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.

Akimba Proliferative Diabetic Retinopathy Model: Understanding Molecular Mechanism and Drug Screening for the Progression of Diabetic Retinopathy.

As the prevalence of diabetes has reached epidemic proportions worldwide, diabetic retinopathy incidence is increasing rapidly. An advanced diabetic retinopathy (DR) stage can lead to a sight-threatening form. There is growing evidence showing diabetes causes a range of metabolic changes that subsequently lead to pathological modifications in the retina and retinal blood vessels. To understand the complex mechanism of the pathophysiology of DR, a precise model is not readily available. By crossbreeding the Akita and Kimba strains, a suitable proliferative DR model was acquired. This new Akimba strain manifests marked hyperglycemia and vascular changes, which resemble the early and advanced stage of DR.Here, we describe the breeding method, colony screening for experiments, and imaging techniques widely used to investigate the DR progression in this model. We elaborate step-by-step protocols to set up and perform fundus, fluorescein angiography, optical coherence tomography, and optical coherence tomography-angiogram to study retinal structural changes and vascular abnormalities. In addition, we show a method to label the leukocytes with fluorescence and laser speckle flowgraphy to examine the inflammation in the retina and retinal vessel blood flow speed, respectively. Lastly, we describe electroretinogram to evaluate the functional aspect of the DR transformations.

Ulmus davidiana 60% edible ethanolic extract for prevention of pericyte apoptosis in diabetic retinopathy.

Diabetic retinopathy (DR) is a disease that causes visual deficiency owing to vascular leakage or abnormal angiogenesis. Pericyte apoptosis is considered one of the main causes of vascular leakage in diabetic retina, but there are few known therapeutic agents that prevent it. Ulmus davidiana is a safe natural product that has been used in traditional medicine and is attracting attention as a potential treatment for various diseases, but its effect on pericyte loss or vascular leakage in DR is not known at all. In the present study, we investigated on the effects of 60% edible ethanolic extract of U. davidiana (U60E) and catechin 7-O-ß-D-apiofuranoside (C7A), a compound of U. davidiana, on pericyte survival and endothelial permeability. U60E and C7A prevented pericyte apoptosis by inhibiting the activation of p38 and JNK induced by increased glucose and tumor necrosis factor alpha (TNF-α) levels in diabetic retina. Moreover, U60E and C7A reduced endothelial permeability by preventing pericyte apoptosis in co-cultures of pericytes and endothelial cells. These results suggest that U60E and C7A could be a potential therapeutic agent for reducing vascular leakage by preventing pericyte apoptosis in DR.

Berberis dictyophylla F. inhibits angiogenesis and apoptosis of diabetic retinopathy via suppressing HIF-1α/VEGF/DLL-4/Notch-1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiao Bopi (XBP, སྐྱེར་བའི་བར་ཤུན།), as a classical Tibetan medicinal plant in China, which derived from the stem bark of Berberis dictyophylla F., has the function of "clearing heat and decreasing mKhris-pa". And it traditionally is utilized to treat the diabetes mellitus and its complications, such as diabetic retinopathy (DR). However, its underlying mechanisms remain unclear. AIM OF THE STUDY: The purpose of this study aimed to explore the microvascular protection of water extract of XBP against the spontaneous retinal damage of db/db mice. Meanwhile, the underlying mechanisms of XBP on angiogenesis and apoptosis were further interpreted. MATERIALS AND METHODS: We firstly used high-performance liquid chromatography to detected the representative chemical ingredients in the water extract of XBP. The DR model of db/db mice was then randomly divided into five groups: model group, calcium dobesilate (0.23 g/kg) group, and the water extract of XBP (0.375, 0.75 and 1.5 g/kg, respectively) groups. After 8 weeks of continuous administration, the parameters including body weight, fasting blood glucose, oral glucose tolerance test and insulin tolerance test were measured. The pathological changes and abnormal angiogenesis of the retina were detected by optical coherence tomography, HE, periodic acid-Schiff staining and transmission electron microscopy. Simultaneously, molecular docking was used to predict the potential connections between representative ingredients in XBP and angiogenesis/apoptosis-related proteins. The level of angiogenesis-related proteins and gene hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth (VEGF), delta-like ligand 4 (DLL-4) and Notch-1 were estimated by immunofluorescence analyses and real time-PCR. Further, TUNEL staining and immunofluorescence analyses were performed to investigate the apoptotic phenomenon and the expression of Bax, Bcl-2, Apaf-1, Cyto-c and cleaved caspase-3 and cleaved caspase-9 in the retina. RESULTS: Phytochemical analysis revealed that magnoflorine, jatrorrhizine, palmatine and berberine were principally representative ingredients in XBP. The results demonstrated that XBP effectively increased glucose tolerance and insulin sensitivity, whereas no effect on body weight of DR mice. Moreover, retinal thickening, pathological and retinal ultrastructure changes in DR mice were evidently ameliorated by XBP. The molecular docking results demonstrated that the main components of XBP and the protein of angiogenesis and apoptosis had a potential bind. XBP restrained the gene and protein levels of HIF-1α, VEGF, DLL-4 and Notch-1 in retina. Additionally, the TUNEL-positive cell rate and the down-regulated proteins of Bax, Apaf-1, Cyto-c, cleaved Caspase-3 and cleaved Caspase 9 and increased Bcl-2 level were revised by XBP. CONCLUSIONS: To sum up, the results suggested that XBP against DR could attribute to alleviating angiogenesis and apoptosis by suppressing the HIF-1α/VEGF/DLL-4/Notch-1 pathway. This evidence sheds a new light on the potential mechanisms of XBP in the treatment of DR.

