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1.
Eye (Lond) ; 36(4): 733-741, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33833415

RESUMO

PURPOSE: To evaluate the diagnostic accuracy of spectral-domain optical coherence tomography (SD-OCT) and swept-source optical coherence tomographic angiography (SS-OCTA) to identify polypoidal lesions in serous or serosanguinous maculopathy. MATERIALS AND METHODS: A retrospective review of patients presenting pigment epithelial detachments (PEDs) with the diagnosis of polypoidal choroidal vasculopathy (PCV), neovascular age-related macular degeneration (nAMD), and central serous chorioretinopathy (CSC), all of which underwent SD-OCT, SS-OCTA, and indocyanine green angiography (ICGA). Typical features of polypoidal lesions on SD-OCT included sharply peaked PED, notched PED, and hyperreflective ring underneath PED. SS-OCTA feature was vascularized PEDs on cross-sectional images corresponding to cluster-like structures on en face images. The parameters of PEDs were measured for analysis. RESULTS: Of 72 eyes, 30 had PCV, 22 had nAMD, and 20 had CSC. A total of 128 localized PEDs were detected on SD-OCT. Typical features on SD-OCT had a high specificity (94.0%) but a limited sensitivity (73.8%). SS-OCTA features provided a higher sensitivity (96.7%). PEDs of the polypoidal lesions unrecognized by SD-OCT were dome-shaped, with smaller ratio of height to base diameter and less area, and almost had heterogeneous internal reflectivity and a connected double-layer sign. Some lesions misidentified by SS-OCTA developed into ICGA-proven polypoidal lesions at follow-up visits. CONCLUSION: A small dome-shaped PED with heterogeneous internal reflectivity and a connected double-layer sign on SD-OCT may suggest a polypoidal lesion of PCV. SS-OCTA may be a helpful tool to investigate preclinical PCV and observe the formation of polypoidal lesions.


Assuntos
Neovascularização de Coroide , Pólipos , Descolamento Retiniano , Corioide/patologia , Neovascularização de Coroide/diagnóstico , Neovascularização de Coroide/patologia , Corantes , Epitélio/patologia , Angiofluoresceinografia/métodos , Humanos , Verde de Indocianina , Pólipos/diagnóstico , Descolamento Retiniano/diagnóstico por imagem , Descolamento Retiniano/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos
2.
Invest Ophthalmol Vis Sci ; 62(15): 5, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34860239

RESUMO

Purpose: Swept-source optical coherence tomography angiography was used to investigate choroidal changes and their association with pigment epithelial detachments (PEDs) in eyes with polypoidal choroidal vasculopathy (PCV) after treatment with vascular endothelial growth factor (VEGF) inhibitors. Methods: Patients with treatment-naïve PCV were included and underwent anti-VEGF therapy. Mean choroidal thickness (MCT), choroidal vascularity index (CVI), and PED volume measurements were obtained before and after treatment. Results: Thirty-four treatment-naïve PCV eyes from 33 patients were included. The PED volume decreased after treatment (P < 0.05). The MCT decreased from 223.0 ± 79.6 µm at baseline to 210.9 ± 76.2 µm after treatment (P < 0.001). The CVI at baseline was 0.599 ± 0.024, and the CVI after treatment was 0.602 ± 0.023 (P = 0.16). There was a correlation between the decreased PED volumes and the decreased MCT measurements (r = 0.47; P = 0.006). Also, there was a correlation between the decreased PED volumes and the increased CVI measurements (r = -0.63; P < 0.001). Conclusions: In treatment-naïve eyes with PCV, the decreases in PED volumes were correlated with the decrease in MCT and the increase in CVI measurements. We propose that, at baseline, the PCV lesions serve as high-volume arteriovenous shunts between choroidal arterial and venous circulation, causing transudation into the choroidal stroma. We propose that, after treatment, the blood flow through the vascular shunt is reduced, the excess stromal transudation is resorbed, and the exudation from the neovascular lesion is reduced, resulting in thinning of the choroid, resolution of the PEDs, and an increase in the CVI due to the resorption of excess choroidal transudation.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Corioide/irrigação sanguínea , Neovascularização de Coroide/tratamento farmacológico , Pólipos/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Corioide/diagnóstico por imagem , Neovascularização de Coroide/diagnóstico por imagem , Neovascularização de Coroide/fisiopatologia , Corantes/administração & dosagem , Feminino , Angiofluoresceinografia , Seguimentos , Humanos , Verde de Indocianina/administração & dosagem , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Pólipos/diagnóstico por imagem , Pólipos/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual
3.
Asian J Pharm Sci ; 16(5): 623-632, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34849167

