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1.
Proc Natl Acad Sci U S A ; 120(22): e2300155120, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37216518

RESUMO

Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute-based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients.


Assuntos
COVID-19 , Malus , Camundongos , Animais , Leptina/genética , Citocinas , COVID-19/complicações , Estudos Retrospectivos , SARS-CoV-2 , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/genética , Interleucina-6 , Camundongos Obesos
2.
Int J Obes (Lond) ; 48(5): 674-682, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38233538

RESUMO

BACKGROUND/OBJECTIVES: Obesity, defined by body mass index (BMI), is a well-known risk factor for the severity of coronavirus disease 2019 (COVID-19). Adipose tissue distribution has also been implicated as an important factor in the body's response to infection, and excess visceral fat (VF), which is prevalent in Japanese, may contribute significantly to the severity. Therefore, this study aimed to evaluate the association of obesity and VF with COVID-19 severe illness in Japan. SUBJECTS/METHODS: This retrospective cohort study involved 550 COVID-19 patients admitted to a tertiary care hospital with BMI and body composition data, including VF. The primary endpoint was severe illness, including death, due to COVID-19 during hospitalization. Logistic regression analysis was applied to examine the quartiles of BMI and VF on severe illness after adjusting for covariates such as age, sex, subcutaneous fat, paraspinal muscle radiodensity, and comorbidities affecting VF (COPD, cancer within 5 years, immunosuppressive agent use). RESULTS: The median age was 56.0 years; 71.8% were males. During hospitalization, 82 (14.9%) experienced COVID-19 severe illness. In the multivariate logistic regression analysis, Q4 of BMI was not significantly associated with severe illness compared to Q1 of BMI (OR 1.03; 95% CI 0.37-2.86; p = 0.95). Conversely, Q3 and Q4 of VF showed a higher risk for severe illness compared to Q1 of VF (OR 2.68; 95% CI 1.01-7.11; p = 0.04, OR 3.66; 95% CI 1.30-10.26; p = 0.01, respectively). Stratified analysis by BMI and adjusted for covariates showed the positive association of VF with severe illness only in the BMI < 25 kg/m2 group. CONCLUSIONS: High BMI was not an independent risk factor for COVID-19 severe illness in hospitalized patients in Japan, whereas excess VF significantly influenced severe illness, especially in patients with a BMI < 25 kg/m2.


Assuntos
Índice de Massa Corporal , COVID-19 , Hospitalização , Gordura Intra-Abdominal , SARS-CoV-2 , Humanos , Masculino , COVID-19/epidemiologia , COVID-19/complicações , Feminino , Pessoa de Meia-Idade , Japão/epidemiologia , Estudos Retrospectivos , Gordura Intra-Abdominal/diagnóstico por imagem , Hospitalização/estatística & dados numéricos , Idoso , Fatores de Risco , Índice de Gravidade de Doença , Adulto , Pandemias , Comorbidade , Obesidade/epidemiologia , Obesidade/complicações
3.
J Med Virol ; 95(1): e28168, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36148941

RESUMO

The effectiveness of remdesivir on survival in coronavirus disease 2019 (COVID-19), especially in cases treated in the intensive care unit (ICU), is controversial. We investigated the effectiveness of remdesivir with corticosteroids on the survival of COVID-19 patients in a real ICU clinical practice. For laboratory-confirmed COVID-19 patients admitted to the ICU of a tertiary hospital in Tokyo (April 2020-November 2021) and who received corticosteroids, the effectiveness of remdesivir for survival, stratified by interval length (within 9 or 10+ days), was retrospectively analyzed using Cox regression model. A total of 168 patients were included: 35 with no remdesivir use (control), 96 with remdesivir use within 9 days, and 37 with remdesivir use with an interval of 10+ days. In-hospital mortality was 45.7%, 10.4%, and 16.2%, respectively. After adjusting for possible covariates including comorbidities, laboratory data, oxygen demand, or level of pneumonia, remdesivir use within 9 days from symptom onset reduced mortality risk (hazard ratio [HR]: 0.10; 95% confidence interval (CI): 0.025-0.428) compared to the control group. However, remdesivir use with an interval of 10+ days showed no significant association with mortality (HR: 0.42; 95% CI: 0.117-1.524). Among COVID-19 patients who received corticosteroids in ICU, remdesivir use within 9 days from symptom onset was associated with reduced in-hospital mortality risk.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Estudos Retrospectivos , Tratamento Farmacológico da COVID-19 , Unidades de Terapia Intensiva , Hospitais , Alanina/uso terapêutico , Corticosteroides/uso terapêutico
4.
Analyst ; 147(22): 4971-4979, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36205380

