Background: Diabeticretinopathy (DR) is a complication of diabetes that affects the eyes and vision. It is a leading cause of visual impairment and blindness in working-age people. Vascular endothelial growth factor-A (VEGF-A) is a primary initiator and potential mediator of DR. Matrix metalloproteinase-9 (MMP-9) plays a progressive role in the onset and severity of DR. Interleukin- 12 (IL-12) is a cytokine of the chemokine family that could reduce the levels of MMP-9 and VEGF- A and suppress tumor angiogenesis. We hypothesize that IL-12 may also have superior therapeutic ef ﬁ cacy against DR. However, protein drugs are prone to degradation by various proteases after drug injection. Therefore, they have short half-lives and low blood concentrations. The objective of this study was to develop IL-12-loaded nanoparticles for long-term and sustained DR treatment. Methods: IL-12-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IL-12-PNP) were developed by double emulsion. The characteristics, anti-DR activity, and mechanisms of IL-12-PNP were examined in vitro and in vivo.
Different conventional and newer diagnostic tools including glycated hemoglobin (HbA1c), thioredoxin- interacting protein, fructosamine, and glycated albumin have been used for detection of retinopathy in diabetic patients. However, most of them are used after it causes signi ﬁ cant damage to patients. 9,10 In addition, they have limited speci ﬁ city, sensitivity, and are imprecise in certain clinical conditions. 11 Moreover, increased cost related to newer diagnostic tools were also a substantial challenge. 12 Hence, the present review was intended to assess the potential role of Netrin-1 and -4 as a novel biomarker and therapeutic option for DR.
Chronic in ﬂ ammation contributes to the pathophysiology of both DR and DME. To that end, several novel thera- peutic targets have been identi ﬁ ed for this disease target- ing those processes that release cytokines and chemokines. These include direct and indirect antagonism of interleu- kins, proteases, chemokines, tumor necrosis factor (TNF), angiopoietin-2 (ANGPT-2) and kallikrein. Currently, there are no active clinical trials for DR and DME involving interleukins or proteases. One of the potent mediators of both in ﬂ ammation and breakdown of the blood retinal barrier is the chemokine ligand, CCL2. 279 A CCR2/5 receptor antagonist (Pf-04634817) (P ﬁ zer) was recently tested in patients with DME. 280 Another compound impli- cated in many systemic in ﬂ ammatory diseases as well as DR is TNF. A clinical trial with in ﬂ iximab, the monoclo- nal antibody antagonist of alpha (TNF- α ), in patients with persistent DME demonstrated signi ﬁ cant improvement in both VA and overall reduction in retinal thickening. 281,282 Angiopoietin-2 is another potent mediator of increased vascular permeability in DR. This growth factor achieves most of its biological effect by binding to the endothelial cell receptor tyrosine kinase Tie-2. A Phase I investigation of a competitive inhibitor of vascular endothelial-protein tyrosine phosphatase that promotes Tie2 activation and reduces vascular leakage in animal models showed no safety signal of concern and led to reduction in DME in a few cases. 283 A Phase II trial is planned. A recent study
diabeticretinopathy, so neovascularization occurs in dia- betic retinopathy in response to retinal ischemia and new vessels may grow on optical discs or elsewhere. Since the blood vessels are abnormal, they can ﬂ ow into the retina and affect the patient ’ s vision. To prevent the growth of abnormal new vessels, bleeding in the retina and other parts of the eye and severe vision loss, a standard treatment method called panretinal photocoagulation (PRP) is used. 6 In a 2014 survey, 98% of the retina specialists reported using PRP for initial proliferative diabeticretinopathy man- agement in the absence of diabetic macular edema. 7 Also, the usage of intravitreal pharmacologic agents in diabetic macular edema treatment reduces the risk of diabetic retino- pathy worsening and increases the chance of improvement. 8 Unfortunately, a third of patients have an incomplete response to anti-VEGF therapy, but the best second-line therapy in these patients remains unknown. 9 The visual evoked potential is an objective and non-invasive method that expresses a mass bioelectrical response from the visual cortex to a speci ﬁ c visual stimulus, so abnormal visual evoked potential responses observed in diabeticretinopathy indicate a general involvement of the visual system or of one of its composing structures and this test is used to evaluate ocular health from macula to cortex. 10,11 Because the visual evoked potential response is mainly due to the macular region, so the changes that occur due to retinopathy and post-PRP in this region will affect the visual evoked potential components. Therefore, the visual evoked poten- tial is a suitable technique for evaluating these changes.
