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Mitochondria import nearly all of their resident proteins from the cytosol, and the TOM complex functions as their entry gate. The TOM complex undergoes a dynamic conversion between the majority population of a three-channel gateway ("trimer") and the minor population that lacks Tom22 and has only two Tom40 channels ("dimer"). Here, we found that the porin Por1 acts as a sink to bind newly imported Tom22. This Por1 association thereby modulates Tom22 integration into the TOM complex, guaranteeing formation of the functional trimeric TOM complex. Por1 sequestration of Tom22 dissociated from the trimeric TOM complex also enhances the dimeric TOM complex, which is preferable for the import of TIM40/MIA-dependent proteins into mitochondria. Furthermore, Por1 appears to contribute to cell-cycle-dependent variation of the functional trimeric TOM complex by chaperoning monomeric Tom22, which arises from the cell-cycle-controlled variation of phosphorylated Tom6.
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Proteínas de Transporte/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Membranas Mitocondriais/metabolismo , Porinas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transporte Biológico , Proteínas de Transporte/genética , Ciclo Celular , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Fosforilação , Porinas/genética , Ligação Proteica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
BACKGROUND: Bisphenol A diglycidyl ether (BADGE) and Bisphenol F diglycidyl ether (BFDGE) are used in medical devices, such as intravenous sets, syringes, and catheters. Several studies have reported that these compounds are endocrine disruptors, cytotoxic, and genotoxic, raising concerns about their adverse effects on infants, in a stage of remarkable growth and development. The present study aimed to measure the serum concentrations of BADGE, derivatives of BADGE, and BFDGE in infants and examine the factors that influence them. METHODS: Ten infants admitted to the neonatal intensive care unit (NICU) were enrolled in the present study. Blood samples from each infant and questionnaires from their mothers were collected twice, at 1-2 months and 7 months of age. BADGE, BADGE·H2O, BADGE·2H2O, and BFDGE were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Serum BADGE·2H2O was identified in all infants, at both 1-2 months (2.30-157.58 ng/ml) and 7 months of age (0.86-122.85 ng/ml). One of the two infants who received invasive ventilation showed a substantially increased BADGE·2H2O concentration. There was no significant difference in BADGE·2H2O concentrations at 7 months of age between the group that ate commercial baby food at least ≥ 1 time per week and the group that did not. CONCLUSIONS: BADGE·2H2O was detected in the serum of all infants with a history of NICU hospitalization. Future studies are needed to determine the source of BADGE exposure and investigate its effects on infant development.
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Unidades de Terapia Intensiva Neonatal , Espectrometria de Massas em Tandem , Humanos , Lactente , Cromatografia Líquida , Hospitalização , JapãoRESUMO
In this study, we demonstrated nano-flow injection analysis (nano-FIA) with quadrupole time-of-flight mass spectrometry (Q-TOFMS) for 17 highly polar intermediates produced during glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway (PPP). We optimized the analytical conditions for nano-flow injection/Q-TOFMS, and set the flow rate and ion source temperature to 1000 nL/min and 150 °C, respectively. Under optimal conditions, a single run was finished within 3 min, and the RSD value of 50 sequential injections was 4.2%. The method also showed quantitativity of four stable-isotope-labeled compounds (r2 > 0.99), demonstrating its robustness, high repeatability, and specificity. In addition, we compared three sample-preparation methods for rodent blood samples and found that protein precipitation with threefold methanol was the most effective. Finally, we applied the method to plasma samples from the serotonin syndrome (SS) model and control rats, the results of which were evaluated by principal component analysis (PCA). The two groups showed clearly separated PCA score plots, suggesting that the method could successfully catch the differences in metabolic profiles between SS and control rats. The results obtained from our new method were further validated by using the established gas chromatography/tandem mass spectrometry method, which demonstrated that there were good correlations between the two methods (R = 0.902 and 0.958 for lactic acid and malic acid, respectively, each at p < 0.001), thus proving the validity of our method. The method described here enables high-throughput analysis of metabolites and will be of use for the rapid analysis of metabolic profiles. Graphical abstract.
