ROS-triggered endothelial cell death mechanisms: Focus on pyroptosis, parthanatos, and ferroptosis

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Nov. 1, 2022

The endothelium is a single layer of epithelium covering the surface vascular system, and it represents physical barrier between blood vessel wall that plays an important role in maintaining intravascular homeostasis. However, endothelial dysfunction or cell death can cause disruption, vasoconstriction diastolic dysfunction, smooth muscle proliferation migration, inflammatory responses, thrombosis, which are closely associated with progression several diseases, such as atherosclerosis, hypertension, coronary atherosclerotic heart disease, ischemic stroke, acute lung injury, kidney diabetic retinopathy, Alzheimer’s disease. Oxidative stress caused by overproduction reactive oxygen species (ROS) mechanism underlying death. Growing evidence suggests ROS trigger various ways, including pyroptosis, parthanatos, ferroptosis. Therefore, this review will systematically illustrate source cells (ECs); reveal molecular ferroptosis ECs; provide new ideas for research treatment dysfunction-related diseases.

Language: Английский

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The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in diabetic retinopathy

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

Published: April 25, 2023

In the working-age population worldwide, diabetic retinopathy (DR), a prevalent complication of diabetes, is main cause vision impairment. Chronic low-grade inflammation plays an essential role in DR development. Recently, concerning pathogenesis DR, Nod-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome retinal cells has been determined as causal factor. eye, NLRP3 activated by several pathways (such ROS and ATP). The activation NPRP3 leads to secretion inflammatory cytokines interleukin-1β (IL-1β) interleukin-18 (IL-18), pyroptosis, rapid form lytic programmed cell death (PCD). Cells that undergo pyroptosis swell rapture, releasing more factors accelerating progression. This review focuses on mechanisms activate leading DR. present research highlighted some inhibitors NLRP3/pyroptosis novel therapeutic measures treatment.

Language: Английский

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P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine

The Journal of Headache and Pain, Journal Year: 2022, Volume and Issue: 23(1)

Published: July 2, 2022

Abstract Migraine is the second most common form of headache disorder and leading cause disability worldwide. Cognitive symptoms ranked resulting in migraine-related disability, after pain. P2X7 receptor (P2X7R) was recently shown to be involved hyperalgesia migraine. However, role P2X7R cognitive impairment still ill-defined. The aim this study explore molecular mechanisms underlying it. Here we used a well-established mouse model migraine that triggered attacks by application inflammatory soup (IS) dura. Our results showed repeated dural IS stimulation upregulation P2X7R, activation NLRP3 inflammasome, release proinflammatory cytokines (IL-1β IL-18) pyroptotic cell death pathway. Gliosis (microgliosis astrogliosis), neuronal loss also occurred IS-induced model. No significant apoptosis or whiter matter damage observed following attacks. These pathological changes mainly cerebral cortex less extent hippocampus, all which can prevented pretreatment with specific antagonist Brilliant Blue G (BBG). Moreover, BBG alleviate stimulation. identified as key contributor may represent potential therapeutic target for mitigating

Language: Английский

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lncRNA ZFAS1 Positively Facilitates Endothelial Ferroptosis via miR-7-5p/ACSL4 Axis in Diabetic Retinopathy

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 17

Published: Aug. 31, 2022

Accumulating evidence has suggested the significant role of long noncoding RNAs (lncRNA) in regulating ferroptosis, while its regulatory mechanism diabetic retinopathy (DR) remains unelucidated. In this work, we first demonstrated that lncRNA zinc finger antisense 1 (ZFAS1) is upregulated high glucose-cultured human retinal endothelial cells (hRECs) and ZFAS1 inhibition attenuated glucose- (HG-) induced which was evidenced by cell viability, total iron ferrous levels, reactive oxygen species (ROS) level, Glutathione Peroxidase 4 (GPX4) expression detection. Mechanistically, validated may act as a competing endogenous RNA competitively binding with microRNA-7-5p (miR-7-5p) modulating downstream molecule acyl-CoA synthetase long-chain family member (ACSL4), now identified classic driver gene ferroptosis process. conclusion, our results demonstrate HG-induced elevation activates hRECs ZFAS1/miR-7-5p/ACSL4 axis serve therapeutic target for dysfunction DR.

Language: Английский

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Implication of lncRNA MSTRG.81401 in Hippocampal Pyroptosis Induced by P2X7 Receptor in Type 2 Diabetic Rats with Neuropathic Pain Combined with Depression

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1186 - 1186

Published: Jan. 18, 2024

Major depressive disorder (MDD) is a common complication of diabetes and often observed alongside diabetic neuropathic pain (DNP) as comorbidity in patients. Long non-coding RNA (lncRNA) plays an important role various pathophysiological processes. The P2X7 receptor responsible for triggering inflammatory responses, such pyroptosis, linked to depression. aim this study was investigate the effect lncRNA MSTRG.81401 on hippocampal pyroptosis induced by rats with DNP combined MDD (DNP + MDD). Our results showed that expression significantly elevated hippocampus compared control group. Following administration shRNA targeting MSTRG.81401, notable elevation mechanical thermal thresholds comorbid MDD. Additionally, significant improvements depression-like behaviors were evident open-field test (OFT), sucrose preference (SPT), forced swim (FST). In rats, levels mRNA protein observed, along increased co-expression astrocytic marker glial fibrillary acidic (GFAP). Meanwhile, heightened NOD-like 3 (NLRP3), apoptosis-associated speck-like (ASC), pyroptosis-related Gasdermin D (GSDMD), caspase-1, IL-1β, IL-18, TNF-α detected, addition serum IL-18 TNF-α. After treatment above abnormal changes indicators inflammation improved. Therefore, our demonstrates can alleviate associated inhibiting receptor-mediated pathway pro-inflammatory responses. This suggests P2X7R/NLRP3/caspase-1 implicated scenario may serve potential target management diabetes.

