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.

Yiqi Tongluo Fang could preventive and delayed development and formation of diabetic retinopathy through antioxidant and anti-inflammatory effects.

BACKGROUND: Yiqi Tongluo Fang (YQTLF) is an effective prescription for the treatment of diabetic retinopathy (DR), but its mechanism of action remains unclear. METHOD: The content of YQTLF was determined using liquid and gas chromatography-mass spectrometry (LC-MS and GC-MS, respectively). Twenty-five Sprague Dawley (SD) rats were randomly selected as the normal control group. One hundred SD streptozotocin-induced diabetes (type 1) rats were randomly divided into diabetic control, diabetic+insulin+ calcium dobesilate (CaD), and diabetic+insulin+ YQTLF groups, with 25 rats in each group. Bodyweight level was measured every 2 weeks. After 12 weeks of gavage, the glucose levels, lipids, oxidative stress, inflammation, retinal histopathology, and the blood-retinal barrier were assessed in each group. The p38 MAPK pathway was changed to explore its internal mechanism. The measurement data were expressed as mean ± standard deviation, and different statistical methods were used according to a normal distribution, square error, or not. RESULTS: A total of 1024 valid peaks were identified in YQTLF using GC-MS. YQTLF significantly lowered the fasting blood glucose levels in diabetic rats. YQTLF early inhibited changes in retinal histology, capillaries, cells, and tight junction proteins (such as ZO-1, occludin, claudin-5, and VE-cadherin) before the formation and development of DR. These findings correlated with the alleviation of glucolipid metabolism, inflammation, and oxidative stress. The lncRNA MALAT1 and the PRC 2/p38 MAPK-related pathway, such as the expression of EZH2, SUZ12, EED, p38 MAPK, MMP-9, and VEGFR, were also correlated. CONCLUSION: We have demonstrated the molecular and cellular mechanisms underlying the preventive and delayed development and formation of DR. YQTLF prevents changes in dyslipidemia, retinal histology, capillaries, cells, and tight junction proteins. These protective effects appear to be linked to its antioxidant and anti-inflammatory effects, which prevent the activation of intracellular signaling pathways, such as the lncRNA MALAT1 and PRC 2/p38 MAPK-related pathway.

Investigation on the Q-markers of Bushen Huoxue Prescriptions for DR treatment based on chemometric methods and spectrum-effect relationship.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is a kind of complex complication of late diabetes mellitus with high incidence and risk of blindness. Bushen Huoxue Prescription (BHP), which consists of Rehmanniae radix (RR), Salviae miltiorrhizae radix et rhizoma (SMRR), Ginseng radix et rhizome (GRR) and Puerariae lobatae radix (PLR), has an active effect on the treatment of DR. However, the quality markers (Q-markers) of BHP are not entirely clear. PURPOSE: This study aimed to screen the Q-markers of BHP for DR treatment based on the establishment of spectrum-effect relationship and verified experiment. MATERIALS AND METHODS: In this study, 12 BHP samples (S1-S12) for fingerprint analysis and pharmacological evaluation were prepared according to a four-factor and twelve-level uniform design. High performance liquid chromatography-ultraviolet detector-evaporative light scattering detector (HPLC-UV-ELSD) was employed to analyze the fingerprint on the basis of the characteristics of BHP components. The evaluation of sample similarity was carried out by similarity analysis (SA) and hierarchical cluster analysis (HCA). The pharmacological indicators, including expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) in the retina of Sprague Dawley (SD) rats induced by streptozotocin (STZ), were detected by enzyme-linked immunosorbent assay (ELISA). Besides, the spectrum-effect relationship between common peaks of fingerprints and the pharmacological results was investigated by partial least squares regression (PLSR) and canonical correlation analysis (CCA). The results of spectrum-effect relationship were verified by the expression of VEGF and HIF-1α on primary culture retinal Müller cells induced by hyperglycemia and hypoxia. RESULTS: In the HPLC-UV-ELSD fingerprint, 23 common peaks in UV and 14 common peaks in ELSD were identified. The pharmacological results indicated that the expression of VEGF and HIF-1α in the retina of SD rats was inhibited by 12 BHP samples to varying degrees compared with the model group. Based on SA and heatmap of HCA, S4 and S8 were clearly distinguished from other samples. The results of PLSR and CCA revealed that the contents of puerarin, daidzin, salvianolic acid B and ginsenoside Rb1 were inversely correlated with the expression of VEGF and HIF-1α. Hence, the four compounds may be the main active components to prevent and treat DR. The results of intervention on primary culture retinal Müller cells showed that puerarin, daidzin, salvianolic acid B, and ginsenoside Rb1 can significantly inhibit the expression of VEGF and HIF-1α. CONCLUSIONS: The spectrum-effect relationship of BHP was successfully established, and the Q-markers of BHP for the prevention and treatment of DR were preliminarily confirmed. It provides a feasible method for the research of quality control.

