RESUMO
The skeletal muscle is a pivotal organ involved in the regulation of both energy metabolism and exercise capacity. There is no doubt that exercise contributes to a healthy life through the consumption of excessive energy or the release of myokines. Skeletal muscles exhibit insulin sensitivity and can rapidly uptake blood glucose. In addition, they can undergo non-shivering thermogenesis through actions of both the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and small peptide, sarcolipin, resulting in systemic energy metabolism. Accordingly, the maintenance of skeletal muscles is important for both metabolism and exercise. Prolyl isomerase Pin1 is an enzyme that converts the cis-trans form of proline residues and controls substrate function. We have previously reported that Pin1 plays important roles in insulin release, thermogenesis, and lipolysis. However, the roles of Pin1 in skeletal muscles remains unknown. To clarify this issue, we generated skeletal muscle-specific Pin1 knockout mice. Pin1 deficiency had no effects on muscle weights, morphology and ratio of fiber types. However, they showed exacerbated obesity or insulin resistance when fed with a high-fat diet. They also showed a lower ability to exercise than wild type mice did. We also found that Pin1 interacted with SERCA and elevated its activity, resulting in the upregulation of oxygen consumption. Overall, our study reveals that Pin1 in skeletal muscles contributes to both systemic energy metabolism and exercise capacity.
Assuntos
Metabolismo Energético , Músculo Esquelético , Peptidilprolil Isomerase de Interação com NIMA , Condicionamento Físico Animal , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Animais , Masculino , Camundongos , Dieta Hiperlipídica , Metabolismo Energético/genética , Resistência à Insulina , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genéticaRESUMO
The compound 15-deacetylcalonectrin (15-deCAL) is a common pathway intermediate in the biosynthesis of Fusarium trichothecenes. This tricyclic intermediate is metabolized to calonectrin (CAL) by trichothecene 15-O-acetyltransferase encoded by Tri3. Unlike other trichothecene pathway Tri gene mutants, the Δtri3 mutant produces lower amounts of the knocked-out enzyme's substrate 15-deCAL, and instead, accumulates higher quantities of earlier bicyclic intermediate and shunt metabolites. Furthermore, evolutionary studies suggest that Tri3 may play a role in shaping the chemotypes of trichothecene-producing Fusarium strains. To better understand the functional role of Tri3p in biosynthesis and evolution, we aimed to develop a method to produce 15-deCAL by using transgenic Fusarium graminearum strains derived from a trichothecene overproducer. Unfortunately, introducing mutant Tri3, encoding a catalytically impaired but structurally intact acetylase, did not improve the low 15-deCAL production level of the ΔFgtri3 deletion strain, and the bicyclic products continued to accumulate as the major metabolites of the active-site mutant. These findings are discussed in light of the enzyme responsible for 15-deCAL production in trichothecene biosynthesis machinery. To efficiently produce 15-deCAL, we tested an alternative strategy of using a CAL-overproducing transformant. By feeding a crude CAL extract to a Fusarium commune strain that was isolated in this study and capable of specifically deacetylating C-15 acetyl, 15-deCAL was efficiently recovered. The substrate produced in this manner can be used for kinetic investigations of this enzyme and its possible role in chemotype diversification.
Assuntos
Fusarium , Mutação , Tricotecenos , Fusarium/genética , Fusarium/metabolismo , Tricotecenos/metabolismo , Acetiltransferases/metabolismo , Acetiltransferases/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Vias Biossintéticas/genéticaRESUMO
A well-tuned inflammatory response is crucial for an effective immune process. Nuclear factor-kappa B (NF-κB) is a key mediator of inflammatory and innate immunity responses, and its dysregulation is closely associated with immune-related diseases. MicroRNAs (miRNAs) are important inflammation modulators. However, miRNA-regulated mechanisms that implicate NF-κB activity are not fully understood. This study aimed to identify a potential miRNA that could modulate the dysregulated NF-κB signaling during inflammation. We identified miR-582-5p that was significantly downregulated in inflamed murine adipose tissues and RAW264.7 cells. S-phase kinase-associated protein 1 (SKP1), a core component of an E3 ubiquitin ligase that regulates the NF-κB pathway, was proposed as a biological target of miR-582-5p by using TargetScan. The binding of miR-582-5p to a 3'-untranslated region site on Skp1 was confirmed using a dual-luciferase reporter assay; in addition, transfection with a miR-582-5p mimic suppressed SKP1 expression in RAW264.7 cells. Importantly, exogenous miR-582-5p attenuated the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 through suppressing the degradation of the NF-κB inhibitor alpha, followed by the nuclear translocation of NF-κB. Therefore, exogenously applied miR-582-5p can attenuate the NF-κB signaling pathway via targeting Skp1; this provides a prospective therapeutic strategy for treating inflammatory and immune diseases.
