Predictive value of optical coherence tomography angiography in management of diabetic macular edema.

BACKGROUND: Optical coherence tomography angiography (OCTA) is a relatively new extension of Optical coherence tomography (OCT) that generates non-invasive, depth-resolved images of the retinal microvasculature which allows for the detection of various features of diabetic retinopathy. OBJECTIVES: This study aimed to detect biomarkers that may predict an early anatomical response to the treatment of diabetic macular edema (DME) with intravitreal ranibizumab (IVR) by means of OCTA. PATIENTS AND METHODS: This prospective interventional study was undertaken on 111 eyes of 102 naïve participants who had diabetic macular edema; enrolled patients were evaluated by taking a complete ophthalmologic history, examination and investigations by use of a pre-designed checklist involving Optical Coherence Tomography Angiography. RESULTS: Regarding the best corrected visual acuity (BCVA) the Mean ± SD was 0.704 ± 0.158 preoperatively and 0.305 ± 0.131 postoperatively in good responder patients; and was 0.661 ± 0.164 preoperatively and 0.54 ± 0.178 postoperatively in poor responders. The central macular thickness (CMT) was 436.22 ± 54.66 µm preoperatively and 308.12 ± 33.09 µm postoperatively in good responder patients; and was 387.74 ± 44.05 µm preoperatively and 372.09 ± 52.86 µm postoperatively in poor responders. By comparing the pre injection size of the foveal avascular zone area (FAZ-A) in both groups, it found that the mean ± SD of FAZ-A was 0.297 ± 0.038 mm in good responder patients compared to 0.407 ± 0.05 mm in non-responder patients. The preoperative superficial capillary plexus (SCP) foveal vascular density (VD) was 24.02 ± 3.01% in good responder patients versus 17.89 ± 3.19% um in poor responders. The preoperative SCP parafoveal VD was 43.06 ± 2.67% in good responder patients versus 37.96 ± 1.82% um in poor responders. The preoperative deep capillary plexus (DCP) foveal VD was 30.58 ± 2.89% in good responder patients versus 25.45 ± 3.14% in poor responders. The preoperative DCP parafoveal VD was 45.66 ± 2.21% in good responder patients versus 43.26 ± 2.35% um in poor responders, this was statistically significant. CONCLUSION: OCTA offers an accurate measurement for VD in the macula as well as the FAZ-A which could be used to predict an early anatomical response of anti-VEGF treatment in DME.

Tropisetron attenuates high glucose-induced oxidative stress and inflammation in ARPE-19 cells in vitro via regulating SIRT1/ROCK1 signaling.

Diabetic retinopathy (DR) is the leading cause of acquired blindness in diabetic patients. Tropisetron (TRO) exerts potent therapeutic effects against diabetic tissues. The present study aimed to investigate the effects of TRO on retinal injury under diabetic condition. Human retinal pigment epithelial cell line ARPE-19 was treated with high glucose (HG) for 48 h to mimic hyperglycemia-induced retinal damage and subsequently treated with multiple concentrations of TRO for therapeutic intervention. Cell viability and lactate dehydrogenase (LDH) release were detected to assess cell damage. The production of inflammatory cytokines and oxidative stress-related factors was evaluated by corresponding commercial kits. Cell apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression of inflammation-, apoptosis-, and SIRT1/ROCK1-related proteins was examined using western blot analysis. Additionally, ARPE-19 cells were transfected with over-express ROCK1 (Ov-ROCK1) or pretreatment with SIRT1 inhibitor EX527 to perform the rescue experiments. TRO alleviated cell damage in HG-induced ARPE-19 cells through elevating cell viability and reducing LDH release. HG-caused excessive production of TNF-α, IL-1ß and IL-6, ROS, malondialdehyde and decreased superoxide dismutase activity were partly inhibited by TRO treatment. HG-induced cell apoptosis, accompanied with the upregulation of proapoptotic proteins and the downregulation of antiapoptotic proteins, was hindered by TRO treatment. HG led to the loss of SIRT1 and an elevation of ROCK1 in ARPE-19 cells, which was reversed following TRO treatment. Furthermore, pretreatment with EX527 or transfected with Ov-ROCK1 partially abolished the protective role of TRO against inflammation, oxidative stress and cell apoptosis in HG-challenged ARPE-19 cells. TRO exerted a protective role against HG-caused ARPE-19 cells inflammation, oxidative stress and cell apoptosis by regulating SIRT1/ROCK1 axis, suggesting that TRO might be therapeutic agent for alleviating retinal pigment epithelial cell damage in DR.

