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Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) degeneration and vision loss. Since irreversible neurodegeneration occurs before diagnosable, early diagnosis and effective neuroprotection are critical for glaucoma management. Small extracellular vesicles (sEVs) are demonstrated to be potential novel biomarkers and therapeutics for a variety of diseases. In this study, it is found that intravitreal injection of circulating plasma-derived sEVs (PDEV) from glaucoma patients ameliorated retinal degeneration in chronic ocular hypertension (COH) mice. Moreover, it is found that PDEV-miR-29s are significantly upregulated in glaucoma patients and are associated with visual field defects in progressed glaucoma. Subsequently, in vivo and in vitro experiments are conducted to investigate the possible function of miR-29s in RGC pathophysiology. It is showed that the overexpression of miR-29b-3p effectively prevents RGC degeneration in COH mice and promotes the neuronal differentiation of human induced pluripotent stem cells (hiPSCs). Interestingly, engineered sEVs with sufficient miR-29b-3p delivery exhibit more effective RGC protection and neuronal differentiation efficiency. Thus, elevated PDEV-miR-29s may imply systemic regulation to prevent RGC degeneration in glaucoma patients. This study provides new insights into PDEV-based glaucoma diagnosis and therapeutic strategies for neurodegenerative diseases.
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BACKGROUND: To report a case of retinitis with multiple intraocular viral infections after second haematopoietic stem cell transplantation. CASE PRESENTATION: A 39-year-old female patient developed retinitis after a second haematopoietic stem cell transplant. Right eye was tested for three viral infections- cytomegalovirus, EpsteinâBarr virus and herpes simplex virus, while left was infected with cytomegalovirus. The patient was subsequently treated with vitreous cavity ganciclovir injections, and 1 week later both eyes tested negative for aqueous humour viruses. DISCUSSION AND CONCLUSION: CMV, EBV and HSV belong to the herpes virus family. They are all commonly observed in the body and represent opportunity infectious viruses. The retinitis they cause have different characteristics. But simultaneous infection of the eye by multiple viruses is quite rare. In this case, three viruses were detected in the patient's eye, but whether the retina was caused by all three viruses at the same time could not be determined. A satisfactory outcome was achieved after treatment with vitreous cavity ganciclovir injection.
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Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Retinite , Viroses , Feminino , Humanos , Adulto , Herpesvirus Humano 4 , Citomegalovirus , Simplexvirus , Infecções por Vírus Epstein-Barr/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Retina , Ganciclovir/uso terapêuticoRESUMO
BACKGROUND: Optical coherence tomography angiography (OCTA) enables fast and non-invasive high-resolution imaging of retinal microvasculature and is suggested as a potential tool in the early detection of retinal microvascular changes in Alzheimer's Disease (AD). We developed a standardised OCTA analysis framework and compared their extracted parameters among controls and AD/mild cognitive impairment (MCI) in a cross-section study. METHODS: We defined and extracted geometrical parameters of retinal microvasculature at different retinal layers and in the foveal avascular zone (FAZ) from segmented OCTA images obtained using well-validated state-of-the-art deep learning models. We studied these parameters in 158 subjects (62 healthy control, 55 AD and 41 MCI) using logistic regression to determine their potential in predicting the status of our subjects. RESULTS: In the AD group, there was a significant decrease in vessel area and length densities in the inner vascular complexes (IVC) compared with controls. The number of vascular bifurcations in AD is also significantly lower than that of healthy people. The MCI group demonstrated a decrease in vascular area, length densities, vascular fractal dimension and the number of bifurcations in both the superficial vascular complexes (SVC) and the IVC compared with controls. A larger vascular tortuosity in the IVC, and a larger roundness of FAZ in the SVC, can also be observed in MCI compared with controls. CONCLUSION: Our study demonstrates the applicability of OCTA for the diagnosis of AD and MCI, and provides a standard tool for future clinical service and research. Biomarkers from retinal OCTA images can provide useful information for clinical decision-making and diagnosis of AD and MCI.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Angiofluoresceinografia/métodos , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Doença de Alzheimer/diagnóstico por imagem , Microvasos/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagemRESUMO
AIM: To introduce and evaluate the clinical efficacy of a new technique, the use of viscoelastic substances (VS) to close leaking sclerotomy in 23G microincision vitrectomy, and to observe its effect on the visual acuity and intraocular pressure (IOP) of patients. METHODS: Patients who underwent 23G vitrectomy in Ningbo Eye Hospital before the use of VS technique (June 2019 to September 2020) and after the use of VS technique (October 2020 to December 2021) were selected as the subjects of this study. The above cases underwent operation by the same surgeon and were retrospectively analyzed. VS technique was used as the alternative to suturing, in which a small amount of VS was injected at the leaking sclerotomy and then gently massaged to confirm leaking sclerotomy closure. RESULTS: A total of 174 eyes were covered in the study, including 84 eyes in the control group (before the use of VS technique) and 90 eyes in the VS technique group. The number of eyes that needed to be sutured decreased considerably from 42.9% in the control group to 3.3% in the VS technique group, and the proportion of subconjunctival hemorrhage at 1-2d after surgery decreased remarkably from 35.7% in the control group to 2.2% in the VS technique group. No substantial differences in the incidence of mean IOP and low IOP were found between 1-2 and 3-20d after surgery in the VS technique group. No major complications associated with VS technique were identified during the study. CONCLUSION: In 23G microincision vitrectomy, VS technique is a safe, simple, and effective method to close leaking sclerotomy.
