Efficacy and safety of atropine at different concentrations in prevention of myopia progression in Asian children: a systematic review and Meta-analysis of randomized clinical trials.

AIM: To assess the efficacy versus the adverse effects of various concentrations of atropine in the prevention of myopia in Asian children. METHODS: Databases (PubMed, EMBASE, the Cochrane Library and Web of science) were comprehensively searched from inception to April 2022. Types of studies included were randomized clinical trials (RCTs). The published languages were limited to English. Two researchers assessed the quality of included studies independently using Cochrane risk of bias tool based on the Cochrane Handbook for Systematic Reviews of Interventions. Funnel plots and Egger's test were used for detection of publication bias. Meta-analyses were conducted using STATA (version 15.0; StataCorp). RESULTS: A total of 15 RCTs involving 2268 patients were included in the study. In the atropine group, spherical equivalent progressed at a significantly lower rate [weighted mean difference (WMD)=0.39, 95% confidence interval (CI): 0.23, 0.54] than in the control group. A WMD of 0.15 mm was associated with less axial elongation (95%CI -0.19, -0.10). Different doses showed statistically significant differences (P<0.05) and an improved effect could result from a higher concentration. Changes in photopic pupil size and mesopic pupil size in atropine group is 0.70 mm (95%CI: 0.33, 1.06) and 0.38 mm (95%CI: 0.22, 0.54) more than the control group. In the present Meta-analysis, no changes in accommodative amplitude (AA) were associated with atropine administration. Atropine administration increased the risk of adverse effects by 1.37 times. CONCLUSION: Concentrations of less than 1% atropine are able to effectively retard diopter and axis growth of myopia in Asian children in a dose-dependent manner. Meanwhile, it caused pupil enlargement, but induced no change in the AA within this range. Further study is required to determine the dosage needed to achieve maximum efficacy and minimal side effects.

Differential analysis of aqueous humor cytokine levels in patients with macular edema secondary to diabetic retinopathy or retinal vein occlusion.

AIM: To evaluate the difference and the correlation between the concentrations of cytokines in the aqueous humor of eyes with macular edema secondary to diabetic retinopathy (DR) or retinal vein occlusion (RVO). METHODS: This is a retrospective case control study. The aqueous humor samples were collected during intravitreal injection of anti-vascular endothelial growth factor (VEGF) for patients diagnosed with macular edema secondary to DR (DME) or RVO (RVO-ME) at Xijing Hospital from August 2021 to July 2022. Meanwhile, aqueous humor samples during vitrectomy from patients with idiopathic macular hole (IMH) were also collected and served as controls. The aqueous humor concentrations of VEGF, platelet-derived factor (PDGF), interleukin (IL)-6, IL-8, IL-18, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) were measured with Human Premixed Multi-Analyte Kit (Luminex). The difference of the aqueous cytokines and the correlation between the two diseases were analyzed. RESULTS: A total of 40 eyes of 38 patients were enrolled in the study, including 13 eyes of 11 DME patients (DME group), 16 eyes of 16 RVO-ME patients (RVO-ME group) and 11 eyes of 11 IMH patients (control group). The VEGF, PDGF, IL-6, IL-8, and MCP-1 levels of the aqueous humor were higher in both DME and RVO-ME groups compared with the control group (all P<0.05), the levels of TNF-α was higher in the DME group than in the control group (P<0.05). The VEGF, IL-6, MCP-1, and TNF-α levels in the aqueous humor were significantly higher in the DR group than those in the RVO group (all P<0.05). Correlation analyses revealed that there were complex positive correlations between IL-6, IL-8, IL-18, MCP-1, and TNF-α levels in the aqueous humor of eyes with two diseases. CONCLUSION: Although ischemic and inflammatory factors are similarly involved in the pathogenesis of DME and RVO-ME, the roles of these factors are more significant or more likely to be activated in DR patients, suggesting different treatment strategies should be considered for the two diseases.

Liver X Receptor Agonist Inhibits Oxidized Low-Density Lipoprotein Induced Choroidal Neovascularization via the NF-κB Signaling Pathway.

