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    The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review). Zhou Hongyan,Zhang Wensong,Bi Miaomiao,Wu Jie International journal of molecular medicine Corneal alkali burns (CAB) are characterized by injury-induced inflammation, fibrosis and neovascularization (NV), and may lead to blindness. This review evaluates the current knowledge of the molecular mechanisms responsible for CAB. The processes of cytokine production, chemotaxis, inflammatory responses, immune response, cell signal transduction, matrix metalloproteinase production and vascular factors in CAB are discussed. Previous evidence indicates that peroxisome proliferator-activated receptor γ (PPAR-γ) agonists suppress immune responses, inflammation, corneal fibrosis and NV. This review also discusses the role of PPAR-γ as an anti-inflammatory, anti-fibrotic and anti-angiogenic agent in the treatment of CAB, as well as the potential role of PPAR-γ in the pathological process of CAB. There have been numerous studies evaluating the clinical profiles of CAB, and the aim of this systematic review was to summarize the evidence regarding the treatment of CAB with PPAR-γ agonists. 10.3892/ijmm.2016.2699
    Olopatadine enhances recovery of alkali-induced corneal injury in rats. Kandeel Samah,Balaha Mohamed Life sciences AIMS:The alkali-induced corneal injury is an ocular emergency that required an immediate and effective management to preserve the normal corneal functions and transparency. Olopatadine is a fast, topically-effective anti-allergic drug, which exhibited potent anti-inflammatory and anti-angiogenic abilities in different allergic animals' models. Therefore, this study aimed to evaluate the therapeutic effect of olopatadine on alkali-induced corneal injury in rats. MATERIALS AND METHODS:Corneal alkali injury (CI) induced in the right eyes of an eight-week-old male Wister rats, by application of 3 mm diameter filter-papers, soaked for 10 s in 1 N-NaOH, to the right eyes' corneal centers for 30 s, afterward, the filter paper removed, and the rat right eye rinsed with 20 ml normal saline. For treatment of CI, either 0.2% or 0.77% olopatadine applied topically daily for 14 days, starting immediately after the induction of CI. KEY FINDINGS:Olopatadine, in the present work, effectively and dose-dependently enhanced the corneal healing after alkali application, with significant reduction of the corneal opacity and neovascularization scores, besides, it suppressed the augmented corneal IL-1β, VEGF, caspase-3 levels, and nuclear NF-κB immunohistochemical expression, meanwhile it abrogated the corneal histopathological changes, induced by alkali application. SIGNIFICANCE:Olopatadine appears to be a potential treatment option for alkali-induced corneal injury. 10.1016/j.lfs.2018.07.002
    Subconjunctival injection of antagomir-21 alleviates corneal neovascularization in a mouse model of alkali-burned cornea. Zhang Yun,Zhang Ting,Ma Xiaoyun,Zou Jun Oncotarget Corneal neovascularization may result in loss of corneal transparency and blindness. However, developing successful and inexpensive medical treatments for corneal neovascularization remains an unresolved issue. Recently, several studies have implicated miRNA functions in the regulation of cornea homeostasis. This study aimed to identify the miRNA expression profile in the neovascularized cornea after an alkali burn and to investigate the related underlying mechanisms. Here, alkali-burned corneas and matched normal tissues were pooled to perform miRNA sequencing. MiR-21 in alkali-burned cornea showed the greatest increment of abundance at 4 and 7 d after injury compared to the healthy cornea. The miR-21 expression was positively correlated with both the mRNA and protein level of key angiogenic factors including vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1α (HIF-1α). At 2 and 8 d after alkali burn, the mice received subconjunctival injections of antagomir-21 (1 or 5 nmol per injection). The injection of antagomir-21 (5 nmol) inactivated miR-21 and attenuated neovascularization progression by inhibiting the expression of VEGF-A and HIF-1α. Western blot analysis of the corneas demonstrated that antagomir-21 restored Sprouty 2/4 expression and silenced p-ERK activation. Therefore, these data reveal that antagomir-21 ameliorates the progression of corneal neovascularization likely via Sprouty 2/4-mediated inactivation of p-ERK. Delivery of antagomir-21 might be a potential therapeutic approach to prevent or treat visual loss caused by corneal neovascularization. 10.18632/oncotarget.14370
