Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Physiological Reviews, Journal Year: 2019, Volume and Issue: 100(1), P. 407 - 461

Published: Sept. 20, 2019

The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis type 2 diabetes, vascular complications several other age-related chronic inflammatory diseases such as cardiovascular disease, cancer, disorders central nervous system. MGO is mainly formed byproduct glycolysis and, under physiological circumstances, detoxified by glyoxalase major precursor nonenzymatic glycation proteins DNA, subsequently leading to advanced end products (AGEs). MGO-derived AGEs can impact on organs tissues affecting their functions structure. In this review we summarize MGO, detoxification system, biochemical pathways through which linked development diseases. Although interventions treat MGO-associated are not yet available clinical setting, strategies lower have developed over years. We will new directions target stress including inducers scavengers. Targeting burden may provide therapeutic applications mitigate plays crucial role.

Language: Английский

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VEGFR1 signaling in retinal angiogenesis and microinflammation

Progress in Retinal and Eye Research, Journal Year: 2021, Volume and Issue: 84, P. 100954 - 100954

Published: Feb. 26, 2021

Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, –C, -D, and placental [PlGF]) constitute the VEGF family. VEGF-A binds receptors 1 2 (VEGFR1/2), whereas VEGF-B PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown importance involvement of VEGFR1 family angiogenesis, permeability, microinflammatory cascades within retina. Expression depends microenvironment, is differentially regulated under hypoxic inflammatory conditions, it detected choroidal cells, pericytes, mononuclear phagocytes (including microglia), Müller photoreceptor pigment epithelium. Whilst decoy function well established, consequences direct signaling are less clear. activation can affect permeability induce macrophage microglia production proinflammatory proangiogenic mediators. However ability PlGF, VEGF-B) compete against each other for binding heterodimerize complicates our understanding relative contribution alone toward pathologic processes seen diabetic retinopathy, occlusions, retinopathy prematurity, age-related macular degeneration. Clinically, anti-VEGF drugs proven transformational these pathologies their impact modulation still an opportunity-rich field further research.

Language: Английский

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Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss

Circulation Research, Journal Year: 2020, Volume and Issue: 128(4)

Published: Dec. 30, 2020

Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described several brain disorders, genetically induced pericyte deficiency the leads to increased macromolecular leakage across blood-brain barrier (BBB). However, molecular details endothelial response remain elusive. Objective: To map transcriptional changes resulting from lack contact at single-cell level correlate them with regional heterogeneities BBB function vascular phenotype. Methods Results: We reveal transcriptional, morphological, functional consequences absence for using combination methodologies, including RNA sequencing, tracer analyses, immunofluorescent detection protein expression pericyte-deficient adult Pdgfb ret/ret mice. find that without retain general BBB-specific gene profile, however, they acquire venous-shifted pattern become transformed regarding numerous growth factors regulatory proteins. Adult brains display ongoing angiogenic sprouting concomitant cell proliferation providing unique insights into tip transcriptome. also heterogeneous modes impairment, where hotspot sites arteriolar-shifted identity pinpoint putative regulators. By testing causal involvement some these reverse genetics, we uncover reinforcing angiopoietin 2 BBB. Conclusions: elucidating complexity cellular resolution, our study provides insight importance arterio-venous zonation, quiescence, limited set functions. The BBB-reinforcing ANGPT2 (angiopoietin 2) is paradoxical given its wider as TIE2 (TEK receptor tyrosine kinase) antagonist may suggest context-dependent brain.

Language: Английский

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Mitochondrial Defects Drive Degenerative Retinal Diseases

Trends in Molecular Medicine, Journal Year: 2019, Volume and Issue: 26(1), P. 105 - 118

Published: Nov. 23, 2019

Language: Английский

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Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

Frontiers in Endocrinology, Journal Year: 2019, Volume and Issue: 10

Published: Dec. 13, 2019

Diabetes mellitus is a world-wide epidemic and diabetic retinopathy, devastating, vision-threatening condition, one of the most common diabetes-specific complications. Diabetic retinopathy now recognized to be an inflammatory, neuro-vascular complication with neuronal injury/dysfunction preceding clinical microvascular damage. Importantly, same pathophysiologic mechanisms that damage pancreatic -cell (e.g. inflammation, epigenetic changes, insulin resistance, fuel excess abnormal metabolic environment), also lead cell tissue causing organ dysfunction, elevating risk all complications, including retinopathy. Viewing within context whereby diabetes its complications arise from factors allows for consideration wider array potential ocular as well systemic treatments this devastating complication. Moreover, it raises importance need methods will provide more timely detection prediction course in order address early neurovascular unit prior observation microangiopathy. Currently, treatment success limited often initiated far too late after significant neurodegeneration has occurred. This forward-thinking approach earlier possible therapies broadens physician's armamentarium increases opportunity prevention preservation good vision, similar destructive processes occurring among other organs.