RESUMO

In light of the intriguing potential of anti-angiogenic approach in suppressing choroidal neovascularization, we attempted to elaborate synthetic gene delivery systems encapsulating anti-angiogenic plasmid DNA as alternatives of clinical antibody-based therapeutics. Herein, block copolymer of cyclic Arg-Gly-Asp-poly(ethylene glycol)-poly(lysine-thiol) [RGD-PEG-PLys(thiol)] with multifunctional components was tailored in manufacture of core-shell DNA delivery nanoparticulates. Note that the polycationic PLys segments were electrostatically complexed with anionic plasmid DNA into nanoscaled core, and the tethered biocompatible PEG segments presented as the spatial shell (minimizing non-specific reactions in biological milieu). Furthermore, the aforementioned self-assembly was introduced with redox-responsive disulfide crosslinking due to the thiol coupling. Hence, reversible stabilities, namely stable in extracellular milieu but susceptible to disassemble for liberation of the DNA payloads in intracellular reducing microenvironment, were verified to facilitate transcellular gene transportation. In addition, RGD was installed onto the surface of the proposed self-assemblies with aim of targeted accumulation and internalization into angiogenic endothelial cells given that RGD receptors were specifically overexpressed on their cytomembrane surface. The proposed anti-angiogenic DNA therapeutics were validated to exert efficient expression of anti-angiogenic proteins in endothelial cells and elicit potent inhibition of ocular neovasculature post intravitreous administration. Hence, the present study approved the potential of gene therapy in treatment of choroidal neovascularization. In light of sustainable gene expression properties of DNA therapeutics, our proposed synthetic gene delivery system inspired prosperous potentials in long-term treatment of choroidal neovascularization, which should be emphasized to develop further towards clinical translations.

4.
Am J Ophthalmol Case Rep ; 22: 101057, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33796797

RESUMO

PURPOSE: To investigate the morphological changes of polyps in eyes with polypoidal choroidal vasculopathy (PCV) after treatment with vascular endothelial growth factor (VEGF) inhibitors using swept source optical coherence tomography angiography (SS-OCTA). OBSERVATIONS: Following anti-VEGF therapy, polyps were found to evolve into typical type 1 macular neovascularization (MNV) in five eyes. In all of these five eyes, a polypoidal lesion was detected adjacent to a serous or hemorrhagic retinal pigment epithelial detachment (PED). CONCLUSIONS AND IMPORTANCE: Polypoidal lesions in PCV can evolve into typical type 1 MNV. This morphological evolution suggests that these polyps are clusters of tangled vessels that can proliferate into a more typical neovascular pattern, and this evolution may be facilitated by being adjacent to a PED. Since this morphological appearance could be associated with a better prognosis, SS-OCTA might be helpful in identifying cases of transformed polyps that may be associated with a decreased risk for vision loss.

5.
Front Med (Lausanne) ; 8: 778117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35004745

RESUMO

Objective: This study aims to investigate the association of sleep duration with vision impairment (VI) in middle-aged and elderly adults. Methods: This cross-sectional study used the data from the baseline survey of the China Health and Retirement Longitudinal Study (CHARLS) 2011-2012, a national survey of adults aged 45 years or older. Weighted multilevel logistic regression models were used to evaluate the association between self-reported sleep duration and VI. Results: Of the 13,959 survey respondents, a total of 4,776 (34.2%) reported VI. The prevalence of short (≤6 h/night) and long (>8 h/night) sleep durations was higher among respondents with VI than those without VI (P < 0.001). Multilevel logistic regression models showed that compared with a sleep duration of 6-8 h/night, a sleep duration of ≤6 h/night was associated with a 1.45-fold [95% confidence interval (CI) = 1.34-1.56] higher VI risk, and a sleep duration of >8 h/night was associated with a 1.18-fold (95% CI = 1.03-1.34) higher VI risk, after adjusting for sociodemographic data, lifestyle factors, and health conditions. Vision impairment was associated with short sleep duration in respondents from all age or gender categories. However, VI was associated with long sleep duration in respondents from the elderly or female categories. The association between VI and long sleep duration disappeared in respondents of middle-aged or male categories. Conclusions: The potential impact of sleep on the risk of visual functions requires further attention. A more comprehensive and integrated health care and rehabilitation system covering vision and sleep is also needed.

