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1.
Gene ; 806: 145920, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34455026

RESUMO

Depression is deemed a mood disorder characterized by a high rate of relapse. Therefore, overcoming of the recurrent depression is globally expecting. Kososan, a traditional Japanese herbal medicine, has been clinically used for mild depressive mood, and our previous studies have shown some evidence for its antidepressive-like efficacy in experimental animal models of depression. However, it remains unclear whether kososan has beneficial effects on recurrent depression. Here, we examined its effect using a mouse model of modified repeated social defeat stress (SDS) paradigm. Male BALB/c mice were exposed to a 5-min SDS from unfamiliar aggressive CD-1 mice for 5 days. Kososan extract (1.0 kg/kg/day) or an antidepressant milnacipran (60 mg/kg/day) was administered orally for 26 days (days 7-32) to depression-like mice with social avoidant behaviors on day 6. Single 5 min of SDS was subjected to mice recovered from the social avoidance on day 31, and then the recurrence of depression-like behaviors was evaluated on day 32. Hippocampal gene expression patterns were also assayed by DNA microarray analysis. Water- or milnacipran-administered mice resulted in a recurrence of depression-like behaviors by re-exposure of single SDS, whereas kososan-administered mice did not recur depression-like behaviors. Distinct gene expression patterns were also found for treating kososan and milnacipran. Collectively, this finding suggests that kososan exerts a preventive effect on recurrent depression-like behaviors in mice. Pretreatment of kososan is more useful for recurrent depression than that of milnacipran.


Assuntos
Antidepressivos/farmacologia , Depressão/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Proteínas do Tecido Nervoso/genética , Derrota Social , Estresse Psicológico/tratamento farmacológico , Administração Oral , Animais , Depressão/genética , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Japão , Masculino , Medicina Kampo/métodos , Camundongos , Camundongos Endogâmicos BALB C , Milnaciprano/farmacologia , Anotação de Sequência Molecular , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Recidiva , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia
3.
Cell Rep ; 36(2): 109380, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34260913

RESUMO

Mechanical stimuli including loading after birth promote bone growth. However, little is known about how mechanical force triggers biochemical signals to regulate bone growth. Here, we identified a periosteal-osteoblast-derived secretory peptide, Osteocrin (OSTN), as a mechanotransducer involved in load-induced long bone growth. OSTN produced by periosteal osteoblasts regulates growth plate growth by enhancing C-type natriuretic peptide (CNP)-dependent proliferation and maturation of chondrocytes, leading to elongation of long bones. Additionally, OSTN cooperates with CNP to regulate bone formation. CNP stimulates osteogenic differentiation of periosteal osteoprogenitors to induce bone formation. OSTN binds to natriuretic peptide receptor 3 (NPR3) in periosteal osteoprogenitors, thereby preventing NPR3-mediated clearance of CNP and consequently facilitating CNP-signal-mediated bone growth. Importantly, physiological loading induces Ostn expression in periosteal osteoblasts by suppressing Forkhead box protein O1 (FoxO1) transcription factor. Thus, this study reveals a crucial role of OSTN as a mechanotransducer converting mechanical loading to CNP-dependent bone formation.

4.
Pain Ther ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34263424

RESUMO

INTRODUCTION: A major goal in neonatal medicine is to reduce stress as much as possible in routine care. Bathing is one of the important routine cares for neonates, but it makes a big environmental change for them. We aimed to examine whether water temperature, room temperature, and position changes in tub bathing serve as noxious stimuli to neonates. METHODS: This prospective trial was performed in full-term and non-low-birth-weight neonates admitted to the hospital between July 2020 and March 2021. Those with underlying diseases, fetal distress, infection, and other medical conditions were excluded. Measurements were taken during the neonates' first tub bath since birth, which was performed by a trained nurse. Changes in regional oxygen saturation (rSO2), determined using near-infrared spectroscopy, and water and room temperature, were examined at five different time points: upon entering the bath, head washing, position change, exiting the bath, and during the 3 min after bathing. RESULTS: In total, 17 neonates were analyzed. No changes in rSO2 due to head washing or position change were observed; however, rSO2 significantly decreased upon entering (78.5 ± 4.1% vs. 75.7 ± 4.1%, p < 0.001) and exiting the bath (75.8 ± 5.7% vs. 74.4 ± 5.4%, p < 0.04). The rate change in rSO2 upon entering the bath showed a significant inverse correlation with water temperature (r = - 0.53, p < 0.03), and there were no significant correlations between rSO2 and water or room temperature upon exiting the bath. There was no change in body skin temperature before and after bathing, but rSO2 gradually decreased during the 3 min after bathing. CONCLUSIONS: Neonates may perceive certain temperatures during bathing as noxious stimuli. Therefore, methods to minimize stress associated with bathing should be implemented to reduce the difference between water temperature and room temperature during bathing. TRIAL REGISTRATION: This trial has been registered at UMIN repository with the trial number UMIN000041045 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046500 ). The date of the final dataset was April 01, 2021.

