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1.
Am J Gastroenterol ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34506308

RESUMO

INTRODUCTION: The necessity of antiviral therapy (AVT) for hepatitis B virus (HBV)-infected compensated cirrhosis with low-level viremia (LLV) is controversial. Herein, we evaluated its natural history. METHODS: From 3 tertiary hospitals, we enrolled untreated patients with compensated cirrhosis with persistent serum HBV-DNA levels <2,000 IU/mL; LLV was defined as having at least 1 detectable serum HBV-DNA (20-2,000 IU/mL) episode, whereas maintained virological response (MVR) was defined as having persistently undetectable serum HBV-DNA (<20 IU/mL). When serum HBV-DNA was ≥2,000 IU/mL during follow-up, AVT was administered according to guidelines. Study end points were development of cirrhotic complication event (CCE) or hepatocellular carcinoma (HCC). RESULTS: Among 567 patients analyzed, cumulative HCC risk at 3, 5, and 7 years was comparable between LLV (n = 391) vs MVR (n = 176) groups (5.7%, 10.7%, and 17.3% vs 7.2%, 15.5%, and 19.4%, respectively [P = 0.390]). CCE risk was also comparable between 2 groups (7.5%, 12.8%, and 13.7% vs 7.8%, 12.3%, and 14.6%, respectively [P = 0.880]). By multivariate analysis, LLV (vs MVR) was not associated with HCC or CCE risks, with adjusted hazard ratios of 1.422 (95% confidence interval [CI] 0.694-2.913; P = 0.336) and 1.816 (95% CI: 0.843-3.911; P = 0.128), respectively. Inverse probability of treatment weighting analysis yielded comparable outcomes between 2 groups, regarding HCC and CCE risks with hazard ratios of 0.903 (95% CI: 0.528-1.546; P = 0.711) and 1.192 (95% CI: 0.675-2.105; P = 0.545), respectively. DISCUSSION: Episodic LLV among untreated patients with compensated cirrhosis does not increase the risk of disease progression compared with MVR status. Thus, the benefits of AVT for episodic LLV should be re-evaluated.

2.
J Viral Hepat ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34435412

RESUMO

It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment-naïve CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF-based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first-line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan-Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person-years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p = .438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis-4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p = .708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p = .446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow-up are required to validate our results.

3.
Nat Biomed Eng ; 5(8): 880-896, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34426676

RESUMO

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.


Assuntos
Células Endoteliais/transplante , Coração/fisiologia , Infarto do Miocárdio/terapia , Miócitos de Músculo Liso/transplante , Regeneração , Animais , Ácido Ascórbico/farmacologia , Proteína Morfogenética Óssea 4/farmacologia , Reprogramação Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Junções Comunicantes/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Neovascularização Fisiológica , Transcriptoma
4.
FASEB J ; 35(10): e21894, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34460995

RESUMO

Neuromyelitis optica (NMO) is an autoimmune disease that primarily targets astrocytes. Autoantibodies (NMO-IgG) against the water channel protein, aquaporin 4 (AQP4), are a serologic marker in NMO patients, and they are known to be responsible for the pathophysiology of the disease. In the brain, AQP4 is mainly expressed in astrocytes, especially at the end-feet, where they form the blood-brain barrier. Following the interaction between NMO-IgG and AQP4 in astrocytes, rapid AQP4 endocytosis initiates pathogenesis. However, the cellular and molecular mechanisms of astrocyte destruction by autoantibodies remain largely elusive. We established an in vitro human astrocyte model system using induced pluripotent stem cells (iPSCs) technology in combination with NMO patient-derived serum and IgG to elucidate the cellular and functional changes caused by NMO-IgG. Herein, we observed that NMO-IgG induces structural alterations in mitochondria and their association with the endoplasmic reticulum (ER) and lysosomes at the ultrastructural level, which potentially leads to impaired mitochondrial functions and dynamics. Indeed, human astrocytes display impaired mitochondrial bioenergetics and autophagy activity in the presence of NMO-IgG. We further demonstrated NMO-IgG-driven ER membrane deformation into a multilamellar structure in human astrocytes. Together, we show that NMO-IgG rearranges cellular organelles and alter their functions and that our in vitro system using human iPSCs offers previously unavailable experimental opportunities to study the pathophysiological mechanisms of NMO in human astrocytes or conduct large-scale screening for potential therapeutic compounds targeting astrocytic abnormalities in patients with NMO.