Evaluation of individualized treatment of nonproliferative diabetic retinopathy: a multicenter, randomized, parallel-controlled study.

OBJECTIVE: To evaluate the differences in the efficacy of stationary treatment and individualized treatment for patients with nonproliferative diabetic retinopathy (NPDR). METHODS: This study was a randomized, controlled, multicenter clinical trial. Participants with NPDR were randomized into the stationary treatment group or the individualized treatment group. The stationary treatment group was given the basic treatment and Qiming granules, and the individualized treatment group was given the basic treatment, Qiming granules, and individualized Chinese herbal medicines over a 12-week period. The individualized therapeutic formula was also changed over time to adjust to the changes in the clinical presentation of the patient. We conducted observations of fundus retinal exudation and hemorrhage, visual acuity, Traditional Chinese Medicine symptom scores and other indicators. RESULTS: A total of 140 participants with NPDR were randomized into the stationary treatment group or the individualized treatment group, and 132 participants completed this study. Following the 12-week treatment, significant improvements in both primary and secondary outcomes were observed in the stationary and individualized treatment groups. No remarkable difference in the primary outcomes between the two groups was observed. However, there was a significant difference in the Traditional Chinese Medicine symptom scores (18 ± 7 vs 15 ± 6; P < 0.05). There were no severe adverse effects. CONCLUSION: Compared with stationary treatment, individualized treatment is more effective at relieving the Traditional Chinese Medicine symptoms and improving vision and fundus lesions at 12 weeks post treatment.

HDC-Net: A hierarchical dilation convolutional network for retinal vessel segmentation.

The cardinal symptoms of some ophthalmic diseases observed through exceptional retinal blood vessels, such as retinal vein occlusion, diabetic retinopathy, etc. The advanced deep learning models used to obtain morphological and structural information of blood vessels automatically are conducive to the early treatment and initiative prevention of ophthalmic diseases. In our work, we propose a hierarchical dilation convolutional network (HDC-Net) to extract retinal vessels in a pixel-to-pixel manner. It utilizes the hierarchical dilation convolution (HDC) module to capture the fragile retinal blood vessels usually neglected by other methods. An improved residual dual efficient channel attention (RDECA) module can infer more delicate channel information to reinforce the discriminative capability of the model. The structured Dropblock can help our HDC-Net model to solve the network overfitting effectively. From a holistic perspective, the segmentation results obtained by HDC-Net are superior to other deep learning methods on three acknowledged datasets (DRIVE, CHASE-DB1, STARE), the sensitivity, specificity, accuracy, f1-score and AUC score are {0.8252, 0.9829, 0.9692, 0.8239, 0.9871}, {0.8227, 0.9853, 0.9745, 0.8113, 0.9884}, and {0.8369, 0.9866, 0.9751, 0.8385, 0.9913}, respectively. It surpasses most other advanced retinal vessel segmentation models. Qualitative and quantitative analysis demonstrates that HDC-Net can fulfill the task of retinal vessel segmentation efficiently and accurately.

