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1.
Bioengineered ; 12(2): 10187-10198, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34860641

RESUMO

Glaucoma, characterized with progressive degeneration of retinal ganglion cells (RGCs), is the second frequently leading cause of sight loss in the word after cataract. Baicalin plays a protective role in age-related macular degeneration, retinopathy of prematurity, branch retinal vein occlusion, and ischemia-induced neurodegeneration in the retina. The present study aimed to investigate the role of baicalin in glaucoma. RGCs were stimulated with N-methyl-D-aspartate (NMDA) to mimic the in vitro model of glaucoma. A mouse model of glaucoma induced by chronic elevated intraocular pressure was also established. The apoptosis, oxidative stress, and autophagy of RGCs were detected by flow cytometry analysis, 2,7-dichlorodihydrofluorescein diacetate staining, and Western blotting, respectively. Retinal pathological changes were exhibited by hemotoxylin and eosin staining. Baicalin restrained the NMDA-induced cell apoptosis, autophagy, and oxidative stress of RGCs by activating the PI3K/AKT signaling in vitro. The elevated intraocular pressure-induced pathological changes in retinas of glaucoma mice were attenuated by baicalin. Moreover, the number of RGCs was significantly decreased in glaucoma mice, and then increased by baicalin treatment. Baicalin also inhibited autophagy and activated PI3K/AKT signaling in vivo. In conclusion, baicalin suppresses glaucoma pathogenesis by regulating the PI3K/AKT signaling in vitro and in vivo.


Assuntos
Flavonoides/uso terapêutico , Glaucoma/tratamento farmacológico , Glaucoma/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Autofagia/efeitos dos fármacos , Contagem de Células , Linhagem Celular , Modelos Animais de Doenças , Flavonoides/química , Flavonoides/farmacologia , Glaucoma/patologia , Masculino , Camundongos Endogâmicos C57BL , N-Metilaspartato , Estresse Oxidativo/efeitos dos fármacos , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia
3.
Invest Ophthalmol Vis Sci ; 61(14): 4, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33263714

RESUMO

Purpose: This study determines if δ-opioid receptor agonist (i.e. SNC-121)-induced epigenetic changes via regulation of histone deacetylases (HDACs) for retinal ganglion cell (RGC) neuroprotection in glaucoma model. Methods: Intraocular pressure was raised in rat eyes by injecting 2M hypertonic saline into the limbal veins. SNC-121 (1 mg/kg; i.p.) was administered to the animals for 7 days. Retinas were collected at days 7 and 42, post-injury followed by measurement of HDAC activities, mRNA, and protein expression by enzyme assay, quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry. Results: The visual acuity, contrast sensitivity, and pattern electroretinograms (ERGs) were declined in ocular hypertensive animals, which were significantly improved by SNC-121 treatment. Class I and IIb HDACs activities were significantly increased at days 7 and 42 in ocular hypertensive animals. The mRNA and protein expression of HDAC 1 was increased by 1.33 ± 0.07-fold and 20.2 ± 2.7%, HDAC 2 by 1.4 ± 0.05-fold and 17.0 ± 2.4%, HDAC 3 by 1.4 ± 0.06-fold and 17.4 ± 3.4%, and HDAC 6 by 1.5 ± 0.09-fold and 15.1 ± 3.3% at day 7, post-injury. Both the mRNA and protein expression of HDACs were potentiated further at day 42 in ocular hypertensive animals. HDAC activities, mRNA, and protein expression were blocked by SNC-121 treatment at days 7 and 42 in ocular hypertensive animals. Conclusions: Data suggests that class I and IIb HDACs are activated and upregulated during early stages of glaucoma. Early intervention with δ-opioid receptor activation resulted in the prolonged suppression of class I and IIb HDACs activities and expression, which may, in part, play a crucial role in RGC neuroprotection.