RESUMO

Antigen tests for SARS-CoV-2 are widely used by the public during the ongoing COVID-19 pandemic, which demonstrates the societal impact of homogeneous immunosensor-related technologies. In this study, we used the PM Q-probe and Quenchbody technologies to develop a SARS-CoV-2 nucleocapsid protein (N protein) homogeneous immunosensor based on a human anti-N protein antibody. For the first time, we uncovered the crowding agent's role in improving the performance of the double-labeled Quenchbody, and the possible mechanisms behind this improvement are discussed. The 5% polyethylene glycol 6000 significantly improved both the response speed and sensitivity of SARS-CoV-2 Quenchbodies. The calculated limit of detection for recombinant N protein was 191 pM (9 ng mL-1) within 15 min of incubation, which was 9- to 10-fold lower than the assay without adding crowding agent. We also validated the developed immunosensor in a point-of-care test by measuring specimens from COVID-19-positive patients using a compact tube fluorometer. In brief, this work shows the feasibility of Quenchbody homogeneous immunosensors as rapid and cost-efficient tools for the diagnosis and high-throughput analysis of swab samples in large-scale monitoring and epidemiological studies of COVID-19 or other emerging infectious diseases.


Assuntos
Técnicas Biossensoriais , COVID-19 , Humanos , SARS-CoV-2 , COVID-19/diagnóstico , Pandemias , Imunoensaio , Proteínas do Nucleocapsídeo
5.
Thorax ; 73(4): 350-360, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28389600

RESUMO

RATIONALE: Primary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown. OBJECTIVE: To define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction. METHODS: Isolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function. RESULTS: In mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours. CONCLUSIONS: These results indicate that lung-marginated intravascular monocytes are retained as a 'passenger' leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.


Assuntos
Transplante de Pulmão , Monócitos/metabolismo , Traumatismo por Reperfusão , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/fisiopatologia , Transplante de Pulmão/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Pneumonia/fisiopatologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Doadores de Tecidos
6.
Pediatr Int ; 58(9): 867-71, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26824516

RESUMO

BACKGROUND: Given that nutritional biotin deficiency in Japanese infants has been reported, a straightforward method for estimating biotin level is needed. The biotin content in infant formula, breast milk, and the sera of infants fed with various types of formula were measured using avidin-binding assay. METHODS: A commercially available ELISA kit was used for the measurement of biotin in 54 types of formula, including hydrolysate formulas for milk allergy, as well as in breast milk and in the sera of 27 infants fed with these formulas. RESULTS: The biotin content reached the recommended value in only five formulas. All of the hydrolysate formulas and more than half of the special formulas contained biotin <0.1 µg/dL. Serum biotin was low in infants fed only with the hydrolysate formulas, and one of them had alopecia related to biotin deficiency. CONCLUSION: While many were asymptomatic, infants fed with formulas lacking biotin are at risk of developing symptomatic disease. The addition of biotin to breast milk substitutes was finally approved in the middle of 2014, however pediatricians in Japan should still be vigilant with regard to nutritional biotin deficiency in infants for the time being.


Assuntos
Biotina/sangue , Fórmulas Infantis/química , Fenômenos Fisiológicos da Nutrição do Lactente/fisiologia , Estado Nutricional , Hidrolisados de Proteína/administração & dosagem , Adulto , Biotina/farmacocinética , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino
7.
Pediatr Int ; 58(9): 872-6, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26933789

