Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy

EMBO Molecular Medicine, Journal Year: 2024, Volume and Issue: 16(2), P. 294 - 318

Published: Jan. 31, 2024

Abstract Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) an N 6 -methyladenosine (m A) demethylase that demethylates RNAs involved energy homeostasis, though its influence on DR not well studied. Herein, we detected elevated FTO expression vitreous fibrovascular membranes patients with proliferative DR. promoted cell cycle progression tip formation endothelial cells (ECs) to facilitate angiogenesis vitro, mice, zebrafish. also regulated EC-pericyte crosstalk trigger diabetic microvascular leakage, mediated EC–microglia interactions induce retinal inflammation neurodegeneration vivo vitro. Mechanistically, affected EC features via modulating CDK2 mRNA stability m A-YTHDF2-dependent manner. up-regulation under conditions was driven by lactate-mediated histone lactylation. FB23-2, inhibitor FTO’s A activity, suppressed angiogenic phenotypes To allow for systemic administration, developed nanoplatform encapsulating FB23-2 confirmed targeting therapeutic efficiency mice. Collectively, our study demonstrates important function homeostasis DR, warrants further investigation as target patients.

Language: Английский

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Pericyte Loss in Diseases

Cells, Journal Year: 2023, Volume and Issue: 12(15), P. 1931 - 1931

Published: July 26, 2023

Pericytes are specialized cells located in close proximity to endothelial within the microvasculature. They play a crucial role regulating blood flow, stabilizing vessel walls, and maintaining integrity of blood–brain barrier. The loss pericytes has been associated with development progression various diseases, such as diabetes, Alzheimer’s disease, sepsis, stroke, traumatic brain injury. This review examines detection pericyte different explores methods employed assess coverage, elucidates potential mechanisms contributing these pathological conditions. Additionally, current therapeutic strategies targeting discussed, along future interventions aimed at preserving function promoting disease mitigation.

Language: Английский

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Enhancing Retinal Resilience: The Neuroprotective Promise of BDNF in Diabetic Retinopathy

Life, Journal Year: 2025, Volume and Issue: 15(2), P. 263 - 263

Published: Feb. 9, 2025

Diabetic retinopathy (DR), a leading cause of vision impairment worldwide, is characterized by progressive damage to the retina due prolonged hyperglycemia. Despite advances in treatment, current interventions largely target late-stage vascular complications, leaving underlying neurodegenerative processes insufficiently addressed. This article explores crucial role neuronal survival, axonal growth, and synaptic plasticity neuroprotective potential Brain-Derived Neurotrophic Factor (BDNF) as therapeutic strategy for enhancing retinal resilience DR. Furthermore, it discusses innovative delivery methods BDNF, such gene therapy nanocarriers, which may overcome challenges achieving sustained targeted levels retina, focusing on early intervention preserve function prevent loss.

Language: Английский

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Pharmacological roles of lncRNAs in diabetic retinopathy with a focus on oxidative stress and inflammation

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 214, P. 115643 - 115643

Published: June 13, 2023

Language: Английский

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Aging Effects on Optic Nerve Neurodegeneration

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2573 - 2573

Published: Jan. 29, 2023

Common risk factors for many ocular pathologies involve non-pathologic, age-related damage to the optic nerve. Understanding mechanisms of changes can facilitate targeted treatments that arise at any point in life. In this review, we examine these age-related, neurodegenerative nerve, contextualize from anatomic molecular level, and appreciate their relationship with pathophysiology. From simple structural mechanical nerve head (ONH), epigenetic biochemical alterations tissue environment, multiple age-dependent drive extracellular matrix (ECM) remodeling, retinal ganglion cell (RGC) loss, lowered regenerative ability respective axons. conjunction, aging decreases myelin preserve maximal conductivity, even “successfully” regenerated Glial cells, however, regeneratively overcompensate result a microenvironment promotes RGC axonal death. Better elucidating neurodegeneration remains interest, specifically investigating human ECM, RGCs, axons, oligodendrocytes, astrocytes; clarifying exact processes aged connective ultrastructural impacts; developing novel technologies pharmacotherapies target known genetic, biochemical, matrisome, neuroinflammatory markers. Management models should account when addressing glaucoma, diabetic retinopathy, other blinding diseases.

Language: Английский

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Relationship between Biochemical Pathways and Non-Coding RNAs Involved in the Progression of Diabetic Retinopathy

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(1), P. 292 - 292

Published: Jan. 4, 2024

Diabetic retinopathy (DR) is a progressive blinding disease, which affects the vision and quality of life patients, it severely impacts society. This complication, caused by abnormal glucose metabolism, leads to structural, functional, molecular, biochemical abnormalities in retina. Oxidative stress inflammation also play pivotal roles pathogenic process DR, leading mitochondrial damage decrease function. DR causes retinal degeneration glial neural cells, while disappearance pericytes blood vessels alterations vascular regulation stability. Clinical changes include dilatation flow response perfusion vessels, leakage, neovascularization, neurodegeneration. The loss cells retina results capillary occlusion ischemia. Thus, highly complex disease with various biological factors, contribute its pathogenesis. interplay between pathways non-coding RNAs (ncRNAs) essential for understanding development progression DR. Abnormal expression ncRNAs has been confirmed promote suggesting that such as miRNAs, lncRNAs, circRNAs have potential diagnostic biomarkers theranostic targets review provides an overview interactions dysregulated under influence hyperglycemic environment