Optimization of individualized faricimab dosing for patients with diabetic macular edema: Protocol for the SWAN open-label, single-arm clinical trial.

PURPOSE: In patients with diabetic macular edema (DME) from YOSEMITE/RHINE, dual angiopoietin-2/vascular endothelial growth factor-A (VEGF-A) inhibition with faricimab resulted in visual/anatomic improvements with extended dosing. The SWAN trial (jRCTs031230213) will assess the efficacy, durability, and safety of faricimab during the treatment maintenance phase in patients with DME using a treat-and-extend (T&E)-based regimen adapted to clinical practice and the characteristics of patients achieving extended dosing intervals. METHODS: SWAN is a 2-year, open-label, single-arm, interventional, multicenter trial enrolling adults with center-involving DME. All patients will receive three initial faricimab 6.0 mg doses every 4 weeks (Q4W). From week 12 onwards, in patients without active DME, dosing intervals will be extended in 8-week increments up to Q24W. In contrast, patients with active DME (central subfield thickness [CST] >325 µm and intraretinal fluid [IRF] or subretinal fluid [SRF] resulting in vision loss/disease aggravation) will receive a dose within a day and the dosing interval will be shortened by 4 weeks to a minimum of Q8W relative to the previous dosing interval. Recruitment commenced in August 2023 across a planned 16 sites in Japan. RESULTS: The primary endpoint is change in best-corrected visual acuity (BCVA) from baseline at 1 year (averaged over weeks 52, 56, and 60). Key secondary endpoints include: change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire scores over time; proportion of patients with BCVA (decimal visual acuity) ≥0.5, ≥0.7, ≥1.0, or ≤0.1; proportion of patients with absence of DME, and IRF and/or SRF over time. Safety endpoints include incidence/severity of ocular/nonocular adverse events. CONCLUSIONS: The SWAN trial is expected to provide evidence to support individualized faricimab dosing regimens, with the potential to reduce the burden of frequent treatments on patients, caregivers, and healthcare systems.

Melatonin Attenuates Diabetic Retinopathy by Regulating EndMT of Retinal Vascular Endothelial Cells via Inhibiting the HDAC7/FOXO1/ZEB1 Axis.

Diabetic retinopathy (DR) is characterized as a microvascular disease. Nonproliferative diabetic retinopathy (NPDR) presents with alterations in retinal blood flow and vascular permeability, thickening of the basement membrane, loss of pericytes, and formation of acellular capillaries. Endothelial-mesenchymal transition (EndMT) of retinal microvessels may play a critical role in advancing NPDR. Melatonin, a hormone primarily secreted by the pineal gland, is a promising therapeutic for DR. This study explored the EndMT in retinal microvessels of NPDR and its related mechanisms. The effect of melatonin on the retina of diabetic rats was evaluated by electroretinogram (ERG) and histopathologic slide staining. Furthermore, the effect of melatonin on human retinal microvascular endothelial cells (HRMECs) was detected by EdU incorporation assay, scratch assay, transwell assay, and tube formation test. Techniques such as RNA-sequencing, overexpression or knockdown of target genes, extraction of cytoplasmic and nuclear protein, co-immunoprecipitation (co-IP), and multiplex immunofluorescence facilitated the exploration of the mechanisms involved. Our findings reveal, for the first time, that melatonin attenuates diabetic retinopathy by regulating EndMT of retinal vascular endothelial cells via inhibiting the HDAC7/FOXO1/ZEB1 axis. Collectively, these results suggest that melatonin holds potential as a therapeutic strategy to reduce retinal vascular damage and protect vision in NPDR.

Optimal Humanized Scg3-Neutralizing Antibodies for Anti-Angiogenic Therapy of Diabetic Retinopathy.