Potential Effects of Sweet Potato (Ipomoea batatas) in Hyperglycemia and Dyslipidemia-A Systematic Review in Diabetic Retinopathy Context.

Hyperglycemia is a condition with high glucose levels that may result in dyslipidemia. In severe cases, this alteration may lead to diabetic retinopathy. Numerous drugs have been approved by officials to treat these conditions, but usage of any synthetic drugs in the long term will result in unavoidable side effects such as kidney failure. Therefore, more emphasis is being placed on natural ingredients due to their bioavailability and absence of side effects. In regards to this claim, promising results have been witnessed in the usage of Ipomoea batatas (I. batatas) in treating the hyperglycemic and dyslipidemic condition. Thus, the aim of this paper is to conduct an overview of the reported effects of I. batatas focusing on in vitro and in vivo trials in reducing high glucose levels and regulating the dyslipidemic condition. A comprehensive literature search was performed using Scopus, Web of Science, Springer Nature, and PubMed databases to identify the potential articles on particular topics. The search query was accomplished based on the Boolean operators involving keywords such as (1) Beneficial effect OR healing OR intervention AND (2) sweet potato OR Ipomoea batatas OR traditional herb AND (3) blood glucose OR LDL OR lipid OR cholesterol OR dyslipidemia. Only articles published from 2011 onwards were selected for further analysis. This review includes the (1) method of intervention and the outcome (2) signaling mechanism involved (3) underlying mechanism of action, and the possible side effects observed based on the phytoconstiuents isolated. The comprehensive literature search retrieved a total of 2491 articles using the appropriate keywords. However, on the basis of the inclusion and exclusion criteria, only 23 articles were chosen for further review. The results from these articles indicate that I. batatas has proven to be effective in treating the hyperglycemic condition and is able to regulate dyslipidemia. Therefore, this systematic review summarizes the signaling mechanism, mechanism of action, and phytoconstituents responsible for those activities of I. batatas in treating hyperglycemic based on the in vitro and in vivo study.

Protective role of vitamin D against oxidative stress in diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus. There is much evidence showing that a high level of mitochondrial overproduction of reactive oxygen species in the diabetic retina contributes in modifying cellular signalling and leads to retinal cell damage and finally to the development of DR pathogenesis. In the last few decades, it has been reported that vitamin D is involved in DR pathogenesis. Vitamin D, traditionally known as an essential nutrient crucial in bone metabolism, has also been proven to be a very effective antioxidant. It has been demonstrated that it modulates the production of advanced glycosylated end products, as well as several pathways including protein kinase C, the polyol pathway leading to the reduction of free radical formation. It prevents the translocation of nuclear factor kappa B, preventing the inflammatory response, acting as an immunomodulator, and modulates autophagy and apoptosis. In this review, we explore the molecular mechanisms by which vitamin D protects the eye from oxidative stress, in order to evaluate whether vitamin D supplementation may be useful to mitigate the deleterious effects of free radicals in DR.

[Structure Activity Relationship Study of Polymethoxylated Flavones Targeted Retinal Müller Cells for Prevention of Retinal Diseases].

Diabetic retinopathy (DR) is a retinal disease representing one of the main causes of vision loss in developed countries. In the early stage of DR, disruption of blood retinal barrier (BRB) is observed, and it will lead to vascular permeability and visual impairment. Therefore, protection against the breakdown of BRB may be useful strategy for prevention of DR. Matrix metalloproteinases (MMPs) plays an important role in the degradation of extracellular matrix proteins. In DR, they attribute to increased vascular permeability by degrading the junction proteins, such as occuldin and cadherin that are important to maintain the BRB junction complex. Müller cells constitute the main glial cells of the retina and are involved in many retinal functions. They are reported to be one of the MMP-producing cells in the retina. In this symposium review, I present the molecular mechanism of MMP expression in retinal Müller cells. In addition, I would like to introduce polymethoxylated flavones, nobiletin and the derivatives isolated from natural resource as novel MMP inhibitors, which may be applicable to prevention of DR.

Association between dietary antioxidants and risk for diabetic retinopathy in a Chinese population.