MiR-195 inhibits the ubiquitination and degradation of YY1 by Smurf2, and induces EMT and cell permeability of retinal pigment epithelial cells.

The dysregulated microRNAs (miRNAs) are involved in diabetic retinopathy progression. Epithelial mesenchymal transition (EMT) and cell permeability are important events in diabetic retinopathy. However, the function and mechanism of miR-195 in EMT and cell permeability in diabetic retinopathy remain largely unclear. Diabetic retinopathy models were established using streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-stimulated ARPE-19 cells. Retina injury was investigated by hematoxylin-eosin (HE) staining. EMT and cell permeability were analyzed by western blotting, immunofluorescence, wound healing, and FITC-dextran assays. MiR-195 expression was detected via qRT-PCR. YY1, VEGFA, Snail1, and Smurf2 levels were detected via western blotting. The interaction relationship was analyzed via ChIP, Co-IP, or dual-luciferase reporter assay. The retina injury, EMT, and cell permeability were induced in STZ-induced diabetic mice. HG induced EMT and cell permeability in ARPE-19 cells. MiR-195, YY1, VEGFA, and Snail1 levels were enhanced, but Smurf2 abundance was reduced in STZ-induced diabetic mice and HG-stimulated ARPE-19 cells. VEGFA knockdown decreased Snail1 expression and attenuated HG-induced EMT and cell permeability. YY1 silence reduced VEGFA and Snail1 expression, and mitigated HG-induced EMT and cell permeability. YY1 could bind with VEGFA and Snail1, and it was degraded via Smurf2-mediated ubiquitination. MiR-195 knockdown upregulated Smurf2 to decrease YY1 expression and inhibited HG-induced EMT and cell permeability. MiR-195 targeted Smurf2, increased expression of YY1, VEGFA, and Snail1, and promoted HG-induced EMT and cell permeability. MiR-195 promotes EMT and cell permeability of HG-stimulated ARPE-19 cells by increasing VEGFA/Snail1 via inhibiting the Smurf2-mediated ubiquitination of YY1.

Amelioration of diabetic retinopathy in db/db mice by treatment with different proportional three active ingredients from Tibetan medicine Berberis dictyophylla F.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberis dictyophylla F., a famous Tibetan medicine, has been used to prevent and treat diabetic retinopathy (DR) for thousands of years in clinic. However, its underlying mechanisms remain unclear. AIM OF THE STUDY: The present study was designed to probe the synergistic protection and involved mechanisms of berberine, magnoflorine and berbamine from Berberis dictyophylla F. on the spontaneous retinal damage of db/db mice. MATERIALS AND METHODS: The 14-week spontaneous model of DR in db/db mice were randomly divided into eight groups: model group, calcium dobesilate (CaDob, 0.23 g/kg) group and groups 1-6 (different proportional three active ingredients from Berberis dictyophylla F.). All mice were intragastrically administrated for a continuous 12 weeks. Body weight and fasting blood glucose (FBG) were recorded and measured. Hematoxylin-eosin and periodic acid-Schiff (PAS) stainings were employed to evaluate the pathological changes and abnormal angiogenesis of the retina. ELISA was performed to assess the levels of IL-6, HIF-1α and VEGF in the serum. Immunofluorescent staining was applied to detect the protein levels of CD31, VEGF, p-p38, p-JNK, p-ERK and NF-κB in retina. In addition, mRNA expression levels of VEGF, Bax and Bcl-2 in the retina were monitored by qRT-PCR analysis. RESULTS: Treatment with different proportional three active ingredients exerted no significant effect on the weight, but decreased the FBG, increased the number of retinal ganglionic cells and restored internal limiting membrane. The results of PAS staining demonstrated that the drug treatment decreased the ratio of endothelial cells to pericytes while thinned the basal membrane of retinal vessels. Moreover, these different proportional active ingredients can markedly downregulate the protein levels of retinal CD31 and VEGF, and serum HIF-1α and VEGF. The gene expression of retinal VEGF was also suppressed. The levels of retinal p-p38, p-JNK and p-ERK proteins were decreased by drug treatment. Finally, drug treatment reversed the proinflammatory factors of retinal NF-κB and serum IL-6, and proapoptotic Bax gene expression, while increased antiapoptotic Bcl-2 gene expression. CONCLUSIONS: These results indicated that DR in db/db mice can be ameliorated by treatment with different proportional three active ingredients from Berberis dictyophylla F. The potential vascular protection mechanisms may be involved in inhibiting the phosphorylation of the MAPK signaling pathway, thus decreasing inflammatory and apoptotic events.

