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1.
Bioconjug Chem ; 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32223219

RESUMO

Targeting less abundant amino acid residues on the protein surface may realize site-selective protein modification of natural proteins. The relative hydrophobicity of tyrosine combined with the π-π stacking tendency of the aromatic rings results in generally low accessibility. In this study, site-selective protein modification was achieved by targeting surface-exposed tyrosine residues without using a genetic encoding system. Tyrosine residues were modified with N-methylated luminol derivative under single-electron transfer (SET) reaction conditions. Horseradish peroxidase (HRP)-catalyzed SET and electrochemically activated SET modified surface-exposed tyrosine residues selectively. N-Methylated luminol derivative modified tyrosine residues more efficiently than 4-arylurazole under tyrosine click conditions using HRP and electrochemistry. Tyrosine residues that are evolutionarily exposed only in the complementarity-determining region (CDR) of an antibody were selectively modified by tyrosine click reactions. CDR-modified antibodies were applied to in vivo imaging and antibody-drug conjugated (ADC).

2.
Open Heart ; 7(1): e001112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341787

RESUMO

Background: It has been reported that recovery of left ventricular ejection fraction (LVEF) is associated with better prognosis in heart failure (HF) patients with reduced EF (rEF). However, change of LVEF has not yet been investigated in cases of HF with preserved EF (HFpEF). Methods and results: Consecutive 1082 HFpEF patients, who had been admitted to hospital due to decompensated HF (EF >50% at the first LVEF assessment at discharge), were enrolled, and LVEF was reassessed within 6 months in the outpatient setting (second LVEF assessment). Among the HFpEF patients, LVEF of 758 patients remained above 50% (pEF group), 138 patients had LVEF of 40%-49% (midrange EF, mrEF group) and 186 patients had LVEF of less than 40% (rEF group). In the multivariable logistic regression analysis, younger age and presence of higher levels of troponin I were predictors of rEF (worsened HFpEF). In the Kaplan-Meier analysis, the cardiac event rate of the groups progressively increased from pEF, mrEF to rEF (log-rank, p<0.001), whereas all-cause mortality did not significantly differ among the groups. In the multivariable Cox proportional hazard analysis, rEF (vs pEF) was not a predictor of all-cause mortality, but an independent predictor of increased cardiac event rates (HR 1.424, 95% CI 1.020 to 1.861, p=0.039). Conclusion: An initial assessment of LVEF and LVEF changes are important for deciding treatment and predicting prognosis in HFpEF patients. In addition, several confounding factors are associated with LVEF changes in worsened HFpEF patients.

3.
J Am Heart Assoc ; 9(7): e013982, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32200713

RESUMO

Background The prognostic impact of benzodiazepines has been unclear in patients with heart failure (HF). Methods and Results This was a historical observational cohort study. A total of 826 patients who had been hospitalized for HF and were being treated for insomnia with either benzodiazepines or Z-drugs (zolpidem, zopiclone, or eszopiclone), were enrolled and divided on the basis of their hypnotics: benzodiazepine group (n=488 [59.1%]) and Z group (n=338 [40.9%]). We compared the patient characteristics and postdischarge prognosis between the groups. The primary end points were rehospitalization for HF and cardiac death. The benzodiazepine group was older (age, 72.0 versus 69.0 years; P=0.010), had a higher prevalence of depression (17.4% versus 8.9%; P<0.001), and showed a higher use of loop diuretics (77.9% versus 67.8%; P=0.001). In the laboratory data, the benzodiazepine group demonstrated lower levels of hemoglobin (12.3 versus 13.0 g/dL; P=0.001), sodium (139.0 versus 140.0 mEq/L; P=0.018), and albumin (3.7 versus 3.9 g/dL; P=0.003). Kaplan-Meier analysis showed that both end points were higher in the benzodiazepine group (rehospitalization for HF, log-rank P=0.001; cardiac death, log-rank P=0.043). Multiple Cox proportional hazard analysis revealed that the use of benzodiazepines was an independent predictor of rehospitalization for HF (hazard ratio, 1.530; 95% CI, 1.025-2.284; P=0.038). Furthermore, rehospitalization for HF was higher in the benzodiazepine group after propensity score matching (log-rank P=0.036). Conclusions Benzodiazepine is associated with higher risk of rehospitalization for HF compared with Z-drugs in patients with HF.

