflife and frequently induces tumor resistance, which can limit its therapeutic efficiency. In the present study, it was hypothesized that combined treatment with TMZ and acteoside has synergistic effects in glioblastoma therapy. Using cell viability and woundhealing assays, it was determined that this treatment regimen reduced cell viability and migration to a greater extent than either TMZ or acteoside alone. Following previous reports that TMZ affected autophagy in glioma cells, the present study examined the effects of TMZ + acteoside combination treatment on apoptosis and autophagy. The TMZ + acteoside combination treatment increased the cleavage of caspase3 and levels of Bcell lymphoma 2 (Bcl2)associated X protein and phosphorylated p53, and decreased the level of Bcl2. The combination treatment increased microtubuleassociated protein 1 light chain 3 and apoptosisrelated gene expression. It was also determined that TMZ + acteoside induced apoptosis and autophagy through the mitogenactivated protein kinase signaling pathway. These findings suggest that acteoside has beneficial effects on TMZbased glioblastoma therapy.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Antineoplásicos Fitogénicos/farmacología , Glucósidos/farmacología , Fenoles/farmacología , Temozolomida/farmacología , Animales , Antineoplásicos Alquilantes/química , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glucósidos/química , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fenoles/química , Ratas , Temozolomida/químicaRESUMEN
Neuropathic pain is a complex, chronic pain state characterized by hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence has indicated that the microglial Toll-like receptor 4 (TLR4) and autophagy are implicated in neurodegenerative diseases, but their relationship and role in neuropathic pain remain unclear. In this study, we examined TLR4 and its association with autophagic activity using a chronic constriction injury (CCI)-induced neuropathic pain model in wild-type (WT) and TLR4-knockout (KO) mice. The mice were assigned into four groups: WT-Contralateral (Contra), WT-Ipsilateral (Ipsi), TLR4 KO-Contra, and TLR4 KO-Ipsi. Behavioral and mechanical allodynia tests and biochemical analysis of spinal cord tissue were conducted following CCI to the sciatic nerve. Compared with the Contra group, mechanical allodynia in both the WT- and TLR4 KO-Ipsi groups was significantly increased, and a marked decrease of allodynia was observed in the TLR4 KO-Ipsi group. Although glial cells were upregulated in the WT-Ipsi group, no significant change was observed in the TLR4 KO groups. Moreover, protein expression and immunoreactive cell regulation of autophagy (Beclin 1, p62) were significantly increased in the neurons, but not microglia, of WT-Ipsi group compared with the WT-Contra group. The level of PINK1, a marker for mitophagy was increased in the neurons of WT, but not in TLR4 KO mice. Together, these results show that TLR4-mediated p62 autophagic impairment plays an important role in the occurrence and development of neuropathic pain. And what is more, microglial TLR4-mediated microglial activation might be indirectly coupled to neuronal autophage.
Asunto(s)
Autofagia , Neuralgia/metabolismo , Neuralgia/patología , Receptor Toll-Like 4/metabolismo , Animales , Astrocitos/metabolismo , Astrocitos/patología , Beclina-1/metabolismo , Enfermedad Crónica , Constricción , Hiperalgesia/complicaciones , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Microglía/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Mitofagia , Modelos Neurológicos , Neuralgia/complicaciones , Nocicepción , Proteínas Quinasas/metabolismo , Proteína Sequestosoma-1/metabolismo , Asta Dorsal de la Médula Espinal/metabolismo , Asta Dorsal de la Médula Espinal/patología , Nervios Espinales/patología , CaminataRESUMEN
BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the effect of pulmonary valve replacement (PVR) on exercise capacity and determine cardiopulmonary exercise (CPEX) parameters associated with improvement in right ventricle (RV) function. SUBJECTS AND METHODS: We retrospectively analyzed CPEX and magnetic resonance imaging parameters in a total of 245 patients who underwent PVR from January 1998 to October 2015. In addition, we analyzed the characteristics of the patients who showed improved exercise capacity after PVR. RESULTS: Twenty-eight patients met the inclusion criteria for the study. CPEX parameters after PVR showed no significant changes in all patients. However, baseline predicted peak oxygen uptake (VO2peak) (%) value was significantly lower in patients with significant improvement in exercise capacity after PVR, as compared to patients who showed decreased exercise capacity after PVR (60.83±10.28 vs. 75.81±13.83) (p=0.003). In addition, patients with improved exercise capacity showed a positive correlation between the change of right ventricular ejection fraction (RVEF) (%) and the change of anaerobic threshold (r=0.733, p=0.007); whereas, patients with decreased exercise capacity showed a negative correlation between the change of RVEF (%) and the change of predicted VO2peak (%) (r=-0.575, p=0.020). CONCLUSION: The importance of predicted VO2peak (%) in evaluating exercise capacity differentiated from other CPEX variables. The change of anaerobic threshold and predicted VO2peak (%) might be a useful predictor of the change in RV function after PVR.
RESUMEN
PURPOSE: Generally, aspirin is used as a protective agent against thrombogenic phenomenon after pulmonary valve replacement (PVR) using a bioprosthetic valve. However, the appropriate duration of aspirin use is unclear. We analyzed the impact of postoperative duration of aspirin use on the longevity of bioprosthetic pulmonary valves in patients who underwent repair for congenital heart diseases. METHODS: We retrospectively reviewed the clinical data of 137 patients who underwent PVR using a bioprosthetic valve between January 2000 and December 2003. Among these patients, 89 were included in our study and divided into groups I (≤12 months) and II (>12 months) according to duration of aspirin use. We analyzed echocardiographic data from 9 to 11 years after PVR. Pulmonary vale stenosis and regurgitation were classified as mild, moderate, or severe. RESULTS: The 89 patients consisted of 53 males and 36 females. Their mean age was 14.3±8.9 years (range, 2.6-48 years) and body weight was 37.6±14.7 kg (range, 14-72 kg). The postoperative duration of aspirin use was 7.3±2.9 months in group I and 32.8±28.4 months in group II. However, no significant difference in sex ratio, age, body weight, type of bioprosthetic valve, and number of early redo-PVRs. In the comparison of echocardiographic data about 10 years later, no significant difference in pulmonary valve function was found. The overall freedom rate from redo-PVR at 10 years showed no significant difference (P=0.498). CONCLUSION: Our results indicated no benefit from long-term aspirin medication (>6 months) in patients who underwent PVR with a bioprosthetic valve.