6.
J Ocul Pharmacol Ther ; 36(8): 618-628, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32552228

RESUMO

Purpose: To explore the effects of 3-methyladenine (3-MA), a selective inhibitor of phosphatidylinositol-3-kinase (PI3K), on experimental subretinal fibrosis (SRF) in mice. Methods: The SRF mouse model was established by 532 nm laser photocoagulation at each fundus of mice on day 0. 3-MA was administered every 2 days from day 0 to 35. Immunofluorescence of choroidal flat mounts was performed to evaluate the size of SRF area, local macrophages, and polarization, respectively. Besides, Western blot analysis was carried out to assess the expression levels of macrophage polarization-related genes, Arg-1, Ym-1, and transforming growth factor-ß2 (TGF-ß2). Co-culture and migration experiments were used to demonstrate the inhibitory effect of 3-MA on fibroblasts. The gene knockout and Western blot analysis were used to explore the signal pathways related to macrophage polarization. Results: Compared with the control group, the 3-MA-treated group showed significantly less size of SRF area. 3-MA treatment reduced both circulating and local macrophages, and counteracted M2 polarization. Moreover, 3-MA inhibited fibroblast recruitment. Mechanistically, we proved that 3-MA inhibits macrophage M2 polarization by suppressing PI3K/Akt signal pathway rather than the PI3K-autophagy-related signal pathway. Conclusions: 3-MA exerts antifibrotic effects on experimental SRF by targeting circulating and local macrophages and M2 polarization, through PI3K/Akt signal pathway. These results support the potential use of 3-MA as a new therapeutic modality for SRF associated with neovascular age-related macular degeneration.


Assuntos
Adenina/análogos & derivados , Fibrose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adenina/administração & dosagem , Adenina/farmacologia , Animais , Doenças da Coroide/metabolismo , Doenças da Coroide/patologia , Fibroblastos/efeitos dos fármacos , Imunofluorescência/métodos , Macrófagos/metabolismo , Degeneração Macular/tratamento farmacológico , Degeneração Macular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Transdução de Sinais/efeitos dos fármacos
7.
World J Gastrointest Oncol ; 12(5): 526-534, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32461784

RESUMO

BACKGROUND: The integrin ß6 gene, which is expressed in epithelial cancer, plays a pivotal role in various aspects of cancer progression. The present research for integrin ß6 regulation mainly focuses on the post-transcription and translation related regulation mechanism and its role in tumorigenesis. The mechanisms of how the integrin ß6 gene is regulated transcriptionally, and the promoter and transcription factors responsible for basic transcription of integrin ß6 gene remain unknown. AIM: To clone and characterize the integrin ß6 promoter. METHODS: Software analysis was used to predict the region of integrin ß6 promoter. Luciferase reporter plasmids, which contained the integrin ß6 promoter, were constructed. Element deletion analysis was performed to identify the location of core promoter and binding sites for transcription factors. RESULTS: The regulatory elements for the transcription of the integrin ß6 gene were located between -286 and -85 and contained binding sites for transcription factors such as STAT3 and Ets-1. CONCLUSION: For the first time, we found the region of ß6 core promoter and demonstrated the binding sites for transcription factors such as Ets-1 and STAT3, which are important for integrin ß6 promoter transcription activity. These findings are important for investigating the mechanism of integrin ß6 activation in cancer progression.

8.
Oncol Res ; 28(3): 311-319, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31987067

RESUMO

Hypopharyngeal squamous cell carcinoma (HSCC) remains one of the most lethal malignancies in the head and neck. Long noncoding RNA (lncRNA) HOXA11-AS is proven to function as an oncogene and a therapeutic target in various tumors. Our previous study and others have demonstrated that HOXA11-AS is one of the most upregulated lncRNAs in HSCC. However, the role of HOXA11-AS in HSCC has not yet been identified. The current study demonstrated that the expression of HOXA11-AS was significantly upregulated in HSCC tumors and was positively associated with lymph node metastasis. Moreover, functional experiments revealed that HOXA11-AS knockdown suppressed the proliferation and migration potential in FaDu cells. Furthermore, luciferase reporter gene assay combined with cellular functional experiments demonstrated that HOXA11-AS functioned as a molecular sponge for miR-155, and inhibition of miR-155 attenuated the suppressive effect of HOXA11-AS knockdown on the aggressive phenotype in HSCC. This study identifies a tumor-promoting role of HOXA11-AS in HSCC and suggests HOXA11-AS might be a potential diagnostic and therapeutic target for HSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Proteínas de Homeodomínio/genética , Neoplasias Hipofaríngeas/genética , MicroRNAs/genética , RNA Antissenso , RNA Longo não Codificante , Apoptose/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Neoplasias Hipofaríngeas/patologia , Metástase Neoplásica , Estadiamento de Neoplasias , Interferência de RNA
9.
Natl Sci Rev ; 7(5): 835-837, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-34692105

