RESUMO
BACKGROUND: To investigate the influence of femtosecond laser-assisted cataract surgery (FLACS) on macula by examining changes in retinal layers after FLACS and to compare these changes with those after conventional cataract surgery (CCS). METHODS: This study included 113 unrelated Korean patients with age-related cataract who underwent CCS or FLACS in Severance Hospital between September 2019 and July 2021. Optical coherence tomography was performed before and 1 month after surgery. The total retinal layer (TRL) was separated into the inner retinal layer (IRL) and outer retinal layer (ORL); moreover, the IRL was subdivided into the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer (INL), outer plexiform layer, and outer nuclear layer. We performed between-group comparisons of the postoperative thickness in each retinal layer and the postoperative differences in retinal thickness. The average retinal thickness of the four inner macular ring quadrants was used for comparative analysis. RESULTS: Compared with the CCS group, the FLACS group exhibited a thicker ORL (P = 0.004) and a thinner INL (P = 0.007) after surgery. All retinal layer thickness values showed significant postoperative changes regardless of the type of surgery (P < 0.05). The postoperative increase in TRL and IRL thickness was significantly smaller in the FLACS group than in the CCS group (P = 0.027, P = 0.012). CONCLUSIONS: The 1-month postoperative retinal changes were less pronounced in the FLACS group than in the CCS group.
Assuntos
Extração de Catarata , Terapia a Laser , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Feminino , Masculino , Tomografia de Coerência Óptica/métodos , Idoso , Terapia a Laser/métodos , Extração de Catarata/métodos , Pessoa de Meia-Idade , Retina/patologia , Retina/diagnóstico por imagem , Estudos Retrospectivos , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologia , Catarata/patologia , Idoso de 80 Anos ou mais , Período Pós-OperatórioRESUMO
Meibomian gland dysfunction is one of the main causes of dry eye disease and has limited therapeutic options. In this study, we investigated the biological function of the beta 2-adrenergic receptor (ADRB2)/protein kinase A (PKA) pathway in lipid synthesis and its underlying mechanisms in human meibomian gland epithelial cells (HMGECs). HMGECs were cultured in differentiation media with or without forskolin (an activator of adenylate cyclase), salbutamol (an ADRB2 agonist), or timolol (an ADRB2 antagonist) for up to 4 days. The phosphorylation of the cAMP-response element-binding protein (CREB) and the expression of peroxisome proliferator activator receptor (PPAR)γ and sterol regulatory element-binding protein (SREBP)-1 were measured by immunoblotting and quantitative PCR. Lipid synthesis was examined by LipidTOX immunostaining, AdipoRed assay, and Oil Red O staining. PKA pathway activation enhanced PPARγ expression and lipid synthesis in differentiated HMGECs. When treated with agonists of ADBR2 (upstream of the PKA signaling system), PPARγ expression and lipid synthesis were enhanced in HMGECs. The ADRB2 antagonist timolol showed the opposite effect. The activation of the ADRB2/PKA signaling pathway enhances lipid synthesis in HMGECs. These results provide a potential mechanism and therapeutic target for meibomian gland dysfunction, particularly in cases induced by beta-blocker glaucoma drugs.
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Antagonistas Adrenérgicos beta , Proteínas Quinases Dependentes de AMP Cíclico , Glaucoma , Disfunção da Glândula Tarsal , Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glaucoma/tratamento farmacológico , Humanos , Lipídeos/biossíntese , PPAR gama/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , Timolol/farmacologiaRESUMO
Cystic fibrosis transmembrane conductance regulator (CFTR) is highly expressed on the ocular epithelium and plays a pivotal role in the fluid secretion driven by chloride transport. Dry eye disease is one of the most common diseases with limited therapeutic options. In this study, a high-throughput screening was performed to identify novel CFTR activators capable of inducing chloride secretion on the ocular surface. The screening of 50,000 small molecules revealed three novel CFTR activators. Among them, the most potent CFTR activator, Cact-3 (7-(3,4-dimethoxyphenyl)-N-(4-ethoxyphenyl)pyrazolo [1,5-α]pyrimidine-2-carboxamide), produced large and sustained Cl- currents in WT-CFTR-expressing FRT cells with no alterations of ANO1 and hERG channel activity. The application of Cact-3 strongly activated CFTR in the ocular epithelia of mice and it also significantly increased CFTR-mediated Cl- transport in a primary cultured human conjunctival epithelium. Cact-3 strongly stimulated tear secretion in normal mice. In addition, Cact-3 significantly reduced ocular surface damage and the expression of proinflammatory factors, including interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in an experimental mouse model of dry eye disease. These results suggest that Cact-3, a novel CFTR activator, may be a potential development candidate for the treatment of dry eye disease.
