Circulating level of homocysteine contributes to diabetic retinopathy associated with dysregulated lipid profile and impaired kidney function in patients with type 2 diabetes mellitus.

BACKGROUND: To test the hypothesis that elevated plasma levels of homocysteine (Hcy) and lipoprotein (a) (LPA) contribute to diabetic retinopathy (DR) associated with dysregulated lipid profile, dyslipidaemia, and kidney function. METHODS: A total of 83 patients with type 2 diabetes mellitus (T2DM) were enrolled in this prospective case-control study. Patients were categorized into those with no DR (DM), non-proliferative DR (NPDR), and proliferative DR (PDR). Age and sex-matched individuals with no diabetes were included in the control group. Biochemical tests, including fasting blood glucose (FBG), glycated hemoglobin (HbA1c), Hcy, LPA, lipid profile, and urine microalbumin (UMA), were evaluated. RESULTS: Hcy was negatively correlated with high-density lipoprotein-cholesterol (HDL-C) (p < 0.05), but positively correlated with [total cholesterol (TC)-HDL-C)/HDL-C] (p < 0.05), low-density lipoprotein cholesterol (LDL-C)/HDL-C (p < 0.05), and UMA (p < 0.05). Traditional risk factors, Hcy, arteriosclerosis-associated plasma indices, and UMA, resulted as the independent risk factors for the occurrence of DM and DR. After controlling for age, sex, duration of DM, and FBG, a multiple ordinal logistic regression model showed that LPA [OR = 2.90, 95% confidence interval (95% CI) 1.16-7.23, p = 0.023)], LDL-C (OR = 4.28, 95% CI 1.24-14.79, p = 0.021), and (TC-HDL-C)/HDL-C (OR = 1.92, 95% CI 1.05-3.53, p = 0.035) were risk factors for DM and DR. CONCLUSIONS: Hcy and LPA contributed to DM and DR. Hcy was positively correlated with kidney dysfunction and the ratios of lipid profiles, and negatively with HDL-C, LPA, LDL-C, and (TC-HDL-C)/HDL-C resulted as predictors of the occurrence of DM and severity of DR.

Plasma Apolipoproteins Predicting the Occurrence and Severity of Diabetic Retinopathy in Patients With Type 2 Diabetes Mellitus.

Objective: Apolipoproteins are amphipathic molecules and the major components of plasma lipoproteins. This study aims to investigate the effects of dysregulated apolipoprotein (apo) profiles and their ratios on type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) further to test the hypothesis that altered serum level of apolipoproteins is strong biomarkers for DR. Research Design and Methods: This case-control study consists of 157 patients with T2DM including DM without DR, non-proliferative DR (NPDR), and proliferative DR (PDR). Fifty-eight age- and sex-matched healthy subjects were enrolled as normal controls. Blood biochemistry profile including serum levels of glucose, glycated hemoglobin (HbA1c), lipid profile [total cholesterol (TC), Triglycerides (TG), high and low-density lipoprotein (HDL-C and LDL-C)] was estimated. Apolipoproteins (apos, A-I, A-II, B, C-II, C-III, and E) was evaluated by protein chips (Luminex technology). Apolipoprotein ratios and arteriosclerosis-associated plasma indices were calculated. The Kruskal-Wallis test, independent sample t-test or Mann-Whitney U test, and multivariate regression analysis were performed to investigate the association of serum lipid biomarkers and the DR severity. Results: Serum level of apoA-I was negatively correlated with TC-(HDL-C)/HDL-C (p < 0.001), fasting glucose (p < 0.001), HbA1c (p < 0.001), and (p<0.001), while apoE, apoC-II/apoC-III, apoA-II/apoA-I were positively correlated with above traditional biomarkers (p < 0.001). Single variable logistic analysis results showed that body mass index (BMI) (p = 0.023), DM duration (p < 0.001), apoE (p < 0.001), apoC-II/apo C-III (p < 0.001), apoE/apoC-II (p < 0.001), atherogenic index (p = 0.013), fasting glucose (p < 0.001), HbA1c (p < 0.001), LPA (p = 0.001), and LDL-C/HDL-C (p = 0.031) were risk factors for the occurrence and severity of DR. Multivariate logistic regression mode showed that apoC-II/apoC-III and apoB/non-HDL-C (p < 0.001) as well as apoE/apoC-II (p = 0.001) were the independent risk factors for the occurrence and severity of DR-apopA-I and apoA-II are protective factors for DR-after controlling for the duration of DM, HbA1c, fasting glucose, and LPA. Conclusions: apoE, apoC-II/apoC-III, apoE/apoC-II, and apoB/non-HDL-C could be used as novel biomarkers for occurrence and severity of DR, whereas apoA-I and apoA-II resulted as protective factors for DR.