RESUMO

RNA-targeting CRISPR system Cas13 offers an efficient approach for manipulating RNA transcripts in vitro. In this perspective, we provide a proof-of-concept demonstration that Cas13-mediated Vegfa knockdown in vivo could prevent the development of laser-induced CNV in mouse model of Age-related macular degeneration.

10.
Invest Ophthalmol Vis Sci ; 60(14): 4596-4605, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675076

RESUMO

Purpose: Choroidal neovascularization (CNV) is the principal pathological factor contributing to blindness in neovascular age-related macular degeneration (nAMD). Infiltration of M2 macrophage is thought to contribute to CNV progress, although the way that regulates its differentiation remains unclear. Here, we investigate the role of CHI3L1 in M2 differentiation and angiogenesis in CNV. Methods: Serums from nAMD patients were tested for CHI3L1 expression. Mice were subjected to laser injury to induce CNV, and lesion expansion were tracked using fundus fluorescence angiography (FFA) and immunofluorescence analysis. Several strategies were taken to verify the contribution of M2 macrophage and CHI3L1: macrophage depletion by clodrosome, local CHI3L1 inhibition using intravitreally injection neutralize antibody (mAY), and depletion of CHI3L1 receptor (IL13-Ra2) by small-interfering RNA (siRNA). Tuber analysis was used to further determine angiogenetic effect of CHI3L1. Anti-VEGFA was used as positive control for mAY. Results: Serum levels of CHI3L1 were highly elevated in nAMD patients. CHI3L1 was expressed by infiltrating M2 macrophages and was elevated as CNV progress in a mice model. System macrophage depletion and local suppression of CHI3L1 alleviated CNV formation while enhancing anti-VEGFA therapeutic effect. Stimulation of macrophage with recombinant CHI3L1 activated MAPK signaling cascade and induced transition to M2, while siRNA knockdown of IL13-Ra2 abolished it. In an in vitro coculture system, supernatants from CHI3L1-stimulated M2 macrophages and promoted tube vascularization. Conclusions: These results unveil novel angiogenic regulation of CHI3L1 and M2 polarized macrophages in CNV development. These mechanistic insights may point to CHI3L1 as a new therapeutic target for treatment for nAMD.


Assuntos
Diferenciação Celular/fisiologia , Proteína 1 Semelhante à Quitinase-3/fisiologia , Neovascularização de Coroide/fisiopatologia , Macrófagos/fisiologia , Degeneração Macular Exsudativa/fisiopatologia , Idoso , Animais , Anticorpos Neutralizantes/farmacologia , Western Blotting , Neovascularização de Coroide/sangue , Neovascularização de Coroide/prevenção & controle , Modelos Animais de Doenças , Angiofluoresceinografia , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Separação Imunomagnética , Injeções Intravítreas , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/sangue , Degeneração Macular Exsudativa/prevenção & controle
11.
JAMA Ophthalmol ; 137(6): 642-650, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30998817