Assuntos
MicroRNAs , NF-kappa B , Animais , Camundongos , Inflamação/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Transdução de SinaisRESUMO
The G protein-coupled receptor GPRC6A regulates various physiological processes in response to its interaction with multiple ligands, such as extracellular basic amino acids, divalent cations, testosterone, and the uncarboxylated form of osteocalcin (GluOC). Global ablation of GPRC6A increases the susceptibility of mice to diet-induced obesity and related metabolic disorders. However, given that GPRC6A is expressed in many tissues and responds to a variety of hormonal and nutritional signals, the cellular and molecular mechanisms underlying the development of metabolic disorders in conventional knockout mice have remained unclear. On the basis of our previous observation that long-term oral administration of GluOC markedly reduced adipocyte size and improved glucose tolerance in WT mice, we examined whether GPRC6A signaling in adipose tissue might be responsible for prevention of metabolic disorders. We thus generated adipocyte-specific GPRC6A knockout mice, and we found that these animals manifested increased adipose tissue weight, adipocyte hypertrophy, and adipose tissue inflammation when fed a high-fat and high-sucrose diet compared with control mice. These effects were associated with reduced lipolytic activity because of downregulation of lipolytic enzymes such as adipose triglyceride lipase and hormone-sensitive lipase in adipose tissue of the conditional knockout mice. Given that, among GPR6CA ligands tested, GluOC and ornithine increased the expression of adipose triglyceride lipase in cultured 3T3-L1 adipocytes in a manner dependent on GPRC6A, our results suggest that the constitutive activation of GPRC6A signaling in adipocytes by GluOC or ornithine plays a key role in adipose lipid handling and the prevention of obesity and related metabolic disorders.
Assuntos
Inflamação/genética , Obesidade/genética , Osteocalcina/genética , Receptores Acoplados a Proteínas G/genética , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Teste de Tolerância a Glucose , Humanos , Inflamação/patologia , Insulina/genética , Resistência à Insulina/genética , Lipase/genética , Lipólise/genética , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologiaRESUMO
Cancer is characterized by uncontrolled proliferation resulting from aberrant cell cycle progression. The activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling, a regulatory pathway for the cell cycle, stabilizes cyclin D1 in the G1 phase by inhibiting the activity of glycogen synthase kinase 3ß (GSK3ß) via phosphorylation. We previously reported that phospholipase C-related catalytically inactive protein (PRIP), a phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] binding protein, regulates PI3K/AKT signaling by competitively inhibiting substrate recognition by PI3K. Therefore, in this study, we investigated whether PRIP is involved in cell cycle progression. PRIP silencing in MCF-7 cells, a human breast cancer cell line, demonstrated PI(3,4,5)P3 signals accumulated at the cell periphery compared to that of the control. This suggests that PRIP reduction enhances PI(3,4,5)P3-mediated signaling. Consistently, PRIP silencing in MCF-7 cells exhibited increased phosphorylation of AKT and GSK3ß which resulted in cyclin D1 accumulation. In contrast, the exogenous expression of PRIP in MCF-7 cells evidenced stronger downregulation of AKT and GSK3ß phosphorylation, reduced accumulation of cyclin D1, and diminished cell proliferation in comparison to control cells. Flow cytometry analysis indicated that MCF-7 cells stably expressing PRIP attenuate cell cycle progression. Importantly, tumor growth of MCF-7 cells stably expressing PRIP was considerably prevented in an in vivo xenograft mouse model. In conclusion, PRIP expression downregulates PI3K/AKT/GSK3ß-mediated cell cycle progression and suppresses tumor growth. Therefore, we propose that PRIP is a new therapeutic target for anticancer therapy.
