Pathogenesis Of Diabetic Cataract Research Articles

High glucose promotes osteogenic differentiation of human lens epithelial cells through hypoxia-inducible factor (HIF) activation.

Cataract, a leading cause of blindness, is characterised by lens opacification. Type 2 diabetes is associated with a two- tofivefold higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia. Hydroxyapatite deposition is present in cataractous lenses that could be the consequence of osteogenic differentiation and calcification of lens epithelial cells (LECs). We hypothesised that hyperglycaemia might promote the osteogenic differentiation of human LECs (HuLECs). Osteogenic medium (OM) containing excess phosphate and calcium with normal (1 g/L) or high (4.5 g/L) glucose was used to induce HuLEC calcification. High glucose accelerated and intensified OM-induced calcification of HuLECs, which was accompanied by hyperglycaemia-induced upregulation of the osteogenic markers Runx2, Sox9, alkaline phosphataseand osteocalcin, as well as nuclear translocation of Runx2. High glucose-induced calcification was abolished in Runx2-deficient HuLECs. Additionally, high glucose stabilised the regulatory alpha subunits of hypoxia-inducible factor 1 (HIF-1), triggered nuclear translocation of HIF-1αand increased the expression of HIF-1 target genes. Gene silencing of HIF-1α or HIF-2α attenuated hyperglycaemia-induced calcification of HuLECs, while hypoxia mimetics (desferrioxamine, CoCl2) enhanced calcification of HuLECs under normal glucose conditions. Overall, this study suggests that high glucose promotes HuLEC calcification via Runx2 and the activation of the HIF-1 signalling pathway. These findings may provide new insights into the pathogenesis of diabetic cataracts, shedding light on potential factors for intervention to treat this sight-threatening condition.

LBODP084 Bilateral Cataracts In A 15-year-old Girl With New-onset Type 1 Diabetes Mellitus

Abstract Background Cataracts secondary to Type 1 or Type 2 Diabetes is not uncommon in adults, however, it is a rare finding in pediatrics patients with Type 1 Diabetes. Clinical Case A 15-year-old girl presented with progressively worsened bilateral vision for 6 months, however, vision rapidly deteriorated over the previous month, prompting visit to optometrist. No history of weight loss, however, did report 1.5 years of polydipsia, polyuria, and polyphagia. Outside optometrist reported concerns for cataracts. She presented to our Ophthalmology department one week later, who found bilateral cataracts with haziness in all layers and swollen lenses. Labs were done due to findings, glucose was 668 mg/dL with HbA1C >20%. She presented next day to ER, reported no symptoms other than blurry vision but was found to be in mild DKA with a venous pH of 7.285, Ketones 5.41 mmol/L, Glucose 480 mg/dL, and C-peptide 0.32 pmol/mL. Patient was started on insulin infusion at 0.1u/kg/hour and transitioned quickly to subcutaneous insulin. Pancreatic antibodies were significant for positive GAD65 and ZnT8 antibodies. She had cataract surgery for her left eye 1 week after presentation, found to have intumescent white cataract with "hand motion" vision. Vision in left eye is now 20/20 with plans to operate on the right eye in the near future. Literature Review: The prevalence of early diabetic cataracts in the pediatric population can range from 0.7%- 3.4% (1); and more common in female patients (2). Pathophysiology includes defect in the polyol pathway, combined with oxidative stress, leading to increased fluid retention (3). Treatment involves cataract surgery and improved glycemic control. Current ISPAD guidelines recommend initial evaluation for cataracts, and subsequent surveillance concomitant with diabetic retinopathy monitoring biennially with those with good glycemic control (4). Conclusion Diabetic cataracts are extremely rare in the pediatric population. However, diabetes should be considered as an etiology for juvenile cataracts. Given the rapid formation and severity of onset of bilateral cataracts for this patient, early and frequent ophthalmologic surveillance should be recommended for Type 1 diabetes pediatric population. Reference: 1. Šimunović, M, et al (2018). Cataract as early ocular complication in children and adolescents with type 1 diabetes mellitus. International Journal of Endocrinology, 2018, 1–6. 2. Lu, W. -L, et al (2020). High risk of early cataracts in young type 1 diabetes group: A nationwide cohort study. International Journal of Endocrinology, 2020, 1–8. 3. Pollreisz, A, et al (2010). Diabetic cataract pathogenesis, epidemiology and treatment. Journal of Ophthalmology, 2010, 1–8. 4. Donaghue, KC, et al (2018). ISPAD Clinical Practice Consensus Guidelines 2018: Microvascular and macrovascular complications in children and adolescents. Pediatric Diabetes, 19, 262–274. Presentation: No date and time listed

3H-1,2-Dithiole-3-Thione Protects Lens Epithelial Cells against Fructose-Induced Epithelial-Mesenchymal Transition via Activation of AMPK to Eliminate AKR1B1-Induced Oxidative Stress in Diabetes Mellitus.