RESUMO

Importance: Polypoidal choroidal vasculopathy (PCV) is a major cause of visual loss worldwide, particularly in Asia, and the appropriate understanding of the structures in PCV previously described as polypoidal lesions is important for understanding their pathogenesis, diagnosis, and prognosis. Objective: To report the morphologic characteristics of polypoidal lesions and their association with branching vascular networks (BVNs) in eyes with PCV using swept-source optical coherence tomographic angiography (SS-OCTA). Design, Setting, and Participants: This cross-sectional observational study included 20 participants recruited from Shanghai General Hospital with a diagnosis of PCV based on the presence of focal hyperfluorescent spots on indocyanine green angiography (ICGA). Data were collected from December 1, 2017, to September 1, 2018, and analyzed from June 1 through September 30, 2018. Main Outcomes and Measures: Polypoidal lesions in eyes with PCV were characterized using multimodal imaging that included fundus photography, fluorescein angiography, ICGA, SS-OCT, and SS-OCTA, and the images were anatomically aligned. Subfoveal choroidal thickness was manually measured as the distance between the Bruch membrane and the sclerochoroidal interface on the SS-OCT images. Results: Of the 20 Asian patients, 5 (25%) were women and 15 (75%) were men. The mean (SD) age was 61.1 (7.6) years, and the mean (SD) logMAR visual acuity was 0.358 (0.294) (Snellen equivalent, 20/50 [20/40]). Twenty-three eyes underwent imaging and were diagnosed with PCV. Indocyanine green angiography identified 43 polypoidal lesions, and all corresponded to the structures that appeared as clusters of tangled vessels on SS-OCTA images. In addition, SS-OCTA detected 16 tangled vascular structures not seen on ICGA. Branching vascular networks were detected on SS-OCTA imaging in all eyes, but ICGA identified BVNs in only 17 of 23 eyes (74%). Of the 43 tangled vascular structures, 40 (93%) were located at the edge of a BVN and 3 (7%) were associated with type 2 neovascularization. Conclusions and Relevance: In eyes with PCV undergoing SS-OCTA imaging, previously described polypoidal lesions may appear as tangled vascular structures associated with BVN or type 2 neovascularization. The identification of polypoidal lesions in patients with PCV as neovascular tangles rather than actual polypoidal lesions or aneurysmal dilatations may help facilitate understanding of their pathogenesis and response to treatment.


Assuntos
Corioide/irrigação sanguínea , Neovascularização de Coroide/diagnóstico por imagem , Pólipos/diagnóstico por imagem , Idoso , Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Corantes/administração & dosagem , Estudos Transversais , Feminino , Angiofluoresceinografia , Humanos , Verde de Indocianina/administração & dosagem , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Pólipos/tratamento farmacológico , Ranibizumab/uso terapêutico , Tomografia de Coerência Óptica/métodos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
12.
Cancer Manag Res ; 11: 1857-1868, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881113

RESUMO

Background: Bladder cancer (BC) is the most common cancer of the urinary tract and invariably predicts a poor prognosis. In this study, we found a reliable gene signature and potential biomarker for predicting clinical prognosis. Methods: The gene expression profiles were obtained from the GEO database. By performing GEO2R analysis, numerous differentially expressed genes (DEGs) were found. Three different microarray datasets were integrated in order to more precisely identify up-expression genes. Functional analysis revealed that these genes were mainly involved in cell cycle, DNA replication and metabolic pathways. Results: Based on protein-protein interactome (PPI) networks that were identified in the current study and previous studies, we focused on KIF15 for further study. The results showed that KIF15 promotes BC cell proliferation via the MEK -ERK pathway, and Kaplan-Meier survival analysis revealed that KIF15 expression was an independent prognostic risk factor in BC patients. Conclusion: KIF15 may represent a promising prognostic biomarker and a potential therapeutic option for BC.

13.
Oncol Lett ; 17(2): 1761-1767, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30675235

RESUMO

The aim of the study was to investigate the effect of paeonol on the apoptosis of hepatocellular carcinoma cells and to explore the possible mechanism of its effect. During the experiment, the human hepatoma (Huh7) cell line was cultured and treated with different concentrations of paeonol. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect the effects of paeonol at different concentrations on the proliferation of Huh7 cells after 24 h, and the optimal concentration of paeonol was selected for follow-up experiments. Huh7 cells were divided into the blank control group (C group), parthenolide [(an inhibitor of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)] group (CE group), paeonol group (PO group), and paeonol + tumor necrosis factor-α (TNF-α) (an activator of NF-κB) group (PN group). The effect of paeonol on the apoptosis of Huh7 cells was detected via flow cytometry and Hoechst staining, respectively. The expression levels of NF-κB and protein apoptosis inhibitor-5 (p-API-5) were detected by semi-quantitative polymerase chain reaction (PCR) and western blot analysis, respectively, and the activity of NF-κB in cells was measured by NF-κB p65/50. After determination of the effects of paeonol at different concentrations on Huh7 cells by MTT assay, it was found that paeonol at the concentration of 200-800 µM could inhibit the proliferation of Huh7 cells (P<0.01), with 500 µM phenol being selected as the treatment concentration for follow-up experiments. Results of flow cytometry and Hoechst staining showed that the apoptotic levels of Huh7 cells in the PO and CE groups were significantly increased compared with that in the C group, and that in the PO group was higher than that in the PN group. The differences were statistically significant (P<0.01). Results of semi-quantitative PCR and western blot analysis revealed that the expression levels of NF-κB and p-API-5 in the PO and CE groups were significantly lower than those in the C group, and those in the PO group were lower than those in the PN group. The differences were statistically significant (P<0.01). The expression level of NF-κB p65/50 in the PO group was significantly lower than that in the C group (P<0.01). The results suggest that paeonol can significantly increase the apoptosis rate of Huh7 cells, and the possible mechanism of inducing apoptosis is related to the downregulation of NF-κB and p-API-5 and inhibition of the NF-κB signaling pathway.

