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1.
Cornea ; 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32141942

RESUMO

PURPOSE: To investigate the effects of an eye wash solution on the ocular surface damage induced by airborne carbon black (CB) exposure. METHODS: Sprague-Dawley rats were exposed to ambient CB for 5 days. During the 5 days, a commercial eye wash solution (Eyebon-W) was used for irrigation twice daily on CB-exposed rat eyes; normal saline was used as the vehicle control. Lactic dehydrogenase (LDH) activity and matrix metallopeptidase (MMP)-9, histamine, and lactoferrin levels were measured in tears. The expression of inflammatory cytokines in the anterior segment of the eyeball was measured by Western blot analysis. RESULTS: The ocular surface staining scores, tear LDH activity, tear MMP-9, histamine, and lactoferrin concentrations, and the expression of interleukin-4 and interferon-γ in the eye were significantly increased in the CB group versus the normal control group. When compared with CB group, the Eyebon-W eye wash treatment significantly reversed these elevations induced by CB, including ocular staining scores, tear LDH activity, histamine and MMP-9 concentrations in the tear fluid, and the expression of interleukin-4 in the eye. On the other hand, saline irrigation only reduced the concentrations of histamine and MMP-9 in tear fluid and the expression of interferon-γ in the eye. CONCLUSIONS: Both Eyebon-W eye wash treatment and saline irrigation reversed CB-induced ocular surface injury, but the efficacy of Eyebon-W was more significant than that of the saline solution when compared with CB group. The use of an eye wash solution seems to play a protective role for the ocular surface when exposed to airborne particulate matter.

2.
PLoS One ; 15(1): e0227618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923257

RESUMO

Alzheimer's disease (AD) is an ageing-related neurodegenerative disease characterized and diagnosed by deposition of insoluble amyloid-ß (Aß) plaques in the brain. The plaque accumulation in the brain directly affects reduced levels of Aß in cerebrospinal fluid (CSF) and blood, as Aß can freely transport the blood-brain barrier, and clinical investigations have suggested these two biofluids as promising samples for in vitro diagnosis. Given that the human eye structurally resembles the brain and Aß accumulation often observed in the ocular region of AD patients, in this study, we examined aqueous humor Aß as another possible surrogate biomarker. First, using the acute Aß-infused AD mouse model by injecting Aß to the CSF in intracerebroventricular region of normal ICR mice, we investigated whether Aß concentration in the aqueous humor in AD models is positively correlated with the concentration in the CSF. Then, we examined the correlation of aqueous humor Aß levels with increased plaque deposition in the brain and reduced Aß levels in both CSF and blood in adult and aged 5XFAD Alzheimer transgenic mice. Collectively, the synthetic Aß injected into CSF immediately migrate to the aqueous humor, however, the age-dependently reducing pattern of Aß levels in CSF and blood was not observed in the aqueous humor.

3.
Invest Ophthalmol Vis Sci ; 61(1): 3, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31995154

RESUMO

Purpose: The purpose of this study was to investigate the expression of death ligands in the lacrimal glands (LGs), identify upstream factors that regulate their expression, and determine the functional roles of these factors in the pathogenesis of dry eye disease (DED). Methods: For DED experiment, ex vivo coculture system with LG and in vivo murine model using a controlled environment chamber were utilized. C57BL/6 mice and hypoxia-inducible factor (HIF)-1α conditional knockout (CKO) mice were used. Immunohistochemical staining, polymerase chain reaction, and immunoblotting were performed to determine levels of death ligands including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in DED-induced LGs. Additionally, acinar cell and CD45+ cell apoptosis was determined with neutralizing TRAIL treatment. Results: Desiccating stress significantly increased HIF-1α expression in LG-acinar cells. Furthermore, HIF-1α deficiency significantly enhanced the infiltration of CD45+ inflammatory cells in LG and induced LG-acinar cell death. Meanwhile, only TRAIL expression was increased in DED-LG, but abrogated in HIF-1α CKO. Interestingly, the main source of TRAIL was the CD45- LG-acinar cells, but not CD45+ immune cells after DED induction. Using ex vivo coculture system, we confirmed LG-induced apoptosis of immune cells via HIF-1α-mediated TRAIL secretion following DED. Consistent with ex vivo, the insufficiency of HIF-1α and TRAIL enhanced recruitment of inflammatory cells to the LG and subsequently exacerbated ocular surface damage in DED mice. Conclusions: Our findings offer novel insight into the regulatory function of acinar cell-derived TRAIL in limiting inflammatory damage and could be implicated in the development of potential therapeutic strategies for DED.


