Increased expression and activity of 12-lipoxygenase in oxygen-induced ischemic retinopathy and proliferative diabetic retinopathy: implications in retinal neovascularization

OBJECTIVEArachidonic acid is metabolized by 12-lipoxygenase (12-LOX) to 12-hydroxyeicosatetraenoic acid (12-HETE) and has an important role in the regulation of angiogenesis and endothelial cell proliferation and migration. The goal of this study was to investigate whether 12-LOX plays a role in retinal neovascularization (NV).RESULTSRetinal NV during OIR was associated with increased 12-LOX expression and 12-, 15-, and 5-HETE production. The amounts of HETEs also were significantly higher in the vitreous of diabetic patients with PDR. Retinal NV was markedly abrogated in mice treated with baicalein or mice lacking 12-LOX. This was associated with decreased VEGF expression and restoration of PEDF levels. PEDF expression was reduced in 12-HETE–treated rMCs, astrocytes, and the retinal pigment epithelium. Only rMCs and astrocytes showed increased VEGF expression by 12-HETE.CONCLUSIONS12-LOX and its product HETE are important regulators of retinal NV through modulation of VEGF and PEDF expression and could provide a new therapeutic target to prevent and treat ischemic retinopathy.Retinal neovascularization (NV) is a vision-threatening complication of ischemic retinopathy that develops in various retinal disorders, including diabetic retinopathy and retinopathy of prematurity (ROP). Retinal NV is controlled by a balanced production of pro- and antiangiogenic factors, including vascular endothelial growth factor (VEGF) and pigment epithelium–derived factor (PEDF), respectively (1). However, under some pathological conditions, including diabetic retinopathy and ROP, this balance is disrupted by enhanced production of proangiogenic and/or downregulation of antiangiogenic factors (2,3).Arachidonic acid metabolites, which are known as eicosanoids, are involved in regulating angiogenesis (4). Once released by cytosolic phospholipase A₂ (5), arachidonic acid is metabolized via different pathways, including the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 pathways. Angiogenesis has been shown to be promoted by the metabolic products of COX2, prostaglandins (6) and the products of the lipoxygenase system, leukotrienes, and hydroxyeicosatetraenoic acids (HETEs) (7,8). LOXs are a group of closely related dioxygenases that catalyze the stereospecific oxygenation of arachidonic acid and other polyunsaturated fatty acids (PUFAs) and are classified as 5-, 8-, 12-, or 15-LOX, according to the site of oxygen insertion within arachidonic acid.Three types of 12-LOX have been characterized: platelet, leukocyte, and epidermal 12-LOX (9), which are detected in various cell types, including smooth muscle cells (SMCs) (10), endothelial cells (10,11), and glial cells (12). The major product of 12-LOX metabolism of arachidonic acid, 12-HETE has a role in various biological processes, including atherogenesis, cancer cell growth, and neuronal apoptosis (13,14). In addition, 12-HETE has proinflammatory effects (15,16) and has been implicated in diabetic vascular complications (13). For example, high glucose treatment increases 12-HETE production in vascular endothelial cells and SMCs, and this increase is linked to vascular endothelial growth factor (VEGF) upregulation (17,18) and leukostasis (19) in the intracellular adhesion molecule-1–dependent pathway (15). Similarly, 12-HETE has been shown to contribute to tumor angiogenesis via a VEGF-dependent pathway (20) and to stimulate endothelial cell mitogenesis (7,8) and tube formation (21).VEGF and PEDF are identified as key angiogenic factors whose altered production contributes to the development of retinal NV. They induce opposite effects in the retina, which causes vasculopathies associated with diabetic retinopathy and ROP. Although VEGF has angiogenic and permeability effects that were shown to be mediated via oxidative stress (22,23) and inflammatory pathways (24), PEDF elicits antiangiogenic and antipermeability effects in part through antioxidant (25,26) and anti-inflammatory mechanisms (27). There are multiple cellular sources for the growth factors involved in retinal NV. Müller cells (rMCs) are known to express several modulators of angiogenesis by responding to hypoxia or hyperglycemia and releasing VEGF (28,29). They also are shown to have an antiangiogenic background attributed to PEDF secretion (30). Moreover, VEGF and PEDF expression in rMCs are altered by a high glucose concentration, which contributes to retinal NV in diabetic retinopathy (31).The role of lipoxygenases in general, and 12-LOX in particular, in the development of retinal NV has not been well investigated. The goal of this study was to explore the changes in 12-LOX expression and activity during retinal NV and to determine whether targeting 12-LOX activity impacts retinal NV perhaps through changes in the level of angiogenic factors.The current study presents, for the first time, that oxygen-induced ischemic retinopathy (OIR) and proliferative diabetic retinopathy (PDR) are associated with increased 12-LOX expression and activity. Inhibition of the LOX pathway or 12-LOX deletion significantly abrogated retinal NV and VEGF expression, while preserving retinal PEDF levels during OIR.     

Retinal thickness as a potential biomarker of neurodegeneration and a predictor of early cognitive impairment in patients with multiple sclerosis

ABSTRACT

Objectives

The purpose of this research is to predict the cognitive impairment and to determine its correlation with retinal thickness, mainly (RFNL and GCIPL) in cases of multiple sclerosis.     