Studies demonstrated that the receptor of advanced glycation end products (RAGE) induced epithelial-mesenchymal transition (EMT) formation in the lens epithelial cells (LECs) of diabetic cataracts. This work investigated how 3H-1,2-dithiole-3-thione (D3T) reduces EMT formation in LECs of the fructose-induced diabetes mellitus (DM). LECs were isolated during cataract surgery from patients without DM or with DM. In a rat model, fructose (10% fructose, eight weeks) with or without D3T (10 mg/kg/day) treatment induced DM, as verified by blood pressure and serum parameter measurements. We observed that the formation of advanced glycation end products (AGEs) was significantly higher in epithelial human lens of DM (+) compared to DM (−) cataracts. Aldose reductase (AKR1B1), AcSOD2, and 3-NT were significantly enhanced in the rat lens epithelial sections of fructose-induced DM, however, the phosphorylation level of AMPKT172 showed a reversed result. Interestingly, administration of D3T reverses the fructose-induced effects in LECs. These results indicated that AMPKT172 may be required for reduced superoxide generation and the pathogenesis of diabetic cataract. Administration of D3T reverses the fructose-induced EMT formation the LECs of fructose-induced DM. These novel findings suggest that the D3T may be a candidate for the pharmacological prevention of cataracts in patients with DM.

Resveratrol protects against high glucose-induced oxidative damage in human lens epithelial cells by activating autophagy.

In the pathogenesis of diabetic cataract, high glucose levels induce oxidative damage in human lens epithelial cells (HLECs). Resveratrol has been demonstrated to be a potent antioxidant in various disease conditions; however, limited information is available on its effects on oxidative damage associated with the pathogenesis of diabetic cataract in HLECs. The present study aimed to determine whether resveratrol prevents high glucose-induced oxidative damage to human lens epithelial cells by activating autophagy. In the present study, HLECs treated with high glucose were used as a cellular model of diabetic cataract and treated with resveratrol for 24 h. Flow cytometry was performed to detect the cellular reactive oxygen species (ROS) content. Autophagy marker protein levels were determined by western blotting. Immunofluorescence assay was performed to analyze in vitro microtubule-associated protein 1 light chain 3 β (LC3B) protein expression. Autophagosome formation in HLECs was observed using transmission electron microscopy. The results demonstrated that high glucose suppressed HLEC viability and proliferation rate compared with normal glucose levels (5 mM), which were significantly reversed by resveratrol treatment. High glucose also increased the ROS content compared with ROS content in normal HLECs, which was reduced following resveratrol treatment. Further experiments demonstrated that resveratrol significantly reversed the high glucose-decreased protein levels of LC3II and beclin-1 proteins and the high glucose-increased protein levels of LC3I and p62 in HLECs. In conclusion, resveratrol inhibited the high glucose-induced oxidative damage in HLECs by promoting autophagy through the activation of the p38 mitogen-activated protein kinase signaling pathway. These results provide a theoretical basis for the application of resveratrol in diabetic cataract prevention and treatment.