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Regulador de Condutância Transmembrana em Fibrose Cística , Síndromes do Olho Seco , Cloretos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Síndromes do Olho Seco/tratamento farmacológico , Humanos , Transporte de Íons , EscopolaminaRESUMO
BACKGROUND: No studies have been reported on the efficacy and safety of long-term (≥12 months) use of topical tacrolimus for refractory ocular surface inflammation in pediatric patients. METHODS: Medical records of pediatric patients who were prescribed topical 0.02% tacrolimus ointment for refractory ocular surface inflammation between January of 2010 and March of 2018 were reviewed retrospectively. Changes in ocular surface signs during slit-lamp examination, clinical symptoms and concurrent steroid use were graded with a scoring system. The presence of side effects was also assessed. The changes in disease severity and patient symptoms were compared between baseline and after the treatment. RESULTS: Among 72 patients (55% males, mean age 10.8 ± 3.9 years, range 3 to 17 years), 25 patients (48% males, mean age 11.4 ± 3.9 years) fully recovered, resulting in discontinuance of the ointment treatment before 12 months. Six patients experienced intolerable burning sensation, which required treatment cessation. Cessation days of those who quit were 1,5,14,20,26, and 35 days. Seven patients were lost during follow-up. Thirty-four patients (56% males, mean age 11.2 ± 4.2 years, range 3 to 17 years) were treated with tacrolimus ointment for over 12 months (average 23.1 ± 19.1 months, range 12 to 98 months). During the follow-up period, all patients showed improved clinical signs and symptoms, and no adverse reaction was noted. CONCLUSIONS: Long-term maintenance of topical tacrolimus 0.02% ointment is safe and effective in improving refractory ocular surface inflammation in pediatric patients.
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Imunossupressores , Tacrolimo , Criança , Feminino , Humanos , Lactente , Inflamação , Masculino , Pomadas , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: To acquire desirable outcomes of penetrating keratoplasty (PKP), various factors affecting graft survival, visual function, and subjective symptom should be considered. As ocular surface and meibomian gland function are associated with these factors, this study aims to investigate changes of ocular surface and meibomian gland parameters after PKP. METHODS: This retrospective case series study included 24 eyes of 24 patients who underwent penetrating keratoplasty. Examinations on lipid layer thickness (LLT), meiboscore, tear meniscus area (TMA), tear breakup time (TBUT), corneal fluorescein staining (CFS), Schirmer I test (SIT), Ocular Surface Disease Index (OSDI), and meibomian gland functions were performed before and at 1 week, 1 month, 6 months, and 12 months after surgery. RESULTS: Compared to baseline (2.9 ± 0.6 s), TBUTs were longer at 1 week (4.4 ± 0.5 s, P = 0.027) and 6 months (4.4 ± 0.5, P = 0.048) after surgery. CFS values improved from baseline (6.5 ± 1.1) to 6 months (3.5 ± 0.6, P = 0.023) and 12 months (3.3 ± 0.7, P = 0.001) after surgery. Meibum quality value worsened at 1 week and 12 months after surgery and meibomian gland expressibility value worsened at 1 week and 6 months after surgery compared to baseline. OSDI scores improved at 6 and 12 months after surgery. Meiboscore showed no change throughout the follow up period. The patients with high preoperative meiboscore had worse meibomian gland expressibility at 6 and 12 months and meibum quality at 6 months postoperatively compared to their baseline and to those of patients with low preoperative meiboscore. CONCLUSIONS: After penetrating keratoplasty, ocular surface parameters including corneal staining, TBUT, and OSDI significantly improved whereas meibomian gland parameters showed deteriorations, which was marked in patients with high preoperative meiboscore. Thus, perioperative management of MGD is recommended for patients who undergo penetrating keratoplasty, especially in patients with advanced MGD.
