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1.
Invest Ophthalmol Vis Sci ; 62(12): 3, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34495288

RESUMO

Purpose: Age-related cataract is the leading cause of blindness worldwide. Variants in the EPHA2 gene increase the disease risk, and its knockout in mice causes cataract. We investigated whether age, sex, and genetic background, risk factors for age-related cataract, and Epha2 genotype influence Epha2-related cataract development in mice. Methods: Cataract development was monitored in Epha2+/+, Epha2+/-, and Epha2-/- mice (Epha2Gt(KST085)Byg) on C57BL/6J and FVB:C57BL/6J (50:50) backgrounds. Cellular architecture of lenses, endoplasmic reticulum (ER) stress, and redox state were determined using histological, molecular, and analytical techniques. Results: Epha2-/- and Epha2+/- mice on C57BL/6J background developed severe cortical cataracts by 18 and 38 weeks of age, respectively, compared to development of similar cataract significantly later in Epha2-/- mice and no cataract in Epha2+/- mice in this strain on FVB background, which was previously reported. On FVB:C57BL/6J background, Epha2-/- mice developed severe cortical cataract by 38 weeks and Epha2+/- mice exhibited mild cortical cataract up to 64 weeks of age. Progression of cataract in Epha2-/- and Epha2+/- female mice on C57BL/6J and mixed background, respectively, was slower than in matched male mice. N-cadherin and ß-catenin immunolabeling showed disorganized lens fiber cells and disruption of lens architecture in Epha2-/- and Epha2+/- lenses, coinciding with development of severe cataracts. EPHA2 immunolabeling showed intracellular accumulation of the mutant EPHA2-ß-galactosidase fusion protein that induced a cytoprotective ER stress response and in Epha2+/- lenses was also accompanied by glutathione redox imbalance. Conclusions: Both, Epha2-/- and Epha2+/- mice develop age-related cortical cataract; age as a function of Epha2 genotype, sex, and genetic background influence Epha2-related cataractogenesis in mice.


Assuntos
Catarata/genética , Regulação da Expressão Gênica , Cristalino/metabolismo , RNA/genética , Receptor EphA2/genética , Animais , Catarata/diagnóstico , Catarata/metabolismo , Modelos Animais de Doenças , Genótipo , Cristalino/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor EphA2/biossíntese
2.
Biomolecules ; 11(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34439816

RESUMO

Cataracts are a leading cause of blindness worldwide. Surgical removal of cataracts is a safe and effective procedure to restore vision. However, a large number of patients later develop vision loss due to regrowth of lens cells and subsequent degradation of the visual axis leading to visual disability. This postsurgical complication, known as posterior capsular opacification (PCO), occurs in up to 30% of cataract patients and has no clinically proven pharmacological means of prevention. Despite the availability of many compounds capable of preventing early steps in PCO development, there is currently no effective means to deliver such therapies into the eye for a suitable duration. To model a solution to this unmet medical need, we fabricated acrylic substrates as intraocular lens (IOL) mimics scaled to place into the capsular bag of the mouse lens following a mock-cataract surgery. Substrates were coated with a hydrophilic crosslinked acrylate nanogel designed to elute Sorbinil, an aldose reductase inhibitor previously shown to suppress PCO. Insertion of the Sorbinil-eluting device into the lens capsule at the time of cataract surgery resulted in substantial prevention of cellular changes associated with PCO development. This model demonstrates that a cataract inhibitor can be delivered into the postsurgical lens capsule at therapeutic levels.


Assuntos
Opacificação da Cápsula/prevenção & controle , Extração de Catarata/efeitos adversos , Portadores de Fármacos , Inibidores Enzimáticos/farmacologia , Imidazolidinas/farmacologia , Lentes Intraoculares , Actinas/genética , Actinas/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Opacificação da Cápsula/etiologia , Opacificação da Cápsula/genética , Opacificação da Cápsula/patologia , Catarata/genética , Catarata/metabolismo , Catarata/patologia , Extração de Catarata/métodos , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Humanos , Cristalino/metabolismo , Cristalino/patologia , Cristalino/cirurgia , Camundongos , Nanogéis/administração & dosagem , Nanogéis/química , Transdução de Sinais , Vimentina/genética , Vimentina/metabolismo
3.
Exp Eye Res ; 211: 108721, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34375588