    Comparative Analysis of KGF-2 and bFGF in Prevention of Excessive Wound Healing and Scar Formation in a Corneal Alkali Burn Model. Cai JianQiu,Zhou Qingde,Wang Zhitao,Guo Ruide,Yang Rongshuai,Yang Xuanxin,Li Wenqing,Ahmad Naveed,Chen Qi,Hui Qi,Wang Xiaojie Cornea PURPOSE:Basic fibroblast growth factor (bFGF) is an effective drug for corneal injury. However, the explicit role of bFGF in corneal scar formation still remains unclear. Keratinocyte growth factor-2 (KGF-2) is associated with the treatment of wound healing. We aimed to compare the efficacy of bFGF and KGF-2 in prevention of excessive wound healing and consequent scar formation in a rat alkali burn model, which provides important clues on the significance of KGF-2 to be developed as a new drug for such injuries. METHODS:The epithelial defect area was evaluated using fluorescein sodium at a concentration of 0.5%. The therapeutic effect of KGF-2 and bFGF on proliferation of rabbit corneal fibroblasts (RCFs) was evaluated by methylthiazoletetrazolium. RCF migration assays were performed with a modified scratch method. Activation of mitogen-activated protein kinase (MAPK) was evaluated by Western blot with specific antibodies. RESULTS:All corneal wounds treated with KGF-2 were found closed within 7 days; however, the wounds treated with bFGF or phosphate buffer saline (PBS) required 14 days to close. RCFs treated with KGF-2 or bFGF showed similar dose-dependent proliferation. The KGF-2 group significantly promoted cell migration compared with the bFGF group. The KGF-2 group showed less expression of α-smooth muscle actin (SMA) and numbers of myofibroblasts compared with the bFGF group. Our findings suggested identification of cascade reaction of extracellular regulated protein kinases (ERK)1/2 and p38 signals in KGF-2- and bFGF-induced proliferation and migration of RCFs. In addition, KGF-2 showed stronger effects during ERK1/2 and p38 phosphorylation in methylthiazoletetrazolium proliferation assay and scratch migration assay. CONCLUSIONS:KGF-2 exhibited better effects than bFGF in reepithelialization, acceleration of migration, and reduction of scar formation, which has potential to become a new drug to cure corneal injury. 10.1097/ICO.0000000000002134
    The role of pirfenidone in alkali burn rat cornea. Jiang Nan,Ma Mingyang,Li Yunyan,Su Ting,Zhou Xue-Zhi,Ye Lei,Yuan Qing,Zhu Peiwen,Min Youlan,Shi Wenqing,Xu Xiaowei,Lv Jinlei,Shao Yi International immunopharmacology To evaluate the effects of pirfenidone in the treatment of HUVEC using an in vitro model and on rat corneal wound healing, edema, cornea neovascularization (CNV) and inflammation after alkali burn in vivo model. In vitro, CCK-8 assay was used to detect the effect of pirfenidone on the viability of HUVECs. The effects of pirfenidone on migration and tube formation of HUVEC were evaluated by HUVEC cell wound closure and tube formation assay. In vivo, Eye drops containing pirfenidone or phosphate buffered saline (PBS) were administered to an alkali-burn-induced corneal inflammatory and neovascularization model four times daily. The clinical evaluations, including fluorescent staining and cornea edema, were performed on days 1, 4, 7 and 14 using slit lamp microscopy. Global specimens were collected on day 7 and processed for immunofluorescent staining Collagen IV, α-smooth muscle actin (α-SMA), vascular endothelial growth factor (VEGF), pigment epithelium derived factor (PEDF) and cluster of differentiation34 (CD34). The levels of α-SMA, VEGF, PEDF, CD34, CD31 and nuclear factor-kappa B (NF-κB) proteins in the corneas were determined by western blot. Pirfenidone affects HUVEC viability, migration and tube formation in a dose-dependent manner. High concentration of pirfenidone can inhibit HUVEC viability, migration and tube formation in vitro and reduce alkali burn rat cornea edema, promote corneal wound healing, inhibit CNV and inflammation after alkali burn in vivo. Pirfenidone promotes corneal wound healing, and inhibits cornea neovascularization and inflammation after alkali burn in vitro and in vivo. Pirfenidone may be the potential anti-inflammation agent for the clinical treatment of CNV. 10.1016/j.intimp.2018.08.032