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OBJECTIVE: To clarify whether fucoxanthin plays a protective role and regulates parkin-mediated mitophagy on retinal ganglion cells (RGCs) against glutamate excitotoxicity. METHODS: The excitotoxicity model of primary RGCs was carried out with glutamate. Mitochondrial membrane potential was measured by JC-1 kit (Abcam, USA). The apoptotic rate and cytotoxicity were detected by Hoechst staining and lactate dehydrogenase (LDH) kit (Takara, Japan). Mitochondria was assessed by MitoTracker staining and confocal microscopy. The mRNA levels and protein expression levels of Bax, Bcl-2, parkin, optineurin, LC3, and LAMP1 in RGCs were analyzed by quantitative PCR and immunoblotting. Finally, the mitochondrial health score and mitophagy were assessed by transmission electron microscopy. RESULTS: Fucoxanthin increased the mitochondrial membrane potential of RGCs, reduced cytotoxicity, and decreased apoptosis in RGCs under glutamate excitotoxicity. It also enhanced expression levels of parkin, optineurin, and LAMP1, and upgraded the ratio of LC3-II to LC3-I. Meanwhile, fucoxanthin increased LC3 and MitoTracker co-localization staining. In addition, up-regulated mitochondrial health score, and the number of autophagosomes and mitophagosomes were observed in fucoxanthin-treated RGCs under glutamate excitotoxicity. CONCLUSION: Fucoxanthin may exert its neuroprotective effect on RGCs via promoting parkin-mediated mitophagy under glutamate excitotoxicity. The neuroprotective effect of fucoxanthin in glaucomatous neurodegeneration and ocular diseases characterized by impaired mitophagy warrants further investigation.
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Fármacos Neuroprotetores , Células Ganglionares da Retina , Células Ganglionares da Retina/metabolismo , Ácido Glutâmico/metabolismo , Mitofagia , Fármacos Neuroprotetores/farmacologia , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
Disturbed circadian rhythms have been a risk factor for type 2 diabetes mellitus (T2DM). Melatonin is the major chronobiotic hormone regulating both circadian rhythm and glucose homeostasis. The rs10830963 (G allele) of the melatonin receptor 1B (MTNR1B) gene has the strongest genetic associations with T2DM according to several genome-wide association studies. The MTNR1B rs10830963 G allele is also associated with disturbed circadian phenotypes and altered melatonin secretion, both factors that can elevate the risk of diabetes. Furthermore, evolutionary studies implied the presence of selection pressure and ethnic diversity in MTNR1B, which was consistent with the "thrifty gene" hypothesis in T2DM. The rs10830963 G risk allele is associated with delayed melatonin secretion onset in dim-light and prolonged duration of peak melatonin. This delayed melatonin secretion may help human ancestors adapt to famine or food shortages during long nights and early mornings and avoid nocturnal hypoglycemia but confers susceptibility to T2DM due to adequate energy intake in modern society. We provide new insight into the role of MTNR1B variants in T2DM via disturbed circadian rhythms from the perspective of the "thrifty gene" hypothesis; these data indicate a novel target for the prevention and treatment of susceptible populations with the thrifty genotype.