Diabeticretinopathy (DR) is a vision-threatening complication of diabetes. It can range in severity from mild, moderate, or severe nonproliferative DR (NPDR) to proliferative DR (PDR; the most severe form of the disease). The most common cause of vision loss in DR is the development of ﬂ uid around the light-sensitive cells in the center of the retina (called diabetic macular edema [DME]). Effective treatments are available, but not all patients achieve the same level or speed of improvement following treatment with the same drug. The purpose of this study was to take a look back at the clinical trials that ﬁ rst demonstrated the ef ﬁ cacy of ranibizumab in eyes with DR and DME in order to determine which factors made it more likely that a patient would achieve a rapid, robust improvement in DR severity during treatment with ranibizumab. This study found that patients with the most robust early improvements in DR severity (by month 6) were more likely to have had moderately severe or severe NPDR or PDR at the start of treatment (rather than less severe DR) and had their DME disappear after just 3 months of treatment.
clinic evaluation with dilated fundus exam (DFE). Cases were identi ﬁ ed through the Informatics for Integrating Biology and the Bedside (i2b2) software, which queried data from the electronic medical record (EMR) of WCMC to identify patients meeting the aforementioned criteria (using diagnosis codes and lab values). Subsequently, inclusion criteria were veri ﬁ ed by manual EMR review. Inclusion criteria for controls were as follows: (1) diag- nosis of DM, (2) no history of diagnosis of HCV by history or laboratory testing, and (3) ophthalmology clinic evaluation with DFE. Exclusion criteria for both groups were as follows: gestational DM, pre-DM, impaired glu- cose tolerance, and receipt of liver transplant at any point during the study period. For the case group, achievement of HCV cure (de ﬁ ned as sustained virologic response or undetectable HCV viral load 12 weeks after completion of treatment) was an additional exclusion criterion. Controls, matched to the case group by age (half-decade) and DM type (type 1 or type 2) in 1:1 fashion, were selected randomly from the pool of subjects meeting inclusion/ exclusion criteria.
Different studies have reported that carotenoids exert retinal protection during oxidative stress, which is the most important underlying mechanism involved in the pathogenesis of DR. 60,61 As previous studies have reported, carotenoids or their active metabolites may act as both free radicals quenching and ROS\RNS scavenging in oxidative milieu. 62 The expression and activity of ret- inal oxidoreductases, including SOD, 36,40,45 glutathione reductase, 48 and glutathione peroxidase, 44,63 as well as intracellular antioxidant molecules including GSH 36 and thioredoxin, 40 increased in the presence of carotenoids. However, the levels of retinal GSH did not improve after intervention with carotenoids. 45 Moreover, retinal gamma- glutamyl transferase, a crucial enzyme involved in glu- tathione metabolism, increased. 48 Forkhead box protein O1 (FOXO1), a factor involved in catalase and SOD upregulation, enhanced after exposure with carotenoids. 40 Carotenoids also have improved mitochondrial dys- function as an important source of ROS/RNS in DR. These compounds enhanced the expression of mitochon- drial dehydrogenase 51 and electron transport complex III 45 in the retinal tissue of diabetic animals. Heat shock protein 60 (HSP60) as a major mitochondrial biomarker of stress ameliorated after treatment with carotenoids. 39 Oxidative stress-induced endoplasmic reticulum (ER) stress has cri- tical effects on retinal cell apoptosis. Both activating tran- scription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK), signaling pathways involved in ER stress, and ER stress sensor protein binding immunoglobulin protein (BiP) ameliorated by carotenoids. 40
The results of this study are supported by an explora- tory analysis of data from the RIDE/RISE trials, which demonstrated that ranibizumab reduced the risk of worsen- ing of DR severity, with improvement in DR severity seen in many patients. 24,25 Among patients who received rani- bizumab 0.3 or 0.5 mg every 4 weeks (n=468), 13.2% and 14.5% of patients, respectively, had an ≥ 3 Early TreatmentDiabeticRetinopathy Study severity level improvement from baseline at 2 years, compared with 1.3% of sham patients (n=239; P<0.001). Furthermore, 37.2% and 35.9% of patients, respectively, had an ≥ 2 Early TreatmentDiabeticRetinopathy Study severity level improvement over the same period, compared with 5.4% of sham patients (P<0.001). 24 Similar proportions of ranibizumab- treated patients maintained this level of improvement through to 3 years post baseline. 