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1.
Eur J Clin Pharmacol ; 2020 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-32591943

RESUMO

PURPOSE: H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. We aimed to identify the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection. METHODS: We consecutively enrolled 430 patients with at least one course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7-14 days. Fourteen patients with positive 13C-urea breath test after the first rescue therapy were retreated with a crossover second rescue therapy. RESULTS: The MTBP regimen had higher eradication success than the ATBP regimen as the first rescue therapy for TR H. pylori (intent-to-treat (ITT) analysis, 70.3 vs. 46.9%, p = 0.048; per protocol (PP) analysis, 78.8% vs. 51.7%, p = 0.025). For MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p < 0.001) with a 14-day treatment duration (p = 0.037) could predict eradication success with 100% accuracy. For the ATBP regimen, amoxicillin MIC selected as ≤ 0.032 mg/L could optimally determine eradication success (72.2 vs. 33.3%, p = 0.025). CONCLUSION: Optimizing the MIC breakpoints of amoxicillin and tetracycline resistance better predicts the outcome of bismuth quadruple therapy. Further prospective studies using the revised MIC breakpoints to select antibiotics are warranted.

2.
Science ; 368(6498): 1487-1490, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32587020

RESUMO

The development of two-dimensional metasurfaces has shown great potential in quantum-optical technologies because of the excellent flexibility in light-field manipulation. By integrating a metalens array with a nonlinear crystal, we demonstrate a 100-path spontaneous parametric down-conversion photon-pair source in a 10 × 10 array, which shows promise for high-dimensional entanglement and multiphoton-state generation. We demonstrate two-, three- and four-dimensional two-photon path entanglement with different phases encoded by metalenses with fidelities of 98.4, 96.6, and 95.0%, respectively. Furthermore, four-photon and six-photon generation is observed with high indistinguishability of photons generated from different metalenses. Our metalens-array-based quantum photon source is compact, stable, and controllable, indicating a new platform for integrated quantum devices.

3.
Oncol Res Treat ; 43(5): 211-220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32101878

RESUMO

INTRODUCTION: The tumor microenvironments of different organs often differ and thus may affect the immunotherapy response. OBJECTIVE: This study elucidated that the efficacy of programmed cell death protein-1 (PD-1) inhibitors varies across different metastatic sites among individuals with advanced hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed treatment outcomes in advanced HCC patients receiving PD-1 inhibitors with or without a combination of tyrosine kinase inhibitors (TKIs). Both the overall response rate (ORR) and organ-specific response rate (OSRR) were assessed using Response Evaluation Criteria in Solid Tumors 1.1 criteria. A survival analysis and its predictors were determined using a multivariate analysis. RESULTS: We analyzed 42 advanced HCC patients (median age: 58.0 years; 78.6% males). Thirty (71.4%) patients were sorafenib-experienced and 27 (64.3%) were administered a combination of TKIs. The ORR was 14.3% and the disease control rate was 33.3%. The median overall survival (OS) and progression-free survival (PFS) were 12.0 and 2.9 months, respectively. The OSRRs were 14.7, 23.8, 28.6, and 50.0% for the liver, lungs, lymph nodes, and vascular response, respectively. The multivariate analysis indicated that the vascular response was significantly associated with PFS. ECOG performance status was a significant independent predictor of OS. CONCLUSIONS: PD-1 inhibitors improved OS and PFS in advanced HCC patients. Their efficacies varied among the metastatic locations regardless of the combination of TKIs; in particular, a higher response in vascular metastases was correlated with a longer PFS. PD-1 inhibitors may deliver a synergistic benefit in patients undergoing traditional therapy and progression in other organs in vascular responders.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular , Feminino , Humanos , Imunoterapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral
4.
Surg Endosc ; 34(4): 1592-1601, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31222633

