Genipin ameliorates diabetic retinopathy via the HIF-1α and AGEs-RAGE pathways.

BACKGROUND: Traditional Chinese medicine (TCM) is useful in disease treatment and prevention. Genipin is an active TCM compound used to treat diabetic retinopathy (DR). In this study, a network pharmacology (NP)-based approach was employed to investigate the therapeutic mechanisms underlying genipin administration in DR. METHODS: The potential targets of DR were identified using the gene expression omnibus (GEO) database. TCM database screening and NP were used to predict the potential active targets and pathways of genipin in DR. Cell viability was tested in vitro to determine the effects of different doses of glucose and genipin on Human Retinal Microvascular Endothelial Cells (hRMECs). CCK-8, CCK-F, colony formation, CellTiter-Lum, Annexin V-FITC, wound healing, Transwell, tube-forming, reactive oxygen species (ROS), and other assay kits were used to detect the effects of genipin on hRMECs during high levels of glucose. In vivo, a streptozotocin (STZ)-mouse intraocular genipin injection (IOI.) model was used to explore the effects of genipin on diabetes-induced retinal dysfunction. Western blotting was performed to identify the cytokines involved in proliferation, apoptosis, angiogenesis, ROS, and inflammation. The protein expression of the AKT/ PI3K/ HIF-1α and AGEs/ RAGE pathways was also examined. RESULTS: Approximately 14 types of TCM, and nearly 300 active ingredients, including genipin, were identified. The NP approach successfully identified the HIF-1α and AGEs-RAGE pathways, with the EGR1 and UCP2 genes, as key targets of genipin in DR. In the in vitro and in vivo models, we discovered that high glucose increased cell proliferation, apoptosis, angiogenesis, ROS, and inflammation. However, genipin application regulated cell proliferation and apoptosis, inhibited angiogenesis, and reduced ROS and inflammation in the HRMECs exposed to high glucose. Furthermore, the retinal thickness in the genipin-treated group was lower than that in the untreated group. AKT/ PI3K/ HIF-1α and AGEs/ RAGE signaling was increased by high glucose levels; however, genipin treatment decreased AKT/ PI3K and AGEs/ RAGE pathway expressions. Genipin also increased HIF-1α phosphorylation, oxidative phosphorylation of ATP synthesis, lipid peroxidation, and the upregulation of oxidoreductase. Genipin was found to protect HG-induced hRMECs and the retina of STZ-mice, based on; 1 the inhibition of UCP2 and Glut1 decreased intracellular glucose, and glycosylation; 2 the increased presence of HIF-1α, which increased oxidative phosphorylation and decreased substrate phosphorylation; 3 the increase in oxidative phosphorylation from ATP synthesis increased lipid peroxidation and oxidoreductase activity, and; 4 the parallel effect of phosphorylation and glycosylation on vascular endothelial growth factor (VEGF), MMP9, and Scg3. CONCLUSION: Based on NP, we demonstrated the potential targets and pathways of genipin in the treatment of DR and confirmed its effective molecular mechanism in vitro and in vivo. Genipin protects cells and tissues from high glucose levels by regulating phosphorylation and glycosylation. The activation of the HIF-1α pathway can also be used to treat DR. Our study provides new insights into the key genes and pathways associated with the prognosis and pathogenesis of DR.

Diabetes in spotlight: current knowledge and perspectives of photobiomodulation utilization.

Introduction: Diabetes is a global health concern characterized by chronic hyperglycemia resulting from insulinopenia and/or insulin resistance. The rising prevalence of diabetes and its associated complications (ulcers, periodontitis, healing of bone defect, neuropathy, retinopathy, cardiopathy and nephropathy) necessitate innovative therapeutic approaches. Photobiomodulation (PBM), involves exposing tissues and cells to low-energy light radiation, leading to biological effects, largely via mitochondrial activation. Methods: This review evaluates preclinical and clinical studies exploring the potential of PBM in diabetes and its complications, as well all clinical trials, both planned and completed, available on ClinicalTrials database. Results: This review highlights the variability in PBM parameters across studies, hindering consensus on optimal protocols. Standardization of treatment parameters and rigorous clinical trials are needed to unlock PBM's full therapeutic potential. 87 clinical trials were identified that investigated PBM in diabetes mellitus (with 5,837 patients planned to be treated with PBM). Clinical trials assessing PBM effects on diabetic neuropathy revealed pain reduction and potential quality of life improvement. Studies focusing on wound healing indicated encouraging results, with PBM enhancing angiogenesis, fibroblast proliferation, and collagen density. PBM's impact on diabetic retinopathy remains inconclusive however, requiring further investigation. In glycemic control, PBM exhibits positive effects on metabolic parameters, including glucose tolerance and insulin resistance. Conclusion: Clinical studies have reported PBM-induced reductions in fasting and postprandial glycemia without an increased hypoglycemic risk. This impact of PBM may be related to its effects on the beta cells and islets in the pancreas. Notwithstanding challenges, PBM emerges as a promising adjunctive therapy for managing diabetic neuropathy, wound healing, and glycemic control. Further investigation into its impact on diabetic retinopathy and muscle recovery is warranted.