Assuntos
Epigênese Genética/efeitos dos fármacos , Glaucoma/metabolismo , Histona Desacetilases/metabolismo , Receptores Opioides delta/agonistas , Animais , Western Blotting , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Glaucoma/enzimologia , Histona Desacetilases/efeitos dos fármacos , Pressão Intraocular , Masculino , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo
4.
J Clin Lab Anal ; 34(3): e23105, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31713905

RESUMO

BACKGROUND: Glaucoma is the irreversible vision loss and contributes second leading cause of blindness worldwide. Matrix metalloproteinase-9 (MMP-9) is involved with remodeling and destruction of extracellular matrix. Elevated MMP-9 levels and various functional variants of MMP-9 have been associated with glaucoma in different population. In the current investigation, we tested association of MMP-9 common variants with different clinical categories of glaucoma in Chinese population. MATERIALS AND METHODS: We enrolled total of 396 glaucoma patients those reported to hospital comprising of 212 primary angle closure glaucoma (PACG) cases and 184 primary open-angle glaucoma POAG patients. In addition, 329 normal individuals from similar geographical areas were enrolled as healthy controls. Five common single nucleotide polymorphisms (rs3918242, rs3918254, rs2250889, rs3918249, and rs17576) were genotyped by PCR-RFLP. Plasma levels of MMP-9 were quantified by ELISA. RESULTS: Heterozygotes (GC) and allele "G" for rs2250889 polymorphism were more frequent in PACG cases compared with healthy controls (GC: P < .0001, OR = 2.26; G: P < .0001, OR = 1.19). Similarly, heterozygous mutant and minor allele for rs3918242 polymorphism were more prevalent in POAG in comparison with healthy controls. Interestingly, distribution of rs17576 variant was statistically higher in both PACG and POAG cases than healthy controls. Furthermore, analysis of plasma MMP-9 with MMP-9 polymorphisms revealed significant association of rs2250889, rs3918242, and rs17576 with plasma levels of the protein. CONCLUSIONS: MMP-9 mutants are associated with elevated plasma MMP-9 and predisposed to development of glaucoma.


Assuntos
Povo Asiático/genética , Predisposição Genética para Doença , Glaucoma/enzimologia , Glaucoma/genética , Hospitais , Metaloproteinase 9 da Matriz/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Feminino , Glaucoma/sangue , Glaucoma de Ângulo Fechado/sangue , Glaucoma de Ângulo Fechado/enzimologia , Glaucoma de Ângulo Fechado/genética , Glaucoma de Ângulo Aberto/sangue , Glaucoma de Ângulo Aberto/enzimologia , Glaucoma de Ângulo Aberto/genética , Humanos , Masculino , Metaloproteinase 9 da Matriz/sangue , Polimorfismo de Fragmento de Restrição
5.
Exp Eye Res ; 190: 107892, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31811822

RESUMO

Neuronal excitotoxicity caused by over activation of N -Methyl-D-Aspartate (NMDA) receptors is an important risk factor for the retinal ganglion cells (RGCs) death in glaucoma. D-serine played a role as a key co-agonist for NMDA receptor activity and neurotoxicity. Our previous studies have demonstrated that increased D-serine and serine racemase (SR) expression in the retina of the chronic intraocular hypertension (COH) model were detected. D-amino acid oxidase (DAAO) treatment significantly increased RGCs survival in the glaucomatous eyes. However, the molecular mechanism remains unclear. In the present study, we investigated the extracellular signal-regulated protein kinase1/2 (ERK1/2) signaling pathway involved in DAAO neuroprotective effects on RGC survival and explore the effect of inhibited ERK1/2 phosphorylation on RGC survival and Müller cell activation in a COH rat model. We found that ERK1/2 phosphorylation and p38 kinase (p38) phosphorylation increased in the COH model, while c-Jun N-terminal kinase (JNK) phosphorylation didn't change. DAAO treatment induced ERK-1/2 MAP kinase phosphorylation and its upstream regulator, p-MEK increased in the COH model. The increased p-ERK was mainly located in retinal Müller cells. In contrast, p-JNK and p-p38 protein expression was not significantly different under these conditions. Quantitative analysis of RGC survival by fluorescent labeling and TdT-mediated dUTP nick-end labeling (TUNEL) assays confirmed that p-ERK1/2 inhibition by PD98059 attenuates DAAO-mediated reductions in RGC apoptosis. Additionally, p-ERK1/2 inhibition induced elevated glial fibrillary acidic protein (GFAP) expression in Müller cells in the COH model. Together, these results suggest that the ERK1/2 signaling pathway is involved in DAAO's neuroprotective effects on RGC survival.