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Ritmo Circadiano , Diabetes Mellitus Tipo 2 , Melatonina , Receptor MT2 de Melatonina , Humanos , Glicemia/genética , Ritmo Circadiano/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Receptor MT2 de Melatonina/genéticaRESUMO
PURPOSE: For the tumor-specific ACE2 expression, this research aimed to establish and verify ACE2-targeted PET imaging in differentiating tumors with distinct ACE2 expression. METHODS: 68Ga-cyc-DX600 was synthesized as tracer of ACE2 PET. NOD-SCID mice were used to prepare the subcutaneous tumor models with HEK-293 or HEK-293T/hACE2 cells to verify ACE2 specificity, with other kinds of tumor cells to evaluate the diagnostic efficiency for ACE2 expression, additionally, immunohistochemical analysis and western blot were used to certify the findings on ACE2 PET, which was then performed on four cancer patients and compared with FDG PET. RESULTS: The metabolic clearance of 68Ga-cyc-DX600 was initially completed in 60 min, realizing an ACE2-dependent and organ-specific background of ACE2 PET; meanwhile, tracer uptake of subcutaneous tumor models was of a definite dependence on ACE2 expression (r = 0.903, p < 0.05), and the latter served as the primary factor when ACE2 PET was used for the differential diagnosis of ACE2-related tumors. In pre-clinical practice, a comparable tumor-to-background ratio was acquired in ACE2 PET of a lung cancer patient at 50 and 80 min post injection; the quantitative values of ACE2 PET and FDG PET were negatively correlated (r = - 0.971 for SUVmax, p = 0.006; r = - 0.994 for SUVmean, p = 0.001) in an esophageal cancer patient, no matter the primary lesion or metastasis. CONCLUSIONS: 68Ga-cyc-DX600 PET was an ACE2-specific imaging for the differential diagnosis of tumors and added complementary value to conventional nuclear medicine diagnosis, such as FDG PET on glycometabolism.
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Neoplasias Pulmonares , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Animais , Camundongos , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioisótopos de Gálio , Enzima de Conversão de Angiotensina 2 , Fluordesoxiglucose F18 , Células HEK293 , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
Purpose: To assess the alteration in the macular microvascular in type 2 diabetic patients with peripheral neuropathy (DPN) and without peripheral neuropathy (NDPN) by optical coherence tomography angiography (OCTA) and explore the correlation between retinal microvascular abnormalities and DPN disease. Methods: Twenty-seven healthy controls (42 eyes), 36 NDPN patients (62 eyes), and 27 DPN patients (40 eyes) were included. OCTA was used to image the macula in the superficial vascular complex (SVC) and deep vascular complex (DVC). In addition, a state-of-the-art deep learning method was employed to quantify the microvasculature of the two capillary plexuses in all participants using vascular length density (VLD). Results: Compared with the healthy control group, the average VLD values of patients with DPN in SVC (p = 0.010) and DVC (p = 0.011) were significantly lower. Compared with NDPN, DPN patients showed significantly reduced VLD values in the SVC (p = 0.006) and DVC (p = 0.001). Also, DPN patients showed lower VLD values (p < 0.05) in the nasal, superior, temporal and inferior sectors of the inner ring of the SVC when compared with controls; VLD values in NDPN patients were lower in the nasal section of the inner ring of SVC (p < 0.05) compared with healthy controls. VLD values in the DVC (AUC = 0.736, p < 0.001) of the DPN group showed a higher ability to discriminate microvascular damage when compared with NDPN. Conclusion: OCTA based on deep learning could be potentially used in clinical practice as a new indicator in the early diagnosis of DM with and without DPN.