RESUMO

BACKGROUND: Biotin deficiency has been reported in Japanese infants fed special formulas for medical reasons, including those with milk allergy and congenital metabolic diseases, because these formulas contain little biotin. Serum biotin measurement is useful for diagnosing biotin deficiency. We applied a simple and rapid method to analyze serum biotin, and established normal ranges for children and adults. METHODS: Serum biotin in 188 healthy Japanese children aged 0-4 years and in 25 healthy adults was analyzed using a Biotin ELISA Kit (immundiagnostik). The effects of various conditions on the measurement of serum biotin were also examined. RESULTS: Median biotin in children aged 0-4 years was 10.4 ng/dL (IQR, 7.9-13.4 ng/dL), and that in adults was 12.9 ng/dL (IQR, 10.8-15.8 ng/dL). Normal range was 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults (calculated using two-sided 95%CI). Measurements obtained with this method were not affected by frozen storage, freeze-thaw, or hemolysis, indicating that serum biotin can be analyzed accurately under these conditions, with a possible application to plasma samples. CONCLUSIONS: Serum biotin was significantly lower in children than in adults, with the normal range being 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults. This simple and accurate enzyme-linked immunosorbent assay method is useful for diagnosing biotin deficiency.


Assuntos
Biotina/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Hipersensibilidade a Leite/sangue , Adulto , Compostos de Cetrimônio , Pré-Escolar , Combinação de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Hipersensibilidade a Leite/diagnóstico , Hipersensibilidade a Leite/epidemiologia , Miristatos , Ácidos Nicotínicos , Reprodutibilidade dos Testes , Simeticone , Ácidos Esteáricos
8.
Am J Physiol Lung Cell Mol Physiol ; 308(12): L1274-85, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26078397

RESUMO

Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-µ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD(+)/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.


Assuntos
Ácidos Cafeicos/farmacologia , Células Epiteliais/enzimologia , Ácido Etacrínico/farmacologia , Glutationa Transferase/antagonistas & inibidores , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/enzimologia , Estresse Oxidativo , Animais , Antioxidantes/farmacologia , Western Blotting , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Peróxido de Hidrogênio/metabolismo , Técnicas Imunoenzimáticas , Lesão Pulmonar/patologia , Metabolômica , Camundongos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Bioorg Med Chem Lett ; 25(18): 3914-20, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26238323

RESUMO

To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.


Assuntos
Benzoatos/farmacologia , Descoberta de Drogas , Hidrocarbonetos Fluorados/farmacologia , Receptores Nucleares Órfãos/agonistas , Animais , Benzoatos/administração & dosagem , Benzoatos/química , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/química , Receptores X do Fígado , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
10.
Crit Care Med ; 42(1): e49-57, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23963135

RESUMO

OBJECTIVES: Ventilator-induced lung injury has substantive impact on mortality of patients with acute respiratory distress syndrome. Although low tidal volume ventilation has been shown to reduce mortality, clinical benefits of open-lung strategy are controversial. In this study, we investigated the impact of two distinct forms of ventilator-induced lung injury, i.e., volutrauma and atelectrauma, on the progression of lung injury and inflammation, in particular alveolar and systemic cytokine production. DESIGN: Ex vivo study. SETTING: University research laboratory. SUBJECTS: C57BL/6 mice. INTERVENTIONS: Isolated, buffer-perfused lungs were allocated to one of three ventilatory protocols for 3 hours: control group received low tidal volume (7 mL/kg) with positive end-expiratory pressure (5 cm H2O) and regular sustained inflation; high-stretch group received high tidal volume (30-32 mL/kg) with positive end-expiratory pressure (3 cm H2O) and sustained inflation; and atelectasis group received the same tidal volume as control but neither positive end-expiratory pressure nor sustained inflation. MEASUREMENTS AND MAIN RESULTS: Both injurious ventilatory protocols developed comparable levels of physiological injury and pulmonary edema, measured by respiratory system mechanics and lavage fluid protein. High-stretch induced marked increases in proinflammatory cytokines in perfusate and lung lavage fluid, compared to control. In contrast, atelectasis had no effect on perfusate cytokines compared to control but did induce some up-regulation of lavage cytokines. Depletion of monocytes marginated within the lung microvasculature, achieved by pretreating mice with i.v. liposome-encapsulated clodronate, significantly attenuated perfusate cytokine levels, especially tumor necrosis factor, in the high-stretch, but not atelectasis group. CONCLUSIONS: Volutrauma (high-stretch), but not atelectrauma (atelectasis), directly activates monocytes within the pulmonary vasculature, leading to cytokine release into systemic circulation. We postulate this as a potential explanation why open-lung strategy has limited mortality benefits in ventilated critically ill patients.


