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1.
J Biol Chem ; 300(3): 105703, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38301895

RESUMEN

Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2α. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Proteína C9orf72 , Expansión de las Repeticiones de ADN , Factor 5 Eucariótico de Iniciación , Degeneración Lobar Frontotemporal , Animales , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Proteína C9orf72/genética , Dipéptidos/genética , Expansión de las Repeticiones de ADN/genética , Drosophila/genética , Drosophila/metabolismo , Factor 5 Eucariótico de Iniciación/genética , Factor 5 Eucariótico de Iniciación/metabolismo , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/fisiopatología , Células HeLa , Humanos , Modelos Animales de Enfermedad
2.
BMC Psychiatry ; 17(1): 99, 2017 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-28320371

RESUMEN

BACKGROUND: Patients with psychiatric disorders have a high rate of suicide. The present study investigated factors influencing hospital stays for Japanese patients with psychiatric disorders attempting suicide by jumping. METHODS: We diagnosed all suicide attempts (n = 113) by jumping based on the International Classification of Diseases 10th Revision (ICD-10) and investigated the mean hospital stays of patients with each diagnosis based on the ICD-10 code. We then analyzed differences in the demographic and clinical characteristics between the diagnostic groups to identify factors influencing the duration of hospital stay. RESULTS: Patients diagnosed with schizophrenia (F2 code) were the most frequent (32.7%) of all diagnoses; therefore, we divided the diagnostic groups into schizophrenia group (n = 37) and other psychiatric diagnoses group (n = 76). The patients with schizophrenia showed a significantly longer hospital stay (125.7 ± 63.9 days) compared with the patients with other psychiatric diagnoses (83.6 ± 63.2) (ß ± SE = 42.1 ± 12.7, p = 0.0013), whereas there was no difference in the jump height between the two groups (the average was the 3rd to 4th floor; p > 0.05). The number of injured parts, particularly lower-limb fractures, was significantly higher (p = 0.017) in patients with schizophrenia than in patients with other psychiatric diagnoses. The duration of psychiatric treatment in patients with schizophrenia were significantly longer (z = 3.4, p = 0.001) than in patients with other psychiatric diagnoses. CONCLUSION: Our findings indicate that the number of injuries and the body parts injured in patients with schizophrenia are associated with a longer duration of hospital stay following a suicide attempt by jumping. The current use of antipsychotics and a longer duration of taking antipsychotics might contribute to the risk of bone fracture via hyperprolactinemia. Further cognitive impairment in patients with schizophrenia might prevent rehabilitation for the management of lower-limb fractures. From these results, we suggest that clinicians should monitor the level of prolactin and cognitive function in patients with schizophrenia in future studies on managing of lower-limb fractures.


Asunto(s)
Tiempo de Internación/estadística & datos numéricos , Trastornos Mentales/epidemiología , Trastornos Mentales/psicología , Esquizofrenia/epidemiología , Psicología del Esquizofrénico , Intento de Suicidio/psicología , Intento de Suicidio/estadística & datos numéricos , Adulto , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Femenino , Fracturas Óseas/inducido químicamente , Humanos , Hiperprolactinemia/inducido químicamente , Japón , Traumatismos de la Pierna/inducido químicamente , Masculino , Trastornos Mentales/tratamiento farmacológico , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Esquizofrenia/tratamiento farmacológico , Heridas y Lesiones/epidemiología , Heridas y Lesiones/psicología , Adulto Joven
3.
Am J Emerg Med ; 35(8): 1211.e1-1211.e2, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28460810

RESUMEN

We present the case of a 47-year-old man with schizophrenia who developed acute and persistent circulatory failure after receiving injections of paliperidone palmitate. We measured blood concentrations of paliperidone and performed resection of hip tissues, where paliperidone palmitate was suspected to be present, in order to reduce the side effects. Unfortunately, the resection could not save the patient from prolonged and severe side effects and he died of multiple organ failure. We suggest that resection of the tissues suspected of containing paliperidone palmitate can help reduce its severe side effects. However, identifying the site of injection is essential.