14.
J Cell Biochem ; 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30230587

RESUMO

As an important chemokine receptor, the role of CCR4 in the progression of bladder cancer (BC) remains unknown. In this study, we have shown that CCR4 expression was upregulated in bladder carcinoma tissues compared with adjacent nontumor tissues. Kaplan-Meier survival analysis revealed that CCR4 expression was an independent prognostic risk factor in BC patients, and the addition of CCL17 induced CCR4 production and promoted migration and invasion of BC cells. In addition, CCR4 knockdown significantly attenuated the migratory and invasive capabilities of BC cells. Mechanistically, CCL17-CCR4 axis is involved in ERK1/2 signaling and could mediate the migration and invasion of BC cells by regulating MMP13 activation. This study suggests that CCR4 might represent a promising prognostic biomarker and a potential therapeutic option for BC.

15.
Int J Ophthalmol ; 11(6): 935-944, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977804

RESUMO

AIM: To investigate protective effects of a novel recombinant decoy receptor drug RC28-E on retinal damage in early diabetic rats. METHODS: The streptozotocin (STZ)-induced diabetic rats were randomly divided into 6 groups: diabetes mellitus (DM) group (saline, 3 µL/eye); RC28-E at low (0.33 µg/µL, 3 µL), medium (1 µg/µL, 3 µL), and high (3 µg/µL, 3 µL) dose groups; vascular endothelial growth factor (VEGF) Trap group (1 µg/µL, 3 µL); fibroblast growth factor (FGF) Trap group (1 µg/µL, 3 µL). Normal control group was included. At week 1 and 4 following diabetic induction, the rats were intravitreally injected with the corresponding solutions. At week 6 following the induction, apoptosis in retinal vessels was detected by TUNEL staining. Glial fibrillary acidic protein (GFAP) expression was examined by immunofluorescence. Blood-retinal barrier (BRB) breakdown was assessed by Evans blue assay. Ultrastructural changes in choroidal and retinal vessels were analyzed by transmission electron microscopy (TEM). Content of VEGF and FGF proteins in retina was measured by enzyme linked immunosorbent assay (ELISA). The retinal expression of intercellular cell adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), VEGF and FGF genes was examined by quantitative polymerase chain reaction (qPCR). RESULTS: TUNEL staining showed that the aberrantly increased apoptotic cells death in diabetic retinal vascular network was significantly reduced by treatments of medium and high dose RC28-E, VEGF Trap, and FGF Trap (all P<0.05), the effects of medium and high dose RC28-E or FGF Trap were greater than VEGF Trap (P<0.01). GFAP staining suggested that reactive gliosis was substantially inhibited in all RC28-E and VEGF Trap groups, but the inhibition in FGF Trap group was not as prominent. Evans blue assay demonstrated that only high dose RC28-E could significantly reduce vascular leakage in early diabetic retina (P<0.01). TEM revealed that the ultrastructures in choroidal and retinal vessels were damaged in early diabetic retina, which was ameliorated to differential extents by each drug. The expression of VEGF and FGF2 proteins was significantly upregulated in early diabetic retina, and normalized by RC28-E at all dosages and by the corresponding Traps. The upregulation of ICAM-1 and TNF-α in diabetic retina was substantially suppressed by RC28-E and positive control drugs. CONCLUSION: Dual blockade of VEGF and FGF2 by RC28-E generates remarkable protective effects, including anti-apoptosis, anti-gliosis, anti-leakage, and improving ultrastructures and proinflammatory microenvironment, in early diabetic retina, thereby supporting further development of RC28-E into a novel and effective drug to diabetic retinopathy (DR).