Assuntos
Síndromes do Olho Seco , Glândulas Tarsais , Humanos , Ceratoplastia Penetrante , Glândulas Tarsais/diagnóstico por imagem , Estudos Retrospectivos , LágrimasRESUMO
BACKGROUND: To investigate the surgical outcomes of implantable collamer lens (ICL) implantation in eyes with residual myopia after primary laser vision correction (LVC) surgeries. METHODS: This study included patients who underwent ICL implantation and had a history of LVC surgery, including photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK). Visual acuity and refractive error were assessed pre and 3-months postoperatively and the efficacy and safety indices calculated accordingly. RESULTS: A total of 30 eyes of 17 patients were included in this study. At 3 months, the mean logMAR uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and spherical equivalent were - 0.03 ± 0.11 (include logMAR), - 0.04 ± 0.09 (include logMAR), and - 0.06 ± 0.33 diopters (D), respectively. The 3-month Snellen UDVA was better than 20/20 for 83% of eyes, and 97% of eyes showed an unchanged or improved CDVA after surgery. The mean efficacy and safety indices were 1.11 ± 0.22 and 1.13 ± 0.20, respectively. Further, 93 and 100% of eyes were within ±0.5 and ± 1.0 D of the attempted spherical equivalent refraction, respectively. CONCLUSIONS: ICL implantation in eyes with myopic regression after previous LVC surgery showed safe, effective, and predictable outcomes. TRIAL REGISTRATION: retrospectively registered.
Assuntos
Ceratomileuse Assistida por Excimer Laser In Situ , Miopia , Ceratectomia Fotorrefrativa , Humanos , Lasers , Lasers de Excimer/uso terapêutico , Miopia/cirurgia , Refração Ocular , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Dry eye disease is one of the most common diseases, with increasing prevalence in many countries, but treatment options are limited. Cystic fibrosis transmembrane conductance regulator (CFTR) is a major ion channel that facilitates fluid secretion in ocular surface epithelium and is a potential target of therapeutic agent for the treatment of dry eye disease. In this study, we performed a cell-based, high-throughput screening for the identification of novel natural products that activate CFTR and restore the aqueous deficiency in dry eye. Screening of 1000 natural products revealed isorhamnetin, a flavonol aglycone, as a novel CFTR activator. Electrophysiological studies showed that isorhamnetin significantly increased CFTR chloride current, both wild type and ∆F508-CFTR. Isorhamnetin did not alter intracellular cAMP levels and the activity of other ion channels, including ANO1, ENaC, and hERG. Notably, application of isorhamnetin on mouse ocular surface induced CFTR activation and increased tear volume. In addition, isorhamnetin significantly reduced ocular surface damage and expression of interleukin (IL)-1ß, IL-8, and tumor necrosis factor (TNF)-α in an experimental mouse model of dry eye. These data suggest that isorhamnetin may be used to treat dry eye disease.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Síndromes do Olho Seco/tratamento farmacológico , Quercetina/análogos & derivados , Animais , Modelos Animais de Doenças , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/patologia , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-8/genética , Camundongos , Quercetina/farmacologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
Many anion channels, frequently referred as Cl- channels, are permeable to different anions in addition to Cl-. As the second-most abundant anion in the human body, HCO3- permeation via anion channels has many important physiological roles. In addition to its classical role as an intracellular pH regulator, HCO3- also controls the activity and stability of dissolved proteins in bodily fluids such as saliva, pancreatic juice, intestinal fluid, and airway surface liquid. Moreover, HCO3- permeation through these channels affects membrane potentials that are the driving forces for transmembrane transport of solutes and water in epithelia and affect neuronal excitability in nervous tissue. Consequently, aberrant HCO3- transport via anion channels causes a number of human diseases in respiratory, gastrointestinal, genitourinary, and neuronal systems. Notably, recent studies have shown that the HCO3- permeabilities of several anion channels are not fixed and can be altered by cellular stimuli, findings which may have both physiological and pathophysiological significance. In this review, we summarize recent progress in understanding the molecular mechanisms and the physiological roles of HCO3- permeation through anion channels. We hope that the present discussions can stimulate further research into this very important topic, which will provide the basis for human disorders associated with aberrant HCO3- transport.