Age-related macular degeneration (AMD) is the most common blindness-causing disease among the elderly. Under oxidative stress, low-density lipoprotein in the outer layer of the retina is easily converted into oxidized low-density lipoprotein (OxLDL), which promotes the development of choroidal neovascularization (CNV), the main pathological change in wet AMD. Liver X receptor (LXR), a ligand-activated nuclear transcription factor, regulates various processes related to CNV, including lipid metabolism, cholesterol transport, inflammation, and angiogenesis. In this study, we evaluated the effects of the LXR agonist TO901317 (TO) on CNV. Our results demonstrated that the TO could inhibit OxLDL-induced CNV in mice as well as inflammation and angiogenesis in vitro. Using siRNA transfection in cells and Vldlr-/- mice, we further confirmed the inhibitory effects of TO against the inflammatory response and oxidative stress. Mechanistically, the LXR agonist reduces the inflammatory response via the nuclear translocation of NF-κB p65 in the pathway for NF-κB activation and by enhancing ABCG1-dependent lipid transportation. Therefore, an LXR agonist is a promising therapeutic candidate for AMD, especially for wet AMD.

Therapeutic effect of a traditional Chinese medicine formulation on experimental choroidal neovascularization in mouse.

AIM: To investigate therapeutic effects of traditional Chinese medicine formulations, Hexuemingmu (HXMM) on laser-induced choroidal neovascularization (CNV) and follow-up effect in mice. METHODS: C57BL/6 mice of 8-week-old were used and CNV was induced with 577 nm laser photocoagulation. Animals were randomly divided into groups and different doses of HXMM were administered daily. One, four, and eight weeks after the intervention, the electroretinogram (ERG), fundus fluorescence angiography, choroidal flat mount and immunofluorescence staining were preformed to evaluate the function and CNV formation. The expression levels of angiogenic proteins were determined by Western blotting and immunofluorescence staining. An analysis of variance and Kruskal-Wallis test were used to test the differences among the groups. RESULTS: The results showed that HXMM effectively increased amplitude of ERG of mice (P<0.05), alleviated fundus CNV leakage (P<0.05), and reduced the area of neovascularization and the expression of angiogenic proteins (P<0.05) after laser-induced CNV. CONCLUSION: HXMM can protect the retinal function of mice after laser-induced CNV, and inhibit the CNV development.

Newly-found functions of metformin for the prevention and treatment of age-related macular degeneration.

Metformin (MET), a first-line oral agent used to treat diabetes, exerts its function mainly by activating adenosine monophosphate-activated protein. The accumulation of oxidized phospholipids in the outer layer of the retina plays a key role in retinal pigment epithelium (RPE) cells death and the formation of choroidal neovascularization (CNV), which mean the development of age-related macular degeneration (AMD). Recent studies have shown that MET can regulate lipid metabolism, inhibit inflammation, and prohibit retinal cell death and CNV formation due to various pathological factors. Here, newly discovered functions of MET that may be used for the prevention and treatment of AMD were reviewed.

Role of Junctional Adhesion Molecule-C in the Regulation of Inner Endothelial Blood-Retinal Barrier Function.

Although JAM-C is abundantly expressed in the retinae and upregulated in choroidal neovascularization (CNV), it remains thus far poorly understood whether it plays a role in the blood-retinal barrier, which is critical to maintain the normal functions of the eye. Here, we report that JAM-C is highly expressed in retinal capillary endothelial cells (RCECs), and VEGF or PDGF-C treatment induced JAM-C translocation from the cytoplasm to the cytomembrane. Moreover, JAM-C knockdown in RCECs inhibited the adhesion and transmigration of macrophages from wet age-related macular degeneration (wAMD) patients to and through RCECs, whereas JAM-C overexpression in RCECs increased the adhesion and transmigration of macrophages from both wAMD patients and healthy controls. Importantly, the JAM-C overexpression-induced transmigration of macrophages from wAMD patients was abolished by the administration of the protein kinase C (PKC) inhibitor GF109203X. Of note, we found that the serum levels of soluble JAM-C were more than twofold higher in wAMD patients than in healthy controls. Mechanistically, we show that JAM-C overexpression or knockdown in RCECs decreased or increased cytosolic Ca2+ concentrations, respectively. Our findings suggest that the dynamic translocation of JAM-C induced by vasoactive molecules might be one of the mechanisms underlying inner endothelial BRB malfunction, and inhibition of JAM-C or PKC in RCECs may help maintain the normal function of the inner BRB. In addition, increased serum soluble JAM-C levels might serve as a molecular marker for wAMD, and modulating JAM-C activity may have potential therapeutic value for the treatment of BRB malfunction-related ocular diseases.