25 Recently, the clinical relevance of these changes has been explored in a post hoc analysis of patients enrolled in the RIDE/RISE trials, showing that improvements in DR severity were asso- ciated with greater VA gains, improved contrast sensitivity, and increased likelihood of resolution of macular edema. 26 In addition, an exploratory analysis by Bressler et al from the DRCR Network Protocol I study of 792 eyes from patients with center-involved DME causing VA impairment suggested that ranibizumab (0.5 mg every 4 weeks for 12 weeks, then as needed with either prompt or deferred [ ≥ 24 weeks] laser) was also associated with a reduced risk of DR worsening in eyes with and without PDR versus sham with prompt laser. 27 Similar ﬁ ndings were noted in uncontrolled case series with ranibizumab 28,29 as well as other anti-VEGF agents used for treatment of DME. 30 Additionally, the 2-year results of the DRCR Network Protocol S study comparing PRP with ranibizumab treatment for PDR demonstrated non- inferiority of ranibizumab (0.5 mg up to every 4 weeks based on a structured re-treatment program) to PRP (com- pleted in 1 – 3 visits, plus ranibizumab for DME); notably, 53% of patients in the PRP group received ranibizumab injections for DME. 8 The ﬁ ndings of this study suggest that anti-VEGF therapy with ranibizumab may have addi- tional utility as a treatment option for PDR when it has developed, including preservation of peripheral visual ﬁ eld that occurs following PRP and a marked reduction in the occurrence of macular edema in patients with PDR with- out concurrent macular edema at the time of diagnosis.
Ranibizumab is commercially available in a vial and pre- ﬁ lled syringe form in two concentrations: 0.5 mg/0.05 mL and 0.3 mg/0.05 mL. To date, large multicenter trials found that the 0.5 mg dose was effective to treat age- related macular degeneration, whereas the 0.3 mg dose was equally ef ﬁ cacious to treat diabetic macular edema and diabeticretinopathy. 35,36 The ﬁ ndings and variable dosing intervals in the adult population support the pre- mise that the dose of anti-VEGF drug may be disease speci ﬁ c or patient speci ﬁ c. Retinal neovascularization appears to be extremely sensitive to anti-VEGF therapy, and potentially lower anti-VEGF doses may be effective for ROP. However, the optimal dosages for both ranibizu- mab and bevacizumab remain unknown and controversial. A dose that results in effective regression of ROP while minimizing systemic penetration would be ideal due to uncertainties regarding how these drugs affect premature infants during neurodevelopmental growth.
As clinical intuition would suggest, results of reopera- tion depended on the indication for initial PPV. A majority of NCVH reoperations yielded successful visual results, but only a minority of TRD reoperations did so. Other than TRD as an initial indication for surgery, the use of silicone oil also portended worse BCVA outcomes. This is likely due to the fact that silicone oil is more likely to be used in more advanced TRD. 18,19 Furthermore, a worse initial BCVA correlated with greater improvement in vision. A ceiling effect in improvement in vision among eyes with better initial acuities most likely explains this ﬁ nding. Treatment with PRP prior to initial visit did not correlate with BCVA outcomes as was also observed in a study by Yorston et al. 17
By 2040, it might be projected that 600 million people will suffer from diabetes worldwide, and one-third of them are expected to have DR. Screening for DR is a univer- sally accepted strategy for detection and prevention of blindness due to disease. Recently, the American Diabetes Association (ADA), the US Centers for Disease Control and Prevention (US CDC) and the American Academy of Ophthalmology (AAO) recommended that patients with diabetes must have a regular dilated exam- ination of the fundus. 12,13 In China, despite increasing awareness of DR screening in recent years, the overall attention to early screening of DR remains insuf ﬁ cient, especially in rural or underdeveloped regions or countries with few ophthalmologists. Although there are some machine learning technologies, such as Deep learning system (DLS) under the broad term of arti ﬁ cial intelli- gence (AI), to detect referable DR and related eye diseases 14,15 by evaluating retinal images, these programs for screening DR are still challenged by issues related to implementation (Fundus Camera), availability of human assessors (taking photos), especially in rural or underde- veloped regions or countries. Therefore, the establishment of an ANN-based DR predicting model can not only calculate the high-risk signals of DR in some patients, but also detect DR early with potential risk, so that the timely referral and treatment can be carried out, improving the prognosis of patients with DR.