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OBJECTIVES: We aimed to explore the shared and specific signalling pathways involved in diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN). METHODS: Differentially expressed mRNAs and lncRNAs were identified by high-throughput sequencing. Subsequently, functional enrichment analysis, protein-protein interaction (PPI) analysis and lncRNAs-mRNAs networks were conducted to determine the pathogenic mechanisms underlying DR, DPN and DN. RESULTS: Twenty-six biological pathways were shared among DR, DPN and DN groups compared to the type 2 diabetes mellitus (T2DM) group without complications, and most of the shared pathways and core proteins were involved in immune and inflammatory responses of microvascular damage. Cytokineâcytokine receptor interactions and chemokine signalling pathway were the most significant and specific pathways for DR, and the lncRNAâmRNA regulatory networks affected DR by targeting these pathways. Sphingolipid metabolism and neuroactive ligand-receptor pathways were found to be specific for the pathogenesis of DPN. Moreover, multiple amino acid metabolic pathways were involved in the occurrence and progression of DN. CONCLUSIONS: Diabetic retinopathy, DPN and DN exhibited commonality and heterogeneity simultaneously. The shared pathologic mechanisms underlying these diabetic complications are involved in diabetic microvascular damage via immune and inflammatory pathways. Our findings predict several biomarkers and therapeutic targets for these diabetic complications.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Neuropatias Diabéticas , Retinopatia Diabética , RNA Longo não Codificante , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/genética , Retinopatia Diabética/patologia , Sequenciamento de Nucleotídeos em Larga Escala , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: To explore the changes in blood supply and structure around the optic nerve head (ONH) in thyroid-associated ophthalmopathy (TAO) patients with suspected dysthyroid optic neuropathy (DON). METHODS: TAO patients [19 with DON; 24 non-DON (NDON); 20 with equivocal DON (EDON)], and 34 control subjects were examined. Optical coherence tomography angiography (OCTA) was used to obtain peripapillary retinal nerve fiber layer (p-RNFL) and vessel density parameters, including the ONH whole image vessel density (ONH-wiVD) and the radial peripapillary capillary vessel density (RPC-VD) in early DON. RESULTS: Although there were no differences in p-RNFL thickness among the groups, there were differences in the ONH-wiVD of each grid section and the RPC-VD in all areas (P < 0.01). Compared with healthy controls, the EDON eyes had significantly lower RPC-VDs in all aeras (P < 0.05).The peripapillary region was further divided into eight sectors, and the RPC-VD in the temporal upper, superior temporal, and temporal lower sectors in the EDON group were significantly lower than in the controls. The visual impairment was closely related to the loss of peripapillary capillary vessel density. Univariate correlation analysis showed that the ONH-wiVD and RPC-VD of the TAO groups were negatively correlated with the intraocular pressure (r = - 0.296, P = 0.006; r = - 0.258, P = 0.016 respectively). CONCLUSIONS: EDON patients had significantly lower ONH-wiVD and RPC-VD than control subjects, and the temporal and upper VDs were more likely to be affected in the early stage of TAO. The combined use of spectral domain optical coherence tomography and OCTA technologies offer a new method for early diagnosis of suspected DON patients.
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BACKGROUND: To report a very rare acute cystoid macular oedema following ganciclovir injection in patients receiving allogeneic haematopoietic stem cell transplantation. CASE PRESENTATION: A 44-year-old male patient experienced vision loss in his left eye eight months after allogeneic stem cell transplantation. Ophthalmologic examination showed posterior retinopathy with retinal haemorrhage, a yellow necrotic border, and a vascular white sheath involved in the superior temporal retina but not the posterior pole. Cytomegalovirus DNA results in both plasma and ocular fluid were positive. All tests combined with the patient's medical history suggested that his ocular disease was cytomegalovirus retinitis. Consequently, he received a weekly ganciclovir vitreous injection. The disease was visibly controlled, and the fundus condition improved after the first three treatments. However, the patient had severe vision loss in his left eye and acute cystic oedema in the macula, while the original lesion was stable two hours after the fourth treatment. The macular oedema subsided significantly on the first day. Over the next week, daily OCT findings indicated that the patient's macular oedema gradually subsided and resolved completely by the second week, and his left eye vision partially improved. CONCLUSION: Macular oedema may occur in patients with cytomegalovirus retinitis, but it rarely occurs during treatment. In this case, the patient's macular oedema appeared and resolved quickly. Macular oedema in patients with cytomegalovirus retinitis receiving vitreous cavity injections of ganciclovir needs to be further studied and discussed.