Assuntos
Citocinas/fisiologia , Monócitos/fisiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Animais , Citocinas/biossíntese , Edema/etiologia , Edema/imunologia , Edema/fisiopatologia , Citometria de Fluxo , Pulmão/citologia , Pulmão/imunologia , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Respiração com Pressão Positiva/efeitos adversos , Respiração com Pressão Positiva/métodos , Volume de Ventilação Pulmonar/fisiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia
11.
Sci Rep ; 13(1): 3574, 2023 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-36864218

RESUMO

Age-based bodyweight estimation is commonly used in pediatric settings, but pediatric ICU patients often have preexisting comorbidity and resulting failure to thrive, hence their anthropometric measures may be small-for-age. Accordingly, age-based methods could overestimate bodyweight in such settings, resulting in iatrogenic complications. We performed a retrospective cohort study using pediatric data (aged < 16 years) registered in the Japanese Intensive Care Patient Database from April 2015 to March 2020. All the anthropometric data were overlaid on the growth charts. The estimation accuracy of 4 age-based and 2 height-based bodyweight estimations was evaluated by the Bland-Altman plot analysis and the proportion of estimates within 10% of the measured weight (ρ10%). We analyzed 6616 records. The distributions of both bodyweight and height were drifted to the lower values throughout the childhood while the distribution of BMI was similar to the general healthy children. The accuracy in bodyweight estimation with age-based formulae was inferior to that with height-based methods. These data demonstrated that the pediatric patients in the Japanese ICU were proportionally small-for-age, suggesting a special risk of using the conventional age-based estimation but supporting the use of height-based estimation of the bodyweight in the pediatric ICU.


Assuntos
Hospitalização , Unidades de Terapia Intensiva Pediátrica , Humanos , Criança , Estudos Retrospectivos , Cuidados Críticos , Antropometria
12.
J Biol Chem ; 286(36): 31409-17, 2011 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-21733845

RESUMO

The retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORγt and suppressed Th17 differentiation without affecting Th1 differentiation. To better understand the structural basis for the inhibitory activity of digoxin, we determined the crystal structure of the RORγt ligand-binding domain in complex with digoxin at 2.2 Å resolution. The structure reveals that digoxin binds to the ligand-binding pocket protruding between helices H3 and H11 from the pocket. In addition, digoxin disrupts the key interaction important for the agonistic activity, resulting in preventing the positioning of helix H12 in the active conformation, thus antagonizing coactivator interaction. Functional studies demonstrated that digoxin inhibited RORγt activity and decreased IL-17 production but not RORα activity. Digoxin inhibited IL-17 production in CD4(+) T cells from experimental autoimmune encephalomyelitis mice. Our data indicates that RORγt is a promising therapeutic target for Th17-derived autoimmune diseases and our structural data will help to design novel RORγt antagonists.


Assuntos
Digoxina/química , Interleucina-17/biossíntese , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células Th17/efeitos dos fármacos , Animais , Doenças Autoimunes/tratamento farmacológico , Linfócitos T CD4-Positivos , Diferenciação Celular/efeitos dos fármacos , Cristalografia por Raios X , Digoxina/farmacologia , Encefalomielite Autoimune Experimental , Interleucina-17/antagonistas & inibidores , Camundongos , Estrutura Molecular , Células Th17/citologia
13.
Bioorg Med Chem Lett ; 22(3): 1348-51, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22225641

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) is a potential drug target for treating type 2 diabetes. The selective PPARγ modulators (SPPARMs), which partially activate the PPARγ transcriptional activity, are considered to improve the plasma glucose level with attenuated PPARγ related adverse effects. However, the relationships between desired pharmacological profiles and ligand specific PPARγ transcriptional profiles have been unclear. And there is also little knowledge of how to control ligand specific PPARγ transcriptional profiles. Herein, we present synthesis of novel derivatives containing substituent at naphthalene C3 position of compound 1. The novel derivatives showed various maximal efficacies as PPARγ partial agonist.


