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.

Analysis of risk factors for progressive fibrovascular proliferation in proliferative diabetic retinopathy.

PURPOSE: To investigate the risk factors associated with progressive fibrovascular proliferation (FVP) in proliferative diabetic retinopathy (PDR). METHODS: We retrospectively reviewed the clinical data of patients who underwent pars plana vitrectomy for PDR between August 2017 and October 2019 at our department of ophthalmology. The FVP was divided into five grades based on the coverage area of proliferative membrane. Then we compared the patients with different severities of FVP to analyze the risk factors for higher grade of FVP in PDR. RESULTS: Univariate analysis showed that positive urinary protein (p = 0.007), higher levels of serum blood urea nitrogen (BUN) (p < 0.001) and serum creatinine (p < 0.001), more severe stage of estimated glomerular filtration rate (p < 0.001), age < 45 years (p = 0.005), longer duration of diabetic retinopathy (p = 0.007), history of hypertension (p = 0.034) and smoking (p = 0.008) were related to FVP grade ≥ 3. Multivariate analysis showed that the level of BUN, age < 45 years and smoking were independent risk factors for FVP grade ≥ 3 in PDR patients. CONCLUSION: This study demonstrated that BUN (odds ratio [OR] = 1.318, 95% confidence interval [CI] = 1.150-1.511, p < 0.001), age ≤ 45 years (OR = 3.774, 95% CI = 1.762-8.082, p = 0.001) and smoking (OR = 2.111, 95% CI = 1.040-4.288, p = 0.039) were independent risk factors for progressive FVP in PDR among northeastern Chinese patients.

3,5-Dimethoxy-4-hydroxy myricanol ameliorates photoreceptor cell degeneration in Pde6brd10 mouse model.

INTRODUCTION: Retinitis pigmentosa (RP) caused by the photoreceptor cell degeneration is currently incurable and leads to partial or complete blindness eventually. 3,5-dimethoxy-4-hydroxy myricanol (DM) is a novel compound isolated from the leaves of Micromelum integerrimum, with proliferative activities on NIH3T3 cells. This study was to investigate whether DM could mitigate retinal degeneration of rd10 mice, a well-characterized mouse model of RP. MATERIALS AND METHOD: Rd10 mice were treated with DM daily by intraperitoneal injection from postnatal day 12 (P12) to P26. Electroretinography (ERG) reflects the mass response of photoreceptor cells and was used to test the outer retinal function after DM treatment. Haematoxylin and Eosin staining was used to show the retinal morphology and evaluate the rod photoreceptor cell loss. TUNEL assay was used to detect the apoptosis-positive cells. Inflammatory factors were measured by ELISA to show the inflammatory response. Real-time PCR and western blot were applied to measure the gene and protein change to explore the underlying mechanisms. RESULTS: Results showed that DM significantly improved the retinal function by increasing the ERG amplitude, preserving the retinal morphology, reducing photoreceptor cell apoptosis, decreasing inflammatory response, and inhibiting endoplasmic reticulum stress in rd10 mice. CONCLUSION: This is the first time when the protective effects of DM against photoreceptor cell degeneration of rd10 mice have been demonstrated, providing scientific rationale to develop DM as a potential agent to treat RP.

Antiapoptotic role of the cellular repressor of E1A-stimulated genes (CREG) in retinal photoreceptor cells in a rat model of light-induced retinal injury.

OBJECTIVE: Light injury-induced apoptosis of retinal photoreceptor cells can lead to vision loss. The mechanism underlying such injury remains unclear, and there are no effective therapies at present. The aim of this study was to examine the potential antiapoptotic role of the cellular repressor of E1A-stimulated genes (CREG) in retinal cells in a rat model of light-induced retinal damage. METHODS: CREG proteins were injected into the vitreous space of rats in which light retinal injury was induced. An equal volume of PBS was injected into the vitreous space of a control group. Retinas were collected for H&E staining and Western blotting analysis 1, 3, and 7 days later. Inhibitors or agonist for P38, JNK, and AKT were injected into the vitreous space to verify CREG function. RESULTS: In rats with light-induced retinal injury, the CREG treatment inhibited the expression of apoptosis-related proteins caspase-3, caspase-8, and caspase-9 and signaling proteins phosphorylated ERK (P-ERK), phosphorylated JNK (P-JNK), phosphorylated P38 (P-P38), and phosphorylated AKT (P-AKT). An inhibitor of PI3K-AKT and an agonists of P38 and JNK abrogated the inhibitory effect of CREG on caspase-3 expression. CONCLUSION: CREG protected retinal cells against apoptosis by inhibiting P38/MAPK and JNK/MAPK signaling pathways and activating the PI3K-AKT signaling pathway.

