RESUMO
BACKGROUND: Vanishing white matter (VWM) is an autosomal recessive disorder characterized by childhood ataxia with central hypomyelination. Adult-onset VWM should be considered as a differential diagnosis for suspected cases of multiple sclerosis (MS). METHODS: Targeted region sequencing (TRS) and Sanger sequencing validation were performed to identify and validate the likely pathogenic mutations in a family with VWM. RESULTS: The main clinical manifestations of the proband included decreased vision and sleepiness accompanied by atrophy of the corpus callosum, affected inner rim of the corpus callosum, decreased apparent diffusion coefficient value or persistent hyperintensity-diffusion-weighted imaging, atrophied optic nerve, and no recordable visual evoked potentials. Due to the slow development and atypical VWM image features, MS was initially suspected. After prednisone was administered, the patient's condition did not improve significantly, and other diseases were considered. The TRS and Sanger sequencing identified compound heterozygous mutations of EIF2B3 in the proband; c.965C > G /p.Ala322Gly in exon 8 and c.130G > A/p.Glu44Lys in exon 2 were missense mutations inherited from the mother and father, respectively. The proband's oldest brother had the same compound heterozygous mutations but showed no symptoms. CONCLUSION: This is the first report of adult-onset VWM in a Chinese family. Initially, MS was suspected, and genetic testing confirmed the diagnosis of VWM. This study may further broaden the clinical spectrum of EIF2B3, thus providing a foundation for further research on the pathogenesis and genetic therapy for VWM.
Assuntos
Leucoencefalopatias , Esclerose Múltipla , Substância Branca , Adulto , Criança , Erros de Diagnóstico , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2B em Eucariotos/metabolismo , Potenciais Evocados Visuais , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Masculino , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/genética , Mutação/genética , Substância Branca/patologiaRESUMO
Pulmonary arterial hypertension (PAH) is a serious and fatal cardiovascular disorder characterized by increased pulmonary vascular resistance and progressive pulmonary vascular remodeling. The underlying pathological mechanisms of PAH are multi-factorial and multi-cellular. Alginate oligosaccharide (AOS), which is produced by depolymerizing alginate, shows better pharmacological activities and beneficial effects. The present study was undertaken to investigate the effects and potential mechanisms of AOS-mediated alleviation of pulmonary hypertension. Pulmonary hypertension was induced in Sprague-Dawley rats by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg). Five weeks after the injection of MCT, AOS (5, 10, and 20 mg·kg-1·d-1) was injected intraperitoneally for another three weeks. The results showed that AOS prevented the development of MCT-induced pulmonary hypertension and right ventricular hypertrophy in a dose-dependent manner. AOS treatment also prevented MCT-induced pulmonary vascular remodeling via inhibition of the TGF-ß1/p-Smad2 signaling pathway. Furthermore, AOS treatment downregulated the expression of malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase, and pro-inflammatory cytokines, decreased macrophage infiltration, and upregulated the expression of anti-inflammatory cytokines. These findings indicate that AOS exerts anti-oxidative and anti-inflammatory effects in pulmonary arteries, which may contribute to the alleviation of pulmonary hypertension and pulmonary vascular remodeling.
Assuntos
Alginatos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Hipertrofia Ventricular Direita/tratamento farmacológico , Monocrotalina/efeitos adversos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Alginatos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/metabolismo , Injeções Intraperitoneais , Masculino , Malondialdeído/metabolismo , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/metabolismo , Distribuição Aleatória , Ratos , Remodelação Vascular/efeitos dos fármacosRESUMO
Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density (BMD) and bone quality and increased bone porosity, which increase the risk of bone fracture. Inflammation, one of the important mechanisms related to aging, is associated with osteoporosis. Treatment with anti-inflammatory agents is effective for alleviating senile osteoporosis. Alginate oligosaccharide (AOS) can prevent and treat diseases related to inflammation, oxidative stress, and immunity. This study evaluates the effect of AOS on osteoporosis and investigates the underlying mechanism. Osteoporosis model was induced by D-galactose (D-gal) (200 mg kg-1 day-1 ) for eight weeks. Three groups were administered via AOS (50, 100, and 150 mg kg-1 day-1 ) for four weeks, while a control group received sterile water (5 ml kg-1 day-1 ) for 8 weeks. The results showed that AOS improved bone density and bone microstructure in D-gal-induced osteoporosis mice. AOS inhibited osteoclast proliferation, probably through the suppression of receptor activator of nuclear factor-kappa B ligand (RANKL)-associated nuclear factor kappa B (NF-κB) and c-Fos signaling pathway. AOS also increased osteoprotegerin (OPG) expression and competitively inhibited the binding between RANK and RANKL in senile osteoporosis. Further, AOS decreased the secretion of serum osteocalcin and reduced bone conversion. Together, these results demonstrate the anti-osteoporosis activity of AOS in mice with osteoporosis.