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Análise de Injeção de Fluxo/instrumentação , Espectrometria de Massas/instrumentação , Metaboloma , Síndrome da Serotonina/metabolismo , Animais , Ciclo do Ácido Cítrico , Análise de Injeção de Fluxo/economia , Análise de Injeção de Fluxo/métodos , Glicólise , Masculino , Espectrometria de Massas/economia , Espectrometria de Massas/métodos , Camundongos Endogâmicos ICR , Via de Pentose Fosfato , Análise de Componente Principal , Ratos , Síndrome da Serotonina/sangue , Fatores de TempoRESUMO
AIM: To evaluate the persistence with oral antidiabetic drug (OAD) treatment characterized by drug class, patient characteristics and severity of renal impairment (RI) in patients with type 2 diabetes (T2DM) in Japan. MATERIALS AND METHODS: This retrospective, observational study extracted data from a large-scale hospital database (April 2008 to September 2016). Patients with T2DM aged ≥40 years on the day of their first prescription (index date) of any OAD (biguanides [BGs], thiazolidinediones [TZDs], sulphonylureas [SUs], glinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, or α-glucosidase inhibitors [α-GIs]) available between January 1, 2014 and September 30, 2016 were identified. Sodium-glucose co-transporter-2 inhibitors were not available at study initiation. Treatment persistence was assessed by Kaplan-Meier survival curves. Patients were also categorized by RI status using estimated glomerular filtration rate: ≥90 mL/min/1.73 m2 (G1); 60 to <90 mL/min/1.73 m2 (G2); 30 to <60 mL/min/1.73 m2 (G3); and <30 mL/min/1.73 m2 (G4+). RESULTS: We identified 206 406 index dates from 162 116 eligible patients. The largest number of index dates (91634) was observed for DPP-4 inhibitors, followed by BGs, SUs, α-GIs, glinides and TZDs. Treatment persistence was longest for DPP-4 inhibitors (median 17.0 months, 95% confidence interval [CI] 16.4-17.5) and BGs (median 17.3 months, 95% CI 16.6-18.2), and shortest for α-GIs (median 5.6 months, 95% CI 5.4-5.9) and SUs (median 4.3 months, 95% CI 4.2-4.6). Persistence was longest with DPP-4 inhibitors at all RI stages (G1-G4+), followed by BGs at stages G1/G2. CONCLUSIONS: The longest OAD persistence was observed for BGs and DPP-4 inhibitors at RI stages G1/G2, and for DPP-4 inhibitors at RI stages G3/G4+.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/patologia , Hipoglicemiantes/administração & dosagem , Insuficiência Renal/patologia , Índice de Gravidade de Doença , Administração Oral , Adulto , Idoso , Biguanidas/administração & dosagem , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/etiologia , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Tiazolidinedionas/administração & dosagem , Resultado do TratamentoRESUMO
Scaffold proteins play a pivotal role in making protein complexes, and organize binding partners into a functional unit to enhance specific signaling pathways. IQ motif-containing GTPase activating protein 1 (IQGAP1) is an essential protein for spine formation due to its role in scaffolding multiple signal complexes. However, it remains unclear how IQGAP1 interacts within the brain. In the present study, we screened novel IQGAP1-interacting proteins by a proteomic approach. As a novel IQGAP1-interacting protein, we identified valosin-containing protein (VCP) which is a causative gene in patients with inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD). The physiological interaction of IQGAP1 with VCP was confirmed by an immunoprecipitation assay. Both the N-terminal (N-half) and C-terminal (C-half) fragments of IQGAP1 interacted with the N-terminal region of VCP. Co-localization of IQGAP1 and VCP was observed in the growth corn, axonal shaft, cell body, and dendrites in cultured hippocampal neurons at 4 days in vitro (DIV4). In cultured neurons at DIV14, IQGAP1 co-localized with VCP in dendrites. When HEK293T cells were co-transfected with IQGAP1 and VCP, an immunoprecipitation assay revealed that binding of IQGAP1 with disease-related mutant (R155H or A232E) VCP was markedly reduced compared to wild-type (WT) VCP. These results suggest that reduction of IQGAP1 and VCP interaction may be associated with the pathophysiology of IBMPFD.
