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1.
Gene ; 760: 144992, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32721474

RESUMO

BACKGROUND AND AIM: Diabetic retinopathy is a severe diabetic complication and a major cause of blindness. In this study, we explored the role of circ_0001879 in retinal vascular dysfunction under diabetic conditions. METHODS: Human retinal microvascular endothelial cells (HRMECs) were divided into normal glucose group (NG, 5.5 mmol/L d-glucose), high glucose group (HG, 25 mmol/L d-glucose), and osmotic control group (5.5 mmol/L d-glucose + 19.5 mmol/L mannitol). The expression of circ_0001879 and miR-30-3p was assessed via qRT-PCR. The circ_0001879/miR-30-3p roles in retinal vascular dysfunction were investigated through Cell Counting Kit-8 and Transwell assay. Bioinformatics analysis and luciferase reporter assays were applied to examine interactions between circ_0001879 and miR-30-3p in HRMECs. RESULTS: The relative circ_0001879 expression was remarkably increased in diabetic retinas group than that in the control group. Silencing circ_0001879 suppressed the proliferation and migration of HRMECs under high-glucose conditions. In addition, circ_0001879 acted as a binding platform and miRNA sponge for miR-30-3p. Circ_0001879 modulated the function of HRMECs via targeting miR-30-3p. CONCLUSION: Silencing circ_0001879 inhibited the proliferation and migration of HRMECs under high-glucose conditions via modulating miR-30-3p, which might shed new light on a novel potentially marker and molecular therapeutic target for diabetic retinopathy.


Assuntos
Retinopatia Diabética/patologia , Glucose/administração & dosagem , MicroRNAs/genética , Vasos Retinianos/patologia , Animais , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucose/metabolismo , Humanos , Masculino , MicroRNAs/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo
2.
Life Sci ; 257: 118072, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32659367

RESUMO

AIMS: Sunitinib (Su), a tyrosine kinase inhibitor, is one of the most commonly used anti-angiogenic drugs. Some studies have described retinal detachment and photoreceptor damage following systemic exposure to Su, despite beneficial effects achieved with local treatment of ocular pathologies. The aim of this study was to explore the role of NADPH oxidase system and oxidative stress in eyes from Su-treated animals. MAIN METHODS: Male Wistar rats were administered 25 mg Su/kg body weight/day incorporated in the chow for 3 weeks. Upon treatment completion, NADPH oxidase activity and ROS levels were measured in ocular tissue by chemiluminescence and dihydroethidium (DHE) staining, respectively. The expression of NADPH oxidase isoforms (NOX1, NOX2 and NOX4), antioxidant enzymes and endothelial/inducible nitric oxidase isoforms (eNOS/iNOS) in the eyecup and/or retina were measured via immunofluorescence, immunoblotting and RT-qPCR. KEY FINDINGS: NADPH oxidase activity/expression increased in eyecup and retinas from Su-treated rats. Immunohistofluorescence studies in retinal layer confirmed a higher signal of NADPH oxidase isoforms after Su treatment. Treated animals also presented with reductions in NO levels and eNOS expression, whereas iNOS was upregulated. Finally, a significant depletion of antioxidant enzyme glutathione peroxidase was measured in eyecups of rats following Su exposure, and the opposite pattern was seen for glutathione reductase and superoxide dismutase. SIGNIFICANCE: This study demonstrates that Su treatment is associated with NADPH oxidase-derived oxidative stress in the eye. Long-term treatment of Su should be properly monitored to avoid retinotoxic effects that might result in ocular pathologies and sight-threatening conditions.


Assuntos
Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Retina/efeitos dos fármacos , Sunitinibe/toxicidade , Animais , Antioxidantes/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Masculino , NADPH Oxidases/metabolismo , Ratos , Ratos Wistar , Retina/patologia , Superóxido Dismutase/metabolismo
3.
PLoS One ; 15(7): e0235016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609726