Assuntos
Dacriocistite/metabolismo , Síndromes do Olho Seco/metabolismo , Regulação da Expressão Gênica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Aparelho Lacrimal/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Animais , Apoptose , Técnicas de Cocultura , Dacriocistite/patologia , Modelos Animais de Doenças , Síndromes do Olho Seco/patologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Immunoblotting , Marcação In Situ das Extremidades Cortadas , Aparelho Lacrimal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Reação em Cadeia da Polimerase em Tempo Real
4.
Cornea ; 39(2): 161-167, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31517720

RESUMO

PURPOSE: Dry eye syndrome (DES) is a common eye disease caused by tear deficiency or excessive tear evaporation. Because the tear film layers play a major role in the pathogenesis of the evaporative dry eye, some previous articles have suggested the possible mechanism of dyslipidemia and DES. However, the previous results were inconsistent and few studies were conducted to find the independent relationship between dyslipidemia and DES. Therefore, we investigated the association of dyslipidemia with DES in middle-aged Korean adults. METHODS: This study was conducted on 2272 participants (854 men and 1418 women) enrolled in the Study Group for Environmental Eye Disease (2013-2017) after excluding people who have taken lipid-lowering medication. Participants with total cholesterol ≥240 mg/dL or high-density lipoprotein cholesterol <40 mg/dL or low-density lipoprotein cholesterol ≥160 mg/dL or triglycerides ≥200 mg/dL are defined as having dyslipidemia. Using the ocular surface disease index, we measured the DES severity and defined DES as an ocular surface disease index score ≥13. RESULTS: Men with dyslipidemia had an odds ratio of 1.29 (95% confidence interval, 0.97-1.71) for DES in an unadjusted model compared with those without DES. After adjusting for age, body mass index, hypertension, diabetes, occupations, smoking and drinking status, exercise, contact lens use, computer use, study cohorts, and calendar year of examinations, the adjusted odds ratio for DES was 1.40 (1.03-1.90) in men. However, there was no significant association between dyslipidemia and DES in women, even after stratifying by menopausal status. CONCLUSIONS: Our findings suggest that dyslipidemia may be associated with the prevalence of DES in Korean men, but not in women.

5.
Invest Ophthalmol Vis Sci ; 60(15): 5035-5044, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31800960

RESUMO

Purpose: To compare the changes in human tear proteome and clinical effects following topical cyclosporine A (CsA) 0.05% or diquafosol tetrasodium (DQS) 3% treatment of dry eye disease (DED), and to identify biomarkers for determining disease severity and treatment effectiveness in DED. Methods: A total of 18 patients were diagnosed with non-Sjögren DED. Nine patients in each group were treated with topical CsA 0.05% or DQS 3% for 4 weeks. Tear samples were collected after evaluation of tear breakup time, corneal and conjunctival erosion staining, and results of Schirmer's test 1 before and after treatment. Proteomes were characterized using liquid chromatography mass spectrometry, and proteins exhibiting a fold change >1.5 or <0.67 (P < 0.05) were considered differentially expressed (DEP). Results: A total of 794 proteins were identified, with no significant difference observed between pretreatment and posttreatment conditions. Proteomic analysis identified 54 and 106 DEPs between treatment groups (CsA and DQS, respectively), with gene ontology analysis indicating that both treatments enhanced innate and adaptive immune responses and cellular detoxification. Protein-network analysis showed that inflammation associated with the immune response was primarily responsible for the therapeutic process in both groups. Conclusions: These results provide insight into the broad scope of changes at the ocular surface in DED and indicated that although both drugs improved the clinical parameters, the activated tear-specific biomarkers differed significantly between treatments. Our findings suggest that the DEPs identified here and those correlated with the clinical parameters might represent candidate biomarkers for DED.