A mechanistic review on growing multiple therapeutic applications of lutein and its global market research.

Lutein is a naturally occurring carotenoid synthesized by plants and algae that has a beneficial effect on several biological processes and associated ailments. Its immediate application is in ophthalmology, where it significantly lowers the incidences of age-related macular degeneration (AMD). It also has anti-inflammatory action, treatment of diabetic retinopathy, and cataracts, and enhancement of visual contrast. To critically assess lutein biosynthesis, therapeutic applicability, and market research literature. We have discussed its theoretical frameworks, experimental evidence, limitations, as well as clinical trial results, and future research prospects. The literature for this review article was mined and compiled by collecting and analyzing articles from several databases, including ScienceDirect, Google Scholar, PubMed, Wiley Online Library, Patentscope, and ClinicalTrials.gov published until March 30, 2022. Patent publications were identified using the search terms like IC:(C07C67/56) AND EN_AB:(lutein) OR EN_TI:(lutein) OR EN_AB:(extraction) OR EN_TI:(process). According to the literature, lutein is an essential nutrient given that it cannot be synthesized in the human body and acts as an antioxidant, affecting AMD, diabetic retinopathy, Rheumatic diseases, inflammation, and cancer. Due to inadequate production and laborious extraction, lutein is expensive despite its high demand and applicability. Market research predicts a 6.3% compound annual growth rate for lutein by 2032. Optimizing lutein extraction for high yield and purity is necessary. Lutein has proven applicability in various ailments as well as cosmetics that can be developed as a candidate drug for various diseases discussed in the review.

Treatment of diabetic retinopathy with herbs for tonifying kidney and activating blood circulation: A review of pharmacological studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes. Chinese medicine believes that kidney deficiency and blood stasis are significant pathogenesis of DR. A characteristic therapeutic approach for this pathogenesis is the kidney-tonifying and blood-activating method. By literature retrieval from several databases, we methodically summarized the commonly used kidney-tonifying and blood-activating herbs for treating DR, including Lycii Fructus, Rehmanniane Radix Praeparata, and Corni Fructus with the function of nourishing kidney; Salvia Miltiorrhizae Radix et Rhizoma with the function of enhancing blood circulation; Rehmanniae Radix with the function of nourishing kidney yin; and Astragali Radix with the function of tonifying qi. It has been demonstrated that these Chinese herbs described above, by tonifying the kidney and activating blood circulation, significantly improve the course of DR. AIM OF THE STUDY: Through literature research, to gain a thorough comprehension of the pathogenesis of DR. Simultaneously, through the traditional application analysis, modern pharmacology research and network pharmacology analysis of kidney-tonifying and blood-activating herbs, to review the effectiveness and advantages of kidney-tonifying and blood-activating herbs in treating DR comprehensively. MATERIALS AND METHODS: PubMed, the China National Knowledge Infrastructure (CNKI), and Wanfang Data were used to filter the most popular herbs for tonifying kidney and activating blood in the treatment of DR. The search terms were "diabetic retinopathy" and "tonifying kidney and activating blood". Mostly from 2000 to 2023. Network pharmacology was applied to examine the key active components and forecast the mechanisms of kidney-tonifying and blood-activating herbs in the treatment of DR. RESULTS: Kidney deficiency and blood stasis are the pathogenesis of DR, and the pathogenesis is linked to oxidative stress, inflammation, hypoxia, and hyperglycemia. Scientific data and network pharmacology analysis have demonstrated the benefit of tonifying kidney and activating blood herbs in treating DR through several channels, multiple components, and multiple targets. CONCLUSIONS: This review first presents useful information for subsequent research into the material foundation and pharmacodynamics of herbs for tonifying kidney and activating blood, and offers fresh insights into the treatment of DR.