RESUMO

Senile cataract is a common age-related disease in ophthalmology. Hsa_circ_0004058 has been reported to be down-regulated in the lens epithelial cells of senile cataract patients, suggesting that hsa_circ_0004058 is associated with senile cataract. However, the underlying mechanism is still unknown. This study attempted to determine the functional role of hsa_circ_0004058 in senile cataract. We treated human lens epithelial cells (SRA01/04) with H2O2 as senile cataract model, and found that cell viability and autophagy of SRA01/04 cells were severely decreased by H2O2 treatment. Hsa_circ_0004058 was notably down-regulated in H2O2-treated SRA01/04 cells. Moreover, hsa_circ_0004058 overexpression reduced apoptotic cells and the expression of Cleaved-caspase-3 and Bax, and enhanced Bcl-2 expression in H2O2-treated SRA01/04 cells. However, hsa_circ_0004058 silencing caused the opposite results. Hsa_circ_0004058 up-regulation accelerated the expression of autophagy-related proteins LC3-II/LC3-I and Beclin-1 in H2O2-treated SRA01/04 cells, which was partly abolished by 3-Methyladenine (autophagy inhibitor). Additionally, hsa_circ_0004058 functioned as a competing endogenous RNA to competitive binding miR-186, and thus accelerated the expression of its down-stream target, ATG7. Hsa_circ_0004058 promoted autophagy of SRA01/04 cells by regulating miR-186/ATG7 axis. In conclusion, these data demonstrates that hsa_circ_0004058 inhibits apoptosis of SRA01/04 cells by promoting autophagy, which attributes to regulate miR-186/ATG7 axis. Thus, hsa_circ_0004058 may be a potential target for senile cataract treatment.


Assuntos
Apoptose/genética , Proteína 7 Relacionada à Autofagia/genética , Autofagia/fisiologia , Células Epiteliais/efeitos dos fármacos , Cristalino/patologia , MicroRNAs/genética , RNA Circular/fisiologia , Western Blotting , Caspase 3/genética , Sobrevivência Celular , Células Cultivadas , Eletroforese em Gel de Poliacrilamida , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Peróxido de Hidrogênio/toxicidade , Cristalino/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Oxidantes/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/genética , Reação em Cadeia da Polimerase em Tempo Real , Transfecção
4.
Aging (Albany NY) ; 13(13): 17568-17591, 2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-34226295

RESUMO

The homeostasis of the ocular lens is maintained by a microcirculation system propagated through gap junction channels. It is well established that the intercellular communications of the lens become deteriorative during aging. However, the molecular basis for this change in human lenses has not been well defined. Here, we present evidence to show that over 90% of Cx46 and Cx50 are lost in the fiber cells of normal human lenses aged 50 and above. From transparent to cataractous lenses, while Cx43 was upregulated, both Cx46 and Cx50 were significantly down-regulated in the lens epithelia. During aging of mouse lenses, Cx43 remained unchanged, but both Cx46 and Cx50 were significantly downregulated. Under oxidative stress treatment, mouse lenses develop in vitro cataractogenesis. Associated with this process, Cx43 was significantly upregulated, in contrast, Cx46 and Cx50 were sharply downregulated. Together, our results for the first time reveal that downregulation in Cx46 and Cx50 levels appears to be the major reason for the diminished coupling conductance, and the aging-dependent loss of Cx46 and Cx50 promotes senile cataractogenesis.


Assuntos
Envelhecimento/fisiologia , Catarata/genética , Catarata/patologia , Conexinas/biossíntese , Conexinas/genética , Cristalino/patologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Epitélio Corneano/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade
5.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208226

RESUMO

We investigated the role of nuclear factor of activated T cells 5 (NFAT5) under hyperosmotic conditions in human lens epithelial cells (HLECs). Hyperosmotic stress decreased the viability of human lens epithelial B-3 cells and significantly increased NFAT5 expression. Hyperosmotic stress-induced cell death occurred to a greater extent in NFAT5-knockout (KO) cells than in NFAT5 wild-type (NFAT5 WT) cells. Bcl-2 and Bcl-xl expression was down-regulated in NFAT5 WT cells and NFAT5 KO cells under hyperosmotic stress. Pre-treatment with a necroptosis inhibitor (necrostatin-1) significantly blocked hyperosmotic stress-induced death of NFAT5 KO cells, but not of NFAT5 WT cells. The phosphorylation levels of receptor-interacting protein kinase 1 (RIP1) and RIP3, which indicate the occurrence of necroptosis, were up-regulated in NFAT5 KO cells, suggesting that death of these cells is predominantly related to the necroptosis pathway. This finding is the first to report that necroptosis occurs when lens epithelial cells are exposed to hyperosmolar conditions, and that NFAT5 is involved in this process.