MicroRNA-199a-5p regulates epithelial-to-mesenchymal transition in diabetic cataract by targeting SP1 gene

BackgroundAs a common ocular complication of diabetes mellitus, diabetic cataract is becoming a leading cause of visual impairment. The progression of diabetic cataract progression involves epithelial-to-mesenchymal transition (EMT), the precise role of which remains to be investigated. As microRNAs (miRNAs) are suggested to be involved in the pathogenesis of many diseases, identification of aberrantly expressed miRNAs in diabetic lens epithelial cells (LECs) and their targets may provide insights into our understanding of diabetic cataract and potential therapeutic targets.MethodsDiabetic cataract capsules and LECs exposed to high glucose (25 mmol/L, 1–5 days) were used to mimic the model. Quantitative RT-PCR was performed to evaluate the differential expression of miRNA. Dual luciferase reporter assay was used to identify the binding target of miR-199a-5p. The expression of EMT-associated proteins was determined by immunofluorescence and Western blot analysis.ResultsOur results showed the differential expression of miR-9, -16, -22, -199a and -204. MiR-199a was downregulated in diabetic cataract capsule and hyperglycemia-conditioned human LECs. Specific protein 1 could be directly targeted and regulated by miR-199a in LECs and inhibit EMT in diabetic LECs.ConclusionOur findings implied miR-199a could be a therapeutic target by regulating SP1 directly to affect EMT in diabetic cataract and provided novel insights into the pathogenesis of diabetic cataract.

Expression of α-Klotho Is Downregulated and Associated with Oxidative Stress in the Lens in Streptozotocin-induced Diabetic Rats

ABSTRACT Purpose: Oxidative stress, an imbalance between the production of reactive oxygen species and antioxidant defenses, plays an important role in the pathogenesis of diabetic cataract. The lens in diabetes mellitus (DM) has been shown to exhibit impaired antioxidant defenses, but the underlying mechanisms remain poorly understood. Accumulating evidence reveals that Klotho family genes can regulate antioxidant defenses and prevent oxidative stress in multiple tissues. Here, we examined whether DM alters Klotho expression in the lens and if so, whether altered Klotho expression is associated with oxidative stress in the lens in DM. Methods: Male Wistar rats were divided into DM and control groups. DM was induced by injection of streptozotocin (STZ, 60 mg/kg ip) and control rats were injected with vehicle. Twelve weeks after DM induction, levels of α-Klotho in plasma, expression of α- and γ-Klotho, and nuclear factor erythroid 2-related factor 2 (Nrf2), and levels of antioxidants superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione (GSH) and oxidative stress marker malondialdehyde (MDA) in the lens were measured. Results: Diabetic rats had markedly higher blood glucose concentrations and lower plasma α-Klotho levels than control rats. Both α- and γ-Klotho were expressed in the lens in diabetic and control rats. The expression of α-Klotho but not γ-Klotho in the lens was downregulated in diabetic rats, which was accompanied by reduced expression of nuclear Nrf2 and levels of all antioxidants and increased levels of MDA. Moreover, expression of α-Klotho in the lens was positively correlated with expression of nuclear Nrf2 and levels of all antioxidants, but negatively correlated with levels of MDA. Conclusions: These findings suggest that DM selectively reduces α-Klotho levels in the circulation and lens, which may attenuate transcriptional activity of Nrf2 and impair antioxidant defenses in response to oxidative insults, contributing to oxidative stress and cataract formation in DM.

Identification of tRNA-derived fragments and their potential roles in diabetic cataract rats.

Aim: To illustrate the expression profile of transfer RNA-derived fragments and reveal their putative role in the pathogenesis of diabetic cataract (DC) rats. Materials & methods: Small RNA sequencing was conducted in the lens epithelium of rats lens. The data were validated by quantitative real-time PCR, and bioinformatic analysis was performed to explore the roles of the fragments in DC pathogenesis. Results: A total of 213 differentially expressed tRNA-related fragments were identified, in which 111 were upregulated and 102 were downregulated in DC rats. Bioinformatics analysis revealed that several associated pathways might participate in the development of DC rats. Conclusion: tRNA-derived fragments may be involved in the pathogenesis of DC rats.

Role of lncRNA NEAT1 mediated by YY1 in the development of diabetic cataract via targeting the microRNA-205-3p/MMP16 axis.

We aimed at investigating the possible role and mechanism of NEAT1 in the pathogenesis of diabetic cataract. YY1 and NEAT1 expressions in anterior lens capsule collected from diabetic cataract (DC) patients and normal controls were examined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and their correlation was analyzed. The binding site between YY1 and NEAT1 sequences was predicted by JASPAR and detected by Dual-Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. The proliferation and apoptosis of high-glucose-induced cells with NEAT1 knockdown were detected. Potential downstream targets of NEAT1 were predicted by bioinformatics and detected by Dual-Luciferase reporter assay. YY1 and NEAT1 expressions in the anterior capsule tissue of DC lens were remarkably reduced and positively correlated. Dual-Luciferase reporter assay and ChIP confirmed that YY1 could bind to locus 2 of NEAT1. Knockdown of NEAT1 inhibited proliferation while promoted apoptosis under high glucose conditions. Further mechanism studies revealed that knockdown of NEAT1 could upregulate microRNA-205-3p, and MMP16 was a potential target of miR-205. The low expression of YY1 induces NEAT1 downregulation, which regulates microRNA-205-3p/MMP16 axis and thus participates in the development of DC.