Crystal structure of bis-{µ-4,4'-[1,3-phenyl-enebis(-oxy)]dibenzoato-κ(4) O,O':O'',O'''}bis[(1,10-phenanthroline-κ(2) N,N')zinc(II)] dihydrate.

Two 4,4'-[1,3-phenyl-enebis(-oxy)]dibenzoate anions bridge two 1,10-phenanthroline-chelated Zn(II) cations about a center of inversion to generate the dinuclear title compound, [Zn2(C20H12O6)2(C12H8N2)2]·2H2O. The geometry about the Zn(II) atom is a distorted octa-hedron. In the crystal, the mol-ecules are connected by classical O-H⋯O hydrogen bonds, weak C-H⋯O hydrogen bonds and C-H⋯π inter-actions, forming a three dimensional network. π-π stacking is also observed between aromatic rings of adjacent mol-ecules, centroid-centroid distances are 3.753 (2), 3.5429 (16) and 3.5695 (17) Å.

Crystal structure of bis-{2-[bis-(2-hy-droxy-eth-yl)amino]-ethanol-κ(3) O,N,O'}zinc terephthalate.

In the title salt, [Zn(C6H15NO3)2](C8H4O4), the Zn(II) cation, located on a centre of inversion, is coordinated by four O atoms and two N atoms from two tridentate 2-[bis-(2-hy-droxy-eth-yl)amino]-ethanol (BHEA) ligands, giving rise to a slightly distorted octa-hedral geometry. The terephthalate dianion, located about a centre of inversion, is not coordinated to Zn(II) but is connected through O-H⋯O contacts with [Zn(BHEA)2](2+) cations, leading to a three-dimensional crystal structure.

Crystal structure of bis-{2-[bis-(2-hy-droxy-eth-yl)amino]-ethanol-κ(4) O,N,O',O''}cadmium terephthalate.

In the title salt, [Cd(C6H15NO3)2](C8H4O4), the Cd(2+) cation is coordinated by six O atoms and two N atoms from two tetra-dentate 2-[bis-(2-hy-droxy-eth-yl)amino]-ethanol ligands, displaying a distorted square-anti-prismatic coordination. The terephthalate dianion does not coordinate to the cation but is connected through O⋯H-O hydrogen bonds of medium strength to the complex cations, leading to a layered structure extending parallel to (100).

Crystal structure of bis-{2-[(2-hy-droxy-eth-yl)amino]-ethanol-κ(3) O,N,O'}copper(II) terephthalate.

The mol-ecular components of the title salt, [Cu(C4H11NO2)2](C8H4O4), are one Cu(II) cation O,N,O'-chelated by two tridentate 2-[(2-hy-droxy-eth-yl)amino]-ethanol ligands, and a terephthalate counter-dianion, located about a centre of inversion. The complex Cu(II) cation is located about a centre of inversion and shows typical Jahn-Teller distortion, with two short Cu-O and two short Cu-N bonds in the equatorial plane and two long Cu-O bonds to the axial atoms. The cations are arranged in sheets parallel to (100), with the centrosymmetric terephthalate anions located between the sheets. Each anion is the acceptor of four O-H⋯O and two N-H⋯O hydrogen bonds, forming a three-dimensional network structure.

Suppressing autophagy protects photoreceptor cells from light-induced injury.

Autophagy, a conserved cellular self-degradation process, not only serves to protect cells at critical times during development and nutrient stress, but also contributes to cell death. Photoreceptor cells are unique neurons which when directly exposed to the light, transduces light stimuli into visual signal. However, intense light exposure can be cytotoxic to the retina. So far, the precise mechanism underlying retina light injury remains unknown, and the effective therapy is still unavailable. Here, we found that visible light exposure activated the mitogen-activated protein kinases (MAPK) pathway and led to remarkable autophagy in photoreceptor cells (661W cells). Directly blocking autophagy with 3MA or LY294002 markedly attenuated light-induced death in 661W cells. Among the activated downstream factors of MAPK pathway, ERK, not JNK or p-38, played a critical role in light-induced death mechanism. Inhibiting the activation of ERK with its specific inhibitor PD98059 significantly suppressed light-induced autophagy and protected 661W cells from light injury. These results indicate that autophagy is an essential event in light-induced photoreceptor death and that directly blocking autophagy or suppressing autophagy by inhibiting the ERK pathway could effectively attenuates light-induced damage. These observations may have a potential application in the treatment of retinal light injury.