Connective tissue growth factor promotes retinal pigment epithelium mesenchymal transition via the PI3K/AKT signaling pathway.

Proliferative vitreoretinopathy (PVR) is a disease leading to the formation of contractile preretinal membranes (PRMs) and is one of the leading causes of blindness. Connective tissue growth factor (CTGF) has been identified as a possible key determinant of progressive tissue fibrosis and excessive scarring. Therefore, the present study investigated the role and mechanism of action of CTGF in PVR. Immunohistochemical staining was performed to detect the expression of CTGF, fibronectin and collagen type III in PRMs from patients with PVR. The effects and mechanisms of recombinant human CTGF and its upstream regulator, TGF­ß1, on epithelial­mesenchymal transition (EMT) and the synthesis of extracellular matrix (ECM) by retinal pigment epithelium (RPE) cells were investigated using reverse transcription­quantitative PCR, western blotting and a [3H]proline incorporation assay. The data indicated that CTGF, fibronectin and collagen type III were highly expressed in PRMs. In vitro, CTGF significantly decreased the expression of the epithelial markers ZO­1 and E­cadherin and increased that of the mesenchymal markers fibronectin, N­cadherin and α­smooth muscle actin in a concentration­dependent manner. Furthermore, the expression of the ECM protein collagen type III was upregulated by CTGF. However, the trends in expression for the above­mentioned markers were reversed after knocking down CTGF. The incorporation of [3H]proline into RPE cells was also increased by CTGF. In addition, 8­Bromoadenosine cAMP inhibited CTGF­stimulated collagen synthesis and transient transfection of RPE cells with a CTGF antisense oligonucleotide inhibited TGF­ß1­induced collagen synthesis. The phosphorylation of PI3K and AKT in RPE cells was promoted by CTGF and TGF­ß1 and the latter promoted the expression of CTGF. The results of the present study indicated that CTGF may promote EMT and ECM synthesis in PVR via the PI3K/AKT signaling pathway and suggested that targeting CTGF signaling may have a therapeutic or preventative effect on PVR.

A modified laser-induced choroidal neovascularization animal model with intravitreal oxidized low-density lipoprotein.

AIM: To investigate whether intravitreal injection of oxidized low-density lipoprotein (OxLDL) can promote laser-induced choroidal neovascularization (CNV) formation in mice and the mechanism involved, thereby to develop a better animal model. METHODS: C57BL6/J mice were randomized into three groups. Immediately after CNV induction with 532 nm laser photocoagulation, 1.0 µL of OxLDL [100 µg/mL in phosphate-buffered saline (PBS)] was intravitreally injected, whereas PBS and the same volume low-density lipoprotein (LDL; 100 µg/mL in PBS) were injected into the vitreous as controls. Angiogenic and inflammatory cytokines were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) after 5d, and CNV severity was analyzed by choroid flat mount and immunofluorescence staining after 1wk. In vitro, retinal pigment epithelial (RPE) cell line (ARPE19) were treated with OxLDL (LDL as control) for 8h. Angiogenic and inflammatory cytokine levels were measured. A specific inhibitor of lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) was used to evaluate the role of LOX1 in this process. RESULTS: At 7d after intravitreal injection of 1 µL (100 µg/mL) OxLDL, T15-labeled OxLDL was mainly deposited around the CNV area, and the F4/80-labeled macrophages, the CD31-labeled vascular endothelial cells number and CNV area were increased. Meanwhile, WB and qRT-PCR results showed that vascular endothelial growth factor (VEGF), CC chemokine receptor 2 (CCR2), interleukin-6 (IL-6), IL-1ß, and matrix metalloproteinase 9 (MMP9) expressions were increased, which was supported by in vitro experiments in RPE cells. LOX1 inhibitors significantly reduced expressions of inflammatory factors IL-1ß and VEGF. CONCLUSION: A modified laser-induced CNV animal model is established with intravitreal injection of 1 µL (100 µg/mL) of OxLDL at 7d, which at least partially through LOX1. This animal model can be used as a simple model for studying the role of OxLDL in age-related macular degeneration.

OxLDL enhances choroidal neovascularization lesion through inducing vascular endothelium to mesenchymal transition process and angiogenic factor expression.