Assuntos
Alginatos/química , Galactose/farmacologia , Oligossacarídeos/química , Oligossacarídeos/uso terapêutico , Osteoporose/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Densidade Óssea/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Oligossacarídeos/farmacologia , Osteoporose/patologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
We have reported that pseudoginsenoside-F11 (PF11) can significantly improve the cognitive impairments in several Alzheimer's disease (AD) models, but the mechanism has not been fully elucidated. In the present study, the effects of PF11 on AD, in particular the underlying mechanisms related with protein phosphatase 2A (PP2A), were investigated in a rat model induced by okadaic acid (OA), a selective inhibitor of PP2A. The results showed that PF11 treatment dose-dependently improved the learning and memory impairments in OA-induced AD rats. PF11 could significantly inhibit OA-induced tau hyperphosphorylation, suppress the activation of glial cells, alleviate neuroinflammation, thus rescue the neuronal and synaptic damage. Further investigation revealed that PF11 could regulate the protein expression of methyl modifying enzymes (leucine carboxyl methyltransferase-1 and protein phosphatase methylesterase-1) in the brain, thus increase methyl-PP2A protein expression and indirectly increase the activity of PP2A. Molecular docking analysis, structural alignment and in vitro results showed that PF11 was similar in the shape and electrostatic field feature to a known activator of PP2A, and could directly bind and activate PP2A. In conclusion, the present data indicate that PF11 can ameliorate OA-induced learning and memory impairment in rats via modulating PP2A.
Assuntos
Ativadores de Enzimas , Ginsenosídeos , Deficiências da Aprendizagem , Transtornos da Memória , Simulação de Acoplamento Molecular , Ácido Okadáico/toxicidade , Proteína Fosfatase 2 , Animais , Ativadores de Enzimas/química , Ativadores de Enzimas/farmacologia , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/tratamento farmacológico , Deficiências da Aprendizagem/enzimologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/enzimologia , Proteína Fosfatase 2/química , Proteína Fosfatase 2/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Astragalus membranaceus (Fisch.) Bunge (AM) has been utilized for the treatment of diabetes mellitus and its complications for centuries. Astragalus polysaccharides (APS), the main bioactive ingredient extracted from the root of AM, is prescribed widely in China and has definite cardioprotective effect during diabetic cardiomyopathy (DCM). Endoplasmic reticulum (ER) stress-induced apoptosis played a crucial role in the progression of DCM. However, the regulatory mechanisms of APS on ER stress pathway haven't been comprehensively studied so far. AIM OF THE STUDY: The aim of this study was to identify the effect of APS on cardiomyocyte apoptosis and to investigate the mechanisms for the anti-apoptotic effect of APS during DCM. MATERIALS AND METHODS: DCM rat model was induced by intraperitoneal streptozotocin (STZ) injection and treated with APS for 16 weeks. Cardiac function, pathological changes and apoptotic cells were assessed by echocardiography, hematoxylin-eosin (HE) staining and TUNEL assay, respectively. Expressions of key molecules in ER stress pathway were detected by Western blot analysis. Cardiomyocytes were exposed to high glucose (HG) and treated with APS for 24â¯h. Cell viability, apoptosis and protein expressions were assessed by MTT, flow cytometer and Western blot analysis, respectively. Moreover, lentivirus over-expressing (OE) C/EBP homologous protein (CHOP) was employed to further investigate the causative role of ER stress pathway in APS-mediated effect on cardiomyocyte apoptosis. RESULTS: In vivo, the results demonstrated that APS could improve heart function and attenuate myocardial apoptosis in DCM rat model. Further study demonstrated that APS could down-regulate the protein expressions of activating transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK) related factors of ER stress pathway. In vitro, APS significantly inhibit HG stimulated H9C2 cell apoptosis and the expressions of ATF6 and PERK related proteins of ER stress pathway. However, after CHOP-OE lentivirus transfection, the protective effects of APS were diminished as increased apoptotic rate and higher expression of CHOP. CONCLUSIONS: APS could attenuate cardiomyocyte apoptosis via down-regulating the expression of ATF6 and PERK related factors of ER stress pathway in DCM rats and HG-stimulated H9C2 cells.
Assuntos
Astrágalo , Cardiotônicos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Cardiomiopatias Diabéticas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Polissacarídeos , Fator 6 Ativador da Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Ratos Sprague-Dawley , eIF-2 Quinase/metabolismoRESUMO
There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism. We previously found that acute morphine treatment significantly increased uridine release in the dorsal striatum of mice, indicating that uridine may contribute to morphine-induced neurobehavioral changes. In the present study, we analyzed the mechanism involved in morphine-induced uridine release and the role of uridine in morphine-induced neurobehavioral changes. Uridine release in the dorsal striatum of mice was assessed by in vivo microdialysis coupled with high performance liquid chromatography (HPLC) after morphine treatment. Western blotting and immunofluorescence were used to evaluate the expression of uridine-related proteins. Morphine-induced neurobehavioral changes were assessed by locomotor activity, behavioral sensitization and conditioned place preference (CPP) test. The expression of NT5E, an extracellular enzyme involved in formation of nucleosides, including uridine, was specifically knocked down in the dorsal striatum of mice using adeno-associated virus (AAV)-mediated short hairpin RNA (shRNA). The results indicated that both acute and chronic morphine administration significantly increased uridine release in the dorsal striatum, and this was associated with upregulation of NT5E but not other uridine-related proteins. Inhibition of NT5E with APCP or shRNA markedly inhibited morphine-induced uridine release in the dorsal striatum and related neurobehavioral changes, including hyperlocomotor activity, behavioral sensitization and CPP. Our data give a better understanding of the contribution of NT5E to morphine-induced uridine release and neurobehavioral changes, and identify NT5E as a potential target for treating morphine abuse.
