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2.
Microbiol Immunol ; 68(5): 179-184, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38433377

RESUMEN

BK polyomavirus (BKPyV) was the first human polyomavirus to be isolated from an immunosuppressed kidney transplant recipient in 1971. BKPyV reactivation causes BKPyV-associated nephropathy and hemorrhagic cystitis. However, the mechanisms underlying BKPyV replication remain unclear. In the present study, we performed the long-term cultivation of COS-7 cells transfected with archetype KOM-5 DNA, which were designated as COS-BK cells. BKPyV derived from COS-BK cells was characterized by analyzing the amount of the virus based on hemagglutination, viral replication, and the production of viral protein 1 (VP1). Immunostaining showed that VP1-positive cells accounted for a small percentage of COS-BK cells. The nucleotide sequences encompassing the origin of the DNA replication of BKPyV derived from COS-BK cells were generated from KOM-5 by the deletion of an 8-bp sequence, which did not involve T antigen binding sites. BKPyV replicated most efficiently in COS-BK cells in DMEM containing 2% fetal bovine serum. These results indicate that COS-BK cells are a suitable culture system for studying the persistent infection of archetype BKPyV.


Asunto(s)
Virus BK , Infecciones por Polyomavirus , Replicación Viral , Virus BK/fisiología , Virus BK/genética , Animales , Chlorocebus aethiops , Células COS , Infecciones por Polyomavirus/virología , Humanos , Proteínas de la Cápside/genética , ADN Viral/genética , Infección Persistente/virología , Antígenos Virales de Tumores/genética , Infecciones Tumorales por Virus/virología
3.
Yakugaku Zasshi ; 143(11): 883-887, 2023.
Artículo en Japonés | MEDLINE | ID: mdl-37914334

RESUMEN

p-Hydroxyamphetamine (p-OHA) is an active metabolite of amphetamine (AMPH) and methamphetamine (METH), and can be detected in the brain for a relatively long period after high-dose administration of AMPH in rodents. p-OHA may be involved in the abnormal behavior observed during the withdrawal period after a chronic administration of AMPH or METH. Therefore, the author investigated the effect of an intracerebroventricular (i.c.v.) administration of p-OHA on the changes of locomotor activity and prepulse inhibition (PPI) in the acoustic startle response in rodents. The i.c.v. administration of p-OHA significantly increased locomotor activity in mice. This effect was prevented by a pretreatment with a dopamine (DA) uptake inhibitor. Furthermore, local infusion of p-OHA into the nucleus accumbens (NAc) significantly increased locomotor activity in rats. Together these results suggest that dopaminergic systems in the rodent NAc may play important roles in p-OHA-induced locomotor activity. Next, the author tested the effects of the i.c.v. administration of p-OHA on PPI in mice. p-OHA induced PPI disruptions that were significantly improved by the pretreatment with a typical or an atypical antipsychotic, D2 or D4 receptor antagonists, respectively. p-OHA-induced PPI disruptions were also improved by a serotonin (5-HT)2A receptor antagonist, a 5-HT synthesis inhibitor or a 5-HT neurotoxin. These results suggest that p-OHA-induced PPI disruptions were mediated by DA and 5-HT release and subsequent stimulation of D2, D4 and 5-HT2A receptors. Our recent series of reports indicate that the study of p-OHA may provide new insights into drug abuse as well as psychiatric disorders such as schizophrenia.


Asunto(s)
Dopamina , Metanfetamina , Humanos , Ratas , Ratones , Animales , Dopamina/metabolismo , p-Hidroxianfetamina , Serotonina/metabolismo , Roedores/metabolismo , Reflejo de Sobresalto , Anfetamina/farmacología , Transmisión Sináptica , Relación Dosis-Respuesta a Droga
4.
Biochem Biophys Res Commun ; 681: 180-185, 2023 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-37783115

RESUMEN

A bioluminescent immunoassay system was developed to determine serine/threonine protein kinase activity using an aequorin-labeled monoclonal antibody and a synthetic peptide as the substrate. A monoclonal antibody against the synthetic phosphorylated serine peptide (K9P peptide) of histone H3 (19 amino acid residues), referred to as the H3S10P antibody, was chemically conjugated to maleimide-activated aequorin to prepare aequorin-labeled H3S10P (AQ-S-H3S10P). For the serine/threonine kinase assay, a non-phosphorylated serine peptide (K9C peptide) coated on a microplate was incubated with serine/threonine protein kinase in the presence of ATP and Mg2+. The resulting phosphorylated K9C peptides (K9P peptide) were identified using AQ-S-H3S10P. Thus, after the removal of unbound AQ-S-H3S10P though washing, the serine/threonine kinase activity was determined by the luminescence activity of aequorin from AQ-S-H3S10P bound to the K9P peptide. This assay system, in combination with the K9C peptide and AQ-S-H3S10P, could be used to screen inhibitors of various serine/threonine protein kinases in general.