Assuntos
Proteínas de Transporte/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Proteínas de Transporte/genética , Células Cultivadas , Ciclina D1/genética , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células MCF-7 , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Nus , Neoplasias/genética , Neoplasias/patologia , Fosfatidilinositóis/sangue , Fosfatidilinositóis/metabolismo , Transdução de Sinais , Transplante Heterólogo , Carga Tumoral/genéticaRESUMO
We present a novel single-MCF connector without any additional or high-precision parts not found on a standard single-SMF connector. The proposed connector realizes rotational fiber alignment and ferrule floating simultaneously by employing a standard MU ferrule with a straight flange edge and a modified LC housing with a tapered hole that can make contact with the ferrule flange. Fabricated connectors achieved an average loss of 0.07â dB in a random connection test and passed the Telcordia GR-326-CORE mechanical and environmental reliability test. Furthermore, we conducted numerical simulations and confirmed these positive results were due to suppression of ferrule rotation from external forces.
RESUMO
SPOCK1 is a calcium-binding matricellular proteoglycan that has been extensively studied in several cancer cells. Previously, we generated a mouse line overexpressing SPOCK1 (Spock1-Tg mouse) and showed that SPOCK1 might play an important role in drug-induced gingival overgrowth, indicating that it possesses physiological functions in non-cancer diseases as well. Although SPOCK1 was reported to be secreted from human adipocytes, its role in adipocyte physiology has not been addressed yet. In this study, SPOCK1 protein expression was confirmed in pancreas, adipose tissues, spleen, and liver of normal diet (ND)-fed mice. Interestingly, SPOCK1 was up-regulated in the pancreas and adipose tissues of the high-fat diet (HFD)-fed mice. Spock1-Tg mice fed with ND showed increased maturation in epididymal and inguinal adipose tissues. In addition, Spock1 overexpression strongly decreased expression of UCP-1 in adipose tissues, suggesting that SPOCK1 might regulate thermogenic function through suppression of UCP-1 expression. Finally, exogenous SPOCK1 treatment directly accelerated the differentiation of 3T3-L1 adipocytes, accompanied by the up-regulation of adipocyte differentiation-related gene expression. In conclusion, we demonstrated for the first time that SPOCK1 induced adipocyte differentiation via the up-regulation of adipogenesis-related genes.
Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Tecido Adiposo/citologia , Regulação da Expressão Gênica/genética , Proteoglicanas/metabolismo , Células 3T3-L1 , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica , Imuno-Histoquímica , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pâncreas/metabolismo , Proteoglicanas/genética , Proteínas Recombinantes , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Regulação para CimaRESUMO
Interleukin-17A (IL-17A) is known to induce inflammatory responses and to be involved in the pathogenesis of not only autoimmune diseases, but also several metabolic and infectious diseases. In this study, IL-17A is shown to induce IL-6 expression in 3T3-L1 mature adipocytes. Interestingly, we found that IL-17A synergistically amplified TNFα-induced secretion of IL-6 and upregulation of IL-17RA expression in 3T3-L1 adipocytes. Its synergistic effects on IL-6 production were inhibited by pre-treatment with inhibitors of IκBα and JNK. Furthermore, IL-17A cooperatively enhanced LPS-mediated IL-6 production in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. In addition, IL-17A also enhanced CCL20 production in 3T3-L1 adipocytes stimulated with TNFα or co-cultured with LPS-stimulated RAW macrophages. In high-fat diet-fed mouse epididymal adipose tissues, IL-17RA and RORγt mRNA levels were significantly increased and the serum level of CCL20 was also upregulated. Taken together, these data show that, in adipose tissues, IL-17A contributes to exacerbating insulin resistance-enhancing IL-6 production and promotes the infiltration of Th17 cells in cooperation with TNFα; these findings represent a novel hypothesis for the association between IL-17A-producing cells and type 2 diabetes.