No causal association between serum vitamin D levels and diabetes retinopathy: A Mendelian randomization analysis.

BACKGROUND AND AIM: Diabetes retinopathy (DR) is a common microvascular complication of diabetes, and it is the main cause of global vision loss. The current observational research results show that the causal relationship between Vitamin D and DR is still controversial. Therefore, we conducted a Mendelian randomization study to determine the potential causal relationship between serum 25-hydroxyvitamin D 25(OH)D and DR. METHODS AND RESULTS: In this study, we selected aggregated data on serum 25(OH)D levels (GWAS ID: ebi-a-GCST90000615) and DR (GWAS ID: finn-b-DM_RETINOPATHY) from a large-scale GWAS database. Then use MR analysis to evaluate the possible causal relationship between them. We mainly use inverse variance weighted (IVW), supplemented by MR Egger and weighted median methods. Sensitivity analysis is also used to ensure the stability of the results, such as Cochran's Q-test, MR-PRESSO, MR-Egger interception test, and retention method. The MR analysis results showed that there was no significant causal relationship between 25(OH)D and DR (OR = 1.0128, 95%CI=(0.9593,1.0693), P = 0.6447); Similarly, there was no significant causal relationship between DR and serum 25 (OH) D levels (OR = 0.9900, 95% CI=(0.9758,1.0045), P = 0.1771). CONCLUSION: Our study found no significant causal relationship between serum 25(OH)D levels and DR, and vice versa. A larger sample size randomized controlled trial is needed to further reveal its potential causal relationship.

Subthreshold micropulse diode laser treatment in diabetic macular edema: biological impact, therapeutic effects, and safety.

PURPOSE: To introduce the treatment of diabetic macular edema (DME) with subthreshold micropulse diode laser (SMPL), to summarize the biological impact, therapeutic effects, and safety of this treatment, and to discuss the response to DME when SMPL is combined with anti-vascular endothelial growth factor (anti-VEGF) or steroid. METHODS: The literature search was performed on the PubMed database, with a selection of English-language articles published from 2000 to 2023 with the following combinations of search terms: diabetes macular (o) edema, micropulse laser or subthreshold micropulse laser, anti-vascular endothelial growth factor, and steroid. RESULTS: SMPL is a popular, invisible retinal laser phototherapy that is inexpensive, safe, and effective in the treatment of DME. It can selectively target the retinal pigment epithelium, reduce the expression of pro-inflammatory factors, promote the absorption of macular edema, and exert a similar and lasting clinical effect to traditional lasers. No significant difference was found in the therapeutic effects of SMPL between different wavelengths. However, HbA1c level and pretreatment central macular thickness (CMT) may affect the therapeutic outcomes of SMPL. CONCLUSION: SMPL has a slow onset and produces lasting clinical effects similar to conventional photocoagulation. It has been reported that SMPL combined with the intravitreal anti-VEGF injection can significantly reduce the number of injections without influencing the therapeutic effect, which is essential for clinical applications and research. Although 577 nm SMPL is widely used clinically, there are no standardized protocols for SMPL. Additionally, some important problems regarding the treatment of SMPL require further discussion and exploration.

Porous Se@SiO2 nanospheres alleviate diabetic retinopathy by inhibiting excess lipid peroxidation and inflammation.

