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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The role of endothelial cell–pericyte interactions in vascularization and diseases

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Endothelial cells (ECs) and pericytes (PCs) are crucial components of the vascular system, with ECs lining inner layer blood vessels PCs surrounding capillaries to regulate flow angiogenesis. Intercellular communication between is vital for formation, stability, function vessels. Various signaling pathways, such as endothelial growth factor/vascular factor receptor pathway platelet-derived factor-B/platelet-derived receptor-β pathway, play roles in PCs. Dysfunctional these associated various diseases, including central nervous system disorders, certain types cancers. review: This review aimed explore diverse formation reshaping focused on essential pathways that facilitate investigated how disruptions may contribute disease. Additionally, explored potential therapeutic targets, future research directions, innovative approaches, investigating impact EC-PCs novel systemic addressing resistance antiangiogenic drugs, developing medications enhance efficacy. Key scientific concepts Disordered EC-PC intercellular plays a role abnormal vessel thus contributing progression diseases development drugs. Therefore, studies interactions have high clinical relevance.

Language: Английский

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Research progress of non-coding RNA regulating the role of PANoptosis in diabetes mellitus and its complications

APOPTOSIS, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Language: Английский

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Common mechanisms underlying diabetic vascular complications: focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: Oct. 30, 2023

Abstract Diabetic vascular complications (DVCs), including macro- and micro- angiopathy, account for a high percentage of mortality in patients with diabetes mellitus (DM). Endothelial dysfunction is the initial role step pathogenesis DVCs. Hyperglycemia lipid metabolism disorders contribute to endothelial via direct injury products, crosstalk between immunity inflammation, as well related interaction network. Although physiological phenotypic differences support their specified changes different targeted organs, there are still several common mechanisms underlying Also, inhibitors these may decrease incidence DVCs effectively. Thus, this review provide new insights into possible measures secondary prevention DM. And we discussed current limitations those present preventive research.

Language: Английский

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The protective roles of citrus flavonoids, naringenin, and naringin on endothelial cell dysfunction in diseases

Heliyon, Journal Year: 2023, Volume and Issue: 9(6), P. e17166 - e17166

Published: June 1, 2023

The endothelial cells (ECs) make up the inner lining of blood vessels, acting as a barrier separating and tissues in several organs. ECs maintain endothelium integrity by controlling constriction relaxation vasculature, fluidity, adhesion, migration. These actions are efficiently coordinated via an intricate signaling network connecting receptors, wide range cellular macromolecules. naturally quiescent i.e.; they not stimulated do proliferate. Upon infection or disease, become activated, this alteration is pivotal pathogenesis spectrum human neurological, cardiovascular, diabetic, cancerous, viral diseases. Considering central position that play disease pathogenesis, therapeutic options have been targeted at improving integrity, assembly, functioning, health. dietary intake flavonoids present citrus fruits has associated with reduced risk dysfunction. Naringenin (NGN) Naringin (NAR), major grapefruit, tomatoes, oranges possess anti-inflammatory, antioxidant properties, cell survival potentials, which improve health vascular endothelium. In review, we provide comprehensive summary advances understanding mechanisms through NGN NAR modulate biomarkers dysfunction protect against unresolved inflammation, oxidative stress, atherosclerosis, angiogenesis. We also perspectives suggest further studies will help assess efficacy therapeutics

Language: Английский

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Klotho’s impact on diabetic nephropathy and its emerging connection to diabetic retinopathy

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

Published: April 18, 2023

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide and a significant burden on healthcare systems. α-klotho (klotho) protein known for its anti-aging properties has been shown to delay onset age-related diseases. Soluble klotho produced by cleavage full-length transmembrane disintegrin metalloproteases, it exerts various physiological effects circulating throughout body. In type 2 diabetes complications DN, decrease in expression observed. This reduction levels may indicate progression DN suggest that be involved multiple pathological mechanisms contribute development DN. article examines potential soluble as therapeutic agent with focus ability impact pathways. These pathways include anti-inflammatory oxidative stress, anti-fibrotic, endothelial protection, prevention vascular calcification, regulation metabolism, maintenance calcium phosphate homeostasis, cell fate through modulation autophagy, apoptosis, pyroptosis retinopathy shares similar targeting offer new insights into treatment both conditions. Finally, this review assesses drugs used clinical practice modulate different their improve impacting levels.

Language: Английский

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Corpora cavernosa fibroblasts mediate penile erection

Science, Journal Year: 2024, Volume and Issue: 383(6683)

Published: Feb. 8, 2024

Penile erection is mediated by the corpora cavernosa, a trabecular-like vascular bed that enlarges upon vasodilation, but its regulation not completely understood. Here, we show perivascular fibroblasts in cavernosa support vasodilation reducing norepinephrine availability. The effect on penile blood flow depends number of fibroblasts, which regulated erectile activity. Erection dynamically alters positional arrangement temporarily down-regulating Notch signaling. Inhibition increases fibroblast numbers and consequently raises flow. Continuous activation lowers reduces perfusion. Recurrent erections stimulate proliferation limit vasoconstriction, whereas aging Our findings reveal adaptive, activity-dependent modulation fibroblasts.

