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.

Comparative Efficacy of Low-Carbohydrate and Ketogenic Diets on Diabetic Retinopathy and Oxidative Stress in High-Fat Diet-Induced Diabetic Rats.

This study examined the effect of a low-carbohydrate diet (LCD) and a low-carbohydrate ketogenic diet (LCKD) on diabetic retinopathy in high-fat diet-induced diabetes mellitus in rats and studied the mechanisms of action. Rats were divided into four groups: the Control group, which was fed a normal diet for 16 weeks; the HFD group, which was fed a high-fat diet (HFD) for the first 8 weeks and then switched to a normal diet for 8 weeks; the HFD+LCD group, fed a HFD for 8 weeks followed by an LCD for 8 weeks, and the HFD+LCKD group, which was fed a HFD for 8 weeks followed by an LCKD for 8 more weeks. Both the LCD and the LCKD effectively reduced the final body and total fat weights and decreased fasting serum levels of glucose, insulin, hemoglobin A1 (HbA1C), triglycerides, cholesterol, and LDL-c. They also reduced the levels of malondialdehyde (MDA), tumor necrosis factor-α, vascular endothelial factor, caspapse-3, and bax. In the HFD rats, we found increased serum levels of ß-Hydroxybutyrate and upregulated expression of Bcl2, glutathione, superoxide dismutase, and hemeoxygenase-1. Moreover, the LCD and LCKD significantly reduced mRNA levels of Kelch-like ECH-associated protein 1 (Keap1) and enhanced mRNA and nuclear concentrations of nuclear factor erythroid factor 2 (Nrf2). All these effects were associated with improved layers of the retina in the HFD - LCD and HFD + LCKD rats but not in HFD animals. The impact of the LCKD was always more profound on all measured parameters and on improving the structure of the retina compared to the LCD. In conclusion, the LCKD is superior to the LCD in preventing diabetic retinopathy in HFD-fed rats. Mechanistically, our results suggest that the hypoglycemic and hypolipidemic conditions and the Nrf2-dependent antioxidant and anti-inflammatory effects may be involved in the preventative effects of the LCD and LCKD.

Effect of the Mediterranean Diet (MeDi) on the Progression of Retinal Disease: A Narrative Review.

Worldwide, the number of individuals suffering from visual impairment, as well as those affected by blindness, is about 600 million and it will further increase in the coming decades. These diseases also seriously affect the quality of life in working-age individuals. Beyond the characterization of metabolic, genetic, and environmental factors related to ocular pathologies, it is important to verify how lifestyle may participate in the induction of the molecular pathways underlying these diseases. On the other hand, scientific studies are also contributing to investigations as to whether lifestyle could intervene in modulating pathophysiological cellular responses, including the production of metabolites and neurohormonal factors, through the intake of natural compounds capable of interfering with molecular mechanisms that lead to ocular diseases. Nutraceuticals are promising in ameliorating pathophysiological complications of ocular disease such as inflammation and neurodegeneration. Moreover, it is important to characterize the nutritional patterns and/or natural compounds that may be beneficial against certain ocular diseases. The adherence to the Mediterranean diet (MeDi) is proposed as a promising intervention for the prevention and amelioration of several eye diseases. Several characteristic compounds and micronutrients of MeDi, including vitamins, carotenoids, flavonoids, and omega-3 fatty acids, are proposed as adjuvants against several ocular diseases. In this review, we focus on studies that analyze the effects of MeDi in ameliorating diabetic retinopathy, macular degeneration, and glaucoma. The analysis of knowledge in this field is requested in order to provide direction on recommendations for nutritional interventions aimed to prevent and ameliorate ocular diseases.

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.

Polyphenol-Rich Extract of Apocynum venetum L. Leaves Protects Human Retinal Pigment Epithelial Cells against High Glucose-Induced Damage through Polyol Pathway and Autophagy.

