Molecules related to diabetic retinopathy in the vitreous and involved pathways

INTRODUCTION

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia and the damage to vessels. Metabolic disorders in carbohydrates, fats and proteins could cause multi-organ damage, which led to organ dysfunctions, further resulting in diabetic complications.According to the 2019 International Diabetes Federation (IDF)Global Diabetes Map (Ninth Edition), there are currently approximately 463 million people with diabetes worldwide,and the prevalence among adults (aged 20-79y) is 9.3%.Among them, China has the largest population of patients with about 116.4 million, accounting for a quarter of the total number of patients in the world. Among them, 35.5 million people are over 65 years old.

Diabetic retinopathy (DR) is one of the most common complications of diabetes, as well as the most common retinal vascular disease. It was reported that DR was the main blindness-causing diseases in people over 50 years old

. The basic pathological changes of DR are retinal microangiopathy,including fundus neovascularization and fibrous proliferation.Current studies on DR have shown that the core molecule involved in the pathophysiology is vascular endothelial growth factor (VEGF), which can specifically stimulate the proliferation of vascular endothelial cells and promote neovascularization

. A great number of studies have confirmed that concentrations of VEGF in the vitreous of DR patients is significantly higher than that of ordinary people

, and drugs targeting VEGF have already been developed, one of which were anti-VEGF drugs and it has been widely accepted as a mainstream treatment method yet. However, recent studies discovered that there are many deficiencies in the application of anti-VEGF drugs, such as long-term drug resistance, high cost of treatment, and potential retinal detachment risk caused by intraocular injection

. In recent years, molecular research on the pathogenesis of DR has become a hot spot. Existing studies have found that although VEGF is the key molecule in the development of DR, there are hundreds of other molecules in the vitreous that participate in the process. Some of them are VEGF-dependent and others work independently

. Here, we present an overview focusing on the pathways and molecules discovered in the vitreous which are found to involve in the development of DR. We hope this review could reveal the intrinsic relationships between these molecules and provide inspirations for research interests and new therapeutic targets.

農(nóng)業(yè)保險(xiǎn)工作，是一項(xiàng)新生事物，既要提高農(nóng)民自身投保的積極性，又離不開政府的支持和引導(dǎo)。在下步工作中，重點(diǎn)抓好以下方面工作：

VITREOUS AND ITS ROLE IN DIABETIC RETINOPATHY Vitreous and Its Relationship with Diabetic Retinopathy Vitreous is the major content of the eye accounting for 80%of the inner volume of the whole globe which could transmit light to the retina and maintain the shape of the ocular tissue.Nowadays, lots of studies find that vitreous contains a variety of molecules that is associated with the function of other parts of the eye. These molecules can provide nutrition, perform anti-oxidant effect and may play a role in the development of some eye diseases

. For the vitreous body is in direct contact with the retina, the factors involved in the development of DR can diffuse into the vitreous, making it possible to study DR by exploring the relevant factors in the vitreous body

.As is widely accepted that VEGF is the core molecule in the development of DR, knowing how VEGF in the vitreous performs its biological function can greatly elaborate the mechanism of DR progression.

Role of Vascular Endothelial Growth Factor in Diabetic Retinopathy DR is clinically divided into non-proliferative DR (NPDR) and proliferative DR (PDR) according to the emergence of neovascularization, in which VEGF is highly involved. In NPDR stages, hyperglycemia causes damage to small blood vessels in the retina, thus leading to the secretion of VEGF, which acts as a protective role on rescuing the retinal neurons, but it also affects blood vessels negatively

.If the damage factors persist for a longer time, high-level of VEGF breaks the balance between pro-angiogenic and antiangiogenic factors, after which VEGF acts destructively on vascular endothelial cells and stimulates the formation of new blood vessels, which is the symbol of PDR stage

. Meanwhile,VEGF in the vitreous can induce new blood vessels to grow into the vitreous cavity, leading to serious complications such as vitreous hemorrhage and tractional retinal detachment.

綜上優(yōu)缺點(diǎn)所述，根據(jù)現(xiàn)場焊縫的實(shí)際情況，適宜選擇這兩種方法或者兩者結(jié)合進(jìn)行檢測，以符合標(biāo)準(zhǔn)要求和質(zhì)量要求。

After that extracellular VEGF binds to VEGFR and activates the receptors through transphosphorylation, thereby activating downstream pathways. In this section, we mainly discussed three downstream pathways: phosphatidylinositol diphosphate(PIP2), phosphoinositide-3-kinase (PI3K), and mitogenactivated protein kinase (MAPK) pathway. The detailed pathway and key molecules are presented in Figure 1.