Differentially Regulated Apolipoproteins and Lipid Profiles as Novel Biomarkers for Polypoidal Choroidal Vasculopathy and Neovascular Age-Related Macular Degeneration.

Lipid dyshomeostasis has been implicated in the pathogenesis of various retinal and choroidal vascular diseases. This study aims to investigate whether apolipoprotein (apo) mediated differential regulation of lipid metabolism contributes to the phenotypes of polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD). This study involved 148 subjects including 53 patients with PCV, 44 patients with nAMD, and 51 age-, sex-matched subjects with normal fundus controls. Routine blood biochemistry profile was evaluated. Apolipoproteins was estimated by Luminex technology. After controlling for age, gender, body mass index, duration of hypertension and type 2 diabetes mellitus, apoB/non-high density lipoprotein cholesterol (HDL-C) (p=0.015) was an independent risk factor for nAMD, apoB was an independent risk factor for PCV(p=0.011), compared with control. Low-density lipoprotein cholesterol (LDL-C) was significantly higher in patients with PCV when compared with nAMD (p=0.037). Furthermore, apoB/non-HDL, LDL-C, triglycerides and were significantly correlated with the pathogenesis of subgroups of PCV and nAMD. We concluded that lipid profiles and apos are differential regulated in PCV, nAMD and their subtypes, indicating different pathogenicity contributed to the different phenotypes of PCV and nAMD. Non-pachy PCV shares pathological similarities with nAMD, which is highly correlated with age-related atherosclerosis.

Characterization of Choroidal Morphology and Vasculature in the Phenotype of Pachychoroid Diseases by Swept-Source OCT and OCTA.

The objective of this study was to characterize the choroidal morphology and vasculature in pachychoroid diseases (PCD). A total of 49 eyes with polypoidal choroidal vasculopathy (PCV), 43 eyes with neovascular age-related macular degeneration (nAMD), and 50 eyes with central serous chorioretinopathy (CSC), along with 80 healthy eyes, were enrolled in this nested case-control study. The swept-source optical coherent tomography (OCT), OCT angiography, and En face images were quantitatively analyzed. Multivariate logistic regression models showed that older age and increased vessel density (VD) in the choriocapillaris (CC) layer were independent risk factors for both PCV (page < 0.001, pVD = 0.004), and nAMD (page < 0.001, pVD = 0.005). Decreased VD in the Sattler's layer was an independent risk factor for PCV (p = 0.014). Increased VD in the Haller's layer was an independent risk factor for CSC (p = 0.001). The proportion of the diffuse type of collateral circulation in the Sattler' layer in CSC group was significantly higher than in the other three groups (p < 0.001). We concluded that the involvement of the blood flow in the CC, Haller's, and Sattler's layers are differently affected in CSC, nAMD, and PCV eyes, indicating the different pathological mechanism underlying the phenotype of PCD. The age-dependent establishment of collateral circulation in the Sattler's layer may play a compensatory role regarding ischemic injury in the development of PCD.

Associations Between Diabetic Retinal Microvasculopathy and Neuronal Degeneration Assessed by Swept-Source OCT and OCT Angiography.