BACKGROUND: Lipid peroxidation is a characteristic metabolic manifestation of diabetic retinopathy (DR) that causes inflammation, eventually leading to severe retinal vascular abnormalities. Selenium (Se) can directly or indirectly scavenge intracellular free radicals. Due to the narrow distinction between Se's effective and toxic doses, porous Se@SiO2 nanospheres have been developed to control the release of Se. They exert strong antioxidant and anti-inflammatory effects. METHODS: The effect of anti-lipid peroxidation and anti-inflammatory effects of porous Se@SiO2 nanospheres on diabetic mice were assessed by detecting the level of Malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), decreased reduced/oxidized glutathione (GSH/GSSG) ratio, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL) -1ß of the retina. To further examine the protective effect of porous Se@SiO2 nanospheres on the retinal vasculopathy of diabetic mice, retinal acellular capillary, the expression of tight junction proteins, and blood-retinal barrier destruction was observed. Finally, we validated the GPX4 as the target of porous Se@SiO2 nanospheres via decreased expression of GPX4 and detected the level of MDA, GSH/GSSG, TNF-α, IFN-γ, IL -1ß, wound healing assay, and tube formation in high glucose (HG) cultured Human retinal microvascular endothelial cells (HRMECs). RESULTS: The porous Se@SiO2 nanospheres reduced the level of MDA, TNF-α, IFN-γ, and IL -1ß, while increasing the level of GPX4 and GSH/GSSG in diabetic mice. Therefore, porous Se@SiO2 nanospheres reduced the number of retinal acellular capillaries, depletion of tight junction proteins, and vascular leakage in diabetic mice. Further, we identified GPX4 as the target of porous Se@SiO2 nanospheres as GPX4 inhibition reduced the repression effect of anti-lipid peroxidation, anti-inflammatory, and protective effects of endothelial cell dysfunction of porous Se@SiO2 nanospheres in HG-cultured HRMECs. CONCLUSION: Porous Se@SiO2 nanospheres effectively attenuated retinal vasculopathy in diabetic mice via inhibiting excess lipid peroxidation and inflammation by target GPX4, suggesting their potential as therapeutic agents for DR.

Alleviation of Diabetic Retinopathy by Glucose-Triggered Delivery of Vitamin D via Dextran-Gated Functionalized Mesoporous Silica Nanoparticles.

Diabetic retinopathy (DR) is the most common retinal disorder, developed in 35% of patients with diabetes mellitus. Lower serum levels of 25-hydroxyvitamin D are associated with the increased risk of developing DR. High doses of the active form of vitamin D (VD), on the contrary, for a long period of time may lead to hypercalcemia and an imbalance in the regulation of bone metabolism. Herein, we studied the efficacy of dextran-gated carboxyphenylboronic acid (CPBA)-functionalized mesoporous silica nanoparticles (MSNs) for glucose-sensitive delivery of 1,25-dihydroxyvitamin D3 to modulate cellular oxidative stress and inflammation for managing DR. The physical adsorption technique was employed to load VD onto nanoparticles (263.63 µg/mg (w/w)). In the presence of glucose, the dextran molecules detach from pores, allowing VD to release since glucose has 1,2-cis diol groups which have very high affinity to CPBA. Approximately 75% of VD was released upon exposure to 25 mM glucose at a time point of 10 h, demonstrating glucose-responsive delivery. Furthermore, MSN-CPBA was able to deliver VD in a glucose-dependent manner and improve the bioavailability of VD. In high-glucose-supplemented human retinal cells, MSN-CPBA increased the bioavailability of VD and reduced cellular oxidative stress and inflammation. The results suggested that the VD-loaded nanocarrier exerted remarkable therapeutic capacity in reducing the risk of developing DR. By using MSN-CPBA as a delivery platform with dextran gating, the research proposes an effective treatment approach for improving the bioavailability and effectiveness of a hydrophobic molecule in the treatment of DR.

Diabetic Retinopathy Leading to Blindness- A Review.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes that damages the retina, leading to blindness. People with type 1 diabetes are at greater risk of developing DR than people with type 2 diabetes. Diabetic retinopathy may be divided into two primary categories: Proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR). There are multiple risk factors for the onset and progression of diabetic retinopathy, such as hypertension, obesity, smoking, duration of diabetes, and genetics. Numerous investigations have evaluated the levels of a wide range of inflammatory chemokines within DR patients' serum, vitreous, and aqueous fluids. In diabetic retinopathy, the vitreous fluid exhibited rises in angiogenic factors like platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) or declines in antiangiogenic factors like pigment epithelium-derived factor (PEDF). For prevention of diabetic retinopathy, more physical activity as well as less sedentary behavior were linked to a reduced likelihood of DR. Supplementing with nutraceuticals containing vitamins (B1, B2, B6, B12, C, D, E, and l-methyl folate) and mineral (zinc) can help decrease or avoid an outbreak of DR. Only laser photocoagulation and Anti-vascular endothelial growth factor (Anti-VEGF) injections are advised as favorable therapies in severe retinopathy. When it comes to treating DR's VEGF levels, inflammation, oxidative stress, apoptosis, and angiogenesis, Traditional Chinese medicine (TCM) has an excellent future.