16.
Cell Physiol Biochem ; 45(2): 505-522, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29402864

RESUMO

BACKGROUND/AIMS: Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia-induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of α-Melanocyte-stimulating hormone (α-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the α-MSH's anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A). METHODS: Sprague Dawley rats were injected through tail vein with streptozotocin to induce diabetes. The rats were intravitreally injected with α-MSH or saline at Week 1 and 3 after hyperglycemia. In another 2 weeks, Evans blue assay, transmission electron microscopy, electroretinogram (ERG), and hematoxylin and eosin (H&E) staining were performed to examine the protective effects of α-MSH in diabetic retinas. The expression of pro-inflammatory factors and tight junction at mRNA and protein levels in retinas was analyzed. Finally, the α-MSH's anti-hyperpermeability was confirmed in a high glucose (HG)-treated RF6A cell monolayer transwell culture by transendothelial electrical resistance (TEER) measurement and a fluorescein isothiocyanate-Dextran assay. Universal or specific melanocortin receptor (MCR) blockers were also employed to elucidate the MCR subtype mediating α-MSH's protection. RESULTS: Evans blue assay showed that BRB breakdown and vascular leakage was detected, and rescued by α-MSH both qualitatively and quantitatively in early diabetic retinas; electron microscopy revealed substantially improved retinal and choroidal vessel ultrastructures in α-MSH-treated diabetic retinas; scotopic ERG suggested partial rescue of functional defects by α-MSH in diabetic retinas; and H&E staining revealed significantly increased thickness of all layers in α-MSH-treated diabetic retinas. Mechanistically, α-MSH corrected aberrant transcript and protein expression of pro-inflammatory factor and tight junction genes in the diseased retinas; moreover, it prevented abnormal changes in TEER and permeability in HG-stimulated RF6A cells, and this anti-hyperpermeability was abolished by a universal MCR blocker or an antagonist specific to MC4R. CONCLUSIONS: This study showed previously undescribed protective effects of α-MSH on inhibiting BRB breakdown and vascular leakage, improving electrophysiological functions and morphology in early diabetic retinas, which may be due to its down-regulating pro-inflammatory factors and augmenting tight junctions. α-MSH acts predominantly on MC4R to antagonize hyperpermeability in retinal microvessel endothelial cells.


Assuntos
Barreira Hematorretiniana/metabolismo , Retinopatia Diabética/patologia , alfa-MSH/farmacologia , Animais , Barreira Hematorretiniana/efeitos dos fármacos , Linhagem Celular , Citratos/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/etiologia , Retinopatia Diabética/prevenção & controle , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Potenciais Evocados/efeitos dos fármacos , Glucose/farmacologia , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Vasos Retinianos/citologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Citrato de Sódio , Estreptozocina/toxicidade , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , alfa-MSH/uso terapêutico
17.
Am J Physiol Renal Physiol ; 314(6): F1077-F1086, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29357418

RESUMO

Bladder pain is a prominent symptom of interstitial cystitis/painful bladder syndrome. Hydrogen sulfide (H2S) generated by cystathionine ß-synthase (CBS) or cystathionine γ-lyase (CSE) facilitates bladder hypersensitivity. We assessed involvement of the H2S pathway in protease-activated receptor 4 (PAR4)-induced bladder pain. A bladder pain model was induced by intravesical instillation of PAR4-activating peptide in mice. The role of H2S in this model was evaluated by intraperitoneal preadministration of d,l-propargylglycine (PAG), aminooxyacetic acid (AOAA), or S-adenosylmethionine or the preintravesical administration of NaHS. SV-HUC-1 cells were treated in similar manners. Assessments of CBS, CSE, and macrophage migration inhibitory factor (MIF) expression, bladder voiding function, bladder inflammation, H2S production, and referred bladder pain were performed. The CSE and CBS pathways existed in both mouse bladders and SV-HUC-1 cells. H2S signaling was upregulated in PAR4-induced bladder pain models, and H2S-generating enzyme activity was upregulated in human bladders, mouse bladders, and SV-HUC-1 cells. Pretreatment with AOAA or NaHS inhibited or promoted PAR4-induced mechanical hyperalgesia, respectively; however, PAG only partially inhibited PAR4-induced bladder pain. Treatment with PAG or AOAA decreased H2S production in both mouse bladders and SV-HUC-1 cells. Pretreatment with AOAA increased MIF protein levels in bladder tissues and cells, whereas pretreatment with NaHS lowered MIF protein levels. Bladder pain triggered by the H2S pathway was not accompanied by inflammation or altered micturition behavior. Thus endogenous H2S generated by CBS or CSE caused referred hyperalgesia mediated through MIF in mice with PAR4-induced bladder pain, without causing bladder injury or altering micturition behavior.