5.
Glob Health Med ; 3(3): 175-179, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34250294

RESUMO

The Japan Drug Information Institute in Pregnancy (JDIIP) was established with the aims of providing information on drug safety to women who are worried about drug use during pregnancy and creating evidence through epidemiological studies based on counseling cases. Since being established, JDIIP has made many contributions to the wellness of mothers and children by promoting the proper use of drugs during pregnancy. A network consisting of Core hospitals in 47 prefectures plays an important role in providing information for women living anywhere in Japan. Because cases of exposure to drugs whose safety we want to analyze are usually rare, networks of domestic and foreign teratology information services are necessary in order to produce high-quality evidence. JDIIP has been contributing to the education of pharmacists and doctors and to the creation of clinical practice guidelines in various medical societies by using keywords such as "pregnancy" and "medication". Future issues include creating an environment that is easily accessible for those seeking consultation, building a mechanism that makes it easy to create a basis for safety, and aiming for the continuing development of the organization.

6.
J Pharm Sci ; 110(10): 3484-3490, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34102205

RESUMO

The likelihood of reoccurrence of acute lymphoblastic leukemia is influenced by the cerebral concentration of the therapeutic agent 6-mercaptopurine (6-MP) during treatment. Therefore, it is important to understand the blood-brain barrier (BBB) transport mechanism of 6-MP. The purpose of this study was to characterize this mechanism using human induced pluripotent stem cell-derived microvascular endothelial cells (hiPS-BMECs). The permeability coefficient of 6-MP across hiPS-BMECs monolayer in the basal-to-apical direction (B-to-A) was significantly greater than that in the opposite direction (A-to-B). The inhibition profiles of 6-MP transport in the A-to-B direction were different from those in the B-to-A direction. Transport in the A-to-B direction was mainly inhibited by adenine (an inhibitor of equilibrative nucleobase transporter 1; ENBT1), while transport in the B-to-A direction was significantly reduced by inhibitors of multidrug resistance-associated proteins (MRPs), especially zaprinast (an MRP5 inhibitor). Immunocytochemical analyses demonstrated the expression of ENBT1 and MRP5 proteins in hiPS-BMECs. We confirmed that the cellular uptake of 6-MP is decreased by ENBT1 inhibitors in hiPS-BMECs and by knockdown of ENBT1 in hCMEC/D3 cells. These results suggest that ENBT1 and MRP5 make substantial contributions to the transport of 6-MP in hiPS-BMECs and hCMEC/D3 cells.


Assuntos
Células-Tronco Pluripotentes Induzidas , Mercaptopurina , Transporte Biológico , Barreira Hematoencefálica , Encéfalo , Células Endoteliais , Humanos
7.
Hinyokika Kiyo ; 67(5): 181-185, 2021 May.
Artigo em Japonês | MEDLINE | ID: mdl-34126660

