Genetics of diabetes-associated microvascular complications

Diabetologia, Journal Year: 2023, Volume and Issue: 66(9), P. 1601 - 1613

Published: July 14, 2023

Abstract Diabetes is associated with excess morbidity and mortality due to both micro- macrovascular complications, as well a range of non-classical comorbidities. Diabetes-associated microvascular complications are those considered most closely related hyperglycaemia in causal manner. However, some individuals (even severe hyperglycaemia) do not develop diseases, which, together evidence co-occurrence diseases families, suggests role for genetics. While genome-wide association studies (GWASs) produced firm multiple genetic variants underlying differential susceptibility type 1 2 diabetes, determinants mostly suggestive. Identified diabetic kidney disease (DKD) diabetes mirror chronic (CKD) without diabetes. As retinopathy neuropathy, reported risk currently lack large-scale replication. The associations between may be explained by hyperglycaemia. More extensive phenotyping, along adjustments unmeasured confounding, including early (fetal) late-life (hyperglycaemia, hypertension, etc.) environmental factors, urgently needed understand the genetics complications. Finally, reduced glycolysis, mitochondrial dysfunction DNA damage sustained cell regeneration protect against illustrating utility who have escaped these Graphical

Language: Английский

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Topically Administered NOX4 Inhibitor, GLX7013114, Is Efficacious in Treating the Early Pathological Events of Diabetic Retinopathy

Diabetes, Journal Year: 2023, Volume and Issue: 72(5), P. 638 - 652

Published: Feb. 23, 2023

NADPH oxidases (NOXs) are major players in generating reactive oxygen species (ROS) and implicated various neurodegenerative ocular pathologies. The aim of this study was to investigate the role a NOX4 inhibitor (GLX7013114) two vivo, experimental streptozotocin (STZ) paradigms depicting early events diabetic retinopathy (DR). Animals treated group received GLX7013114 topically (20 μL/eye, 10 mg/mL, once daily) for 14 days (paradigm A: preventive) 7 B: treated) at 48 h 4 weeks after STZ injection, respectively. Several methodologies were used (immunohistochemistry, Western blot, real-time PCR, ELISA, pattern electroretinography [PERG]) assess diabetes-induced DR, namely oxidative stress, neurodegeneration, neuroinflammation, effect on insults. GLX7013114, administered as eye drops (paradigms A B), beneficial treating nitrative activation caspase-3 micro- macroglia, attenuation neuronal markers. It also attenuated increase vascular endothelial growth factor, Evans blue dye leakage, proinflammatory cytokine (TNF-α protein, IL-1β/IL-6 mRNA) levels. PERG amplitude values suggested that protected retinal ganglion cell function B). This provides new findings regarding pharmacological profile novel promising therapeutic candidate treatment stage DR. Article Highlights pathological administered, reduced damage apoptosis rat model neurons expression pro-inflammatory cytokines retina. diminished factor levels leakage tissue. exhibits neuroprotective, anti-inflammatory, vasculoprotective properties suggest it may have putative

Language: Английский

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Assessing and projecting the global burden of thyroid cancer, 1990–2030: Analysis of the Global Burden of Disease Study

Journal of Global Health, Journal Year: 2024, Volume and Issue: 14

Published: April 5, 2024

Abstract Background This study aims to assess the global incidence, mortality, and disability-adjusted life years (DALYs) of thyroid cancer between 1990 2030. Methods Our analysed Global Burden Disease (GBD) 2019 data from 204 countries, spanning 1990–2019. It focused on age-standardised (DALYs), using sociodemographic index (SDI) for assessing socioeconomic levels. Generalised additive models (GAMs) projected trends 2020–2030. Results The burden is predicted increase significantly number incidence cases rise 233 846.64 in 305 078.08 by 2030, representing an approximate 30.46% increase. ASIR (age-standardised rate) expected continue its upward trend (estimated annual percentage change (EAPC) = 0.83). death rate (ASDR) decline both genders, more notably women (EAPC −0.34) compared men −0.17). disease escalates with advancing age, significant regional disparities. Regions lower SDI, particularly South Asia, are anticipated witness substantial increases 2020 overall rise, especially countries low middle reflecting broader socio-economic health care shifts. Conclusions highlights gender-specific variations cancer, notable rates, areas like Asia. These suggest improvements diagnostic capabilities influence factors. Additionally, observed mortality rates across various regions reflects advancements management. findings underline critical importance regionally tailored prevention strategies, robust registries, public initiatives address evolving landscape mitigate disparities globally.

Language: Английский

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What else can we do to prevent diabetic retinopathy?

Diabetologia, Journal Year: 2023, Volume and Issue: 66(9), P. 1614 - 1621

Published: June 6, 2023

Abstract The classical modifiable factors associated with the onset and progression of diabetic retinopathy are suboptimal control blood glucose levels hypertension, as well dyslipidaemia. However, there other less recognised that can play a relevant role, such presence obesity or abnormal distribution adipose tissue, others related to lifestyle type diet, vitamin intake, exercise, smoking sunlight exposure. In this article we revisit prevention based on modulating risk factors, commenting potential impact glucose-lowering drugs condition. emerging concept neurodegeneration is an early event in development points neuroprotection therapeutic strategy prevent advanced stages disease. regard, better phenotyping very opportunity arresting its using treatments targeting neurovascular unit (NVU) discussed.