Assuntos
5'-Nucleotidase/metabolismo , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Corpo Estriado/metabolismo , Locomoção/efeitos dos fármacos , Morfina/farmacologia , Uridina/metabolismo , 5'-Nucleotidase/antagonistas & inibidores , Animais , Fosfatos de Dinucleosídeos/farmacologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Masculino , Camundongos , Microdiálise , RNA Interferente Pequeno/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Several lines of evidence suggest that uridine, as a neuromodulator, plays an important role in drug addiction. We previously found that uridine circumvents morphine-induced behavioral sensitization by decreasing the extracellular dopamine levels in the dorsal striatum. In the present study, the effects of uridine on morphine-induced conditioned place preference (CPP) and the possible roles of glutamate and GABA in the stress-induced reinstatement of CPP were investigated. First, the effects of uridine (1, 10 and 100mg/kg, i.p.) on the four defined phases - acquisition, expression, extinction and reinstatement (drug priming and restraint stress) - of morphine-induced CPP were studied. The results showed that pretreatment with uridine significantly blocked the acquisition and expression phases of CPP. Additionally, uridine also facilitated CPP extinction and inhibited stress-induced CPP reinstatement, although it failed to affect drug-induced CPP reinstatement. Since glutamatergic and GABAergic systems are both involved in CPP reinstatement, the extracellular levels of glutamate and GABA in the mPFC during the stress-induced CPP reinstatement were determined using in vivo microdialysis. The results showed that uridine attenuated the stress-induced glutamate increase in the mPFC without influencing the basal glutamate levels, and increased the levels of extracellular GABA in the mPFC both under normal physiological conditions and after the stress stimulus. Thus, our results indicate that uridine depresses the stress-induced reinstatement of CPP, simultaneously regulating glutamatergic and GABAergic neurotransmission in the mPFC. The present work provides further understanding of the role of uridine in morphine-induced neurobehavioral changes.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Morfina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Uridina/farmacologia , Ácido gama-Aminobutírico/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Camundongos , Microdiálise , Córtex Pré-Frontal/metabolismoRESUMO
BACKGROUND: Nitroglycerin (NTG) is one of the few immediate treatments for acute angina. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in the human body that facilitates the biological metabolism of NTG. The biological mechanism of NTG serves an important function in NTG efficacy. Some reports still contradict the results that the correlation between ALDH2 gene polymorphisms and NTG and its clinical efficacy is different. However, data on NTG measurement by pain relief are subjective. This study aimed to investigate the influence of ALDH2 gene polymorphism on intervention with sublingual NTG using noninvasive hemodynamic parameters of cardiac output (CO) and systemic vascular resistance (SVR) in Northern Chinese Han population. METHODS: This study selected 559 patients from the Affiliated Hospital of Qingdao University. A total of 203 patients presented with coronary heart disease (CHD) and 356 had non-CHD (NCHD) cases. All patient ALDH2 genotypes (G504A) were detected and divided into two types: Wild (GG) and mutant (GA/AA). Among the CHD group, 103 were wild-type cases, and 100 were mutant-type cases. Moreover, 196 cases were wild-type, and 160 cases were mutant type among the NCHD volunteers. A noninvasive hemodynamic detector was used to monitor the CO and the SVR at the 0, 5, and 15 minute time points after medication with 0.5 mg sublingual NTG. Two CO and SVR indicators were used for a comparative analysis of all case genotypes. RESULTS: Both CO and SVR indicators significantly differed between the wild and mutant genotypes at various time points after intervention with sublingual NTG at 5 and 15 minutes in the NCHD (F = 16.460, 15.003, P = 0.000, 0.000) and CHD groups (F = 194.482, 60.582, P = 0.000, 0.000). All CO values in the wild-type case of both NCHD and CHD groups increased, whereas those in the mutant type decreased. The CO and ΔCO differences were statistically significant (P < 0.05; P < 0.05). The SVR and ΔSVR changed between the wild- and mutant-type cases at all-time points in both NCHD and CHD groups had statistically significant differences (P < 0.05; P < 0.05). CONCLUSION: ALDH2 (G504A) gene polymorphism is associated with changes in noninvasive hemodynamic parameters (i.e. CO and SVR) after intervention with sublingual NTG. This gene polymorphism may influence the effect of NTG intervention on Northern Chinese Han population.