RESUMO

OBJECTIVE: Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two formulations, with and without propylene glycol (Alkeran vs. Evomela, respectively). METHODS: A retrospective cohort study of retinoblastoma patients who received intravitreal injections of Alkeran and Evomela at 30 µg from September 2012 to January 2019 at a single tertiary care center were enrolled. Retinal toxicity was measured using electroretinogram (ERG) and compared using a multivariate analysis of 338 injections in 101 eyes of 96 patients. Ocular survival of 163 eyes in 150 patients was compared across formulations using Cox proportional hazards model. Eyes were censored at the time a patient received a dose other than 30 µg. RESULTS: Overall, ERG decline (mean, 95% CI) for each injection was -5.58 µV (-7.17, -3.99). No significant differences in ERG decrement were found between Alkeran (with alcohol) -5.52uV (-6.99, -4.05). and Evomela (without alcohol) -5.65uV (-8.31 to -2.98) formulations (p = 0.93). Ocular survival at 24 months was 93.6% (95% CI 86.2, 97.1) with alcohol and 91.7% (95% CI 53.9, 98.8) without alcohol. The hazard ratio (HR) for without vs with alcohol was 0.50 (95% CI 0.06 to 4.07); no significant difference in ocular survival was found between formulations (p = 0.52). CONCLUSIONS AND RELEVANCE: No differences were found in retinal toxicity and ocular survival between 30 µg intravitreal injections of Alkeran or Evomela for intraocular retinoblastoma. Given the increased stability of Evomela, intravitreal treatment could be expanded to centers without the ability to supply Alkeran due to its shorter safety window; however, Alkeran is less expensive. For those with existing infrastructure, Alkeran is a comparable, cost-effective alternative.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Melfalan/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Adolescente , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Criança , Pré-Escolar , Humanos , Lactente , Injeções Intravítreas , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Retina/efeitos dos fármacos , Resultado do Tratamento
4.
J Environ Pathol Toxicol Oncol ; 39(1): 89-99, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479015

RESUMO

Oxidative stress and inflammation are regarded as prime reasons for the progression and development of diabetic retinopathy. Currently, nuclear factor erythroid-2-related factor 2 (Nrf2), thioredoxin interacting protein (TXNIP) and NLRP3 inflammasome pathways are under increasing focus in research on oxidative stress and inflammation-related diseases. On the other hand, tilianin (TN) has received much attention because of its various pharmacological properties. Based on results of these studies, this investigation was performed to inspect the therapeutic efficiency of TN on the retina in diabetic rats. Rats were arbitrarily assigned to three groups: control group, diabetic group, and diabetic plus TN (20 mg/ kg body weight for 42 days, orally) group. TN supplementation in diabetic rats, their food intake, fasting blood glucose status, glycosylated hemoglobin (HbA1c) levels were drastically reduced, and there was a marked augmentation in serum insulin status. TN treatment of diabetic rats increased mRNA expression of Nrf2 and its target gene, HO-1, and noticeably decreased the malondialdehyde status. Activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidases (GPX) were increased relative to diabetic rats. Furthermore, administering TN to the diabetic rats resulted in decreased expression of TXNIP, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1ß proteins and decreased distribution of TXNIP, NLRP3, ASC, and caspase-1 proteins in retinas. In addition, TN treatment ameliorated morphological and morphometric changes in the retinas of diabetic rats. Together, all of these findings provide clear evidence that TN treatment of diabetic rats attenuated diabetic retinal changes through its hypoglycemic, antioxidant, and anti-inflammatory properties. The antioxidant and anti-inflammatory effects in diabetic retinas occur at least in part through the modulation of Nrf2/TXNIP/NLRP3 inflammasome pathways, which may have remedial benefits in the healing of diabetic retinopathy.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Flavonoides/farmacologia , Glicosídeos/farmacologia , Inflamassomos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Retina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ração Animal/análise , Animais , Dieta , Suplementos Nutricionais/análise , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Retina/patologia
5.
Am J Pathol ; 190(5): 1080-1094, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32354571