BACKGROUND: Diabetic retinopathy (DR) is related to oxidative stress and insufficient intake of dietary antioxidants may be associated with the onset and progression of DR. This study aimed to detect the association between main dietary antioxidants intake and the risk for DR. METHODS: This is a cross-sectional study of a Chinese urban population. Four hundred and fifty-five subjects with type 2 diabetes were recruited and divided into diabetic patients without retinopathy (DWR) group and DR group based on their retinal status. CSMO (clinically significant macular oedema) was diagnosed by stereoscopic photography. Demographic and lifestyle characteristics were ascertained by questionnaire. General physical and ophthalmic examinations were completed for all subjects. Dietary antioxidants were assessed by 3-day food records. Subjects who have taken any type of vitamin supplements were excluded from the study. The association of dietary antioxidants with the risk for DR was analysed by logistic regression with adjustment of other factors. The dietary antioxidants levels of the CSMO subjects and non-CSMO subjects were compared using the Wilcoxon rank sum test. RESULTS: One hundred and nineteen subjects in DR group and 336 subjects in DWR group participated in the study. Only ten DR subjects had CSMO. The results showed that higher vitamin E (OR (95% CI):0.97 (0.95, 1.00), P = 0.036) and selenium (OR (95% CI):0.98 (0.96, 1.00), P = 0.017) intake appear to be the protective factors of DR. The dietary antioxidants levels of CSMO and non-CSMO subjects had no statistical differences (P > 0.05). CONCLUSIONS: Dietary antioxidants intake, particularly vitamin E and selenium, were observed to have protective effects on DR.

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.

The effects of Bushen Yiqi Huoxue prescription and its disassembled prescriptions on a diabetic retinopathy model in Sprague Dawley rats.

BACKGROUND: Diabetic retinopathy (DR) is one of the most serious complications in the late stages of diabetes, with a complex mechanism. As a complication affecting local lesions, few studies have compared differences of cytokine expression in the serum and retina. Owing to the specific value of traditional Chinese medicine (TCM) to complex diseases, TCM research has recently boomed in the prevention and treatment of diabetes. Bushen Yiqi Huoxue (BYH) prescription is a Chinese herbal compound that has been independently developed by our research group and has been proved to have a positive effect on DR; however, its specific mechanism and compatibility rule remain to be further explored. OBJECTIVE: To construct a DR model of Sprague Dawley (SD) rats, simultaneously detect multiple factor expression in the serum and retina of rats, explore the effect of BYH prescription and its disassembled prescriptions on DR, and discuss the influence of various compatibility combinations. METHODS: BYH prescription was disassembled into two new compatibilities in the absence of Rehmanniae Radix (Yiqi Huoxue prescription, YH prescription) or Ginseng Radix et Rhizoma (Bushen Huoxue prescription, BH prescription). Male SD rats were induced using streptozotocin + high-fat and high-sugar diet to establish DR models and were divided into groups, then the intragastric administration and sampling. The body weight and fasting blood glucose of rats were continuously recorded during feeding; pathophysiological status observation of the retina by haematoxylin and eosin (HE) staining; advanced glycation end products (AGEs) and haemoglobin A1c (HbA1c) level detection in the rat serum by enzyme-linked immunosorbent assay; and the Luminex technique was used to detect the ICAM-1, IL-1ß, IL-6, TNF-α and vascular endothelial growth factor (VEGF) expression concentrations in the retinal tissue and serum. RESULTS: The results of blood glucose, body weight and HE staining proved that the model was successfully constructed, and the three combinations could reduce the retinal injury in DR rats. Serum AGEs and HbA1c levels of the model group increased compared with the control group (CG). Compared with the DR model group, only AGEs decreased in the BYH group, while the AGEs and HbA1c levels were significantly inhibited in the YH and BH groups, showing a significant correlation between the expression of AGEs and HbA1c in the serum of DR rats. In the serum of rats, IL-1ß, IL-6, TNF-α and VEGF concentrations in the DR model group increased, although no statistical difference was observed in the ICAM-1 data compared with the CG. Compared with the DR model group, the IL-1ß, IL-6 and TNF-α expression decreased in the BYH group. Moreover, the IL-6 and TNF-α expression decreased in the YH group and only the IL-6 expression decreased in the BH group. In the retina tissue, the model group had higher ICAM-1, IL-1ß, IL-6, TNF-α and VEGF levels than the CG. Compared with the DR model group, TNF-α in the BYH group rats decreased, and the ICAM-1, IL-6 and TNF-α concentrations decreased in the YH and BH groups. Furthermore, differences in the ICAM-1 and VEGF expression in the serum and retina existed. CONCLUSION: BYH compound and its disassembled prescriptions could improve the DR model rats induced with streptozotocin + high-fat and high-sugar diet, respectively, by inhibiting chronic blood glucose, AGEs, or inflammation response. The expression level and location of each factor are different, confirming that the effect of TCM prescriptions is not the simple addition of each single drug or its chemical components, but the rationality of its internal compatibility combination. Further, ICAM-1 and VEGF have exactly different expression levels, suggesting more attention to be paid by other researchers or doctors in future studies.