Language: Английский

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A single cell atlas of circulating immune cells involved in diabetic retinopathy

iScience, Journal Year: 2024, Volume and Issue: 27(2), P. 109003 - 109003

Published: Jan. 26, 2024

This study focused on examining the exact role of circulating immune cells in development diabetic retinopathy (DR). In vitro co-culture experiments showed that peripheral blood mononuclear (PBMCs) from patients with type 1 DR crucially modulated biological functions human retinal microvascular endothelial (HRMECs), consequently disrupting their normal functionality. Single-cell RNA sequencing (scRNA-seq) revealed unique differentially expressed genes and pathways among healthy controls, non-diabetic (NDR) patients, patients. Of significance was observed upregulation JUND each subset PBMCs DR. Further studies downregulating patient-derived led to amelioration HRMEC dysfunction. These findings highlighted notable alterations transcriptomic patterns underscored as a key factor for participating pathogenesis

Language: Английский

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Targeting inflammasomes and pyroptosis in retinal diseases—molecular mechanisms and future perspectives

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 101, P. 101263 - 101263

Published: April 23, 2024

Retinal diseases encompass various conditions associated with sight-threatening immune responses and are leading causes of blindness worldwide. These include age-related macular degeneration, diabetic retinopathy, glaucoma uveitis. Emerging evidence underscores the vital role innate response in retinal diseases, beyond previously emphasized T-cell-driven processes adaptive system. In particular, pyroptosis, a newly discovered programmed cell death process involving inflammasome formation, has been implicated loss membrane integrity release inflammatory cytokines. Several disease-relevant animal models have provided that formation inflammasomes induction pyroptosis cells contribute to inflammation diseases. this review article, we summarize current knowledge about system We also provide insights into translational targeting approaches, including novel drugs countering improve diagnosis treatment

Language: Английский

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Microglia‐Derived Interleukin‐6 Triggers Astrocyte Apoptosis in the Hippocampus and Mediates Depression‐Like Behavior

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Abstract In patients with major depressive disorder (MDD) and animal models of depression, key pathological hallmarks include activation microglia as well atrophy loss astrocytes. Under certain conditions, can inflict damage to neurons However, the precise mechanisms underlying how activated induced astrocyte remain enigmatic. this study, a depression model by chronic social defeat stress (CSDS) is utilized. The results show that CSDS induces significant anxiety‐ depression‐like behaviors, along notable apoptosis, microglial activation, elevated levels interleukin‐6 (IL‐6). Subsequent studies demonstrate IL‐6 released from promotes apoptosis. Furthermore, knockdown P2X7 receptor (P2X7R) in microglia, which implicated response, reduces stress‐induced release, Direct inhibition minocycline corroborates these effects. selective receptors astrocytes effectively mitigates behaviors atrophy. This study identifies factor contributes apoptosis symptoms. Consequently, IL‐6/IL‐6R pathway has emerged promising target for treatment depression.

Language: Английский

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Blockade of P2X7 receptors preserves blood retinal barrier integrity by modulating the plasmalemma vesicle‐associated protein: Implications for diabetic retinopathy

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Plasmalemma vesicle-associated protein (PLVAP) regulates transcytosis in vascular endothelial cells. PLVAP expression is increased pathological conditions, such as diabetic retinopathy. P2X7 receptor antagonists have been shown to preserve blood-retinal barrier (BRB) integrity. Here, we tested the hypothesis that tightly linked activity, leading breakdown of BRB an vitro model We integrated network approaches with retinopathy using primary human retinal microvascular cells (HRMECs). Cells were treated a antagonist, JNJ47965567, and several genes predicted belong signalling assessed. Levels localisation PLVAP, VE-cadherin zonula occludens-1 (ZO-1) HRMECs evaluated. In vivo, effects JNJ47965567 on retinas mice High levels glucose HRMECs, which was blocked by JNJ47965567. Furthermore, preserved ZO-1. choroidal vasculature mice, immunostaining increased, compared non-diabetic mice. This increase significantly attenuated treatment CONCLUSIONS AND IMPLICATIONS: study showed important component complex gene regulatory network, including mediating pathophysiology The antagonist good pharmacodynamic profile, suggesting this approach could be value

Language: Английский

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NLRP3 inflammasome in cognitive impairment and pharmacological properties of its inhibitors

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: Nov. 2, 2023

Abstract Cognitive impairment is a multifactorial and multi-step pathological process that places heavy burden on patients the society. Neuroinflammation one of main factors leading to cognitive impairment. The inflammasomes are multi-protein complexes respond various microorganisms endogenous danger signals, helping initiate innate protective responses in inflammatory diseases. NLRP3 produce proinflammatory cytokines (interleukin IL-1β IL-18) by activating caspase-1. In this review, we comprehensively describe structure functions inflammasome. We also explore intrinsic relationship between inflammasome impairment, which involves immune cell activation, apoptosis, oxidative stress, mitochondrial autophagy, neuroinflammation. Finally, antagonists as targeted therapies improve

Language: Английский

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