Secretogranin III (Scg3) is a diabetic retinopathy (DR)-restricted angiogenic factor identified in preclinical studies as a target for DR therapy. Previously, our group generated and characterized ML49.3, an anti-Scg3 monoclonal antibody (mAb) which we then converted into an EBP2 humanized antibody Fab fragment (hFab) with potential for clinical application. We also generated anti-Scg3 mT4 mAb and related EBP3 hFab. In this study, to identify the preferred hFab for DR therapy, we compared all four antibodies for binding, neutralizing and therapeutic activities in vitro and in vivo. Octet binding kinetics analyses revealed that ML49.3 mAb, EBP2 hFab, mT4 mAb and EBP3 hFab have Scg3-binding affinities of 35, 8.7, 0.859 and 0.116 nM, respectively. Both anti-Scg3 EBP2 and EBP3 hFabs significantly inhibited Scg3-induced proliferation and migration of human umbilical vein endothelial cells in vitro, and alleviated DR vascular leakage and choroidal neovascularization with high efficacy. Paired assays in DR mice revealed that intravitreally injected EBP3 hFab is 26.4% and 10.3% more effective than EBP2 hFab and aflibercept, respectively, for ameliorating DR leakage. In conclusion, this study confirms the markedly improved binding affinities of hFabs compared to mAbs and further identifies EBP3 hFab as the preferred antibody to develop for anti-Scg3 therapy.

Preoperative Intravitreal Conbercept Injection Reduced Both Angiogenic and Inflammatory Cytokines in Patients With Proliferative Diabetic Retinopathy.

Aims: To investigate the impact of intravitreal injection of conbercept, a recombinant fusion protein with decoy receptors for the vascular endothelial growth factor (VEGF) family, on intraocular concentrations of angiogenic and inflammatory mediators in patients with proliferative diabetic retinopathy (PDR), analyzed its potential impact on surgical outcomes. Methods: Forty eyes from 40 patients with PDR were included in this prospective study. Patients received intravitreal injection of conbercept followed by vitrectomy or phacovitrectomy in 1 week. Aqueous humor samples were collected before and 1 week after the conbercept injection. The concentrations of angiogenic and inflammatory cytokines and chemokines were measured by flow cytometry. Follow-up clinical data were collected and analyzed. Results: Intravitreal conbercept injection significantly decreased aqueous concentrations of VEGF (325.5 (baseline) versus 22.3 pg/mL (postinjection), p < 0.0001), PlGF (39.5 versus 24.5 pg/mL, p < 0.0001), and PDGF-A (54.1 versus 47.0 pg/mL, p = 0.0016), while no impact on bFGF levels. For inflammatory mediators, the concentration of TNF-α (0.79 versus 0.45 pg/mL, p = 0.0004) and IL-8 (180.6 versus 86 pg/mL, p < 0.0001) were decreased, while IL-6 (184.1 versus 333.7 pg/mL, p = 0.0003) and IL-10 (1.1 versus 1.5 pg/mL, p = 0.0032) were increased. No significant changes in IFN-γ or MCP-1 were detected. Three months after surgery, the mean best-corrected visual acuity improved from a baseline of 1.8 ± 0.1 logMAR to 0.7 ± 0.1 logMAR (p < 0.0001), with 36 eyes (90%) achieving an improvement of visual function. Conclusions: Intravitreal conbercept injection presents dual effects of antiangiogenesis and anti-inflammation and can be served as an adjuvant treatment to vitrectomy for PDR patients.

The role of high mobility group box-1 on the development of diabetes complications: A plausible pharmacological target.

BACKGROUND: Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s. PURPOSE: Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. CONCLUSIONS: HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications.

Optical coherence tomography angiography for microaneurysms in anti-vascular endothelial growth factor treated diabetic macular edema.

BACKGROUND: We aimed to evaluate microaneurysms (MAs) after treatment with anti-vascular endothelial growth factor (anti-VEGF) therapy to understand causes of chronic edema and anti-VEGF resistance. METHODS: Patients with non-proliferative diabetic retinopathy, with or without macular edema were recruited. Optical coherence tomography angiography (OCTA) MAs-related parameters were observed, including the maximum diameter of overall dimensions, material presence, and flow signal within the lumen. OCTA parameters also included central macular thickness (CMT), foveal avascular zone, superficial and deep capillary plexuses, and non-flow area measurements on the superficial retinal slab. RESULTS: Overall, 48 eyes from 43 patients were evaluated. CMT differed significantly between the diabetic macular edema (DME ) and non-DME (NDME) groups at 1st, 2nd, 3rd, and 6th months of follow-up (P < 0.001; <0.001; 0.003; <0.001, respectively). A total of 55 and 59 MAs were observed in the DME (mean = 99.40 ± 3.18 µm) and NDME (mean maximum diameter = 74.70 ± 2.86 µm) groups at baseline, respectively (significant between-group difference: P < 0.001). Blood flow signal was measurable for 46 (83.6%) and 34 (59.3%) eyes in the DME and NDME groups, respectively (significant between-group difference: P < 0.001). CONCLUSIONS: Compared to the NDME group, the DME group had larger MAs and a higher blood-flow signal ratio. Following anti-VEGF therapy, changes in the diameter of MAs were observed before changes in CMT thickness.