Protective antioxidant effects of saffron extract on retinas of streptozotocin-induced diabetic rats.

Objective: Oxidative stress plays an important role in the pathogenesis of diabetic retinopathy. The aim of the present study was to investigate the effect of Crocus sativus L. styles (saffron) extract on oxidative stress indices of retina in streptozotocin (STZ)-induced diabetic rats. Methods: Adult male Wistar rats (n=20) were randomized into the following 4 groups (n=6-7/ group): Control group (C): normal, Control + Saffron group (CS): non-diabetic rats treated with 60 mg/ kg of saffron extract, Diabetic group (D) and Diabetic + Saffron group (DS): diabetic rats treated with 60 mg/ kg saffron extract. We determined the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) as markers of antioxidant response, as well as malondialdehyde (MDA) as a marker of lipid peroxidation. Results: Induction of diabetes caused a significant decline in the activities of CAT (76.43%), SOD (53.43%) and GPx (77.58%). MDA levels were significantly lower in the DS group (0.878 ± 0.375 nmol MDA/ mg protein) as compared to D group (1.950 ± 0.299 nmol MDA/ mg protein, p<0.01) and in the CS group (0.503 ± 0.221) in comparison to C group (1.699 ± 0.454, p<0.01). Moreover, SOD and GPx activities were significantly higher (more than 1.5 and 3.5-fold respectively) after treatment with saffron (p<0.01). Regarding the retinas of non-diabetic animals, the administration of the extract caused an > 1.8-fold increase in the activity of CAT (p<0.05) and a 3-fold decrease in MDA levels (p<0.01). Conclusions: This study showed that saffron extract has a protective antioxidant action in retinas of diabetic rats. Abbreviations: C = Control group, CS = non-diabetic rats diabetic rats treated with 60 mg/ kg saffron extract, D = diabetic group, DS = diabetic rats treated with 60 mg/ kg saffron extract, SOD = superoxide dismutase, GPx = glutathione peroxidase, CAT = catalase, MDA = malondialdehyde, DM = diabetes mellitus, DR = diabetic retinopathy, ROS = reactive oxygen species, STZ = streptozotocin, GSH = reduced glutathione.

The Benefits of Flavonoids in Diabetic Retinopathy.

Diabetic retinopathy (DR), one of the most common complications of diabetes, is the leading cause of legal blindness among adults of working age in developed countries. After 20 years of diabetes, almost all patients suffering from type I diabetes mellitus and about 60% of type II diabetics have DR. Several studies have tried to identify drugs and therapies to treat DR though little attention has been given to flavonoids, one type of polyphenols, which can be found in high levels mainly in fruits and vegetables, but also in other foods such as grains, cocoa, green tea or even in red wine. Flavonoids have anti-inflammatory, antioxidant and antiviral effects. Since it is known that diabetes induces oxidative stress and inflammation in the retina leading to neuronal death in the early stages of the disease, the use of these compounds can prove to be beneficial in the prevention or treatment of DR. In this review, we summarize the molecular and cellular effects of flavonoids in the diabetic retina.

Benefits of micronutrient supplementation for reducing the risk of wet age-related macular disease and diabetic retinopathy: An update.

Age-related macular disease and diabetic retinopathy are chronic degenerative diseases characterised by progressive visual impairment. In Europe, age-related macular disease accounts for over 15% of blindness in adults over 50 years of age, and although the burden of diabetic retinopathy in terms of vision impairment is lower, vision loss associated with diabetic retinopathy is increasing with the rising prevalence of diabetes mellitus and the ageing of the population. Late-stage age-related macular disease can be subdivided into dry (non-neovascular) or wet (neovascular or exudative) forms. The large Age-Related Eye Disease Study 2 showed that supplementation with antioxidant nutrients reduces choroids neovascularisation and reduces the risk of progression of neovascular age-related macular disease. Antioxidant micronutrient supplements have also shown promising results in preventing the pathogenesis of retinopathy in animal models of diabetes. Age-related macular disease and diabetic retinopathy are understood to share some common pathophysiological characteristics, suggesting that micronutrients have an important role in ocular health in both conditions. This article will review the current evidence for the utility of micronutrients in preventing the development and progression of neovascular age-related macular disease and diabetic retinopathy.