RESUMO

BACKGROUND: The Forrest classification is widely applied to guide endoscopic hemostasis for peptic ulcer bleeding. Accordingly, practice guidelines suggest medical treatment only for ulcer with a Forrest IIc lesion because it has low rebleeding risk even without endoscopic therapy, ranging from 0 to 13%. However, the risk ranges widely and it is unclear who is at risk of rebleeding with such a lesion. This study assessed whether the Rockall score, which evaluates patients holistically, could indicate the risk of recurrent bleeding among patients with a Forrest IIc lesion at the second-look endoscopy. METHODS: Patients who had peptic ulcer bleeding with Ia-IIb lesions received endoscopic hemostasis at the primary endoscopy, and they were enrolled if their Ia-IIb lesions had been fading to IIc at the second-look endoscopy after 48- to 72-h intravenous proton pump inhibitor (PPI) infusion. Primary outcomes were rebleeding during the 4th-14th day and 4th-28th day after the first bleeding episode. RESULTS: The prospective cohort study enrolled 140 patients, who were divided into a Rockall scores ≥ 6 group or a Rockall scores < 6 group. The rebleeding rates in the Rockall scores ≥ 6 group and the Rockall scores < 6 group during the 4th-14th day and the 4th-28th day were 13/70 (18.6%) versus 2/70 (2.9%), p = 0.003 and 17/70 (24.3%) versus 3/70 (4.3%), p = 0.001, respectively, based on an intention-to-treat analysis and 5/62 (8.1%) versus 0/68 (0%), p = 0.023 and 6/59 (10.2%) versus 0/67 (0%), p = 0.009, respectively, based on a per-protocol analysis. The Kaplan-Meier curves showed that the Rockall scores ≥ 6 group had a significantly lower cumulative rebleeding-free proportion than the Rockall scores < 6 group (p = 0.01). CONCLUSIONS: Combined Rockall scores ≥ 6 on arrival with a Forrest IIc lesion at the second-look endoscopy can identify patients at risk of recurrent peptic ulcer bleeding following initial endoscopic and intravenous PPI treatment. Trial registration Trial registration identifier: NCT01591083.

5.
Light Sci Appl ; 8: 99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31728191

RESUMO

Tomography is an informative imaging modality that is usually implemented by mechanical scanning, owing to the limited depth-of-field (DOF) in conventional systems. However, recent imaging systems are working towards more compact and stable architectures; therefore, developing nonmotion tomography is highly desirable. Here, we propose a metalens-based spectral imaging system with an aplanatic GaN metalens (NA = 0.78), in which large chromatic dispersion is used to access spectral focus tuning and optical zooming in the visible spectrum. After the function of wavelength-switched tomography was confirmed on cascaded samples, this aplanatic metalens is utilized to image microscopic frog egg cells and shows excellent tomographic images with distinct DOF features of the cell membrane and nucleus. Our approach makes good use of the large diffractive dispersion of the metalens and develops a new imaging technique that advances recent informative optical devices.

6.
J Dent Sci ; 14(3): 234-240, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31528250

RESUMO

Background/purpose: Immediate implant placement has been considered to be a successful treatment procedure. The bone plate perforation (BPP) may be one of severe complication and potentially life-threatening situation. The aim of this virtual study is to evaluate the influences of angled implant insertion on BPP during immediate implant installation in the posterior mandible. Materials and methods: Cone beam computed tomography images of 488 posterior teeth from 61 patients were selected. Virtual immediate implant placement (VIIP) was performed at each posterior tooth following the appropriate axis with the prosthetic-driven planning and different deviation angles of 3-, 6-, or 9-degree. BPP was then examined from cross-sectional images obtained. Furthermore, the relation of lingual bony morphology and BPP were also determined. Results: The incidence of buccal and lingual BPP increased as the deviation angle increased in posterior mandible area. Incidence of lingual BPP was significantly influenced by angular deviation and type of lingual bony morphology after adjusting for age, gender, tooth type, and right/left side. An increase in incidence odds of over 6-fold (OR = 6.583) was noted for placements angled by 9° compared with placements made without angulation, and an increase in incidence odds of over 3-fold (OR = 3.622) was noted for teeth with the undercut-type lingual morphology compared with the other types. Conclusion: The present Results indicate that accurate selection of the implant insertion angle and full awareness of the bony anatomy at the implant recipient site are essential to prevent BPP in the posterior mandible.