4.
Exp Cell Res ; 390(2): 111914, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32142854

RESUMO

"Genomically" humanized animals are invaluable tools for generating human disease models and for biomedical research. Humanized animal models have generally been developed via conventional transgenic technologies; however, conventional gene delivery vectors such as viruses, plasmids, bacterial artificial chromosomes, P1 phase-derived artificial chromosomes, and yeast artificial chromosomes have limitations for transgenic animal creation as their loading gene capacity is restricted, and the expression of transgenes is unstable. Transchromosomic (Tc) techniques using mammalian artificial chromosomes, including human chromosome fragments, human artificial chromosomes, and mouse artificial chromosomes, have overcome these limitations. These tools can carry multiple genes or Mb-sized genomic loci and their associated regulatory elements, which has facilitated the creation of more useful and complex transgenic models for human disease, drug development, and humanized animal research. This review describes the history of Tc animal development, the applications of Tc animals, and future prospects.

5.
Clin Nucl Med ; 45(5): 407-409, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32209877

RESUMO

PHAT (pleomorphic hyalinizing angiectatic tumor) is a rare, locally aggressive, low-grade mesenchymal neoplasm of uncertain lineage with a predilection for the lower extremities. We report a 74-year-old woman with an enlarging mass on the right popliteal fossa undergoing FDG PET/CT to characterize its biological activity. Increased accumulation of FDG (SUVmax, 23.0) in the solid component of the tumor was seen. Diagnosis of PHAT was confirmed by examination of the surgical resection specimens. This case showed significant FDG accumulation relative to its pathological low-grade malignant nature.

6.
Int Heart J ; 61(2): 281-288, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-31956135

RESUMO

It has been recently recognized that recovery of left ventricular ejection fraction (EF), termed "recovered EF", occurs in a proportion of heart failure patients with reduced EF (HFrEF), and is associated with better prognosis. However, the clinical characteristics of "recovered EF" have not been fully examined.Consecutive 567 patients hospitalized due to HFrEF (EF < 40% at 1st assessment at hospital discharge) were enrolled, and EF was re-assessed within half a year in an outpatient setting (2nd assessment). Among these HFrEF patients, 235 remained EF < 40% (reduced, rEF group), 82 changed to EF 40-49% (midrange, mrEF group), and 250 recovered to EF > 50% (preserved, pEF group "recovered EF" ) at the 2nd examination. Age was lower and body mass index and systolic blood pressure were higher in pEF than in rEF. The prevalence of atrial fibrillation (AF) and usage of an implantable cardiac defibrillator and cardiac resynchronization therapy were highest in pEF. Left ventricular end diastolic dimension (LVDd) was the smallest in the pEF group. Multivariable logistic regression analysis revealed that younger age, presence of AF, and lower levels of LVDd were predictors of "recovered EF". Kaplan-Meier analysis found that pEF presented the lowest cardiac event rate (P = 0.003) and all-cause mortality (P = 0.001). In multivariable Cox proportional hazard analyses, pEF (versus rEF) was an independent predictor of both cardiac event rate (HR = 0.668, 95%CI 0.450-0.994, P = 0.046) and all-cause mortality (HR = 0.655, 95%CI 0.459-0.934, P = 0.019).Hospitalized HFrEF patients with recovered EF are associated with younger age, higher presence of AF, and better prognosis.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Recuperação de Função Fisiológica , Volume Sistólico , Idoso , Idoso de 80 Anos ou mais , Feminino , Insuficiência Cardíaca/diagnóstico , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
8.
BMC Cancer ; 19(1): 890, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492159