Assuntos
Ânions/metabolismo , Bicarbonatos/metabolismo , Permeabilidade da Membrana Celular/fisiologia , Canais Iônicos/imunologia , Animais , Transporte Biológico/fisiologia , HumanosRESUMO
Nephrolithiasis, a condition in which urinary supersaturation leads to stone formation in the urinary system, affects about 5%-10% of individuals worldwide at some point in their lifetime and results in significant medical costs and morbidity. To date, mutations in more than 30 genes have been described as being associated with nephrolithiasis, and these mutations explain about 15% of kidney stone cases, suggesting that additional nephrolithiasis-associated genes remain to be discovered. To identify additional genes whose mutations are linked to nephrolithiasis, we performed targeted next-generation sequencing of 18 hypothesized candidate genes in 348 unrelated individuals with kidney stones. We detected biallelic mutations in SLC26A1 (solute carrier family 26 member 1) in two unrelated individuals with calcium oxalate kidney stones. We show by immunofluorescence, immunoblotting, and glycosylation analysis that the variant protein mimicking p.Thr185Met has defects in protein folding or trafficking. In addition, by measuring anion exchange activity of SLC26A1, we demonstrate that all the identified mutations in SLC26A1 result in decreased transporter activity. Our data identify SLC26A1 mutations as causing a recessive Mendelian form of nephrolithiasis.
Assuntos
Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Mutação/genética , Nefrolitíase/etiologia , Sequência de Aminoácidos , Proteínas de Transporte de Ânions/química , Bicarbonatos/metabolismo , Imunofluorescência , Glicosilação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Immunoblotting , Nefrolitíase/patologia , Conformação Proteica , Dobramento de Proteína , Transporte Proteico , Reação em Cadeia da Polimerase em Tempo Real , Homologia de Sequência de Aminoácidos , Transportadores de Sulfato , Sulfatos/metabolismoRESUMO
Alzheimer's disease (AD) primarily affects the brain and is the most common form of dementia worldwide. Despite more than a century of research, there are still no early biomarkers for AD. It has been reported that AD affects the eye, which is more accessible for imaging than the brain; however, links with the cornea have not been evaluated. To investigate whether the cornea could be used to identify possible diagnostic indicators of AD, we analyzed the proteolytic processing and isoforms of amyloid precursor protein (APP) and evaluated the expression of AD-related genes and proteins in corneal fibroblasts from wild-type (WT) corneas and corneas from patients with granular corneal dystrophy type 2 (GCD2), which is related to amyloid formation in the cornea. Reverse transcription polymerase chain reaction (RT-PCR) analysis was used to assess the expression of AD-related genes, i.e., APP, ADAM10, BACE1, BACE2, PSEN1, NCSTN, IDE, and NEP. RT-PCR and DNA sequencing analysis demonstrated that isoforms of APP770 and APP751, but not APP695, were expressed in corneal fibroblasts. Moreover, the mRNA ratio of APP770/APP751 isoforms was approximately 4:1. Western blot analysis also demonstrated the expression of a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), beta-site APP-cleaving enzyme 1 (BACE1), nicastrin, insulin degradation enzyme, and neprilysin in corneal fibroblasts. Among these targets, the levels of immature ADAM10 and BACE1 protein were significantly increased in GCD2 cells. The expression levels of APP, ADAM10, BACE1, and transforming growth factor-beta-induced protein (TGFBIp) were also detected by western blot in human corneal epithelium. We also investigated the effects of inhibition of the autophagy-lysosomal and ubiquitin-proteasomal proteolytic systems (UPS) on APP processing and metabolism. These pathway inhibitors accumulated APP, α-carboxy-terminal fragments (CTFs), ß-CTFs, and the C-terminal APP intracellular domain (AICD) in corneal fibroblasts. Analysis of microRNAs (miRNAs) revealed that miR-9 and miR-181a negatively coregulated BACE1 and TGFBIp, which was directly associated with the pathogenesis of AD and GCD2, respectively. Immunohistochemical analysis indicated that APP and BACE1 were distributed in corneal stroma cells, epithelial cells, and the retinal layer in mice. Collectively, we propose that the cornea, which is the transparent outermost layer of the eye and thus offers easy accessibility, could be used as a potential biomarker for AD diagnosis and progression.