Effect of anti-vascular endothelial growth factor on early-stage post-vitrectomy macular edema in patients with proliferative diabetic retinopathy.

PURPOSE: To investigate the effectiveness of anti-vascular endothelial growth factor (VEGF) therapy on post-vitrectomy macular edema (PVME) and determine the risk factors for PVME recovery. METHODS: This retrospective study included 179 eyes of 179 patients who underwent pars plana vitrectomy for proliferative diabetic retinopathy and developed PVME within 3 months after surgery. Eyes were grouped according to postoperative anti-VEGF treatment. RESULTS: Central retinal thickness (CRT) decreased significantly from baseline to 3-month follow-up in groups with (509.9 ± 157.2 µm vs. 401.2 ± 172.1 µm, P < 0.001) or without (406.1 ± 96.1 µm vs. 355.1 ± 126.0 µm, P = 0.008) postoperative anti-VEGF treatment. Best-corrected visual acuity (BCVA) did not differ between the two groups during follow-up. In the group not receiving anti-VEGF therapy, BCVA was significantly improved at 1, 2, and 3 months (P = 0.007, P < 0.001, and P < 0.001, respectively), while in the anti-VEGF group, BCVA was significantly improved at 1 and 3 months (P = 0.03 and P < 0.001). A thicker baseline CRT (ß = 0.44; 95% confidence interval, 0.26-0.61; P < 0.001) was significantly associated with decreasing CRT. CONCLUSION: PVME tends to spontaneously resolve in the early postoperative period. The effect of anti-VEGF therapy in the first 3 months after diagnosis appears to be limited.

Effectiveness of dexamethasone implants in treating diabetic macular edema with hard exudates: a clinical observation.

OBJECTIVE: This study seeks to explain the relationship between systemic conditions and hard exudate formations in diabetic macular edema patients. Besides, the study aimed to quantitatively examine changes in the area, location, and impact on visual function of hard exudates following intravitreal dexamethasone implant injections. METHODS: A retrospective analysis was conducted, including 40 patients (40 eyes) diagnosed with non-proliferative diabetic retinopathy and concurrent macular edema between January 1, 2022, and January 1, 2024. Preoperative evaluations included glycated hemoglobin, lipid profile, and renal function examinations. Based on the location of HE, patients were divided into two groups: Group A, with HE in 1 mm of the central fovea, and Group B, with HE outside 1 mm of the central fovea. Selected eyes were subject to pre- and postoperative examinations, including best-corrected visual acuity (BCVA), intraocular pressure, slit-lamp biomicroscopy, scanning laser ophthalmoscopy (SLO), optical coherence tomography, and multifocal electroretinography. Following screening and examination, patients received an immediate intravitreal injection of the DEX implant, with an injection administered at the four-month mark. Hard exudate (HE) areas were measured utilizing SLO fundus imaging. RESULTS: Total cholesterol, low-density lipoprotein, and triglyceride levels were found to be positively correlated with the presence of HE. Following surgical intervention, all patients demonstrated an improvement in BCVA. The mean BCVA increased from a preoperative measurement of 0.79 ± 0.04 to 0.39 ± 0.02 at the 6 month follow-up, indicating a statistically significant difference (p < 0.001). The baseline HE area for the entire patient cohort was 2.28 ± 0.22. One month post-operation, the HE area exhibited a slight increase to 2.27 ± 0.22. However, by the 6 month follow-up, the HE area had significantly decreased to 0.8 ± 0.87, representing a 35.09% reduction from the baseline measurement (p < 0.001). It is worth noting that Patient P1 did not exhibit a statistically significant difference between preoperative and six-month postoperative HE area (p = 0.032). Preoperative BCVA measurements for Group A and Group B were 0.81 ± 0.03 and 0.77 ± 0.03, respectively, with no statistically significant intergroup difference (p = 0.333). The baseline HE area for Group A was 2.61 ± 0.16, which decreased to 0.38 ± 0.20 at the six-month follow-up, representing a 14.60% reduction from the baseline total area. For Group B, the baseline HE area was measured at 1.95 ± 0.09, then decreasing to 1.21 ± 0.13 at the six-month follow-up, indicating a 62.05% reduction from the baseline total area. A statistically significant difference in the postoperative 6 month HE area was observed between Group A and Group B (p < 0.001). In Group A, the reduction in HE area (initial HE area-final HE area) was positively correlated with the improvement in P1 (initial P1-final P1) (r = 0.610, p = 0.004). In Group B, a similar positive correlation was found (initial HE area-final HE area with initial P1-final P1) (r = 0.488, p = 0.029). In Group B, the reduction in HE area (initial HE area-final HE area) correlated positively with the improvement in BCVA (initial BCVA-final BCVA) (r = 0.615, p = 0.004). Additionally, in Group B, the reduction in HE area (initial HE area-final HE area) was positively correlated with the improvement in CMT (initial CMT-final CMT) (r = -0.725, p< 0.001). Aggravated cataracts were observed in thirteen eyes during a follow-up examination 6 months later. CONCLUSION: HE formation is associated with lipid levels. Dexamethasone implants demonstrate effectiveness in reducing HE areas in the short term, reducing macular edema, improving retinal structure, and enhancing visual function. The incidence of postoperative complications such as cataracts and glaucoma remains low.