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Adenosina Trifosfatases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Adenosina Trifosfatases/química , Adenosina Trifosfatases/genética , Substituição de Aminoácidos , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Células HEK293 , Células HeLa , Hipocampo/metabolismo , Humanos , Imuno-Histoquímica , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Mutagênese Sítio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/metabolismo , Neurônios/metabolismo , Osteíte Deformante/genética , Osteíte Deformante/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteômica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteína com Valosina , Proteínas Ativadoras de ras GTPase/química , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
Multi-wall carbon nanotubes (MWCNT) are a form of flexible fibrous nanomaterial with high electrical and thermal conductivity. However, 50-nm MWCNT in diameter causes malignant mesothelioma (MM) in rodents and, thus, the International Agency of Research on Cancer has designated them as a possible human carcinogen. Little is known about the molecular mechanism through which MWCNT causes MM. To elucidate the carcinogenic mechanisms of MWCNT in mesothelial cells, we used a variety of lysates to comprehensively identify proteins specifically adsorbed on pristine MWCNT of different diameters (50 nm, NT50; 100 nm, NT100; 150 nm, NT150; and 15 nm/tangled, NTtngl) using mass spectrometry. We identified >400 proteins, which included hemoglobin, histone, transferrin and various proteins associated with oxidative stress, among which we selected hemoglobin and transferrin for coating MWCNT to further evaluate cytotoxicity, wound healing, intracellular catalytic ferrous iron and oxidative stress in rat peritoneal mesothelial cells (RPMC). Cytotoxicity to RPMC was observed with pristine NT50 but not with NTtngl. Coating NT50 with hemoglobin or transferrin significantly aggravated cytotoxicity to RPMC, with an increase in cellular catalytic ferrous iron and DNA damage also observed. Knockdown of transferrin receptor with ferristatin II decreased not only NT50 uptake but also cellular catalytic ferrous iron. Our results suggest that adsorption of hemoglobin and transferrin on the surface of NT50 play a role in causing mesothelial iron overload, contributing to oxidative damage and possibly subsequent carcinogenesis in mesothelial cells. Uptake of NT50 at least partially depends on transferrin receptor 1. Modifications of NT50 surface may decrease this human risk.
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Carcinógenos/toxicidade , Hemoglobinas/fisiologia , Mesotelioma/metabolismo , Nanotubos de Carbono/toxicidade , Transferrina/fisiologia , Adsorção , Animais , Carcinógenos/química , Linhagem Celular , Epitélio/efeitos dos fármacos , Epitélio/patologia , Feminino , Hemoglobinas/química , Masculino , Mesotelioma/induzido quimicamente , Nanotubos de Carbono/química , Tamanho da Partícula , Ratos Endogâmicos F344 , Receptores da Transferrina/metabolismo , Transferrina/químicaRESUMO
High-resolution mass spectrometry and accurate mass measurement by liquid chromatography/quadrupole-time of flight mass spectrometry (LC/Q-TOFMS) was applied to postmortem plasma and urine specimens from an autopsy of a fatal case involving synthetic cannabinoid use, resulting in the detection of three synthetic cannabinoids: MAM-2201, AM-1220, and AM-2232. We searched for their metabolites existing in postmortem plasma or urine by LC/Q-TOFMS and were able to detect N-dealkylated metabolites, defluorinated and further oxidized metabolites of MAM-2201, and some hydroxylated metabolites. Postmortem plasma concentrations of the parent drugs, N-dealkylated metabolites, and fluorinated and further oxidized metabolites of MAM-2201 were measured, and quantitation results revealed site differences between heart and femoral postmortem plasma concentrations of parent drugs and some metabolites, suggesting postmortem redistribution of the synthetic cannabinoids and their metabolites. Quantitation results suggest that defluorination is a major metabolic pathway for MAM-2201, and N-dealkylation is a common but minor pathway for the naphthoylindole-type synthetic cannabinoids in human.