Expression and significance of HIF-1 α and VEGF in rats with diabetic retinopathy.

OBJECTIVE: To investigate the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR) rats and its effect on the DR occurrence and development. METHODS: A total of 120 SD rats were randomly divided into trial group and control group with 60 in each. STZ i.p. was used in the trial group to establish the DM model, citrate buffer salt of same amount was used i.p. to the control group. 1, 3 and 6 months after injection, respective 20 rats were sacrificed in each group to observe expression of HIF-1α and VEGF in the rat retina tissue at different time points. RESULTS: Expression of HIF-1α and VEGF were negative in the control group; expression of HIF-1α and VEGF protein in retinal tissue were weak after 1 month of DR mold formation. It showed progressive enhancement along with the progression in different organizations, differences between groups were significant (P<0.05). CONCLUSIONS: Expressions of HIF-1α and VEGF were correlated with disease progression in early diabetic retinopathy. Retinal oxygen can induce over-expression of HIF-1α and VEGF. It shows that HIF-1α and VEGF play an important role in the pathogenesis of DR.

catena-Poly[[zinc-bis-(µ-2-sulfido-1H-benzimidazol-3-ium-5-carboxyl-ato)-κO:S;κS:O] trihydrate].

In the title compound, {[Zn(C(8)H(5)N(2)O(2)S)(2)]·3H(2)O}(n), the Zn(II) atom, lying on a twofold rotation axis, is four-coordinated by two S atoms and two O atoms from four 2-sulfido-1H-benzimidazol-3-ium-5-carboxyl-ate (H(2)mbidc) ligands in a distorted tetra-hedral geometry. Two H(2)mbidc ligands bridge two Zn(II) atoms, generating a double-chain along [[Formula: see text]01]. Adjacent chains are linked by N-H⋯O and O-H⋯O hydrogen bonds, forming a three-dimensional supra-molecular network. One of the two water molecules also lies on a twofold rotation axis.

[Experimental study on inhibition of retinal neovascularisation by gene transfer of extracellular 1-3 domain of VEGF receptor KDR].

OBJECTIVE: To evaluate the effect of liposome mediated plasmids KDRn3 injected into the vitreous to inhibit experimental retinal neovascularization. METHODS: One-week-old C57BL/6N mice were exposed to 75% ± 2% oxygen for 5 days, then returned to the room air to induce retinal neovascularization. Cationic liposome mediated KDRn3 comp-lex (1 µl) was injected into the vitreous in the treatment group. PBS 1µl or liposome were injected in the control group. The pEGFP-N1/KDRn3 expression was observed by using fluorescence microscope. Retinal neovascularization was evaluated by counting the number of vascular endothelial cell nuclei on the vitreal side of the inner limiting membrane of the retina and measuring the areas of non-perfusions in central retina. RESULTS: KDRn3 protein was expressed both in the ganglion layer and in the inner layer. Retinal wholemount preparation of retinal neovascular animal model showed that prominent neovascular tuft and fluorescein leakage and large areas of non-perfusions in central retina. Fewer neovascular tufts and fewer areas of non-perfusions could be seen after pEGFP-N1/KDRn3 injection. There were statistic differences between control group and pEGFP-N1/KDRn3 injecting group with the number of vascular endothelial cell nuclei on the vitreal side of the inner limiting membrane of the retina (0.20 ± 0.51, 13.58 ± 2.48, 23.05 ± 3.40, 21.70 ± 2.89; F = 1085.25, P < 0.05) and the areas of non-perfusions in central retina [(1.33 ± 0.49), (2.75 ± 0.70), (2.12 ± 0.35) mm(2); F = 17.61, P < 0.01]. CONCLUSION: pEGFP-N1/KDRn3 gene transfer can inhibit retinal neovascularisation in C57Bl/6J mice of ischaemia-induced retinal neovascularisation on some extent.