Assuntos
Adipócitos/imunologia , Quimiocina CCL20/imunologia , Interleucina-17/imunologia , Interleucina-6/imunologia , Macrófagos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Interleucina-17/administração & dosagem , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para CimaRESUMO
We have demonstrated previously that Japanese sake yeast improves sleep quality in humans. In the present study, we examined the molecular mechanisms of sake yeast to induce sleep by monitoring locomotor activity, electromyogram and electroencephalogram in mice. Oral administration of Japanese sake yeast (100, 200, and 300 mg kg-1 ) decreased the locomotor activity by 18, 46 and 59% and increased the amount of non-rapid eye movement (NREM) sleep by 1.5-, 2.3- and 2.4-fold (to 37 ± 6, 57 ± 8, and 60 ± 4 min from 25 ± 6 min in the vehicle-administered group, respectively) in a dose-dependent manner for 4 h after oral administration. However, Japanese sake yeast did not change the amount of rapid eye movement (REM) sleep, the electroencephalogram power density during NREM sleep or show any adverse effects, such as rebound of insomnia, during 24 h postadministration and on the next day. An intraperitoneal pretreatment with an adenosine A2A receptor-selective antagonist, ZM241385 (15 mg kg-1 ), reduced the amount of NREM sleep of sake yeast-administered mice to the basal level, without changing basal amount of sleep. Conversely, an A1 receptor-selective antagonist, 8-cyclopentyltheophylline (10 mg kg-1 ), did not affect the sleep-promoting effect of Japanese sake yeast. Thus, Japanese sake yeast promotes NREM sleep via activation of adenosine A2A but not A1 receptors.
Assuntos
Bebidas Alcoólicas/microbiologia , Movimentos Oculares/fisiologia , Receptor A2A de Adenosina/metabolismo , Saccharomyces cerevisiae/classificação , Sono/fisiologia , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Eletroencefalografia , Eletromiografia , Movimentos Oculares/efeitos dos fármacos , Japão , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sono/efeitos dos fármacos , Sono REM/fisiologia , Teofilina/análogos & derivados , Teofilina/farmacologia , Fatores de Tempo , Triazinas/farmacologia , Triazóis/farmacologiaRESUMO
Activation of adenosine A2a receptors in cerebral neurons induces sleep in various mammals. It was previously found that Japanese sake yeast enriched in adenosine analogues activates A2a receptors in vitro and induces sleep in mice. Here it is reported that sake yeast activated A2a receptors in a cultured human cell line and improved human sleep quality in a clinical trial. Sake yeast activated A2a receptors in HEK cells in a dose-dependent manner with an EC50 of 40 µg mL(-1), and the activation was attenuated almost completely by the A2a receptor antagonist ZM241385 with an IC50 of 73 nm. In a double-blind placebo-controlled crossover clinical study, 68 healthy participants ingested tablets containing either 500 mg of sake yeast powder or a placebo (cellulose) 1 h before sleep for 4 days. Electroencephalograms were recorded during sleep at home with a portable device for 4 week days. Electroencephalogram analyses revealed that sake yeast supplementation significantly (P = 0.03) increased delta power during the first cycle of slow-wave sleep by 110%, without changing other sleep parameters. Sake yeast supplementation also significantly increased growth hormone secretion in the urine on awakening by 137% from 3.17 ± 0.41 (placebo) to 4.33 ± 0.62 (sake yeast) pg mg(-1) creatinine (P = 0.03). Subjective sleepiness (P = 0.02) and fatigue (P = 0.06) in the morning were improved by sake yeast. Given these benefits and the absence of adverse effects during the study period, it was concluded that sake yeast supplementation is an effective and safe way to support daily high-quality, deep sleep.
Assuntos
Bebidas Alcoólicas/microbiologia , Extratos Celulares/administração & dosagem , Extratos Celulares/farmacologia , Saccharomyces cerevisiae/química , Sono/efeitos dos fármacos , Sono/fisiologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Adulto , Extratos Celulares/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Eletroencefalografia , Feminino , Células HEK293 , Humanos , Masculino , Pós , Receptor A2A de Adenosina/metabolismo , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , Triazinas/farmacologia , Triazóis/farmacologiaRESUMO
A 49-year-old woman was scheduled for endoscopic cholecystectomy under general anesthesia in another hospital. The anesthesia was performed by a surgeon, but the operation was cancelled because of anaphylac- tic shock, and the surgeon performed emergency treatment Afterward, the surgeon declined operation, and she could not receive medical treatment. She visited our hospital for complete examination and 'operation. Drug-induced lymphocyte stimulation test (DLST) and standard perioperative test results were almost normal, and we could not find the cause of anaphylaxis preoperatively. After induction of anesthesia, the erythema ap- peared with hypotension and tachycardia. She was responsive to symptomatic treatment such as transfu- sion, antihistamine agent and streroid administration. After the recovery from the shock state, the operation proceeded without complications and she recovered from anesthesia uneventfully. She had no major post- operative complication.