Assuntos
Ciclosporina/administração & dosagem , Síndromes do Olho Seco/tratamento farmacológico , Polifosfatos/administração & dosagem , Proteoma/metabolismo , Lágrimas/metabolismo , Nucleotídeos de Uracila/administração & dosagem , Administração Tópica , Túnica Conjuntiva/metabolismo , Túnica Conjuntiva/patologia , Córnea/metabolismo , Córnea/patologia , Relação Dose-Resposta a Droga , Síndromes do Olho Seco/metabolismo , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/administração & dosagem , Estudos Prospectivos , Método Simples-Cego , Lágrimas/efeitos dos fármacos , Resultado do Tratamento
6.
Cells ; 8(12)2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817755

RESUMO

Interleukin-22 (IL-22) is a cytokine with important functions in host defense and inflammatory responses and has recently been suggested to play a role in immune-inflammatory system in the context of obesity and its metabolic consequences. The specific cellular targets and mechanisms of IL-22-mediated obesity are largely unknown however. We here identified a previously unknown subset of monocyte-derived Duffy antigen receptors for chemokines (DARC)+ macrophages in epididymal fat adipose tissue and found that they are preferentially recruited into the crown-like structures of adipose tissue in the mouse upon high fat diet-induced obesity. Importantly, DARC+ macrophages highly express the IL-22 receptor (IL-22Ra1). Exposure to recombinant IL-22 shifts macrophages to an alternative M2 polarization pathway and augments DARC expression via a STAT5b signaling axis. STAT5b directly binds to the DARC promoter and a STAT5 inhibitor abrogates the IL-22-mediated induction of DARC. These M2-like DARC+ subpopulations of monocytes/macrophages were elevated in obese db/db mice compared to WT lean mice. Furthermore, subsets of CD14+ and/or CD16+ monocytes/macrophages within human peripheral blood mononuclear cell populations express DARC and the prevalence of these subsets is enhanced by IL-22 stimuli. This suggested that IL-22 is a critical cytokine that promotes the infiltration of adipose tissue macrophages, that regulate inflammatory processes. Taken together, our present findings provide important insights into the molecular mechanism by which IL-22 signal modulates DARC expression in M2-like macrophages.

7.
Korean J Ophthalmol ; 33(5): 451-457, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612656

RESUMO

PURPOSE: To describe current cataract surgery practice patterns and changing trends among Korean ophthalmologists. METHODS: A survey of members of the Korean Society of Cataract and Refractive Surgery was performed in July 2018. One hundred and two (12.7%) of 801 questionnaires were returned for analysis. The data were analyzed using descriptive statistics and compared with previous surveys. RESULTS: Most of the respondents (75%) had been in practice for 6 or more years and performed an average of 31 cataract surgeries per month. The preferred method for cataract surgery was phacoemulsification (95%); 5% used a femtosecond laser. The use of topical anesthesia markedly increased from 69% (2012) to 80% (2018). The use of optical biometry exceeded that of ultrasound A-scan biometry. A multifocal intraocular lens was used by 76% of the respondents compared with 44% of the respondents in 2012. Topical nonsteroidal anti-inflammatory drugs were used by 70% of the respondents postoperatively. Most (59%) of these anti-inflammatory drugs were prescribed for 4 weeks. CONCLUSIONS: This survey provided a comprehensive update of the present cataract surgery practices in the Republic of Korea. The results emphasized the increasing use of premium intraocular lenses, optical biometry, and topical anesthesia.


Assuntos
Extração de Catarata/estatística & dados numéricos , Oftalmologia , Sociedades Médicas , Inquéritos e Questionários , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos
8.
J Mater Chem B ; 7(45): 7120-7128, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31602453

RESUMO

Methods of the early detection of diseases are based on recognition of the smallest change in the levels of a disease-specific biomarker in body fluids. Among them, monitoring protein concentrations is crucial because most diseases are caused by dysregulated protein levels, rather than DNA or RNA levels. Recent studies have indicated that the proteins in the aqueous humor can be used as biomarkers to predict brain diseases. Therefore, mounting an insertion type sensor on the intraocular lens is a compelling candidate platform for monitoring potential brain disease patients. In particular, molecular reactive sensors that use affinity binding, such as molecularly imprinted hydrogels, allow simple label-free detection, as well as high bio-applicability and biocompatibility. Herein, we describe the fabrication of an optical sensor using a silica nanoparticle conjugated bioresponsive hydrogel to analyze protein biomarkers by measuring light interference in smartphone images. Conformational changes in biotin-conjugated hydrogels were observed through the presence of avidin, as a substitution for a novel biomarker, in interconnecting hydrogel networks. Uniformly arrayed nanoparticles interfered with light differently when the distance between the silica nanoparticles was varied according to target moiety binding. A blue-shift of the reflected light was evident in avidin solutions of up to 100 nM and was induced by shrinkage of the hydrogel. The results indicate that our well-defined, label-free bioresponsive hydrogel demonstrated strong potential to be widely applied as a bioresponsive light interfering hydrogel sensor.