Asunto(s)
Antipsicóticos/administración & dosificación , Inyecciones Intramusculares/efectos adversos , Insuficiencia Multiorgánica/inducido químicamente , Palmitato de Paliperidona/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Choque/inducido químicamente , Antipsicóticos/efectos adversos , Nalgas , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resultado Fatal , Humanos , Japón , Masculino , Persona de Mediana Edad , Palmitato de Paliperidona/efectos adversos , Cooperación del Paciente/psicología
5.
Biochem Biophys Res Commun ; 437(1): 151-5, 2013 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-23806691

RESUMEN

Due to chemotherapy, the majority of breast cancer patients survive, but frequently complain of chemotherapy-associated cognitive impairment. This phenomenon is termed "chemobrain" or "chemofog" in the literature. However, its mechanisms are unclear. The objective of this study was to investigate the mechanisms of paclitaxel (Px)-induced neurotoxicity, with a focus on endoplasmic reticulum (ER) stress. To investigate Px-induced neurotoxicity and ER stress induction, SK-N-SH cells were treated with 1, 10, 50, and 100 µM Px for 24 h. Neurotoxicity was assessed using MTS viability assays, and ER stress was assessed by evaluating the expression of phosphorylated elF2α (phospho-eIF2α), C/EBP homologous protein (CHOP), and cleaved caspase 4 and caspase 3 (the active form of each caspase). Furthermore, to investigate whether immunoglobulin heavy-chain binding protein (BiP) inducer X (BIX), which induces the molecular chaperone BiP, could attenuate Px-induced neurotoxicity, SK-N-SH cells were pre-treated for 12 h with 3.5 µM BIX before Px treatment. Neurotoxicity was observed in SK-N-SH cells treated with Px in a dose-dependent manner compared with vehicle control. Furthermore, phospho-eIF2α, CHOP, and activated caspase 4 and caspase 3 were significantly induced in Px-treated cells. In addition, pre-treatment with BIX significantly attenuated the induction of CHOP and activated caspase 4 and caspase 3. The viability of BIX pre-treated cells prior to Px treatment was significantly increased compared with cells that were not treated with BIX. Our results suggest that Px induces neurotoxicity in part through activating the ER stress response. Our findings should contribute to novel approaches regarding the mechanism of Px-induced neurotoxicity, including chemobrain.


Asunto(s)
Estrés del Retículo Endoplásmico/efectos de los fármacos , Neurotoxinas/toxicidad , Paclitaxel/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/metabolismo , Humanos
6.
Biochem Biophys Res Commun ; 430(2): 500-4, 2013 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-23237806

RESUMEN

Tauopathy is a pathological condition with an abnormal intracellular accumulation of tau protein in neurons and glias, which is a feature of Alzheimer's disease (AD) as well as frontotemporal lobar degenerations (FTLD). Recent reports showed that tauopathy occupies an important position for pathological process of dementia generally. Previously, we reported that endoplasmic reticulum (ER) stress has an influence on the onset of AD. In addition, some reports on brain autopsy findings suggest that ER stress is associated with AD and tauopathy. However, the mechanism underlying the association between ER stress and tauopathy is still unknown. Here, we show that ER stress, induced by glucose deprivation or chemicals, increases total endogenous tau protein in cultured neurons and primary cultured neurons. Under ER stress, no significant differences were observed in the transcription of tau, and no differences were observed in the translation of tau with or without the 5'-untranslated region (5'UTR) of tau. In contrast, the degradation rate of tau was decreased by 20% under ER stress. ER stress reduced the binding between tau and carboxyl terminus of Hsc70-interacting protein (CHIP), ubiquitin E3 ligase for tau. These results suggest that ER stress increases total tau protein and its mechanism is due to the decrease in the binding between tau and CHIP, which delays the degradation of tau protein through the ubiquitin-proteasome pathway. This mechanism may provide clue to treatment for tauopathy.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Estrés del Retículo Endoplásmico , Neuronas/metabolismo , Tauopatías/metabolismo , Proteínas tau/biosíntesis , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Humanos , Factores de Transcripción del Factor Regulador X , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
7.
Neurol India ; 70(4): 1668-1669, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36076681