Assuntos
Células Epiteliais/metabolismo , Células Epiteliais/patologia , Cristalino/patologia , Pressão Osmótica , Estresse Fisiológico , Fatores de Transcrição/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Humanos , Soluções Hipertônicas/toxicidade , Inflamação/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Pressão Osmótica/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Estresse Fisiológico/efeitos dos fármacos
6.
PLoS One ; 16(7): e0254370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34252119

RESUMO

PURPOSE: Lens opacification is a common complication after pars plana vitrectomy (PPV) and knowing its progression would facilitate consulting patients. The purpose of this study was to evaluate a quantitative model for lens-status-monitoring after PPV with C3F8 gas. Our model was evaluated in rhegmatogenous retinal detachment (RRD) patients of various age and lens densitometry (LD). METHODS: Data between March 2018 and March 2020 were evaluated retrospectively. LD measurements of the PentacamHR® Nucleus Staging mode (PNS) were used to quantify lens opacification over time. A mixed-effect regression model was designed, to enable LD predictions at any time postoperatively. Calculations were based on patient's age and baseline LD as dependent variables. Six patients were randomly excluded during model development, to be used for testing its power afterwards. RESULTS: 34 patients (male 19 [55.9%], female 15 [44.1%]) matched the inclusion criteria. Average age was 58.5 years (32-77;±4.3) and average follow-up was 7.2 months (3,4-23.1;±1,8). Mean baseline LD of the treated and fellow eye before surgery were 10.9% (8.7%-14.8%;±0.8) and 10.7% (8.5%-14.1%;±0.6), respectively. Using our prediction model, LD values for the six pre-selected patients closely match the observed data with an average deviation of 1.07%. CONCLUSIONS: Evaluation of age and baseline LD using a mixed-effect regression model might predict cataract progression in RRD patients treated with PPV and C3F8-gas. Such a tool could be considered during cataract surgery consultation in these patients.


Assuntos
Catarata/diagnóstico , Densitometria , Progressão da Doença , Cristalino/patologia , Descolamento Retiniano/cirurgia , Vitrectomia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios , Estatística como Assunto
7.
Aging (Albany NY) ; 13(11): 15255-15268, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34096886

RESUMO

Cataract is the leading cause of visual impairment globally. Racemization of lens proteins may contribute to cataract formation in aging individuals. As a special type of age-related cataract (ARC), diabetic cataract (DC) is characterized by the early onset of cortical opacification and finally developed into a mixed type of cortical and nuclear opacification. We compared racemization of Asp 58 residue, a hotspot position in αA-crystallin, from the cortex and nucleus of diabetic and age-matched senile cataractous lenses, by identifying L-Asp/L-isoAsp/D-Asp/D-isoAsp by mass spectrometry. Compared to nondiabetic cataractous lenses, DC lenses showed a significantly increased cortex/nucleus ratio of D-Asp 58, which originated primarily from an increased percentage of D-Asp 58 in the lens cortex of DC. Moreover, patients diagnosed with diabetes for over 10 years showed a lower cortex/nucleus ratio of D-isoAsp 58 in the lens compared with those who had a shorter duration of diabetes, which originated mainly from an increased percentage of D-isoAsp 58 in the lens nucleus of DC with increasing time of hyperglycemia. Further analysis confirmed decreased protein solubility in diabetic cataractous lenses. The different racemization pattern in DC may be distinguished from ARC and influence its phenotype over the protracted duration of diabetes.


Assuntos
Ácido Aspártico/metabolismo , Catarata/patologia , Cristalinas/química , Cristalino/patologia , Idoso , Envelhecimento/patologia , Núcleo Celular/metabolismo , Feminino , Humanos , Isomerismo , Masculino , Solubilidade
8.
Medicine (Baltimore) ; 100(22): e26094, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087854

RESUMO

RATIONALE: Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a genetic disease that affects multiple organs. The report here concerns a patient with MSMDS, who is known so far as the youngest among all the reported patients. In addition to the typical manifestations, we observed previously unreported ocular abnormalities, including persistent anterior tunica vasculosa lentis (TVL) and early-onset retinal arteriolar tortuosity, by the fluorescein angiography (FA). PATIENT CONCERNS: The patient was admitted to the neonatal intensive care unit immediately after birth for a diagnosis of urinary system dysplasia during fetal life. After a thorough examination, the patient was found with patent ductus arteriosus, pulmonary hypertension, cerebrovascular disease, hypotonic bladder, intestinal malrotation, and congenital mydriasis. The FA of the eyes undertaken in her 6-week demonstrated perfused vasculature in the persistent anterior TVL and prominent retinal arteriolar tortuosity. The whole exome sequencing revealed a de novo heterozygous ACTA2 gene missense mutation p.R179H. DIAGNOSES: The patient was diagnosed with MSMDS. INTERVENTIONS: Follow-up observation. OUTCOMES: At the 3-month follow-up, no change of the ocular disease was observed. LESSONS: The persistent anterior TVL in this case implies that ACTA2 p.R179H mutation affects not only the smooth muscle cells but also the pericytes, and further affects the TVL regression. The prominent retinal arteriolar tortuosity in this 6-week-old infant indicates that the retinal arteriolar tortuosity can present early in MSMDS.