Qi-Ju-Di-Huang-Pill delays the progression of diabetic retinopathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Qi-Ju-Di-Huang-Pill (QJDH pill) is a Chinese decoction. Although it is commonly used to treat eye conditions, such as diabetic retinopathy (DR), its exact mechanism of action is unknown. AIM OF THE STUDY: To investigate the specific mechanism by which QJDH pill slows the progression of diabetic retinopathy (DR) based on animal and cellular experiments. MATERIAL AND METHODS: The major components of QJDH pill were characterized by ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLCMS/MS). C57BL/6J mice were randomly divided into five groups as follows: normal group (control group), model group (STZ group), low-dosage QJDH pill group (QJDH-L group), medium-dosage QJDH pill group (QJDH-M group) and high-dosage QJDH pill group (QJDH-H group). Changes in water intake, urination, food intake, and body mass were monitored weekly, while changes in blood glucose were monitored monthly. Fluorescein fundus angiography (FFA), optical coherence tomography angiography (OCTA), and optical coherence tomography (OCT) were utilized to analyze the changes in fundus imaging indications. Hematoxylin & eosin (H&E) and transmission electron microscopy (TEM) were employed to examine histopathologic and ultrastructural changes in retina. The levels of interleukin-6 (IL-6), interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF) in peripheral blood were detected using Enzyme-linked immunosorbent assay (ELISA). The mouse retina apoptotic cells were labeled with green fluorescence via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (Tunel). The protein levels of Bcl-2-Associated X (Bax), B cell lymphoma 2 (Bcl-2), Caspase-3, PI3K, phosphorylated PI3K (p-PI3K), protein kinase B (AKT) and phosphorylated AKT (p-AKT) were quantified by Western blot (WB). The retinal pigment epithelium (RPE) cells were cultured and classified into five groups as follows: normal glucose group (NG group), high glucose group (HG group), high glucose + QJDH pill group (HG + QJDH group), high glucose + inhibitor group (HG + LY294002 group), and high glucose + inhibitor + QJDH pill group (HG + LY294002 + QJDH group). Cell viability and apoptosis were detected via Cell Counting Kit-8 (CCK8) and then analyzed by flow cytometry. RESULTS: In vivo experiments revealed that the QJDH pill effectively reduced blood glucose, symptoms of increased water intake, elevated urination, increased food intake and decreased body mass in DR mice. QJDH pill also slowed the development of a series of fundus imaging signs, such as retinal microangiomas, tortuous dilatation of blood vessels, decreased vascular density, and thinning of retinal thickness, downregulated IL-6, IL-17, TNF-α, and VEGF levels in peripheral blood, and inhibited retinal cell apoptosis by activating the PI3K/AKT signaling pathway. Moreover, in vitro experiments showed that high glucose environment inhibited RPE cell viability and activated RPE cell apoptosis pathway. In contrast, lyophilized powder of QJDH pill increased RPE cell viability, protected RPE cells from high glucose-induced damage, and decreased apoptosis of RPE cells by activating the pi3k pathway. CONCLUSION: QJDH pill induces hypoglycemic, anti-inflammatory effects, anti-VEGF and anti-retinal cell apoptosis by activating PI3K/AKT signaling pathway, and thus can protect the retina and slow the DR progression.

Effectiveness Differences of Ranibizumab and Aflibercept Action in the Treatment of Diabetic Retinopathy.

Objective: To compare the difference in the effectiveness of ranibizumab (LU) and aflibercept (AF) in the treatment of diabetic retinopathy (DR). Methods: Ninety-four patients with DR admitted to Sunshine Union Hospital from August 2020 to February 2022 were selected for the study and were divided into LU group (n = 47) and AF group (n = 47) according to the random number table method. Both groups underwent 25G vitrectomy in our hospital, with LU injected into the vitreous before surgery in the LU group and AF in the AF group. Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in the pre-and post-injection atrial water were compared between the two groups, and the operative time, intraoperative bleeding, and the occurrence of medically induced fissures were recorded in both groups. In addition, the expression of best corrected visual acuity (BCVA), Central Macular Thickness (CMT), and inflammatory factors were compared before and after surgery. Finally, patients were counted for adverse reactions and prognosis of DR recurrence during treatment. Results: After injection, VEGF decreased and PEDF increased in both groups (P < .001). There were no differences in operative time (P = .604), intraoperative bleeding rate (P = .694), the incidence of medically induced fissure (P = .557), BCVA [P = .665 (T0), P > .999 (T1), P = .727 (T2)], and CMT [P = .688 (T0), P = .065 (T1), P = .148 (T2)] between the two groups, while IL-6, IL-8, and MMP-9 were lower in the AF group than in the LU group at 2 months after surgery (P < .001). Finally, there was no difference between both groups in terms of adverse effects and prognosis of DR recurrence rate (P = 1.000, .478). Conclusion: Both vitreous cavity injections of LU and AF can effectively reduce the expression of vascular-related factors in the atrial fluid of DR patients, but AF has a more significant inhibitory effect on the level of inflammatory factors in patients in the short term after treatment.