RESUMO

Gemcitabine (GEM) is currently a standard chemotherapeutic agent for metastatic urothelial carcinoma (mUC). Fever isknown to be an adverse effect of GEM ; however, itsincidence, etiology and clinical significance have not been evaluated. The objective of this study was to elucidate the characteristics and clinical significance of fever associated with GEM in patients with mUC receiving GEM plus cisplatin (GC) chemotherapy. Between 2005 and 2014, 184 patientswith mUC who received first-line GC therapy at 10 institutions were enrolled. GEM-associated fever (GEMAF) was defined as a body temperature ≥37.5ºC within 96 hours after administration of GEM with no evidence of specific conditions causing fever including infection. Clinical parametersbefore GC therapy were evaluated to determine predictorsof GEMAF. Furthermore, the impact of GEMAF on clinical outcomeswasals o evaluated. The median age was70 years and median follow-up was14.2 months. GEMAF wasobs erved in 44 patients (23.9%). In multivariate analysis, elevated C-reactive protein (CRP) before chemotherapy was an independent predictive factor for GEMAF (oddsratio 2.450, p=0.041). There was a significant difference in progression-free survival (median 6.7 vs 8.0 months, p=0.031) and cancer-specific survival (median 12.0 vs 15.8 months, p=0.045) between patients with and without GEMAF. Results of this study suggest that GEMAF is a common adverse event of GC therapy for mUC and can be a poor prognostic factor. GEMAF may be associated with systemic inflammatory response induced by the tumor in patients with mUC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células de Transição , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Cisplatino/efeitos adversos , Desoxicitidina/análogos & derivados , Humanos , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
8.
Sci Rep ; 11(1): 9168, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33911096

RESUMO

Spaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g; AG) and microgravity (µg; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.


Assuntos
Regulação da Expressão Gênica , Músculo Esquelético/fisiologia , Atrofia Muscular/genética , Ausência de Peso , Adaptação Biológica/genética , Animais , Canais de Cálcio/genética , Linhagem Celular , Perfilação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiopatologia , Voo Espacial
9.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807264

RESUMO

Skeletal muscle regeneration is a well-organized process that requires remodeling of the extracellular matrix (ECM). In this study, we revealed the protective role of periostin, a matricellular protein that binds to several ECM proteins during muscle regeneration. In intact muscle, periostin was localized at the neuromuscular junction, muscle spindle, and myotendinous junction, which are connection sites between muscle fibers and nerves or tendons. During muscle regeneration, periostin exhibited robustly increased expression and localization at the interstitial space. Periostin-null mice showed decreased muscle weight due to the loss of muscle fibers during repeated muscle regeneration. Cultured muscle progenitor cells from periostin-null mice showed no deficiencies in their proliferation, differentiation, and the expression of Pax7, MyoD, and myogenin, suggesting that the loss of muscle fibers in periostin-null mice was not due to the impaired function of muscle stem/progenitor cells. Periostin-null mice displayed a decreased number of CD31-positive blood vessels during muscle regeneration, suggesting that the decreased nutritional supply from blood vessels was the cause of muscle fiber loss in periostin-null mice. These results highlight the novel role of periostin in maintaining muscle mass during muscle regeneration.


Assuntos
Moléculas de Adesão Celular/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Regeneração/fisiologia , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/fisiologia , Diferenciação Celular , Junções Célula-Matriz/metabolismo , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Tendões/metabolismo , Cicatrização/fisiologia
10.
J Biol Chem ; 296: 100620, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33811862

RESUMO

Mouse models of various neuropsychiatric disorders, such as schizophrenia, often display an immature dentate gyrus, characterized by increased numbers of immature neurons and neuronal progenitors and a dearth of mature neurons. We previously demonstrated that the CRMP5-associated GTPase (CRAG), a short splice variant of Centaurin-γ3/AGAP3, is highly expressed in the dentate gyrus. CRAG promotes cell survival and antioxidant defense by inducing the activation of serum response factors at promyelocytic leukemia protein bodies, which are nuclear stress-responsive domains, during neuronal development. However, the physiological role of CRAG in neuronal development remains unknown. Here, we analyzed the role of CRAG using dorsal forebrain-specific CRAG/Centaurin-γ3 knockout mice. The mice revealed maturational abnormality of the hippocampal granule cells, including increased doublecortin-positive immature neurons and decreased calbindin-positive mature neurons, a typical phenotype of immature dentate gyri. Furthermore, the mice displayed hyperactivity in the open-field test, a common measure of exploratory behavior, suggesting that these mice may serve as a novel model for neuropsychiatric disorder associated with hyperactivity. Thus, we conclude that CRAG is required for the maturation of neurons in the dentate gyrus, raising the possibility that its deficiency might promote the development of psychiatric disorders in humans.