Assuntos
D-Aminoácido Oxidase/farmacologia , Modelos Animais de Doenças , Glaucoma/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Western Blotting , Células Ependimogliais/metabolismo , Flavonoides/farmacologia , Técnica Indireta de Fluorescência para Anticorpo , Glaucoma/enzimologia , Proteína Glial Fibrilar Ácida/metabolismo , Marcação In Situ das Extremidades Cortadas , Masculino , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/enzimologia
6.
Expert Opin Ther Pat ; 29(10): 781-792, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31596641

RESUMO

Introduction: Glaucoma affects more than 70 million people worldwide. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1). CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. Areas covered: This review is intended to cover the major contributions in terms of patent literature reports for the treatment of ophthalmic diseases by means of CAIs in a time frame spanning from 2013 to date. Expert opinion: The patent literature is dominated by innovative pharmaceutical formulations including a CAI alone or in combination with other therapeutic agents. Very few novelties within drug discovery are currently present and they mainly account for new CAI moieties and classical CAIs merged into scaffolds bearing additional chemical functionalities beneficial for the pharmacological treatment of the disease. It is reasonable to expect that in the near future the so-called 'old drugs' will achieve pharmacological performances in the management of ocular hypertension beyond any expectations and thus open a new era of drug repurposing merely based on material science advancements.


Assuntos
Inibidores da Anidrase Carbônica/administração & dosagem , Glaucoma/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Animais , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Desenho de Fármacos , Reposicionamento de Medicamentos , Glaucoma/enzimologia , Humanos , Hipertensão Ocular/enzimologia , Patentes como Assunto
7.
Expert Opin Ther Pat ; 29(10): 817-827, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31573364

RESUMO

Introduction: Glaucoma is a group of progressive optic neuropathies in which elevated intraocular pressure (IOP) as a consequence of an increased aqueous humor (AH) outflow resistance, is the main and only clinically modifiable risk factor for its development and progression. Relaxing Trabecular meshwork (TM) tissue, Rho-Kinase (ROCK) inhibitors directly decrease resistance in the conventional AH outflow, thus resulting in a significant IOP-lowering effect. Areas covered: The progress made in the field of ROCK inhibitors for glaucoma treatment will be discussed, referring to the recent patent literature published mainly in the last 3 years. Development and last studies conducted on the recently approved ripasudil and netarsudil will be described, along with newly reported combinations with other antiglaucoma agents. New molecular entities as ROCK inhibitors will be reported as well as new biological approaches to affect the Rho/ROCK pathway. Expert opinion: With three drugs currently available on the market belonging to this class, ROCK inhibitors have been definitely validated as therapeutic agents for glaucoma treatment. The literature of the last 3 years confirmed the success of the soft-drug and bis-functional approaches in the design of ROCK inhibitors. However, few completely new molecular scaffolds have been reported.


Assuntos
Glaucoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Progressão da Doença , Desenvolvimento de Medicamentos , Glaucoma/enzimologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Patentes como Assunto , Inibidores de Proteínas Quinases/administração & dosagem , Quinases Associadas a rho/metabolismo
8.
Elife ; 82019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621585

RESUMO

Elevated intraocular pressure (IOP) due to insufficient aqueous humor outflow through the trabecular meshwork and Schlemm's canal (SC) is the most important risk factor for glaucoma, a leading cause of blindness worldwide. We previously reported loss of function mutations in the receptor tyrosine kinase TEK or its ligand ANGPT1 cause primary congenital glaucoma in humans and mice due to failure of SC development. Here, we describe a novel approach to enhance canal formation in these animals by deleting a single allele of the gene encoding the phosphatase PTPRB during development. Compared to Tek haploinsufficient mice, which exhibit elevated IOP and loss of retinal ganglion cells, Tek+/-;Ptprb+/- mice have elevated TEK phosphorylation, which allows normal SC development and prevents ocular hypertension and RGC loss. These studies provide evidence that PTPRB is an important regulator of TEK signaling in the aqueous humor outflow pathway and identify a new therapeutic target for treatment of glaucoma.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Glaucoma/genética , Receptor TIE-2/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Células Ganglionares da Retina/enzimologia , Alelos , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Animais , Humor Aquoso/enzimologia , Contagem de Células , Modelos Animais de Doenças , Deleção de Genes , Glaucoma/enzimologia , Glaucoma/patologia , Heterozigoto , Humanos , Pressão Intraocular/fisiologia , Camundongos , Camundongos Knockout , Fosforilação , Receptor TIE-2/deficiência , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/deficiência , Células Ganglionares da Retina/patologia , Fatores de Risco , Transdução de Sinais , Malha Trabecular/enzimologia , Malha Trabecular/patologia
9.
Cell Death Dis ; 10(4): 293, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926772