Asunto(s)
Aequorina , Anticuerpos Monoclonales , Aequorina/metabolismo , Anticuerpos Monoclonales/metabolismo , Inmunoensayo/métodos , Péptidos/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas/metabolismo , Treonina/metabolismo , Especificidad por Sustrato
5.
Haematologica ; 108(3): 811-821, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36200417

RESUMEN

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).


Asunto(s)
Linfoma de Células T Periférico , Neutropenia , Trombocitopenia , Humanos , Inhibidores de Histona Desacetilasas/efectos adversos , Recurrencia Local de Neoplasia/patología , Benzamidas/uso terapéutico , Neutropenia/tratamiento farmacológico , Trombocitopenia/tratamiento farmacológico , Resultado del Tratamiento
6.
Biol Pharm Bull ; 45(8): 1203-1207, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35908903

RESUMEN

The opioid system in the central nervous system regulates depressive-like behavior in animals. Opioid receptors and their endogenous ligands have been focused on as novel therapeutic targets for depression. We synthesized dermorphin (DRM)-dynorphin (DYN) analogs (DRM-DYN001-004) using the message-address concept concerning interactions with opioid receptors. It has previously been reported that DRM-DYN001, 003, and 004 have shown high affinities for µ- and κ-opioid receptors, whereas all analogs had a lower affinity for the δ-opioid receptor than for other receptors using a receptor binding assay. However, it remains unknown whether these analogs show antidepressant-like effects in mice. We examined the effects of DRM-DYN analogs on the duration of immobile behavior in a tail suspension test. Intracerebroventricular administration of DRM-DYN001 in mice shortened the duration of immobile behavior, but did not affect locomotion. The DRM-DYN001-induced antidepressant-like effect was inhibited by co-administration of naloxone (non-selective opioid receptor antagonist), naloxonazine (selective µ1-opioid receptor antagonist), or nor-BNI (κ-opioid receptor antagonist), but not naltrindole (δ-opioid receptor antagonist). These data suggest that DRM-DYN001 exerts an antidepressant-like effect via activation of the central µ1- and κ-opioid receptors in mice and may represent a new lead peptide for further investigation for the development of novel therapeutic approaches for depression.


Asunto(s)
Antidepresivos , Dinorfinas , Péptidos Opioides , Receptores Opioides kappa , Animales , Antidepresivos/administración & dosificación , Antidepresivos/farmacología , Dinorfinas/administración & dosificación , Dinorfinas/química , Ratones , Antagonistas de Narcóticos/farmacología , Péptidos Opioides/administración & dosificación , Péptidos Opioides/química , Receptores Opioides , Receptores Opioides kappa/metabolismo
7.
Jpn J Clin Oncol ; 52(9): 1014-1020, 2022 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-35649345

RESUMEN

OBJECTIVE: HBI-8000 (tucidinostat) is a novel, oral histone deacetylase inhibitor that selectivity inhibits Class I (histone deacetylase 1, 2, 3) and Class II (histone deacetylase 10) with direct anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It has been approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma. METHODS: This multicenter, prospective phase I dose-escalation trial evaluating the safety of twice weekly HBI-8000 was conducted in Japan. Eligible patients had non-Hodgkin's lymphoma and no available standard therapy. The primary endpoint was maximum tolerated dose; secondary endpoints included anti-tumor activity, safety and pharmacokinetics. RESULTS: Fourteen patients were enrolled in the study. Twelve patients were assessed for dose-limiting toxicity: six patients in the 30 mg BIW cohort had no dose-limiting toxicitys; two of six patients in the 40 mg BIW cohort had asymptomatic dose-limiting toxicitys. Treatment was well tolerated; adverse events were predominantly mild to moderate hematologic toxicities and were managed with dose modification and supportive care. Thirteen patients were included in the efficacy analysis. Objective response was seen in five of seven patients in the 40 mg BIW cohort; three partial responders had adult T-cell leukemia-lymphoma. In the 30 mg BIW cohort, three of six patients had stable disease after the first cycle. CONCLUSIONS: Treatment with HBI-8000 30 and 40 mg BIW were well-tolerated and safe, with hematological toxicities as expected from other studies of histone deacetylase inhibitor. The maximum tolerated dose and recommended dosage for phase II studies of HBI-8000 is 40 mg BIW. Preliminary efficacy results are encouraging.