Assuntos
Giro Denteado/patologia , GTP Fosfo-Hidrolases/fisiologia , Células-Tronco Neurais/patologia , Neurogênese , Neurônios/patologia , Prosencéfalo/patologia , Agitação Psicomotora/patologia , Animais , Giro Denteado/metabolismo , Comportamento Exploratório , Feminino , Masculino , Camundongos , Camundongos Knockout , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Prosencéfalo/metabolismo , Agitação Psicomotora/etiologia , Agitação Psicomotora/metabolismo
11.
Commun Biol ; 4(1): 192, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33580194

RESUMO

Mitochondrial pathophysiology is implicated in the development of Alzheimer's disease (AD). An integrative database of gene dysregulation suggests that the mitochondrial ubiquitin ligase MITOL/MARCH5, a fine-tuner of mitochondrial dynamics and functions, is downregulated in patients with AD. Here, we report that the perturbation of mitochondrial dynamics by MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in a mouse model with AD-related Aß pathology. Notably, MITOL deletion in the brain enhanced the seeding effect of Aß fibrils, but not the spontaneous formation of Aß fibrils and plaques, leading to excessive secondary generation of toxic and dispersible Aß oligomers. Consistent with this, MITOL-deficient mice with Aß etiology exhibited worsening cognitive decline depending on Aß oligomers rather than Aß plaques themselves. Our findings suggest that alteration in mitochondrial morphology might be a key factor in AD due to directing the production of Aß form, oligomers or plaques, responsible for disease development.


Assuntos
Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/enzimologia , Mitocôndrias/enzimologia , Proteínas Mitocondriais/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Animais , Comportamento Animal , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Cognição , Modelos Animais de Doenças , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Placa Amiloide , Proteínas de Ligação a Poli(A)/genética , Proteínas de Ligação a Poli(A)/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Agregados Proteicos , Agregação Patológica de Proteínas , Ubiquitina-Proteína Ligases/genética
12.
EMBO Rep ; 22(3): e49097, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33565245

RESUMO

Parkin promotes cell survival by removing damaged mitochondria via mitophagy. However, although some studies have suggested that Parkin induces cell death, the regulatory mechanism underlying the dual role of Parkin remains unknown. Herein, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) regulates Parkin-mediated cell death through the FKBP38-dependent dynamic translocation from the mitochondria to the ER during mitophagy. Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine-tunes mitophagy by controlling the quantity of Parkin. Deletion of MITOL leads to accumulation of the phosphorylated active form of Parkin in the ER, resulting in FKBP38 degradation and enhanced cell death. Thus, we have shown that MITOL blocks Parkin-induced cell death, at least partially, by protecting FKBP38 from Parkin. Our findings unveil the regulation of the dual function of Parkin and provide a novel perspective on the pathogenesis of PD.


Assuntos
Mitofagia , Ubiquitina-Proteína Ligases , Sobrevivência Celular , Células HeLa , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
13.
Int Urogynecol J ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33580329

RESUMO

INTRODUCTION AND HYPOTHESIS: Little is known about the prevalence of pelvic organ prolapse (POP). We aimed to evaluate the prevalence of POP and identify its risk factors in Japan. METHODS: This was a single-centre, cross-sectional study. We recruited Japanese women seen for a Pap smear from July 2018 through May 2019. After providing their informed consent, subjects were asked to complete questionnaires. Pelvic organ support was assessed using the POP quantification (POP-Q) system by an examiner. Logistic regression analyses were conducted to identify risk factors for POP. RESULTS: There were 1032 women aged 21 to 84 years. The distribution of POP-Q stage was stage 0, 38.0%; stage I, 45.0%; stage II, 16.4%; stage III, 0.6%; and stage IV, 0%. Rates (95% confidence interval [CI]) of stage II or greater in each age group were 6.6% (2.4-10.8) in 20 s-30 s; 17.6% (13.3-21.9) in 40 s; 17.1% (12.9-21.3) in 50 s; 18.0% (12.6-23.4) in 60 s; and 28.7% (19.6-37.9) in 70 s and over. Multivariate analysis revealed the following risk factors for POP, with odds ratio (95% CI): body mass index [BMI] ≥ 25 kg/m2, 1.63 (1.05-2.51); BMI < 18.5 kg/m2, 0.40 (0.17-0.94); hysterectomy, 4.09 (1.55-10.80); ≥ 3 vaginal deliveries, 2.26 (1.19-4.28); and ≥ 1 cup of coffee per day, 0.63 (0.43-0.92). CONCLUSION: Among Japanese women undergoing routine gynaecological examinations, 17.1% (14.7-19.5) had POP-Q stage II or greater. Overweight, hysterectomy and ≥ 3 vaginal deliveries increased the risk for POP, whereas underweight and daily coffee consumption decreased it.