Therapeutic potential of curcumin in diabetic retinopathy (Review).

Diabetic retinopathy (DR) is a type of retinal microangiopathy caused by diabetes mellitus. It has become the leading cause of blindness among working individuals worldwide. DR is becoming increasingly common among younger diabetic patients and there is a need for lifelong treatment. The pathogenic mechanisms of DR are influenced by a number of factors, such as hyperglycemia, hyperlipidemia, inflammatory response and oxidative stress, among others. Currently, the treatment methods for DR mainly include retinal photocoagulation, vitrectomy, or anti­vascular endothelial growth factor (VEGF) therapy. However, these methods have some disadvantages and limitations. Therefore, it is a matter of great interest and urgency to discover drugs that can target the pathogenesis of DR. Since ancient times, traditional Chinese medicine practitioners have accumulated extensive experiences in the use of Chinese herbal medicine for the prevention and treatment of diseases. In the theory of traditional Chinese medicine, curcumin has the effects of promoting blood circulation and relieving pain. A number of studies have also demonstrated that curcumin has multiple biological activities, including exerting anti­apoptotic, anti­inflammatory, antioxidant and antitumor properties. In recent years, studies have also confirmed that curcumin can prevent a variety of diabetic complications, including diabetic nephropathy (DN). However, the preventive and curative effects of curcumin on DR and its mechanisms of action have not yet been fully elucidated. The present review aimed to explore the therapeutic potential of curcumin in diabetes mellitus and DR.

Coumestrol mitigates retinal cell inflammation, apoptosis, and oxidative stress in a rat model of diabetic retinopathy via activation of SIRT1.

Diabetes-induced oxidative stress is vital in initiating neuronal damage in the diabetic retina, leading to diabetic retinopathy (DR). This study investigates the possible effects of coumestrol (CMS) on streptozotocin (STZ)-induced DR. First, we established a rat model of DR by STZ injection and a cell model involving high-glucose (HG) exposure of human retinal microvascular endothelial cells (hRMECs). We characterized the expression patterns of oxidative stress indicators, pro-inflammatory cytokines, and pro-apoptotic proteins in hRMECs. Polymerase chain reaction showed sirtuin 1 (SIRT1) to be poorly expressed in the retinal tissues of STZ-treated rats and HG-exposed hRMECs, but its expression was upregulated upon treatment with CMS treatment. Furthermore, CMS treatment attenuated the STZ-induced pathologies such as oxidative stress, inflammation, and cell apoptosis. Consistent with the in vivo results, CMS activated the expression of SIRT1, thereby inhibiting oxidative stress, inflammation, and apoptosis of HG-treated hRMECs. From these findings, we concluded that CMS ameliorated DR by inhibiting inflammation, apoptosis and oxidative stress through activation of SIRT1.