Morin alleviates fructose-induced metabolic syndrome in rats via ameliorating oxidative stress,inflammatory and fibrotic markers

Metabolic syndrome (MBS) is a widespread disease that has strongly related to unhealthy diet and low physical activity, which initiate more serious conditions such as obesity, cardiovascular diseases and type 2 diabetes mellitus. This study aimed to examine the therapeutic effects of morin, as one of the flavonoids constituents, which widely exists in many herbs and fruits, against some metabolic and hepatic manifestations observed in MBS rats and the feasible related mechanisms. MBS was induced in rats by high fructose diet feeding for 12 weeks. Morin (30 mg/kg) was administered orally to both normal and MBS rats for 4 weeks. Liver tissues were used for determination of liver index, hepatic expression of glucose transporter 2 (GLUT2) as well as both inflammatory and fibrotic markers. The fat/muscle ratio, metabolic parameters, systolic blood pressure, and oxidative stress markers were also determined. Our data confirmed that the administration of morin in fructose diet rats significantly reduced the elevated systolic blood pressure. The altered levels of metabolic parameters such as blood glucose, serum insulin, serum lipid profile, and oxidative stress markers were also reversed approximately to the normal values. In addition, morin treatment decreased liver index, serum liver enzyme activities, and fat/muscle ratio. Furthermore, morin relatively up-regulated GLUT2 expression, however, down-regulated NF-κB, TNF-α, and TGF-β expressions in the hepatic tissues. Here, we revealed that morin has an exquisite effect against metabolic disorders in the experimental model through, at least in part, antioxidant, anti-inflammatory, and anti-fibrotic mechanisms.     

Cumyl-CBMICA: A new synthetic cannabinoid receptor agonist containing a cyclobutyl methyl side chain

Since the beginning of the phenomenon of new psychoactive substances (NPS), synthetic cannabinoid receptor agonists (SCRAs) have been the largest and most prevalent subclass of these drugs in Europe. Many countries implemented specific legislation scheduling classes of substances defined on the basis of their chemical structure to reduce supply. We describe the identification and analytical characterization within the EU project ADEBAR plus of 1-(cyclobutylmethyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide which resulted in the formal notification through the Early Warning System of the European Monitoring Centre for Drug and Drug Addiction (EMCDDA). This is the first identification of this new SCRA worldwide and the analytical data was distributed (inter-)nationally right after identification in 2019. First, the substance was isolated from the herbal material using preparative high-performance liquid chromatography (HPLC). Structure elucidation and analytical characterization were performed using gas chromatography–mass spectrometry (GC–MS), gas chromatography-solid state infrared spectroscopy (GC-sIR), liquid chromatography-electrospray ionization-quadrupole time of flight-mass spectrometry (LC-ESI-qToF-MS), Raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. The new compound contains a cyclobutyl methyl group as a side chain and has not been described in any patent to our knowledge. Based on the semisystematic nomenclature of SCRAs, we propose Cumyl-CBMICA as a short name for the compound.     

Role of MR spectroscopy and diffusion-weighted imaging in diagnosis of orbital masses

Purpose

To assess the value of (MRI), (DWI) and (MRS) in the diagnosis of different orbital masses and differentiation between benign and malignant masses.

Evaluation of miRNA-21 and miRNA Let-7 as Prognostic Markers in Patients With Breast Cancer

Background

Breast cancer remains one of the top threats to women’s health. The current lack of tumor markers with desirable sensitivity and specificity is a major obstacle toward the future management of breast cancer. Many studies are directed to reveal the diagnostic and prognostic potentials of circulating miRNAs in breast cancer. In this study, we attempt to evaluate the feasibility and clinical utility of circulating miRNA-21 and let-7 as prognostic biomarkers for breast cancer.

Amino acid changes during transition to a vegan diet supplemented with fish in healthy humans

Purpose

To explore whether changes in dietary protein sources can lower plasma branched-chain amino acids (BCAAs), aromatic amino acids and sulfur amino acids (SAAs) that are often elevated in the obese, insulin-resistant state and in type 2 diabetes.

Methods

Thirty-six subjects (mean age 31 ± 2 years) underwent a voluntary abstinence from meat, poultry, eggs, and dairy products for 6 weeks, while enriching the diet with fish, in fulfillment of a religious fast. Subjects were assessed 1 week before the fast (V1), 1 week after initiation of the fast (V2) and in the last week of the fast (V3). Thirty-four subjects completed all three visits.

Results

Fasting plasma BCAAs decreased at V2 and remained low at V3 (P < 0.001 for all). Valine showed the greatest decline, by 20 and 19 % at V2 and V3, respectively. Phenylalanine and tryptophan, but not tyrosine, also decreased at V2 and V3. The two proteinogenic SAAs, methionine and cysteine, remained stable, but the cysteine product, taurine, decreased from 92 ± 7 μmol/L to 66 ± 6 (V2; P = 0.003) and 65 ± 6 μmol/L (V3; P = 0.003). A progressive decline in plasma glutamic acid, coupled with an increase in glutamine, was observed. Plasma total and LDL cholesterol decreased at V2 and V3 (P < 0.001 for all).

Conclusion

Changing dietary protein sources to plant- and fish-based sources in an ad libitum setting lowers the plasma BCAAs that have been linked to diabetes risk. These findings point to habitual diet as a potentially modifiable determinant of fasting plasma BCAA concentrations.