The percentage change in a- and b-wave amplitudes at each post-PRP visit when compared to baseline pre- treatment ERG is outlined in Table 3. When the total mean changes in percentage were compared, a-wave amplitude reduction was found to be higher than the b-wave amplitude reduction. The amplitude changes in Table 3 represent cumu- lative measurements since retinal tissue changes after each session sums with preceding treatments. It should be noted that the difference between sessions involves the summation of prior retinal tissue loss (resulting in reduced amplitude) with the possible post-treatment recovery in amplitudes which may be beginning by the second post-treatment week. Figure 2 provides a graphical breakdown of ERG changes in a sample patient from this study.
Inclusion criteria were subjects with DR without DME, with best corrected visual acuity (BCVA) of 0.2 or better in Snellen eye chart, age over 18 years old, spherical equivalent less than ﬁ ve diopters, no signi ﬁ cant media opacities or other pathology that could interfere in RS. Exclusion criteria were macular laser in the past, treatment with antiangiogenic intravitreal therapies in the previous 3 months or dexamethasone implant in the previous 6 months. Normal control eyes were obtained from contral- ateral eyes of unilateral eye diseases, from patient compa- nions and from health care providers.
carcinogenic status. 25 On this basis, we collected the serum level of CA125 in patients with type 2 diabetes and examined possible associations between this tumor biomarker and the presence as well as severity of DR. Serum CA125 level was signi ﬁ cantly related to the presence of DR in Chinese adult patients with type 2 diabetes. In addition, when DR was analyzed categorically, a statistically signi ﬁ cant association between CA125 level and different DR severity strata was also observed. CA125 level was exceedingly higher in parti- cipants with more advanced DR such as VTDR, and there was no difference in mild or moderate NPDR participants inver- sely. After using multiple adjusted models and accounting for clinical confounders, there was still an increasing trend of VTDR risk, accompanying with the improvement of CA125 quartiles. Therefore, it was speculated that elevated CA125 level was consider as an independent predictor for the pre- sence of DR and VTDR. Serum CA125 is an easily assessed laboratory parameter in clinical practice and could be expected to become a potential indicator to early detection of DR, enabling the clinicians to make timely treatment, and prevent the development of vision impairment.
Through the use of LTSL, the drug is internal loaded and remains in the liquid phase of the LTSL at body tempera- ture, but released at the melting phase transition temperature of the bimolecular lipid layer at the range of 40 – 45°C. 30 In a recent study, Maples et al 33 developed echogenic low temperature-sensitive liposomes (E-LTSL) as highly ef ﬁ cient drug delivery carrier for in vivo doxor- ubicin (Dox) uptake by a 3D tumor spheroid model. As showed in Figure 3A, 1,3-PD was validated to be encap- sulated into E-LTSL composed of amphiphilic phospholi- pids and per ﬂ uoropentane (PFP). The resulting 1,3-PD- based E-LTSL were used for imaging of the xenograft model in nude mice (Figure 3B). Furthermore, in combi- nation with high intensity focused ultrasound (HIFU). The Dox release of E-LTSL group was clearly mapped (Figure 3C). Also, Zhang et al 34 designed a thermosensitive lipo- some drug delivery system consisted of ammonium bicar- bonate to allow both ultrasound imaging and the release of Dox with local hyperthermia. The key point, ammonium bicarbonate, provides a rapid, controlled release of Dox to come to an effective drug concentration at the tumor site.