Klotho ameliorates the onset and progression of cataract via suppressing oxidative stress and inflammation in the lens in streptozotocin-induced diabetic rats

Increased oxidative stress and inflammation play an important role in the pathogenesis of diabetic cataract. Klotho, known as an anti-ageing protein, has antioxidative and anti-inflammatory properties. Klotho is expressed in limited tissues including the lens. Here we examined whether klotho expression is decreased in diabetic lens and, if so, whether klotho treatment can prevent diabetic cataract formation. Streptozotocin (STZ)-induced diabetic rats and age-matched control rats were treated with vehicle or klotho protein, starting at 1 week after STZ injection. Twelve weeks after treatment, cataract formation was observed in diabetic rats but not control rats. Cataract formation and scores were significantly less in klotho-treated diabetic rats than vehicle-treated diabetic rats. Levels of klotho in plasma, aqueous humor and lens were significantly decreased in vehicle-treated diabetic rats, compared with control rats, but were restored in klotho-treated diabetic rats. Additionally, vehicle-treated diabetic rats had increased oxidative stress and inflammation in the lens, which were associated with decreased antioxidant transcriptional master regulator Nrf2 activity and increased transcription factor NF-κB activity. All of these findings were ameliorated in klotho-treated diabetic rats. Notably, klotho treatment did not alter blood glucose in diabetic rats. These results indicate that klotho reduction may increase susceptibility of the lens to oxidative and inflammatory insults, promoting cataract formation under diabetic conditions. Klotho treatment can ameliorate the onset and progression of diabetic cataract via enhancing Nrf2-mediated antioxidant defense and suppressing NF-κB-mediated inflammatory responses. Klotho in the lens may be a novel therapeutic target for prevention of cataract formation in diabetes.

AKR1B1‐Induced epithelial‐mesenchymal transision Mediated by RAGE‐ Oxidative Stress in the Lens of DM Cataracts

Background and purposeCataracts in patients with diabetes are a major cause of blindness in developed and developing countries. It’s been known that lens epithelial cells (LECs) would undergo epithelial‐mesenchymal transision (EMT) that formed to cataract. Great deals of studies have demonstrated that overproduction of AKR1B1 and RAGE played a central role in the pathogenesis of diabetic cataract. The aim of this study was to examine whether EMT formation in the DM cataract through an AKR1B1 enhanced AGE and ROS generation in LECs from DM patients.MethodsFluorescence was used to estimate the AKR1B1, RAGE, AMPK and EMT biomarkers in the human lens epithelial sections from DM or non‐DM cataracts. All data were expressed as the mean ± SEM (n=12 for each group). A one‐way analysis of variance (ANOVA) with Scheffe’s post hoc comparison was employed to compare the group differences.ResultsImmunohistochemistry staining founding that the pathologic phases and N‐cadherin expression levels were significantly enhanced in the human lens epithelial sections from DM (+) than DM (−) cataract patients. Immunofluorescent staining also demonstrated that AKR1B1 and RAGE were significantly enhanced in the human lens epithelial sections from DM (+) than DM (−) cataract patients. Interestingly, AcSOD2 levels were significantly higher in the LECs of the patients with DM, not in non‐DM cataracts, however, the phosphorylation level of AMPKT172 was has reverse effect. These results indicated that AMPKT172 may be required for reduced superoxide generation and the pathogenesis of diabetic cataract formation.ConclusionsCollectively, our results revealed that AKR1B1 overexpression would abolish AMPK activation, thereby increasing AcSOD2 and RAGE‐induced EMT formation in the LECs of diabetic cataracts as potentially important elements in the pathogenesis of diabetic cataract.Support or Funding Information108‐2320‐B‐075B‐002 ‐

AKR1B1-Induced Epithelial-Mesenchymal Transition Mediated by RAGE-Oxidative Stress in Diabetic Cataract Lens.