14.
Int J Urol ; 28(4): 444-449, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33458939

RESUMO

OBJECTIVE: To determine whether cognitive behavioral therapy using a self-check sheet is effective in improving night-time frequency of patients with nocturia. METHODS: We carried out a multicenter, open-labeled, randomized controlled trial in eight institutions. Patients having two or more episodes of nocturia were randomly assigned to either cognitive behavioral therapy with completion of frequency volume charts regularly (cognitive behavioral therapy group) or frequency volume charts regularly alone (frequency volume charts group). The cognitive behavioral therapy checklist was composed of eight items: wake up time/bedtime, mealtime, napping, alcohol/caffeine intake, water intake, salt intake, exercise and taking a bath. A physician explained cognitive behavioral therapy within 5 min using a brief manual. The patients in the cognitive behavioral therapy group filled out the self-check sheet every day. The primary end-point was the difference in night-time frequency based on the International Prostate Symptom Score Q7 at 4 weeks. RESULTS: Of the 100 first-visit patients randomly allocated, 37 in the cognitive behavioral therapy group and 41 in the frequency volume charts group completed the protocol. No difference was observed in the mean ± standard deviation of night-time frequency at 4 weeks between the cognitive behavioral therapy group (2.6 ± 1.0) and the frequency volume charts group (3.1 ± 1.2; P = 0.056). However, when six patients with achievement of cognitive behavioral therapy of <50% were excluded from the analysis, night-time frequency at 4 weeks was significantly lower in the cognitive behavioral therapy group (2.5 ± 1.0) than in the frequency volume charts group (3.1 ± 1.2; P = 0.027). CONCLUSIONS: The efficacy of cognitive behavioral therapy using a self-check sheet for nocturia remains to be shown. However, strictly practicing cognitive behavioral therapy might be beneficial to these patients.


Assuntos
Terapia Cognitivo-Comportamental , Noctúria , Humanos , Masculino
15.
Exp Gerontol ; 142: 111109, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33069781

RESUMO

Aging causes psychological dysfunction and neurodegeneration, and can lead to cognitive impairments. Although numerous studies have reported that neurodegeneration and subsequent cognitive impairments are involved in neuroinflammation, relationship between psychological disturbance and neuroinflammation with aging (neuroinflammaging) remains unclear. Here, to clarify the relationship, we examined whether neuroinflammaging affects emotional behaviors in senescence-accelerated mouse prone 8 (SAMP8) mice. Microglial inflammatory responses to a subsequent lipopolysaccharide (LPS) challenge were significantly enhanced in male SAMP8 mice relative to normal aging senescence-accelerated mouse resistant 1 (SAMR1) mice at 17 weeks, but not 8 weeks of age. LPS injection also significantly increased brain and systemic inflammation in SAMP8 mice at 17 weeks. In a battery of behavioral tests, SAMP8 mice at 17 weeks, but not 8 weeks, exhibited anxiety- and depression-like behaviors and circadian rhythm disruption. Taken together, SAMP8 mice at 17 weeks possess a brain microenvironment in which it is easier to trigger neuroinflammatory priming; this may lead to an emergence of anxiety- and depression-like behaviors and circadian rhythm disruption. These findings provide new insights into the temporal relationship between neuroinflammaging and emotion.