Diabetic retinopathy (DR) is a specific microvascular problem of diabetes, which is mainly caused by hyperglycemia and may lead to rapid vision loss. Dietary polyphenols have been reported to decrease the risk of DR. Apocynum venetum L. leaves are rich in polyphenolic compounds and are popular worldwide for their health benefits as a national tea drink. Building on previous findings of antioxidant activity and aldose reductase inhibition of A. venetum, this study investigated the chemical composition of polyphenol-rich extract of A. venetum leaves (AVL) and its protective mechanism on ARPE-19 cells in hyperglycemia. Ninety-three compounds were identified from AVL by LC-MS/MS, including sixty-eight flavonoids, twenty-one organic acids, and four coumarins. AVL regulated the polyol pathway by decreasing the expression of aldose reductase and the content of sorbitol, enhancing the Na+K+-ATPase activity, and weakening intracellular oxidative stress effectively; it also could regulate the expression of autophagy-related proteins via the AMPK/mTOR/ULK1 signaling pathway to maintain intracellular homeostasis. AVL could restore the polyol pathway, inhibit oxidative stress, and maintain intracellular autophagy to protect cellular morphology and improve DR. The study reveals the phytochemical composition and protective mechanisms of AVL against DR, which could be developed as a functional food and/or candidate pharmaceutical, aiming for retina protection in diabetic retinopathy.

Targeting the PINK1/Parkin pathway: A new perspective in the prevention and therapy of diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes characterized by neurovascular impairment of the retina. The dysregulation of the mitophagy process occurs before apoptotic cell death and the appearance of vascular damage. In particular, mitochondrial alterations happen during DR development, supporting the hypothesis that mitophagy is negatively correlated to disease progression. This process is mainly regulated by the PTEN-induced putative kinase protein 1 (PINK1)/Parkin pathway whose activation promotes mitophagy. In this review, we will summarize the evidence reported in the literature demonstrating the involvement of the PINK1/Parkin pathway in diabetic retinopathy-induced retinal degeneration.

Diabetic retinopathy: Screening, prevention, and treatment.

Internists are integral in the multidisciplinary approach to diabetic retinopathy, contributing significantly to the management of diabetes and diabetes-related complications. Effective screening processes, timely referrals, and strategic diabetes management are imperative to prevent and mitigate the consequences of diabetic retinopathy. The evolution of treatments for diabetic retinopathy has markedly improved vision outcomes and reduced the burden on patients. Despite these advances, a collaborative approach to care is essential to prevent the progression of vision impairment and manage associated complications.

VEGF-B prevents chronic hyperglycemia-induced retinal vascular leakage by regulating the CDC42-ZO1/VE-cadherin pathway.

Non-proliferative diabetic retinopathy (NPDR) is the early stage of diabetic retinopathy (DR) and is a chronic oxidative stress-related ocular disease. Few treatments are approved for early DR. This study aimed to investigate the pathogenic mechanisms underlying the retinal micro-vasculopathy induced by diabetes and to explore an early potential for treating early DR in a mouse model. The mouse model of type 1 diabetes was established by intraperitoneal injection of streptozotocin (STZ, 180 mg/kg), which was used as the early DR model. The body weight and blood glucose mice were measured regularly; The retinal vascular leakage in the early DR mice was determined by whole-mount staining; Label-free quantitative proteomic analysis and bioinformatics were used to explore the target proteins and signaling pathways associated with the retinal tissues of early DR mice; To detect the effects of target protein on endothelial cell proliferation, migration, and tube formation, knockdown and overexpression of VEGF-B were performed in human retinal vascular endothelial cells (HRECs); Western blotting was used to detect the expression of target proteins in vitro and in vivo; Meanwhile, the therapeutic effect of VEGF-B on vascular leakage has also been evaluated in vitro and in vivo. The protein expressions of vascular endothelial growth factor (VEGF)-B and the Rho GTPases family member CDC42 were reduced in the retinal tissues of early DR. VEGF-B upregulated the expression of CDC42/ZO1/VE-cadherin and prevented hyperglycemia-induced vascular leakage in HRECs. Standard intravitreal VEGF-B injections improved the retinal vascular leakage and neurovascular response in early DR mice. Our findings demonstrated, for the first time, that in diabetes, the retinal vessels are damaged due to decreased VEGF-B expression through downregulation of CDC42/ZO1/VE-cadherin expression. Therefore, VEGF-B could be used as a novel therapy for early DR.

A new population for primary prevention of retinal diseases; a step toward improved global eye health beyond diabetes and prediabetes.

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New Data on GLP-1s, Diabetic Retinopathy, and CGMs-Highlights From the ADA's Scientific Sessions.

This Medical News article is an interview with Robert Gabbay, MD, PhD, the American Diabetes Association's chief scientific and medical officer.

Underlying mechanisms of traditional Chinese medicine in the prevention and treatment of diabetic retinopathy: Evidences from molecular and clinical studies.