Assuntos
Doenças do Cristalino/complicações , Doenças do Cristalino/patologia , Doenças Musculares/complicações , Doenças Musculares/patologia , Feminino , Humanos , Recém-Nascido , Cristalino/patologia , Músculo Liso/patologia , Doenças Retinianas/complicações , Doenças Retinianas/patologia
9.
Sci Rep ; 11(1): 12685, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135449

RESUMO

The aim of this study is to investigate the impact of age-related lens opacities and advanced cataract, quantified by LOCS III grading, on quantitative autofluorescence (qAF) measurements in patients before and after cataract surgery. Images from a randomized controlled trial evaluating the impact of femtosecond-laser assisted cataract surgery (FLACS) on retinal thickness were analyzed post-hoc. One-hundred and twenty eyes from 60 consecutive patients with age-related cataract were included and assessed with qAF and optical coherence tomography (OCT) before, 1, 3 and 6 weeks after cataract surgery (randomized 1:1 to FLACS or phacoemulsification). LOCS III grading was performed before surgery. Pre- to post-surgical qAF values, as well as the impact of LOCS III gradings, surgery technique, gender, axial length and age on post-surgery qAF values was investigated using generalized linear mixed models. For this analysis, 106 eyes from 53 patients were usable. No difference in qAF was found between FLACS and phacoemulsification (p > 0.05) and results were pooled for the total cohort. Mean pre-surgical qAF was 89.45 ± 44.9 qAF units, with a significant mean increase of 178.4-191.6% after surgery (p < 0.001). No significant difference was found between the three follow-up visits after surgery (p > 0.05). Higher LOCS III cortical opacity quantifications were associated with a significantly greater increase in qAF after surgery (estimate: 98.56, p = 0.006) and nuclear opacities showed a trend toward an increased change (estimate: 48.8, p = 0.095). Considerable interactions were identified between baseline qAF and cortical opacities, nuclear opacities and posterior subcapsular opacities, as well as nuclear opacities and cortical opacities (p = 0.012, p = 0.064 and p = 0.069, respectively). Quantitative autofluorescence signals are significantly reconstituted after cataract surgery and LOCS III gradings are well associated with post-surgical qAF values. Careful consideration of age-related lens opacities is vital for the correct interpretation of qAF, especially in retinal diseases affecting the elderly.ClinicalTrials.gov Identifier: NCT03465124.


Assuntos
Extração de Catarata , Catarata/patologia , Cristalino/patologia , Imagem Óptica , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluorescência , Humanos , Masculino , Pessoa de Meia-Idade , Facoemulsificação , Tomografia de Coerência Óptica
10.
Exp Eye Res ; 209: 108645, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34087204

RESUMO

Lens-specific beaded filament (BF) proteins CP49 and filensin interact with the C-terminus of the water channel protein Aquaporin 0 (AQP0). Previously we have reported that a C-terminally end-deleted AQP0-expressing transgenic mouse model AQP0ΔC/ΔC developed abnormal optical aberrations in the lens. This investigation was undertaken to find out whether the total loss of the BF structural proteins alter the optical properties of the lens and cause optical aberrations similar to those in AQP0ΔC/ΔC lenses; also, to map the changes in the optical quality as a function of age in the single or double BF protein knockouts as well as to assess whether there is any significant change in the water channel function of AQP0 in these knockouts. A double knockout mouse (2xKO) model for CP49 and filensin was developed by crossing CP49-KO and filensin-KO mice. Wild type, CP49-KO, filensin-KO, and 2xKO lenses at different ages, and AQP0ΔC/ΔC lenses at postnatal day-17 were imaged through the optical axis and compared for optical quality and focusing property. All three knockout models showed loss of transparency, and development of abnormal optical distortion aberration similar to that in AQP0ΔC/ΔC. Copper grid focusing by the lenses at 6, 9 and 12 months of age showed an increase in aberrations as age advanced. With progression in age, the grid images produced by the lenses of all KO models showed a transition from a positive barrel distortion aberration to a pincushion distortion aberration with the formation of three distinct aberration zones similar to those produced by AQP0ΔC/ΔC lenses. Water permeability of fiber cell membrane vesicles prepared from CP49-KO, filensin-KO and 2xKO models, measured using the osmotic shrinking method, remained similar to that of the wild type without any statistically significant alteration (P > 0.05). Western blotting and quantification revealed the expression of comparable quantities of AQP0 in all three BF protein KOs. Our study reveals that loss of single or both beaded filament proteins significantly affect lens refractive index gradient, transparency and focusing ability in an age-dependent manner and the interaction of BF proteins with AQP0 is critical for the proper functioning of the lens. The presence of BF proteins is necessary to prevent abnormal optical aberrations and maintain homeostasis in the aging lens.