Assuntos
Envelhecimento , Ritmo Circadiano , Animais , Ansiedade , Encéfalo , Emoções , Masculino , Camundongos
16.
Neuroscience ; 443: 148-163, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32707290

RESUMO

Prolonged stress triggers neuroinflammation, which plays a significant role in the development of depression; however, stressed people do not always suffer from depression because of individual differences in stress vulnerability. Negative cognitive bias (NCB) toward pessimistic judgment often underlies depressive episodes. However, a relationship between stress vulnerability, neuroinflammation, and NCB remains elusive. In addition, an animal model with all the traits would be a powerful tool for studying the etiology of depression and its therapeutic approaches. Accordingly, this study evaluated the effect of stress vulnerability on neuroinflammation and depression-related behaviors, including NCB in males, using a modified version of repeated social defeat stress (mRSDS) paradigm, a validated animal model of psychosocial stress. Exposure to mRSDS, consisting of 5 min of social defeat by unfamiliar CD-1 aggressor mice for five consecutive days, caused NCB, which co-occurred with depressive- and anxiety-like behaviors, and neuroinflammation in male BALB/c mice. Treatment with minocycline, an antibiotic with anti-inflammatory property, blocked mRSDS-induced depressive-like behaviors and neuroinflammation, but not NCB, indicating the limited effect of an anti-inflammatory intervention. In addition, marked differences were found in neuroinflammatory profiles and hippocampal gene expression patterns between resilient and unstressed mice, as well as between susceptible and resilient mice. Therefore, mice resilient to mRSDS are indeed not intact. Our findings provide insights into the unique features of the mRSDS model in male BALB/c mice, which could be used to investigate the etiological mechanisms underlying depression as well as bridge the gap in the relationship between stress vulnerability, neuroinflammation, and NCB in males.


Assuntos
Derrota Social , Estresse Psicológico , Animais , Ansiedade , Depressão/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
17.
J Infect Chemother ; 26(10): 1021-1025, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32576436

RESUMO

Due to the increase in the number of azole-resistant Aspergillus fumigatus, there is an urgent need of data to predict future trends and prevent further spreading. The intercountry transfer of resistant A. fumigatus on plant bulbs have been reported. We investigated existence and characteristics of resistant isolates attached to agricultural products imported to Japan. We purchased 292 samples in Japan. All samples were screened for the existence of azole-resistant A. fumigatus. For positive isolates, minimum inhibitory concentrations of the drugs were determined. We also analyzed Cyp51A, Hmg1, and Erg6 mutations of these isolates and conducted microsatellite genotyping. Fourteen azole-resistant isolates were detected, of which 13 were cultured from flower bulbs imported from the Netherlands. Among them 5 were from 11 bulbs of Hippeastrum (45.5%), 5 were from 24 bulbs of Gladiolus (20.8%), 2 were from 4 bulbs of Ixia (50.0%), and 1 was from 22 bulbs of Tulipa (4.5%). Only 1 resistant isolate was cultured from the 10 bulbs of Narcissus (10.0%) originating in Japan. Various novel mutations including Y121F/T289A in Cyp51A with no tandem repeat in promoter region were discovered from imported strains. Our study provides important data showing that agricultural imports provide a possible route for their intercontinental spread and raises the concern that strains harboring highly diverse Cyp51A mutations might increase in clinical settings in the future.


Assuntos
Aspergilose , Aspergillus fumigatus , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/genética , Azóis/farmacologia , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Humanos , Japão , Testes de Sensibilidade Microbiana
18.
J Biochem ; 168(3): 305-312, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302394

RESUMO

In mitochondrial disorders, short stature and growth failure are common symptoms, but their underlying mechanism remains unknown. In this study, we examined the cause of growth failure of mice induced by nestin promoter-driven knockout of the mitochondrial ubiquitin ligase MITOL (MARCH5), a key regulator of mitochondrial function. MITOL-knockout mice have congenital hypoplasia of the anterior pituitary caused by decreased expression of pituitary transcript factor 1 (Pit1). Consistently, both mRNA levels of growth hormone (GH) and prolactin levels were markedly decreased in the anterior pituitary of mutant mice. Growth failure of mutant mice was partly rescued by hypodermic injection of recombinant GH. To clarify whether this abnormality was induced by the primary effect of MITOL knockdown in the anterior pituitary or a secondary effect of other lesions, we performed lentiviral-mediated knockdown of MITOL on cultured rat pituitary GH3 cells, which secrete GH. GH production was severely compromised in MITOL-knockdown GH3 cells. In conclusion, MITOL plays a critical role in the development of the anterior pituitary; therefore, mice with MITOL dysfunction exhibited pituitary dwarfism caused by anterior pituitary hypoplasia. Our findings suggest that mitochondrial dysfunction is commonly involved in the unknown pathogenesis of pituitary dwarfism.