Intraocular Concentration of Stem Cell Factor/c-KIT and Galectin-1 in Retinal Diseases.

Purpose: To investigate the intraocular concentration profiles of stem cell factor (SCF)/c-KIT, galectin-1 (GAL-1), and vascular endothelial growth factor (VEGF)-A with regard to retinal disease and treatment response. Methods: The study group included 13 patients with dry age-related macular degeneration (AMD), 196 with neovascular AMD (nAMD), 21 with diabetic macular edema (DME), 10 with retinal vein occlusion (RVO), and 34 normal subjects with cataracts. Aqueous humor levels of SCF, c-KIT, GAL-1, and VEGF-A were analyzed by immunoassay according to disease group and treatment response. Results: Increased aqueous levels of SCF, c-KIT, and GAL-1 were observed in eyes with nAMD (2.67 ± 3.66, 296.84 ± 359.56, and 3945.61 ± 5976.2 pg/mL, respectively), DME (1.64 ± 0.89, 238.80 ± 265.54, and 3701.23 ± 4340.54 pg/mL, respectively), and RVO (4.62 ± 8.76, 509.63 ± 647.58, and 9079.60 ± 11909.20 pg/mL, respectively) compared with controls (1.13 ± 0.24, 60.00 ± 0.00, and 613.27 ± 1595.12 pg/mL, respectively). In the eyes of nAMD, the levels of all three cytokines correlated positively with VEGF-A levels. After intravitreal injections of anti-VEGF agents, the levels of GAL-1 and VEGF-A decreased significantly, whereas those of SCF and c-Kit showed no significant change. Eyes of nAMD patients with improved vision after treatment had significantly lower levels of c-KIT, GAL-1, and VEGF-A at baseline. Conclusions: The intraocular levels of cytokines were significantly elevated in eyes with nAMD, DME, and RVO compared to the controls and they showed different response to anti-VEGF treatment. With this result and their known association with angiogenesis, these cytokines may be potential therapeutic targets for future research.

From Vineyard to Vision: Efficacy of Maltodextrinated Grape Pomace Extract (MaGPE) Nutraceutical Formulation in Patients with Diabetic Retinopathy.

Despite recent advances, pharmacological treatments of diabetic retinopathy (DR) do not directly address the underlying oxidative stress. This study evaluates the efficacy of a nutraceutical formulation based on maltodextrinated grape pomace extract (MaGPE), an oxidative stress inhibitor, in managing DR. A 6-month, randomized, placebo-controlled clinical trial involving 99 patients with mild to moderate non-proliferative DR was conducted. The MaGPE group showed improvement in best-corrected visual acuity (BCVA) values at T3 (p < 0.001) and T6 (p < 0.01), a reduction in CRT (at T3 and T6, both p < 0.0001) and a stabilization of vascular perfusion percentage, with slight increases at T3 and T6 (+3.0% and +2.7% at T3 and T6, respectively, compared to baseline). Additionally, the levels of reactive oxygen metabolite derivatives (dROMs) decreased from 1100.6 ± 430.1 UCARR at T0 to 974.8 ± 390.2 UCARR at T3 and further to 930.6 ± 310.3 UCARR at T6 (p < 0.05 vs. T0). Similarly, oxidized low-density lipoprotein (oxLDL) levels decreased from 953.9 ± 212.4 µEq/L at T0 to 867.0 ± 209.5 µEq/L at T3 and markedly to 735.0 ± 213.7 µEq/L at T6 (p < 0.0001 vs. T0). These findings suggest that MaGPE supplementation effectively reduces retinal swelling and oxidative stress, contributing to improved visual outcomes in DR patients.