RESUMO

This study explored the anti-inflammatory effects of a glucagon-like peptide-1 receptor agonist (GLP-1RA), known as lixisenatide, on the eyes of early type 2 diabetic mice. Diabetic (db/db) mice were divided into three groups: GLP-1RA [lixisenatide (LIX)], insulin (INS) with controlled hyperglycemia based on the glucose concentration of lixisenatide, and diabetic control (D-CON). Nondiabetic control mice (db/dm) were also characterized for comparison. After 8 weeks of treatment, mRNA levels of inflammatory markers, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, immunohistochemical staining; Western blot of glial fibrillary acidic protein (GFAP) and thioredoxin-interacting protein; and retinal thickness were assessed in the central and peripheral neurosensory retina. LIX showed decreased immunohistochemical staining for both thioredoxin-interacting protein and GFAP in the central and peripheral neurosensory retina compared with D-CON and INS, and decreased expression of these proteins in the neurosensory retina and immunohistochemical staining in the optic nerve head for GFAP compared with D-CON. The inner nuclear layer in the peripheral retina in LIX was only thinner than those of D-CON and INS. In an early type 2 diabetic mouse model, lixisenatide treatment showed superior anti-inflammatory effects on the retina and optic nerve head independent of hyperglycemia. Thus, the neuroprotective effects of lixisenatide treatment in the peripheral inner nuclear layer should be evaluated in early type 2 diabetic retinopathy.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos/farmacologia , Retina/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2 , Retinopatia Diabética/patologia , Hipoglicemiantes , Camundongos
7.
Cochrane Database Syst Rev ; 5: CD012208, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32374423

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is one of the leading causes of permanent blindness worldwide. The current mainstay of treatment for neovascular AMD (nAMD) is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents: aflibercept, ranibizumab, and off-label bevacizumab. Injections can be given monthly, every two or three months ('extended-fixed'), or as needed (pro re nata (PRN)). A variant of PRN is 'treat-and-extend' whereby injections are resumed if recurrence is detected and then delivered with increasing intervals. Currently, injection frequency varies among practitioners, which underscores the need to characterize an optimized approach to nAMD management. OBJECTIVES: To investigate the effects of monthly versus non-monthly intravitreous injection of an anti-VEGF agent in people with newly diagnosed nAMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, and three trials registers from 2004 to October 2019; checked references; handsearched conference abstracts; and contacted pharmaceutical companies to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared different treatment regimens for anti-VEGF agents in people with newly diagnosed nAMD. We considered standard doses only (ranibizumab 0.5 mg, bevacizumab 1.25 mg, aflibercept 2.0 mg, or a combination of these). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for trial selection, data extraction, and analysis. MAIN RESULTS: We included 15 RCTs. The total number of participants was 7732, ranging from 37 to 2457 in each trial. The trials were conducted worldwide. Of these, six trials exclusively took place in the US, and three included centers from more than one country. Eight trials were at high risk of bias for at least one domain and all trials had at least one domain at unclear risk of bias. Seven trials (3525 participants) compared a PRN regimen with a monthly injection regimen, of which five trials delivered four to eight injections using standard PRN and three delivered nine or 10 injections using a treat-and-extend regimen in the first year. The overall mean change in best-corrected visual acuity (BCVA) at one year was +8.8 letters in the monthly injection group. Compared to the monthly injection, there was moderate-certainty evidence that the mean difference (MD) in BCVA change at one year for the standard PRN subgroup was -1.7 letters (95% confidence interval (CI) -2.8 to -0.6; 4 trials, 2299 participants), favoring monthly injections. There was low-certainty evidence of a similar BCVA change with the treat-and-extend subgroup (0.5 letters, 95% CI -3.1 to 4.2; 3 trials, 1226 participants). Compared to monthly injection, there was low-certainty evidence that fewer participants gained 15 or more lines of vision with standard PRN treatment at one year (risk ratio (RR) 0.87, 95% CI 0.76 to 0.99; 4 trials, 2299 participants) and low-certainty evidence of a similar gain with treat-and-extend versus monthly regimens (RR 1.11, 95% CI 0.91 to 1.36; 3 trials, 1169 participants). The mean change in central retinal thickness was a decrease of -166 µm in the monthly injection group; the MD compared with standard PRN was 21 µm (95% CI 6 to 32; 4 trials, 2215 participants; moderate-certainty evidence) and with treat-and extend was 22 µm (95% CI 37 to -81 µm; 2 trials, 635 participants; low-certainty evidence), in favor of monthly injection. Only one trial (498 participants) measured quality of life and reported no evidence of a difference between regimens, but data could not be extracted (low-certainty evidence). Both PRN regimens (standard and 'treat-and-extend') used fewer injections than monthly regimens (standard PRN: MD -4.6 injections, 95% CI -5.4 to -3.8; 4 trials, 2336 participants; treat-and-extend: -2.4 injections, 95% CI -2.7 to -2.1 injections; moderate-certainty evidence for both comparisons). Two trials provided cost data (1105 participants, trials conducted in the US and the UK). They found that cost differences between regimens were reduced if bevacizumab rather than aflibercept or ranibizumab were used, since bevacizumab was less costly (low-certainty evidence). PRN regimens were associated with a reduced risk of endophthalmitis compared with monthly injections (Peto odds ratio (OR) 0.13, 95% CI 0.04 to 0.46; 6 RCTs, 3175 participants; moderate-certainty evidence). Using data from all trials included in this review, we estimated the risk of endophthalmitis with monthly injections to be 8 in every 1000 people per year. The corresponding risk for people receiving PRN regimens was 1 in every 1000 people per year (95% CI 0 to 4). Three trials (1439 participants) compared an extended-fixed regimen (number of injections reported in only one large trial: 7.5 in one year) with monthly injections. There was moderate-certainty evidence that BCVA at one year was similar for extended-fixed and monthly injections (MD in BCVA change compared to extended-fixed group: -1.3 letters, 95% CI -3.9 to 1.3; RR of gaining 15 letters or more: 0.94, 95% CI 0.80 to 1.10). The change in central retinal thickness was a decrease of 137 µm in the monthly group; the MD with the extended-fixed group was 8 µm (95% CI -11 to 27; low-certainty evidence). The frequency of endophthalmitis was lower in the extended-fixed regimen compared to the monthly group, but this estimate was imprecise (RR 0.19, 95% CI 0.03 to 1.11; low-certainty evidence). If we assumed a risk of 8 cases of endophthalmitis in 1000 people receiving monthly injections over one year, then the corresponding risk with extended-fixed regimen was 2 in 1000 people (95% CI 0 to 9). Other evidence comparing different extended-fixed or PRN regimens yielded inconclusive results. AUTHORS' CONCLUSIONS: We found that, at one year, monthly regimens are probably more effective than PRN regimens using seven or eight injections in the first year, but the difference is small and clinically insignificant. Endophthalmitis is probably more common with monthly injections and differences in costs between regimens are higher if aflibercept or ranibizumab are used compared to bevacizumab. This evidence only applies to settings in which regimens are implemented as described in the trials, whereas undertreatment is likely to be common in real-world settings. There are no data from RCTs on long-term effects of different treatment regimens.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Degeneração Macular/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/economia , Bevacizumab/administração & dosagem , Bevacizumab/economia , Viés , Esquema de Medicação , Endoftalmite/epidemiologia , Endoftalmite/etiologia , Humanos , Injeções Intravítreas/efeitos adversos , Degeneração Macular/patologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Ranibizumab/administração & dosagem , Ranibizumab/economia , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/economia , Retina/efeitos dos fármacos
9.
Asia Pac J Ophthalmol (Phila) ; 9(2): 85-87, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-157679