RESUMO

Hydrogen sulfide (H2S) serves as a gasotransmitter in the regulation of organ development and maintenance of homeostasis in tissues. Its abnormal levels are associated with multiple human diseases, such as neurodegenerative disease, myocardial injury, and ophthalmic diseases. Excessive exposure to H2S could lead to cellular toxicity, orchestrate pathological process, and increase the risk of various diseases. Interestingly, under physiological status, H2S plays a critical role in maintaining cellular physiology and limiting damages to tissues. In mammalian species, the generation of H2S is catalyzed by cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), 3-mercapto-methylthio pyruvate aminotransferase (3MST) and cysteine aminotransferase (CAT). These enzymes are found inside the mammalian eyeballs at different locations. Their aberrant expression and the accumulation of substrates and intermediates can change the level of H2S by orders of magnitude, causing abnormal structures or functions in the eyes. Detailed investigations have demonstrated that H2S donors' administration could regulate intraocular pressure, protect retinal cells, inhibit oxidative stress and alleviate inflammation by modulating the function of intra or extracellular proteins in ocular tissues. Thus, several slow-releasing H2S donors have been shown to be promising drugs for treating multiple diseases. In this review, we discuss the biological function of H2S metabolism and its application in ophthalmic diseases.


Assuntos
Retinopatia Diabética/metabolismo , Glaucoma/metabolismo , Sulfeto de Hidrogênio/farmacologia , Pressão Intraocular/efeitos dos fármacos , Degeneração Retiniana/metabolismo , Neurônios Retinianos/efeitos dos fármacos , Epitélio Pigmentado da Retina/enzimologia , Animais , Barreira Hematorretiniana/efeitos dos fármacos , Barreira Hematorretiniana/metabolismo , AMP Cíclico/metabolismo , Retinopatia Diabética/enzimologia , Glaucoma/enzimologia , Produtos Finais de Glicação Avançada/química , Produtos Finais de Glicação Avançada/genética , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , Pressão Intraocular/genética , Estresse Oxidativo/efeitos dos fármacos , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/genética , Neurônios Retinianos/química , Neurônios Retinianos/enzimologia , Epitélio Pigmentado da Retina/irrigação sanguínea , Transplante de Células-Tronco
10.
J Cell Physiol ; 234(2): 1730-1744, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30144071

RESUMO

Glaucoma, a progressive and irreversible optic neuropathy, is one of the leading causes of vision impairment worldwide. Elevation of intraocular pressure (IOP) due to transforming growth factor-ß (TGF-ß)-induced dysfunction of the trabecular meshwork is a risk factor for glaucoma, but the underlying molecular mechanisms remain elusive. Here, we show that Src kinase is involved in TGF-ß-induced IOP elevation. We observed that dasatinib, a potent Src inhibitor, suppressed TGF-ß2-induced IOP in rat eyes. Mechanistic analyses in human trabecular meshwork cells showed that TGF-ß2 activated Src signaling and concomitantly increased cytoskeletal remodeling, cell adhesion, and extracellular matrix (ECM) accumulation. Src was activated via TGF-ß2-induced upregulation of the Src scaffolding protein CasL, which mediates the assembly of focal adhesions, cytoskeletal remodeling, and ECM deposition. Activation of Src suppressed the expression of tissue plasminogen activator, thereby attenuating ECM degradation. Furthermore, the Src inhibitor ameliorated TGF-ß2-induced changes in the contractile and adhesive characteristics of trabecular meshwork cells, and ECM deposition. These findings underscore the crucial role of Src activity in TGF-ß-induced IOP elevation and identify Src signaling as a potential therapeutic target in glaucoma.


Assuntos
Glaucoma/enzimologia , Pressão Intraocular , Malha Trabecular/enzimologia , Fator de Crescimento Transformador beta2 , Quinases da Família src/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células Cultivadas , Dasatinibe/farmacologia , Modelos Animais de Doenças , Ativação Enzimática , Glaucoma/induzido quimicamente , Glaucoma/patologia , Glaucoma/fisiopatologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Inibidores de Proteínas Quinases/farmacologia , Ratos Endogâmicos BN , Transdução de Sinais , Ativador de Plasminogênio Tecidual/genética , Ativador de Plasminogênio Tecidual/metabolismo , Malha Trabecular/efeitos dos fármacos , Malha Trabecular/patologia , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/genética
11.
Cell Death Dis ; 9(6): 705, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899326