RESUMO

BACKGROUND: Soft-tissue sarcomas (STS) are rare malignant tumors those are resistant to chemotherapy. We have previously reported the 3-year follow-up result on the efficacy of perioperative chemotherapy with doxorubicin (DXR) and ifosfamide (IFM) for high-risk STS of the extremities (JCOG0304). In the present study, we analyzed the 10-year follow-up results of JCOG0304. METHODS: Patients with operable, high-risk STS (T2bN0M0, AJCC 6th edition) of the extremities were treated with 3 courses of preoperative and 2 courses of postoperative chemotherapy, which consisted of 60 mg/m2 of DXR plus 10 g/m2 of IFM over a 3-week interval. The primary study endpoint was progression-free survival (PFS) estimated by Kaplan-Meier methods. Prognostic factors were evaluated by univariable and multivariable Cox proportional hazards model. RESULTS: A total of 72 patients were enrolled between March 2004 and September 2008, with 70 of these patients being eligible. The median follow-up period was 10.0 years for all eligible patients. Local recurrence and distant metastasis were observed in 5 and 19 patients, respectively. The 10-year PFS was 65.7% (95% CI: 53.4-75.5%) with no PFS events being detected during the last 5 years of follow-up. The 10-year overall survival was 78.1% (95% CI: 66.3-86.2%). Secondary malignancy was detected in 6 patients. The subgroup analysis demonstrated that there was significant difference in survival with regard to primary tumor size. CONCLUSIONS: Only a few long-term results of clinical trials for perioperative chemotherapy treatment of STS have been reported. Our results demonstrate that the 10-year outcome of JCOG0304 for patients with operable, high-risk STS of the extremities was stable and remained favorable during the last 5 years of follow-up. TRIAL REGISTRATION: This trial was registered at the UMIN Clinical Trials Registry as C000000096 on August 30, 2005.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Extremidades/patologia , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Esquema de Medicação , Feminino , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/uso terapêutico , Japão , Masculino , Razão de Chances , Período Perioperatório , Sarcoma/mortalidade , Sarcoma/patologia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Taxa de Sobrevida , Resultado do Tratamento
9.
Regen Med Res ; 7: 1, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31381498

RESUMO

INTRODUCTION: There is a growing need for chondrocyte implantation for reconstructing cartilage defect. However, ossification of the implanted cartilage is a challenging problem. Implant-type tissue-engineered cartilage from human auricular chondrocytes is a three-dimensional implant type cartilage using PLLA as a scaffold for chondrocytes. Although there is a study which evaluated the ossification of this cartilage in subcutaneous area, there is no study which clarify the possibility of ossification in osteoinductive surroundings. The purpose of this study was to elucidate the possibility of the ossification of implant-type tissue-engineered cartilage using human auricular chondrocyte in an osteoinductive environment. METHODS: Human chondrocytes were harvested from ear cartilage. After dispersion by enzyme digestion, they were put into either a poly-L-lactic acid (PLLA) or poly lactic-co-glycolic acid (PLGA) scaffold, with collagen gel. Implant-type tissue-engineered cartilage was interposed between pieces of human iliac bone harvested from the same donor and implanted subcutaneously in nude rats. Scaffold without chondrocytes was used as a control. After 1, 3, and 6 months, ossification and cartilage formation were evaluated by X-ray, hematoxylin-eosin (HE) stain and toluidine blue (TB) stain. RESULTS: There was no ossification of implant-type cartilage using human chondrocytes, even under osteoinductive conditions. HE staining showed that perichondrium formed around the constructs and chondrocytes were observed 6months after the implantation. TB staining showed metachromasia in every sample, with the area of metachromasia increasing over time, suggesting maturation of the cartilage. CONCLUSIONS: In conclusion, adjacent iliac bone had no apparent effect on the maturation of cartilage in implant-type tissue-engineered cartilage. Cartilage retention and maturation even in the presence of iliac bone could have been due to a scarcity of mesenchymal stem cells in the bone and surrounding area.

10.
Mol Pharmacol ; 96(5): 600-608, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31455676

RESUMO

Induction of cytochrome P450 enzyme 3A (CYP3A) in response to pregnane X receptor (PXR) activators shows species-specific differences. To study the induction of human CYP3A in response to human PXR activators, we generated a double-humanized mouse model of PXR and CYP3A. CYP3A-humanized mice generated by using a mouse artificial chromosome (MAC) vector containing the entire genomic human CYP3A locus (hCYP3A-MAC mouse line) were bred with PXR-humanized mice in which the ligand-binding domain of mouse PXR was replaced with that of human PXR, resulting in double-humanized mice (hCYP3A-MAC/hPXR mouse line). Oral administration of the human PXR activator rifampicin increased hepatic expression of CYP3A4 mRNA and triazolam (TRZ) 1'- and 4-hydroxylation activities, CYP3A probe activities, in the liver and intestine microsomes of hCYP3A-MAC/hPXR mice. The plasma concentration of TRZ after oral dosing was significantly decreased by rifampicin treatment in hCYP3A-MAC/hPXR mice but not in hCYP3A-MAC mice. In addition, mass spectrometry imaging analysis showed that rifampicin treatment increased the formation of hydroxy TRZ in the intestine of hCYP3A-MAC/hPXR mice after oral dosing of TRZ. The plasma concentration of 1'- and 4-hydroxy TRZ in portal blood was also increased by rifampicin treatment in hCYP3A-MAC/hPXR mice. These results suggest that the hCYP3A-MAC/hPXR mouse line may be a useful model to predict human PXR-dependent induction of metabolism of CYP3A4 substrates in the liver and intestine. SIGNIFICANCE STATEMENT: We generated a double-humanized mouse line for CYP3A and PXR. Briefly, CYP3A-humanized mice generated by using a mouse artificial chromosome vector containing the entire genomic human CYP3A locus were bred with PXR-humanized mice in which the ligand-binding domain of mouse PXR was replaced with that of human PXR. Expression of CYP3A4 and metabolism of triazolam, a typical CYP3A substrate, in the liver of CYP3A/PXR-humanized mice were enhanced in response to rifampicin, a typical human PXR activator. Enhancement of triazolam metabolism in the intestine of CYP3A/PXR-humanized mice was firstly shown by combination of mass spectrometry imaging of sliced intestine and liquid chromatography with tandem mass spectrometry analysis of metabolite concentration in portal blood after oral dosing of triazolam.