Topical anesthesia versus topical and subconjunctival anesthesia combined in diabetic retinopathy photocoagulation.

PURPOSE: comparison between two anesthetic techniques on the ability to reduce pain during panretinal photocoagulation (PRP) treatment. METHODS: Observational retrospective single center study. Medical charts of patients who underwent PRP for proliferative diabetic retinopathy were revised. Patients were included if they had the first eye treated with oxybuprocaine hydrochloride drops, and in case of severe pain, the fellow eye received topical anesthesia in combination with 2% subconjunctival lidocaine. The groups were compared for pain perception using an analog visual scale (VAS), number of laser spots, number of interruptions, and laser session duration. RESULTS: Forty-two eyes of 21 patients (mean age: 58.3 ± 7.6 years) were analyzed. The mean number of laser spots was significantly higher under combined anesthesia (+84.2 ± 155.9 spots, p = 0.01), with a reduced time for laser execution (-2.5 ± 3.12, p = 0.0008). The use of combined anesthesia significantly decreased the number of interruptions (-40.8%, p < 0.0001) into a single session. On the pain grading scale, the pain perception was significantly lower in the combined anesthesia group (p < 0.0001). In eyes receiving topical anesthesia the treatment was stopped for pain in 5 eyes (23.8%), while 5 eyes under combined anesthesia presented subconjunctival hemorrhage (23.8%). CONCLUSION: Using combined anesthesia in patients subjected to PRP appeared to reduce pain perception limiting the treatment duration and the interruptions for pain without significant complications. Further studies on a larger scale would be desirable to replicate such findings and standardize the analgesic procedures in ophthalmology.

Risk Factors for Nondiagnostic Imaging in a Real-World Deployment of Artificial Intelligence Diabetic Retinal Examinations in an Integrated Healthcare System: Maximizing Workflow Efficiency Through Predictive Dilation.

OBJECTIVE: In the pivotal clinical trial that led to Food and Drug Administration De Novo "approval" of the first fully autonomous artificial intelligence (AI) diabetic retinal disease diagnostic system, a reflexive dilation protocol was used. Using real-world deployment data before implementation of reflexive dilation, we identified factors associated with nondiagnostic results. These factors allow a novel predictive dilation workflow, where patients most likely to benefit from pharmacologic dilation are dilated a priori to maximize efficiency and patient satisfaction. METHODS: Retrospective review of patients who were assessed with autonomous AI at Johns Hopkins Medicine (8/2020 to 5/2021). We constructed a multivariable logistic regression model for nondiagnostic results to compare characteristics of patients with and without diagnostic results, using adjusted odds ratio (aOR). P < .05 was considered statistically significant. RESULTS: Of 241 patients (59% female; median age = 59), 123 (51%) had nondiagnostic results. In multivariable analysis, type 1 diabetes (T1D, aOR = 5.82, 95% confidence interval [CI]: 1.45-23.40, P = .01), smoking (aOR = 2.86, 95% CI: 1.36-5.99, P = .005), and age (every 10-year increase, aOR = 2.12, 95% CI: 1.62-2.77, P < .001) were associated with nondiagnostic results. Following feature elimination, a predictive model was created using T1D, smoking, age, race, sex, and hypertension as inputs. The model showed an area under the receiver-operator characteristics curve of 0.76 in five-fold cross-validation. CONCLUSIONS: We used factors associated with nondiagnostic results to design a novel, predictive dilation workflow, where patients most likely to benefit from pharmacologic dilation are dilated a priori. This new workflow has the potential to be more efficient than reflexive dilation, thus maximizing the number of at-risk patients receiving their diabetic retinal examinations.