Fufang Xueshuantong alleviates diabetic retinopathy by activating the PPAR signalling pathway and complement and coagulation cascades.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Xueshuantong (FXST) is a traditional Chinese patent medicine composed of Panax notoginseng (Burkill) F.H.Chen (Araliaceae), Salvia miltiorrhiza Bunge (Lamiaceae), Astragalus propinquus Schischkin (Leguminosae), and Scrophularia ningpoensis Hemsl. (Scrophulariaceae). It has been widely used for the treatment of diabetic retinopathy (DR) and exerts a positive clinical therapeutic effect. AIM OF THE STUDY: The aim of this study was to observe the effect of FXST on diabetic rat retinas and investigate its pharmacological mechanism for improving DR. METHODS: The diabetic rat model was established by intraperitoneal injection of streptozotocin. The rats were divided into a normal group, diabetic group, and FXST group. The rats in the FXST group were treated with FXST by intragastric administration for 12 weeks while other rats were given the same volume of normal saline. The haemodynamic parameters of the central retinal artery in the rats were measured by ultrasound. Haematoxylin-eosin staining was utilised to observe the pathological structural changes in the retina. The apoptosis of retinal nerve cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling. RNA sequencing was used to screen the differentially expressed genes (DEGs), and enrichment analyses were performed. The DEGs were validated through real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The peak systolic velocity, end diastolic velocity, and mean velocity decreased while the resistance index and pulsatility index increased in the diabetic rat retinas. FXST also improved haemodynamics. In contrast with the diabetic group, FXST allayed the disorder and oedema of the retinal structure in addition to reversing the reductions in retinal thickness and retinal ganglion cell number. It also decreased the apoptosis index of retinal cells. A total of 1134 DEGs were identified by RNA sequencing in the FXST group compared to the diabetic group, including 814 upregulated genes and 320 downregulated genes. These genes were enriched in the complement and coagulation cascades as well as the peroxisome proliferator-activated receptor (PPAR) signalling pathway. Several DEGs, including PPAR gamma, perilipin 4, acyl-CoA dehydrogenase long chain, CD55 molecule, and plasminogen activator urokinase, were identified by qRT-PCR, and the results were consistent with the RNA sequencing data. CONCLUSIONS: FXST alleviates DR by improving the haemodynamics and morphological alterations of diabetic rat retinas, which are mediated by complement and coagulation cascades and the PPAR signalling pathway.

Terminalia catappa Fruit Extract Reverses Streptozotocin-Induced Diabetic Retinopathy in Rats.

OBJECTIVE AND BACKGROUND: Diabetic retinopathy is amongst the most common microvascular complications associated with diabetes. Controlling blood glucose level alone cannot manage diabetes associated complications. Thus, mechanisms that additionally prevent diabetes associated complications are the need of the hour, driving the researchers towards herbal therapies. Terminalia catappa is renowned for its anti-inflammatory, antioxidant, anti-hyperglycemic and anti-angiogenic activity. The current study explores the effect of Terminalia catappa fruit extract on streptozotocin-induced diabetic retinopathy in rats. METHODS: Streptozotocin-induced chronic diabetic rat model was utilized in the study. The hydroalcoholic fruit extract of T. catappa in 20mg/kg, 30mg/kg and 40mg/kg dose and standard anti-diabetic drug, glibenclamide (10mg/kg) was given orally. Retinopathy was evaluated by monitoring lenticular, fundus images and measuring arteriole and venule tortuosity index. Oxidative, angiogenic and inflammatory biomarkers were assessed at the 12th week in the retinal homogenate. Histopathological changes in the retina were also examined. Data was analyzed using one-way Repeated Measure ANOVA followed by the Mann-Whitney test. RESULTS: The hydro-alcoholic fruit extract of T. catappa significantly decreased blood glucose (p<0.001) in a dose-dependent manner in diabetic rats. Cataract lens was observed in all experimental groups and became clear (grade 0) with 40mg/kg and with 40mg/kg along with glibenclamide at the eighth and sixth week, respectively. The hydro-alcoholic fruit extract in all three doses significantly reduced (p<0.01) arteriole and venule tortuosity in diabetic rats. T. catappa in all three doses in diabetic rats showed a modulatory effect in oxidative, angiogenic and inflammatory biomarkers. CONCLUSION: T. catappa reverses diabetes-induced retinopathy by anti-hyperglycemic, anti-oxidant, anti-angiogenic and anti-inflammatory actions, and thus has a potential to be used in diabetes-induced retinopathy.

Protective effect of metformin on rat diabetic retinopathy involves suppression of toll-like receptor 4/nuclear factor-k B expression and glutamate excitotoxicity.