9.
Sci Rep ; 9(1): 12659, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477748

RESUMO

Dry eye disease (DED) after cataract surgery has become a critical concern, and various therapeutic options have been developed. Recently, preservative-free diquafosol ophthalmic solution has been introduced; however, its therapeutic effect on DED after cataract surgery has not been reported. We investigated the efficacy of preservative-free diquafosol in patients with pre-existing DED after cataract surgery. We divided subjects who were diagnosed with DED and scheduled to undergo cataract surgery, into 3 groups (preservative-free diquafosol, group 1; preservative-containing diquafosol, group 2; preservative-free hyaluronate, group 3), and each eye drops was administered 6 times daily after surgery. Tear break up time (TBUT), Ocular Surface Disease Index (OSDI), corneal staining score, lid margin abnormality, and meibum quality improved over time in group 1. Groups 1 and 2 had significantly superior TBUT, meibomian gland dysfunction grade, and meibomian gland expressibility throughout the study period than group 3. Meibum quality of group 1 was significantly better than group 2 at 1 and 3 months after surgery. Preservative-free diquafosol showed better efficacy in treating DED after cataract surgery than preservative-containing diquafosol or preservative-free hyaluronate. Preservative-free diquafosol may serve as a reliable option for the management of patients with pre-existing DED after phacoemulsification.

10.
Korean J Ophthalmol ; 33(4): 343-352, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31389210

RESUMO

PURPOSE: To evaluate the efficacy and safety of cyclosporine nanoemulsion 0.05% compared to cyclosporine emulsion 0.05% and diquafosol sodium 3%. METHODS: This was a multicenter, randomized, evaluator-masked, active control, parallel, phase IV study. A total of 227 patients were randomly allocated to instill cyclosporine nanoemulsion 0.05% (CN) twice daily, cyclosporine emulsion 0.05% (CE) twice daily, or diquafosol sodium 3% (DQ) six times daily. Non-inferiority of CN was analyzed by primary endpoint (cornea and conjunctival staining scores at week 12). The secondary endpoints were scores of corneal staining, conjunctival staining, tear break-up time, Schirmer test, and Ocular Surface Disease Index at weeks 4 and 12. RESULTS: Primary endpoints showed statistically significant improvements in all groups. Primary endpoints were -6.60 for the CN group, -5.28 for the CE group, and -6.63 for the DQ group (National Eye Institute scale from 0 to 33), verifying the non-inferiority of CN compared to CE (95% confidence interval, -0.15 to 2.80, Δ>-2.88). In intergroup comparison between CN and CE groups, the CN group had significantly more decreased conjunctival staining score at week 12. Intergroup comparison between CN and DQ groups showed consistent statistically significant improvements in TBUT and Schirmer test in the CN group. In the DQ group, TBUT showed late statistically significant improvement at week 12 and Schirmer test showed relatively short-term statistically significant improvement at week 4. CONCLUSIONS: Cyclosporine nanoemulsion 0.05% was equivalently efficient compared to cyclosporine emulsion 0.05% and diquafosol sodium 3%. In addition, CN showed significant improvements in several parameters for treatment of dry eyes.


Assuntos
Ciclosporina/administração & dosagem , Síndromes do Olho Seco/tratamento farmacológico , Polifosfatos/administração & dosagem , Nucleotídeos de Uracila/administração & dosagem , Administração Tópica , Adulto , Relação Dose-Resposta a Droga , Síndromes do Olho Seco/diagnóstico , Emulsões/administração & dosagem , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nanotecnologia , Estudos Prospectivos , Método Simples-Cego , Lágrimas/metabolismo , Resultado do Tratamento
11.
BMC Ophthalmol ; 19(1): 131, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208393