11.
World J Gastroenterol ; 25(20): 2503-2513, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31171893

RESUMO

BACKGROUND: Shear wave speed has been widely applied to quantify a degree of liver fibrosis. However, there is no standardized procedure, which makes it difficult to utilize the speed universally. AIM: To provide procedural standardization of shear wave speed measurement. METHODS: Point shear wave elastography (pSWE) was measured in 781 patients, and two-dimensional shear wave elastography (2dSWE) was measured on the same day in 18 cases. Regions-of-interest were placed at 12 sites, and the median and robust coefficient-of-variation (CVR) were calculated. A residual sum-of-square (Σdi 2) was computed for bootstrap values of 1000 iterations in 18 cases with each assumption of 1 to 12 measurements. The proportion of the Σdi 2 (%Σdi 2) was calculated as the ratio of Σdi 2 to pSWE after converting it based on the correlation between pSWE and 2dSWE. RESULTS: The CVR showed a significantly broader distribution in the left lobe (P < 0.0001), and the smallest CVR in the right anterior segment that covered 95% cases was 40.4%. pSWE was significantly higher in the left lobe than in the right lobe (1.63 ± 0.78 m/s vs 1.61 ± 0.78 m/s, P = 0.0004), and the difference between the lobes became further discrete when the subjects were limited to the cases with a CVR less than 40.4% in any segment (1.76 ± 0.80 m/s vs 1.70 ± 0.82 m/s, P < 0.0001). The highest values of the CVR in every 0.1 m/s interval were plotted in convex upward along pSWE and peaked at 1.93 m/s. pSWE and 2dSWE were significantly correlated (P < 0.0001, r = 0.95). In 216000 resamples from 18 cases, the %Σdi 2 of 12 sites was 8.0% and gradually increased as the acquisition sites decreased to reach a significant difference with a %Σdi 2 of 7 sites (P = 0.027). CONCLUSION: These data suggest that shear wave speed should be measured at 8 or more sites of spreading in both lobes.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico , Fígado/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Lactente , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
12.
Circ J ; 83(8): 1709-1717, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31243245

RESUMO

BACKGROUND: Heart failure (HF) and cancer (CA) are becoming increasingly prevalent as the population ages. We aimed to evaluate prior history and occurrence of CA and its prognostic impact on HF.Methods and Results:Consecutive hospitalized HF patients (n=2,103) were divided into 2 groups according to prior history of CA: non-prior-CA group (n=1,828) and prior-CA group (n=275). Compared with the non-prior-CA group, the prior-CA group were older, and had higher prevalence of chronic kidney disease, anemia, and atrial fibrillation (P<0.05). In contrast, sex, other comorbidities, levels of natriuretic peptide and ejection fraction were comparable between groups. We focused on newly diagnosed CA after discharge for HF. In the follow-up period (median 623 days), 114 (6.2%) patients in the non-prior-CA and 17 (6.2%) patients in the prior-CA groups were newly diagnosed as having CA. Additionally, 83 (3.9%) CA-related patient deaths occurred (median 776 days). In the Kaplan-Meier analysis (median 1,037 days), not only all-cause death but also cardiac event rate was significantly higher in the prior-CA group than in the non-prior-CA group (log-rank P<0.01). In the Cox proportional hazard analysis, CA history was a predictor of cardiac event rate (HR 1.450, 95% CI 1.134-1.822), as well as all-cause death (HR 2.483, 95% CI 2.034-3.030). CONCLUSIONS: Prior-CA history was associated with high cardiac event and mortality rates. CA is notable comorbidity in HF patients.