RESUMO

The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. Irreversible retinal damage can occur if the exposure to the safe doses is >5 years. It is not known whether exposure to high doses over a short period of time can also cause the damage. We recommend that before prescribing CQ or HCQ, history of ocular disease should be obtained to avoid the prescription if appropriate. If either agent is to be used, routine baseline ocular examination is not absolutely necessary. Patients who do not have ocular disease should also be informed about the potential risk of retinal toxicity. Both agents, however, have not yet been proven to be beneficial to COVID-19.


Assuntos
Cloroquina/toxicidade , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/toxicidade , Pneumonia Viral/tratamento farmacológico , Retina/efeitos dos fármacos , Betacoronavirus , Cloroquina/administração & dosagem , Humanos , Hidroxicloroquina/administração & dosagem , Pandemias , Retina/patologia , Doenças Retinianas/induzido quimicamente , Fatores de Risco
10.
Zhonghua Yan Ke Za Zhi ; 56(4): 279-285, 2020 Apr 11.
Artigo em Chinês | MEDLINE | ID: mdl-32306620

RESUMO

Objective: To elevated the retinal toxicity of intravitreal ganciclovir in albino rabbit eyes. Methods: Experimental study. Twenty-four New Zealand albino rabbits (forty-eight eyes) were divided into four groups by random. Three groups were prepared for ganciclovir experiment, named A, B, C. Each group received intravitreal injection ganciclovir dose at 400 µg/0.05 ml, 2 mg/0.05 ml and 5 mg/0.05 ml respectively. The other group named D served as a control accepted intravitreal injection 0.9% normal saline 0.1 ml. Before and after 1, 2 and 4 weeks, flicker full field electroretina gram (ERG) was recorded. After 1, 2 and 4 weeks light and electron microscopic tests were recorded for further toxicity study. Results: There was significant difference in amplitude of maximal combined response a wave in one week(χ(2)=8.319, P=0.04), and pairwise comparison the 5 mg group (140.50 µV) was significantly lower than the control group (165.00 µV) (χ(2)=-2.830, P=0.028). Maximal combined response b wave in four weeks(χ(2)=-10.626, P=0.014), and pairwise comparison the 5 mg group (261.50 µV) was significantly lower than the control group (398.00 µV) (χ(2)=-2.973, P=0.018). 30 Hz flicker response in one, two and four weeks(χ(2)=17.589, 8.225, 8.997, P=0.001, 0.042, 0.02), and pairwise comparison the 5 mg group (71.3µV, 106.00µV, 63.60µV) was significantly lower than the control group (118.50µV, 129.00µV, 116.50µV) (χ(2)=-4.142, -2.826, -2.713, P=0.000, 0.028, 0.040). There was no histologic retinal toxicity evidence of group 400 µg and control group observed by light microscopy in any stage of the study. Histologic changes of group 2 mg four week later, group 5 mg two and four week later include inner nuclear layer loose arranged, nuclear of ganglia were widened and outer plexiform layer stained less in four week later. By electron microscopic observation, the ultrastructure of retina changed to different degrees and became worse in each experimental group with significant mitochondrial swelling and hydropic changes were seen in the inner segments of photoreceptors, loosely arranged and disordered in the outer segment of photoreceptors four weeks later. Conclusions: The retinal function and morphology were normal in group 400 µg. Group 2 mg and 5 mg had retinal toxicity, and 5 mg was more severe. Therefore, the clinical application of ganciclovir in the treatment of acute retinal necrosis (ARN) should select the minimum effective dose to avoid the occurrence of retinal toxicity. (Chin J Ophthalmol, 2020, 56:279-285).


Assuntos
Ganciclovir/toxicidade , Retina/efeitos dos fármacos , Animais , Injeções Intravítreas , Coelhos , Distribuição Aleatória , Retina/patologia , Retina/ultraestrutura , Testes de Toxicidade
11.
Asia Pac J Ophthalmol (Phila) ; 9(2): 85-87, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32349115

RESUMO

The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. Irreversible retinal damage can occur if the exposure to the safe doses is >5 years. It is not known whether exposure to high doses over a short period of time can also cause the damage. We recommend that before prescribing CQ or HCQ, history of ocular disease should be obtained to avoid the prescription if appropriate. If either agent is to be used, routine baseline ocular examination is not absolutely necessary. Patients who do not have ocular disease should also be informed about the potential risk of retinal toxicity. Both agents, however, have not yet been proven to be beneficial to COVID-19.


Assuntos
Cloroquina/toxicidade , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/toxicidade , Pneumonia Viral/tratamento farmacológico , Retina/efeitos dos fármacos , Betacoronavirus , Cloroquina/administração & dosagem , Humanos , Hidroxicloroquina/administração & dosagem , Pandemias , Retina/patologia , Doenças Retinianas/induzido quimicamente , Fatores de Risco
12.
Proc Natl Acad Sci U S A ; 117(18): 9952-9963, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32345717