Purpose: Cataracts are a major cause of visual acuity deterioration in diabetes mellitus (DM) in developed and developing countries. Studies have demonstrated that overproduction of AKR1B1 and receptor for advanced glycation end products (RAGE) plays a major role in the pathogenesis of diabetic cataracts, but it is unclear whether the prevalence of diabetic cataracts is related to epithelial–mesenchymal transition (EMT) in lens epithelial cells. This study aimed to analyze the role of EMT in cataract formation of DM patients. Methods: Immunofluorescence and immunohistochemistry assays were used to estimate AKR1B1, RAGE, AMPK, and EMT levels in epithelial human lens of DM or non-DM cataracts. Results: Immunohistochemical staining demonstrated that pathologic phases and N-cadherin expression levels were significantly higher in epithelial human lens of DM (+) compared to DM (−) cataracts. Immunofluorescent staining showed that AKR1B1 and RAGE were significantly higher in epithelial human lens of DM (+) compared to DM (−) cataracts. Interestingly, acetyl superoxide dismutase 2 (AcSOD2) levels were significantly higher in DM patients’ lens epithelial cells (LECs), whereas AMPKT172 phosphorylation was significantly increased in non-DM patients. This indicates that AMPKT172 might be related to superoxide reduction and diabetic cataract formation. Conclusions: Our results suggest that AKR1B1 overexpression can decrease AMPK activation, thereby increasing AcSOD2 and RAGE-induced EMT in epithelial human lens of DM cataracts. These novel findings suggest that AKR inhibitors may be candidates for the pharmacological prevention of cataracts in patients with DM.

Concentrations of Selected Cytokines and Vascular Endothelial Growth Factor in Aqueous Humor and Serum of Diabetic Patients

ABSTRACTPurpose: To investigate the aqueous humor and serum levels of selected cytokines and vascular endothelial growth factor (VEGF) in diabetic patients, implicating their role in the pathogenesis of diabetic eye complications.Materials and methods: Atotal of 65 patients (27 males and 38 females) who underwent cataract surgery were recruited into the study. The study group consisted of 30 cataract patients with type 2 diabetes mellitus, and this group was divided into two subgroups: 14 patients with diabetic retinopathy (DR group) and 16 patients without DR (NDR group). The control group consisted of 35 non-diabetic cataract subjects.Results: Patients in the DR group had significantly higher aqueous humor concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, monocyte chemotactic protein (MCP-1) and VEGF. Likewise, serum concentrations of IL-1β, IL-6, IL-8, IL-12, TNF-α and IFN-γ were significantly higher in the DR group as compared to the controls. Aqueous humor concentrations of IL-1β, IL-8, MCP-1 and VEGF were significantly higher in the DR group as compared with the NDR group.Conclusion: Our findings support the hypothesis that chronic inflammation and a disturbance of the immune system play important roles in the pathogenesis of diabetic cataract and DR.

Preventive Effects of Aphanothece sacrum on Diabetic Cataracts

Approximately 20% of diabetic patients develop diabetic cataracts. As lens proteins are known to be only slightly metabolized during the lifetime, cataracts are difficult to recover from once they have progressed. Therefore, the daily intake of natural compounds would be an important strategy for the prevention of diabetic cataracts. Aphanothece sacrum Okada (Asa) is a freshwater blue-green algae endemic to Japan. It has been eaten since the Edo period in Kyushu. In this study, the inhibitory effects of Asa on the pathogenesis of diabetic cataracts were evaluated. Furthermore, the inhibitory effects of Asa on the formation of Nε-(carboxymethyl) lysine (CML), an oxidation-dependent advanced glycation end-product, were also measured. After 3-month administration, the CML contents in the lens were measured by liquid chromatography tandem mass spectrometry using an internal standard of CML or lysine. Asa significantly inhibited the progression of cataractogenesis and accumulation of CML in diabetic lens compared with the normal diet group. These results suggested that daily intake of Asa reduces oxidative stress and prevents the pathogenesis of cataracts.