Assuntos
Aquaporinas/genética , Catarata/genética , Proteínas do Olho/genética , Regulação da Expressão Gênica , Proteínas de Filamentos Intermediários/genética , Cristalino/metabolismo , RNA/genética , Animais , Aquaporinas/biossíntese , Western Blotting , Catarata/metabolismo , Catarata/fisiopatologia , Modelos Animais de Doenças , Proteínas do Olho/biossíntese , Proteínas de Filamentos Intermediários/biossíntese , Cristalino/patologia , Cristalino/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
Exp Eye Res ; 209: 108664, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34126081

RESUMO

Immune cells, both tissue resident immune cells and those immune cells recruited in response to wounding or degenerative conditions, are essential to both the maintenance and restoration of homeostasis in most tissues. These cells are typically provided to tissues by their closely associated vasculatures. However, the lens, like many of the tissues in the eye, are considered immune privileged sites because they have no associated vasculature. Such absence of immune cells was thought to protect the lens from inflammatory responses that would bring with them the danger of causing vision impairing opacities. However, it has now been shown, as occurs in other immune privileged sites in the eye, that novel pathways exist by which immune cells come to associate with the lens to protect it, maintain its homeostasis, and function in its regenerative repair. Here we review the discoveries that have revealed there are both innate and adaptive immune system responses to lens, and that, like most other tissues, the lens harbors a population of resident immune cells, which are the sentinels of danger or injury to a tissue. While resident and recruited immune cells are essential elements of lens homeostasis and repair, they also become the agents of disease, particularly as progenitors of pro-fibrogenic myofibroblasts. There still remains much to learn about the function of lens-associated immune cells in protection, repair and disease, the knowledge of which will provide new tools for maintaining the core functions of the lens in the visual system.


Assuntos
Células Epiteliais/imunologia , Traumatismos Oculares/imunologia , Imunidade Celular , Cristalino/lesões , Cicatrização/imunologia , Animais , Células Epiteliais/patologia , Traumatismos Oculares/patologia , Fibrose/imunologia , Fibrose/patologia , Humanos , Cristalino/imunologia , Cristalino/patologia
12.
Biochem J ; 478(12): 2285-2296, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34143864

RESUMO

Transforming growth factor-ß2 (TGFß2)-mediated epithelial to mesenchymal transition (EMT) in lens epithelial cells (LECs) has been implicated in fibrosis associated with secondary cataracts. In this study, we investigated whether the receptor for advanced glycation end products (RAGE) plays a role in TGFß2-mediated EMT in LECs. Unlike in the LECs from wild-type mice, TGFß2 failed to elicit an EMT response in LECs from RAGE knockout mice. The lack of RAGE also diminished TGFß2-mediated Smad signaling. In addition, treatment with TGFß2 increased IL-6 levels in LECs from wild-type mice but not in those from RAGE knockout mice. Treatment of human LECs with the RAGE inhibitor FPS-ZM1 reduced TGFß2-mediated Smad signaling and the EMT response. Unlike that in wild-type lenses, the removal of fiber cell tissue in RAGE knockout lenses did not result in elevated levels of α-smooth muscle actin (α-SMA), fibronectin (FN), and integrin ß1 in capsule-adherent LECs. Taken together, these results suggest that TGFß2 signaling is intricately linked to RAGE. Targeting RAGE could be explored as a therapeutic strategy against secondary cataracts.