Corilagin alleviates ferroptosis in diabetic retinopathy by activating the Nrf2 signaling pathway.

BACKGROUND AND PURPOSE: Diabetic retinopathy (DR) is a prevalent complication of diabetes, with a rising global incidence, and can result in significant vision impairment and potential blindness in adults. Corilagin (COR) has been shown to regulate several pathological processes. However, the specific protective role and mechanism of action of COR in DR remain unknown. EXPERIMENTAL APPROACH: The protective effects and mechanisms of COR in DR were examined using the ARPE-19 cell line and C57BL/6 mice. Intraretinal tissue damage and molecular markers were evaluated to investigate the impact of COR on oxidative stress and cell death pathways. KEY RESULTS: In vitro, COR significantly reduced the cytotoxic effects of high glucose (HG) on ARPE-19 cells. Furthermore, COR also effectively decreased HG-induced lipid peroxidation, iron deposition, and ferroptosis and reduced damage to retinal tight junction proteins. Similarly, an in vivo study of streptozotocin (STZ)-induced DM mice showed that the daily gavage of COR for eight weeks notably alleviated DR. Mechanistically, COR activated the Nrf2 antioxidant signaling pathway both in vivo and in vitro, preventing HG-induced alterations in morphological and biochemical parameters. Notably, our study demonstrated that compared with controls, Nrf2 knockout mice and siNrf2-treated cells were more vulnerable to ferroptosis under HG conditions, and the protective effect of COR on DR was substantially diminished in these models. CONCLUSION AND IMPLICATIONS: These data indicate that COR has a protective effect against HG-induced retinal injury via a mechanism associated with the Nrf2-dependent antioxidant pathway and ferroptosis regulation.

TNFα and IL-8 vitreous concentrations variations with two antidiabetic therapies in patients with proliferative diabetic retinopathy: an observational study.

BACKGROUND: Antidiabetic therapies are effective, but could indirectly modify the inflammatory response in the ocular microenvironment; therefore, a study was developed to evaluate the inflammatory cytokine profile in the vitreous humor of diabetic patients with retinopathy under treatment with antidiabetic drugs. METHODS: Observational, comparative, retrospective, cross-sectional study. Interleukins 1ß, 6, 8, 10, and tumor necrosis factor-alpha (TNFα) were evaluated in the vitreous humor obtained from patients with type 2 diabetes mellitus, proliferative diabetic retinopathy, and concomitant retinal detachment or vitreous hemorrhage, and who were already on antidiabetic treatment with insulin or metformin + glibenclamide. The quantification analysis of each cytokine was performed by the cytometric bead array (CBA) technique; medians and interquartile ranges were obtained, and the results were compared between groups using the Mann-Whitney U test, where a p-value < 0.05 was considered significant. RESULTS: Thirty-eight samples; quantification of TNFα concentrations was higher in the group of patients administered insulin, while interleukin-8 was lower; in the metformin + glibenclamide combination therapy group, it occurred inversely. In the stratified analysis, the highest concentrations of interleukin-8 and TNFα occurred in patients with vitreous hemorrhage; however, the only statistical difference existed in patients with retinal detachment, whose TNFα concentration in the combined therapy group was the lowest value found (53.50 (33.03-86.66), p = 0.03). Interleukins 1ß, 6, and 10 were not detected. CONCLUSION: Interleukin-8 and TNFα concentrations are opposite between treatment groups; this change is more accentuated in patients with proliferative diabetic retinopathy and vitreous hemorrhage, where the highest concentrations of both cytokines are found, although only TNFα have statistical difference.

Polysaccharides from Ostrea rivularis alleviate type II diabetes induced-retinopathy and VGEF165-induced angiogenesis via PI3K/AKT signaling pathway.