RESUMEN

Delayed neuropsychiatric sequelae (DNS), which are related to neuropsychiatric symptoms and severe sequelae, occur within a few days of recovery from acute poisoning. They may involve a slowly progressing demyelinating white matter lesion caused by carbon monoxide cytotoxicity; moreover, the involvement of immune mechanisms has been reported. However, there remains no established treatment or therapeutic gain factors. A 29-year-old man with DNS who experienced carbon monoxide poisoning underwent corticosteroid therapy with concomitant measurements of cerebrospinal fluid levels of MBP, IL-6, and pNF-H. Treatment led to an improvement in symptoms and lesions on magnetic resonance imaging. Corticosteroid therapy and monitoring can be used to treat and monitor DNS.


Asunto(s)
Intoxicación por Monóxido de Carbono , Sustancia Blanca , Corticoesteroides , Adulto , Biomarcadores , Intoxicación por Monóxido de Carbono/complicaciones , Humanos , Imagen por Resonancia Magnética , Masculino , Sustancia Blanca/patología
8.
Biochem Biophys Res Commun ; 415(3): 519-25, 2011 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-22079628

RESUMEN

Sigma-1 receptors (Sig-1Rs) are the ER resident proteins. Sig-1Rs in the brain have been reported to be significantly reduced in patients with schizophrenia. The impediment of regulating Sig-1Rs expression levels increases the risk for schizophrenia. Thus elucidating the mechanism regulating Sig-1Rs expression might provide the strategy to prevent mental disorders. In this study, we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. Moreover, ATF4 directly bounds to the 5' flanking region of Sig-1R gene. The reporter activities using this region were enhanced in ER stress, or by ATF4 alone. The reporter activities with the pathogenic polymorphisms (GC-241-240TT, T-485A) were reduced. In addition, the processing of Caspase-4 was inhibited by Sig-1Rs. These results indicate that Sig-1Rs are transcriptionally upregulated via the PERK/eIF2α/ATF4 pathway and ameliolate cell death signaling. This study is the first report identifying the transcription factor regulating Sig-1Rs expression.


Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Factor 2 Eucariótico de Iniciación/metabolismo , Regulación de la Expresión Génica , Receptores sigma/genética , Estrés Fisiológico/genética , eIF-2 Quinasa/metabolismo , Caspasas Iniciadoras/metabolismo , Retículo Endoplásmico/metabolismo , Genes Reporteros , Humanos , Regiones Promotoras Genéticas , Transcripción Genética , Regulación hacia Arriba , Receptor Sigma-1
10.
Intern Med ; 57(7): 1011-1013, 2018 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-29225271

RESUMEN

We report a rare case of anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis presenting clinical relapse in association with recurrence of thymoma. Anti-AMPAR encephalitis is an autoimmune-mediated neurological disease, frequently accompanied by the presence of neoplasms, thus comprising the spectrum of paraneoplastic syndrome. A patient had been in remission for 34 months showed clinical relapse 3 months after the detection of recurrent thymoma. Clinical relapse of anti-AMPAR encephalitis after the recurrence of an initially detected neoplasm has not been previously reported. Our case therefore highlights the pathogenic relevance of specific tumor antigens as a trigger of anti-AMPAR antibody production and induction of the disease.


Asunto(s)
Corticoesteroides/uso terapéutico , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Encefalitis Antirreceptor N-Metil-D-Aspartato/etiología , Enfermedad Crónica/terapia , Recurrencia Local de Neoplasia/etiología , Timoma/complicaciones , Neoplasias del Timo/complicaciones , Adulto , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico por imagen , Femenino , Humanos , Resultado del Tratamiento
11.
Case Rep Psychiatry ; 2016: 1805414, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27478670

RESUMEN

We report the case of a 41-year-old woman with schizophrenia who developed persistent hypoglycemia following paliperidone administration. After discontinuing paliperidone, the hypoglycemia resolved, but symptoms of diabetes emerged. Therefore, it appears that the hypoglycemia induced by paliperidone may mask symptoms of diabetes. Paliperidone may induce hypoglycemia by increasing insulin secretion. This report could help elucidate the relationship between atypical antipsychotics and glucose metabolism.

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