Assuntos
Anafilaxia/induzido quimicamente , Anestesia Geral/efeitos adversos , Rocurônio/efeitos adversos , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
The patient(woman, approximately 46 years old)began pazopanib (PAZ) treatment (800 mg/day)f ollowing the recurrence of retroperitoneal leiomyosarcoma. Prior to treatment, the patient's platelet count was 18.6×10(4)/µl and her neutrophil count was 1.61×10(3)/µl . The platelet count decreased to 9.2×10(4)/µl on day 7 and to 5.4×10(4)/µl on day 21 after commencement of treatment. The neutrophil count was 0.97×10(3)/µl on day 28 and 0.68×10(3)/µl on day 35 after commencement of treatment. Thus, PAZ treatment was stopped on day 35. The blood sampling results on day 42 after commencement of treatment showed that the platelet count was 13.0×10(4)/µl and that the neutrophil count had recovered to 1.28×10(3)/µl . At that time, PAZ treatment was resumed at a reduced dose of 600 mg/day. By day 84 after commencement of treatment, the platelet count had increased from 12.7 to 13.8×10(4)/µl and the neutrophil count had increased from 1.02 to 1.34×10(3)/µl ; treatment was subsequently continued. The main adverse effects that have been reported for PAZ are hypertension and frequent liver dysfunction; these reports also indicate that the incidence of severe cytopenia(thrombocytopenia, neutropenia)is quite low. However, our patient exhibited cytopenia after commencement of PAZ treatment and her blood cell counts recovered once treatment was ceased, independent of other possible medications. Our findings suggest that cytopenia should be considered as an adverse effect of PAZ.
Assuntos
Indutores da Angiogênese/efeitos adversos , Leiomiossarcoma/tratamento farmacológico , Neutropenia/induzido quimicamente , Pirimidinas/efeitos adversos , Neoplasias Retroperitoneais/tratamento farmacológico , Sulfonamidas/efeitos adversos , Trombocitopenia/induzido quimicamente , Indutores da Angiogênese/uso terapêutico , Feminino , Humanos , Indazóis , Leiomiossarcoma/secundário , Pessoa de Meia-Idade , Neutropenia/tratamento farmacológico , Pirimidinas/uso terapêutico , Recidiva , Neoplasias Retroperitoneais/secundário , Sulfonamidas/uso terapêutico , Trombocitopenia/tratamento farmacológicoRESUMO
Dipeptidyl peptidase IV (DPP-IV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitate-induced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 µM), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IκBα and phosphorylations of p65, JNK, and p38, as well as NF-κB and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF-κB and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNFα. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 µM concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF-κB transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events.
Assuntos
Adipócitos Brancos/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fígado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Pirimidinas/farmacologia , Células 3T3-L1 , Adipócitos Brancos/imunologia , Adipócitos Brancos/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Linhagem Celular Transformada , Técnicas de Cocultura , Citocinas/agonistas , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/agonistas , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Pirimidinas/uso terapêutico , Elementos de Resposta/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controleRESUMO
Cedar pollinosis in Japan affects nearly 25 % of Japanese citizens. To develop a treatment for cedar pollinosis, it is necessary to understand the relationship between the time of its occurrence and the amount of airborne cedar pollen. In the spring of 2009, we conducted daily Internet-based epidemiologic surveys, which included 1453 individuals. We examined the relationship between initial date of onset of pollinosis symptoms and daily amount of airborne cedar pollen to which subjects were exposed. Approximately 35.2 % of the subjects experienced the onset of pollinosis during a one-week interval in which the middle day coincided with the peak pollen count. The odds ratio for this one-week time interval was 4.03 (95 % confidence interval: 3.34-4.86). The predicted date of the cedar pollen peak can be used to determine the appropriate date for initiation of self-medication with anti-allergy drugs and thus avoid development of sustained and severe pollinosis.