Language: Английский

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The ideal treatment timing for diabetic retinopathy: the molecular pathological mechanisms underlying early-stage diabetic retinopathy are a matter of concern

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 9, 2023

Diabetic retinopathy (DR) is a prevalent complication of diabetes, significantly impacting patients’ quality life due to vision loss. No pharmacological therapies are currently approved for DR, excepted the drugs treat diabetic macular edema such as anti-VEGF agents or steroids administered by intraocular route. Advancements in research have highlighted crucial role early intervention DR halting delaying disease progression. This holds immense significance enhancing and alleviating societal burden associated with medical care costs. The non-proliferative stage represents phase DR. In comparison proliferative stage, pathological changes primarily manifest microangiomas hemorrhages, while at cellular level, there loss pericytes, neuronal cell death, disruption components functionality within retinal vascular unit encompassing pericytes neurons. Both neurodegenerative microvascular abnormalities stages Therefore, our focus lies on we initially summarized mechanisms involved its development, including pathways polyols, that revolve around occurring during this stage. We also integrate cutting-edge mechanisms, leukocyte adhesion, neutrophil extracellular traps, multiple RNA regulation, microorganisms, death (ferroptosis pyroptosis), other related mechanisms. current status drug therapy early-stage discussed provide insights development pharmaceutical interventions targeting treatment

Language: Английский

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Parallelism and non-parallelism in diabetic nephropathy and diabetic retinopathy

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 14, 2024

Diabetic nephropathy (DN) and diabetic retinopathy (DR), as microvascular complications of diabetes mellitus, are currently the leading causes end-stage renal disease (ESRD) blindness, respectively, in adult working population, they major public health problems with social economic burdens. The parallelism between two process occurrence development manifests high overlap disease-causing risk factors pathogenesis, rates comorbidity, mutually predictive effects, partial concordance clinical use medications. However, since organs, eye kidney, have their unique internal environment physiological processes, each specific influencing molecules, target organs non-parallelism due to different pathological changes responses various factors, this article provides an overview DN DR further recognize commonalities differences diseases provide references for early diagnosis, guidance on medication, new drugs.

Language: Английский

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Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats

Annals of Translational Medicine, Journal Year: 2023, Volume and Issue: 11(5), P. 197 - 197

Published: March 1, 2023

To determine the anti-inflammatory effects of IMD-0354, a specific NF-κB blocker, on glial cells in rats with streptozotocin (STZ)-induced diabetic retinopathy (DR).The following four groups were used: control, control + STZ, and STZ IMD-0354. After six weeks injection, nondiabetic received IMD-0354 (30 mg/kg) or an equal volume 4% dimethyl sulfoxide (DMSO) phosphate-buffered saline intraperitoneally for consecutive weeks. The primary rat retinal microglia Müller (5 mM), high glucose (20 nuclear factor-κB (NF-κB) activation, oxidative stress strength, expression inflammatory cytokines VEGF (vascular endothelial growth factor), activation cells, apoptosis neuron evaluated by immunohistochemistry, assays, western blot, enzyme linked immunosorbent assay (ELISA) terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining respectively.Nuclear translocation was markedly increased retina treated cells. Systemic administration significantly inhibited both ameliorated injury, responses, production cell protected neurons from apoptosis.Our findings indicated that is acritical step abnormal reactivity STZ-induced rats. Inhibition effect may represent promising therapeutic strategy DR via variety mechanisms, including inflammation reduction regulation.

Language: Английский

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Pharmacological depletion of microglia alleviates neuronal and vascular damage in the diabetic CX3CR1-WT retina but not in CX3CR1-KO or hCX3CR1I249/M280-expressing retina

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: March 22, 2023

Diabetic retinopathy, a microvascular disease characterized by irreparable vascular damage, neurodegeneration and neuroinflammation, is leading complication of diabetes mellitus. There no cure for DR, medical interventions marginally slow the progression disease. Microglia-mediated inflammation in diabetic retina regulated via CX3CR1-FKN signaling, where FKN serves as calming signal microglial activation several neuroinflammatory models. Polymorphic variants CX3CR1 , hCX3CR1 I249/M280 found 25% human population, result receptor with lower binding affinity FKN. Furthermore, disrupted signaling -KO mice leads to exacerbated activation, robust neuronal cell loss substantial damage retina. Thus, studies characterize effects -expression microglia-mediated diseased are relevant identify mechanisms which microglia contribute progression. Our results show that significantly more susceptible microgliosis production Cxcl10 TNFα under acute inflammatory conditions. Inflammation conditions coincides comparison -WT mice. Therefore, further investigate role responses, we pharmacologically depleted using PLX-5622, CSF-1R antagonist. PLX-5622 treatment led (~70%) reduction Iba1 + all non-diabetic antagonism prevented TUJ1 axonal loss, angiogenesis fibrinogen deposition. In contrast, depletion did not alleviate or angiogenesis. Interestingly, reduced deposition but mice, suggesting expressing influences pathology differently compared microglia. Currently most commonly used strain on this study indicate may serve complementary model dysregulated signaling. summary, protective -dependent retinal degeneration nor morphological observed

Language: Английский

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