Asunto(s)
Linfoma de Células T Periférico , Neoplasias , Adulto , Aminopiridinas , Benzamidas , Histona Desacetilasa 1 , Inhibidores de Histona Desacetilasas/efectos adversos , Histona Desacetilasas , Humanos , Japón , Dosis Máxima Tolerada , Estudios Prospectivos , Piridinas
8.
Cancer Sci ; 113(8): 2778-2787, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35579212

RESUMEN

This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.


Asunto(s)
Leucemia-Linfoma de Células T del Adulto , Linfoma Folicular , Adulto , Benzamidas , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Linfoma Folicular/tratamiento farmacológico , Estudios Prospectivos , Piridinas , Recurrencia , Resultado del Tratamiento
9.
Front Behav Neurosci ; 16: 1008623, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36620856

RESUMEN

Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the N-methyl-D-aspartate receptor and the GABAA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.

10.
Cell Chem Biol ; 28(8): 1132-1144.e9, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-33561428

RESUMEN

Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3-G12-biased agonist that promotes nitric oxide production and oxidative stress. The oxidative stress triggered by ALESIA resulted in the exhaustion of glucose, cellular NADPH deficiency, and then cancer cell death. Intraperitoneal administration of ALESIA improved the survival of mice with peritoneally disseminated rhabdomyosarcoma, indicating its potential as a new type of anticancer drug for glucose starvation therapy.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Glucosa/metabolismo , Neoplasias/tratamiento farmacológico , Receptores de Esfingosina-1-Fosfato/agonistas , Animales , Antineoplásicos/química , Línea Celular , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Estrés Oxidativo/efectos de los fármacos , Receptores de Esfingosina-1-Fosfato/metabolismo
11.
Behav Brain Res ; 377: 112226, 2020 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-31521737

RESUMEN

Neonatal ventral hippocampal-lesioned (NVHL) rats have been shown to display neurochemical and behavioral abnormalities at adulthood, analogous to some of those seen in schizophrenia. Serotonergic neurotransmission is implicated the pathophysiology and treatment of schizophrenia. In this study, we evaluated possible role of serotonergic transmission is the behaviors of NVHL-lesioned rats. Bilateral lesions to the ventral hippocampus (VH) in rat pups were made using the excitotoxin ibotenic acid. We investigated 5-HT2A-receptor and SERT binding sites in cortical and subcortical areas in post-pubertal NVHL and sham-lesioned rats, using quantitative receptor autoradiography. We compared a 5-HT-dependent behavior in NVHL and sham animals, the wet-dog shake response (WDSr) to a 5-HT2A receptor agonist DOI. In addition, we studied prepulse inhibition (PPI) of startle responses in NVHL and Sham-lesioned animals treated with antipsychotic drugs haloperidol, risperidone and clozapine and 5-HT2A antagonists ketanserin or MDL100907. The WDSr elicited by DOI was enhanced in post-pubertal NVHL rats compared to sham-lesioned controls. Moreover, post-pubertal NVHL rats exhibited PPI deficits which was reversed by atypical antipsychotics, ketanserin and MDL100907. A significant increase in 5-HT2A-like receptor binding was observed in the medial prefrontal cortex (mPFC) in post-pubertal NVHL rats without any significant change in the striatum and ventral pallidum. A significant increase in SERT-like binding was also observed in the mPFC and striatum of NVHL rats at pre-pubertal period; however, at post-pubertal age, the binding remained elevated in mPFC only. These data suggest that increased prefrontal cortical 5-HT transmission may play a role in the behavioral deficits observed in this neurodevelopmental model of schizophrenia.


Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/fisiología , Hipocampo/patología , Corteza Prefrontal/metabolismo , Inhibición Prepulso/fisiología , Receptor de Serotonina 5-HT2A/metabolismo , Esquizofrenia , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Autorradiografía , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Corteza Prefrontal/efectos de los fármacos , Inhibición Prepulso/efectos de los fármacos , Ratas , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Maduración Sexual/fisiología
12.
J Neuroinflammation ; 16(1): 201, 2019 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-31672153

RESUMEN

BACKGROUND: Patients with inflammatory bowel disease (IBD), including those with ulcerative colitis and Crohn's disease, have higher rates of psychiatric disorders, such as depression and anxiety; however, the mechanism of psychiatric disorder development remains unclear. Mice with IBD induced by dextran sulfate sodium (DSS) in drinking water exhibit depressive-like behavior. The presence of Lactobacillus in the gut microbiota is associated with major depressive disorder. Therefore, we examined whether Enterococcus faecalis 2001 (EF-2001), a biogenic lactic acid bacterium, prevents DSS-induced depressive-like behavior and changes in peripheral symptoms. METHODS: We evaluated colon inflammation and used the tail suspension test to examine whether EF-2001 prevents IBD-like symptoms and depressive-like behavior in DSS-treated mice. The protein expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), X-linked inhibitor of apoptosis protein (XIAP), and cleaved caspase-3 in the rectum and hippocampus was assessed by western blotting. Hippocampal neurogenesis, altered nuclear factor-kappa B (NFκB) p65 morphometry, and the localization of activated NFκB p65 and XIAP were examined by immunohistochemistry. RESULTS: Treatment with 1.5% DSS for 7 days induced IBD-like pathology and depressive-like behavior, increased TNF-α and IL-6 expression in the rectum and hippocampus, activated caspase-3 in the hippocampus, and decreased hippocampal neurogenesis. Interestingly, these changes were reversed by 20-day administration of EF-2001. Further, EF-2001 administration enhanced NFκB p65 expression in the microglial cells and XIAP expression in the hippocampus of DSS-treated mice. CONCLUSION: EF-2001 prevented IBD-like pathology and depressive-like behavior via decreased rectal and hippocampal inflammatory cytokines and facilitated the NFκB p65/XIAP pathway in the hippocampus. Our findings suggest a close relationship between IBD and depression.


Asunto(s)
Colitis/microbiología , Colitis/fisiopatología , Depresión/fisiopatología , Enterococcus faecalis , Neuroinmunomodulación/fisiología , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Colitis/inducido químicamente , Depresión/etiología , Sulfato de Dextran/toxicidad , Masculino , Ratones
13.
Neuropharmacology ; 150: 1-14, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-30831160

RESUMEN

Methylazoxymethanol (MAM)-treated pregnant rat at gestation day (GD) 17 has been shown to be a valuable developmental animal model for schizophrenia. Yet, this model remains to be established in mice. In the present study, we examined behavioral, cytoarchitectural, and neurochemical changes in the offspring of MAM-treated mice and validated the model's face, construct and predictive validities. We found that in contrast to a single injection of MAM to dams at GD 15, 16 or 17, its daily administration from GD 15 to 17 led to deficits in prepulse inhibition (PPI) of startle in the post-pubertal offspring. In addition, we observed behavioral deficits in working memory and social interactions, as well as an increase in locomotor activity induced by the NMDA antagonist MK-801 in GD15-17 MAM offspring. These animals also showed a reduction in the volume of the prefrontal cortex (PFC) and hippocampus, neuroanatomical changes such as discontinuities and heterotopias in the hippocampus, and an increase of DA level and DOPAC/DA ratio in the medial PFC. Atypical antipsychotic drugs clozapine, risperidone, and aripiprazole, but not the typical drug haloperidol, reversed the deficit in PPI and social withdrawal in the offspring of MAM-treated dams. In contrast, MK-801-induced hyperactivity in MAM mice was reversed by both and typical or atypical antipsychotic drugs. Taken together, the treatment of pregnant mice with MAM during GD 15-17 offers a new approach to study neurobiological mechanisms involved in the pathogenesis of schizophrenia.