Assuntos
Canabinoides , Indóis , Naftalenos , Mudanças Depois da Morte , Canabinoides/sangue , Canabinoides/farmacocinética , Canabinoides/urina , Cromatografia Líquida , Drogas Desenhadas/análise , Drogas Desenhadas/farmacocinética , Toxicologia Forense , Humanos , Drogas Ilícitas/sangue , Drogas Ilícitas/farmacocinética , Drogas Ilícitas/urina , Indóis/sangue , Indóis/farmacocinética , Indóis/urina , Masculino , Espectrometria de Massas/métodos , Naftalenos/sangue , Naftalenos/farmacocinética , Naftalenos/urina , Transtornos Relacionados ao Uso de Substâncias/sangue , Transtornos Relacionados ao Uso de Substâncias/urina , Adulto JovemRESUMO
This study explores the adhesive properties of copolymers comprising glycidyl methacrylate (GMA) and 3-(trimethoxysilyl)propyl methacrylate (MPTMS), focusing on their suitability for adhesive applications. Peel resistance measurements revealed a substantial impact of the GMA/MPTMS ratio on adhesion capabilities, identifying an optimal ratio of 30/70 for copolymerization with tert-butyl acrylate (tBA) to improve foaming performance. tBA, a foaming monomer activated by a photoacid generator and heat, enhances the copolymerized adhesive's adhesion strength and foamability for postuse delamination. Chemical structure analysis through Nuclear magnetic resonance (NMR) and Fourier-transform infrared spectroscopy (FTIR) confirmed successful polymerization, while rheological properties indicated decreased complex viscosity and adhesive strength with an increasing tBA content. The deprotection of the t-butyl group facilitated foam formation, supported by morphology analysis. These findings provide insights into foamable adhesive development with potential applications in delamination processes and implications for further exploration in polymer adhesion.
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The plastication of pellets in a co-rotating twin-screw extruder is a significant concern for product homogeneity and stability in the plastic industry. We developed a sensing technology for pellet plastication in a plastication and melting zone in a self-wiping co-rotating twin-screw extruder. The collapse of the solid part of the pellets emits an elastic wave as an acoustic emission (AE) that is measured on the kneading section of the twin-screw extruder using homo polypropylene pellets. The recorded power of the AE signal was used as an indicator of the molten volume fraction (MVF) in the range of zero (fully solid) to unity (fully melted). MVF decreased with increasing feed rate monotonically in the range of 2-9 kg/h at a screw rotation speed of 150 rotations per minute (rpm) because of the reduction in the residence time of pellets in the extruder. However, the increase in feed rate from 9 to 23 kg/h at 150 rpm resulted in an increase in the MVF as the friction and compaction of pellets caused their melting. The AE sensor could elucidate the pellet's plastication phenomena caused by friction, compaction of pellets, and melt removal in the twin-screw extruder.
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This 36-week, open-label, single-arm, phase 3 study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia undergoing peritoneal dialysis. Molidustat was titrated every 4 weeks to maintain Hb levels within the target range (≥11.0 and <13.0 g/dL). The primary efficacy outcome was the responder rate, defined as the proportion of patients who met all of the following criteria: (1) mean Hb levels in the target range during the evaluation period (Weeks 30-36); (2) ≥50% of Hb values within the target range during the evaluation period; and (3) no rescue treatment before the end of the evaluation period. Overall, 51 patients received molidustat. The responder rate (95% CI) during the evaluation period was 54.9% (40.3, 68.9). Overall, 98.0% of patients experienced at least 1 adverse event during the study. No deaths were reported. Molidustat maintained Hb levels in the prespecified range in more than half of the patients and was well tolerated.