RESUMO

The cJun N-terminal kinases (JNKs; JNK1, JNK2, and JNK3) promote degenerative processes after neuronal injury and in disease. JNK2 and JNK3 have been shown to promote retinal ganglion cell (RGC) death after optic nerve injury. In their absence, long-term survival of RGC somas is significantly increased after mechanical optic nerve injury. In glaucoma, because optic nerve damage is thought to be a major cause of RGC death, JNKs are an important potential target for therapeutic intervention. To assess the role of JNK2 and JNK3 in an ocular hypertensive model of glaucoma, null alleles of Jnk2 and Jnk3 were backcrossed into the DBA/2J (D2) mouse. JNK activation occurred in RGCs following increased intraocular pressure in D2 mice. However, deficiency of both Jnk2 and Jnk3 together did not lessen optic nerve damage or RGC death. These results differentiate the molecular pathways controlling cell death in ocular hypertensive glaucoma compared with mechanical optic nerve injury. It is further shown that JUN, a pro-death component of the JNK pathway in RGCs, can be activated in glaucoma in the absence of JNK2 and JNK3. This implicates JNK1 in glaucomatous RGC death. Unexpectedly, at younger ages, Jnk2-deficient mice were more likely to develop features of glaucomatous neurodegeneration than D2 mice expressing Jnk2. This appears to be due to a neuroprotective effect of JNK2 and not due to a change in intraocular pressure. The Jnk2-deficient context also unmasked a lesser role for Jnk3 in glaucoma. Jnk2 and Jnk3 double knockout mice had a modestly increased risk of neurodegeneration compared with mice only deficient in Jnk2. Overall, these findings are consistent with pleiotropic effects of JNK isoforms in glaucoma and suggest caution is warranted when using JNK inhibitors to treat chronic neurodegenerative conditions.


Assuntos
Glaucoma/enzimologia , Glaucoma/patologia , Proteína Quinase 9 Ativada por Mitógeno/deficiência , Degeneração Neural/enzimologia , Degeneração Neural/patologia , Hipertensão Ocular/enzimologia , Hipertensão Ocular/patologia , Animais , Axônios/metabolismo , Morte Celular , Ativação Enzimática , Regulação da Expressão Gênica , Glaucoma/fisiopatologia , Pressão Intraocular , Camundongos Endogâmicos DBA , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Degeneração Neural/fisiopatologia , Hipertensão Ocular/fisiopatologia , Nervo Óptico/enzimologia , Nervo Óptico/patologia , Nervo Óptico/fisiopatologia , Retina/enzimologia , Retina/patologia , Retina/fisiopatologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia
12.
Adv Exp Med Biol ; 1074: 351-357, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29721963

RESUMO

c-Jun N-terminal kinase (JNK), a member of stress-induced mitogen-activated protein (MAP) kinase family, has been shown to modulate a variety of biological processes associated with neurodegenerative pathology of the retina. In particular, various retinal cell culture and animal models related to glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa indicate that JNK signaling may contribute to disease pathogenesis. This mini-review discusses the impact of JNK signaling in retinal disease, with a focus on retinal ganglion cells (RGCs), photoreceptor cells, retinal pigment epithelial (RPE) cells, and animal studies, with particular attention to modulation of JNK signaling as a potential therapeutic target for the treatment of retinal disease.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Sistema de Sinalização das MAP Quinases , Degeneração Retiniana/enzimologia , Transtornos da Visão/enzimologia , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Glaucoma/enzimologia , Glaucoma/genética , Glaucoma/fisiopatologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/deficiência , Degeneração Macular/enzimologia , Degeneração Macular/genética , Degeneração Macular/fisiopatologia , Camundongos , Terapia de Alvo Molecular , Células Fotorreceptoras de Vertebrados/enzimologia , Células Fotorreceptoras de Vertebrados/fisiologia , Degeneração Retiniana/genética , Degeneração Retiniana/terapia , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/fisiologia , Transtornos da Visão/genética , Transtornos da Visão/terapia
13.
Nitric Oxide ; 77: 75-87, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29723581

RESUMO

Glaucoma is a prevalent optic neuropathy characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs) and their optic nerve axons, which leads to irreversible visual field loss. Multiple risk factors for the disease have been identified, but elevated intraocular pressure (IOP) remains the primary risk factor amenable to treatment. Reducing IOP however does not always prevent glaucomatous neurodegeneration, and many patients progress with the disease despite having IOP in the normal range. There is increasing evidence that nitric oxide (NO) is a direct regulator of IOP and that dysfunction of the NO-Guanylate Cyclase (GC) pathway is associated with glaucoma incidence. NO has shown promise as a novel therapeutic with targeted effects that: 1) lower IOP; 2) increase ocular blood flow; and 3) confer neuroprotection. The various effects of NO in the eye appear to be mediated through the activation of the GC- guanosine 3:5'-cyclic monophosphate (cGMP) pathway and its effect on downstream targets, such as protein kinases and Ca2+ channels. Although NO-donor compounds are promising as therapeutics for IOP regulation, they may not be ideal to harness the neuroprotective potential of NO signaling. Here we review evidence that supports direct targeting of GC as a novel pleiotrophic treatment for the disease, without the need for direct NO application. The identification and targeting of other factors that contribute to glaucoma would be beneficial to patients, particularly those that do not respond well to IOP-dependent interventions.