7.
Helicobacter ; 24(3): e12578, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30990573

RESUMO

BACKGROUND AND AIMS: Spasmolytic polypeptide-expressing metaplasia (SPEM) is a preneoplastic gastric cancer lesion related to epigenetic microRNA (miRNA) expression. This study elucidated whether Helicobacter pylori-infected first-degree relatives of patients with gastric cancer (GCF) are susceptible to have SPEM and correlated with miR-21, 155, and 223 expressions. We also validated whether SPEM and these miRNAs can be regressed after H pylori eradication. METHODS: We prospectively enrolled 148 GCF and 148 nonulcer dyspepsia (NUD) subjects without gastric cancer familial history as controls. Each case had received a panendoscopy to determine H pylori status and gastric histology, including SPEM. The cases with SPEM were followed after H pylori eradication to determine SPEM regression. The total RNA was extracted to analyze tissues miR-21, 155, and 223 before and after eradication. RESULTS: GCF subjects had a higher prevalence of H pylori infection (73% vs 32%) and SPEM (42% vs 14%, P < 0.01) than controls. The tissue miR-21, 155, and 223 in antrum were higher in cases with SPEM than in those without SPEM (P <= 0.05). There was similar SPEM reversibility after H pylori eradication between GCF subjects and controls (72% vs 69%, P = 0.852). In the SPEM regressed cases, tissue miR-21, 155, and 223 decreased after H pylori eradication (P < 0.05). CONCLUSION: The H pylori-infected GCF subjects were prone to have SPEM with higher tissues miR-21, 155, and 223 expressions. H pylori eradication can result in a 70% SPEM regression, accompanied by a decline in miR-21, 155, and 233 expression levels.


Assuntos
Infecções por Helicobacter/metabolismo , Helicobacter pylori/fisiologia , Metaplasia/metabolismo , MicroRNAs/genética , Peptídeos/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Feminino , Infecções por Helicobacter/microbiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Metaplasia/microbiologia , Pessoa de Meia-Idade , Neoplasias Gástricas/microbiologia
8.
Nat Nanotechnol ; 14(3): 227-231, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30664753

RESUMO

A light-field camera captures both the intensity and the direction of incoming light1-5. This enables a user to refocus pictures and afterwards reconstruct information on the depth of field. Research on light-field imaging can be divided into two components: acquisition and rendering. Microlens arrays have been used for acquisition, but obtaining broadband achromatic images with no spherical aberration remains challenging. Here, we describe a metalens array made of gallium nitride (GaN) nanoantennas6 that can be used to capture light-field information and demonstrate a full-colour light-field camera devoid of chromatic aberration. The metalens array contains an array of 60 × 60 metalenses with diameters of 21.65 µm. The camera has a diffraction-limited resolution of 1.95 µm under white light illumination. The depth of every object in the scene can be reconstructed slice by slice from a series of rendered images with different depths of focus. Full-colour, achromatic light-field cameras could find applications in a variety of fields such as robotic vision, self-driving vehicles and virtual and augmented reality.

9.
J Biomed Sci ; 26(1): 4, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611258

RESUMO

BACKGROUND: H. pylori CagL-Y58/E59 increase gastric cancer risk by stronger binding with integrin to faciliate type IV secretory system (T4SS). H. pylori can secrete high temperature requirement A (HtrA) to mediate E-Cadherin cleavage for gastric epithelial junction disruption, so H. pylori CagL can adhere to integrin located on basolateral side of epithelium. The study test whether H. pylori HtrA amino acid polymorphisms can increase gastric cancer risk synergistically with CagL-Y58/E59. METHODS: One-hundred and sixty-four H. pylori-positive patients, including 71 with non-ulcer dyspepsia (NUD), 63 with peptic ulcers (PU), and 30 with gastric cancers (GC), were enrolled to receive upper gastrointestinal endoscopy to obtain gastric biopsies for H. pylori culture and histology by the updated Sydney system. Each isolate was screened for htrA & cagL genotype by polymerase chain reaction and HtrA & CagL-Y58/E59 amino acid sequence polymorphisms by sequencing. RESULTS: The prevalence rates of htrA & cagL gene were both 100%. The HtrA amino acid sequence polymorphisms were not different between NUD and PU. The H. pylori isolates of GC had higher rates of HtrA residue 171 as leucine than those of NUD (73.3% vs. 50.7%, P = 0.036, OR[95%CI] = 2.7[1.1-6.8]). The risk of the H. pylori-infected subjects to get gastric cancer was increased up to 15.4-fold, if the infected isolates had presence of both HtrA-L171 and CagL-Y58/E59 (P < 0.001). CONCLUSIONS: The H. pylori isolates of gastric cancer subjects had a higher rate of HtrA-L171. H. pylori isolates with presence of both HtrA-171 & CagL-Y58/E59 can synergistically increase the risk of gastric cancer.