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.

Synthesis of mulberry leaf extract mediated gold nanoparticles and their ameliorative effect on Aluminium intoxicated and diabetic retinopathy in rats during perinatal life.

The present report showed the green synthesis of Silver nanoparticles (AgNPs) using Mulberry leaf extract via an environment friendly approach and investigated to know the probable ameliorative effect via biochemical assessment on retinopathy of rats that are maternally subjected to Al intoxication and diabetes. Mulberry leaf extract biomolecules act as capping and reducing agent for fabrication of AgNPs. Later, the fabricated AgNPs were characterized by using spectroscopic and microscopic instrumental techniques such as HR-TEM, UV-Vis, XRD and FT-IR. EDS, XRD and TEM have confirmed the synthesis of AgNPs. HRTEM results exhibited that the formed AgNPs are polydispersed and spherical in nature with mean particle size of 35 nm. Microscopic observation of retina in Al-intoxicated and diabetic mother rats showed abnormal changes in retinal cell layers. Yet, the retina of rats that are maternally received AgNPs plus diabetes or Al-intoxicated exhibited noticeable amelioration. However, lower ameliorations were found in rat's retina that are maternally undergone for combined exposure. Additionally, biochemical assessment revealed that the application of AgNPs caused the amelioration of the changes in Al concentration and maternal serum glucose. The present study revealed that AgNPs are active against diabetic and Aluminium-persuaded developmental retinopathy.

Effect of Fenofibrate on the Expression of Inflammatory Mediators in a Diabetic Rat Model.

Purpose: To investigate the mechanisms of anti-inflammatory and anti-oxidative effects of fenofibrate, a peroxisome proliferator-activated receptors-α agonist, in preventing diabetic retinopathy (DR) progression via a diabetic rat model. Methods: Diabetes was induced by intraperitoneal injection of streptozotocin in 6-week-old female Wistar rats. Diabetic rats were divided into diabetes without treatment (n = 10), diabetes treated with low dose fenofibrate (30 mg/kg/day) (n = 10) and high dose fenofibrate (100 mg/kg/day) (n = 10). Serum aqueous humor (AqH) and ocular tissues were gathered after 3-month treatment. Expressions of NF-κB and inflammatory chemokines (monocyte chemoattractant protein-1, fractalkine, and intercellular adhesion molecule-1) were detected by reverse transcription-polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and electrophoretic mobility shift assay. The levels of oxidative biomarkers, including acrolein, nitrotyrosine, and 8-hydroxy-2'-deoxyguanosin (8-OHdG), were determined by IHC and ELISA. The reactive oxygen species (ROS) levels in serum and AqH were measured by chemiluminescence methods. Results: After 3 months of treatment, the expressions of mRNA and protein of monocyte chemoattractant protein-1, fractalkine, and intercellular adhesion molecule-1 in the retina of diabetic rats were significantly inhibited by fenofibrate in a dose-dependent manner. These effects were mediated by inhibition of NF-κB by fenofibrate. The levels of oxidative markers, including acrolein, nitrotyrosine, and 8-OHdG, decreased in the retina of diabetic rats after fenofibrate treatment. The ROS levels in the AqH of diabetic rats also suppressed by fenofibrate. Conclusions: Fenofibrate significantly inhibited the expressions of NF-κB and inflammatory chemokines and reduced oxidative products within diabetic retina. Treatment of fenofibrate might be beneficial to preventing DR progression.

Improvement in Diabetic Retinopathy through Protection against Retinal Apoptosis in Spontaneously Diabetic Torii Rats Mediated by Ethanol Extract of Osteomeles schwerinae C.K. Schneid.