Language: Английский

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Mediation of endothelial activation and stress index in the association between vitamin B6 turnover rate and diabetic retinopathy: an analysis of the National Health and Nutrition Examination Survey

Frontiers in Nutrition, Journal Year: 2025, Volume and Issue: 11

Published: Jan. 14, 2025

Aim This study aimed to explore the association between ratio of 4-pyridoxine (4-PA) pyridoxal 5′-phosphate (PLP) (4-PA/PLP) and diabetic retinopathy (DR) further assess mediating effect Endothelial Activation Stress Index (EASIX) on 4-PA/PLP DR. Methods In this cross-sectional study, 1,698 patients with diabetes from National Health Nutrition Examination Survey were included. According median, was categorized into a high-level group (≥0.89) low-level (<0.89). As EASIX had skewed distribution, it log-transformed before analysis. Weighted logistic regression models used investigate DR The distribution-of-product method adopted effect. Subgroup analysis performed based age duration diabetes. Results A total 362 classified as having After adjusting for all covariates, higher level associated an increased log [odds (OR) = 1.56, 95% confidence interval (CI): 1.06–2.30]. odds compared reference lower levels (OR 1.94, 95%CI: 1.40–2.67). addition, we found that may play role in DR, CI distribution product 0.31 (95% CI: 0.02–0.67). proportion mediation 69.06%. also observed individuals who aged≥60 years (proportion mediation: 50.63%) or ≥10 71.83%). Conclusion positive high risk relationship being partially mediated by EASIX.

Language: Английский

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Association between the hemoglobin A1c/High-density lipoprotein cholesterol ratio and stroke incidence: a prospective nationwide cohort study in China

Lipids in Health and Disease, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 25, 2025

Abstract Background Stroke has emerged as an escalating public health challenge among middle-aged and older individuals in China, closely linked to glycolipid metabolic abnormalities. The Hemoglobin A1c/High-Density Lipoprotein Cholesterol (HbA1c/HDL-C) ratio, integrated marker of homeostasis, may serve a novel predictor stroke risk. Methods Our investigation utilized data from the China Health Retirement Longitudinal Study cohort (2011–2018). cases were identified based on self-reported, physician-confirmed diagnoses. Logistic regression models established determine correlation between HbA1c/HDL-C prevalence (2011) well cumulative mean (2011–2015) new incidence (2015–2018). Additionally, smoothed curve fitting, subgroup analyses, interaction tests conducted ensure robustness findings. Results In cross-sectional analysis, 8,502 participants enrolled, whom 189 had history stroke. findings revealed significant positive linear relationship after adjusting for covariates (OR: 1.26, 95% CI: 1.09–1.45). When was categorized into tertiles, only highest tertile (T3) showed with compared lowest (T1) (OR:1.71, 1.05–2.77). longitudinal analysis 5,165 participants, 336 new-onset over follow-up period 7 years. Adjusting confounders, higher exhibited increased likelihood 1.14, 1.01–1.29). Using T1 reference, fully adjusted OR 1.65 (95% 1.21–2.24) T2 1.54 1.08–2.19) T3. predictive value risk assessment have been significantly improved traditional HDL-C HbA1c. Consistent associations observed across most stratified subgroups. Conclusions Elevated baseline levels are associated underscoring potential clinical long-term prevention strategies.

Language: Английский

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Endothelial Markers in Type 2 Diabetic Patients with Acute Decompensated Heart Failure: A Pilot Study

Metabolites, Journal Year: 2025, Volume and Issue: 15(2), P. 91 - 91

Published: Feb. 3, 2025

Background: Impaired endothelial function has been associated with vascular complications in type 2 diabetes (T2D), but its role T2D-related heart failure (HF) remains indeterminate. The aim of this study was to assess selected markers T2D patients acute decompensated HF. Methods: A pilot prospective on HF requiring in-hospital admission carried out. growth factor (VEGF), intercellular adhesion molecule 1 (ICAM-1), and cell (VCAM-1) were assessed at after decongestion. Subsequently, differences these between non-diabetic (ND) studied. Results: In total, 39 (21 18 ND patients) enrolled. Twenty-eight presented preserved ejection fraction (EF), 11 reduced EF. Looking the VEGF levels patients, admission, a median 233.0 pg/mL (1.7–598 pg/mL) found compared 106.0 (1.7–888 individuals; reached statistical significance (p = 0.04). There no significant decongestion, VCAM-1 (2237 ± 1195 vs. 2699 1093 ng/mL, p 0.37) ICAM-1 (596 268 638 437 0.79) upon value EF (preserved or reduced) affected admission. Conclusions: This identified significantly higher due patients.

Language: Английский

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