Assuntos
Proteínas de Bactérias/genética , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/genética , Polimorfismo Genético , Neoplasias Gástricas/epidemiologia , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Infecções por Helicobacter/microbiologia , Humanos , Prevalência , Risco , Serina Endopeptidases/química , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Neoplasias Gástricas/microbiologia , Taiwan/epidemiologia
10.
Nat Nanotechnol ; 13(3): 227-232, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29379204

RESUMO

Metalenses consist of an array of optical nanoantennas on a surface capable of manipulating the properties of an incoming light wavefront. Various flat optical components, such as polarizers, optical imaging encoders, tunable phase modulators and a retroreflector, have been demonstrated using a metalens design. An open issue, especially problematic for colour imaging and display applications, is the correction of chromatic aberration, an intrinsic effect originating from the specific resonance and limited working bandwidth of each nanoantenna. As a result, no metalens has demonstrated full-colour imaging in the visible wavelength. Here, we show a design and fabrication that consists of GaN-based integrated-resonant unit elements to achieve an achromatic metalens operating in the entire visible region in transmission mode. The focal length of our metalenses remains unchanged as the incident wavelength is varied from 400 to 660 nm, demonstrating complete elimination of chromatic aberration at about 49% bandwidth of the central working wavelength. The average efficiency of a metalens with a numerical aperture of 0.106 is about 40% over the whole visible spectrum. We also show some examples of full-colour imaging based on this design.

12.
Future Oncol ; 13(16): 1415-1425, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28685609

RESUMO

AIM: Whether genetic polymorphisms of osteopontin (OPN) coding gene, SPP1, determine the risk of gastric precancerous intestinal metaplasia (IM) in Helicobacter pylori infected patients. PATIENTS & METHODS: Helicobacter pylori infected patients (100 with and 210 without IM) were recruited to evaluate the associations of SPP1 promoter polymorphisms with gastric IM and adjusted for age, sex and smoking. Gastric OPN expression and inflammation were evaluated by immunohistochemistry, and haemotoxylin and eosin stain. RESULTS: Only in males, but not females, carriage of both GG genotype at rs11730059 and C-G-C haplotype at rs6833161-rs2853744-rs11730582 significantly increased the IM risk (OR: 4.92; 95% CI: 1.65-14.65; p = 0.004). Nearly 87.5% of males with IM carried risky genotype or haplotype. Carriers of the risky genotype or haplotype also had increased gastric OPN expression (p = 0.038) and inflammation (p = 0.007). CONCLUSION: SPP1 polymorphisms predispose to IM development in H. pylori infected males.


Assuntos
Infecções por Helicobacter/genética , Metaplasia/genética , Osteopontina/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genótipo , Haplótipos , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Humanos , Masculino , Metaplasia/microbiologia , Metaplasia/patologia , Pessoa de Meia-Idade , Polimorfismo Genético , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Fumar/efeitos adversos , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
13.
Helicobacter ; 22(4)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28326664

RESUMO

BACKGROUND: Corpus-predominant gastritis index (CGI) is an early histological marker to identify Helicobacter pylori-infected gastric cancer relatives at risk of cancer. This study validated whether CGI is more prevalent in H. pylori-infected nonulcer dyspepsia (NUD) subjects than in duodenal ulcer (DU) controls and whether it is reversible after H. pylori eradication or is correlated with noninvasive biomarkers. MATERIALS AND METHODS: In this longitudinal cohort study, 573 H. pylori-infected subjects were enrolled, including 349 NUD and 224 DU. Gastric specimens were provided to assess CGI, spasmolyic polypeptide-expressing metaplasia (SPEM), and Operative Link on Gastric Intestinal Metaplasia assessment (OLGIM). Serum pepsinogen I and II levels were assessed using enzyme-linked immunosorbent assay. CGI subjected were followed up at least 1 year after H. pylori eradication. RESULTS: NUD subjects had higher prevalence rates of CGI (47.0% vs 29.9%, P<.001) and OLGIM stages III-IV (24.1% vs 15.2%, P=.01) than controls. CGI was highly prevalent in NUD subjects after the age of 40, which was 10 years earlier than atrophic gastritis and intestinal metaplasia. NUD subjects with CGI had higher risk of SPEM (OR 2.86, P<.001) and lower serum pepsinogen I/II ratios (P<.001) than those without CGI. Serum pepsinogen I/II ratios <9 could predict CGI modestly (AUROC 0.69, 95% CI: 0.63-0.74). CGI was regressed after eradication (P<.001). CONCLUSIONS: CGI was more prevalent in H. pylori-infected NUD subjects than in controls, was correlated with SPEM, and may serve as a marker earlier than OLGIM to indicate risk of gastric cancer. Moreover, CGI could be regressed after eradication.