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Retinite por Citomegalovirus , Macula Lutea , Edema Macular , Adulto , Retinite por Citomegalovirus/diagnóstico , Retinite por Citomegalovirus/tratamento farmacológico , Retinite por Citomegalovirus/patologia , Ganciclovir/uso terapêutico , Humanos , Macula Lutea/patologia , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Edema Macular/etiologia , Masculino , Retina/patologiaRESUMO
Background: Circular RNAs (circRNAs), a class of non-coding and undegradable RNAs, play many pathological functions by acting as miRNA sponges, interacting with RNA-binding proteins, and others. The recent literature indicates that circRNAs possess the advanced superiority for the early screening of diabetic retinopathy (DR). Methods: CircRNA sources of peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 4), diabetes mellitus patients (DM) (n = 4), and DR patients (n = 4) were extracted for circular RNA microarray analysis. Enriched biological modules and signaling pathways were analyzed by Gene Ontology Enrichment and Kyoto Encyclopedia of Genes and Genomes analysis, respectively. Real-time quantitative reverse transcription PCR (RT-qPCR) was performed to validate differentiated levels of several circRNAs (fold change ≥2, p < .05) in different groups of healthy control subjects (n = 20), DM patients (n = 60), and DR patients (n = 42). Based on our clinical data from DR, the diagnostic performance of candidate circRNAs was measured by operating characteristic curves (ROCs). Subsequently, their circRNA-miRNA networks were constructed by bioinformatics analysis. Results: Circular RNA microarray analysis was performed, and 2,452 and 289 circRNAs were screened with differential expression in DR patients compared to healthy controls and DM patients, respectively. Enrichment analyses showed that circRNAs in DR patients were enriched in extracellular matrix (ECM)-receptor interaction and focal adhesion pathways. The top 5 differential circRNAs in circRNA microarray analysis were subsequently quantified and verified by RT-qPCR. Consistently, a significant 2.2-fold reduction of hsa_circ_0095008 and 1.7-fold increase in hsa_circ_0001883 were identified in DR patients compared to DM patients. Meanwhile, the area under curves of hsa_circ_0095008 and hsa_circ_0001883 were 0.6710 (95% CI, 0.5646-0.7775) (p = 0.003399) and 0.6071 (95% CI, 0.4953-0.7189) (p = 0.06644), respectively, indicating a good diagnostic value. Conclusion: Our study provided a new sight for the pathological mechanism of DR and revealed the potential value of hsa_circ_0095008 and hsa_circ_0001883 as diagnostic biomarkers for the early diagnosis of DR patients.
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PURPOSE: To explore the mechanisms underlying stemness maintenance of retinoblastoma (RB) stem cells (RSCs). METHODS: The retinoblastoma stem-like cells (RSLCs) were isolated by single cell cloning in combination of examination of sphere-forming capacities. The stemness of the cells were characterized by the sphere-forming capacity and the expression levels of RSCs markers. Gene manipulation was performed by lentivirus system. Transcriptional regulation was identified by qRT-PCR, luciferase reporter, nuclear run-on and DNA pull-down assay. Spearman analysis was employed for correlation analysis of genes in tumor tissues of RB patients. RESULTS: The isolated RSLCs exhibited enhanced sphere-forming capacity and constantly higher levels of CD44, ABCG2, SOX2 and PAX6, but not CD133. SOX2 positively regulated the stemness of RSLCs. SOX2 directly binds to the promoters of WWTR1 and YAP and transcriptionally activates WWTR1 and YAP. Knockdown of WWTR1 or YAP partially abolished the effect of SOX2 on the stemness of RSLCs. CONCLUSIONS: SOX2, as a key deriver, maintains RB stemness by activating Hippo/YAP signaling. Inhibition of Hippo/YAP signaling would be an effective strategy for human RB caused by SOX2 upregulation.