Assuntos
Benzofuranos/química , Modelos Moleculares , Naftalenos/química , PPAR gama/agonistas , Benzofuranos/síntese química , Benzofuranos/farmacologia , Cristalografia por Raios X , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Estrutura Molecular
14.
Am J Ophthalmol Case Rep ; 26: 101529, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35479517

RESUMO

Purpose: To determine whether the Mizuo-Nakamura phenomenon, which is an important diagnostic sign of Oguchi's disease, also occurs in patients with genetically proven X-linked retinoschisis (XLRS). Methods: We examined three patients with a clinical and genetic diagnosis of XLRS and one patient who was clinically diagnosed with Oguchi's disease, with an emphasis on the Mizuo-Nakamura phenomenon. We obtained color fundus photographs, especially in the fully dark-adapted state, using the non-mydriatic mode on a digital retinal camera and infrared observation monitor to avoid the bleaching effects caused by the viewing light, which alters the fundus color in a short time. Results: The Mizuo-Nakamura phenomenon was observed in all patients with molecularly proven XLRS, similar to that in the patient with Oguchi's disease. The sets of photographs were obtained in the light- and dark-adapted states using our newly devised techniques needed to witness the Mizuo-Nakamura phenomenon. Conclusions and Importance: The Mizuo-Nakamura phenomenon was identified in three patients with genetically proven XLRS. To the best of our knowledge, this study provided the first genetic evidence of the Mizuo-Nakamura phenomenon in a patient with molecularly proven XLRS without the causative genetic abnormalities for Oguchi's disease. Our findings suggest that XLRS is responsible for the Mizuo-Nakamura phenomenon and its presence in XLRS is not a rare exception but may be a consistent manifestation of XLRS.

15.
Clin Case Rep ; 10(12): e6687, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36483877

RESUMO

Laryngeal venous malformations rarely but do cause airway obstruction resulting in life-threatening events. The perioperative airway management for the patients with them has not been well established. We suggest a strategy for laryngeal venous malformations management in the patients who undergo surgery in addition to planning for airway management.

16.
J Immunol ; 182(2): 1155-66, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19124759

RESUMO

The specialized role of mouse Gr-1(high) monocytes in local inflammatory reactions has been well documented, but the trafficking and responsiveness of this subset during systemic inflammation and their contribution to sepsis-related organ injury has not been investigated. Using flow cytometry, we studied monocyte subset margination to the pulmonary microcirculation during subclinical endotoxemia in mice and investigated whether marginated monocytes contribute to lung injury in response to further septic stimuli. Subclinical low-dose i.v. LPS induced a rapid (within 2 h), large-scale mobilization of bone marrow Gr-1high monocytes and their prolonged margination to the lungs. With secondary LPS challenge, membrane TNF expression on these premarginated monocytes substantially increased, indicating their functional priming in vivo. Zymosan challenge produced small increases in pulmonary vascular permeability, which were markedly enhanced by the preadministration of low-dose LPS. The LPS-zymosan-induced permeability increases were effectively abrogated by pretreatment (30 min before zymosan challenge) with the platelet-activating factor antagonist WEB 2086 in combination with the phosphatidylcholine-phospholipase C inhibitor D609, suggesting the involvement of platelet-activating factor/ceramide-mediated pathways in this model. Depletion of monocytes (at 18 h after clodronate-liposome treatment) significantly attenuated the LPS-zymosan-induced permeability increase. However, restoration of normal LPS-induced Gr-1high monocyte margination to the lungs (at 48 h after clodronate-liposome treatment) resulted in the loss of this protective effect. These results demonstrate that mobilization and margination of Gr-1high monocytes during subclinical endotoxemia primes the lungs toward further septic stimuli and suggest a central role for this monocyte subset in the development of sepsis-related acute lung injury.


Assuntos
Lesão Pulmonar Aguda/patologia , Células da Medula Óssea/patologia , Movimento Celular/imunologia , Endotoxemia/patologia , Mediadores da Inflamação/toxicidade , Monócitos/patologia , Receptores de Quimiocinas/biossíntese , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Permeabilidade Capilar/imunologia , Diferenciação Celular/imunologia , Relação Dose-Resposta Imunológica , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Endotoxemia/induzido quimicamente , Endotoxemia/imunologia , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Monócitos/metabolismo , Receptores de Quimiocinas/sangue , Receptores de Quimiocinas/fisiologia , Sepse/sangue , Sepse/imunologia , Sepse/patologia , Zimosan/toxicidade
17.
Biol Pharm Bull ; 34(7): 1094-104, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21720019