Purpose: To provide clinical evidence of the associations between retinal neuronal degeneration and microvasculopathy in diabetic retinopathy (DR). Methods: This case-control study included 76 patients (76 eyes) with type 2 diabetes mellitus (DM), and refraction error between -3.0 and +3.0 D. The eyes were assigned into DM (without DR), non-proliferative DR (NPDR), and proliferative DR (PDR) groups. Age-, sex-, and refractive error-matched normal subjects were enrolled as controls. The mean retinal thickness (mRT), the relative mean thickness of the retinal nerve fiber layer (rmtRNFL, mtRNFL/mRT), ganglion cell layer (rmtGCL), ganglion cell complex (rmtGCC) layer, foveal avascular zone area (FAZa), FAZ perimeter (FAZp), FAZ circularity index (FAZ-CI), and vessel density (VD) in superficial capillary plexus (SCP) and deep capillary plexus (DCP) were assessed by swept-source optical coherence tomography (OCT) and OCT angiography (OCTA). Group comparison and Spearman's partial correlation coefficient analysis were applied to evaluate the correlation between these morphological parameters. Results: rmtRNFL, FAZa, and FAZp in SCP and DCP increased with the DR severity (p rmtRNFL < 0.001; p FAZa, SCP = 0.001; p FAZa , DCP = 0.005; p FAZp , SCP < 0.001; p FAZp , DCP < 0.001). The rmtGCL, FAZ-CI in SCP and DCP, and VD in DCP decreased with the DR severity (p rmtGCL = 0.002, p FAZ-CI , SCP = 0.002; p FAZ-CI, DCP < 0.001, p VD , DCP < 0.001). After controlling age, sex, duration of diabetes, and hypertension, the rmtRNFL, FAZa in SCP and DCP, and FAZp in SCP and DCP were correlated with the severity of DR (p < 0.05), while VD in SCP and DCP, FAZ-CI, and rmtGCL were negatively correlated with the severity of DR (p < 0.05). The rmtGCL was negatively correlated with the FAZa in SCP (r = -0.34, p = 0.002) and DCP (r = -0.23, p = 0.033), and FAZp in SCP (r = -0.37, p = 0.001) and DCP (r = -0.32, p = 0.003), but positively correlated with VD in SCP (r = 0.26, p = 0.016), VD in DCP (r = 0.28, p = 0.012), and FAZ-CI in DCP (r = 0.31, p = 0.006). Conclusions: rmtRNFL, FAZ-CI in SCP and DCP, and FAZp in SCP are strong predictors of the severity of DR. The ganglion cell body loss is highly correlated with increased FAZp and FAZa, decreased FAZ-CI, and reduced VD with the severity of DR.

Evaluation of Choroidal Thickness Using Optical Coherent Tomography: A Review.

The choroid is the main source of blood and nourishment supply to the eye. The dysfunction of the choroid has been implicated in various retinal and choroidal diseases. The identification and in-depth understanding of pachychoroid spectrum disorders are based on the tremendous progress of optical coherence tomography (OCT) technology in recent years, although visibility of choroid is challenging in the era of the time or spectral domain OCT. The recent rapid revolution of OCTs, such as the enhanced depth imaging OCT and the swept-source OCT, has greatly contributed to the significant improvement in the analysis of the morphology and physiology of the choroid precisely, especially to the choroid-scleral boundary and vasculature. The present review highlights the recently available evidence on the measurement methodology and the clinical significance of choroidal thickness in retinal or choroidal disorders.

Dysregulated Serum Lipid Metabolism Promotes the Occurrence and Development of Diabetic Retinopathy Associated With Upregulated Circulating Levels of VEGF-A, VEGF-D, and PlGF.

Purpose: This study aims to explore the correlations of arteriosclerosis-associated plasma indices with various severity levels of diabetic retinopathy (DR) and to test the hypothesis that elevated circulating level of known angiogenic cytokines induced by hyperglycemia is associated with dyslipidemia on DR. Methods: This cross-sectional study consists of 131 patients with type 2 diabetes. The patients were categorized based on their DR status into those with no DR (diabetes mellitus, DM), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) groups. The biochemical profile including fasting glucose, glycated hemoglobin (HbA1c), lipid profile were estimated, plasma angiogenic cytokines (vascular endothelial growth factor, VEGF-A, -C, -D) and placental growth factor (PlGF) were analyzed by protein microarrays. The atherogenic plasma index (API) was defined as low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C); atherogenic index (AI) was calculated as (TC-(HDL-C))/HDL-C and atherogenic index of plasma (AIP) was defined as log (TG/HDL-C). Results: No significant differences were detected in the duration of hypertension, age, and gender between the three groups. Serum TC and LDL-C, AI, and API in the NPDR group and PDR group were significantly higher than those in the DM group. The circulating level of PlGF, VEGF-A, and VEGF-C were significantly correlated with the severity of DR. VEGF-D is a risk factor independent of API (Z = -2.61, P = 0.009) and AI (Z = -2.40, P = 0.016). Multivariate logistic regression showed that AI and API are strong risk factors for the occurrence and severity of DR. Associated with AI and API, VEGF-D and PlGF contribute to DR: VEGF-D [AI: P = 0.038, odd ratio (OR) = 1.38; VEGF-D: P = 0.002, OR = 1.00. API: P = 0.027, OR = 1.56, VEGF-D:P = 0.002, OR = 1.00] and PlGF [AI: P = 0.021, OR = 1.43; VEGF-D: P = 0.004, OR = 1.50. API: P = 0.011, OR = 1.66; VEGF-D: P = 0.005, OR = 1.49]. Conclusions: Total cholesterol (TC) and LDL-C are risk factors for presence of any DR. Atherogenic index and API are novel and better predictive indicators for the occurrence and severity of DR in comparion with the traditional lipid profiles. Abnormal lipid metabolism are associated with the upregulation of circulating cytokines that are linked to the severity of DR.