RESUMO

Genetic polymorphisms in the region of the trimeric serine hydrolase high-temperature requirement 1 (HTRA1) are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remain undefined. In this study, we have developed an HtrA1-blocking Fab fragment to test the therapeutic hypothesis that HtrA1 protease activity is involved in the progression of AMD. Next, we generated an activity-based small-molecule probe (ABP) to track target engagement in vivo. In addition, we used N-terminomic proteomic profiling in preclinical models to elucidate the in vivo repertoire of HtrA1-specific substrates, and identified substrates that can serve as robust pharmacodynamic biomarkers of HtrA1 activity. One of these HtrA1 substrates, Dickkopf-related protein 3 (DKK3), was successfully used as a biomarker to demonstrate the inhibition of HtrA1 activity in patients with AMD who were treated with the HtrA1-blocking Fab fragment. This pharmacodynamic biomarker provides important information on HtrA1 activity and pharmacological inhibition within the ocular compartment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Anticorpos Anti-Idiotípicos/farmacologia , Atrofia Geográfica/tratamento farmacológico , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Degeneração Macular/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/isolamento & purificação , Idoso , Animais , Anticorpos Anti-Idiotípicos/genética , Anticorpos Anti-Idiotípicos/imunologia , Biomarcadores/sangue , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Atrofia Geográfica/sangue , Atrofia Geográfica/genética , Atrofia Geográfica/imunologia , Serina Peptidase 1 de Requerimento de Alta Temperatura A/antagonistas & inibidores , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/farmacologia , Degeneração Macular/sangue , Degeneração Macular/genética , Degeneração Macular/imunologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Proteoma/genética , Proteoma/imunologia , Ratos , Retina/efeitos dos fármacos , Retina/imunologia , Retina/patologia , Bibliotecas de Moléculas Pequenas/farmacologia
14.
Am J Pathol ; 190(7): 1505-1512, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32275905

RESUMO

Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness among the working-age population. Diabetic patients often experience functional deficits in dark adaptation, contrast sensitivity, and color perception before any microvascular pathologies on the fundus become detectable. Previous studies showed that the regeneration of 11-cis-retinal and visual pigment is impaired in a type 1 diabetes animal model, which negatively affects visual function at the early stage of DR. Here, Akita mice, type 1 diabetic model, were treated with the visual pigment chromophore, 9-cis-retinal. This treatment rescued a- and b-wave amplitudes of scotopic electroretinography responses, compared with vehicle-treated Akita mice. In addition, the administration of 9-cis-retinal alleviated oxidative stress significantly as shown by reduced 3-nitrotyrosine levels in the retina of Akita mice. Furthermore, the 9-cis-retinal treatment decreased retinal apoptosis as shown by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and DNA fragment enzyme-linked immunosorbent assay. Overall, these findings showed that 9-cis-retinal administration restored visual pigment formation and decreased oxidative stress and retinal degeneration, which resulted in improved visual function in diabetic mice, suggesting that chromophore deficiency plays a causative role in visual defects in early DR.


Assuntos
Retinopatia Diabética/fisiopatologia , Diterpenos/farmacologia , Retina/efeitos dos fármacos , Retinaldeído/farmacologia , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Estresse Oxidativo/efeitos dos fármacos , Retina/fisiopatologia
15.
Acta Diabetol ; 57(7): 867-874, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32114643

RESUMO

AIMS: To evaluate the timing and spectral-domain optical coherence tomography (SD-OCT) features of diabetic macular oedema (DME) recurrence according to baseline OCT patterns in patients treated with dexamethasone implant (DEX-I). METHODS: This is a retrospective observational study (72 eyes/65 patients). Best-corrected visual acuity, timing of DME recurrence, and SD-OCT pattern [intraretinal cysts (IRC), IRC plus subretinal fluid (mixed), external limiting membrane (ELM), ellipsoid (IS/OS) layer integrity] were assessed at baseline and monthly until first DME recurrence. RESULTS: Forty-two (58.3%) and 30 (41.6%) DME eyes had an IRC and mixed DME pattern at baseline, respectively. Twenty-four out of thirty mixed eyes (80%) relapsed without subretinal fluid. At baseline, mixed eyes showed similar changes in ELM and IS/OS (60 and 76.6% of eyes, respectively) versus IRC eyes (42.8 and 80.9% of eyes). After DME recurrence, more mixed eyes at baseline showed ELM and IS/OS changes (63.3 and 86.6%) than IRC eyes (50 and 76.2%). 33.3% of mixed eyes had DME recurrence at ≥ 6 months from first DEX-I implant versus 19% of IRC eyes. CONCLUSIONS: Mixed DME eyes were treated with DEX-I relapse later and more frequently without subretinal fluid than IRC eyes. SD-OCT characteristics of different DME patterns at baseline can predict morphological features and timing of DME recurrence.