Assuntos
Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Cristalino/patologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Animais , Células Epiteliais/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Cristalino/metabolismo , Cristalino/cirurgia , Camundongos , Receptor para Produtos Finais de Glicação Avançada/genética , Transdução de Sinais , Fator de Crescimento Transformador beta2/genética
13.
FASEB J ; 35(6): e21593, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33991133

RESUMO

Diabetes is a major risk factor for cataract, the leading cause of blindness worldwide. There is an unmet need for a realistic model of diabetic cataract for mechanistic and longitudinal studies, as existing models do not reflect key aspects of the complex human disease. Here, we introduce and characterize diabetic cataract in the Nile grass rat (NGR, Arvicanthis niloticus), an established model of metabolic syndrome and type 2 diabetes (T2D). We conducted a longitudinal study of cataract in over 88 NGRs in their non-diabetic, pre-diabetic, and diabetic stages of metabolism. Oral glucose tolerance test (OGTT) results distinguished the metabolic stages. Diverse cataract types were observed in the course of diabetes, including cortical, posterior subcapsular (PSC), and anterior subcapsular (ASC), all of which succeeded a characteristic dotted ring stage in all animals. The onset ages of diabetes and cataract were 44 ± 3 vs 29 ± 1 (P < .001) and 66 ± 5 vs 58 ± 6 (not significant) weeks in females and males, respectively. Histological analysis revealed fiber disorganization, vacuolar structures, and cellular proliferation and migration in cataractous lenses. The lens epithelial cells (LECs) in non-diabetic young NGRs expressed the stress marker GRP78, as did LECs and migrated cells in the lenses of diabetic animals. Elucidating mechanisms underlying LEC proliferation and migration will be clinically valuable in prevention and treatment of posterior capsule opacification, a dreaded complication of cataract surgery. Marked changes in N-cadherin expression emphasized a role for LEC integrity in cataractogenesis. Apoptotic cells were dispersed in the equatorial areas in early cataractogenesis. Our study reveals diverse cataract types that spontaneously develop in the diabetic NGR, and which uniquely mirror the cataract and its chronic course of development in individuals with diabetes. We provide mechanistic insights into early stages of diabetic cataract. These unique characteristics make NGR highly suited for mechanistic studies, especially in the context of metabolism, diabetes, and aging.


Assuntos
Catarata/patologia , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Células Epiteliais/patologia , Cristalino/patologia , Animais , Catarata/etiologia , Movimento Celular , Proliferação de Células , Complicações do Diabetes/etiologia , Feminino , Estudos Longitudinais , Masculino , Fenótipo , Ratos
14.
Transl Res ; 236: 52-71, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34051364

RESUMO

The eye is regarded as an immune privileged site. Since the presence of a vasculature would impair vision, the vasculature of the eye is located outside of the central light path. As a result, many regions of the eye evolved mechanisms to deliver immune cells to sites of dysgenesis, injury, or in response to the many age-related pathologies. While the purpose of these immune responses is reparative or protective, cytokines released by immune cells compromise visual acuity by inducing inflammation and fibrosis. The response to traumatic or pathological injury is distinct in different regions of the eye. Age-related diseases impact both the anterior and posterior segment and lead to reduced quality of life and blindness. Here we focus attention on the role that inflammation and fibrosis play in the progression of age-related pathologies of the cornea and the lens as well as in glaucoma, the formation of epiretinal membranes, and in proliferative vitreoretinopathy.


Assuntos
Traumatismos Oculares/imunologia , Traumatismos Oculares/patologia , Imunidade , Fibrose , Humanos , Inflamação/patologia , Cristalino/patologia
15.
Chem Biol Interact ; 344: 109495, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961834

RESUMO

Cataracts, a clouding of the eye lens, are a leading cause of visual impairment and are responsible for one of the most commonly performed surgical procedures worldwide. Although generally safe and effective, cataract surgery can lead to a secondary lens abnormality due to transition of lens epithelial cells to a mesenchymal phenotype (EMT) and opacification of the posterior lens capsular bag. Occurring in up to 40% of cataract cases over time, posterior capsule opacification (PCO) introduces additional treatment costs and reduced quality of life for patients. Studies have shown that PCO pathogenesis is driven in part by TGF-ß, signaling through the action of the family of Smad coactivators to effect changes in gene transcription. In the present study, we evaluated the ability of Smad-7, a well characterized inhibitor of TGF-ß -mediated Smad signaling, to suppress the EMT response in lens epithelial cells associated with PCO pathogenesis. Treatment of lens epithelial cells with a cell-permeable form of Smad7 variant resulted in suppressed expression of EMT markers such as alpha smooth muscle actin and fibronectin. A single application of cell-permeable Smad7 variant in the capsular bag of a mouse cataract surgery model resulted in suppression of gene transcripts encoding alpha smooth muscle actin and fibronectin. These results point to Smad7 as a promising biotherapeutic agent for prevention or substantial reduction in the incidence of PCO following cataract surgery.