Language: Английский

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Nutraceuticals for the Treatment of Diabetic Retinopathy

Nutrients, Journal Year: 2019, Volume and Issue: 11(4), P. 771 - 771

Published: April 2, 2019

Diabetic retinopathy (DR) is one of the most common complications diabetes mellitus and characterized by degeneration retinal neurons neoangiogenesis, causing a severe threat to vision. Nowadays, principal treatment options for DR are laser photocoagulation, vitreoretinal surgery, or intravitreal injection drugs targeting vascular endothelial growth factor. However, these treatments only act at advanced stages DR, have short term efficacy, cause side effects. Treatment with nutraceuticals (foods providing medical health benefits) early may represent reasonable alternative upstream disease, preventing its progression. In particular, in vitro vivo studies revealed that variety significant antioxidant anti-inflammatory properties inhibit diabetes-driven molecular mechanisms induce reducing both neural damage typical DR. Although limited animal models there problem low bioavailability many nutraceuticals, use compounds natural method standard treatments.

Language: Английский

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Retinal Vascular Endothelial Cell Dysfunction and Neuroretinal Degeneration in Diabetic Patients

Journal of Clinical Medicine, Journal Year: 2021, Volume and Issue: 10(3), P. 458 - 458

Published: Jan. 25, 2021

Diabetes mellitus (DM) has become a vital societal problem as epidemiological studies demonstrate the increasing incidence of type 1 and 2 diabetes. Lesions observed in retina course diabetes, referred to diabetic retinopathy (DR), are caused by vascular abnormalities ischemic nature. Vascular lesions diabetes pertain small vessels (microangiopathy) involve precapillary arterioles, capillaries veins. Pericyte loss, thickening basement membrane, damage proliferation endothelial cells observed. Endothelial (monolayer squamous epithelium) form smooth internal lining indispensable for normal blood flow. Breaking its continuity initiates coagulation at that site. The endothelium controls process exchange chemical substances (nutritional, regulatory, waste products) between retina, cell passing through wall. produce biologically active involved coagulation, regulating wall tension stimulating neoangiogenesis. On other hand, recent have demonstrated may be not only microvascular disease, but is result neuroretinal degeneration. Neuroretinal degeneration appears structurally, neural apoptosis amacrine Muller cells, reactive gliosis, ganglion layer/inner plexiform (GCL) thickness, retinal nerve fiber layer reduction rim minimum width (MRW) functionally an abnormal electroretinogram (ERG), dark adaptation, contrast sensitivity, color vision, microperimetric test. findings early stages precede changes this disease. Furthermore, article’s objective characterize factors mechanisms conducive retinopathy. Only when all measures preventing dysfunction determined will risk complications minimized.

Language: Английский

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Pericytes, inflammation, and diabetic retinopathy

Inflammopharmacology, Journal Year: 2019, Volume and Issue: 28(3), P. 697 - 709

Published: Oct. 14, 2019

Language: Английский

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The role of CD44 in pathological angiogenesis

The FASEB Journal, Journal Year: 2020, Volume and Issue: 34(10), P. 13125 - 13139

Published: Aug. 23, 2020

Angiogenesis is required for normal development and occurs as a pathological step in variety of disease settings, such cancer, ocular diseases, ischemia. Recent studies have revealed the role CD44, widely expressed cell surface adhesion molecule, promoting angiogenesis its associated diseases through regulation diverse function endothelial cells, proliferation, migration, adhesion, invasion, communication with microenvironment. Conversely, absence CD44 expression or inhibition impairs progression. Here, we summarize current understanding roles underlying cellular molecular mechanisms.

Language: Английский

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Inflammatory resolution and vascular barrier restoration after retinal ischemia reperfusion injury

Journal of Neuroinflammation, Journal Year: 2021, Volume and Issue: 18(1)

Published: Aug. 26, 2021

Several retinal pathologies exhibit both inflammation and breakdown of the inner blood-retinal barrier (iBRB) resulting in vascular permeability, suggesting that treatments trigger resolution may also promote iBRB restoration.Using mouse ischemia-reperfusion (IR) injury model, we followed time course neurodegeneration, inflammation, disruption repair to examine relationship between restoration determine if minocycline, a tetracycline derivative shown reverse microglial activation, can hasten these processes.A 90-min ischemic insult by reperfusion retina induced cell apoptosis thinning progressed for approximately 2 weeks. IR increased permeability within hours, which resolved 3 4 weeks after injury. Increased coincided with alteration loss endothelial tight junction (TJ) protein content disorganization TJ complexes. Shunting blood flow away from leaky vessels dropout capillaries were eliminated as possible mechanisms restoring iBRB. Repletion contents occurred days injury, long before In contrast, eventual re-organization complexes at border barrier. A robust inflammatory response was evident 1 day over 4-week course. The included rapid transient infiltration granulocytes Ly6C+ classical monocytes, slow accumulation Ly6Cneg monocyte/macrophages, proliferation, mobilization resident microglia. Extravasation majority CD45+ leukocytes superficial plexus. presence monocyte/macrophages numbers microglia sustained until eventually restored. Intervention minocycline activation week promoted early coinciding decreased expression mRNAs M1 markers TNF-α, IL-1β, Ptgs2 (Cox-2) secreted serine protease inhibitor Serpina3n mRNA.These results suggest occurs are reorganized following functionally linked.

Language: Английский

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