Assuntos
Alérgenos/imunologia , Cryptomeria , Pólen/imunologia , Rinite Alérgica Sazonal/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Lactente , Japão/epidemiologia , Pessoa de Meia-Idade , Rinite Alérgica Sazonal/induzido quimicamente , Estações do Ano , Adulto JovemRESUMO
With increasing Internet coverage, the use of a web-based survey for epidemiological study is a possibility. We performed an investigation in Japan in winter 2008 using the web-based daily questionnaire for health (WDQH). The WDQH is a web-based questionnaire survey formulated to obtain information about the daily physical condition of the general public on a real-time basis, in order to study correlations between changes in physical health and changes in environmental factors. Respondents were asked whether they felt ill and had specific symptoms including fever. We analysed the environmental factors along with the health conditions obtained from the WDQH. Four factors were found to influence health: minimum temperature, hours of sunlight, median humidity and weekday or holiday. The WDQH allowed a daily health survey in the general population in real time via the Internet.
Assuntos
Meio Ambiente , Nível de Saúde , Luz Solar , Temperatura , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Inquéritos Epidemiológicos , Humanos , Umidade , Internet , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Fatores de Tempo , Adulto JovemRESUMO
A 72-year-old man with a malignant retroperitoneal soft tissue tumor was treated with ifosfamide (IFO) for 5 consecutive days (1.8 g/m2/d×5 d, expected dose 9 g/m2). The patient developed neurological symptoms such as mild somnolence, seizures, and inability to write from Day 1, and became delirious on Day 3, so IFO was discontinued on Day 4 (dose: 7.2 g/m2). Since there are reports of drug interactions that increase the frequency of encephalopathy when combined with aprepitant (Apr), Dexamethasone was increased and IFO was administered without the use of Apr after the second course, and there was no recurrence of encephalopathy in the second and third courses. IFO-induced encephalopathy is considered to occur due to an increase in blood concentration of IFOs caused by high dosage, decreased renal function, or other factors. In this case, encephalopathy was observed even though the dose of IFO was reduced due to the patient's advanced age and impaired renal function. The combination use of Apr with IFO should be considered with caution for the occurrence of adverse events, including encephalopathy, and if possible, control of gastrointestinal toxicity with other antiemetic agents should be considered.
Assuntos
Antieméticos , Encefalopatias , Masculino , Humanos , Idoso , Ifosfamida/efeitos adversos , Aprepitanto , Encefalopatias/induzido quimicamente , Encefalopatias/tratamento farmacológico , Antieméticos/efeitos adversos , Interações MedicamentosasRESUMO
In Japan, although oral oxycodone is widely used for cancer pain treatment, there is no injection preparation of oxycodone used as a single ingredient. Only the compound injection of oxycodone and hydrocotarnine has received approval. Subcutaneous administration of the drug is approved, but there are few efficacy and safety reports about its intravenous administration. We compared 245 patients(187 intravenous administration patients and, 58 subcutaneous administration patients)to whom the compound injection of oxycodone and hydrocotarnine was administered from April, 2008 to September, 2011, in order to investigate the drug's efficacy and safety. The reasons for injection were the impossibility of oral administration in 105 patients, a need for dose adjustment in 56 patients, and that other drugs were not as effective in 37 patients, and side effect reduction in 33 patients. The average change in the numeric rating scale(0-10)was 3. 7â1. 8 in intravenous administration, and 3. 4â1. 2 in subcutaneous administration. The incidence of main adverse events(intravenous administration/subcutaneous administration)were constipation(37%/28%), vomiting(31%/34%), and somnolence(52%/50%). There was no significant difference in efficacy and safety. The conversion ratio differed in a case due to a change, and about 20 to 40% of addition was needed within four days after the start. It is considered that compound injection of oxycodone and hydrocotarnine is effective for cancer pain treatment.
Assuntos
Analgésicos Opioides/administração & dosagem , Neoplasias/complicações , Oxicodona/administração & dosagem , Dor/tratamento farmacológico , Tetra-Hidroisoquinolinas/administração & dosagem , Administração Cutânea , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Oxicodona/efeitos adversos , Oxicodona/uso terapêutico , Dor/etiologia , Estudos Retrospectivos , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto JovemRESUMO
Menopausal women are susceptible to visceral obesity, which increases the risk of metabolic disorders. However, the mechanisms of menopause-induced visceral fat accumulation are not fully understood. Circulating levels of receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) are elevated in an animal model of menopause. RANKL, a multifunctional cytokine, activates the NF-κB pathway, which serves as a pivotal mediator of inflammatory responses. Here, we investigated whether RANKL-induced non-canonical NF-κB pathway activation induces inflammation and lipid accumulation in adipose tissues. RANKL induced Tnfa expression via the non-canonical NF-κB pathway in bone marrow cells. We therefore analyzed aly/aly mice, in which the non-canonical NF-κB pathway is not activated, owing to an inactive form of NF-κB-inducing kinase. A postmenopausal obesity model was generated by ovariectomy and subsequent high-fat and high-sucrose diet feeding. In aly/aly mice with postmenopausal obesity, serum RANKL levels were elevated, and hepatic lipid accumulation and adipocyte hypertrophy were suppressed, resulting in reduced macrophage infiltration and inflammatory cytokine mRNA expression in visceral adipose tissue. Furthermore, aly/aly mice showed protection from glucose intolerance and insulin resistance, which were observed in ovariectomized WT obese mice. These findings indicate that non-canonical NF-κB pathway activation via serum RANKL elevation contributes to postmenopausal obesity.