Microvascular complications of diabetes mellitus are progressively significant reasons for mortality. Metformin (MET) is considered as the first-line therapy for type 2 diabetes patients, and may be especially beneficial in cases of diabetic retinopathy although the precise mechanisms of MET action are not fully elucidated. The current study was designed to inspect the antioxidant and modulatory actions of MET on DRET in streptozotocin-induced diabetic rats. The effect of MET on the toll-like receptor 4/nuclear factor kappa B (TLR4/NFkB), inflammatory burden and glutamate excitotoxicity was assessed. Twenty-four male rats were assigned to four experimental groups: (1) Vehicle group, (2) Diabetic control: developed diabetes by injection of streptozotocin (60 mg/kg, i.p.). (3&4) Diabetic + MET group: diabetic rats were left for 9 weeks without treatment and then received oral MET 100 and 200 mg/kg for 6 weeks. Retinal samples were utilized in biochemical, histological, immunohistochemical and electron microscopic studies. MET administration significantly decreased retinal level of insulin growth factor and significantly suppressed the diabetic induced increase of malondialdehyde, glutamate, tumor necrosis factor-α and vascular endothelial growth factor (VEGF). Further, MET decreased the retinal mRNA expression of NFkB, tumor necrosis factor-α and TLR4 in diabetic rats. The current findings shed the light on MET's efficacy as an adjuvant therapy to hinder the development of diabetic retinopathy, at least partly, via inhibition of oxidative stress-induced NFkB/TLR4 pathway and suppression of glutamate excitotoxicity.

An innovative method for screening and evaluating the degree of diabetic retinopathy and drug treatment based on artificial intelligence algorithms.

Current methods of evaluating the degree of diabetic retinopathy are highly subjective and have no quantitative standard. To objectively evaluate the slight changes in tissue structure during the early stage of retinal diseases, a subjective interpretation and qualitative analysis of the pathological sections of retinal HE in diabetic animals is required for screening and evaluating the degree of diabetic retinopathy and drug efficacy. To develop an innovative method for screening and evaluating the degree of diabetic retinopathy and drug treatment based on artificial intelligence algorithms. Based on the change law of the early nerve fiber layer and the ganglion cells, we get disparate characteristics of the microscopic image of diabetes animal retina HE slices. Using image recognition and deep learning methods on these HE slices, we can identify the changes in the ganglion cells and nerve fiber layer for diagnosing early retinopathy and evaluated the therapeutic effect of the potential drugs. We conduct quantitative calculation per unit length of the nerve fiber layer and total area of the nerve fiber layer to identify biology significance of edema. Additionally, we also perform quantitative calculation with the number of unit area ganglion cells to identify the section in biology cell hyperplasia. Finally, we get the significance of quantitative calculation on the unit cell area to identify ganglion cell shriveling in biology. In addition to the evaluation of the disease degree and changes, we also obtained retinal HE sections after different drug interventions and evaluated the therapeutic effect of the drugs. This study presents a novel quantitative method for screening and evaluating of diabetic retinopathy and drug efficacy.

Risuteganib-a novel integrin inhibitor for the treatment of non-exudative (dry) age-related macular degeneration and diabetic macular edema.

INTRODUCTION: Non-exudative (dry) age-related macular degeneration (AMD) and diabetic macular edema (DME) are leading causes of vision loss worldwide. Besides age-related eye disease study (AREDS) vitamin supplements, there are no efficacious pharmaceutical interventions for dry AMD available. While numerous pharmacologics are available to treat diabetic macular edema (DME), many patients respond suboptimally to existing therapies. Risuteganib is a novel anti-integrin peptide that targets the multiple integrin heterodimers involved in the pathophysiology of dry AMD and DME. Inhibiting these selected integrin heterodimers may benefit patients with these conditions. AREAS COVERED: This article offers a brief overview of current pharmaceuticals available for dry AMD and DME. The proposed role of integrins in AMD and DME is reviewed and later, risuteganib, a novel anti-integrin peptide is introduced. The data from initial Phase 1 and Phase 2 risuteganib clinical trials are discussed in the latter part of the paper. EXPERT OPINION: While there are currently limited treatment options for dry AMD, more data are needed before we can truly evaluate the benefits of adopting risuteganib into the clinic. Conversely, several effective treatment options exist for DME; hence, risuteganib must show that it can add to these results, especially in those with refractory disease, before retina specialists adopt risuteganib into their treatment regimens.

Protective Effect of Palm Oil-Derived Tocotrienol-Rich Fraction Against Retinal Neurodegenerative Changes in Rats with Streptozotocin-Induced Diabetic Retinopathy.