Asunto(s)
Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Acetato de Metilazoximetanol/administración & dosificación , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Esquizofrenia/fisiopatología , Animales , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Aripiprazol/farmacología , Aripiprazol/uso terapéutico , Clozapina/farmacología , Clozapina/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Haloperidol/farmacología , Haloperidol/uso terapéutico , Ratones , Actividad Motora/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Inhibición Prepulso/efectos de los fármacos , Risperidona/farmacología , Risperidona/uso terapéutico , Esquizofrenia/tratamiento farmacológico
14.
Clin Cancer Res ; 24(18): 4518-4528, 2018 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-29712686

RESUMEN

Purpose: Cervical cancer is one of the leading causes of cancer-related deaths among women worldwide. The purpose of this study is to assess the therapeutic effect of the newly developed cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on cervical neoplasia induced by human papillomavirus (HPV) infection.Experimental Design: We examined FIT-039 for its effect on HPV gene expression in HPV+ cervical cancer cells. Primary keratinocytes monolayer and organotypic raft culture models were used to evaluate HPV viral replication and cervical intraepithelial neoplasia (CIN) phenotypes. Preclinical pharmacokinetics and toxicity tests for FIT-039 were also conducted. Finally, the anti-HPV effect of FIT-039 was further examined in vivo, using HPV+ cervical cancer xenografts.Results: FIT-039 inhibits HPV replication and expression of E6 and E7 viral oncogenes, restoring tumor suppressors p53 and pRb in HPV+ cervical cancer cells. The therapeutic effect of FIT-039 was demonstrated in CIN model of an organotypic raft culture, where FIT-039 suppressed HPV18-induced dysplasia/hyperproliferation with reduction in viral load. FIT-039 also repressed growth of HPV16+, but not HPV- cervical cancer xenografts without any significant adverse effects. Safety and pharmacokinetics of FIT-039 were confirmed for systemic and topical routes.Conclusions: The CDK9 inhibitor FIT-039 showed potent anti-HPV activity without significant toxicity in preclinical studies. Thus, FIT-039 is expected to be a novel therapeutic for CIN to prevent cervical cancer. Clin Cancer Res; 24(18); 4518-28. ©2018 AACR.


Asunto(s)
Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Infecciones por Papillomavirus/tratamiento farmacológico , Piridinas/farmacología , Displasia del Cuello del Útero/tratamiento farmacológico , Animales , Proliferación Celular/efectos de los fármacos , Quinasa 9 Dependiente de la Ciclina/genética , Femenino , Regulación Viral de la Expresión Génica/efectos de los fármacos , Xenoinjertos , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/patogenicidad , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/virología , Ratones , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Cultivo Primario de Células , Proteínas Represoras/genética , Proteína p53 Supresora de Tumor/genética , Replicación Viral/efectos de los fármacos , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virología
15.
Stud Health Technol Inform ; 225: 1060-1, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27332483

RESUMEN

A survey was conducted about nursing information in volunteer activities of nursing faculty members and students after the Great East Japan Earthquake. Results indicated that it was important to attempt collecting information in every possible way and to always be prepared. During activities, it is important to record information, to share information with individuals other than nursing professionals and to make good use of it.


Asunto(s)
Terremotos , Docentes de Enfermería , Informática Aplicada a la Enfermería , Estudiantes de Enfermería , Voluntarios , Desastres , Humanos , Japón , Encuestas y Cuestionarios
16.
Behav Brain Res ; 297: 315-22, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26497104

RESUMEN

We have reported that the carborane compound BE360 is a novel selective estrogen receptor modulator and new therapy option for osteoporosis. The aim of this study was to explore the effects and underlying mechanisms of BE360 on depressive-like behavior and memory impairment in the olfactory bulbectomized (OBX) mice, an experimental animal model of depression and dementia. BE360 was administered subcutaneously to mice using a mini-osmotic pump for 2 weeks. Depressive-like behavior was measured as the reduced intake of a sweet solution in the sucrose preference test. Short-term memory was assessed using the Y-maze test. Cell proliferation was assessed by the analysis of cells expressing 5-bromo-2'-deoxyuridine (BrdU) uptake. The expression of phosphorylated cyclic-AMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were measured by immunoblot. The depressive-like behavior and memory impairment in OBX mice were improved by the chronic treatment with BE360. Immunohistochemical analysis showed that the number of BrdU-positive cells in the dentate gyrus of the hippocampus significantly decreased in OBX mice whereas they increased after the chronic treatment with BE360. Immunoblotting studies revealed that pCREB and BDNF were significantly increased in the hippocampus of OBX mice treated with BE360. The present study has shown that BE360 has antidepressant and antidementia effects characterized by hippocampal cell proliferation potentially activated via CREB/BDNF signaling pathways. These results indicate that BE360 may have valuable therapeutic potential against depression and neurodegenerative diseases.