Assuntos
Astrócitos/imunologia , Autoanticorpos/imunologia , Retículo Endoplasmático/imunologia , Imunoglobulina G/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Mitocôndrias/imunologia , Neuromielite Óptica/imunologia , Aquaporina 4/imunologia , Humanos
5.
Stem Cell Reports ; 16(9): 2128-2137, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34450034

RESUMO

The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer's disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-ß (Aß) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aß production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aß secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aß production through an oversupply of cholesterol.

6.
Hepatol Int ; 15(5): 1083-1092, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34402025

RESUMO

BACKGROUND AND AIMS: Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC. METHODS: From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method. RESULTS: In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743). CONCLUSIONS: These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.

7.
J Craniofac Surg ; 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34292252

RESUMO

ABSTRACT: The present study is to identify primarily the morphological characteristics in the growth proportion of the head and face for young Korean (8-24 years) and compare the magnitude of growth changes to the sex-related differences. Total 1255 were divided into 3 age groups: childhood (8-10 years), adolescence (14-16 years), and young adult (20-24 years). The anthropometric assessments were performed with 11 landmarks on the head and facial dimensions. The standardized frontal and lateral head and face photographs were analyzed the craniofacial growth proportions and morphological features for the comparison of both sexes. The noteworthy differences of anthropometric measurements between sexes with growing were noted on the lower head height (22.6%, 17.8%), midface height (22.0%, 19.6%), lower face height (23.5%, 14.7%), and face length (21.1%, 14.9%), face breadth (14.8%, 11.3%) of males and females, respectively. Whereas the upper head height (7.9%, 6.0%) and upper face height (4.2%, 0%, respectively) were less growing features. The most remarkable changes are the dimension of midface height and lower face height in both sexes. The present study could demonstrate a fundamental example to elucidate the sex-related dimensional differences for the analysis of the growth proportion of both sexes in Koreans.

8.
J Mater Chem B ; 9(19): 4015-4023, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33954328

RESUMO

Nanozymes are nanostructure-based materials which mimic the enzymatic characteristics of natural enzymes. Biological applications of nanozymes have been highlighted in basic research, industry, and translational medicine as a new cutting-edge tool. In this work, and for the first time, we disclose a tumor alleviation property of a nanozyme that is made up of amine-terminated sixth-generation polyamidoamine dendrimers with encapsulated tiny platinum nanoparticles. We systematically conducted the synthesis and characterization of the dendrimer-encapsulated Pt nanoparticles (denoted Pt-dendrimer) and confirmed their enzymatic function (hydrogen peroxide (H2O2) decomposition) within various cell lines (normal, cancerous), including glioblastoma (GBM) cells. By understanding the effects of the Pt-dendrimer at the gene level, especially related to cancer cell metastasis, we have thoroughly demonstrated its ability for tumor alleviation and suppressing GBM migration, invasion, and adhesion. The present findings show great promise for the application of the nanozyme for use in GBM-related basic research as well as at clinical sites.


Assuntos
Dendrímeros/química , Platina/química , Actinas/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dendrímeros/síntese química , Dendrímeros/farmacologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Nanopartículas Metálicas/química , RNA Mensageiro/metabolismo
9.
J Cancer Res Clin Oncol ; 147(10): 3123-3133, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33893539

RESUMO

BACKGROUND: We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC). METHODS: Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates. RESULTS: The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group. CONCLUSIONS: The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/patologia , Quimiorradioterapia/mortalidade , Neoplasias Hepáticas/patologia , Quimioterapia de Manutenção/mortalidade , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Cisplatino/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Sorafenibe/administração & dosagem , Taxa de Sobrevida
10.
J Viral Hepat ; 28(6): 951-958, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33763928