Oxidized lowdensity lipoprotein (OxLDL) can impact the formation of choroidal neovascularization (CNV) via regulating endothelial cell proliferation and secretion of inflammatory and angiogenic factors, but the specific molecular mechanism is not clear. In this study, we evaluated the role of molecular pathways that affect angiogenesis at different stages. In vivo, we found that intravitreal injection of OxLDL following the laser photocoagulation significantly enhanced the CNV size. In vitro experiment confirmed that OxLDL impacts the formation of CNV via regulating endothelial cell proliferation in Rhesus monkey choroid-retinal vascular endothelial cells (RF/6A) and secretion of inflammatory and angiogenic factors. OxLDL promotes angiogenesis through increasing VEGF and some other pro-angiogenic factors expression. Treatment with LY294002, a specific inhibitor of the PI3K pathway, could abrogate VEGF-increased angiogenesis. OxLDL induced the TGF-ß2/Smad signaling axis to participate in the maintenance of neovascular formation. Treatment with PD98059, a specific inhibitor of the MEK pathway, could abrogate it. We also found that OxLDL increased the level of pro-angiogenic factors and promoted the endothelium-mesenchymal transition (EndMT) process, which is important for early tube formation and late maintaining of angiogenesis respectively. In summary, our results indicate that OxLDL affects CNV formation by increasing VEGF expression in the early stage, with activation of the MEK/ERK pathway. And OxLDL induces the TGF-ß2/Smad signaling axis, which leads to EndMT, to affects the later stage of CNV formation by activating the PI3K/AKT pathway.

HTRA1 synergizes with oxidized phospholipids in promoting inflammation and macrophage infiltration essential for ocular VEGF expression.

Understanding oxidative stress and HTRA1 locus in abnormal angiogenesis resulting in wet AMD pathology is an important step in developing a novel therapeutic approach. Using subretinal injection of oxLDL into C57BL/6 mice, we observed a lesion resembling the features of choroidal neovascularization (CNV), including macrophage infiltration, increased VEGF expression, and neovascularization. However, incubating ARPE-19 cells with oxLDL-a carrier of oxidized phospholipids-resulted in increased expression of inflammatory cytokines and chemoattractant proteins that recruited monocytes, but no substantial increase in expression of VEGF. Furthermore, incubation of ARPE-19 with oxLDL induced higher expression of HTRA1, which we showed to synergize with oxLDL in elevating the expression of inflammatory cytokines and chemoattractant factors. To investigate the role of macrophage infiltration on these expression changes, we treated cultured J774 macrophages with oxLDL and applied the conditioned medium onto ARPE-19 cells. This treatment was found to greatly enhance the expression of VEGF in ARPE-19, indicating the necessity of macrophage secretory products to induce increased expression of VEGF in retinal pigment epithelium. Gene expression analysis revealed that oxLDL induced the expression of Wnt3A in macrophages, a key activator of canonical Wnt signaling pathways. In addition, western blot analysis showed that the macrophage conditioned media further enhanced the reduction of phosphorylated ß-catenin induced by oxLDL. Lastly, we investigated HTRA1 as a potential target for AMD therapeutics. We demonstrated the ability of anti-HTRA1 antibody in vitro to neutralize the protease activity of HTRA1 and reduce the inflammatory and angiogenic response to oxidative stress. Finally, we validated the neutralizing effect of anti-HTRA1 antibody in vivo by evaluating lesion size and protein expression in a laser-photocoagulation murine model of CNV. We found that the combination of oxLDL and HTRA1 enhanced CNV size, which was reversed by the addition of anti-HTRA1 antibody. This study not only provides preliminary evidence that HTRA1 may be a viable target for AMD therapeutics but also elucidates the biochemical mechanisms by which this therapeutic effect may be mediated.

MicroRNA miR-24-3p Reduces Apoptosis and Regulates Keap1-Nrf2 Pathway in Mouse Cardiomyocytes Responding to Ischemia/Reperfusion Injury.