Exploring the mechanism of Bushen Huoxue prescription in the treatment of early diabetic retinal edema from the perspective of inner blood-retinal barrier injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is one of the most severe complications of diabetes mellitus, diabetes belongs to the category of "emaciation-thirst disease" in traditional Chinese medicine (TCM). Bushen Huoxue Prescription (BHP) is composed of traditional Chinese materia medica, which has therapeutic effects on DR and early diabetic retinal edema (EDRE). However, the therapeutic mechanism is unclear. AIM OF THE STUDY: Exploring the mechanism of BHP against EDRE. METHODS: Feeding Sprague Dawley (SD) rats a high-fat, high-sugar diet as well as providing intraperitoneal injections of streptozotocin (STZ) to promote inner blood-retinal barrier (iBRB) damage that can trigger EDRE, evaluating the therapeutic effect of BHP by the level of expressiveness of TJ proteins (ZO-1,Occludin) of the iBRB and the leakage of rhodamine B isothiocyanate (RITC) in the retina. The combination of network pharmacology and metabolomics was employed to study the mechanism of BHP in preventing of EDRE, then four proteins which were closely to the damage of iBRB were chosen for the validation by employing Western Blot (WB). RESULTS: Research of network pharmacology had shown that BHP had efficacy against EDRE by regulating targets such as AKT1, ALB, TNF, PPARG, etc, its potential pathways mainly involving signaling pathways such as HIF-1. In untargeted metabolomics analysis of serum, 15 differential metabolites were identified, with the metabolic pathways focusing on ketone body metabolism and synthesis, sphingolipid metabolism and phenylalanine metabolism. The conclusions of metabolomics and network pharmacology revealed that BHP can treat EDRE by alleviating hypoxia and oxidative stress and exerting protection of the iBRB. Finally, BHP's protection behavior of the iBRB was validated by WB experiments. CONCLUSION: Through integrating pharmacodynamics, network pharmacology and metabolomics, BHP was discovered to have a crucial function in EDRE therapy by preserving the integrity of iBRB. This comprehensive strategy also provided a reasonable way to reveal the multi-components, multi-targets, multi-pathways mechanism of TCM.

Discussing pathologic mechanisms of Diabetic retinopathy & therapeutic potentials of curcumin and ß-glucogallin in the management of Diabetic retinopathy.

Diabetic retinopathy (DR) is a form of retinal microangiopathy that occurs as a result of long-term Diabetes mellitus (DM). Patients with Diabetes mellitus typically suffer from DR as a progression of the disease that may be due to initiation and dysregulation of pathways like the polyol, hexosamine, the AGE/RAGE, and the PKC pathway, which all have negative impacts on eye health and vision. In this review, various databases, including PubMed, Google Scholar, Web of Science, and Science Direct, were scoured for data relevant to the aforementioned title. The three most common therapies for DR today are retinal photocoagulation, anti-vascular endothelial growth factor (VEGF) therapy, and vitrectomy, however, there are a number of drawbacks and limits to these methods. So, it is of critical importance and profound interest to discover treatments that may successfully address the pathogenesis of DR. Curcumin and ß-glucogallin are the two potent compounds of natural origin that are already being used in various nutraceutical formulations for several ailments. They have been shown potent antiapoptotic, anti-inflammatory, antioxidant, anticancer, and pro-vascular function benefits in animal experiments. Their parent plant species have been used for generations by practitioners of traditional herbal medicine for the treatment and prevention of various eye ailments. In this review, we will discuss about pathophysiology of Diabetic retinopathy and the therapeutic potentials of curcumin and ß-glucogallin one of the principal compounds from Curcuma longa and Emblica officinalis in Diabetic retinopathy.

Association Between Atrial Fibrillation and Diabetes-Related Complications: A Nationwide Cohort Study.

OBJECTIVE: This study aimed to investigate the associations between concurrent atrial fibrillation and diabetes-related complications among patients with diabetes. RESEARCH DESIGN AND METHODS: This nationwide observational cohort study used the health checkup database from the Korean National Health Insurance Service. Patients diagnosed with diabetes who underwent health checkups between 2009 and 2012 were investigated. The patients with atrial fibrillation were matched in a 1:5 ratio with those without atrial fibrillation using propensity scores. Study outcomes included macrovascular, microvascular (diabetic retinopathy and diabetic nephropathy), and diabetic foot complications. The risks of clinical outcomes were measured using hazard ratios (HRs) with 95% CIs. RESULTS: A total of 65,760 patients with diabetes were analyzed (54,800 without atrial fibrillation and 10,960 with atrial fibrillation). After well-balanced propensity score matching, atrial fibrillation was associated with significantly higher risks of macrovascular complications (HR 1.12, 95% CI 1.09-1.16), diabetic nephropathy (HR 1.23, 95% CI 1.16-1.30), and diabetic foot complications (HR 1.13, 95% CI 1.09-1.17) compared with no atrial fibrillation, while the risk of diabetic retinopathy was comparable (HR 0.99, 95% CI 0.96-1.03). Patients with atrial fibrillation had a significantly higher risk of diabetic foot amputation (HR 4.12, 95% CI 1.98-8.56). CONCLUSIONS: Among patients with diabetes, concurrent atrial fibrillation was associated with increased risks for diabetes-related macrovascular complications, diabetic nephropathy, and diabetic foot. Such patients require holistic management to reduce the risk of adverse outcomes.