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Via de Sinalização Hippo/fisiologia , Células-Tronco Neoplásicas/patologia , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Fatores de Transcrição SOXB1/fisiologia , Proteínas de Sinalização YAP/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Western Blotting , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias da Retina/metabolismo , Retinoblastoma/metabolismo , Fatores de Transcrição/genética , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Purpose: To investigate the thickness changes of outer retinal layers in subjects with white matter hyperintensities (WMH) and Parkinson's Disease (PD). Methods: 56 eyes from 31 patients with WMH, 11 eyes from 6 PD patients, and 58 eyes from 32 healthy controls (HC) were enrolled in this study. A macular-centered scan was conducted on each participant using a spectral-domain optical coherence tomography (SD-OCT) device. After speckle noise reduction, a state-of-the-art deep learning method (i.e., a context encoder network) was employed to segment the outer retinal layers from OCT B-scans. Thickness quantification of the outer retinal layers was conducted on the basis of the segmentation results. Results: WMH patients had significantly thinner Henle fiber layers, outer nuclear layers (HFL+ONL) and photoreceptor outer segments (OS) than HC (p = 0.031, and p = 0.005), while PD patients showed a significant increase of mean thickness in the interdigitation zone and the retinal pigment epithelium/Bruch complex (IZ+RPE) (19.619 ± 4.626) compared to HC (17.434 ± 1.664). There were no significant differences in the thickness of the outer plexiform layer (OPL), the myoid and ellipsoid zone (MEZ), and the IZ+RPE layer between WMH and HC subjects. Similarly, there were also no obvious differences in the thickness of the OPL, HFL+ONL, MEZ and the OS layer between PD and HC subjects. Conclusion: Thickness changes in HFL+ONL, OS, and IZ+RPE layers may correlate with brain-related diseases such as WMH and PD. Further longitudinal study is needed to confirm HFL+ONL/OS/IZ+RPE layer thickness as potential biomarkers for detecting certain brain-related diseases.
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Glutamate excitotoxicity may contribute to the death of retinal ganglion cell (RGC) in glaucoma and other retinal diseases such as ischemia. Deubiquitinating enzyme (DUB) inhibitors are emerging as attractive targets for pharmacological intervention in neurodegenerative diseases. However, the role of PR-619, the broad spectrum DUB inhibitor, on RGCs under different stressful environment remains largely unknown. This study was designed to investigate the role of PR-619 in regulating mitophagy of RGCs under glutamate excitotoxicity. Primary cultured RGCs were incubated with PR-619 or vehicle control in the excitotoxicity model of 100 µM glutamate treatment. Mitochondrial membrane potential was assessed by JC-1 assay. Cytotoxicity of RGCs was measured by LDH activity. Proteins levels of parkin, optineurin, LAMP1, Bax, Bcl-2 and the LC3-II/I ratio were analyzed by western blot. The distribution and morphology of mitochondria in RGCs was stained by MitoTracker and antibody against mitochondria membrane protein, and examined by confocal microscopy. We show here that in the presence of glutamate-induced excitotoxicity, PR-619 stabilized the mitochondrial membrane potential of RGCs, decreased cytotoxicity and apoptosis, attenuated the expression of Bax. Meanwhile, PR-619 promoted the protein levels of Bcl-2, parkin, optineurin, LAMP1 and the LC3-II/I ratio. While knockdown of parkin by siRNA diminished the neuroprotective effect of PR-619 on RGCs. These findings demonstrate that PR-619 exerted a neuroprotective effect and promoted parkin-mediated mitophagy on cultured RGCs against glutamate excitotoxicity. DUB inhibitors may be useful in protecting RGCs through modulating the parkin-mediated mitophagy pathway against excitotoxicity.
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Aminopiridinas/farmacologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Glutâmico/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Tiocianatos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Potencial da Membrana Mitocondrial/fisiologia , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/metabolismoRESUMO
BACKGROUND: Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression. METHODS: Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro. RESULTS: All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia. INTERPRETATION: Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors. FUNDING: National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.
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Interação Gene-Ambiente , Predisposição Genética para Doença , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Miopia/genética , Animais , Modelos Animais de Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Miopia/metabolismo , Miopia/patologia , Esclera/metabolismo , Esclera/patologia , Transdução de SinaisRESUMO
Long noncoding RNAs (lncRNAs) have been reported to play vital roles in various human cancers. The aim of this study was to explore the critical role of lncRNA HOXA11-AS in uveal melanoma (UM) progression. Briefly, we found that HOXA11-AS is overexpressed in UM tissues and cells; HOXA11-AS could regulate UM cell growth, invasion, and apoptosis. Mechanistically, RNA immunoprecipitation demonstrated that HOXA11-AS could simultaneously interact with enhancer of zeste homolog 2 (EZH2) to suppress its target p21 protein expression. In addition, we demonstrated that HOXA11-AS functioned as a molecular sponge for miR-124, and overexpression of miR-124 attenuated the proliferation and invasion-promoting effect of HOXA11-AS. Collectively, our findings reveal an oncogenic role for HOXA11-AS in UM tumorigenesis.