Assuntos
Dispepsia/complicações , Gastrite/complicações , Gastrite/patologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Adulto , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Histocitoquímica , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pepsinogênio A/sangue , Prognóstico , Estudos Prospectivos , Medição de Risco , Estômago/patologia
14.
Helicobacter ; 22(1)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27220894

RESUMO

BACKGROUND & AIMS: Gastric cancer has familial clustering in incidence, and the familial relatives of gastric cancer sufferers are prone to have spasmolytic polypeptide-expressing metaplasia (SPEM), and intestinal metaplasia (IM) after H. pylori infection. This study tested whether serum pepsinogen I/II and trefoil factor family (TFF) proteins can predict SPEM or IM in the H. pylori-infected relatives of patients with gastric cancer. METHODS: We prospectively enrolled 119 H. pylori-infected relatives of gastric cancer patients of noncardiac gastric cancer patients, who then received panendoscopy to obtain gastric biopsy to define the presence of corpus gastritis index (CGI), SPEM, and IM. The advanced SPEM in histology was defined by TFF2 immunohistochemistry. Each patient also had checkups of serum TFF2, TFF3, and pepsinogen I/II by enzyme-linked immunosorbent assay (ELISA). RESULTS: The 119 H. pylori-infected relatives included 61 with SPEM, and 34 with IM. The presence of either IM or SPEM was not related to the serum TFF2, TFF3, and pepsinogen I/II levels (p > .05). Serum TFF2 levels were higher in relatives with CGI who also had advanced SPEM (p = .032). For relatives without CGI, the elevated serum TFF2 levels correlated with higher H. pylori density and more severe gastritis in antrum (p = .001). CONCLUSION: The serum TFF2 level cannot predict SPEM or IM in H. pylori-infected relatives of patients with gastric cancer. For H. pylori-infected relatives with CGI, serum TFF2 levels may predict the advanced severity of SPEM. Elevated serum TFF2 levels may indicate severe H. pylori-related inflammation, at risk of development or progression of SPEM in relatives without CGI.


Assuntos
Infecções por Helicobacter/complicações , Intestinos/patologia , Peptídeos/análise , Soro/química , Estômago/patologia , Fator Trefoil-2/sangue , Adulto , Biópsia , Família , Saúde da Família , Feminino , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Metaplasia/diagnóstico , Metaplasia/patologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos
15.
Biomaterials ; 103: 207-218, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27392289

RESUMO

Aging-related oxidative stress is considered a major risk factor of cardiovascular diseases (CVD) and could be associated with mitochondrial dysfunction and reactive oxygen species (ROS) overproduction. Cisd2 is an outer mitochondrial membrane protein and plays an important role in controlling the lifespan of mammals. Ferulic acid (FA), a natural antioxidant, is able to improve cardiovascular functions and inhibit the pathogenetic CVD process. However, directly administering therapeutics with antioxidant molecules is challenging because of stability and bioavailability issues. In the present study, thermosensitive chitosan-gelatin-based hydrogel containing FA was used to treat Cisd2-deficient (Cisd2(-/-)) cardiomyocytes (CM) derived from induced pluripotent stem cells of Cisd2(-/-) murine under oxidative stress. The results revealed that the developed hydrogel could provide a sustained release of FA and increase the cell viability. Post-treatment of FA-loaded hydrogel effectively decreased the oxidative stress-induced damage in Cisd2(-/-) CM via increasing catalase activity and decreasing endogenous reactive oxygen species (ROS) production. The in vivo biocompatibility of FA-loaded hydrogel was confirmed in subcutaneously injected rabbits and intramyocardially injected Cisd2(-/-) mice. These results suggest that the thermosensitive FA-loaded hydrogel could rescue Cisd2(-/-) CM from oxidative stress-induced damage and may have potential applications in the future treatment of CVD.