RESUMO

BACKGROUND: This study is aim to compare the clinical effectiveness between the two most prominent dry eye disease (DED)-specific eye drops, 0.05% cyclosporine (CN) and 3% diquafosol (DQ). METHODS: This is a multi-centered, randomized, masked, prospective clinical study. A total of 153 DED patients were randomly allocated to use CN twice per day or DQ six times daily. Cornea and conjunctival staining scores (NEI scale), tear break-up time (TBUT), Schirmer test scores, and ocular surface disease index (OSDI) score were measured at baseline, 4 and 12 weeks after treatment. RESULTS: At 12 weeks after treatment, NEI scaled scores were significantly reduced from the baseline by - 6.60 for CN and - 6.63 for DQ group (all P < 0.0001, P = 0.9739 between groups). TBUT and Schirmer values for CN were significantly improved from the baseline at 4 and 12 weeks (P = 0.0034, P < 0.0001 for TBUT, P = 0.0418, P = 0.0031 for Schirmer test). However, for DQ, TBUT showed significant improvement at 12 weeks only (P = 0.0281). Mean OSDI score differences from the baseline to 12 weeks were improved by - 13.03 ± 19.63 for CN and - 16.11 ± 20.87 for DQ, respectively (all P < 0.0001, P = 0.854 between groups). Regarding drug compliance, the mean instillation frequency of CN was less than that of DQ (P < 0.001). There were no statistically significant intergroup differences in safety evaluation. CONCLUSIONS: The level of improvement regarding NEI, TBUT, and OSDI scores were not significantly different between the two treatment groups. However, with regards to the early improvement of TBUT and patient compliance, patients using CN improved faster and with greater adherence to drug usage than did those treated with DQ. TRIAL REGISTRATION: KCT0002180 , retrospectively registered on 23 December 2016.


Assuntos
Ciclosporina/uso terapêutico , Síndromes do Olho Seco/tratamento farmacológico , Imunossupressores/uso terapêutico , Soluções Oftálmicas/uso terapêutico , Polifosfatos/uso terapêutico , Nucleotídeos de Uracila/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Túnica Conjuntiva/patologia , Feminino , Humanos , Lubrificantes Oftálmicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Lágrimas/fisiologia , Adulto Jovem
12.
Invest Ophthalmol Vis Sci ; 60(1): 255-264, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30649152

RESUMO

Purpose: Exposure to airborne particulate matter can induce ocular surface damage and inflammation. We evaluated the effects of a topical mucin secretagogue on the mitigation of ocular surface damage induced by exposure to airborne carbon black (CB). Methods: Sprague-Dawley rats were exposed to ambient CB for 2 hours twice daily for 5 days. Corneal staining score and tear lactic dehydrogenase (LDH) activity were measured to evaluate ocular surface damage. Serum immunoglobulin (Ig) G and IgE levels and the sizes of cervical lymph nodes were also measured. The expressions of interleukin (IL)-4, IL-17, and interferon (IFN)-γ were measured by Western blot analysis. Diquafosol tetrasodium was instilled six times a day for 5 days, and the extent of ocular surface damage was evaluated. Results: After exposure to airborne CB, the median corneal staining score and LDH activity were significantly increased. Serum IgG and IgE levels and the sizes of cervical lymph nodes were also significantly increased. Additionally, the expression of IL-4 and IFN-γ was elevated in the anterior segment of the eyeball. Furthermore, the expression of IL-4, IL-17, and IFN-γ was elevated in the cervical lymph nodes. When exposed to airborne black carbon, topical diquafosol tetrasodium significantly increased tear MUC5AC concentration and decreased tear LDH activity. Conclusions: Exposure to airborne CB induced ocular surface damage and increased proinflammatory cytokines in the eyes and cervical lymph nodes. Topical mucin secretagogues seem to have a protective effect on the ocular surface against exposure to airborne particulate matters.


Assuntos
Doenças da Córnea/prevenção & controle , Reação a Corpo Estranho/prevenção & controle , Mucina-5AC/metabolismo , Material Particulado/efeitos adversos , Polifosfatos/uso terapêutico , Agonistas do Receptor Purinérgico P2/uso terapêutico , Secretagogos/metabolismo , Nucleotídeos de Uracila/uso terapêutico , Animais , Western Blotting , Doenças da Córnea/etiologia , Doenças da Córnea/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Reação a Corpo Estranho/etiologia , Reação a Corpo Estranho/metabolismo , Imunoglobulina E/sangue , Imunoglobulina G/sangue , L-Lactato Desidrogenase/metabolismo , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Pescoço , Ratos , Ratos Sprague-Dawley , Fuligem/efeitos adversos , Lágrimas/enzimologia
13.
Xenotransplantation ; 26(1): e12446, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30063072