Asunto(s)
Antidepresivos/farmacología , Compuestos de Boro/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Nootrópicos/farmacología , Anhedonia/efectos de los fármacos , Anhedonia/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Trastorno Depresivo/patología , Trastorno Depresivo/fisiopatología , Modelos Animales de Enfermedad , Femenino , Hipocampo/patología , Hipocampo/fisiopatología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/efectos de los fármacos , Memoria a Corto Plazo/fisiología , Ratones , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Bulbo Olfatorio/fisiopatología , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Transducción de Señal/efectos de los fármacos
17.
Proc Natl Acad Sci U S A ; 112(9): 2764-9, 2015 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-25675486

RESUMEN

Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by missplicing of exon 20, resulting from an intronic mutation in the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene encoding IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1). A newly established splicing reporter assay allowed us to visualize pathogenic splicing in cells and to screen small chemicals for the ability to correct the aberrant splicing of IKBKAP. Using this splicing reporter, we screened our chemical libraries and identified a compound, rectifier of aberrant splicing (RECTAS), that rectifies the aberrant IKBKAP splicing in cells from patients with FD. Here, we found that the levels of modified uridine at the wobble position in cytoplasmic tRNAs are reduced in cells from patients with FD and that treatment with RECTAS increases the expression of IKAP and recovers the tRNA modifications. These findings suggest that the missplicing of IKBKAP results in reduced tRNA modifications in patients with FD and that RECTAS is a promising therapeutic drug candidate for FD.


Asunto(s)
Proteínas Portadoras/metabolismo , Disautonomía Familiar/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacología , Intrones , Empalme del ARN/efectos de los fármacos , Proteínas Portadoras/genética , Disautonomía Familiar/tratamiento farmacológico , Disautonomía Familiar/genética , Células HeLa , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Mutación , Empalme del ARN/genética , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Factores de Elongación Transcripcional
18.
J Clin Invest ; 124(8): 3479-88, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25003190

RESUMEN

A wide range of antiviral drugs is currently available; however, drug-resistant viruses have begun to emerge and represent a potential public health risk. Here, we explored the use of compounds that inhibit or interfere with the action of essential host factors to prevent virus replication. In particular, we focused on the cyclin-dependent kinase 9 (CDK9) inhibitor, FIT-039, which suppressed replication of a broad spectrum of DNA viruses through inhibition of mRNA transcription. Specifically, FIT-039 inhibited replication of herpes simplex virus 1 (HSV-1), HSV-2, human adenovirus, and human cytomegalovirus in cultured cells, and topical application of FIT-039 ointment suppressed skin legion formation in a murine HSV-1 infection model. FIT-039 did not affect cell cycle progression or cellular proliferation in host cells. Compared with the general CDK inhibitor flavopiridol, transcriptome analyses of FIT-039-treated cells revealed that FIT-039 specifically inhibited CDK9. Given at concentrations above the inhibitory concentration, FIT-039 did not have a cytotoxic effect on mammalian cells. Importantly, administration of FIT-039 ameliorated the severity of skin lesion formation in mice infected with an acyclovir-resistant HSV-1, without noticeable adverse effects. Together, these data indicate that FIT-039 has potential as an antiviral agent for clinical therapeutics.


Asunto(s)
Antivirales/farmacología , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Virus ADN/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Replicación Viral/efectos de los fármacos , Aciclovir/farmacología , Adenovirus Humanos/efectos de los fármacos , Adenovirus Humanos/fisiología , Animales , Antivirales/química , Antivirales/toxicidad , Citomegalovirus/efectos de los fármacos , Citomegalovirus/fisiología , Virus ADN/genética , Virus ADN/fisiología , Modelos Animales de Enfermedad , Farmacorresistencia Viral , Flavonoides/farmacología , Células HEK293 , Células HeLa , Herpes Simple/tratamiento farmacológico , Herpes Simple/patología , Herpes Simple/virología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/fisiología , Herpesvirus Humano 2/efectos de los fármacos , Herpesvirus Humano 2/fisiología , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/genética , Humanos , Ratones , Ratones Endogámicos ICR , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/toxicidad , Piridinas/química , Piridinas/toxicidad , Ratas , Ratas Wistar , Transcripción Genética/efectos de los fármacos , Transcriptoma/efectos de los fármacos
19.
Life Sci ; 92(2): 119-24, 2013 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-23159642