Expression of SIRT1 and P53 in Rat Lens Epithelial cells in Experimentally Induced DM

ABSTRACTPurpose: To determine the etiopathogenesis of diabetic cataract by studying changes in relative expressions of silent information regulator protein-1 (SIRT1) and P53 in rat lens epithelial cells (LECs) in experimentally induced diabetes mellitus (DM).Methods: Six-week-old male SD rats (n = 120) were randomly divided into experimental (n = 80 rats) and control (n = 40 rats) groups. DM was induced in the experimental group (diabetic model) by intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin (STZ). Control group rats were injected similarly with phosphate-buffered saline (PBS). Four and eight weeks after successful induction of DM, relative expressions of SIRT1 and P53 in LECs were analyzed using quantitative real-time (qRT) fluorescence polymerase chain reaction (qRT-PCR) and Western blot analysis.Results: Expression of both SIRT1 and P53 was observed in LECs of control and experimental group rats at 4 and 8 weeks but was significantly greater in experimental compared with control group rats (p < 0.05).Conclusions: Expression of both SIRT1 and P53 increases in the early stages of diabetic cataract formation, indicating that they play potentially important roles in the pathogenesis of diabetic cataract.

Characterization of Emodin as a Therapeutic Agent for Diabetic Cataract.

Aldose reductase (AR) in the lens plays an important role in the pathogenesis of diabetic cataract (DC) by contributing to osmotic and oxidative stress associated with accelerated glucose metabolism through the polyol pathway. Therefore, inhibition of AR in the lens may hold the key to prevent DC formation. Emodin, a bioactive compound isolated from plants, has been implicated as a therapy for diabetes. However, its inhibitory activity against AR remains unclear. Our results showed that emodin has good selectively inhibitory activity against AR (IC50 = 2.69 ± 0.90 μM) but not other aldo-keto reductases and is stable at 37 °C for at least 7 days. Enzyme kinetic studies demonstrated an uncompetitive inhibition against AR with a corresponding inhibition constant of 2.113 ± 0.095 μM. In in vivo studies, oral administration of emodin reduced the incidence and severity of morphological markers of cataract in lenses of AR transgenic mice. Computational modeling of the AR-NADP(+)-emodin ternary complex indicated that the 3-hydroxy group of emodin plays an essential role by interacting with Ser302 through hydrogen bonding in the specificity pocket of AR. All the findings above provide encouraging evidence for emodin as a potential therapeutic agent to prevent cataract in diabetic patients.

The significance and expressions of MMP-3, Fn and α-SMA in lens epithelium cells of the experimental diabetic cataract rats

Objective To investigate pathological changes of lens epithelium cells (LECs) and expressions of matrix metalloproteinase-3 (MMP-3), alpha-smooth muscle actin (α-SMA), and fibronectin (Fn) in lens epithelial cells of experimental diabetic cataract rats, and to evaluate the roles of MMP-3, α-SMA, and Fn in the pathogenesis of diabetic cataract. Methods A total of 105 healthy Sprague-Dawley (SD) rats without lens diseases was randomly divided into normal control (n=45) and diabetic model (n=60) groups. Diabetic model rats were subjected to intraperitoneal injection of streptozotocin (STZ) (60 mg/kg), and those in the normal control group received injection with 0.1 mmol/L citric acid buffer solution of the same volume. The diabetic models were affirmed upon a fasting blood ≥16.65 mmol/L at the 3rd days after the injection. Once a week, the changes of blood glucose and body weight were monitored and the progression of cataract formation in both lenses of all rats was recorded with slit lamp observation. At end of 4 weeks, 8 weeks, and 12 weeks after STZ injection, lenses were isolated and embedded in paraffin. The LECs histopathology was examined with HE staining. Immunohistochemical method was used to detect expressions of MMP-3, α-SMA, and Fn in normal and diabetic LECs. The related comparisons and statistic analysis were carried out. Results The lenses of control group were always completely transparent throughout the period of experiment with 31.48%, 77.78%, and 100% of lenses in diabetic model group swelling at 4th, 8th, and 12th week, respectively. Under the light microscopic level, it has been showed that lens epithelium cells, which was occurred aggregate plaque and arranged in many layers, presented some morphologic characteristics of fibroblasts by HE staining. In control group LECs regularly, MMP-3, α-SMA, and Fn did not express equally; MMP-3, α-SMA, and Fn expressions increased obviously highly, difference had statistical significance compared to diabetic cataract group LECs (P<0.01). With the development of course of disease, the differences in expression of MMP-3, α-SMA, and Fn were significant between the diabetic cataract LECs and the control group (P<0.01). During the progression of diabetic cataract, the expression of Fn was positively correlated with that of α-SMA and MMP-3 (r=0.994, P<0.01; r=0.993, P<0.01). Conclusions The diabetic cataract living body animal model was established successfully, which has laid down necessary basis to expound the morbidity mechanism of diabetic cataract. In the lens of diabetic cataract group, the expressions of α-SMA, MMP-3, and Fn were significantly increased. They participated in the occurrence and development of diabetic cataract. The expression of Fn was positively correlated with α-SMA and MMP-3. The lens epithelium cells which took on elongated aspect like fibroblast cells appeared epithelial-mesenchymal transformation (EMT), which mediated the occurrence and development of LECs fibrosis. Key words: Cataract/CO/ME; Diabetes complications/ME; Lens, crystalline/CY/PA; Epithelial cells/PA; Matrix metalloproteinase 3/ME; Actins/ME; Fibronectins/ME