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Transformação Celular Neoplásica/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Homeodomínio/genética , Melanoma/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias Uveais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Melanoma/patologia , Fatores de Transcrição/genética , Neoplasias Uveais/patologiaRESUMO
The body changes markedly during pregnancy; each system behaves differently from a nonpregnant state. As the eyes are the only windows to see directly what is going on in the internal environment, more and more researches have been done to explain the association between ocular changes and the physiological and pathological changes during pregnancy. The choroid is one of the critical parts of the eye, providing nutrition. And abnormal choroid may result in ocular dysfunction and visual problems. As the optical coherence tomography develops, a rapid, direct, noninvasive, and nontoxic way is available to obtain the choroid situation of pregnant women, which may explain the mechanism of pregnancy-related eye diseases. This review would summarize relevant original articles published from January 1, 2008 to December 1, 2016 to assess the changes of choroidal thickness (CT) with enhanced depth imaging optical coherence tomography (EDI-OCT) during pregnancy. And the relationship between choroidal thickness changes and pregnancy remains uncertain. To our knowledge, this is the first review of EDI-OCT in assessing the choroidal thickness of the pregnant women.
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PURPOSE: To investigate the association of interleukin (IL)-6 with proliferative diabetic retinopathy (PDR) of type 2 diabetes (T2D) in a Chinese population. METHODS: Two subtypes of the IL-6 promoter (-174 and -572 G/C) were genotyped in 215 T2D patients with PDR and 207 T2D patients with a normal retinal function (controls) using the PCR-RFLP method. The mRNA and protein expression of IL-6 was examined by real-time PCR. RESULTS: T2D patients with PDR had a significantly higher frequency of IL-6 -174 GC (OR 0.58; 95% CI 0.34-0.99; p = 0.011) and IL-6 -572 GG (OR 0.53; 95% CI 0.24-1.14; p = 0.016) than T2D controls. The mRNA expressions of the rs1800795 GC and rs1800796 GG genotype were significantly increased compared to other cases (Fsig = 0.002, p = 0.001, respectively), followed by a relative increase in IL-6 in protein. CONCLUSIONS: IL-6 genotypes of rs1800795 GC and rs1800796 GG might point to a relatively high risk for T2D patients suffering from PDR in a Chinese population and they were associated with elevation of IL-6 expression in both mRNA and protein.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/genética , Predisposição Genética para Doença , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , China/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Retinopatia Diabética/sangue , Retinopatia Diabética/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Frequência do Gene , Genótipo , Humanos , Incidência , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos RetrospectivosRESUMO
We conducted a meta-analysis of analytic and observational studies to evaluate the association between smoking and epiretinal membrane (ERM). The pertinent studies were identified via a literature search using three databases (MEDLINE, Cochrane Library, Embase) and the reference lists of retrieved studies. Cohort, case-control and cross-sectional studies meeting the predefined criteria were included. We extracted the odds ratios (OR) and 95% confidence intervals (CI) from each study. Overall risk estimates were pooled using random-effects models. Subgroup analyses based on several stratified factors were also performed. Two cohort studies and six cross-sectional studies involving 46,837 subjects were included. The pooled effect of all eight studies showed an unexpected significant decreased association between smoking and the occurrence of ERM (OR, 0.72; 95% CI 0.61-0.84; p = 0.29, I2 = 17.9%). Subgroup analyses supported this finding, except for the age-unadjusted group (OR, 0.87; 95% CI 0.63-1.22), the ERM classification group (cellophane macular reflex (CMR) OR, 0.93; 95% CI 0.68-1.28; preretinal macular fibrosis (PMF) OR, 0.74; 95% CI 0.41-1.32), the Asian group (OR, 0.75; 95% CI 0.52-1.09) and the past smoker group (OR, 1.02; 95% CI 0.85-1.22). The pooled effects from the current literature suggested a declining association between smoking and ERM, which requires further studies to confirm.