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AbstractDiabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM) causing vision impairment even at young ages. There are numerous mechanisms involved in its development such as inflammation and cellular degeneration leading to endothelial and neural damage. These mechanisms are interlinked thus worsening the diabetic retinopathy outcome. In this review, we propose oxidative stress as the focus point of this complication onset. IntroductionDiabetes mellitus (DM) is expected to affect around 550 million people all over the world according to global estimates of the prevalence of diabetes.
DM is characterized by constant hyperglycemia that damages various organs and manifests in macrovascular complications like premature atherosclerosis resulting in strokes, peripheral vascular disease, and myocardial infarctions and microvascular complications such as nephropathy, neuropathy, and retinopathy.Diabetic retinopathy (DR) is the number one cause of blindness in people between 27 and 75 years of age. Prevalence of DR is around 25% and 90% at 5 and 20 years, respectively, from diagnosis; it is calculated that 191 million people will be diagnosed with this microvascular complication by the year 2030.
It consists of progressive retinal structure and function loss due to vessel damage such producing blood-retina barrier rupture and promoting new vessel formation in the presence of chronic hyperglycemia.The first clinical signs of DR are microaneurysms in the retina found in the mild version of the disease. In moderate diabetic retinopathy, exudates, hemorrhages, and minimum intraretinal microvascular abnormalities are present up to being prominent in severe stages among with more than 20 hemorrhages and venous rosaries in at least 2 quadrants. Neovascularization is the main clinical change in proliferative diabetic retinopathy (PDR).Through the last three decades, extensive scientific reports have shown ROS to play an important role in DM complications such as diabetic neuropathy, nephropathy, and retinopathy due to alterations on the biomechanisms involved in the instauration and progression of microvascular complications. These three microvascular complications share high glucose levels as a starting point; nonetheless, according to Barret et al., such condition is necessary, but may not be enough to initiate the damage present in the peripheral nervous system (neuropathy), kidneys (nephropathy), and retinas (retinopathy) of diabetic patients ,. In addition, the activation of various pathways involving proinflammatory factors and reactive oxygen species overproduction has been linked to vascular injury in the structures previously mentioned –. With this in mind, multiple molecules and nutraceuticals have been studied in recent years by their antioxidant effects due to their apparent benefits over diabetes and its complications –.As will be seen in this document, hyperglycemic states favor the activation of alternative pathways leading to reactive oxygen species (ROS) formation and augmented concentrations locally and in the rest of the body even at the point of surpassing the antioxidant capacity, a state known as oxidative stress affecting retinal integrity.
Pathophysiology of Diabetic RetinopathyThe retina is a high energy-demanding organ, which makes it susceptible to high levels of free radicals or ROS. Multiple factors are implicated in DR pathophysiology. Along with hyperglycemia that promotes changes in vascular and neuronal structures through ischemic or hyperosmotic damage, it also leads to oxidative stress (OS). Oxidative stress produces inflammation, mitochondrial dysfunction, and cell death, via pyroptosis, apoptosis or autophagia, and neurodegeneration that in conjunction leads to neural, vascular, and retinal tissue damage. In recent years, it has been found that such damages are present in a sequential order, in which neurodegeneration takes place before microvascular dysfunction, then clinical characteristics may be found, and finally symptoms appear.
However, one could believe that these steps occur in a timely manner and that each biomechanism happens only in one direction; study findings show that different biomechanisms are active at the same time and have an influence between them. As seen in Figure, the retina consists different types of cells that form identifiable layers, from the endothelial layer in the inner side of the eye through the retinal pigmented cell layer in the outer side close to the choroidal surface. At each layer, various biomechanisms such as inflammation, pyroptosis, and neurodegeneration could appear simultaneously and have an intricate relationship with high levels of reactive oxygen species and oxidative stress. Damage at each retinal layer. A series of events occur in early DR development. Neurodegeneration of horizontal, bipolar, amacrine, and ganglion cells. These damages may be determined by proNGF concentrations as NLRP3 and NLRP1 are related to eye degenerative diseases.