Assuntos
Doença de Alzheimer/complicações , Precursor de Proteína beta-Amiloide/genética , Distrofias Hereditárias da Córnea/genética , Epitélio Corneano/metabolismo , Regulação da Expressão Gênica , RNA/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/biossíntese , Animais , Biomarcadores/metabolismo , Western Blotting , Células Cultivadas , Distrofias Hereditárias da Córnea/metabolismo , Distrofias Hereditárias da Córnea/patologia , Ensaio de Imunoadsorção Enzimática , Epitélio Corneano/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , CamundongosRESUMO
BACKGROUND: To compare the clinical outcomes of wavefront-optimized (WFO) transepithelial photorefractive keratectomy (trans-PRK) and corneal wavefront-guided (CWFG) trans-PRK for myopic eyes with moderate to high astigmatism. METHODS: One hundred ninety-six eyes (196 patients) with moderate to high astigmatism (≥ 1.75 D) treated with WFO or CWFG trans-PRK (101 and 95 eyes, respectively) were retrospectively registered. Safety, efficacy, predictability, vector analysis, and corneal aberrations were compared between groups preoperatively and at 6 months postoperatively. RESULTS: At postoperative 6 months, the mean logMAR uncorrected distance visual acuity was similar in the WFO (- 0.07 ± 0.08) and CWFG (- 0.07 ± 0.07) groups. Safety, efficacy, and predictability of refractive and visual outcomes were also similar. The correction indices were 1.02 ± 0.14 and 1.03 ± 0.13 in the WFO and CWFG groups, respectively, with no significant difference. The absolute values of the angle of error were significantly higher in the WFO group (2.28 ± 2.44 vs. 1.40 ± 1.40; P = 0.002). Corneal total root mean square higher-order aberrations and corneal spherical aberrations increased postoperatively in both groups; however, the change was smaller in the CWFG group. Corneal coma showed a significant increase postoperatively only in the WFO group. CONCLUSIONS: WFO and CWFG trans-PRK are safe and effective for correcting moderate to high astigmatism. However, CWFG trans-PRK provides a more predictable astigmatism correction axis and fewer induced corneal aberrations.
Assuntos
Astigmatismo/cirurgia , Aberrações de Frente de Onda da Córnea/etiologia , Epitélio Corneano/cirurgia , Lasers de Excimer/uso terapêutico , Miopia/cirurgia , Ceratectomia Fotorrefrativa/métodos , Refração Ocular , Adolescente , Adulto , Astigmatismo/complicações , Astigmatismo/fisiopatologia , Topografia da Córnea , Aberrações de Frente de Onda da Córnea/diagnóstico , Aberrações de Frente de Onda da Córnea/cirurgia , Epitélio Corneano/patologia , Feminino , Seguimentos , Humanos , Masculino , Miopia/complicações , Miopia/fisiopatologia , Período Pós-Operatório , Estudos Retrospectivos , Resultado do Tratamento , Acuidade Visual , Adulto JovemRESUMO
BACKGROUND: Anoctamin (ANO)/transmembrane member 16 (TMEM16) proteins mediate diverse physiological and pathophysiological functions including cancer cell proliferation. The present study aimed to identify the role of ANOs in pancreatic cancer. METHODS: In an initial screen of ANOs, ANO9/TMEM16J was overexpressed in pancreatic cancer cells, and its role in the pathogenesis of pancreatic cancer was evaluated using an integrated in vitro and in vivo approach. To determine clinical relevance of the experimental findings, the prognostic value of ANO9 was evaluated in patients with pancreatic cancer. RESULTS: The ANO9 mRNA and protein levels were increased in pancreatic cancer-derived cells. Exogenous expression of ANO9 in PANC-1 cells significantly increased cell proliferation in cell cultures and in mice. In contrast, knockdown of ANO9 in AsPC-1, BxPC-3, and Capan-2 cells strongly inhibited cell proliferation. Mechanistic analysis suggested that physical association of ANO9 with epidermal growth factor receptor (EGFR) underlies ANO9-induced cell proliferation. Knockdown of ANO9 augmented the effects of the EGFR inhibitor and the cytotoxic agent on pancreatic cancer cell proliferation. In addition, high ANO9 expression is a poor prognostic factor in patients with pancreatic cancer. CONCLUSIONS: The ANO9/TMEM16J appears to be a clinically useful prognostic marker for pancreatic cancer and a potential therapeutic target.