Assuntos
Nanismo/genética , Nanismo/metabolismo , Proteínas Mitocondriais/genética , Adeno-Hipófise/metabolismo , Ubiquitina-Proteína Ligases/genética , Animais , Linhagem Celular Tumoral , Nanismo/tratamento farmacológico , Técnicas de Silenciamento de Genes , Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Prolactina/genética , Prolactina/metabolismo , RNA Mensageiro/genética , Ratos , Transdução de Sinais/genética , Transfecção
19.
Biomolecules ; 10(3)2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32183225

RESUMO

Mitochondria are highly dynamic organelles that constantly fuse, divide, and move, and their function is regulated and maintained by their morphologic changes. Mitochondrial disease (MD) comprises a group of disorders involving mitochondrial dysfunction. However, it is not clear whether changes in mitochondrial morphology are related to MD. In this study, we examined mitochondrial morphology in fibroblasts from patients with MD (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome). We observed that MD fibroblasts exhibited significant mitochondrial fragmentation by upregulation of Drp1, which is responsible for mitochondrial fission. Interestingly, the inhibition of mitochondrial fragmentation by Drp1 knockdown enhanced cellular toxicity and led to cell death in MD fibroblasts. These results suggest that mitochondrial fission plays a critical role in the attenuation of mitochondrial damage in MD fibroblasts.


Assuntos
Dinaminas/metabolismo , Fibroblastos/metabolismo , Doença de Leigh/metabolismo , Síndrome MELAS/metabolismo , Mitocôndrias/metabolismo , Pele/metabolismo , Morte Celular , Células Cultivadas , Fibroblastos/patologia , Humanos , Doença de Leigh/patologia , Síndrome MELAS/patologia , Mitocôndrias/patologia , Pele/patologia
20.
Sci Rep ; 10(1): 2737, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066765

RESUMO

Astronauts on interplanetary missions - such as to Mars - will be exposed to space radiation, a spectrum of highly-charged, fast-moving particles that includes 56Fe and 28Si. Earth-based preclinical studies show space radiation decreases rodent performance in low- and some high-level cognitive tasks. Given astronaut use of touchscreen platforms during training and space flight and given the ability of rodent touchscreen tasks to assess functional integrity of brain circuits and multiple cognitive domains in a non-aversive way, here we exposed 6-month-old C57BL/6J male mice to whole-body space radiation and subsequently assessed them on a touchscreen battery. Relative to Sham treatment, 56Fe irradiation did not overtly change performance on tasks of visual discrimination, reversal learning, rule-based, or object-spatial paired associates learning, suggesting preserved functional integrity of supporting brain circuits. Surprisingly, 56Fe irradiation improved performance on a dentate gyrus-reliant pattern separation task; irradiated mice learned faster and were more accurate than controls. Improved pattern separation performance did not appear to be touchscreen-, radiation particle-, or neurogenesis-dependent, as 56Fe and 28Si irradiation led to faster context discrimination in a non-touchscreen task and 56Fe decreased new dentate gyrus neurons relative to Sham. These data urge revisitation of the broadly-held view that space radiation is detrimental to cognition.


Assuntos
Cognição/efeitos da radiação , Radiação Cósmica , Giro Denteado/efeitos da radiação , Aprendizagem por Associação de Pares/efeitos da radiação , Reconhecimento Visual de Modelos/efeitos da radiação , Reversão de Aprendizagem/efeitos da radiação , Animais , Astronautas , Ciências Biocomportamentais , Cognição/fisiologia , Giro Denteado/fisiologia , Isótopos de Ferro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/fisiologia , Neurônios/efeitos da radiação , Aprendizagem por Associação de Pares/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Reversão de Aprendizagem/fisiologia , Voo Espacial , Irradiação Corporal Total
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