NFL: nerve fiber layer; GCL: ganglion cell layer; IPL: inner plexiform layer; INL: inner nuclear layer; OPL: outer plexiform layer; ONL: outer nuclear layer; PL: photoreceptor layer. Hyperglycemia in Diabetic RetinopathyThrough the glycolytic pathway, glucose suffers various biotransformations up to pyruvate that enters the Krebs cycle in the mitochondria to follow the respiratory chain in order to synthesize adenosine triphosphate (ATP). It is known that high concentrations of serum glucose can cause damage to cell structure and function. In the retina, pericytes are key cells in normal retinal function. As shown in Figure, these cells suffer from edema due to intracellular accumulation of sorbitol, which is formed by aldose reductase in the presence of high blood sugar through the polyol pathway, leading to a blood-retinal barrier (BRB) dysfunction ,. Edema causes vessels to swallow impeding adequate perfusion especially in the inner retina where blood supply is sparse compared to the outer retina. Ischemia upregulates the expression of vascular endothelial growth factor (VEGF), known to play a role in angiogenesis, increased permeability, and activation of proinflammatory proteins.
All of them are important mechanisms involved in the development of diabetic retinopathy ,. On the other hand, the presence of glucose forms glyceraldehyde-3 phosphate (DHAP) through the glycolysis pathway; these two phosphates are very reactive to the nonenzymatic formation of methylglyoxal (MG). Such dicarbonyl (methylglyoxal) has been implicated in the activation of the hexosamine pathway, loss of pericytes, and decreased function of bipolar cells in the retina even in the absence of hyperglycemia. The hexosamine pathway transforms fructose 6-phosphate into UDP-N-acetyl glucosamine (UDP-GlcNAc).
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When this very last molecule exceeds its normal concentrations, it promotes protein modifications by O-glycosyl-N-acetylation (O-GlcNAc) inducing an exacerbated activity; one of those proteins is nuclear factor- κB (NF- κB), a factor known to be implicated in DR worsening –. Author (year)PopulationPolymorphismConclusionsAldose reductase (Alr)Abhary et.al. (2010) Australianrs9640883Association with duration of diabetes rather than a direct association to DRWang et al. (2003) ChineseRs759853 T alleleProtective effect against DR in DM type 1Santos et al. (2003) Euro-BrazilianALR C(-106)TNo association to DRNitric oxide synthase (NOS)Zhao et al. (2012) ChineseNOS3 4b/aNegative association with DR (protective effect)Cheema et al. (2012) Asian Indianrs3138808No association with DRSantos et al.
(2012) Caucasian-BrazilianNOS3b/aNo association to DRReceptor for advanced glycation end products (RAGEs)Ng et al. (2012) Malaysian-429T/C and -374T/ANo association with DRVanita (2014) IndianGly82SerPositive association with DRYang et al.
(2013) ChineseGly82SerAssociated to DR riskVascular endothelial growth factor (VEGF)Kangas-Kontio et al. (2009) Multiethnicrs3095039No associationAbhary et al. (2009) Multiethnicrs3025021Positive associationQiu et al.
(2013) Chinesers2010963Positive associationGluthatione S-transferase (GST)Dadbinpour et al. (2013) IranianGSTM1Positive association with DRManganese superoxide dismutase (MnSOD)Haghighi et al. (2015) IranianA16VPositive association with DRVanita (2014) IndianVal16AlaNo association with DRIntercellular adhesion molecule1 (ICAM-1)Fan et al. (2015) Asianrs5498Negative association with DRRs13306430Positive association with DRTransforming growth factor beta 1 (TGF- β1)Rodrigues et al. (2015) BrazilianRs1800471Positive association with DRBazzaz et al. (2014) Caucasian+869 C/T+915 G/CNo association with DR.