Retinal apoptosis plays a critical role in the progression of diabetic retinopathy (DR), a common diabetic complication. Currently, the tight control of blood glucose levels is the standard approach to prevent or delay the progression of DR. However, prevalence of DR among diabetic patients remains high. Focusing on natural nutrients or herbal medicines that can prevent or delay the onset of diabetic complications, we administered an ethanol extract of the aerial portion of Osteomeles schwerinae (OSSCE), a Chinese herbal medicine, over a period of 17 weeks to spontaneously diabetic Torii (SDT) rats. OSSCE was found to ameliorate retinal apoptosis through the regulation of advanced glycation end product (AGE) accumulation, oxidative stress, and mitochondrial function via the inhibition of NF-κB activity, in turn, through the downregulation of PKCδ, P47phox, and ERK1/2. We further demonstrated in 25 mM glucose-treated human retinal microvascular endothelial cells (HRMECs) that hyperoside (3-O-galactoside-quercetin), quercitrin (3-O-rhamnoside-quercetin), and 2″-O-acetylvitexin (8-C-(2″-O-acetyl-glucoside)-apigenin) were the active components of OSSCE that mediated its pharmacological action. Our results provide evidence that OSSCE is a powerful agent that may directly mediate a delay in the development or disease improvement in patients of DR.

Phyllanthus virgatus forst extract and it's partially purified fraction ameliorates oxidative stress and retino-nephropathic architecture in streptozotocin-induced diabetic rats.

Diabetic retinopathy and nephropathy are questionably the most dreaded complications of diabetes; contribute to serious morbidity and mortality. The current study was undertaken with the aim of exploring the anti-lipoperoxidative and antioxidant status including nephroprotective and retinoprotective potential of Phyllanthus virgatus methanolic extract and its partially purified fraction in streptozotocin (STZ)-induced diabetic stressed rats. Diabetes was induced by intraperitoneal injection of Streptozotocin (60mg/kg B. Wt of rat). Among all the treatment groups, P. virgatus methanolic extract and its partially purified fraction at a dose of 50mg/kg (PET-1) and 0.5mg/kg (CT-1), respectively, showed significant protection against STZ-induced diabetic oxidative stress in rats with marked amelioration in lipid peroxidation byproducts level, antioxidant enzymes, nephroprotective and retinoprotective effects and plasma total antioxidant levels after treatment of 28 days. The combined results demonstrated significant protection against STZ-induced oxidative stress, nephropathy and retinopathy condition by P. virgatus methanolic extract and its bioactive compound.

Lisosan G Protects the Retina from Neurovascular Damage in Experimental Diabetic Retinopathy.

Lisosan G (LG), a fermented powder obtained from whole grains, is a recognized antioxidant compound that improves the bioactivity and survival of different cell types. The purpose of this study was to investigate whether LG ameliorates both the neural and the vascular damage characterizing early stages of diabetic retinopathy (DR). The effects of LG were studied in cultured explants of mouse retinas challenged with oxidative stress (OS) or in retinas of streptozotocin (STZ)-treated rats. Apoptosis, vascular endothelial growth factor (VEGF) expression, OS markers, blood-retinal barrier (BRB) integrity, and inflammation were assessed, while retinal function was evaluated with electroretinogram (ERG). LG extensively inhibited apoptosis, VEGF expression, and OS both in retinal explants and in STZ rats. In addition, STZ rats treated with LG displayed an almost total BRB integrity, reduced levels of inflammatory markers and a partially restored visual function as evaluated with ERG. In summary, we demonstrated that LG exhibits antioxidant and anti-inflammatory effects that exert powerful protective actions against neural and vascular defects characteristic of DR. Therefore, LG-containing foods or supplements may be considered to implement DR treatments.

Omega-3 from Flaxseed Oil Protects Obese Mice Against Diabetic Retinopathy Through GPR120 Receptor.

The chronic and low-grade inflammation induced by obesity seem to be the "first hit" to retinopathy associated to diabetes type 2. Herein, we hypothesized that omega-3 fatty acids from flaxseed oil enriched diet disrupt the pro-inflammatory status in the retina, protecting against retinopathy development. For eight weeks under a high-fat diet (HF), several physiological parameters were monitored to follow the metabolic homeostasis disruption. After this period, mice were treated with a HF substituted in part of lard by flaxseed oil (FS) for another eight weeks. Food behavior, weight gain, glucose and insulin sensitivity, electroretinography, RT-qPCR and western blots were carried out. The HF was able to induce a pro-inflammatory background in the retina, changing IL1ß and TNFα. VEGF, a master piece of retinopathy, had early onset increased also induced by HF. The FS-diet was able to decrease inflammation and retinopathy and improved retinal electro stimuli compared to HF group. GPR120 and GPR40 (G Protein-Coupled Receptors 120 and 40), an omega-3 fatty acid receptors, were detected in the retina for the first time. FS-diet modulated the gene expression and protein content of these receptors. Thus, unsaturated fatty acids protect the retina from diabetes type 2 mice model from disease progression.