As one of the most serious microvascular complications of diabetes mellitus (DM), diabetic retinopathy (DR) can cause visual impairment and even blindness. With the rapid increase in the prevalence of DM, the incidence of DR is also rising year by year. Preventing and effectively treating DR has become a major focus in the medical field. Traditional Chinese medicine (TCM) has a wealth of experience in treating DR and has achieved significant results with various herbs and TCM prescriptions. Traditional Chinese Medicine (TCM) provides a comprehensive therapeutic strategy for diabetic retinopathy (DR), encompassing anti-inflammatory and antioxidant actions, anti-neovascularization, neuroprotection, regulation of glucose metabolism, and inhibition of apoptosis. This review provides an overview of the current status of TCM treatment for DR in recent years, including experimental studies and clinical researches, to explore the clinical efficacy and the underlying modern mechanisms of herbs and TCM prescriptions. Besides, we also discussed the challenges TCM faces in treating DR, such as drug-drug interactions among TCM components and the lack of high-quality evidence-based medicine practice, which pose significant obstacles to TCM's application in DR.

PLK-3-mediated phosphorylation of BAP1 prevents diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus, and its main clinical manifestation is retinal vascular dysfunction. DR causes blindness and is a problem with significant global health implications. However, treating DR is still challenging. In this study, we aimed to explore the role of polo-like kinase-3 (PLK-3) and the potential regulatory mechanism in DR. Sprague-Dawley rats were injected intraperitoneally with streptozotocin (STZ, 60 mg/kg) to induce a rat model of DR, and rat retinal microvascular endothelial cells (RRMECs) were treated with high glucose (HG, 25 mmol/L glucose) to develop a cell model of DR. We found that PLK-3 was significantly downregulated in the retinal tissues of STZ-induced diabetic rats and HG-induced RRMECs. Lentivirus-mediated PLK-3 overexpression alleviated the histological damages in DR rats. After HG stimulation, cell proliferation, migration, and angiogenesis in RRMECs were inhibited after PLK-3 upregulation. By using label-free proteomics, we identified 82 differentially expressed proteins downstream of PLK-3, including BRCA1-associated protein 1 (BAP1), which was significantly upregulated in PLK-3-overexpressed RRMECs compared to control cells under the HG condition. In vivo and in vitro assays indicated that the forced expression of PLK-3 increased the phosphorylation of BAP1 at serine 592 and caspase-8 expression. Detailed evidence showed that BAP1-shRNA-mediated knockdown restored the cell function in HG-treated RRMECs when PLK-3 was overexpressed. Collectively, this study shows that PLK-3 alleviates retinal vascular dysfunction in DR by inhibiting the phosphorylation of BAP1. Thus, PLK-3 may develop as a promising target for the therapy of DR.

Analysis of the association between high antioxidant diet and lifestyle habits and diabetic retinopathy based on NHANES cross-sectional study.

Oxidative stress plays a crucial role in increasing the risk of developing diabetic retinopathy (DR). The oxidative balance score (OBS) and the composite dietary antioxidant index (CDAI) are two tools for assessing the effects of diet and lifestyle on oxidative stress. The aim of this study was to investigate the association between OBS, CDAI and the occurrence of DR. After controlling for potential confounders, OBS was negatively associated with DR with an odds ratio (OR) of 0.976 and a 95% confidence interval (CI) of 0.956-0.996, suggesting that for every unit increase in OBS, the risk of DR was reduced by 2.4%. In contrast, the relationship between OBS and CDAI was not significant (P > 0.05), suggesting that it was OBS, not CDAI, that contributed to the reduced risk of diabetic retinopathy. After adjusting for potential confounders, OBS was negatively associated with DR (OR: 0.976; 95% CI 0.956-0.996), but this association was not found in CDAI (P > 0.05), suggesting that for every one-unit increase in OBS, there was a 2.4% reduction in the risk of developing DR. This study suggests that a diet and lifestyle high in OBS reduces the risk of developing DR, which provides a rationale for nutritional interventions to prevent DR.

Effect of High-Sucrose Diet on the Occurrence and Progression of Diabetic Retinopathy and Dietary Modification Strategies.