markers of oxidative stress in dyslipidaemic patients . It has also been found to prevent inflammation by blocking AGE-induced NF-κB activation in animal mod- els . Fenofibrate has been found to ameliorate vascu- lar function, improving blood flow in diabetics . One recent study investigated the combined effects of fenofi- brate on oxidative stress, inflammation and vascular tone in an animal model of diabetes . This study found that fenofibrate improved vascular relaxation and increased expression of the antioxidant enzymes, super- oxide dismutase and catalase . Interestingly, they also observed a decrease in the level of a proinflamma- tory marker, myeloperoxidase (MPO) . Importantly, a comprehensive screen of donated human retinal pig- ment epithelia (RPE) revealed that PPARα (the receptor for fenofibrate) was highly expressed while PPARγ was absent from the RPE . Further, laboratory studies using human RPE cells under hyperglycaemic conditions found that fenofibrate reduced RPE monolayer perme- ability  via blocking activation of AMP-activated pro- tein kinase (AMPK) [53,54] and the reduction in permeability was dose-dependent, indicating that intrao- cular delivery of fenofibrate could be highly efficacious. In summary, there is an expanding molecular basis for the positive effects of fenofibrate observed in the FIELD and ACCORD Eye studies.
Since NPF/siPLK1 showed good targeted effect to FA over- expressed cells, we conducted cellular experiments to detect the silencing and therapeutic effect on SGC-7901 cells. First of all, three different siPLK1 targeted different sequences of PLK1 mRNA were designed for PLK1 silencing, noted as 420, 501, and 671. The most effective siPLK1 was chosen by a simple screening of the silencing effect by PEI in Figure S7. PLK1 was proved to be an early trigger for G2/M transi- tion, which supported the functional maturation of the cen- trosome in late G2/early prophase and the establishment of the bipolar spindle. 24 Therefore, inhibition of PLK1 should exhibit the obvious cell cycle arrest in G2 phase. As shown in Figure 3A and B, the treatment of NP/siPLK1 for 6 hrs did not show signi ﬁ cant arrest in the G2 phase of SGC-7901 cells compared with the control group. However, the cells incubation with NPF/siPLK1 arrested about 45% of cells in G2 phase, resulting from the depletion of PLK1. The enhanced cell cycle arrest mediated by NPF/siPLK1
Anonymized data were remotely extracted from 19 centers using the same EMR system (Medisoft Ophthalmology, Medisoft Limited, Leeds, UK) in November 2014. Each site is the only NHS provider of diabeticretinopathy care to their local population and very few patients switch between providers or access care privately. All patients were first time presenters to eye providers after being referred from UK national diabeticretinopathy screening program, a nationwide program implemented through the National Health Service (NHS) and maintained by rigorous quality assurance measures. 15 Patients who received anti-vascular endothelial growth factor (anti-VEGF) injections during the study period were excluded. Data was extracted through the EMR compulsory DR structured assessment module as described previously. 16 Demographic data was extracted from the hospital’s patient administration system to the EMR. All patients had data extracted from the time of their first DR structured assessment entry onto the EMR to the date of their last clinical entry before the data extraction on November 26 th , 2014.
treatment with PKD inhibitor decreased the level of phos- pho Akt, indicating that the mechanism by which PKD inhibitor confers resistance against IL-1 β is not dependent on Akt signaling mechanism, but rather PKD might mod- ulate IL-1 β receptor signal transduction leading to Akt activation. Future studies are needed to explore the role of PKD in the pathways, leading to the activation of NF κ B in chondrocytes. In cells of the human and mouse immune systems, we previously found that PKD1 is activated by all TLRs that utilize MyD88 as a signaling adaptor, IL-1R via a MyD88, IRAK-dependent mechanisms, and PKD1 which plays an indispensable role on TLR/IL-1R-mediated NF- κ B activation and subsequent proin ﬂ ammatory gene expression and production. 23,29 In addition to IL-1R, TLR1 and TLR2 are also expressed in human normal healthy chondrocytes as well as degenerated chondrocytes in OA cartilage, and the cognate ligand binding to these TLRs can lead to proin ﬂ ammatory cytokines including TNF α in human chondrocytes. 50 In turn, TNF α can induce the expression of TLRs in human chondrocytes. 50 These ﬁ ndings by Nordstrom et al imply that cartilage matrix/ chondrocyte-derived danger signals or degradation pro- ducts may activate TLRs leading to the production of in ﬂ ammatory mediators. These in ﬂ ammatory mediators in turn further upregulate expression of TLRs producing more proin ﬂ ammatory mediators establishing a vicious feedforward cycle of joint in ﬂ ammation and cartilage damage in OA. Taken together, previous ﬁ ndings by others, in addition to our ﬁ ndings from this study, support the notion that PKD might be a very effective target for OA therapy.