Assuntos
Anemia , Eritropoetina , Hematínicos , Diálise Peritoneal , Insuficiência Renal Crônica , Anemia/tratamento farmacológico , Anemia/etiologia , Eritropoetina/uso terapêutico , Hemoglobinas/análise , Humanos , Japão , Diálise Peritoneal/efeitos adversos , Pirazóis , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/terapia , Resultado do Tratamento , TriazóisRESUMO
Ideal cancer treatments specifically target and eradicate tumor cells without affecting healthy cells. Therefore, antibody-based therapies that specifically target cancer antigens can be considered ideal cancer therapies. Antibodies linked with small-molecule drugs (i.e., antibody-drug conjugates [ADCs]) are widely used in clinics as antibody-based therapeutics. However, because tumors express antigens heterogeneously, greater target specificity and stable binding of noncleavable linkers in ADCs limit their antitumor effects. To overcome this problem, strategies, including decreasing the binding strength, conjugating more drugs, and targeting tumor stroma, have been applied, albeit with limited success. Thus, further technological advancements are required to remotely control the ADCs. Here, we described a drug that is photo-releasable from an ADC created via simple double conjugation and its antitumor effects both on target and nontarget tumor cells. Specifically, noncleavable T-DM1 was conjugated with IR700DX to produce T-DM1-IR700. Although T-DM1-IR700 itself is noncleavable, with NIR-light irradiation, it can release DM1-derivatives which elicited antitumor effect in vitro mixed culture and in vivo mixed tumor model which are mimicking heterogeneous tumor-antigen expression same as real clinical tumors. This cytotoxic photo-bystander effect occurred in various types mixed cultures in vitro, and changing antibodies also exerted photo-bystander effects, suggesting that this technology can be used for targeting various specific cancer antigens. These findings can potentially aid the development of strategies to address challenges associated with tumor expression of heterogeneous antigen.
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BACKGROUND: The role of peroxisome proliferator-activated receptor delta (PPAR δ) in the development and progression of colorectal cancer (CRC) remains controversial. AIMS: We investigated the impact of PPAR δ expression in tissues on liver metastasis of CRC. METHODS: We analyzed samples of primary CRC and matched normal adjacent tissues from 52 patients for the expression of PPAR δ, cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF)-A, and CXC chemokine receptor 4 (CXCR4). Correlations of the molecules expressions with clinical characteristics and prognosis of patients were studied. RESULTS: The number of patients positive for PPAR δ, COX-2, CXCR4, and VEGF-A was 25, 33, 18, and 19, respectively. Among the PPAR δ (+)/COX-2 (+), PPAR δ (-)/COX-2 (+), PPAR δ (+)/COX-2 (-), and PPAR δ (-)/COX-2 (-) patient groups, PPAR δ (+)/COX-2 (+) patients had the highest incidence of liver metastasis (p<0.01). PPAR δ (+)/COX-2 (+) expression was a significant independent prognostic factor (HR=7.108, 95% CI 1.231-41.029, p=0.0283) by Cox proportional analysis. PPAR δ (+)/COX-2 (+) patients had the highest positivity for CXCR4 or VEGF-A in tissues (p<0.01). Among the patients in the CXCR4 (+)/VEGF-A (+), CXCR4 (+)/VEGF-A (-), CXCR4 (-)/VEGF-A (+), and CXCR4 (-)/VEGF-A (-) groups, CXCR4 (+)/VEGF-A (+) patients had the highest incidence of liver metastasis (p<0.01). CONCLUSIONS: The expression of both PPAR δ and COX-2 in tissues may lead to liver metastasis and consequent poor prognosis in CRC patients.
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Carcinoma/secundário , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 2/biossíntese , Neoplasias Hepáticas/secundário , PPAR delta/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores CXCR4/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
A 67-year-old woman underwent partial gastrectomy (por2+sig, stage IIIA) for gastric cancer. She was admitted to our hospital because of swelling of her left neck lymph nodes 20 years after surgery. A biopsy specimen revealed poorly differentiated adenocarcinoma with signet-ring cell carcinoma. We diagnosed recurrence of gastric cancer and gave chemotherapy, but she died of myelosuppression and disseminated intravascular coagulation 2 years later. On autopsy, we examined all organs except the brain, but the primary lesion was not recognized. We concluded that this case was late recurrence after partial gastrectomy for advanced gastric cancer.