Assuntos
Proteínas de Transporte/metabolismo , Ácidos Cumáricos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antioxidantes/administração & dosagem , Proteínas Relacionadas à Autofagia , Células Cultivadas , Ácidos Cumáricos/química , Preparações de Ação Retardada/química , Hidrogéis/administração & dosagem , Hidrogéis/química , Injeções , Camundongos , Camundongos Knockout , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo
16.
Exp Cell Res ; 344(1): 40-52, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27086164

RESUMO

Inhibition of histone deacetylases (HDACi) has emerged as a promising approach in the treatment of many types of cancer, including leukemias. Among the HDACs, Class III HDACs, also known as sirtuins (SIRTs), are unique in that their function is directly related to the cell's metabolic state through their dependency on the co-factor NAD(+). In this study, we examined the relation between SIRTs and the growth, survival, and differentiation of K562 erythroleukemia cells. Using a mass spectrometry approach we previously developed, we show that SIRT expression and deacetylase activity in these cells changes greatly with differentiation state (undifferentiated vs. megakaryocytic differentiation vs. erythroid differentiation). Moreover, SIRT1 is crucially involved in regulating the differentiation state. Overexpression of wildtype (but not deacetylase mutant) SIRT1 resulted in upregulation of glycophorin A, ~2-fold increase in the mRNA levels of α, γ, ε, and ζ-globins, and spontaneous hemoglobinization. Hemin-induced differentiation was also enhanced by (and depended on) higher SIRT1 levels. Since K562 cells are bipotent, we also investigated whether SIRT1 modulation affected their ability to undergo megakaryocytic (MK) differentiation. SIRT1 was required for commitment to the MK lineage and subsequent maturation, but was not directly involved in polyploidization of either K562 cells or an already-MK-committed cell line, CHRF-288-11. The observed blockage in commitment to the MK lineage was associated with a dramatic decrease in the formation of autophagic vacuoles, which was previously shown to be required for K562 cell MK commitment. Autophagy-associated conversion of the protein LC3-I to LC3-II was greatly enhanced by overexpression of wildtype SIRT1, further suggesting a functional connection between SIRT1, autophagy, and MK differentiation. Based on its clear effects on autophagy, we also examined the effect of SIRT1 modulation on stress responses. Consistent with results of prior studies, we found that SIRT1 silencing modestly promoted drug-induced apoptosis, while overexpression was protective. Furthermore, pan-SIRT inhibition mediated by nicotinamide pre-treatment substantially increased imatinib-induced apoptosis. Altogether, our results suggest a complex role for SIRT1 in regulating many aspects of K562 cell state and stress response. These observations warrant further investigation using normal and leukemic primary cell models. We further suggest that, ultimately, a well-defined mapping of HDACs to their substrates and corresponding signaling pathways will be important for optimally designing HDACi-based therapeutic approaches.


Assuntos
Diferenciação Celular , Sirtuína 1/metabolismo , Autofagia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citosol/metabolismo , Células Eritroides/citologia , Células Eritroides/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Células K562 , Megacariócitos/citologia , Megacariócitos/efeitos dos fármacos , Niacinamida/farmacologia , Poliploidia , Acetato de Tetradecanoilforbol/farmacologia
17.
J Agric Food Chem ; 62(3): 742-9, 2014 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-24380443

RESUMO

Whole-bean soymilk has been prepared by using media-milling. Some characteristics of media-milled soymilk have been determined and compared with filtered soymilk (similar to commercial ones) and whole-bean soymilk prepared by blending. There existed particles in the nano/submicrometer scale in both media-milled and filtered soymilk. The particles in blended soymilk were greater than 1 µm. Media-milled soymilk was the most stable among three samples, even after autoclaving. Solid recovery (98.44 ± 0.16%), viscosity (160.59 ± 4.26 cps), dietary fiber (22.68 ± 0.97% on dry basis), total polyphenol recovery (95.15 ± 7.09%), and isoflavone content (4.42 ± 0.03 mg/g dry solid) of media-milled samples were greater than those of filtered ones. Aglycones, the most bioactive form of isoflavone, in autoclaved media-milled soymilk were more than 2-fold those in autoclaved filtered soymilk. With almost no okara generated, the media-milled soymilk retained fiber in soybeans which would be beneficial to human health.