A novel parallel interpenetrating two-dimensional (4,4) network: poly[[mu2-1,4-bis(imidazol-1-ylmethyl)benzene](mu2-naphthalene-1,4-dicarboxylato)zinc(II)].

In the title coordination compound, [Zn(C(12)H(6)O(4))(C(14)H(14)N(4))](n), the two Zn(II) centers exhibit different coordination environments. One Zn(II) center is four-coordinated in a distorted tetrahedral environment surrounded by two carboxylate O atoms from two different naphthalene-1,4-dicarboxylate (1,4-ndc) anions and two N atoms from two distinct 1,4-bis(imidazol-1-ylmethyl)benzene (1,4-bix) ligands. The coordination of the second Zn(II) center comprises two N atoms from two different 1,4-bix ligands and three carboxylate O atoms from two different 1,4-ndc ligands in a highly distorted square-pyramidal environment. The 1,4-bix ligand and the 1,4-ndc anion link adjacent Zn(II) centers into a two-dimensional four-connected (4,4) network. The two (4,4) networks are interpenetrated in a parallel mode.

Acute energy reduction induces caspase-dependent apoptosis and activates p53 in retinal ganglion cells (RGC-5).

The energy reduction-induced death of retinal ganglion cells is associated with many ophthalmic diseases. The present study was designed to investigate the apoptosis pathway of retinal ganglion cells (RGC-5) following acute ATP reduction by using glucose deprivation (GD). RGC-5 cells were cultured in glucose-free or normal DMEM for 3 days. The changes in intracellular ATP and cell viability were monitored by ATP assay and MTT assay. APOPercentage and in situ TUNEL assays were used to determine the cell death pattern. The involvement of oxidative stress was assessed by measuring intracellular ROS generation, the HO-1 expression, the effect of antioxidants, and the ratio of GSSG to total GSH. The activation of p53 and apoptosis markers was evaluated by Western blotting. We found that glucose deprivation caused an acute decline of intracellular ATP level, concomitantly decreasing cell viability. The cell death exhibited typical features indicative of apoptosis, including cell shrinkage, phosphatidylserine externalization and DNA fragmentation. Oxidative stress was involved in the cell death process; an antioxidant significantly protected the cells against glucose deprivation. p53 and apoptosis markers, caspase-3 and PARP-1 were activated after RGC-5 cells were cultured in glucose-free media for 32 h. Z-VAD-fmk, a pan-caspase inhibitor, was sufficient to prevent apoptosis. These results suggest that acute energy reduction induced by glucose deprivation triggers caspase-dependent apoptosis and activates p53. Blocking the critical steps in this cell death pathway may have therapeutic effects, rescuing the retinal ganglion cells from damages associated with acute energy reduction.

catena-Poly[[[aqua-(1,10-phenanthro-line)zinc(II)]-µ-3,3'-(p-phenyl-ene)di-acrylato] hemihydrate].

In the title compound, {[Zn(C(12)H(8)O(4))(C(12)H(8)N(2))(H(2)O)]·0.5H(2)O}(n), each Zn(II) atom is six-coordinated by two N atoms from one 1,10-phenanthroline (phen), three carboxyl-ate O atoms from two different L ligands [H(2)L = 3,3'-(p-phenyl-ene)diacrylic acid] and one water mol-ecule in a distorted octa-hedral environment. The two L dianions are situated across inversion centres and bridge neighbouring Zn(II) centres, yielding a chain propagating parallel to [100]. O-H⋯O hydrogen bonds between the coordinated water molecule, the solvent water molecule (half-occupied) and the carboxylate O atoms further stabilize the structure.

[Pigment epithelium-derived factor and its application in retinal angiogenic diseases].

Retinal neovascularization (RNV) is one of the most important causes of blindness. No efficient treatment for RNV is available. Pigment epithelium-derived factor (PEDF) is a natural inhibitor of angiogenesis. It plays an important role in the modulation of ocular neovascularization. It has been demonstrated recently that the ischemia-induced retinal neovascularization can be dramatically inhibited by the recombinant PEDF protein or local viral vector-mediated delivery of PEDF cDNA, which predicts PEDF to be an optional strategy for intractable retinal angiogenic diseases like diabetic retinopathy, retinopathy of prematurity, and central retinal vein occlusion. Therefore, it is necessary to review the biological aspects of PEDF, its effect on the inhibition of angiogenesis and the prospect of using PEDF for the treatment of retinal neovascularization.