Assuntos
Opacificação da Cápsula/prevenção & controle , Peptídeos Penetradores de Células/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Produtos do Gene tat/uso terapêutico , Cristalino/efeitos dos fármacos , Proteína Smad7/uso terapêutico , Actinas/metabolismo , Animais , Opacificação da Cápsula/etiologia , Opacificação da Cápsula/patologia , Catarata/complicações , Catarata/patologia , Células Epiteliais/efeitos dos fármacos , Cristalino/patologia , Camundongos Transgênicos , Domínios Proteicos , Proteínas Recombinantes/uso terapêutico
16.
Sci Rep ; 11(1): 9702, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958690

RESUMO

Optical opacity reduces quality of biometry images, making it potentially difficult to find the correct location for irradiation during femtosecond laser-assisted cataract surgery (FLACS). After experiencing a case of posterior capsule (PC) rupture because of optical opacity, we started lens thickness (LT) inspection, which indicates comparison of between intra- and pre-operatively measured LT. We retrospectively investigated the effectiveness of the LT inspection. One observer reviewed all FLACS treatment summaries for 3 years by CATALYS in the Jikei University Hospital, Tokyo. Based on the lines defining the PC on intraoperative OCT images, all cases were classified into three groups: undescribed, appropriate and inappropriate PC. Among the 1070 cases, 1047 cases had appropriate PC. In 19 cases, the PC line was undescribed because of dense cataract. Among 474 cases with no inspection, 4 cases had an inappropriate PC. Whereas, in 596 cases with the LT inspection, there was no case of an inappropriate PC. LT inspection significantly reduced the cases with inappropriate PC. The safety margins normally work to prevent severe complications. However, rare outlier cases had a high risk of severe complications. We propose LT inspection could be the most practical and convenient way for safety surgery.


Assuntos
Biometria/métodos , Extração de Catarata/métodos , Cristalino/patologia , Cápsula Posterior do Cristalino/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cápsula Posterior do Cristalino/cirurgia , Período Pré-Operatório , Tomografia de Coerência Óptica , Adulto Jovem
17.
Biomed Res Int ; 2021: 9385293, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33834076

RESUMO

Purpose: The purpose of this study is to investigate the clinical characteristics of presenile cataract and compare that to ten years ago in southern Taiwan. Methods: The subjects who received cataract surgeries aged 30 to 54 years were recruited in Kaohsiung Chang Gung Memorial Hospital during September 2015 and August 2016. Patients with uveitis or those who received combined cataract surgeries were excluded. Retrospective chart review was performed in this study. Results: A total number of 2439 cataract surgeries were performed, and 302 (12.38%) eyes were having presenile cataract. Mean age was 47.55 ± 5.64 years old, and mean axial length was 26.00 ± 2.89 mm. Among 302 presenile cataract eyes, the leading cause was high myopia (defined as mean axial length ≥ 26 mm, 47.02%), followed by diabetes mellitus (26.82%). In types of lens opacity analysis, 67.55% of the patients were nuclear sclerosis dominant. Compared to the previous study 10 years ago, the leading cause of presenile cataract changed from idiopathy to high myopia, whereas the lens opacity types changed from posterior subcapsular opacity dominant to nuclear sclerosis dominant. Conclusions: High myopia has become the most important clinical characteristic associated with presenile cataract in a myopia epidemic area, and the most common type of lens opacity was nuclear sclerosis. With the increasing prevalence of high myopia, we should pay more attention to the management of presenile cataracts in high myopes to avoid complications.


Assuntos
Catarata/epidemiologia , Comprimento Axial do Olho , Catarata/complicações , Diabetes Mellitus/patologia , Feminino , Humanos , Incidência , Cristalino/patologia , Masculino , Pessoa de Meia-Idade , Miopia/complicações , Taiwan/epidemiologia
18.
PLoS One ; 16(4): e0250277, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33857260

RESUMO

Post-translational modifications are often detected in age-related diseases associated with protein misfolding such as cataracts from aged lenses. One of the major post-translational modifications is the isomerization of aspartate residues (L-isoAsp), which could be non-enzymatically and spontaneously occurring in proteins, resulting in various effects on the structure and function of proteins including short peptides. We have reported that the structure and function of an αA66-80 peptide, corresponding to the 66-80 (66SDRDKFVIFLDVKHF80) fragment of human lens αA-crystallin, was dramatically altered by the isomerization of aspartate residue (Asp) at position 76. In the current study, we observed amyloid-like fibrils of L-isoAsp containing αA66-80 using electron microscopy. The contribution of each amino acid for the peptide structure was further evaluated by circular dichroism (CD), bis-ANS, and thioflavin T fluorescence using 14 alanine substituents of αA66-80, including L-isoAsp at position 76. CD of 14 alanine substituents demonstrated random coiled structures except for the substituents of positively charged residues. Bis-ANS fluorescence of peptide with substitution of hydrophobic residue with alanine revealed decreased hydrophobicity of the peptide. Thioflavin T fluorescence also showed that the hydrophobicity around Asp76 of the peptide is important for the formation of amyloid-like fibrils. One of the substitutes, H79A (SDRDKFVIFL(L-isoD)VKAF) demonstrated an exact ß-sheet structure in CD and highly increased Thioflavin T fluorescence. This phenomenon was inhibited by the addition of protein-L-isoaspartate O-methyltransferase (PIMT), which is an enzyme that changes L-isoAsp into Asp. These interactions were observed even after the formation of amyloid-like fibrils. Thus, isomerization of Asp in peptide is key to form fibrils of αA-crystallin-derived peptide, and L-isoAsp on fibrils can be a candidate for disassembling amyloid-like fibrils of αA-crystallin-derived peptides.