Assuntos
Dexametasona/administração & dosagem , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Tomografia de Coerência Óptica/métodos , Idoso , Retinopatia Diabética/patologia , Implantes de Medicamento/administração & dosagem , Feminino , Angiofluoresceinografia , Humanos , Injeções Intravítreas , Edema Macular/patologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Prognóstico , Recidiva , Retina/diagnóstico por imagem , Retina/efeitos dos fármacos , Retina/patologia , Retina/fisiopatologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Acuidade Visual/efeitos dos fármacos
16.
PLoS One ; 15(2): e0229068, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053676

RESUMO

Kyoto University Substance (KUS) 121, an ATPase inhibitor of valosin-containing protein, is a novel neuroprotectant. We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an investigator-initiated, first-in-humans, phase 1/2 clinical trial. Nine patients with non-arteritic CRAO symptoms lasting for 4-48 h were enrolled. These patients received daily intravitreal injections of KUS121 for 3 days: 25 µg (low-dose) in the first three patients and 50 µg (high-dose) in the next six patients. The primary endpoint was the safety of the drug. As a secondary endpoint, pharmacokinetics was evaluated. Other key secondary endpoints were changes in best-corrected visual acuity (BCVA), measured using the Early Treatment Diabetic Retinopathy Study chart, visual field scores, and retinal sensitivities between baseline and week 12; and decimal BCVA at week 12. Administration of KUS121 did not result in serious adverse events. All nine patients (100%) showed significant improvement of BCVA. Average readable letter counts, visual field scores, and retinal sensitivities also improved. Decimal BCVA at week 12 was better than 0.1 in four patients (44%) and equal to or better than 0.05 in seven patients (78%). This first-in-humans clinical trial provides support for the safety and efficacy of intravitreal KUS121 injection. To substantiate the safety and effectiveness for patients with acute CRAO, further larger scale clinical studies will be needed.


Assuntos
Fármacos Neuroprotetores/uso terapêutico , Oclusão da Artéria Retiniana/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Edema Macular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Retina/efeitos dos fármacos , Oclusão da Veia Retiniana/tratamento farmacológico , Acuidade Visual/efeitos dos fármacos
17.
Cell Physiol Biochem ; 54(1): 142-159, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028545

RESUMO

BACKGROUND/AIMS: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. METHODS: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood-brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. RESULTS: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. CONCLUSION: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.


Assuntos
Isotiocianatos/uso terapêutico , Melatonina/análogos & derivados , Fator 2 Relacionado a NF-E2/agonistas , Retinite Pigmentosa/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/química , Isotiocianatos/farmacologia , Masculino , Melatonina/química , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia , Fator de Necrose Tumoral alfa/metabolismo , Acuidade Visual/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
PLoS One ; 15(2): e0227524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32101556

RESUMO

Experimental autoimmune uveitis (EAU) in rodents recapitulates many features of the disease in humans and has served as a useful tool for the development of therapeutics. A peptide from C-terminus of interferon α1, conjugated to palmitoyl-lysine for cell penetration, denoted as IFNα-C, was tested for its anti-inflammatory properties in ARPE-19 cells, followed by testing in a mouse model of EAU. Treatment with IFNα-C and evaluation by RT-qPCR showed the induction of anti-inflammatory cytokines and chemokine. Inflammatory markers induced by treatment with TNFα were suppressed when IFNα-C was simultaneously present. TNF-α mediated induction of NF-κB and signaling by IL-17A were attenuated by IFNα-C. Differentiated ARPE-19 cells were treated with TNFα in the presence or absence IFNα-C and analyzed by immmunhistochemistry. IFNα-C protected against the disruption integrity of tight junction proteins. Similarly, loss of transepithelial resistance caused by TNFα was prevented by IFNα-C. B10.RIII mice were immunized with a peptide from interphotoreceptor binding protein (IRBP) and treated by gavage with IFNα-C. Development of uveitis was monitored by histology, fundoscopy, SD-OCT, and ERG. Treatment with IFNα-C prevented uveitis in mice immunized with the IRBP peptide. Splenocytes isolated from mice with ongoing EAU exhibited antigen-specific T cell proliferation that was inhibited in the presence of IFNα-C. IFNα-C peptide exhibits anti-inflammatory properties and protects mice against damage to retinal structure and function suggesting that it has therapeutic potential for the treatment of autoimmune uveitis.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Interferon Tipo I/química , Peptídeos/uso terapêutico , Retina/patologia , Uveíte/tratamento farmacológico , Administração Oral , Animais , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Impedância Elétrica , Eletrorretinografia , Proteínas do Olho/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-17/metabolismo , Camundongos , NF-kappa B/metabolismo , Retina/efeitos dos fármacos , Retina/fisiopatologia , Proteínas de Ligação ao Retinol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Uveíte/patologia , Uveíte/fisiopatologia
19.
Invest Ophthalmol Vis Sci ; 61(2): 17, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32053727