Language: Английский

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New Insights on Dietary Polyphenols for the Management of Oxidative Stress and Neuroinflammation in Diabetic Retinopathy

Antioxidants, Journal Year: 2023, Volume and Issue: 12(6), P. 1237 - 1237

Published: June 8, 2023

Diabetic retinopathy (DR) is a neurodegenerative and vascular pathology that considered one of the leading causes blindness worldwide, resulting from complications advanced diabetes mellitus (DM). Current therapies consist protocols aiming to alleviate existing clinical signs associated with microvascular alterations limited disease stages. In response low resolution limitations DR treatment, there an urgent need develop more effective alternative optimize glycemic, vascular, neuronal parameters, including reduction in cellular damage promoted by inflammation oxidative stress. Recent evidence has shown dietary polyphenols reduce inflammatory parameters various diseases modulating multiple cell signaling pathways gene expression, contributing improvement several chronic diseases, metabolic diseases. However, despite growing for bioactivities phenolic compounds, still lack data, especially human studies, on therapeutic potential these substances. This review aims comprehensively describe clarify effects compounds pathophysiological mechanisms involved DR, those nature, through experimental studies. Finally, highlights as prophylactic strategy further studies approaching efficacy substances management.

Language: Английский

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Electroretinographic responses to periodic stimuli in primates and the relevance for visual perception and for clinical studies

Visual Neuroscience, Journal Year: 2024, Volume and Issue: 41

Published: Jan. 1, 2024

Abstract Currently, electroretinograms (ERGs) are mainly recorded while using flashes as stimuli. In this review, we will argue that strong not ideal for studying visual information processing. ERG responses to periodic stimuli may be more strongly associated with the activity of post-receptoral neurons (belonging different retino-geniculate pathways) and, therefore, relevant perception. We also use an attractive addition clinically available retinal electrophysiological methods.

Language: Английский

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Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8796 - 8796

Published: May 15, 2023

The etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements retinal neurovascular unit (NVU). This complication has a chronic low-grade inflammatory component involving multiple mediators adhesion molecules. milieu promotes reactive gliosis, pro-inflammatory cytokine production leukocyte recruitment, which contribute to disruption blood barrier. understanding continuous research mechanisms behind strong disease allows design new therapeutic strategies address this unmet medical need. In context, aim review article recapitulate latest on role inflammation in DR discuss efficacy currently administered anti-inflammatory treatments those still under development.

Language: Английский

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RG7774 (Vicasinabin), an orally bioavailable cannabinoid receptor 2 (CB2R) agonist, decreases retinal vascular permeability, leukocyte adhesion, and ocular inflammation in animal models

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

Published: July 12, 2024

Introduction Preclinical studies suggest that cannabinoid receptor type 2 (CB2R) activation has a therapeutic effect in animal models on chronic inflammation and vascular permeability, which are key pathological features of diabetic retinopathy (DR). A novel CB2R agonist, triazolopyrimidine RG7774, was generated through lead optimization high-throughput screening hit. The aim this study to characterize the pharmacology, absorption, distribution, metabolism, elimination, toxicity (ADMET) profile explore its potential for managing associated with retinal disease rodents. Methods vitro pharmacology RG7774 investigated binding using recombinant human mouse expression Chinese hamster ovary cells, endogenous Jurkat rat spleen cells. ADMET evaluated effects leukocyte adhesion, choroidal neovascularization (CNV) were rodent disease. Pharmacokinetic (PK) parameters exposure-response relationship characterized healthy animals laser-induced CNV. Results found be potent (EC 50 : 2.8 nM K i 51.3 nM), selective, full agonist no signs 1 (CB1R) or activation. ligand showed favorable exhibited systemic ocular exposure after oral delivery. Functional potency translated from systems. In vivo , orally administered reduced permeability adhesion rodents lipopolysaccharide (LPS)-induced uveitis streptozotocin (STZ)-induced DR, lesion areas rats CNV an ED 0.32 mg/kg. Anatomically, migration microglia lesions. Discussion is novel, highly bioavailable acceptable PK profile, beneficial models. support development as treatment diseases similar pathophysiologies addressed by

Language: Английский

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Endothelial-pericyte interactions regulate angiogenesis via VEGFR2 signaling during retinal development and disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Abstract Pericytes stabilize the microvasculature by enhancing endothelial barrier integrity, resulting in functional networks. During retinal development, pericyte recruitment is crucial for stabilizing nascent angiogenic vasculature. However, adulthood, disrupted endothelial-pericyte interactions lead to vascular dropout and pathological angiogenesis ocular microvascular diseases, strategies vasculature are lacking. We demonstrate that direct contact downregulates pVEGFR2 cells, which enhances migration promotes cell function. Intravitreal injection of a VEGFR2 inhibitor mouse models developing retina oxygen-induced retinopathy increased aided stability. The further rescued ischemic vascularization tissue growth while reducing permeability. Our findings offer druggable target support mature diseases regeneration overall.

Language: Английский

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Changes in Circulating Acylated Ghrelin and Neutrophil Elastase in Diabetic Retinopathy

Medicina, Journal Year: 2024, Volume and Issue: 60(1), P. 118 - 118

Published: Jan. 8, 2024

: The role and the levels of ghrelin in diabetes-induced retinal damage have not yet been explored. present study aimed to measure serum total (TG), its acylated (AG) des-acylated (DAG) forms patients with two stages diabetic retinopathy (DR), non-proliferative (NPDR) proliferative (PDR). Moreover, correlation between neutrophil elastase (NE) was investigated.

Language: Английский

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