Assuntos
Anoctaminas/genética , Anoctaminas/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Receptores ErbB/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas de Transferência de Fosfolipídeos/genética , Proteínas de Transferência de Fosfolipídeos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibacterianos/uso terapêutico , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese , Carcinoma Ductal Pancreático/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Intervalo Livre de Doença , Doxiciclina/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Prognóstico , RNA Mensageiro/metabolismo , Taxa de Sobrevida , Ensaio Tumoral de Célula-Tronco , GencitabinaRESUMO
KEY POINTS: Cellular stimuli can modulate the ion selectivity of some anion channels, such as CFTR, ANO1 and the glycine receptor (GlyR), by changing pore size. Ion selectivity of CFTR, ANO1 and GlyR is critically affected by the electric permittivity and diameter of the channel pore. Pore size change affects the energy barriers of ion dehydration as well as that of size-exclusion of anion permeation. Pore dilatation increases the bicarbonate permeability (P HC O3/ Cl ) of CFTR, ANO1 and GlyR. Dynamic change in P HC O3/ Cl may mediate many physiological and pathological processes. ABSTRACT: Chloride (Cl(-) ) and bicarbonate (HCO3 (-) ) are two major anions and their permeation through anion channels plays essential roles in our body. However, the mechanism of ion selection by the anion channels is largely unknown. Here, we provide evidence that pore dilatation increases the bicarbonate permeability (P HC O3/ Cl ) of anion channels by reducing energy barriers of size-exclusion and ion dehydration of HCO3 (-) permeation. Molecular, physiological and computational analyses of major anion channels, such as cystic fibrosis transmembrane conductance regulator (CFTR), anoctamin-1(ANO1/TMEM16A) and the glycine receptor (GlyR), revealed that the ion selectivity of anion channels is basically determined by the electric permittivity and diameter of the pore. Importantly, cellular stimuli dynamically modulate the anion selectivity of CFTR and ANO1 by changing the pore size. In addition, pore dilatation by a mutation in the pore-lining region alters the anion selectivity of GlyR. Changes in pore size affected not only the energy barriers of size exclusion but that of ion dehydration by altering the electric permittivity of water-filled cavity in the pore. The dynamic increase in P HC O3/ Cl by pore dilatation may have many physiological and pathophysiological implications ranging from epithelial HCO3 (-) secretion to neuronal excitation.
Assuntos
Bicarbonatos/metabolismo , Canais de Cloreto/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Proteínas de Neoplasias/metabolismo , Poro Nuclear/metabolismo , Receptores de Glicina/metabolismo , Anoctamina-1 , Canais de Cloreto/química , Regulador de Condutância Transmembrana em Fibrose Cística/química , Células HEK293 , Humanos , Proteínas de Neoplasias/química , Permeabilidade , Estrutura Terciária de Proteína , Receptores de Glicina/químicaRESUMO
Anoctamin 6 (ANO6) is a member of the recently identified TMEM16/anoctamin protein family comprising Ca(2+)-activated Cl(-) channels that generate outward-rectifying ionic currents in response to intracellular Ca(2+) increase. ANO6 is also essential for Ca(2+)-dependent phospholipid scrambling required for blood coagulation. Selective serotonin reuptake inhibitors (SSRIs)--fluoxetine, sertraline, and paroxetine-that are used for the treatment of major depressive disorders can increase the risk of upper gastrointestinal bleeding after chronic treatment. However, at the earlier stage of intake, which is 1-7 days after the treatment, the possibility of blood coagulation might also increase, but transiently. Therefore, in this study, we investigated whether therapeutic SSRI concentrations affected the Cl(-) current or phospholipid scrambling activity of ANO6 by assessing ANO6 currents (I ANO6), phosphatidylserine (PS) exposure, and platelet aggregation. In the whole-cell patch mode, SSRIs facilitated Ca(2+)-dependent activation of IANO6 in ANO6-transfected cells, as evidenced by a significant decrease in the delay of IANO6 generation. On the other hand, in the inside-out patch clamp configuration, SSRIs showed an inhibitory effect on ANO6 currents, suggesting that SSRIs activate ANO6 via an indirect mechanism in intact cells. SSRIs also facilitated Ca(2+)-dependent PS exposure and α-thrombin-induced platelet aggregation. These results indicate that SSRIs at clinically relevant concentrations promote Ca(2+)-dependent activation of ANO6, which may have potential clinical implications such as the underlying mechanism of SSRI-induced adverse drug reactions.