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Adenocarcinoma/patologia , Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/cirurgia , Idoso , Carcinoma de Células em Anel de Sinete/cirurgia , Evolução Fatal , Feminino , Gastrectomia , Humanos , Recidiva Local de Neoplasia , Neoplasias Gástricas/cirurgia , Fatores de TempoRESUMO
Manufacturing meltblown nonwoven fabrics requires special grades of resin with very low viscosity, which are not dealt with so much on market and cost quite high compared to the standard grades. We propose a high-shear rate processing method that can quickly and easily produce such low-viscosity resin from the commercial one without using organic peroxides. In this method, we apply high-shear stress to molten resin by using a high-shear extruder, which is a single screw extruder with high screw rotation speed, and the resin is thermally decomposed of its shear-induced heat which is quickly generated. We found that polypropylene with a value of melt flow rate over a thousand, which was required for the meltblown process, was produced from the standard grade with the high-shear extruder at the screw rotation speed of 3600 min-1 and the barrel temperature over 300 ∘C. Using the degradated polypropylene, a meltblown nonwoven fabric sheet was successfully fabricated. We also developed a numerical simulator of the high-shear extruder which can handle a wide range of the screw rotation speed and barrel temperature by the Nusselt number modulated with the operational conditions. The experimental values of the zero-shear viscosity and temperature at the exit of the extruder agreed well with the simulation results. Our high-shear rate processing method will enable us to quickly and easily produce various meltblown nonwoven fabric sheets at low costs.
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We developed a highly sensitive method for quantifying 21 bile acids (BAs) in the rat liver by capillary liquid chromatography tandem mass spectrometry (cLC/MS/MS) with one-pot extraction. High recovery rates were obtained for the one-pot methods with either methanol (MeOH) extraction or MeOH/acetonitrile (ACN) (1:1, v/v) mixture extraction; the results obtained for the MeOH/ACN mixture solution were better than the results obtained for MeOH. Thus, we determined that the one-pot method with MeOH/ACN was the most suitable method for the efficient extraction of BAs in the liver. Targeted BAs were well separated by cLC with gradient elution using ammonium acetate (NH4OAc)-MeOH mobile phases. Method validation proved that the intra-day and inter-day accuracies and precisions were primarily less than ±20 and 20% relative standard deviation, respectively. Also, the limit of detection (LOD) and the limit of quantitation (LOQ) were 0.9-10 and 2.3-27 ng/g liver, which proves the high sensitivity of the method. Finally, we quantitated 21 BA concentrations in the liver samples of normal and nonalcoholic steatohepatitis (NASH) rats, both of which were derived from stroke-prone spontaneously hypertensive five (SHRSP5) /Dmcr rat. The hepatic BA profiles were found to be substantially different between the normal and NASH groups; the two groups were clearly separated along the first component axis in the score plots of the principal component analysis. In particular, 10 BAs (ß-muricholic acid (MCA), glyco (G-) cholic acid (CA), G-chenodeoxycholic acid (CDCA), tauro (T-) CA, T-CDCA, T-ursodeoxycholic acid (UDCA), T-lithocholic acid (LCA), T-hiodeoxycholic acid (HDCA), T-α-MCA, and T-ß-MCA) were significantly different between the two groups using Welch's t-test with the false discovery rate correction method, demonstrating BA disruption in the NASH model rat. In conclusion, this method was able to quantify 21 BAs in the rat liver and will evaluate the hepatic BA pathophysiology of rat disease models.
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OBJECTIVE: To evaluate glycemic variability associated with two different premixed insulin analogue formulations when used in a twice-daily regimen. PATIENTS AND METHODS: Subjects comprised type 2 diabetic patients aged 20-79 years, treated with twice daily premixed insulin or insulin analogue formulations. All subjects were hospitalized for 6 days and randomized to receive either Humalog Mix 25 (Mix 25) or Humalog Mix 50 (Mix 50). They were then crossed over to the other arm between day 3 and day 4 of the study. Continuous glucose monitoring (CGM) was performed on all subjects to examine the differences in glycemic variability. RESULTS: Eleven type 2 diabetic patients were enrolled. No significant difference was found in 24-hour mean glucose values and their SDs, pre-meal glucose values, increases from pre-meal to peak glucose values, or time to peak glucose levels between either group. However, the mean glucose values observed during 0-8 hrs were significantly lower with Mix 25 compared to Mix 50 (128 vs. 147 mg/dL; p = 0.024). CONCLUSIONS: The twice-daily Mix 25 regimen provided superior overnight glycemic control compared to the Mix 50 regimen in Japanese patients with type 2 diabetes. However, both twice-daily regimens with either Mix 25 or Mix 50 provided inadequate post-lunch glycemic control. TRIAL REGISTRATION: Current Controlled Trials UMIN000001327.