RESUMO

BACKGROUND: Xenotransplantation using fresh porcine corneas has been suggested as a feasible alternative to overcome the shortage of human donor corneas. Successful long-term survival of grafts without evidence of xenozoonosis in clinically applicable pig-to-non-human primate corneal transplantation model has brought researchers close to human clinical trials. Accordingly, we aimed to prepare a clinical trial protocol to conduct the first corneal xenotransplantation. METHODS: We developed the clinical trial protocol based on international consensus statement on conditions for undertaking clinical trials of corneal xenotransplantation developed by the International Xenotransplantation Society. Detailed contents of the protocol have been modified with reference to comments provided by ophthalmologists and multidisciplinary experts, including an infectionist, an organ transplantation specialist, a clinical pharmacologist, a neuropsychiatrist, a laboratory medicine doctor, and a microbiologist. RESULTS: Two patients with bilateral legal corneal blindness (best-corrected visual acuity ≤20/200 in the better eye and ≤20/1000 in the candidate eye) or with (impending) corneal perforation will be enrolled. During the screening period, participants and their family members will have two separate deep consideration periods before signing informed consent forms. Each patient will undergo corneal xenotransplantation using fresh corneas from Seoul National University miniature pigs. Commercially available immunosuppressants will be administered and systemic infection prophylaxis will be performed according to the program schedule. After transplantation, each patient will be monitored at a specialized clinic to investigate safety up to 2 years and efficacy up to 1 year. CONCLUSIONS: A detailed clinical trial protocol for the first corneal xenotransplantation reflecting the global guidelines is provided.


Assuntos
Opacidade da Córnea/cirurgia , Perfuração da Córnea/cirurgia , Transplante de Córnea , Transplante Heterólogo , Adulto , Animais , Transplante de Córnea/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Suínos , Doadores de Tecidos , Transplante Heterólogo/métodos , Transplantes/cirurgia , Adulto Jovem
15.
Eur J Pharmacol ; 843: 240-250, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30502343

RESUMO

Several antimuscarinics have been commonly used for overactive bladder patients, but dry mouth as a major anticholinergic side effect remains a shortcoming to limit long-term use. The aim of this study was to elucidate the pharmacological properties of DA-8010, a novel muscarinic receptor antagonist selective for urinary bladder over salivary gland. DA-8010 exhibited a high binding affinity for human muscarinic M3 receptor with pKi of 8.81 ±â€¯0.05 and great potencies for human M3 receptor and rat bladder preparation. The potency of DA-8010 for bladder smooth muscle cells was 3.6-fold higher than that for salivary gland cells isolated from mice. Intravenous administration of DA-8010 dose-dependently inhibited rhythmic urinary bladder contractions induced by distension in rats, indicating the most potent activity (ID30 = 0.08 mg/kg) among the antimuscarinics tested. Taken together with the inhibitory effects of DA-8010 and other antimuscarinics on carbachol-induced salivary secretion in rats, the in vivo functional selectivity of DA-8010 for urinary bladder over salivary gland was 3.1-fold, 3.2-fold and 5.2-fold greater than those observed for solifenacin, oxybutynin and darifenacin, respectively. Furthermore, oral administration of DA-8010 in mice resulted in more selective and persistent binding for muscarinic receptors in the bladder rather than in the submaxillary gland, in comparison with other antimuscarinics. These findings suggest that DA-8010 is a potent muscarinic M3 receptor antagonist to be highly selective for bladder over salivary gland, which might be a promising agent with greater efficacy and less dry mouth in the treatment of overactive bladder.


Assuntos
Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M3/antagonistas & inibidores , Glândulas Salivares/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Feminino , Masculino , Camundongos Endogâmicos ICR , Ratos Sprague-Dawley , Receptor Muscarínico M3/fisiologia , Glândulas Salivares/fisiologia , Bexiga Urinária/fisiologia
16.
ACS Chem Biol ; 14(1): 11-19, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30507149

RESUMO

Angiogenesis generates new blood vessels from pre-existing vessels. Tumors induce the formation of new blood vessels to ensure sufficient oxygen and nutrients for their growth. Normally, angiogenesis is induced by various pro-angiogenesis factors, including vascular endothelial growth factor (VEGF). Inhibition of VEGF is a promising approach to cancer treatment. A guanidine-based synthetic compound, E2, was identified as a potent hit from 68 guanidine-based derivatives by screening for angiogenesis inhibitors showing antiproliferative activity in human umbilical vein endothelial cells (HUVECs). To explore the mode of action of E2, target proteins were investigated using phage display biopanning, and acid ceramidase 1 (ASAH1) was identified as an E2-binding protein. Drug affinity responsive target stability (DARTS) and ASAH1 activity assays revealed the direct binding of E2 to ASAH1. Moreover, siRNA knockdown of ASAH1 demonstrated its role as an angiogenesis factor. Consequently, E2 inhibited chemoinvasion and tube formation of HUVECs in a dose-dependent manner. E2 also potently suppressed neo-vascularization of chorioallantoic membranes in vivo. Collectively, these data suggest that E2 is a novel angiogenesis inhibitor and ASAH1 is proposed to be a new antiangiogenesis target.