Assuntos
Amiloide/química , Ácido Aspártico/metabolismo , Ácido Isoaspártico/metabolismo , Processamento de Proteína Pós-Traducional , Cadeia A de alfa-Cristalina/metabolismo , Envelhecimento/genética , Alanina/química , Alanina/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Amiloide/genética , Amiloide/metabolismo , Ácido Aspártico/química , Benzotiazóis/química , Catarata/genética , Catarata/metabolismo , Catarata/patologia , Corantes Fluorescentes/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ácido Isoaspártico/química , Isomerismo , Cristalino/metabolismo , Cristalino/patologia , Microscopia Eletrônica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/química , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/metabolismo , Eletricidade Estática , Cadeia A de alfa-Cristalina/genética
19.
Nat Commun ; 12(1): 2102, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833231

RESUMO

High myopia is a leading cause of blindness worldwide. Myopia progression may lead to pathological changes of lens and affect the outcome of lens surgery, but the underlying mechanism remains unclear. Here, we find an increased lens size in highly myopic eyes associated with up-regulation of ß/γ-crystallin expressions. Similar findings are replicated in two independent mouse models of high myopia. Mechanistic studies show that the transcription factor MAF plays an essential role in up-regulating ß/γ-crystallins in high myopia, by direct activation of the crystallin gene promoters and by activation of TGF-ß1-Smad signaling. Our results establish lens morphological and molecular changes as a characteristic feature of high myopia, and point to the dysregulation of the MAF-TGF-ß1-crystallin axis as an underlying mechanism, providing an insight for therapeutic interventions.


Assuntos
Cristalino/patologia , Fatores de Transcrição Maf/metabolismo , Miopia Degenerativa/patologia , Fator de Crescimento Transformador beta1/metabolismo , beta-Cristalinas/biossíntese , gama-Cristalinas/biossíntese , Animais , Feminino , Humanos , Cristalino/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Proteínas Smad/metabolismo , Regulação para Cima/genética
20.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760112

RESUMO

Age-related cataract (ARC) is the primary cause of blindness worldwide. Abnormal expression of microRNAs (miRNAs/miRs) has been reported to be associated with multiple diseases, including ARC. However, the potential role of miR-124 in ARC remains unclear. The present study used the human lens epithelial cell line, SRA01/04, to investigate the potential role of miR-124 in ARC. Reverse transcription-quantitative PCR analysis was performed to detect the expression levels of miR-124, protein sprouty homolog 2 (SPRY2) and matrix metalloproteinase-2 (MMP-2) in ARC tissues, while western blotting was performed to detect the protein levels of SPRY2 and MMP-2. Cell viability and apoptosis of SRA01/04 cells were assessed via Cell Counting Kit-8 and TUNEL assays, respectively. The interaction between miR-124 and SPRY2 or MMP-2 was confirmed via the dual-luciferase reporter and RNA immunoprecipitation assays. The results of the present study demonstrated that miR-124 expression was significantly upregulated in ARC tissues, and knockdown of miR-124 increased SRA01/04 cell viability and suppressed apoptosis. In addition, SPRY2 and MMP-2 expression was decreased in ARC tissues, and were demonstrated to directly bind to miR-124. Overexpression of SPRY2 or MMP-2 increased SRA01/04 cell viability and repressed apoptosis, the effects of which were reversed following overexpression of miR-124. Taken together, these results suggested that miR-124 facilitates lens epithelial cell apoptosis by modulating SPRY2 or MMP-2 expression, providing a novel treatment approach for ARC.


Assuntos
Catarata/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cristalino/metabolismo , Metaloproteinase 2 da Matriz/genética , Proteínas de Membrana/genética , MicroRNAs/genética , Idoso , Apoptose/genética , Catarata/metabolismo , Catarata/patologia , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Cristalino/patologia , Masculino , Pessoa de Meia-Idade
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