Liposome-Mediated Delivery Improves the Efficacy of Lisosan G against Retinopathy in Diabetic Mice.

Nutraceuticals are natural substances whose anti-oxidant and anti-inflammatory properties may be used to treat retinal pathologies. Their efficacy is limited by poor bioavailability, which could be improved using nanocarriers. Lisosan G (LG), a fermented powder from whole grains, protects the retina from diabetic retinopathy (DR)-induced damage. For this study, we tested whether the encapsulation of LG in liposomes (LipoLG) may increase its protective effects. Diabetes was induced in mice via streptozotocin administration, and the mice were allowed to freely drink water or a water dispersion of two different doses of LG or of LipoLG. Electroretinographic recordings after 6 weeks showed that only the highest dose of LG could partially protect the retina from diabetes-induced functional deficits, while both doses of LipoLG were effective. An evaluation of molecular markers of oxidative stress, inflammation, apoptosis, vascular endothelial growth factor, and the blood-retinal barrier confirmed that the highest dose of LG only partially protected the retina from DR-induced changes, while virtually complete prevention was obtained with either dose of LipoLG. These data indicate that the efficacy of LG in contrasting DR is greatly enhanced by its encapsulation in liposomes and may lay the ground for new dietary supplements with improved therapeutic effects against DR.

Exploring the protective effects of herbal monomers against diabetic retinopathy based on the regulation of autophagy and apoptosis: A review.

Diabetic retinopathy (DR) has become one of the top 3 blinding eye diseases in the world. In spite of recent therapeutic breakthroughs, it is not yet possible to cure DR through pharmacotherapy. Cell death is thought to play a key role in the pathogenesis of DR. Moderate modulation of cellular autophagy and inhibition of apoptosis have been identified as effective targets for the treatment of DR. Numerous phytochemicals have emerged as potential new drugs for the treatment of DR. We collected basic DR research on herbal monomers through keywords such as autophagy and apoptosis, and conducted a systematic search for relevant research articles published in the PubMed database. This review provides the effects and reports of herbal monomers on various DR cellular and animal models in vivo and in vitro in the available literature, and emphasizes the importance of cellular autophagy and apoptosis as current DR therapeutic targets. Based on our review, we believe that herbal monomers that modulate autophagy and inhibit apoptosis may be potentially effective candidates for the development of new drugs in the treatment of DR. It provides a strategy for further development and application of herbal medicines for DR treatment.

Folate and retinal vascular diseases.

Folate, a pteroylglutamic acid derivative, participates in fundamental cellular metabolism. Homocysteine, an amino acid, serves as an intermediate of the methionine cycle and can be converted back to methionine. Hyperhomocysteinemia is a recognized risk factor for atherosclerotic and cardiovascular diseases. In recent decades, elevated plasma homocysteine levels and low folate status have been observed in many patients with retinal vascular diseases, such as retinal vascular occlusions, diabetic retinopathy, and age-related degeneration. Homocysteine-induced toxicity toward vascular endothelial cells might participate in the formation of retinal vascular diseases. Folate is an important dietary determinant of homocysteine. Folate deficiency is the most common cause of hyperhomocysteinemia. Folate supplementation can eliminate excess homocysteine in plasma. In in vitro experiments, folic acid had a protective effect on vascular endothelial cells against high glucose. Many studies have explored the relationship between folate and various retinal vascular diseases. This review summarizes the most important findings that lead to the conclusion that folic acid supplementation might be a protective treatment in patients with retinal vascular diseases with high homocysteine or glucose status. More research is still needed to validate the effect of folate and its supplementation in retinal vascular diseases.