Previous studies have measured various inflammatory molecules in the vitreous specimens and evaluated their role in the development of DR. We divided these inflammatory molecules into three groups: pro-inflammatory molecules,anti-inflammatory molecules and pleiotropic cells factors.Pro-inflammatory molecules referred to factors which can promote inflammation, including interleukin (IL)-1β, IL-6,IL-8, Interferon-γ (IFN-γ), CCL-2/MCP-1, tumor necrosis factor α (TNF-α), intercellular cell adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1),chemokines CCL2, CCL5, CXCL8, CXCL10, CXCL12

,CXCL16, ADAM10 and ADAM17

. Among them, studies have found that the levels of all above factors except IL-6 in the vitreous of patients with DR are higher than those in the control group, but there is no significant difference between IL-6

. However, other studies draw different conclusions.One study has shown that in patients with PDR after partial vitrectomy, the levels of MCP-1/CCL-2 and IL-6 in the vitreous increase. It is speculated that the increase of these two substances in the postoperative period is indicative of longterm inflammation, thus having a certain predictive value on postoperative DME

. Anti-inflammatory molecules referred to factors which can inhibit inflammation, including IL-37.A study pointed out that IL-37 is also elevated in the vitreous of PDR patients, and its content is related to VEGF-A and Ang-2, suggesting that it plays a role in PDR

. Although anti-inflammatory immune regulators like IL-37 are found to be up-regulated, they are more of a passive compensation and are not strong enough to reverse the inflammatory process

.Pleiotropic cells factors referred to factors which can both promote and inhibit inflammation under different conditions,include IL-2, IL-4, IL-13 and NO. Among them, studies have found that IL-13 is down-regulated, NO is up-regulated in the vitreous of PDR patients, and there is no significant difference as for IL-2 and IL-4

.

IRS-2蛋白陽性表達(dá)位置主要在細(xì)胞質(zhì)中出現(xiàn)棕黃色顆粒，每例隨機(jī)觀察5個(gè)高倍鏡(400倍)視野，根據(jù)陽性細(xì)胞數(shù)和著色深度計(jì)分，陽性表達(dá)<5%為0分，5%～24%為1分，25%～49%為2分，50%～74%為3分，≥75%為4分。陽性細(xì)胞表達(dá)的著色深度:基本不著色為0分，淡黃色為1分，黃色為2分，棕黃色3分。兩者得分相乘，<3分判定為表達(dá)陰性，其余判定為表達(dá)陽性。所有切片均采用雙盲法由2位病理科主任醫(yī)師閱片，2人結(jié)果一致則記錄結(jié)果，如有爭議請第3位病理科醫(yī)生看片，以2個(gè)相同結(jié)果為準(zhǔn)。

改革開放前，由于當(dāng)時(shí)受技術(shù)等因素所限，我國農(nóng)藥工業(yè)發(fā)展較為緩慢，農(nóng)藥產(chǎn)品供應(yīng)數(shù)量少、生產(chǎn)規(guī)模小，適應(yīng)不了農(nóng)業(yè)發(fā)展的需要。上世紀(jì)80年代，改革開放促進(jìn)農(nóng)業(yè)發(fā)展與農(nóng)藥市場擴(kuò)容加快，作為支農(nóng)行業(yè)的農(nóng)藥，國家鼓勵(lì)和政策支持其引進(jìn)國外先進(jìn)技術(shù)裝備，吸引國外優(yōu)秀人才來加快企業(yè)發(fā)展，同時(shí)，農(nóng)業(yè)豐收帶來的巨大市場需求也推動(dòng)一部分農(nóng)藥企業(yè)走出去、請進(jìn)來，促使我國農(nóng)藥產(chǎn)量的扶搖而上。

Molecules From Kallikrein-Kinin System KKS is a set of regulatory systems including kallikrein and kinin in the human body. Kallikrein is a collective name for polypeptides including a variety of bradykinins (BK). KKS is composed of two independently regulated proteolytic pathways mediated by tissue kallikrein (TK) and plasma kallikrein (PK) in human,both of which are expressed in eye and found to be related to the progression of DR

the production of bradykinin and spontaneous stimulation of bradykinin receptors

.After the activation of BK receptors, KKS performs a variety of physiological effects such as coagulation, fibrinolysis,angiogenesis,

.

女孩畢業(yè)后，這條連接兩所大學(xué)的窄街拆遷了，煎餅攤被挪到了更偏的地方，很難找。但根深蒂固的記憶幫了女孩，她一路尋一路問：要找那家鏊子有80厘米的煎餅攤，門口，攤煎餅的人放著好幾盆茉莉花和珠珠花。對了，就是那個(gè)既攤棕色煎餅又?jǐn)偯S煎餅的老徐煎餅檔。

Up to now, there have been a few studies on the role of KKS in the vitreous of DR patients. In normal eyes, with the function of blood-retinal barrier, some circulating substances can’t diffuse into vitreous. However, under DR conditions,substances diffuse becomes easier since the breakdown of the barrier. A group of molecules in plasma KKS family,including high molecular weight kininogen, prekallikrein(PK), coagulation factor XII (FXII) and complement 1 esterase inhibitor (C1-INH) have been identified to accumulate in the vitreous of DR patients by proteomic analysis

. First three molecules participate in the activation of KKS, while C1-INH can inhibit KKS by preventing PK from activation. In retinal tissues, the activation of KKS promotes the aggregation of neutrophils and microglia

, and at the same time may increase vascular permeability and vascular edema, change the diameter of the vascular and the hemodynamics, and affect inflammation, angiogenesis, and neuronal functions

. The detailed mechanism of KKS system was shown in Figure 3.

大型科學(xué)研究儀器設(shè)備對前沿科學(xué)研究起著重要的保障作用，是進(jìn)行高精尖科學(xué)研究的物質(zhì)基礎(chǔ)，一個(gè)國家大型科學(xué)儀器設(shè)備的數(shù)量從一定程度上可以反映該國在科學(xué)領(lǐng)域的研究地位?！?br>