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) is known as a key regulator of adipocytogenesis and the molecular target of thiazolidinediones (TZDs), also known as antidiabetic agents. Despite the clinical benefits of TZDs, their use is often associated with adverse effects including peripheral edema, congestive heart failure, and weight gain. Here we report the identification and characterization of a non-thiazolidinedione PPARγ partial agonist, Cerco-A, which is a derivative of the natural product, (-)-cercosporamide. Cerco-A was found to be a binder of the PPARγ ligand-binding domain in a ligand competitive binding assay and showed a unique cofactor recruitment profile compared to rosiglitazone. A crystal structure analysis revealed that Cerco-A binds to PPARγ without direct hydrogen bonding to helix12. In PPARγ transcriptional activation assay and an adipocyte differentiation assay, Cerco-A was a potent partial agonist of PPARγ. After a 14-day oral administration, once per day of Cerco-A in Zucker diabetic fatty (ZDF) rats, an apparent decrease of plasma glucose and triglyceride was observed, as with pioglitazone. To evaluate drug safety, Cerco-A was administered for 13 days orally in non-diabetic Zucker fatty (ZF) rats. Each of the hemodilution parameters (hematocrit, red blood cells number, and hemoglobin), which are considered as undesirable effects of TZDs, was improved significantly compared to pioglitazone. While Cerco-A showed body weight gain, as with pioglitazone, Cerco-A had significantly lower effects on heart and white adipose tissues weight gain. The results suggest that Cerco-A offers beneficial effects on glycemic control with attenuated undesirable side effects.


Assuntos
Benzofuranos/farmacologia , PPAR gama/farmacologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Sequência de Bases , Benzofuranos/administração & dosagem , Benzofuranos/química , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Primers do DNA , Polarização de Fluorescência , Humanos , Ligantes , Estrutura Molecular , PPAR gama/genética , PPAR gama/metabolismo , Ratos , Ratos Zucker
18.
ACS Med Chem Lett ; 12(5): 817-821, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34055231

RESUMO

A novel class of estrogen-related receptor α (ERRα) agonists has been discovered. A structure-activity relationship study of high-throughput screening hits 1 and 2 led to the discovery of benzimidazole 3d (DS20362725) and acetophenone analogue 5c (DS45500853). The X-ray crystal structure of the ERRα ligand-binding domain in complex with 5c and PGC-1α coactivator peptide revealed conformational changes in the ligand-binding pocket to accommodate 5c and the key interaction between the protein and ligand. Since both analogues avoided PPARγ transcriptional activity, they can be useful tool compounds for investigating biological ERRα functions.

19.
Bioorg Med Chem Lett ; 20(7): 2095-8, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20219371

RESUMO

In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.


Assuntos
Benzofuranos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Glucose/metabolismo , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , PPAR gama/agonistas , Animais , Benzofuranos/química , Benzofuranos/farmacologia , Cristalografia por Raios X , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Modelos Moleculares , PPAR gama/química , PPAR gama/metabolismo
20.
Prog Rehabil Med ; 5: 20200016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32844129

RESUMO

OBJECTIVE: The aim of this study was to investigate the effect and risk management of early mobilization in the intensive care unit (ICU) with multidisciplinary collaboration and daily goal planning. METHODS: Rehabilitation of ICU patients in our hospital between April 1, 2019, and September 30, 2019, was investigated retrospectively. The following factors were evaluated: age and sex of the subjects; diseases; the total number of early mobilization therapy sessions done at a lowered goal level; the clinical course of the step-down sessions; reasons for lowering goal levels that corresponded to the cancellation criteria from the officially issued guidelines of the Japanese Association of Rehabilitation Medicine, the expert consensus on ICU, or other reasons for step down; and the rate of planned goals that were achieved. RESULTS: Of the 1908 overall rehabilitation sessions carried out during the period of investigation, 9.6% had the planned level lowered; changes in vital signs accounted for 54.6% of the reasons for lowering the level. Of the step-down sessions, 92.3% corresponded with the cancellation criteria of rehabilitation. Early mobilization in the ICU in accordance with daily goal planning via collaboration within the multidisciplinary team during rounds was accomplished in 90.4% of sessions. No serious mobilization-related adverse events were noted during the study period. CONCLUSION: Early mobilization should be performed with daily goal planning by a multidisciplinary team during rounds and should be governed by the cancellation criteria of rehabilitation.

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