Assuntos
Manipulação de Alimentos/métodos , Leite de Soja/química , Soja/química , Fibras na Dieta/análise , Filtração , Tamanho da Partícula , Viscosidade
18.
Anal Chem ; 85(22): 10635-10642, 2013 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-24088168

RESUMO

The development of arrays that can profile molecular activities in cells is important to understanding signaling pathways in normal and pathological settings. While oligonucleotide arrays are now routinely used to profile global gene expression, there is still a lack of tools for profiling enzyme activities in cell lysates. This paper describes the combination of peptide arrays formed on self-assembled monolayers and mass spectrometry to provide a label-free approach for identifying patterns of enzyme activities in cell lysates. The approach is demonstrated by profiling lysine deacetylase (KDAC) activities in cell lysates of the CHRF megakaryocytic (Mk) cell line. Class-specific deacetylase inhibitors were used to show that terminal Mk differentiation of CHRF cells is marked by a pronounced decrease in sirtuin activity and by little change in activity of KDACs 1-11. This work establishes a platform that can be used to identify changes in global activity profiles of cell lysates for a wide variety of enzymatic activities.


Assuntos
Histona Desacetilases/metabolismo , Espectrometria de Massas/métodos , Megacariócitos/metabolismo , Fragmentos de Peptídeos/análise , Análise Serial de Proteínas , Acetilação , Western Blotting , Células Cultivadas , Citometria de Fluxo , Humanos , Megacariócitos/citologia , Biblioteca de Peptídeos , Transdução de Sinais , Especificidade por Substrato
19.
Science ; 342(6158): 1243417, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24051248

RESUMO

Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD(+)-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD(+) supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD(+) bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding.


Assuntos
Relógios Circadianos/fisiologia , Metabolismo Energético , Mitocôndrias Hepáticas/metabolismo , NAD/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Acetilação , Animais , Relógios Circadianos/genética , Jejum , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Camundongos Knockout , Oxirredução , Consumo de Oxigênio , Sirtuína 3/genética , Sirtuína 3/metabolismo
20.
Am J Nephrol ; 37(1): 50-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23296044

RESUMO

BACKGROUND: Long-term exposure to bioincompatible peritoneal dialysis solutions is frequently complicated with peritoneal fibrosis and ultrafiltration failure. As cannabinoid receptor (CBR) ligands have been reported to be beneficial to ameliorate the process of liver fibrosis, we strove to investigate their therapeutic potential to prevent peritoneal fibrosis. METHODS: We used the rat model of peritoneal fibrosis induced by intraperitoneal injection of methylglyoxal and in vitro mesothelial cell culture to test the effects of CBR ligands, including the type 1 CBR (CB(1)R) antagonist and the type 2 CBR (CB(2)R) agonist. RESULTS: In the methylglyoxal model, both intraperitoneal CB(1)R antagonist (AM281) and CB(2)R agonist (AM1241) treatment significantly ameliorated peritoneal fibrosis. In addition, CB(1)R antagonist was able to alleviate TGF-ß(1)-induced dedifferentiation of mesothelial cells and to maintain epithelial integrity in vitro. CONCLUSIONS: Intraperitoneal administration of CBR ligands (CB(1)R antagonist and CB(2)R agonist) offers a potential therapeutic strategy to reduce dialysis-induced peritoneal fibrosis and to prolong the peritoneal survival in peritoneal dialysis patients.


Assuntos
Agonistas de Receptores de Canabinoides/uso terapêutico , Antagonistas de Receptores de Canabinoides/uso terapêutico , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/prevenção & controle , Receptores de Canabinoides/metabolismo , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/metabolismo , Aldeído Pirúvico , Ratos , Ratos Sprague-Dawley
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