The purpose of this study was to investigate the role of polysaccharides from Ostrea rivularis Gloud (ORPs) in the progression of diabetic retinopathy (DR) and its anti-angiogenic effect on endothelial cell. Transgenic db/db mice with DR model were used to evaluate the protective effect of ORPs on retinal damage. It was found that ORPs could down-regulated levels of random blood glucose and fasting insulin, and further ameliorate retinal structure abnormalities as well as vascular network structure. Moreover, ORPs could reduce the expression of VEGF in retinal tissue and lessen pathological angiogenesis, thus slowing the progression of DR. In vitro, the proliferation, migration and tube formation of VGEF165-induced EA.hy926 cells were inhibited with ORPs administration. Furthermore, the expression of related proteins in the PI3K/AKT pathway and angiogenesis related factors were improved after ORPs intervention. Overall, these findings suggested that ORPs could effectively control the development of DR, and inhibit VGEF165-induced EA.hy926 cells proliferation, migration and tube formation, which effects might work through blocking the activation of PI3K/AKT signaling pathway.

Development of dual drug loaded-hydrogel scaffold combining microfluidics and coaxial 3D-printing for intravitreal implantation.

Treating diabetic retinopathy (DR) effectively is challenging, aiming for high efficacy with minimal discomfort. While intravitreal injection is the current standard, it has several disadvantages. Implantable systems offer an alternative, less invasive, with long-lasting effects drug delivery system (DDS). The current study aims to develop a soft, minimally invasive, biodegradable, and bioadhesive material-based hydrogel scaffold to prevent common issues with implants. A grid-shaped scaffold was created using coaxial 3D printing (3DP) to extrude two bioinks in a single filament. The scaffold comprises an inner core of curcumin-loaded liposomes (CUR-LPs) that prepared by microfluidics (MFs) embedded in a hydrogel of hydroxyethyl cellulose (HEC), and an outer layer of hyaluronic acid-chitosan matrix with free resveratrol (RSV), delivering two Sirt1 agonists synergistically activating Sirt1 downregulated in DR. Optimized liposomes, prepared via MFs, exhibit suitable properties for retinal delivery in terms of size (<200 nm), polydispersity index (PDI) (<0.3), neutral zeta potential (ZP), encapsulation efficiency (∼97 %), and stability up to 4 weeks. Mechanical studies confirm scaffold elasticity for easy implantation. The release profiles show sustained release of both molecules, with different patterns related to different localization of the molecules. RSV released initially after 30 min with a total release more than 90 % at 336 h. CUR release starts after 24 h with only 4.78 % of CUR released before and gradually released thanks to its internal localization in the scaffold. Liposomes and hydrogels can generate dual drug-loaded 3D structures with sustained release. Microscopic analysis confirms optimal distribution of liposomes within the hydrogel scaffold. The latter resulted compatible in vitro with human retinal microvascular endothelial cells up to 72 h of exposition. The hydrogel scaffold, composed of hyaluronic acid and chitosan, shows promise for prolonged treatment and minimally invasive surgery.

Evaluation of the effect of vitreomacular interface disorders on anti-VEGF treatment in patients with diabetic macular edema in real life: MARMASIA study group report No. 10.