Assuntos
Fosfatidilserinas/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Anoctaminas , Coagulação Sanguínea/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Canais de Cloreto/metabolismo , Células HEK293 , Humanos , Técnicas de Patch-Clamp , Proteínas de Transferência de Fosfolipídeos/efeitos dos fármacos , Plasmídeos/genética , Agregação Plaquetária/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Trombina/farmacologia , TransfecçãoRESUMO
Background: To determine the differences in the effects of intense pulsed light (IPL) treatment when including the upper and lower lid or lateral canthus area in patients with meibomian gland dysfunction (MGD). Methods: Patients who underwent three IPL treatment sessions at 3-week intervals were divided into three groups according to the treatment sites: group A, lower lid; group B, upper and lower lids; and group C, lower lid and lateral canthal area. Before and after the IPL treatment sessions, we obtained the lid abnormality score (LAS), meibum expressibility (ME), meibum quality (MQ), lipid layer thickness (LLT), type I Schirmer test (ST), tear break-up time (TBUT) test, corneal fluorescein staining scores (CFSs), and Ocular Surface Disease Index (OSDI). Results: IPL treatment significantly improved LASs, ME, MQ, TBUT, CFS, and OSDI values in all groups. Differences in LAS values before and after IPL treatment were significantly greater in groups B and C than those in group A. Conclusions: IPL treatment encompassing the upper lid and lateral canthus together with the lower lid elicited additional improvement in patients with MGD. The additional effect on treating the lateral canthus was similar to the effect observed on the additional treatment of the upper lid.
RESUMO
PURPOSE: To investigate the impact of aqueous deficiency on lipid layer thickness (LLT) measurement in dry eye disease before and after treatment of aqueous-deficient dry eye (ADDE) using dynamic tear interferometry. METHODS: This prospective comparative study included 230 eyes from 230 patients with ADDE. The treatment group with punctal plug insertion was compared with the control group. The average LLT (LLTave) was measured with a LipiView II tear interferometer at baseline and after 1 month. Correlation analyses were performed with the indices of the dynamics of the tear film lipid layer (TFLL). RESULTS: Baseline LLTave values were 116.1 ± 26.7 and 112.3 ± 27.6 nm in the treatment group (n = 121) and the control group (n = 109), respectively. At 1 month, LLTave significantly decreased in the treatment group (difference -41.8 [95% confidence interval (CI) -47.2 to -36.3], P = 0.003). The values of tear meniscus height (TMH) at baseline and 1-month follow-up were negatively correlated with LLTave (both P < 0.001). Spreading time of TFLL to equilibrium and the deviation of TFLL were positively correlated with LLTave (all P < 0.001) and negatively correlated with TMH (P < 0.001 and 0.009). In multivariate analysis (adjusted R2 = 0.411, P < 0.001), LLTave was associated with TMH (B = -1.068; P < 0.001), adjusting for age, sex, and meibomian gland expressibility. CONCLUSIONS: In ADDE, the TFLL was measured to be thicker than the normal range of 60 to 99 nm and became thinner with treatment. LLT was affected by not only meibum secretion but also aqueous status due to changes in the dynamics of TFLL.
RESUMO
This prospective single-arm study aimed to evaluate the clinical efficacy and safety of a refractive multifocal contact lens for the correction of presbyopia in 22 patients. The participants underwent clinical examinations before and 1 week after wearing a refractive multifocal contact lens (OptaCon ZOOM). The primary endpoints were the corrected distance visual acuity (CDVA) and distance-corrected near visual acuity (DCNVA). Defocus curve, contrast sensitivity, and ocular surface disease index (OSDI) were analyzed. A slit-lamp examination was performed for safety analysis. Contact lens comfort and patient satisfaction were assessed using a questionnaire. No significant difference in CDVA was observed before and 1 week after refractive multifocal contact lens use (p = 0.127), whereas DCNVA was significantly improved after 1 week (p < 0.001). The contrast sensitivity was not significantly affected at any spatial frequency under mesopic or photopic conditions. OSDI was significantly increased (p = 0.023). The patient-reported satisfaction scores were 96.2, 91.9, and 85.0 out of 100 at far, intermediate, and near distances, respectively. No significant adverse events were observed. Refractive multifocal contact lenses improved near vision while maintaining distance vision in presbyopic patients, without compromising contrast sensitivity. The study results suggest that OptaCon ZOOM can be considered safe and effective for the correction of presbyopia.