Beneficial influence of fungal metabolite nigerloxin on eye lens abnormalities in experimental diabetes

Osmotic and oxidative stress have been implicated in the pathogenesis of diabetic cataract. Nigerloxin, a fungal metabolite, has been shown to possess aldose reductase inhibitory and free radical scavenging potential, in vitro. In the present study, the beneficial influence of nigerloxin was investigated on diabetes-induced alteration in the eye lens of rats treated with streptozotocin. Groups of diabetic rats were administered nigerloxin orally (100mg·(kg body mass)(-1)·day(-1)) for 30days. The activity of lens polyol pathway enzymes(aldose reductase and sorbitol dehydrogenase), lipid peroxides, and advanced glycation end products (AGEs) were increased in the diabetic animals. Levels of glutathione as well as the activity of antioxidant enzymes(superoxide dismutase, glutathione-S-transferase, and glutathione peroxidase) were decreased in the eye lens of the diabetic animals. The administration of nigerloxin significantly decreased levels of lipid peroxides and AGEs in the lens of the diabetic rats. Increase in the activity of aldose reductase and sorbitol dehydrogenase in the lens was countered by nigerloxin treatment. The activity of glutathione and antioxidant enzyme in the lens was significantly elevated in nigerloxin-treated diabetic rats. Examination of the treated rats' eyes indicated that nigerloxin delayed cataractogenesis in the diabetic rats. The results suggest the beneficial countering of polyol pathway enzymes and potentiation of the antioxidant defense system by nigerloxin in diabetic animals, implicating its potential in ameliorating cataracts in diabetics.

Expression of aquaporin-1 in human lens epithelial cells by hyperosmotic stimuli

目的 研究水通道蛋白-1(AQP-1)在糖尿病性白内障发病机制中的作用.方法 从健康的供体眼中分离出人晶状体囊膜,用组织块培养法将人晶状体囊膜分别置于1g/L葡萄糖+体积分数15%胎牛血清的DMEM培养液中(对照组)或4.5g/L葡萄糖+15%胎牛血清的DMEM培养液中进行培养(高糖组).培养3d、28d后观察2组人晶状体上皮细胞(LECs)的生长状态.采用免疫荧光技术和流式细胞术检测AQP-1在人LECs中表达的平均荧光强度,应用流式细胞术检测2组人LECs的凋亡和坏死情况,并进行比较.结果 培养第3天2组LECs的生长形态近似,但培养28d高糖组坏死细胞增加.培养3d后高糖组人LECs的AQP-1免疫荧光表达较对照组明显增强,2组间平均荧光强度的差异有统计学意义(t=3.934,P=0.004),但2组间LECs的凋亡率和坏死率差异均无统计学意义(t=1.681,P=0.131;t=1.064,P=0.318).培养28d后高糖组人LECs的AQP-1免疫荧光表达较对照组弱,差异有统计学意义(t=3.069,P=0.015),LECs凋亡率、坏死率较对照组升高,差异均有统计学意义(t=11.213,P＜0.01;t=15.778,P＜0.01).结论 AQP-1的异常表达在糖尿病性白内障的发生发展中起重要作用。

New Horizons in Research on Diabetic Complications of the Eye: Special Emphasis on Diabetic Cataracts and Retinopathy