Assuntos
Ceramidase Ácida/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Inibidores Enzimáticos/farmacologia , Guanidina/química , Neovascularização Patológica/prevenção & controle , Ceramidase Ácida/genética , Inibidores da Angiogênese/metabolismo , Técnicas de Visualização da Superfície Celular , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Proteínas/genética , Proteínas/metabolismo , RNA Interferente Pequeno/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Invest Ophthalmol Vis Sci ; 59(13): 5693-5703, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30489629

RESUMO

Purpose: Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation (R124H) in the TGF-ß-induced gene (TGFBI). However, the mechanisms underlying the accumulation of TGF-ß-induced protein (TGFBIp) are poorly understood. Therefore, we evaluated the signaling cascade affecting the expression of TGFBIp using patient-derived cells. Methods: Keratocyte primary cultures were prepared from corneas from the eye bank or from heterozygous or homozygous patients with GCD2 after penetrating or lamellar keratoplasty. GCD2 diagnoses were based on the results of a DNA analysis for the R124H TGFßI mutation. Keratocytes were treated with various cytokines and then analyzed using quantitative PCR (qPCR) array, qPCR, flow cytometry, ELISA, and Western blotting. Results: TGFBI expression was counterregulated by IL-7 in corneal fibroblasts. IL-7 expression was significantly reduced in corneal fibroblasts from patients with GCD2. TGF-ß and TGFBI expression were reduced on IL-7 treatment in corneal fibroblasts. Interestingly, the interplay between TGF-ß and IL-7 was regulated by the RANKL/RANK signaling cascade. Also, IL-7 regulates the expression of a membrane-type matrix metalloproteinase (MT-MMP), which plays a crucial role in migration and neovascularization in the cornea. Conclusions: These studies demonstrate that impaired IL-7 expression in patients with GCD2 affects disease pathogenesis via a failure to control TGF-ß expression. The RANKL/RANK axis regulates TGF-ß and TGFBI expression via IL-7-mediated MT-MMP regulation in corneal fibroblasts. These findings improve our understanding of the pathogenesis of GCD2.


Assuntos
Distrofias Hereditárias da Córnea/metabolismo , Ceratócitos da Córnea/metabolismo , Regulação para Baixo/fisiologia , Interleucina-7/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Receptores de Interleucina-7/metabolismo , Adolescente , Adulto , Western Blotting , Células Cultivadas , Criança , Distrofias Hereditárias da Córnea/diagnóstico , Ensaio de Imunoadsorção Enzimática , Proteínas da Matriz Extracelular/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto Jovem
18.
Sensors (Basel) ; 18(11)2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30413086

RESUMO

This paper proposes an efficient multi-sensor system to complement GNSS (Global Navigation Satellite System) for improved positioning in urban area. The proposed system augments GNSS by low-cost MEMS IMU (Micro Electro Mechanical Systems Inertial Measurement Unit), OBD (On-Board Diagnostics)-II, and digital altimeter modules. For improved availability of time synchronization in urban area, an adaptive synchronization method is proposed to combine the external PPS (Pulse Per Second) signal and the internal onboard clock. For improved positioning accuracy and availability, a 17-state Kalman filter is formulated for efficient multi-sensor fusion, including OBD-II and digital altimeter modules. A strategy to apply different types of measurement updates is also proposed for improved performance in urban area. Four experiment results with field-collected measurements evaluates the performance of the proposed GNSS/IMU/OBD-II/altimeter system in various aspects, including accuracy, precision, continuity, and availability.