Assuntos
Lentes de Contato , Presbiopia , Humanos , Estudos Prospectivos , Refração Ocular , Acuidade VisualRESUMO
Importance: Taking ω-3 supplements has been associated with a reduction in symptoms of dry eye disease (DED) associated with meibomian gland dysfunction (MGD). However, a recent relatively large clinical trial concluded that treating DED with ω-3 consumption was ineffective, potentially warranting additional investigations. Objectives: To investigate the effect of re-esterified triglyceride (rTG) ω-3 fatty acid supplementation on DED associated with MGD. Design, Setting, and Participants: This double-masked, parallel-group, randomized clinical trial was conducted at 7 institutions from September 2020 to January 2023. Patients with DED associated with MGD were included and randomly assigned to the ω-3 group (received 1680 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid), whereas those in the grape-seed group received 3000 mg of grape-seed oil daily. Interventions: rTG ω-3 Fatty acid supplementation vs grape-seed oil. Main Outcome Measures: The primary end point was the Ocular Surface Disease Index (OSDI) from baseline to 6 and 12 weeks. The safety parameters were visual acuity and intraocular pressure change. Results: A total of 132 patients (mean [SD] age, 50.6 [13.8] years; 103 female [78.0%]) were included in this study. The mean (SD) baseline OSDI scores of the ω-3 and grape-seed groups were 43.5 (16.5) and 44.1 (16.6), respectively. A total of 58 patients (87.9%) and 57 patients (86.4%) in the ω-3 and grape-seed groups, respectively, completed 12 weeks of follow-up. There were no differences in compliance with the dietary supplement intake between groups (ω-3, 95.8% and grape-seed, 95.4%). The OSDI (SD) change from baseline to 6 and 12 weeks was -20.5 (16.0) and -22.7 (15.7), respectively, in the ω-3 group and -15.1 (20.2) and -18.8 (21.7), respectively, in the grape-seed control group (difference at 6 weeks = -5.4; 95% CI, -12.15 to 1.33; P = .12 and at 12 weeks = -3.9; 95% CI, -10.90 to 3.13; P = .28). There were no changes in safety parameters or adverse events related to taking the dietary supplement in either group. Conclusions and Relevance: This randomized clinical trial did not show a benefit of the rTG form of ω-3 for ameliorating symptoms of DED associated with MGD, although fewer than 60 participants were evaluated in each group. Any secondary outcomes from this study should be considered for hypothesis generation of future evaluations of the effect of the rTG form of ω-3 on DED associated with MGD. Trial Registration: CRIS Identifier: KCT0004927.
Assuntos
Suplementos Nutricionais , Síndromes do Olho Seco , Ácidos Graxos Ômega-3 , Disfunção da Glândula Tarsal , Triglicerídeos , Humanos , Feminino , Masculino , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/fisiopatologia , Método Duplo-Cego , Pessoa de Meia-Idade , Disfunção da Glândula Tarsal/fisiopatologia , Disfunção da Glândula Tarsal/tratamento farmacológico , Ácidos Graxos Ômega-3/administração & dosagem , Triglicerídeos/sangue , Glândulas Tarsais/efeitos dos fármacos , Glândulas Tarsais/metabolismo , Adulto , Lágrimas/metabolismo , Idoso , Acuidade Visual/fisiologia , Resultado do Tratamento , SeguimentosRESUMO
Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant corneal stromal dystrophy that is caused by p.Arg124His mutation of transforming growth factor ß induced (TGFBI) gene. It is characterized by well demarcated granular shaped opacities in central anterior stroma and as the disease progresses, extrusion of the deposits results in ocular pain due to corneal epithelial erosion. Also, diffuse corneal haze which appears late, causes decrease in visual acuity. The prevalence of GCD2 is high in East Asia including Korea. Homozygous patients show a severe phenotype from an early age, and the heterozygote phenotype varies among patients, depending on several types of compound heterozygous TGFBI mutations. In the initial stage, conservative treatments such as artificial tears, antibiotic eye drops, and bandage contact lenses are used to treat corneal erosion. Different surgical methods are used depending on the depth and extent of the stromal deposits. Phototherapeutic keratectomy removes anterior opacities and is advantageous in terms of its applicability and repeatability. For deeper lesions, deep anterior lamellar keratoplasty can be used as the endothelial layer is not always affected. Recurrence following these treatments are reported within a wide range of rates in different studies due to varying definition of recurrence and follow-up period. In patients who have undergone corneal laser vision-correction surgeries such as photorefractive keratectomy, LASEK, or LASIK including SMILE surgery, corneal opacity exacerbates rapidly with severe deterioration of visual acuity. Further investigations on new treatments of GCD2 are necessary.