: Oxidative stress plays an important role in retinal neurodegeneration and angiogenesis associated with diabetes. In this study, we investigated the effect of the tocotrienol-rich fraction (TRF), a potent antioxidant, against diabetes-induced changes in retinal layer thickness (RLT), retinal cell count (RCC), retinal cell apoptosis, and retinal expression of vascular endothelial growth factor (VEGF) in rats. Additionally, the efficacy of TRF after administration by two different routes was compared. The diabetes was induced in Sprague-Dawley rats by intraperitoneal injection of streptozotocin. Subsequently, diabetic rats received either oral or topical treatment with vehicle or TRF. Additionally, a group of non-diabetic rats was included with either oral or topical treatment with a vehicle. After 12 weeks of the treatment period, rats were euthanized, and retinas were collected for measurement of RLT, RCC, retinal cell apoptosis, and VEGF expression. RLT and RCC in the ganglion cell layer were reduced in all diabetic groups compared to control groups (p < 0.01). However, at the end of the experimental period, oral TRF-treated rats showed a significantly greater RLT compared to topical TRF-treated rats. A similar observation was made for retinal cell apoptosis and VEGF expression. In conclusion, oral TRF supplementation protects against retinal degenerative changes and an increase in VEGF expression in rats with streptozotocin-induced diabetic retinopathy. Similar effects were not observed after topical administration of TRF.

The effect of total lignans from Fructus Arctii on Streptozotocin-induced diabetic retinopathy in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Arctii is the dried ripe fruit of Arctium lappa L. (family Asteraceae). It is a well-known Chinese Materia Medica that was included in the Chinese pharmacopoeia because of its traditional therapeutic actions, such as heat removal, detoxification, and elimination of swelling. Since ancient times Fructus Arctii has been used extensively in a number of classical drug formulas to treat type 2 diabetes mellitus. Modern pharmacological studies have shown that certain components of Fructus Arctii have multiple physiological activities on type 2 diabetes and its complications. AIM OF THE STUDY: We have reported the inhibitory effect of total lignans from Fructus Arctii (TLFA) on aldose reductase, the key enzyme in the polyol pathway, which is considered to be closely related to the onset of diabetic retinopathy (DR). The present study aimed to observe the preventive and therapeutic effects of TLFA on DR in Streptozotocin (STZ)-induced DR rats. MATERIALS AND METHODS: TLFA was prepared from Fructus Arctii and its content was determined using UV spectrophotometry. The DR model was induced by STZ in Wistar rats. For DR prevention, the animals were gavaged once daily for 9 weeks with TLFA (1.38, 0.69, and 0.35 g/kg/day) as soon as they were confirmed as diabetes models. Pathological changes to retinal tissues and the expression of vascular endothelial growth factor (VEGF) and protein kinase C (PKC) in the retina were detected after TLFA treatment. The effects of TLFA on blood glucose levels and body weight were also observed. For DR treatment, the animals were gavaged once daily for 12 weeks with TLFA (1.38 and 0.69 g/kg/day) at 3 months after they were confirmed as diabetes models. The therapeutic effect was studied using quantitative detection of blood-retina barrier (BRB) breakdown via an Evans Blue leakage assay. RESULTS: For DR prevention, after 9 weeks of TLFA administration, histopathological examination of retinal tissue showed that TLFA improved the lesions in the retina. Changes to retinal microstructures such as capillaries, ganglion cells, bipolar cells, and the membrane disk examined by electron microscopy further confirmed that TLFA has a preventive effect on retinopathy. Terminal deoxynucleotidyl Transferase-mediated dUTP nick end labeling (TUNEL) detection showed that TLFA could inhibit retinal cell apoptosis in the diabetic rats, and fasting blood glucose (FBG) levels of rats in the TLFA-treated groups decreased during the experiment. For DR treatment, after 3 months of administration, the amount of dye leakage in the TLFA-administered groups was reduced by more than 50% compared with that in the model group, which indicated that TLFA has a therapeutic effect on middle and late DR. Messenger RNA (mRNA) expression of VEGF and PKCß2 in the retina detected by real-time fluorescent quantitative reverse transcription-polymerase chain reaction (FQ-RT-PCR) showed that TLFA could inhibit the expression of them, which was consistent with the results of immunohistochemistry (IHC). CONCLUSION: TLFA has a preventive and therapeutic effect on DR. Its mechanism of action on DR is related to inhibiting PKC activation and blocking VEGF elevation.