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Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/análogos & derivados , Monitorização Ambulatorial , Adulto , Idoso , Povo Asiático , Biomarcadores/sangue , Insulinas Bifásicas , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Esquema de Medicação , Ingestão de Energia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/administração & dosagem , Insulina Lispro , Insulina Isófana , Japão , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Período Pós-Prandial , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Additive manufacturing is a versatile technology for producing customized 3D products. In 2015, the Continuous Liquid Interface Production (CLIP) system was developed as a part of projection-type, UV-curable resin 3D printers. The CLIP system utilized the dead zone where oxygen inhibition occurs and prevents the UV-cured product from adhering to the UV illumination window. The CLIP system successfully produced complex shapes in a short time. This study investigated how the relationship between the photopolymerization rate, oxygen inhibition rate, and oxygen diffusion rate affects the shape of the product by means of a numerical simulation of the photopolymerization kinetics with oxygen diffusion and reaction. The results indicate that the vertical production speed and transmittance of UV light are crucial to controlling the conversion and shape precision of products.
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This paper investigates the photo-initiated cationic polymerization of diglycidyl ether of bisphenol A (DGEBA) modified with bisphenol A (BPA)/polyethylene glycol (PEG) hyperbranched epoxy resin. The relationship between curing behavior, rheological, and thermal properties of the modified DGEBA is investigated using photo-differential scanning calorimetry (DSC) and photo-rheometer techniques. It is seen that the addition of the hyperbranched epoxy resin can increase UV conversion (αUV) and reduce gelation time (tgel). After photo-initiation polymerization (dark reaction) occurred, a second exothermic peak in the DSC thermogram takes place: namely, the occurrence of curing reaction owing to the activated monomer (AM) mechanism. Consequently, the glass transition temperature decreased, and at the same time, UV intensity increased which was due to the molecular weight between crosslinking points (Mc). Furthermore, the radius of gyration (Rg) of the network segment is determined via small-angle X-ray scattering (SAXS). It is noted that the higher the Mc, the larger the radius of gyration proves to be, resulting in low glass transition temperature.
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OBJECTIVE: To evaluate insulin treatment satisfaction, safety, and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice for Japanese patients with type 2 diabetes mellitus (T2DM) who switched from originator insulin glargine (100 U/mL) or insulin degludec treatment to GLY treatment. METHODS: The Insulin Treatment Satisfaction Questionnaire (ITSQ) was used to assess treatment satisfaction in a subgroup analysis of a post-marketing safety study. Hypoglycemia incidence rates and blood glucose control are also reported during the 12-month observation period for GLY-switched patients. RESULTS: Of 1104 patients with T2DM enrolled to participate, 565 patients switched from either insulin glargine U100/mL (n = 470) or insulin degludec (n = 95) to GLY. The mean total change from baseline to 3 months for total ITSQ score was 1.35 (95% confidence interval [CI] - 0.13 to 2.83, p = .073) for patients who switched from insulin glargine and 2.63 (95% CI -1.43 to 6.70, p = .195) for patients who switched from insulin degludec to GLY treatment. The mean change from baseline to 12 months in hypoglycemia events reported per month was -0.04% (95% CI -0.12 to 0.03, p = .236) for patients who switched from insulin glargine and no change for patients who switched from insulin degludec (0.00, 95% CI -0.20 to 0.20, p = 1.000). Non-significant mean changes from baseline to 12 months were observed for hemoglobin A1c and fasting plasma glucose in GLY-switched patients. CONCLUSIONS: Treatment satisfaction does not change significantly in Japanese patients with T2DM who switch to GLY from the reference product or from insulin degludec. Safety and effectiveness over a 12-month period were similar in GLY-treated patients who switched from either insulin glargine or insulin degludec. CLINICALTRIALS.GOV: Not applicable.