RESUMO

Purpose: Vigabatrin (VGB) is an effective antiepileptic that increases concentrations of inhibitory γ-aminobutyric acid (GABA) by inhibiting GABA transaminase. Reports of VGB-associated visual field loss limit its clinical usefulness, and retinal toxicity studies in laboratory animals have yielded conflicting results. Methods: We examined the functional and morphologic effects of VGB in C57BL/6J mice that received either VGB or saline IP from 10 to 18 weeks of age. Retinal structure and function were assessed in vivo by optical coherence tomography (OCT), ERG, and optomotor response. After euthanasia, retinas were processed for immunohistochemistry, and retinal GABA, and VGB quantified by mass spectrometry. Results: No significant differences in visual acuity or total retinal thickness were identified between groups by optomotor response or optical coherence tomography, respectively. After 4 weeks of VGB treatment, ERG b-wave amplitude was enhanced, and amplitudes of oscillatory potentials were reduced. Dramatic rod and cone bipolar and horizontal cell remodeling, with extension of dendrites into the outer nuclear layer, was observed in retinas of VGB-treated mice. VGB treatment resulted in a mean 3.3-fold increase in retinal GABA concentration relative to controls and retinal VGB concentrations that were 20-fold greater than brain. Conclusions: No evidence of significant retinal thinning or ERG a- or b-wave deficits were apparent, although we describe significant alterations in ERG b-wave and oscillatory potentials and in retinal cell morphology in VGB-treated C57BL/6J mice. The dramatic concentration of VGB in retina relative to the target tissue (brain), with a corresponding increase in retinal GABA, offers insight into the pathophysiology of VGB-associated visual field loss.


Assuntos
Anticonvulsivantes/farmacologia , GABAérgicos/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Retina/efeitos dos fármacos , Vigabatrina/farmacologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Músculos Oculomotores/efeitos dos fármacos , Distribuição Aleatória , Retina/fisiopatologia , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/fisiopatologia , Tomografia de Coerência Óptica , Campos Visuais/fisiologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-31922896

RESUMO

Proliferative diabetic retinopathy (PDR) is a progressive disease predominantly involving pathological angiogenesis and is characterized by the development of immature, fragile, and easily hemorrhagic new vessels. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play important roles in the progression of diabetic retinopathy. Our previous studies demonstrated that AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/Rho-associated protein kinase (ROCK) pathway. The aim of this study was to further confirm AGE-induced angiogenesis in vivo and the involvement of RAGE, ROCK, and moesin phosphorylation in this process. We performed the study in an AGE-treated mouse model with various angiogenesis assays in multiple in vivo and ex vivo models. The results demonstrated that AGEs promoted significant neovascularization in whole mount retina and mouse aortic ring of adult and postnatal mice and in Matrigel plug as well, which were consistently accompanied by increased moesin phosphorylation. The increase of AGE-evoked neovascularization and moesin phosphorylation were both attenuated by RAGE knockout or ROCK inhibitor Y27632 administration in mice. We also revealed the pathological characteristics of AGE-promoted angiogenesis by demonstrating the decrease of pericyte coverage and the disarranged endothelial alignment in microvessels. In conclusion, this study provides in vivo evidences that AGEs induce immature angiogenesis by binding to RAGE, activating the RhoA/ROCK signal pathway and inducing moesin phosphorylation.NEW & NOTEWORTHY Advanced glycation end product (AGE)-induced formation of neovessels and phosphorylation of moesin in retina and aortic ring required AGE receptors. AGEs increased neovessels and the phosphorylation of moesin in retina and aortic ring via RhoA/ROCK pathway. AGE-induced immature angiogenesis in AGE-treated mouse retina and aortic ring. The AGE-RAGE axis and moesin could be candidate targets for overcoming relative diseases.


Assuntos
Produtos Finais de Glicação Avançada/farmacologia , Neovascularização Patológica/metabolismo , Retina/efeitos dos fármacos , Neovascularização Retiniana/metabolismo , Amidas/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos
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