An In Vitro Model of Diabetic Retinal Vascular Endothelial Dysfunction and Neuroretinal Degeneration.

BACKGROUND: Diabetic retinopathy (DR) is a leading cause of blindness in working-age populations. Proper in vitro DR models are crucial for exploring pathophysiology and identifying novel therapeutic targets. This study establishes a rational in vitro diabetic retinal neuronal-endothelial dysfunction model and a comprehensive downstream validation system. METHODS: Human retinal vascular endothelial cells (HRMECs) and retinal ganglion cells (RGCs) were treated with different glucose concentrations with mannitol as matched osmotic controls. Cell proliferation and viability were evaluated by the Cell Counting Kit-8. Cell migration was measured using a transwell migration assay. Cell sprouting was assessed by a tube formation assay. The VEGF expression was assessed by ELISA. RGCs were labeled by neurons and RGC markers TUJ1 and BRN3A for quantitative and morphological analysis. Apoptosis was detected using PI/Hoechst staining and TUNEL assay and quantified by ImageJ. RESULTS: Cell proliferation and migration in HRMECs were significantly higher in the 25 mM glucose-treated group (p < 0.001) but lower in the 50 mM and 100 mM groups (p < 0.001). The permeability and the apoptotic index in HRMECs were statistically higher in the 25 mM, 50 mM, and 100 mM groups (p < 0.05). The tube formation assay found that all the parameters were significantly higher in the 25 mM and 50 mM groups (p < 0.001) concomitant with the elevated VEGFA expression in HRMECs (p = 0.016). Cell viability was significantly lower in the 50 mM, 100 mM, and 150 mM groups in RGCs (p 50mM = 0.013, p 100mM = 0.019, and p 150mM = 0.002). Apoptosis was significantly elevated, but the proportion of RGCs with neurite extension was significantly lower in the 50 mM, 100 mM, and 150 mM groups (p 50mM < 0.001, p 100mM < 0.001, and p 150mM < 0.001). CONCLUSIONS: We have optimized glucose concentrations to model diabetic retinal endothelial (25-50 mM) or neuronal (50-100 mM) dysfunction in vitro, which have a wide range of downstream applications.

Abnormal expression of miR-135a in patients with depression and its possible involvement in the pathogenesis of the condition.

At present, due to the increasing pressures on society and the stress of everyday living, the number of individuals suffering from depression has increased. Therefore, the treatment of depression has also received increasing attention. MicroRNA (miRNA/miR)-135a is a well-studied miRNA. It has been reported that miR-135a is significantly downregulated in patients with depression and may be a potential marker for the diagnosis of the condition. However, the specific mechanisms of action of miR-135a in patients with depression remain unclear. In the present study, it was found that miR-135a was downregulated in patients with depression, and in a mouse model of depression. The effects of miR-135a on depression-related symptoms in mice were then explored. In the mice with chronic unpredictable mild stress (CUMS) that were treated with miR-135a for 3 weeks, a significantly reduced level of weight gain was observed in comparison with the control group. In addition, treatment with miR-135a mimic significantly increased sucrose preference in the sucrose preference test in the mice, and reduced the immobility time in the forced swimming test and tail suspension test. Treatment with miR-135a mimic also inhibited CUMS-induced hippocampal cell apoptosis. Furthermore, treatment with miR-135a mimic and fluoxetine significantly reduced the CUMS-induced increase in the expression levels of inflammatory factors (IL-1ß, IL-6 and TNF-α) in the hippocampus of the mice. Subsequently, reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that treatment with miR-135a mimic significantly inhibited the expression of Toll-like receptor 4 in the mouse hippocampus. In conclusion, the findings of the present study indicate that miR-135a may be a novel potential target for the treatment of depression.