PURPOSE: The aim of this study is to investigate the effect of vitreomacular interface disorders (VMID) on treatment response in patients treated with anti-vascular endothelial growth factor (anti-VEGF) due to diabetic macular edema (DME). METHODS: Three hundred seventy-seven eyes of 239 patients in the MARMASIA Study Group who received intravitreal anti-VEGF treatment (IVT) due to DME were included in the study. The group 1 consisted of 44 eyes of the patients who had not received any treatment before, were followed up regularly for 24 months after at least a 3-month loading dose, and suffered from VMID such as epiretinal membrane, vitreomacular adhesion or traction, and lamellar hole. The group 2 consisted of 333 eyes of the patients without VMID. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) of the patients at baseline, 3rd month, 6th month, 1st year and 2nd year follow-ups were measured. RESULTS: The mean age of the Groups 1 and 2 was 67.1 ± 11.3 and 61.9 ± 10.2 years, respectively. 61.3% of the group 1 and 58.8% of the group 2 were female (p > 0.05). The duration of diabetes was 19.2 ± 3.7 and 15.8 ± 3.2 years, respectively, and the number of follow-ups was 16.09 ± 4.68 and 12.06 ± 4.58, respectively in the groups (p < 0.001, 0.001, respectively). The number of IVT was 7.13 ± 2.71 and 7.20 ± 2.22, respectively in the groups 1 and 2 and no statistically significant difference was observed between them (p = 0.860). According to logMAR, BCVA values at baseline were 0.63 ± 0.24 and 0.59 ± 0.26 (p = 0.29), respectively, in the groups and the amount of change in BCVA at the end of the 2nd year was - 0.02 ± 0.48 in the group 1 and - 0.12 ± 0.48 in the group 2. It was observed as 0.48 (p = 0.13). Although the increase in BCVA was greater at all follow-ups in the group 2 compared to their initial examination, no significant difference was observed between the groups in terms of BCVA change. The CMT values of the groups at baseline were 442.5 ± 131.3 µm and 590.9 ± 170.6 µm, respectively (p = 0.03) The decrease in CMT after IVT was significantly greater in the group 2 at all follow-ups when compared to the first group (p < 0.05). CONCLUSION: While the presence of VMID in DME patients receiving IVT did not affect visual results, it negatively affected the anatomical response and macular edema morphology. The presence of VMID at baseline affected the success of IVT. It should be taken into consideration that VMID may resolve spontaneously or with IVT, and new cases of VMID may occur in patients during the treatment process.

Efficacy, safety, and cost-effectiveness of biosimilars of bevacizumab in näive patients with diabetic macular edema.

OBJECTIVES: Anti-vascular endothelial growth factor (VEGF) therapy restores retinal architecture and enhances vision in diabetic macular edema (DME). Bevacizumab is an off-label anti-VEGF drug that effectively treats DME. The safety and efficacy of bevacizumab biosimilars, which are more affordable than the original medication, still need to be established. This study aimed to assess the cost-effectiveness, efficacy, and safety of biosimilars for treating patients with naïve DME across various price ranges that are accessible in the Indian market. MATERIALS AND METHODS: Two biosimilars, BevaciRelTM (Reliance Life Sciences Pvt. Ltd.) and ZyBev (Cadila Healthcare Limited), were compared to their original, Avastin (Roche Products [India] Pvt. Ltd.), in a randomized, control study. Three end-notes were used to assess safety and efficacy: persistence, improvement, and adverse events. Cost-effective analysis was carried out using a decision-tree analysis model. RESULTS: This study included 69 (59%) men and 54 (41%) women with naïve DME. The cohort had an average log MAR visual acuity of 0.87 ± 0.22, and the central retinal thickness at baseline on OCT was 398.5 ± 37.61 µm. The visual acuity showed a similar improvement, and there was a decrease in central retinal thickness as observed on OCT across the groups. The incremental cost-effectiveness ratio was 10.8. CONCLUSIONS: The biosimilars of bevacizumab are safe and efficacious in treating DME in a cost-effective manner.

Therapeutic potential of histamine H4 receptor antagonist as a preventive treatment for diabetic retinopathy in mice.

Diabetic retinopathy (DR) is a prevalent complication of diabetes, often resulting in vision loss and blindness. Existing treatments primarily aim to control blood sugar levels and inhibit angiogenesis. However, current therapies for DR, such as anti-VEGF and laser photocoagulation, are frequently invasive, and can cause adverse side effects. Consequently, there is a critical need for new preventive therapeutics to address DR more effectively. This study aimed to examine the therapeutic potential of a histamine H4 receptor (HRH4) antagonist as a preventive treatment for DR in mice. A mouse model of DR was established by intraperitoneally injecting 200 mg/kg of streptozotocin (STZ). Immune cell infiltration into the retina of mice with STZ-induced diabetes was measured using fluorescence-activated cell sorting (FACS) 12 weeks after STZ injection. The preventive effects of the HRH4 antagonist on inflammation and pathological retinal vessel leakage were determined in a mouse model of DR. Infiltration of HRH4-expressing macrophages increased in the retina of mice with STZ-induced DR. The HRH4 antagonist prevented macrophage infiltration and retinal vascular leakage to prevent STZ-induced DR in mice without causing any retinal toxicity. The infiltration of macrophages increased in the retina of mice with STZ-induced diabetes through HRH4, indicating that HRH4 is potentially a novel preventative therapeutic target in DR. These findings suggest that targeting HRH4 is a promising strategy for the prevention and treatment of DR.