13.
Cancer Manag Res ; 11: 4437-4448, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191006

RESUMO

Background: Sorafenib (SOR) is an anti-angiogenic chemotherapeutic that prolongs the survival rates of patients with hepatocellular carcinoma. However, SOR also damages normal vasculature and causes associated adverse events, including hand-foot syndrome and hypertension (HT). We previously reported in an animal study that vascular damage resulted in the narrowing of the normal vascular dimension area in medaka fish (Oryzias), and histidine (HIS), a major amino acid contained in dried bonito broth (DBB), prevented these changes. Therefore, in the study, we analyzed the effects of DBB and HIS on SOR-related vascular damages and associated adverse events in patients. Materials and methods: Three-dimensional (3D) vascular images of abdominal regions reconstituted from computed tomography were assessed to compare vascular diameter prior to and following SOR administration in groups receiving SOR monotherapy, DBB+SOR, and HIS+SOR. The clinical courses of hand-foot syndrome and HT and the toxicities of SOR in biochemical assays were monitored and compared between the groups. Correlations between hepatic function and SOR-related changes in the portal venous area dimension were also assessed. Results: SOR-related vascular damage revealed narrowing of the normal abdominal vasculature in the human body, which was monitored using 3D images. The damage was ameliorated by DBB and HIS, however, HIS had a more marked effect, particularly on the renal arteries and portal vein (PV). Maintenance of blood flow contributed to the maintenance of total cholesterol, prothrombin time, albumin (ALB), and renal functions. Changes in the 3D vascular area dimension of the PV and level of serum ALB were significantly correlated. The occurrences of the clinical symptoms of hand-foot syndrome and HT were lower in the DBB- and HIS-treated groups. Conclusion: Our results clearly demonstrate that DBB and HIS prevented SOR-related abdominal vascular damage and effectively maintained hepatic function, and prevented clinical symptoms and toxicity. Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000025937 and UMIN000026898).

15.
Radiother Oncol ; 137: 77-82, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078014

RESUMO

BACKGROUND AND PURPOSE: To determine whether bone matching (BM) or marker matching (MM) is the better positioning technique for carbon ion radiotherapy (CIRT) of primary hepatocellular carcinoma (HCC), we prospectively evaluated accumulated dose distributions with respect to intra- and inter-fractional anatomical changes. MATERIALS AND METHODS: The accumulated doses in ten patients with HCC were evaluated, with the doses being calculated with respect to inter-fractional changes (InterDose) on treatment-room CT images on day 1 or day 2 of therapy (RefCT). This was accomplished by warping 3-day CT dose distributions to the RefCT through deformable registration. The accumulated doses were also calculated with respect to intra-fractional change (IntraDose) calculated by warping dose distributions for three 4DCT phases to the RefCT. Each dose was evaluated using dose-volume parameters for the clinical target volume (CTV) percentages receiving greater than 95% of the prescription dose (V95). RESULTS: The InterDose CTV V95 values (mean [range]) were BM: 98.74% (95.62-100%), MM: 99.79% (98.55-100%), and the IntraDose values were BM: 99.46% (98.10-100%), MM: 99.74% (98.91-100%). Although all cases were acceptable with either matching method, MM provided better values than BM. CONCLUSION: MM is a better positioning technique than BM for ensuring the target dose during and between fractions of CIRT. However, further analysis is required as our study included only a low number of cases.

17.
Dalton Trans ; 48(26): 9759-9764, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-30993287

RESUMO

Spherical protein cages with highly symmetrical structures provide unique environments for the conjugation of metal ions and metal nanoparticles. Ferritin has been widely studied as a template for the coordination of metal ions and metal nanoparticles in fundamental research and applications. However, it remains difficult to design metal coordination sites precisely. In this work, we describe the design and construction of new metal coordination sites by introducing Cys residues at the 4-fold symmetrical hydrophobic channel of apo-ferritin. X-ray crystal structure analyses of the mutants containing Cd(ii) ions show that the four or eight binding sites for Cd(ii) ions are located at the 4-fold symmetrical axis channel of apo-ferritin. It was found that the coordination number and configuration of Cd(ii) ions can be varied by adjusting the positions of the Cys residues at the symmetrical channels of the apo-ferritin cage.