RESUMO

CAGE-B and SAGE-B scores, consisting of age and fibrotic burden as cirrhosis and/or liver stiffness, were recently proposed to predict hepatocellular carcinoma (HCC) risk among Caucasian chronic hepatitis B (CHB) patients undergoing long-term antiviral therapy. We externally validated their predictive performances among an independent cohort from Asia, compared to other conventional prediction models. We consecutively recruited CHB patients with well-controlled viremia (serum HBV DNA < 2000 IU/mL) receiving antiviral therapy. Patients with decompensated cirrhosis or HCC at baseline were excluded. Among 1763 patients, CAGE-B score provided the highest Heagerty's integrated area under the curve (iAUC) (0.820), followed by SAGE-B (0.804), mREACH-B (0.800), CAMD (0.786), mPAGE-B (0.748) and PAGE-B (0.721) scores. CAGE-B score showed a significantly better performance than SAGE-B, CAMD, PAGE-B and mPAGE-B scores, but was similar to mREACH-B. SAGE-B score also showed significantly better performance than mPAGE-B and PAGE-B, but was similar to CAMD and mREACH-B. According to CAGE-B score 0-5, 6-10 and ≥11, the annual HCC incidences were 0.18, 1.34 and 6.03 per 100 person-years, respectively (all p < 0.001 between each pair). Likewise, by SAGE-B score 0-5, 6-10 and ≥11, those were 0.31, 1.49 and 8.96 per 100 person-years, respectively (all p < 0.001 between each pair). Hence, CAGE-B and SAGE-B scores showed acceptable predictive performances for Asian CHB patients undergoing antiviral therapy, with the higher performance by CAGE-B score. They show a trend towards better prognostic capability to predict HCC risk than previous models.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Fatores de Risco , Viremia/tratamento farmacológico
11.
Mol Neurobiol ; 58(6): 2608-2619, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33479841

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects more than 30 million people worldwide. Despite growing knowledge of AD pathophysiology, a complete understanding of the pathogenic mechanisms underpinning AD is lacking, and there is currently no cure for AD. Extant literature suggests that AD is a polygenic and multifactorial disease underscored by complex and dynamic pathogenic mechanisms. Despite extensive research and clinical trials, there has been a dearth of novel drugs for AD treatment on the market since memantine in 2003. This lack of therapeutic success has directed the entire research community to approach the disease from a different angle. In this review, we discuss growing evidence for the close link between altered glucose metabolism and AD pathogenesis by exploring how genetic risk factors for AD are associated with dysfunctional glucose metabolism. We also discuss modification of genes responsible for metabolic pathways implicated in AD pathology.

12.
J Anat ; 237(6): 1006-1014, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33085100

RESUMO

The seminal vesicles are the glands of male reproductive organs that produce the fluid and nutrient constituents of semen. It has been believed for a long time that the lumen of a seminal vesicle was a single-coiled tubular structure with irregular diverticula. There are several previous reports on the symmetry, differences in morphological sizes and classification of the seminal vesicles. However, a three-dimensional-coiled tubular structure is difficult to understand using a classical anatomical methodology, and hence, three-dimensional reconstruction is needed to understand the structure of the lumen. Thirty-one seminal vesicles harvested from 21 formalin-embalmed cadavers were investigated. The seminal vesicle along with the ampulla of the ductus deferens was separated, and the length and width of each seminal vesicle were measured. The vesicles were then embedded in coloured paraffin, and the resulting paraffin block was sectioned transversely and photographed at an interval of 500 µm, with the sectioned surfaces then utilized in three-dimensional reconstruction performed by 'Reconstruct' software. The mean length and width of the seminal vesicles were 39.4 mm and 13.4 mm, respectively, and the right seminal vesicle was a little larger than the one on the left. The size differed from previous reports, while the luminal structure was similar to the classification of Aboul-azm (Archives of Andrology, 3, 1979, 287-292) but differed from that of Pereira (AJR. American Journal of Roentgenology, 69, 1953, 361-379). The seminal vesicles typically comprised about 9 curls and had about 12 diverticula. The seminal vesicles resembled a skein of coral rather than comprising a single strand. These findings will help in improving the understanding of pathophysiologies of the seminal vesicles, such as recurrent inflammation of the gland.