Assuntos
Glaucoma/enzimologia , Glaucoma/metabolismo , Guanilato Ciclase/metabolismo , Óxido Nítrico/metabolismo , Animais , Humanos , Transdução de Sinais
14.
Jpn J Ophthalmol ; 62(2): 109-126, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29445943

RESUMO

Rho-associated protein kinase (ROCK), a ubiquitously expressed signaling messenger and downstream effector of Rho, is activated by several bioactive factors in the aqueous humor (AH). Rho-ROCK signaling regulates a wide spectrum of fundamental cellular events, including cell adhesion, motility, proliferation, differentiation, and apoptosis. Previous studies, including our own, found that ROCK inhibitor lowers intraocular pressure (IOP) via a direct effect on the conventional AH outflow pathway, by regulation of contractile properties, fibrotic activity, and permeability of the trabecular meshwork (TM) and Schlemm's canal (SC) tissues, influencing extracellular matrix (ECM) production. Recently, a novel ROCK inhibitor, ripasudil, has been introduced in Japan. Other ROCK inhibitors are now in clinical trials as new IOP-lowering drugs for glaucoma patients. To date, ripasudil, administered together with other glaucoma medications, has proved safe and efficient in lowering IOP as well as additional effects such as prostaglandin analogs, beta-blockers, and carbonic anhydrase inhibitors, all of which help lower IOP by different mechanisms. In addition, we found that long-term treatment with ripasudil exerted an additional IOP-lowering effect, especially in eyes with high IOP, suggesting that late-onset remodeling of the ECM in glaucomatous eyes may elicit mild and delayed changes in IOP levels. ROCK inhibitors have also shown several additional effects, including increased retinal blood flow, direct protection of neurons against various types of stress, and regulation of wound healing; these benefits may potentially be useful in glaucoma treatment.


Assuntos
Humor Aquoso/enzimologia , Glaucoma , Pressão Intraocular/efeitos dos fármacos , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Glaucoma/tratamento farmacológico , Glaucoma/enzimologia , Glaucoma/fisiopatologia , Humanos , Quinases Associadas a rho/biossíntese
15.
Expert Opin Pharmacother ; 18(15): 1669-1673, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28893104

RESUMO

INTRODUCTION: Among the intraocular pressure (IOP)-lowering drugs used in a clinical setting, Rho kinase (ROCK) inhibitors lower IOP by a unique mechanism, namely the depolymerization of intracellular actin in the conventional outflow tissues: the trabecular meshwork (TM) and Schlemm's canal (SC). Furthermore, ROCK inhibitors suppress the production of extracellular matrix by TM cells, which represents a potential alternative method of lowering IOP. Considering that conventional outflow is a dominant pathway in humans, IOP-lowering ROCK inhibitors, delivered in conjunction with other drugs, may be able to treat the glaucomatous eye. Areas covered: Ripasudil hydrochloride hydrate is the first ROCK inhibitor approved for clinical use in Japan (and worldwide) against glaucoma and ocular hypertension. The efficacy of ripasudil, as monotherapy and as an adjunctive medication to prostaglandin analogs and/or adrenergic ß-receptor antagonists, has been confirmed in clinical trials. Expert opinion: Considering the unique ROCK-inhibiting mechanism by which ripasudil lowers IOP via its actions on TM and SC endothelial cells, it may be an ideal adjunctive medication for treating glaucoma in the clinic.


Assuntos
Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/uso terapêutico , Quimioterapia Combinada , Glaucoma/enzimologia , Humanos , Isoquinolinas/administração & dosagem , Japão , Soluções Oftálmicas , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/administração & dosagem , Malha Trabecular/efeitos dos fármacos
16.
Molecules ; 22(9)2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28885588

RESUMO

The biochemical properties of erythrocyte or human red blood cell (RBC) membrane acetylcholinesterase (AChE) and its applications on laboratory class and on research are reviewed. Evidence of the biochemical and the pathophysiological properties like the association between the RBC AChE enzyme activity and the clinical and biophysical parameters implicated in several diseases are overviewed, and the achievement of RBC AChE as a biomarker and as a prognostic factor are presented. Beyond its function as an enzyme, a special focus is highlighted in this review for a new function of the RBC AChE, namely a component of the signal transduction pathway of nitric oxide.