18.
FEBS Open Bio ; 9(4): 643-652, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30984539

RESUMO

The rise in the incidence of nonalcoholic steatohepatitis (NASH) has necessitated the development of an effective prevention methodology. An antidiabetic drug, belonging to the group of sodium glucose cotransporter 2 (SGLT2) inhibitors, has been tested for its therapeutic effect on NASH; however, no studies to date have demonstrated the preventive effect of an SGLT2 inhibitor on the histological progression of steatosis and fibrosis in a sequential manner in animal models. In the present study, we examined the effect of the SGLT2 inhibitor, tofogliflozin (Tofo), on NASH liver tissue using medaka as an animal model, maintaining a feeding amount and drug concentration in all animal bodies. We generated a medaka NASH model by feeding d-rR/Tokyo medaka a high-fat diet and administered Tofo by dissolving the drug directly in the water of the feeding tank. Thereafter, the effects of Tofo on body weight (BW), liver weight, hepatotoxicity, fatty infiltration, and fibrotic changes in the liver were examined. We report here that SGLT2 is expressed in medaka fish and that Tofo inhibits the accumulation of fatty tissue and delays the progression of liver fibrosis in the medaka NASH model by inhibiting increases in blood sugar, serum lipids, and transaminase, irrespective of changes in BW. These results suggest that Tofo is effective for treating NASH and that the medaka model may be useful for developing new therapeutic drugs for this disease.


Assuntos
Compostos Benzidrílicos/farmacologia , Fígado Gorduroso/tratamento farmacológico , Proteínas de Peixes/metabolismo , Glucosídeos/farmacologia , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Proteínas de Peixes/antagonistas & inibidores , Fígado/metabolismo , Oryzias
19.
Chem Sci ; 10(4): 1046-1051, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30774900

RESUMO

Investigations involving the design of protein assemblies for the development of biomaterials are receiving significant attention. In nature, proteins can be driven into assemblies frequently by various non-covalent interactions. Assembly of proteins into supramolecules can be conducted under limited conditions in solution. These factors force the assembly process into an equilibrium state with low stability. Here, we report a new method for preparing assemblies using protein crystals as non-equilibrium molecular scaffolds. Protein crystals provide an ideal environment with a highly ordered packing of subunits in which the supramolecular assembled structures are formed in the crystalline matrix. Based on this feature, we demonstrate the self-assembly of supramolecular nanotubes constructed from protein crystals triggered by co-oxidation with cross-linkers. The assembly of tubes is driven by the formation of disulfide bonds to retain the intermolecular interactions within each assembly in the crystalline matrix after dissolution of the crystals.

20.
Proc Natl Acad Sci U S A ; 116(8): 3072-3081, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718425

RESUMO

Although "genomically" humanized animals are invaluable tools for generating human disease models as well as for biomedical research, their development has been mainly restricted to mice via established transgenic-based and embryonic stem cell-based technologies. Since rats are widely used for studying human disease and for drug efficacy and toxicity testing, humanized rat models would be preferred over mice for several applications. However, the development of sophisticated humanized rat models has been hampered by the difficulty of complex genetic manipulations in rats. Additionally, several genes and gene clusters, which are megabase range in size, were difficult to introduce into rats with conventional technologies. As a proof of concept, we herein report the generation of genomically humanized rats expressing key human drug-metabolizing enzymes in the absence of their orthologous rat counterparts via the combination of chromosome transfer using mouse artificial chromosome (MAC) and genome editing technologies. About 1.5 Mb and 700 kb of the entire UDP glucuronosyltransferase family 2 and cytochrome P450 family 3 subfamily A genomic regions, respectively, were successfully introduced via the MACs into rats. The transchromosomic rats were combined with rats carrying deletions of the endogenous orthologous genes, achieved by genome editing. In the "transchromosomic humanized" rat strains, the gene expression, pharmacokinetics, and metabolism observed in humans were well reproduced. Thus, the combination of chromosome transfer and genome editing technologies can be used to generate fully humanized rats for improved prediction of the pharmacokinetics and drug-drug interactions in humans, and for basic research, drug discovery, and development.


Assuntos
Citocromo P-450 CYP3A/genética , Edição de Genes , Glucuronosiltransferase/genética , Inativação Metabólica/genética , Animais , Técnicas de Transferência de Genes , Genoma , Humanos , Taxa de Depuração Metabólica/genética , Camundongos , Camundongos Transgênicos , Ratos
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