The incidence of diabetes is increasing at an alarming rate all over the world. As a consequence, the complications related to diabetes, including those affecting the eye (cataracts and retinopathy), nerve, and kidneys, are also becoming more prevalent. In the eye, diabetes affects both lens and retina resulting in devastating effects on vision. Although significant advances have been made towards understanding their pathophysiology using animal models of diabetes, progress in the area of development of pharmacological means for their prevention and treatment is still very minimal, if any. The pathogenetic mechanisms underlying both of these ocular complications of diabetes are considered multifactorial. The major factors considered to be involved in diabetic cataractogenesis are the hyperglycemia-induced excessive generation of free radicals and consequent oxidative stress as well as aberrations in tissue metabolism. Free radicals have also been implicated in the pathogenesis of diabetic retinopathy (DR). In addition, DR is considered to be associated with aberrations in several other cellular signaling pathways mediated via inflammatory intermediators, pigment epithelium-derived factor, various kinases, and Rho and Ras GTPases. Identification of pathways/molecules that can be targeted for modification by appropriate compounds is highly essential for the development of pharmacological therapy for these highly prevalent blinding diseases. In this special issue intended to present new research on diabetic cataracts and retinopathy, we have invited papers that address these issues. The first four articles in this issue are focused on cataract formation in diabetes. The first one provides an overview of the pathogenesis of diabetic cataracts, clinical studies investigating the association between diabetes and the development of cataract, and current treatment of cataracts in the diabetic population. The anticataractogenic potential of aldose reductase inhibitors and antioxidants has also been discussed. The article by Petrash et al. focuses on the role of aldo-ketoreductases in the eye. The expression profiles of the AKR1B1 and AKRB10 have been characterized in various human ocular tissues and their implications in the pathogenesis of diabetic cataract have been discussed. The next article examines the role of glyoxalase I in the inhibition of methylglyoxal advanced glycation end products-AGEs formation in lenses of transgenic mice overexpressing human glyoxalase I, and the fourth one reviews the pathophysiological characteristics of ocular complications in the Spontaneously Diabetic Torii rat such as the formation of cataracts which can become hypermature. It also suggests the suitability of this model for the study of DR. Subsequent articles in this issue focus on the pathogenesis of DR and examine possible targets for pharmacological intervention. The article by Daniel Ng reviews the genetic aspects of DR, and the next article identifies genes associated with DR among Mexican Americans from Starr County in Texas using genome-wide association study. The seventh paper examines the possibility of treatment with the angiotensin-converting enzyme inhibitor, trandolapril, for regression of DR, and the 8th paper discusses the role of toxic AGEs receptor in the pathogenesis of DR. This is followed by a review implicating Rho/ROCK (Rho Kinase) pathway in DR and suggests the possibility of this pathway being a target for therapeutic intervention. The article by Wu et al. investigates the role of extracellular signal-regulated kinase 5 (ERK5) mediated signaling in modulating glucose-induced expression of VEGF. The final paper in this issue compares NADPH oxidase versus mitochondria-derived reactive oxygen species in glucose-induced apoptosis of pericytes in early DR. This special issue will therefore provide the readers an insight into some of the latest research being pursued to elucidate the mechanisms underlying DR and cataracts. It also presents some interesting targets which could be manipulated pharmacologically for potential clinical use. Kavita R. Hegde Renu A. Kowluru Susanne Mohr Ram H. Nagaraj J. Mark Petrash

Diabetic Cataract—Pathogenesis, Epidemiology and Treatment

Cataract in diabetic patients is a major cause of blindness in developed and developing countries. The pathogenesis of diabetic cataract development is still not fully understood. Recent basic research studies have emphasized the role of the polyol pathway in the initiation of the disease process. Population-based studies have greatly increased our knowledge concerning the association between diabetes and cataract formation and have defined risk factors for the development of cataract. Diabetic patients also have a higher risk of complications after phacoemulsification cataract surgery compared to nondiabetics. Aldose-reductase inhibitors and antioxidants have been proven beneficial in the prevention or treatment of this sightthreatening condition in in vitro and in vivo experimental studies. This paper provides an overview of the pathogenesis of diabetic cataract, clinical studies investigating the association between diabetes and cataract development, and current treatment of cataract in diabetics.