Assuntos
Cistite Intersticial/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hiperalgesia/metabolismo , Limiar da Dor , Receptores de Trombina/metabolismo , Bexiga Urinária/metabolismo , Alcinos/farmacologia , Ácido Amino-Oxiacético/farmacologia , Analgésicos/farmacologia , Animais , Linhagem Celular , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Cistite Intersticial/patologia , Cistite Intersticial/fisiopatologia , Cistite Intersticial/prevenção & controle , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Oxirredutases Intramoleculares/metabolismo , Ligantes , Liases/antagonistas & inibidores , Liases/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Limiar da Dor/efeitos dos fármacos , Transdução de Sinais , Sulfetos/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia
18.
Onco Targets Ther ; 10: 5541-5550, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29200869

RESUMO

Background and objectives: Among the cancers of the urogenital system, bladder cancer is ranked second both in incidence and mortality, and hence, a more accurate estimate of the prognosis for individual patients with non-muscle-invasive bladder cancer (NMIBC) is urgently needed. Prognostic nutritional index (PNI) which is based on serum albumin levels and peripheral lymphocyte count has been confirmed to have prognostic value in various cancers. The aim of this study was to clarify the prognostic value of PNI in patients with NMIBC. Methods: Data of 329 patients with NMIBC were evaluated retrospectively. Recurrence-free survival (RFS) was assessed using the Kaplan-Meier method, and the equivalences of survival curves were tested by log-rank tests. The univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Discrimination of the nomogram was measured by the concordance index. A p-value of <0.05 was considered statistically significant. Results: In univariate analysis, age, tumor focality, tumor size, tumor grade, pathological T stage and preoperative PNI were significantly associated with RFS. Multivariate analysis identified PNI as an independent predictor of RFS in patients with NMIBC. According to these independent predictors, a nomogram for the prediction of recurrence was developed. Conclusion: PNI can be regarded as an independent prognostic factor for predicting RFS in NMIBC. The nomogram could be useful to improve personalized therapy for patients with NMIBC.

19.
J Cancer ; 8(16): 3268-3273, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158799

RESUMO

Objectives: To clarify the potential role of fluid intake-to-bed time and nocturia frequency on bladder cancer risk in a hospital-based case-control study with Chinese people. Materials and Methods: Four hundred and seven patients with histologically diagnosed bladder cancer and 400 matched controls were enrolled in this study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression model. Results: After adjustment for potential confounders, the fluid intake-to-bed time was associated with a decreased risk of BCa, with an OR of 0.586 (95% CI= 0.375-0.916, ≤1h) and 0.257 (95% CI= 0.162-0.407, >1h). The adjusted OR of BCa for subjects with more nocturia frequency (≥2 times) was 2.268 (95 % CI= 1.481-3474), compared to those with no nocturia. Conclusion: We suggested strong protective effect of long fluid intake-to-bed time on BCa risk, especially in ones with ≥2 times nocturia frequency. These results provide evidence for identifying high-risk individuals and modifying their behaviors and lifestyle.

20.
Medicine (Baltimore) ; 96(1): e5808, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28072736

RESUMO

RATIONALE: Von Hippel-Lindau (VHL) disease is a rare inherited, autosomal-dominant syndrome caused by heterozygous germline mutations in the VHL gene. VHL patients are prone to develop benign and malignant tumors and cysts in multiple organ systems involving kidneys, pancreas and central nervous system (CNS). The varied and complex clinical manifestations and radiological findings of VHL are of interest. PATIENT CONCERNS: We report a 38-year-old woman with a ten-year history of VHL disease involving both pancreas and biliary system. To the best of our knowledge, direct involvement of the biliary system in VHL disease has never been reported. DIAGNOSES: The diagnosis was established via computed tomography scan and was confirmed by genetic testing. INTERVENTIONS: The patient chose to receive conservative treatment and was followed up by magnetic resonance cholangiopancreatography and magnetic resonance imaging examination. OUTCOMES: Renal angiomas and cysts were found during follow-up and there were no evidence of malignant change of the pancreas and biliary system. LESSONS: We described the first case of VHL-associated choledochal cysts and may present new visceral manifestations of VHL disease. Gastroenterologists should be aware of the clinical presentations of this rare disease for early detection of its life-threatening manifestations.


Assuntos
Sistema Biliar , Pâncreas , Doença de von Hippel-Lindau , Adulto , Sistema Biliar/diagnóstico por imagem , Sistema Biliar/patologia , Colangiopancreatografia por Ressonância Magnética/métodos , Tratamento Conservador/métodos , Feminino , Testes Genéticos , Humanos , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Tomografia Computadorizada por Raios X/métodos , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/fisiopatologia , Doença de von Hippel-Lindau/terapia
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