Assuntos
Processamento de Imagem Assistida por Computador , Glândulas Seminais/anatomia & histologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Imageamento Tridimensional , Masculino , Glândulas Seminais/diagnóstico por imagem
13.
Langmuir ; 36(19): 5359-5368, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32321248

RESUMO

This work presents an improvement in the activity and catalytic lifetime of Pt deposits on Bi-modified Pt nanoparticles (Bi/Pt NP) toward formic acid oxidation (FAO). Using an irreversible adsorption method, Bi was deposited on Pt NP to form Bi/Pt NP and sequentially Pt was deposited on Bi/Pt NP to form Pt/Bi/Pt NP. Voltammetric studies of Pt NP, Bi/Pt NP, and Pt/Bi/Pt NPs supported that Pt deposits of Pt/Bi/Pt NPs provided quite a unique behavior: simultaneous surface oxidation of deposited Pt and Bi and significant resistance to the oxidative removal of Bi. Furthermore, combined spectroscopic investigations revealed that the concentration of the employed Pt precursor ion solution determined the amount of deposited Pt from ∼0.2 to ∼0.4 in coverage. The best Pt/Bi/Pt NP catalyst with a Pt coverage of ∼0.25 enhanced the dehydrogenation processes below ∼0.4 V by a factor of more than 2 and increased the FAO current at ∼0.8 V roughly by 15 times, referring to those of Bi/Pt NP. The lifetime measurement works revealed that after the 1000th voltammetric cycle to 0.4 V, the FAO currents of Pt/Bi/Pt NPs were 2 and 4 times higher than those of Bi/Pt NP and Pt NP, respectively. The Pt deposits on Bi/Pt NP were concluded to play two roles in FAO: the promotion of FAO processes to increase the activity and the retardation of Bi oxidative removal to maintain the activity much longer.

14.
J Plast Reconstr Aesthet Surg ; 73(6): 1130-1134, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32115380

RESUMO

BACKGROUND: The deep temporal fascia (DTF) is known to separate into two layers that descend to attach to the zygomatic arch. When surgeons reduce an isolated fracture of the zygomatic arch through a temporal approach, the temporal incision site needs to be superior to the split line of the DTF. MATERIALS AND METHODS: Sixty-seven hemifacial cadavers were investigated after removing the skin, subcutaneous tissue, and superficial temporal fascia. The superficial layer of the DTF was exposed. We cut the superficial layer along the line along, which it adhered to the deep layer inseparably. The heights of the split line of the DTF from the superior border of the zygomatic arch and from the top of the helix were measured at three points: at the jugale, zygion, and 3 cm from the tragus. RESULTS: In all cases there were thick identifiable deep layers of the DTF. The mean heights of the split line of the DTF from the superior border of the zygomatic arch were 49.8, 46.7, and 42.6 mm at the jugale, zygion, and 3 cm from the tragus, respectively; the corresponding mean heights of the split line from the top of the helix were 19.1, 15.6, and 11.4 mm. CONCLUSIONS: Knowledge of the mean height of the split line of the DTF will be helpful for surgeons to determine the temporal incision site for ensuring the safe reduction of a zygomatic arch fracture.


Assuntos
Músculo Temporal/cirurgia , Zigoma/lesões , Fraturas Zigomáticas/cirurgia , Idoso , Idoso de 80 Anos ou mais , Cadáver , Redução Fechada/métodos , Fáscia/anatomia & histologia , Fasciotomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Temporal/anatomia & histologia , Zigoma/cirurgia
15.
Colloids Surf B Biointerfaces ; 189: 110829, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32036332

RESUMO

Chlorin e6 (Ce6), with its high phototoxic potential, has wide applications in photodynamic therapy (PDT) for many human diseases. However, poor cancer cell localization of Ce6 has limited its direct application for PDT. Here, we developed cancer-targeting peptide p 18-4/chlorin e6 (Ce6)-conjugated polyhedral oligomeric silsesquioxane (PPC) nanoparticles for improving the targeting ability of Ce6 to breast cancer cells, thereby enhancing PDT efficacy. The synthesized PPC nanoparticles exhibited a spherical shape with an average diameter of 127.2 ± 11.3 nm in aqueous solution. Compared with free Ce6, the immobilization of p 18-4 enhanced the in vitro cellular uptake and targeting ability of PPC nanoparticles in breast cancer cell line MDA-MB-231. In addition, the intracellular uptake of PPC nanoparticles in MDA-MB-231 cells was dramatically increased compared with other cancer cells, indicating an obvious targeting ability of PPC nanoparticles on breast cancer cells. Upon light irradiation, PPC nanoparticles revealed significantly improved phototoxicity to MDA-MB-231 cells, mainly due to apoptotic cell death. In vivo PDT study suggested that PPC nanoparticles exhibited increased retention in tumor tissues and effectively inhibited the growth of MDA-MB-231 tumors in a target-specific manner. Overall, these results indicate that PPC nanoparticles are highly effective PDT agents for breast cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Nanopartículas/química , Compostos de Organossilício/farmacologia , Peptídeos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Compostos de Organossilício/química , Tamanho da Partícula , Peptídeos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Propriedades de Superfície , Células Tumorais Cultivadas
16.
Mol Cells ; 42(11): 739-746, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31711277