Assuntos
Resistência à Insulina , NF-kappa B , Animais , Feminino , Humanos , Lipídeos , Camundongos , Camundongos Obesos , NF-kappa B/metabolismo , Obesidade/etiologiaRESUMO
The expression profiles of exosomal microRNAs (miRNAs) are regulated by the microenvironment, and appropriate priming with mesenchymal stem cells (MSCs) is one of the strategies to enhance the paracrine potency of MSCs. Our previous work demonstrated that exosomes from tumor necrosis factor (TNF)-α-primed human gingiva-derived MSCs (GMSCs) could be a therapeutic tool against periodontitis, and that TNFα-inducible exosomal miR-1260b is essential for the inhibition of alveolar bone loss. However, the precise molecular mechanism underlying miR-1260b-mediated inhibition of osteoclastogenesis is not yet fully understood. Here, we found that the activating transcription factor (ATF)-6ß, a novel miR-1260b-targeting gene, is critical for the regulation of osteoclastogenesis under endoplasmic reticulum (ER) stress. An experimental periodontal mouse model demonstrated that induction of ER stress was accompanied by enhanced ATF6ß expression, and local administration of miR-1260b and ATF6ß siRNA using polyethylenimine nanoparticles (PEI-NPs) significantly suppressed the periodontal bone resorption. In periodontal ligament (PDL) cells, the ER stress inducer, tunicamycin, enhanced the expression of the receptor activator of NF-κB ligand (RANKL), while miR-1260b-mediated downregulation of ATF6ß caused RANKL inhibition. Furthermore, the secretome from miR-1260b/ATF6ß-axis-activated PDL cells inhibited osteoclastogenesis in human CD14+ peripheral blood-derived monocytes. These results indicate that the miR-1260b/ATF6ß axis mediates the regulation of ER stress, which may be used as a novel therapeutic strategy to treat periodontal disease.
RESUMO
AIMS: Pancreatic ß-cell apoptosis may be involved in the onset and progression of type 2 diabetes mellitus, although its mechanism remains unclear. We previously demonstrated that macrophage-derived interferon (IFN) ß induced X-linked inhibitor of apoptosis-associated factor 1 (XAF1) expression in ß-cells and accelerated ß-cell apoptosis in vitro. Here, we explored the effects of XAF1 on ß-cell function and progression of diabetes in vivo. METHODS: Pancreatic ß-cell-selective XAF1 overexpressing (Xaf1 Tg) mice were generated. Xaf1 Tg mice and their wild-type (WT) littermates were fed either a normal diet or a 40% or 60% high-fat diet (HFD). The effects of ß-cell XAF1 on ß-cell apoptosis and exacerbation of diabetes were investigated. RESULTS: Palmitic acid induced IFNß expression in macrophages, and HFD intake promoted macrophage infiltration in pancreatic islets, both of which cooperatively upregulated XAF1 expression in mouse islets. Furthermore, HFD-fed Xaf1 Tg mice demonstrated increased ß-cell apoptosis, lowered insulin expression, and impaired glucose tolerance compared with WT mice fed the same diet. These effects were more pronounced in the 60%HFD group than in the 40%HFD group. CONCLUSIONS: Pancreatic ß-cell XAF1 expression was enhanced via HFD-induced, macrophage-derived IFNß, which promoted ß-cell apoptosis and led to a reduction in insulin secretion and progression of diabetes. To our knowledge, this is the first report to demonstrate an association between pancreatic ß-cell XAF1 overexpression and exacerbation of diabetes, thus providing insight into the mechanism of ß-cell mass reduction in diabetes.