    Role of microRNA 146a on the healing of cornea alkali burn treated with mesenchymal stem cells. Luo Xu,Li Jianmin,Yin Lihui,Pan Jian,Zhang Yang,Jiang Zipei Molecular medicine reports The aim of the present study was to investigate the effect of microRNA 146a (miR146a) on promoting the repair of corneal alkali burn with bone marrow mesenchymal stem cells (MSCs). A total of 24 Sprague‑Dawley female rats were divided into a normal group (Control), a normal MSC treatment group (Normal MSCs), an miR146a knockout MSC treatment group (miR146a‑low MSCs) and an miR146a high‑expression MSC treatment group (miR146a‑high MSCs) according to the random number table. Quantitative polymerase chain reaction was used to evaluate the expression levels of miR146a. MTT assay was performed to measure the cell viability of mesenchymal stem cells (MSCs) and apoptosis was measured by flow cytometry. The expression levels of p65 nuclear factor (NF)‑κB, proliferating cell nuclear antigen (PCNA) and Fas proteins were analyzed by western blotting. MSCs were tested for the secretion levels of vascular endothelial growth factor (VEGF), CD45, interferon (IFN)‑γ and interleukin (IL)‑10 by ELISA. The miR146a‑high MSCs improved cell viability of MSCs and inhibited apoptosis of MSCs following alkali burn. miR146a‑high MSCs decreased the expression levels of p65NF‑κB and PCNA, and enhanced the expression level of Fas. Furthermore, miR146a‑high MSCs improved the cornea opacity and enhanced the inhibition of neovascularization in the rats following alkali burn. miR146a‑high MSCs inhibit the expression of VEGF, CD45, IFN‑γ, while enhanced the expression of IL‑10. Therefore, miR146a promotes the repair of corneal alkali burn in rats treated with MSCs. 10.3892/mmr.2018.9328
    Tetramethylpyrazine (TMP) ameliorates corneal neovascularization via regulating cell infiltration into cornea after alkali burn. Wu Yihui,Xu Zhuojun,Yang Ying,Qiu Jin,Yang Meng,Wu Chuangran,Lai Zhipeng,Tang Mingjun,Ge Jian,Yu Keming,Zhuang Jing Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie In the present study, we investigated the underlying mechanism of tetramethylpyrazine (TMP)-medicated inhibition of corneal neovascularization (CNV). Our data showed that TMP could effectively downregulate the expression levels of CXCR4 mRNA and protein, as well as inhibit HUVECs, endothelial cells, tubule formation in vitro. In vivo, alkali burn (1 M NaOH) could remarkably upregulate CXCR4 expression and increase the migration of TNF-α-positive cells to corneal stroma. TMP drops could significantly downregulate CXCR4 expression in cornea, compared to the control. However, there was no difference in the downregulation of CXCR4 between TMP and FK506, an immunosuppressive drug. Moreover, the immunofluorescent staining of CD45 showed TMP and FK506 could significantly restrain the bone marrow (BM)-derived infiltration while the F4/80 staining reflects the suppression of macrophage aggregation. Meanwhile TMP could regulate the Interleukin 10 (IL-10) and FK506 could restrain the Interleukin 2 (IL-2). Furthermore, TMP and FK506 significantly ameliorate corneal opacity and neovascularization. Clinical assessment detected an obvious improvement in TMP and FK506 treatment groups, compared to controls in vivo. Thus, TMP had similar effects in inhibition of immune response and CNV by suppressing BM-infiltrating cells into cornea as FK506. TMP could be a potential agent in eye-drop therapy for cornea damaged by Alkali Burn. 10.1016/j.biopha.2018.10.091