The effect of Shengpuhuang-tang on retinal inflammation in streptozotocin-induced diabetic rats by NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is a terrible microvascular disorder causing blindness. Retinal inflammation is the early stage in DR, which is believed to play a crucial role in the development of it. Shengpuhuang-tang (ST), a traditional herbal formula, which has effective treatment of fundus bleeding disorder. ST exerts protective effects against DR in rats, but its underlying mechanism of this efficacy remains unknown. Thus, the objective of this study is to examine the mechanism and the efficacy of ST on retinal inflammation in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The administration of ST was initiated at 4 weeks after diabetes induction and continued for 12 weeks. Retinal vessel permeability was evaluated by using FITC-dextran and Evans blue. Retinal leukostasis was evaluated with FITC-coupled concanavalin A lectin (ConA). Moreover, western blotting was performed to detect TNF-α, ICAM-1 and the relative expression levels of IκBα, IKKß, and p65 in vivo. RESULTS: The results showed that the retinal inflammation in streptozotocin-induced diabetic rats was significantly decreased by ST. ST could decreased the expression levels of TNF-α, ICAM-1 and inhibited the expression of p-IKKß, p-p65 and IκBα. It could also inhibited the nuclear transfer of p65. CONCLUSIONS: In conclusion, these data suggested that ST may have potential treatment strategies against early stage of diabetic retinopathy through NF-κB pathway.

The effects of hyperbaric oxygen therapy on diabetic retinopathy: A preliminary study.

PURPOSE: The objective of this study was to prospectively assess the effect of hyperbaric oxygen therapy (HBOT) on diabetic retinopathy lesions and macular edema in patients undergoing the treatment for diabetic foot ulcers. METHODS: We compared two groups: a first group including 25 patients with non-proliferative diabetic retinopathy treated by HBOT for foot ulcers, and a second group (control group) composed of 25 patients with diabetic retinopathy who did not receive HBOT. The HBOT protocol performed for the patients in the first group was: 30 sessions of 90 minutes each at 2.5 ATA with a mean frequency of five sessions per week. All patients had an ophthalmological exam at baseline (visual acuity, intraocular pressure, fundus exam), fundus photography and an OCT exam. A follow-up exam was performed at the conclusion of the HBOT. RESULTS: Compared to the control group, patients treated with HBOT showed a regression or stabilization of diabetic retinopathy lesions and a decrease in central macular thickness (CMT). CONCLUSION: Hyperbaric oxygen therapy may improve diabetic retinopathy and diabetic macular edema. This therapy may serve as an adjunctive treatment in the management of retinal ischemia and capillary hyperpermeability in diabetic retinopathy.

Thiamine transporter 2 is involved in high glucose-induced damage and altered thiamine availability in cell models of diabetic retinopathy.

Thiamine prevents high glucose-induced damage in microvasculature, and progression of retinopathy and nephropathy in diabetic animals. Impaired thiamine availability causes renal damage in diabetic patients. Two single-nucleotide polymorphisms in SLC19A3 locus encoding for thiamine transporter 2 are associated with absent/minimal diabetic retinopathy and nephropathy despite long-term type 1 diabetes. We investigated the involvement of thiamine transporter 1 and thiamine transporter 2, and their transcription factor specificity protein 1, in high glucose-induced damage and altered thiamine availability in cells of the inner blood-retinal barrier. Human endothelial cells, pericytes and Müller cells were exposed to hyperglycaemic-like conditions and/or thiamine deficiency/over-supplementation in single/co-cultures. Expression and localization of thiamine transporter 1, thiamine transporter 2 and transcription factor specificity protein 1 were evaluated together with intracellular thiamine concentration, transketolase activity and permeability to thiamine. The effects of thiamine depletion on cell function (viability, apoptosis and migration) were also addressed. Thiamine transporter 2 and transcription factor specificity protein 1 expression were modulated by hyperglycaemic-like conditions. Transketolase activity, intracellular thiamine and permeability to thiamine were decreased in cells cultured in thiamine deficiency, and in pericytes in hyperglycaemic-like conditions. Thiamine depletion reduced cell viability and proliferation, while thiamine over-supplementation compensated for thiamine transporter 2 reduction by restoring thiamine uptake and transketolase activity. High glucose and reduced thiamine determine impairment in thiamine transport inside retinal cells and through the inner blood-retinal barrier. Thiamine transporter 2 modulation in our cell models suggests its major role in thiamine transport in retinal cells and its involvement in high glucose-induced damage and impaired thiamine availability.