Assuntos
Acetilcolinesterase/metabolismo , Esclerose Lateral Amiotrófica/diagnóstico , Hipertensão Essencial/diagnóstico , Glaucoma/diagnóstico , Hemoglobinúria Paroxística/diagnóstico , Doença de Hirschsprung/diagnóstico , Acetilcolina/metabolismo , Esclerose Lateral Amiotrófica/enzimologia , Biomarcadores/metabolismo , Membrana Eritrocítica/enzimologia , Hipertensão Essencial/enzimologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Glaucoma/enzimologia , Hemoglobinúria Paroxística/enzimologia , Doença de Hirschsprung/enzimologia , Humanos , Cinética , Masculino , Óxido Nítrico/metabolismo , Fatores Sexuais , Transdução de Sinais
17.
Invest Ophthalmol Vis Sci ; 58(6): BIO106-BIO113, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28586796

RESUMO

Purpose: To evaluate the differential expression of tear matrix metalloproteinases (MMP) 2 and 9 in of patients with various forms of glaucoma. Methods: Tear samples were collected with a Schirmer's strip from 148 eyes of 113 patients (medically naïve patients with primary open-angle [POAG] or angle closure glaucoma [PACG] and those with pseudoexfoliation syndrome [PXF] or glaucoma [PXG]). These were compared to patients undergoing cataract surgery (controls) for this cross-sectional study. Functional activities of tear MMP-9 and MMP-2 were analyzed by gelatin zymography. Tenon's capsules (n = 15) were harvested from the inferior quadrant in those undergoing cataract surgery and protein expression of MMP-9 was analyzed by immunohistochemistry (IHC). Hydrogen peroxide (H2O2) stress-induced effects on in vitro activities of MMP-9 in human trabecular meshwork (HTM) cells were analyzed. Results: The MMP-9 activity in tears was increased significantly in POAG, (n = 27), PACG (n = 24), and PXF (n = 40) eyes compared to controls (n = 35), and was increased significantly in eyes with glaucoma compared to moderate/severe glaucoma (P < 0.001). The MMP-9 expression was significantly lower in PXG (n = 22) eyes. Immunohistochemistry of Tenon's capsule revealed increased expression of MMP-9 in primary glaucoma eyes. Increased MMP-9 activity was seen in in vitro by gelatin zymography and was confirmed by Western and immunofluorescent assay on HTM upon 800 and 1000 µM H2O2-induced stress for 2 to 3 hours with approximately 80% cell death. Conclusions: Increased tear MMP-9 activity in early glaucoma and pseudoexfoliation syndrome suggesting activation of extracellular matrix (ECM) degradation can be used as a tear-based predictive biomarker. Decreased expression in advanced stages suggests exhaustion of the degradation response.


Assuntos
Glaucoma/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Lágrimas/enzimologia , Idoso , Análise de Variância , Western Blotting , Estudos de Casos e Controles , Estudos Transversais , Síndrome de Exfoliação/enzimologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Cápsula de Tenon/enzimologia , Malha Trabecular/enzimologia
18.
BMC Ophthalmol ; 17(1): 48, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28431514

RESUMO

BACKGROUND: Matrix metalloproteinases (MMPs) polymorphisms have been implicated in the pathogenesis of glaucoma risk. However, the results were controversial. We performed a meta-analysis to evaluate the precise associations between MMPs polymorphisms and glaucoma risk. METHODS: Related studies were reviewed by searching electronic databases within four databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association between the most common polymorphisms of MMPs and glaucoma risk. Heterogeneity, publication bias and sensitivity analysis were conducted to guarantee the statistical power. RESULTS: Overall, 11 selected articles involving 2,388 cases and 2,319 controls were included in this meta-analysis. Significant associations were only found between MMP-9 rs17576 G > A polymorphism (GA vs. GG: OR = 0.80, 95%CI = 0.67-0.97, P = 0.02, I2 = 0%), MMP-9 rs3918249 C > T polymorphism (TT vs. CC + CT: OR = 0.71, 95%CI = 0.51-0.98, P = 0.04, I2 = 0%) and glaucoma risk in the general population. Subgroup analysis also suggested that MMP-9 rs17576 G > A was related to glaucoma in the Caucasian population (GA vs. GG: OR = 0.67, 95%CI = 0.45-1.00, P = 0.05; GA + AA vs. GG: OR = 0.66, 95%CI = 0.45-0.97, P = 0.03, I2 = 0%). CONCLUSIONS: Our meta-analysis demonstrates that MMP-9 rs17576 G > A polymorphism might be a protective factor against the development of glaucoma in Caucasian population.