As the most serious of the many worse new pathological changes caused by diabetes, there are many risk factors for the occurrence and development of diabetic retinopathy (DR). They mainly include hyperglycemia, hypertension, hyperlipidemia and so on. Among them, hyperglycemia is the most critical cause, and plays a vital role in the pathological changes of DR. High-sucrose diets (HSDs) lead to elevated blood glucose levels in vivo, which, through oxidative stress, inflammation, the production of advanced glycation end products (AGEs) and vascular endothelial growth factor (VEGF), cause plenty of pathological damages to the retina and ultimately bring about loss of vision. The existing therapies for DR primarily target the terminal stage of the disease, when irreversible visual impairment has appeared. Therefore, early prevention is particularly critical. The early prevention of DR-related vision loss requires adjustments to dietary habits, mainly by reducing sugar intake. This article primarily discusses the risk factors, pathophysiological processes and molecular mechanisms associated with the development of DR caused by HSDs. It aims to raise awareness of the crucial role of diet in the occurrence and progression of DR, promote timely changes in dietary habits, prevent vision loss and improve the quality of life. The aim is to make people aware of the importance of diet in the occurrence and progression of DR. According to the dietary modification strategies that we give, patients can change their poor eating habits in a timely manner to avoid theoretically avoidable retinopathy and obtain an excellent prognosis.

Continuous Glucose Monitoring Is Associated with Lower Risk of Diabetic Retinopathy.

According to this study: In adults with type 1 diabetes, continuous glucose monitoring (CGM) was associated with lower odds of developing diabetic retinopathy and proliferative diabetic retinopathy.No associations were found between CGM use, insulin pump use, or the use of both CGM and an insulin pump with progression of diabetic retinopathy.

Correlation between omega-3 intake and the incidence of diabetic retinopathy based on NHANES from 2005 to 2008.

AIMS: To identify correlations between omega-3 intake and incidence of diabetic retinopathy (DR). METHODS: This was a cross-sectional study using data from participants over age 40 in the National Health and Nutrition Examination Survey (NHANES) 2005-2008. Metrics included participants' intake of omega-3 fatty acids, specifically three types of representative polyunsaturated fatty acids, DR prevalence, and demographic characteristics. Multiple logistic regression models were used to assess the relationship between omega-3 intake and DR. RESULTS: Of the 1243 participants included in this study, omega-3 intake was lower in patients with DR relative to those without DR. Of the three polyunsaturated fatty acids within the omega-3 fatty acid family that we focused on, participants without DR consumed more docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) than those with DR. In contrast, there was no significant difference in the intake of eicosapentaenoic acid (EPA). Higher omega-3 intake was associated with a decreased risk of DR. In a crude model, the odds ratio (OR) was 0.548 (95% CI 0.315, 0.951; p = 0.033). In the fully adjusted model of omega-3 (model II), the adjusted OR was 0.525 (95% CI 0.306, 0.901; p = 0.021). DPA and DHA were also associated with a decreased risk of DR. In the full adjustment model (model II) of DPA and DHA, the adjusted ORs were 0.0002 (95% CI 0.000, 0.166; p = 0.014) and 0.293 (95% CI 0.105, 0.819; p = 0.020). Subgroup analysis showed that the protective effect of omega-3 against DR was more significant in younger patients (p value = 0.015). CONCLUSIONS: In this cross-sectional study of the U.S. general population, we found that increased intake of omega-3 and its components, specifically DPA and DHA were negatively associated with DR incidence. This suggests that omega-3 may be a potential protective factor for DR and may help to prevent or delay the onset and progression of DR.

[Evaluation of the management and follow-up of diabetic patients in the prevention of diabetic retinopathy]. / Evaluación del manejo y seguimiento de los pacientes diabéticos en la prevención de la retinopatía diabética.

OBJECTIVE: Diabetes mellitus is a chronic disease with high morbidity and mortality, affecting 537 million adults worldwide. Spain is the second European country in prevalence, with 14.8% in the population aged twenty/seventy-nine years; with 11.6 cases per 1,000 people/year. Diabetic retinopathy (DR) is the fifth cause of vision loss worldwide and the seventh cause of blindness/visual impairment among members of the National Organization of the Blind in Spain (ONCE). Early detection of DR prevents blindness in diabetics and is conditioned by glycosylated hemoglobin. The aim of this paper was to analyze the management of diabetic patients in Aljarafe region (Seville) and identify opportunities for improvement in the coordination of their follow-up between the Primary Care physician and the ophthalmologist. METHODS: A retrospective observational study (2016-2019) was carried out, with patients registered in the diabetic census of the twenty-eight municipalities of Aljarafe. The primary care and hospital health history, and telemedicine program were consulted. About statistical analysis, for qualitative variables, totals and percentages were calculated; for quantitative variables, mean and standard deviation (if normally distributed) and median and quartiles (if non-normally distributed). RESULTS: There were 17,175 diabetics registered in Aljarafe (5.7% of the population); 14,440 patients (84.1%) had some determination of hemoglobin during the period, 9,228 (63.9%) had all of them in the appropriate range. Fundoscopic control was performed on 12,040 diabetics (70.1%), and of those who did not, 346 (10.6%) had all of them out of range. There were 1,878 (10.9%) patients without fundoscopic or metabolic control, 1,019 (54.3%) were women, 1,219 (64.9%) were under sixty-five years of age, 1,019 (54.3%) had severe comorbidity. CONCLUSIONS: Most patients have adequate screening, and more than half have determinations within range. However, a significant percentage with no glycated hemoglobin within range lack fundoscopic control, and another smaller group lack fundoscopic or metabolic control, with inter-municipal variability. We propose to improve communication channels between levels.

