Melatonin alleviates ischemic stroke by inhibiting ferroptosis through the CYP1B1/ACSL4 pathway

Environmental Toxicology, Год журнала: 2024, Номер 39(5), С. 2623 - 2633

Опубликована: Янв. 11, 2024

Abstract This study utilized middle cerebral artery occlusion (MCAO) mouse models and HT‐22 cell oxygen glucose deprivation/reoxygenation (OGD/R) to investigate the therapeutic effects of melatonin on ischemic brain injury. In experiments, MCAO mice were treated with 5 10 mg/kg doses melatonin, H‐T22 cells underwent OGD/R treatment administered different concentrations melatonin. The results showed that significantly reduced area, neural damage, edema, neuronal apoptosis in mice. model, also improved proliferation ability, apoptosis, ROS production. Further mechanistic studies found exerts protective by inhibiting ferroptosis, an iron‐dependent form regulated death, through regulation ACSL4/CYP1B1 pathway. mice, decreased lipid peroxidation, production, ACSL4 protein expression. Overexpression CYP1B1 increased ubiquitination degradation, thereby increasing tolerance reducing levels, decreasing knockdown obtained opposite results. metabolite 20‐HETE induces expression E3 ubiquitin ligase FBXO10 activating PKC signaling, which promotes degradation. inhibition reversed summary, this demonstrates protects from injury ferroptosis pathway, providing evidence for new targets

Язык: Английский

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Mechanisms of inflammation after ischemic stroke in brain-peripheral crosstalk

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Июнь 12, 2024

Stroke is a devastating disease with high morbidity, disability, and mortality, among which ischemic stroke more common. However, there still lack of effective methods to improve the prognosis reduce incidence its complications. At present, evidence that peripheral organs are involved in inflammatory response after stroke. Moreover, interaction between central inflammation includes activation resident immune cells, as well inflammation-related signaling pathways, all play an important role pathophysiology In this review, we discuss mechanisms stroke, interactions through circulatory pathways (such gut, heart, lung spleen) brain mediate regulate We also propose potential meningeal lymphatic vessels (MLVs)-cervical lymph nodes (CLNs) brain-peripheral crosstalk pathway addition, summarize anti-inflammatory drugs treatment

Язык: Английский

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Mitochondrial Melatonin: Beneficial Effects in Protecting against Heart Failure

Life, Год журнала: 2024, Номер 14(1), С. 88 - 88

Опубликована: Янв. 5, 2024

Cardiovascular disease is the cause of physical infirmity and thousands deaths annually. Typically, during heart failure, cardiomyocyte mitochondria falter in terms energy production metabolic processing. Additionally, inflammation accumulation non-contractile fibrous tissue contribute to cardiac malfunction. Melatonin, an endogenously produced molecule, experimentally reduces initiation progression atherosclerotic lesions, which are often basis coronary artery disease. The current review critically analyzes published data related experimental use melatonin forestall pathologies. Collectively, these studies document melatonin’s anti-atherosclerotic actions reducing LDL oxidation triglyceride levels, lowering endothelial malfunction, limiting adhesion molecule formation, preventing macrophage polarization M1 pro-inflammatory phenotype, changing cellular metabolism, scavenging destructive reactive oxygen species, proliferation invasion arterial smooth muscle cells into lesioned area, restricting ingrowth blood vessels from vasa vasorum, solidifying plaque cap reduce chance its rupture. Diabetic hyperglycemia, aggravates also inhibited by supplementation animals. potential value non-toxic as a possible inhibitor pathology humans should be seriously considered performing clinical trials using this multifunctional molecule.

Язык: Английский

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Protective effects of melatonin on stroke in diabetic mice: central and peripheral inflammation modulation

Stroke and Vascular Neurology, Год журнала: 2025, Номер unknown, С. svn - 003442

Опубликована: Фев. 24, 2025

Background Melatonin protects against ischaemic stroke in diabetic animal models, though the mechanisms involving brain and peripheral immune responses remain underexplored. We aimed to clarify how melatonin interacts with these protect mice. Methods Type 1 diabetes mellitus (T1DM) was induced mice using streptozotocin. RNA sequencing of tissue blood mononuclear cells (PBMCs) performed 24 hours poststroke. Inflammatory were evaluated 72 after ischaemia/reperfusion. Results reduced infarction improved neurological function T1DM In brain, downregulated inflammatory factor expression, bioinformatics identifying 62 differentially expressed genes (DEGs) related inflammation 11 associated inflammasomes. Western blotting confirmed reductions NLRP3, HMGB1 Cleaved Caspase-1 expression. Flow cytometry showed infiltration CD8+T neutrophils. decreased IL-6, IL-1β IL-4 levels. PBMCs, revealed 939 DEGs following treatment. Kyoto Encyclopaedia Genes Genomes analysis indicated that involved metabolic pathways, upregulated enriched Jak-STAT signalling pathway. GO cytosol, macromolecule modification. Protein–protein interaction affected 38 inflammation-associated linked key cytokines (Il6, Il1b, Ifng, Il4). increased cells, monocytes neutrophils blood, suggesting a reversal immunosuppression. Multiplex cytokine assays IL-6 IFN-γ Conclusion Poststroke therapy reduces damage by modulating central responses.

Язык: Английский

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In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm

PLoS ONE, Год журнала: 2020, Номер 15(10), С. e0240149 - e0240149

Опубликована: Окт. 2, 2020

From January 2020, COVID-19 is spreading around the world producing serious respiratory symptoms in infected patients that some cases can be complicated by severe acute syndrome, sepsis and septic shock, multiorgan failure, including kidney injury cardiac injury. Cost time efficient approaches to reduce burthen of disease are needed. To find potential treatments among whole arsenal existing drugs, we combined system biology artificial intelligence-based approaches. The drug combination pirfenidone melatonin has been identified as a candidate treatment may contribute virus infection. Starting from different targets effect drugs converges on human proteins with known role SARS-CoV-2 infection cycle. Simultaneously, GUILDify v2.0 web server used an alternative method corroborate against SARS-CoV-2. We have also predicted therapeutic over associated pathology, thus tackling at same two important issues COVID-19. These evidences, together fact medical point view both considered safe current standard care for makes this very attractive treating stage II, non-severe symptomatic presence those who risk developing pulmonary complications.

Язык: Английский

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