Assuntos
Predisposição Genética para Doença , Glaucoma/genética , Metaloproteinases da Matriz/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Glaucoma/enzimologia , Humanos , Fatores de Risco
19.
PLoS One ; 12(4): e0176386, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28448622

RESUMO

Mutations in the CYP1B1 gene are currently the main known genetic cause of primary congenital glaucoma (PCG), a leading cause of blindness in children. Here, we analyze for the first time the CYP1B1 genotype activity and the microscopic and clinical phenotypes in human PCG. Surgical pieces from trabeculectomy from patients with PCG (n = 5) and sclerocorneal rims (n = 3) from cadaver donors were processed for transmission electron microscopy. Patients were classified into three groups depending on goniodysgenesis severity, which was influenced by CYP1B1 enzymatic activity. The main histological changes observed in the outflow pathway of patients with PCG and mutations in CYP1B1 were: i) underdeveloped collector channels and the Schlemm's canal; ii) abnormal insertion of the ciliary muscle; iii) death of the trabecular endothelial cells. Our findings could be useful in improving treatment strategy of PCG associated with CYP1B1 mutations.


Assuntos
Citocromo P-450 CYP1B1/genética , Genótipo , Glaucoma/congênito , Glaucoma/genética , Adolescente , Criança , Feminino , Glaucoma/complicações , Glaucoma/enzimologia , Humanos , Masculino , Mutação , Linhagem , Fenótipo
20.
J Cell Physiol ; 232(9): 2447-2460, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27591737

RESUMO

Glaucoma, a leading cause of irreversible blindness, is commonly associated with elevated intraocular pressure (IOP) due to impaired aqueous humor (AH) drainage through the trabecular meshwork (TM). Although dysregulated production and organization of extracellular matrix (ECM) is presumed to increase resistance to AH outflow and elevate IOP by altering TM cell contractile and adhesive properties, it is not known whether regulation of ECM protein phosphorylation via the secretory vertebrate lonesome kinase (VLK) influences TM cellular characteristics. Here, we tested this possibility. Experiments carried out in this study reveal that the 32 kDa protein is a prominent VLK isoform detectable in lysates and conditioned media (CM) of human TM cells. Increased levels of VLK were observed in CM of TM cells subjected to cyclic mechanical stretch, or treated with dexamethasone, TGF-ß2, and TM cells expressing constitutively active RhoA GTPase. Downregulation of VLK expression in TM cells using siRNA decreased tyrosine phosphorylation (TyrP) of ECM proteins and focal adhesions, and induced changes in cell shape in association with reduced levels of actin stress fibers and phospho-paxillin. VLK was also demonstrated to regulate TGF-ß2-induced TyrP of ECM proteins. Taken together, these results suggest that VLK secretion can be regulated by external cues, intracellular signal proteins, and mechanical stretch, and VLK can in turn regulate TyrP of ECM proteins secreted by TM cells and control cell shape, actin stress fibers, and focal adhesions. These observations indicate a potential role for VLK in homeostasis of AH outflow and IOP, and in the pathobiology of glaucoma. J. Cell. Physiol. 232: 2447-2460, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Adesão Celular , Forma Celular , Proteínas da Matriz Extracelular/metabolismo , Proteínas Tirosina Quinases/metabolismo , Malha Trabecular/enzimologia , Adulto , Idoso , Humor Aquoso/metabolismo , Adesão Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Dexametasona/farmacologia , Adesões Focais/enzimologia , Glaucoma/enzimologia , Glaucoma/patologia , Glaucoma/fisiopatologia , Humanos , Pressão Intraocular , Mecanotransdução Celular , Pessoa de Meia-Idade , Mutação , Paxilina/metabolismo , Fosforilação , Proteínas Tirosina Quinases/genética , Interferência de RNA , Fibras de Estresse/enzimologia , Fatores de Tempo , Malha Trabecular/efeitos dos fármacos , Transfecção , Fator de Crescimento Transformador beta2/farmacologia , Tirosina , Adulto Jovem , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
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