OBJECTIVE: La diabetes mellitus es una enfermedad crónica con alta morbimortalidad que afecta a 537 millones de adultos en el mundo. España es el segundo país europeo en prevalencia, con un 14,8% en población de veinte-setenta y nueve años, con 11,6 casos por cada 1.000 personas/año. La retinopatía diabética (RD) es la quinta causa de pérdida de visión a nivel mundial y la séptima causa de ceguera/discapacidad visual entre afiliados a la Organización Nacional de Ciegos de España (ONCE). La detección precoz de RD previene la ceguera en diabéticos y está condicionada por la hemoglobina glicosilada. El objetivo de este trabajo fue analizar el manejo de los pacientes diabéticos en la comarca del Aljarafe (Sevilla) e identificar oportunidades de mejora en la coordinación de su seguimiento entre el médico de Atención Primaria y el médico oftalmólogo. METHODS: Se realizó un estudio observacional retrospectivo (2016-2019) con los pacientes registrados en el censo de diabéticos de los veintiocho municipios del Aljarafe. Se consultó la historia de salud de Atención Primaria y Hospital, así como el programa de Telemedicina. En cuanto al análisis estadístico, para variables cualitativas se calcularon totales y porcentajes; para variables cuantitativas, media y distribución estándar (si distribución normal), y la mediana y cuartiles (distribución no normal). RESULTS: Se registraron 17.175 diabéticos en el Aljarafe (5,7% de población); 14.440 pacientes (84,1%) tenían alguna determinación de hemoglobina durante el periodo, 9.228 (63,9%) las tenían todas en rango adecuado. Tenían control fundoscópico 12.040 diabéticos (70,1%), y de los que no, 346 (10,6%) tenían todas fuera de rango. Hubo 1.878 (10,9%) pacientes sin control fundoscópico ni metabólico, 1.019 (54,3%) eran mujeres, 1.219 (64,9%) menores de sesenta y cinco años, 1.019 (54,3%) con comorbilidad grave. CONCLUSIONS: La mayoría de los pacientes presentan un cribado adecuado y, más de la mitad, determinaciones en rango. Sin embargo, un porcentaje relevante con ninguna hemoglobina glicosilada en rango carecen de control fundoscópico, y otro grupo menor está sin control fundoscópico ni metabólico, con variabilidad intermunicipios. Planteamos mejorar los circuitos de comunicación entre niveles.

The protective role of water intake in age-related eye diseases: insights from a Mendelian randomization study.

Age-related eye diseases (AREDs), including age-related cataracts (ARCs), age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma, are a leading cause of visual loss globally. This study aimed to explore the effects of dietary water intake on AREDs using Mendelian randomization. In the European population, genome-wide association study (GWAS) summary statistics of water intake and AREDs were obtained from the UK Biobank database and the FinnGen Consortium, respectively. The causal associations between water intake and ARED risks were explored by univariable and multivariable MR analyses, followed by sensitivity analyses to test the robustness of the results and detect potential pleiotropy bias. Water intake was associated with reduced risks of ARCs (odds ratio [OR]: 0.61; 95% confidence interval [CI]: 0.46-0.83; P = 1.44 × 10-3) and DR (OR: 0.52; 95% CI: 0.36-0.76; P = 5.47 × 10-4), and a suggestive reduced risk of AMD (OR: 0.42; 95% CI: 0.20-0.88; P = 2.18 × 10-2). Water intake had no effect on glaucoma (OR: 1.16; 95% CI: 0.72-1.88; P = 0.549). After adjusting confounders, the causal effects of water intake on ARCs and DR persisted. Our study provides evidence of the preventive role of water intake in ARCs and DR from a genetic perspective.