RESUMO

Significant knowledge about the pathophysiology of Alzheimer's disease (AD) has been gained in the last century; however, the understanding of its causes of onset remains limited. Late-onset AD is observed in about 95% of patients, and APOE4-encoding apolipoprotein E4 (ApoE4) is strongly associated with these cases. As an apolipoprotein, the function of ApoE in brain cholesterol transport has been extensively studied and widely appreciated. Development of new technologies such as human-induced pluripotent stem cells (hiPSCs) and CRISPR-Cas9 genome editing tools have enabled us to develop human brain model systems in vitro and readily manipulate genomic information. In the context of these advances, recent studies provide strong evidence that abnormal cholesterol metabolism by ApoE4 could be linked to AD-associated pathology. In this review, we discuss novel discoveries in brain cholesterol dysregulation by ApoE4. We further elaborate cell type-specific roles in cholesterol regulation of four major brain cell types, neurons, astrocytes, microglia, and oligodendrocytes, and how its dysregulation can be linked to AD pathology.


Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Encéfalo/citologia , Humanos , Microglia/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo
17.
Plant Physiol Biochem ; 141: 477-486, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31252253

RESUMO

The induction of leaf injuries, including leaf chlorosis and epinasty, by continuous light in tomato plants is one of the most interesting and mysterious phenomena regarding plant interactions with light, the mechanism of which has not yet been revealed. To gain further insights into this particular response of tomato plants, we cultivated tomato seedlings (Solanum lycopersicum cv. Momotaro) for 14 days under continuous light with different ratios of red and blue light and compared their performance to those grown under continuous or 14/10-h photoperiodic white light using novel methods to quantitatively evaluate the level of leaf chlorosis and epinasty. Continuous monochromatic blue light induced severe chlorosis but almost completely alleviated epinasty in tomato leaf. In contrast, continuous monochromatic red light caused a lower level of leaf chlorosis but very severe epinasty. The combination of red and blue light at different ratios significantly reduced both leaf chlorosis and epinasty under continuous light condition. Carbohydrate contents showed no correlation with leaf chlorosis, while glucose and fructose contents showed correlations with the petiole and leaflet curvatures. Histochemical staining with 3,3'-diaminobenzidine and nitro blue tetrazodium chloride also did not reveal any significant buildup of hydrogen peroxide and superoxide anion in monochromatic blue light treatment. Taken together, these results suggest that chlorosis and epinasty are two distinctive leaf injuries caused by continuous light that may follow very different mechanisms, and an overaccumulation of carbohydrates in the leaf may not be the main cause of continuous light-induced leaf chlorosis in tomato.


Assuntos
Luz , Lycopersicon esculentum/efeitos da radiação , Folhas de Planta/efeitos da radiação , 3,3'-Diaminobenzidina/química , Carboidratos/química , Cor , Frutose/química , Glucose/química , Peróxido de Hidrogênio/química , Lycopersicon esculentum/crescimento & desenvolvimento , Oxigênio/química , Fotoquímica , Fotoperíodo , Fotossíntese , Doenças das Plantas , Proteínas de Plantas/metabolismo , Plântula/metabolismo , Sais de Tetrazólio/química
18.
Front Mol Neurosci ; 12: 27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863281