In recent years, microRNAs (miRNAs) have received increasing attention for their role in ischemia/reperfusion injury (I/RI), and many miRNAs have been demonstrated to play a very important role in cardiac I/RI. The miRNA miR-24-3p is a tumor suppressor that regulates multiple tumors; however, it remains unclear whether the expression level of miR-24-3p is altered in cardiac cells under I/RI. In this study, we used mouse primary cardiomyocytes and the H9C2 cardiomyocyte cell line to perform in vitro stimulated ischemia/reperfusion (SI/R) and then detected miR-24-3p expression level using quantitative real-time PCR (qRT-PCR). We discovered that the expression of miR-24-3p was significantly increased in cardiomyocytes following SI/R, and that the miR-24-3p level was inversely correlated to the ischemia marker HIF-1a. Furthermore, we transfected cardiomyocytes with miR-24-3p mimic or inhibitor to explore the role of miR-24-3p in cardiomyocyte ischemia/reperfusion injury in vitro. We performed flow cytometry to detect the apoptotic rate of H9C2 cardiomyocytes and found that the transfection of miR-24-3p mimic resulted in the decrease of the apoptosis rate of cardiomyocytes after SI/R, whereas the transfection of miR-24-3p inhibitor increased the number of apoptotic cardiomyocytes. These data suggest that the overexpression of miR-24-3p could reduce in vitro myocardial cell apoptosis induced by I/R injury. Finally, we applied the dual luciferase reporter gene system to verify whether miR-24-3p targets the Keap1 gene, and found that the luciferase signal intensity from a vector carrying the Keap1 wild-type reporter gene was significantly reduced after transfection with miR-24-3p mimic. The Keap1 protein level was also reduced following the transfection of miR-24-3p. The results from this study suggest a novel function of miR-24-3p in protecting cardiomyocytes from ischemia/reperfusion injury by the activation of the Nrf2-Keap1 pathway.

Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis.

Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.

Oxidative stress, innate immunity, and age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer's disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have previously hypothesized that the tight homeostatic control of inflammation via the innate immune system is likely critical for avoidance of disease progression. However, the presence of a multitude of potential triggers of inflammation results in a sensitive balance in which perturbations thereof would subsequently alter the inflammatory state of the retina, leading to a state of chronic inflammation and pathologic progression. In this review, we will highlight the background literature surrounding the known genetic and environmental contributors to AMD risk, as well as a discussion of the potential mechanistic interplay of these factors that lead to disease pathogenesis with particular emphasis on the delicate control of inflammatory homeostasis and the centrality of the innate immune system in this process.

[Clinical evaluation of ocriplasmin as a vitreolytic agent].

Incomplete perifoveal posterior vitreous detachment (PVD) associated with abnormal vitreomacular adhesion (VMA) can cause vitreomacular traction (VMT) and macular hole (MH) formation, which require vitrectomy treatment. Pharmacologic vitreolysis, which is intravitreal injection with vitreolytic enzymes to resolve VMA, may be used as an alternative therapy.Ocriplasmin, formerly known as microplasmin, is a recombinant truncated form of plasmin with proteolytic activity against fibronectin and laminin.It was recently approved for VMA treatment in the European Union and USA. Phase III studies indicated that ocriplasmin injection was a safe and effective treatment for selected cases of symptomatic VMA and MH. VMA release was achieved in 26.5% of ocriplasmin-injected eyes versus 10.1% of the placebo group. MH closure was achieved in 40.6% as compared with 10.6% of the placebo group.In comparison with the outcome after vitrectomy, the success rate of ocriplasmin was still far below expectation. Ocular adverse events included vitreous floaters, photopsia and profound visual decline. Its efficacy and safety need to be further evaluated in more clinical trials.

The influence of long term hydrochlorothiazide administration on the relationship between renin-angiotensin-aldosterone system activity and plasma glucose in patients with hypertension.

OBJECTIVE: To observe the relationship between changes in renin-angiotensin-aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension. METHODS: 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment. RESULTS: After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (-0.26 ± 0.26 mmol/L) and the nonelevated PRA group (-1.36 ± 0.23 mmol/L) was statistically significant (P < 0.05). The decrease of plasma glucose in the elevated Ang II group (-0.17 ± 0.18 mmol/L) compared to the nonelevated Ang II group (-1.07 ± 0.21 mmol/L) was statistically significant (P < 0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P < 0.05). The relative oxLDL level was not affected by the treatment. CONCLUSIONS: Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy.

Neural Stem Cells Derived by Small Molecules Preserve Vision.