19.
J Ocul Pharmacol Ther ; 34(9): 612-620, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30325678

RESUMO

PURPOSE: To determine the mucinogenic effect of dry eye (DE) treatment drugs currently in use, we compared the levels of mucin production and inflammatory cytokine expression on the ocular surfaces using a DE-induced mice model. METHODS: C57BL/6 mice were separated into 6 groups: a control group, DE-induced mice with the vehicle and treated with cyclosporine A (CsA), rebamipide (Reb), diquafosol tetrasodium (DQS), or prednisolone (Pred). The mRNA expression of MUC 1, 4, 16, 5AC, and proinflammatory cytokines on the corneal epithelia were determined by quantitative real-time polymerase chain reaction. Expression of each MUC was evaluated using flow cytometry and immunohistostaining. Conjunctival goblet cells were analyzed through periodic acid-Schiff (PAS) staining. RESULTS: Desiccating stress significantly decreased both mRNA and protein levels of all MUCs in the cornea. CsA mainly enhanced MUC5AC, with an increase in PAS-positive cells, whereas DQS chiefly increased membrane-associated mucins (MM). However, Reb only minimally increased expression of MUC5AC and Pred only increased MUC4. MUC16 did not show any significant change in any group. On the contrary, the mRNA levels of interleukin (IL)-1ß, -6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were increased in the DE corneas of the control mice and were reduced by all treatments; in particular, IL-6 was significantly suppressed. CONCLUSION: Topical DQS and CsA not only ameliorated ocular surface inflammation under desiccating stress but also upregulated both MM and secretory mucins (SM) and contributed to conjunctival goblet cell recovery, compared to Reb and Pred. Both anti-inflammatory and secretory factors should be considered simultaneously when measuring the treatment effect of DE drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Síndromes do Olho Seco/tratamento farmacológico , Epitélio Anterior/efeitos dos fármacos , Mucinas/antagonistas & inibidores , Soluções Oftálmicas/farmacologia , Administração Tópica , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Ciclosporina/administração & dosagem , Ciclosporina/farmacologia , Modelos Animais de Doenças , Síndromes do Olho Seco/induzido quimicamente , Síndromes do Olho Seco/metabolismo , Epitélio Anterior/metabolismo , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mucinas/genética , Mucinas/metabolismo , Soluções Oftálmicas/administração & dosagem , Polifosfatos/administração & dosagem , Polifosfatos/farmacologia , Quinolonas/administração & dosagem , Quinolonas/farmacologia , Nucleotídeos de Uracila/administração & dosagem , Nucleotídeos de Uracila/farmacologia
20.
Invest Ophthalmol Vis Sci ; 59(7): 3104-3114, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30025127

RESUMO

Purpose: A topical mucolytic agent, N-acetylcysteine (NAC), has been used to create an animal model without the intestinal mucus layer. In this study, we investigated the effects of topical NAC on the tears and ocular surface. Methods: NAC-treated models were established by topically administering 10% NAC four times daily for 5 days in male Sprague-Dawley rats. Clinical parameters and the expression of mucin proteins and genes were evaluated. Alterations in the conjunctival epithelium and goblet cells were observed. Results: The NAC group showed significant decreases in tear secretion, corneal wetting ability, tear MUC5AC concentration, and conjunctival goblet cell numbers as compared with the control group (all P < 0.01). In addition, significant increases in corneal fluorescein score and rose bengal scores were observed in the NAC group versus in the control group (P < 0.05 and P < 0.01, respectively). Hematoxylin and eosin (H&E) staining and scanning electron microscopy clearly showed damage in the epithelial cell layer and microvilli of the NAC group. Although there was no significant difference in MUC16 gene expression, the MUC16 concentration of the tear film and ocular surface tissue was significantly increased in the NAC group versus in the control group (P < 0.01 and P < 0.05, respectively). Five-day treatment with 3% diquafosol had minimal therapeutic effect in NAC-treated rat eyes. Conclusions: Topical administration of 10% NAC induced ocular surface damage and tear film instability by prompting MUC16 disruption and release from the ocular surface. This animal model could be used to study dry eye disease, especially the mucin-deficiency subtype.


Assuntos
Acetilcisteína/efeitos adversos , Túnica Conjuntiva/efeitos dos fármacos , Modelos Animais de Doenças , Síndromes do Olho Seco/induzido quimicamente , Expectorantes/efeitos adversos , Mucina-5AC/deficiência , Lágrimas/metabolismo , Acetilcisteína/administração & dosagem , Administração Oftálmica , Animais , Contagem de Células , Túnica Conjuntiva/metabolismo , Córnea/efeitos dos fármacos , Córnea/metabolismo , Síndromes do Olho Seco/metabolismo , Síndromes do Olho Seco/patologia , Ensaio de Imunoadsorção Enzimática , Expectorantes/administração & dosagem , Células Caliciformes/patologia , Masculino , Microscopia Eletrônica de Varredura , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
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