RESUMO

In humans, some forms of early life stress (ELS) have been linked with precocious puberty, altered brain maturation, and increased risk for a variety of forms of pathology. Interestingly, not all forms of ELS have been found to equally impact these metrics of maturation. In recent work, we have found that ELS in the form of limited bedding (LB) from P4 to P11, was associated with precocious hippocampus maturation in males and increased risk for depressive-like pathology and attentional disturbance in female mice. Here, we sought to test whether ELS in the form of LB also impacted the timing of sexual maturation in female mice. To establish rate of somatic and sexual development, distinct cohorts of mice were tested for weight gain, timing of vaginal opening, and development of estrous cycling. ELS animals weighed significantly less than controls at every timepoint measured. Onset of vaginal opening was tracked from P21 to 40, and ELS was found to significantly delay the onset of vaginal opening. To test the impact of ELS on estrous cycle duration and regularity, vaginal cytology was assessed in independent groups of animals using either a continuous sampling (daily from P40 to P57) or random sampling approach (single swab at P35, P50, or P75). ELS did impact measures of estrous cycling, but these effects were dependent upon the sampling method used. We also tested the impact of ELS on anxiety-like behaviors over development and across the estrous cycle. We observed a developmental increase in anxiety-like behavior in control but not ELS mice. No effect of estrous cycle stage was found on anxiety-like behavior for either group of mice. Together these results provide evidence that ELS in the form of LB delays somatic and sexual development. Additional work will be required to determine the mechanism by which ELS impacts these measures, and if these effects are common to other models of ELS in rodents.

19.
Neuropsychopharmacology ; 44(4): 711-720, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30188513

RESUMO

Childhood trauma and neglect influence emotional development and increase the risk for and severity of mental illness. Women have a heightened susceptibility to the effects of early life stress (ELS) and are twice as likely as men to develop debilitating, stress-associated disorders later in life, such as major depressive disorder (MDD). Until now, mouse models of depression have been largely unsuccessful at replicating the diverse symptomatology of this disease and the sex bias in vulnerability. From P4 to P11, a limited bedding model that leads to fragmented maternal care, was used to induce ELS. Early adolescent and young adult mice were tested on an array of assays to test for depressive-like behavior. This included our newly developed automated home cage behavioral recognition system, where the home cage behavior of ELS and control mice could be monitored over a continuous 5-10 day span. ELS females, but not males, exhibited depressive-like behaviors on traditional assays. These effects emerged during adolescence and became more severe in adulthood. Using the novel home cage video monitoring method, we identified robust and continuous markers of depressive-like pathology in ELS females that phenocopy many of the behavioral characteristics of depression in humans. ELS effects on home cage behavior were rapidly rescued by ketamine, a fast-acting antidepressant. Together, these findings highlight that limited bedding ELS (1) produces an early emerging, female-specific depressive phenotype that responds to a fast-acting antidepressant and (2) this model has the potential to inform sex-selective risk for the development of stress-induced mental illness.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/fisiologia , Depressão/tratamento farmacológico , Depressão/etiologia , Ketamina/farmacologia , Caracteres Sexuais , Estresse Psicológico/complicações , Fatores Etários , Animais , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Depressão/fisiopatologia , Modelos Animais de Doenças , Feminino , Ketamina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Eur J Clin Pharmacol ; 74(11): 1417-1426, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30039199

RESUMO

PURPOSE: CYP3A4, CYP2C19, and CYP3A5 are primarily involved in the metabolism of cilostazol. We investigated the effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its two active metabolites. METHODS: Thirty-three healthy Korean volunteers were administered a single 100-mg oral dose of cilostazol. The concentrations of cilostazol and its active metabolites (OPC-13015 and OPC-13213) in the plasma were determined by HPLC-MS/MS. RESULTS: Although the pharmacokinetic parameters for cilostazol were similar in different CYP2C19 and CYP3A5 genotypes, CYP2C19PM subjects showed significantly higher AUC0-∞ for OPC-13015 and lower for OPC-13213 compared to those in CYP2C19EM subjects (P < 0.01 and P < 0.001, respectively). Pharmacokinetic differences in OPC-13015 between CYP3A5 non-expressors and expressors were significant only within CYP2C19PM subjects. The amount of cilostazol potency-adjusted total active moiety was the greatest in subjects with CYP2C19PM-CYP3A5 non-expressor genotype. CONCLUSION: These results suggest that CYP2C19 and CYP3A5 genetic polymorphisms affect the plasma exposure of cilostazol total active moiety. CYP2C19 plays a crucial role in the biotransformation of cilostazol.


Assuntos
Cilostazol/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Inibidores da Fosfodiesterase 3/farmacocinética , Tetrazóis/sangue , Administração Oral , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático/genética , Cromatografia Líquida de Alta Pressão/métodos , Cilostazol/administração & dosagem , Cilostazol/sangue , Genótipo , Humanos , Masculino , Inibidores da Fosfodiesterase 3/administração & dosagem , Polimorfismo Genético , Espectrometria de Massas em Tandem , Adulto Jovem
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