PURPOSE: The advances in stem cell biology hold a great potential to treat retinal degeneration. Importantly, specific cell types can be generated efficiently with small molecules and maintained stably over numerous passages. Here, we investigated whether neural stem cell (NSC) derived from human embryonic stem cells (hESC) by small molecules can preserve vision following grafting into the Royal College Surgeon (RCS) rats; a model for retinal degeneration. METHODS: A cell suspension containing 3 × 104 NSCs or NSCs labeled with green fluorescent protein (GFP) was injected into the subretinal space or the vitreous cavity of RCS rats at postnatal day (P) 22; animals injected with cell-carry medium and those left untreated were used as controls. The efficacy of treatment was evaluated by testing optokinetic response, recording luminance threshold, and examining retinal histology. RESULTS: NSCs offered significant preservation of both photoreceptors and visual function. The grafted NSCs survived for long term without evidence of tumor formation. Functionally, NSC treated eyes had significantly better visual acuity and lower luminance threshold than controls. Morphologically, photoreceptors and retinal connections were well preserved. There was an increase in expression of cillary neurotrophic factor (CNTF) in Müller cells in the graft-protected retina. CONCLUSIONS: This study reveals that NSCs derived from hESC by small molecules can survive and preserve vision for long term following subretinal transplantation in the RCS rats. These cells migrate extensively in the subretinal space and inner retina; there is no evidence of tumor formation or unwanted changes after grafting into the eyes. TRANSLATIONAL RELEVANCE: The NSCs derived from hESC by small molecules can be generated efficiently and provide an unlimited supply of cells for the treatment of some forms of human outer retinal degenerative diseases. The capacity of NSCs migrating into inner retina offers a potential as a vehicle to delivery drugs/factors to treat inner retinal disorders.

JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of registered blindness among the elderly and affects over 30 million people worldwide. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in pathogenesis of AMD. In advanced wet AMD, although, most of the severe vision loss is due to bleeding and exudation of choroidal neovascularization (CNV), and it is well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels. VEGF suppression therapy improves visual acuity in AMD patients. However, there are unresolved issues, including safety and cost. Here we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit decreased inflammation, reduced CNV, lower levels of choroidal VEGF, and impaired choroidal macrophage recruitment in a murine model of wet AMD (laser-induced CNV). Interestingly, we also detected a substantial reduction in choroidal apoptosis of JNK1-deficient mice. Intravitreal injection of a pan-caspase inhibitor reduced neovascularization in the laser-induced CNV model, suggesting that apoptosis plays a role in laser-induced pathological angiogenesis. Intravitreal injection of a specific JNK inhibitor decreased choroidal VEGF expression and reduced pathological CNV. These results suggest that JNK1 plays a key role in linking oxidative stress, inflammation, macrophage recruitment apoptosis, and VEGF production in wet AMD and pharmacological JNK inhibition offers a unique and alternative avenue for prevention and treatment of AMD.

Negative correlation between serum syndecan-1 and apolipoprotein A1 in patients with type 2 diabetes mellitus.

Heparan sulfate proteoglycans (HSPGs) are involved in the regulation of cell growth, apoptosis and lipid metabolism in vitro. Syndecans are the primary form of HSPGs. Syndecan-1 is involved in the processes of cell growth, differentiation, adhesion, wound healing and inflammation. Additionally, as a sinusoidal transmembrane HSPG facing the plasma compartment, syndecan-1 is a promising target to be involved in lipoprotein physiology. We aimed to examine the possible correlation of syndecan-1 and lipid profile in type 2 diabetes mellitus. In this study, serum syndecan-1 was detected by ELISA, and potential correlations between syndecan-1 and triglyceride, cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein a, apolipoprotein (apo) B, apoA1 and apoB/apoA1 were analyzed. Forty-one patients with type 2 diabetes and 31 age-matched, non-diabetic healthy subjects (controls) were enrolled. Syndecan-1 in patients with diabetes (26.15 ± 2.42 ng/ml) was significantly higher than that of the controls (16.85 ± 1.98 ng/ml, t = -2.98, P = 0.005). Serum syndecan-1 level correlated negatively with apoA1 (r = -0.46, P = 0.003). Multiple regression analysis showed that apoA1 (b = -0.43, P = 0.003) was a predictor of serum syndecan-1 levels in subjects with type 2 diabetes.