RESUMEN

AIMS: Olfactory bulbectomy (OBX) in rodents represents a valuable experimental model of depression. This study was designed to shed further light on the impact of putative serotonergic neuronal degeneration in OBX mice and to assess the effect of a widely used antidepressant on serotonergic related behavioral changes induced by OBX. MAIN METHODS: Adult male ddY mice were subject to bilateral OBX or sham surgery. The serotonin (5-HT)(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) enhanced a head-twitch response (HTR) in OBX mice. Effects of 5-HT(2A), 5-HT(2C) antagonists and fluvoxamine were observed in OBX mice following DOI administration. KEY FINDINGS: The HTR elicited by the administration of DOI (0.5 mg/kg and 1 mg/kg, i.p.) was increased about twofold in OBX mice when compared with controls on the 14th day after the surgery. The injection of ketanserin (0.025 mg/kg, i.p.), a 5-HT(2A) receptor antagonist, inhibited the enhancement of the DOI-induced HTR after OBX. Likewise, the administration of SB 242084 (1 mg/kg, s.c.), a 5-HT(2C) receptor antagonist, also inhibited the DOI-induced HTR in OBX mice. Chronic but not acute treatment with the antidepressant fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), suppressed the enhancement of DOI-induced HTR after OBX. SIGNIFICANCE: These findings indicate that OBX, and the subsequent degeneration of neurons projecting from the olfactory bulb, caused a supersensitivity of 5-HT(2A/2C) receptors which may be involved in symptoms of depression.


Asunto(s)
Trastorno Depresivo/tratamiento farmacológico , Fluvoxamina/uso terapéutico , Bulbo Olfatorio/cirugía , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Anfetaminas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Fluvoxamina/farmacología , Movimientos de la Cabeza/efectos de los fármacos , Movimientos de la Cabeza/fisiología , Masculino , Ratones , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología
20.
PLoS One ; 6(8): e23246, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21858043

RESUMEN

Dengue virus (DENV) is the etiologic agent for dengue fever, for which there is no approved vaccine or specific anti-viral drug. As a remedy for this, we explored the use of compounds that interfere with the action of required host factors and describe here the characterization of a kinase inhibitor (SFV785), which has selective effects on NTRK1 and MAPKAPK5 kinase activity, and anti-viral activity on Hepatitis C, DENV and yellow fever viruses. SFV785 inhibited DENV propagation without inhibiting DENV RNA synthesis or translation. The compound did not cause any changes in the cellular distribution of non-structural 3, a protein critical for DENV RNA synthesis, but altered the distribution of the structural envelope protein from a reticulate network to enlarged discrete vesicles, which altered the co-localization with the DENV replication complex. Ultrastructural electron microscopy analyses of DENV-infected SFV785-treated cells showed the presence of viral particles that were distinctly different from viable enveloped virions within enlarged ER cisternae. These viral particles were devoid of the dense nucleocapsid. The secretion of the viral particles was not inhibited by SFV785, however a reduction in the amount of secreted infectious virions, DENV RNA and capsid were observed. Collectively, these observations suggest that SFV785 inhibited the recruitment and assembly of the nucleocapsid in specific ER compartments during the DENV assembly process and hence the production of infectious DENV. SFV785 and derivative compounds could be useful biochemical probes to explore the DENV lifecycle and could also represent a new class of anti-virals.


Asunto(s)
Antivirales/farmacología , Azocinas/farmacología , Virus del Dengue/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Tiourea/análogos & derivados , Proteínas del Envoltorio Viral/metabolismo , Ensamble de Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Azocinas/química , Peso Corporal/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Virus del Dengue/genética , Virus del Dengue/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/ultraestructura , Retículo Endoplásmico/virología , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepacivirus/metabolismo , Humanos , Ratones , Ratones Endogámicos ICR , Microscopía Electrónica , Microscopía Fluorescente , Estructura Molecular , Nucleocápside/efectos de los fármacos , Nucleocápside/metabolismo , Nucleocápside/ultraestructura , Inhibidores de Proteínas Quinasas/química , Tiourea/química , Tiourea/farmacología , Células Vero , Proteínas del Envoltorio Viral/genética , Virión/efectos de los fármacos , Virión/metabolismo , Virión/ultraestructura
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