Mitophagy and cGAS–STING crosstalk in neuroinflammation

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(8), P. 3327 - 3361

Published: May 13, 2024

Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS–STING pathway, crucial innate immunity. This pathway responds DNA and associated with cellular stress. Our review explores molecular details regulatory mechanisms of mitophagy pathway. We critically evaluated literature demonstrating how dysfunctional leads neuroinflammatory conditions, primarily through accumulation mitochondria, activating activation prompts production proinflammatory cytokines, exacerbating neuroinflammation. emphasizes interaction between Effective might suppress offering protection against Conversely, impaired may activate potentially leading chronic Additionally, we explored this influences neurodegenerative disorders, suggesting a common mechanism in such diseases. In conclusion, there need additional targeted research unravel complexities mitophagy–cGAS–STING interactions their role neurodegeneration. highlights potential therapies targeting these pathways, which could lead new treatments conditions. synthesis enhances our understanding foundations neuroinflammation opens therapeutic avenues disease research.

Language: Английский

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The Crucial Role of the Blood–Brain Barrier in Neurodegenerative Diseases: Mechanisms of Disruption and Therapeutic Implications

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(2), P. 386 - 386

Published: Jan. 9, 2025

The blood-brain barrier (BBB) is a crucial structure that maintains brain homeostasis by regulating the entry of molecules and cells from bloodstream into central nervous system (CNS). Neurodegenerative diseases such as Alzheimer's Parkinson's disease, well ischemic stroke, compromise integrity BBB. This leads to increased permeability infiltration harmful substances, thereby accelerating neurodegeneration. In this review, we explore mechanisms underlying BBB disruption, including oxidative stress, neuroinflammation, vascular dysfunction, loss tight junction integrity, in patients with neurodegenerative diseases. We discuss how breakdown contributes neurotoxicity, abnormal accumulation pathological proteins, all which exacerbate neuronal damage facilitate disease progression. Furthermore, potential therapeutic strategies aimed at preserving or restoring function, anti-inflammatory treatments, antioxidant therapies, approaches enhance integrity. Given role neurodegeneration, maintaining its represents promising approach slow prevent progression

Language: Английский

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Ginsenoside Rb1 protects hippocampal neurons in depressed rats based on mitophagy-regulated astrocytic pyroptosis

Phytomedicine, Journal Year: 2023, Volume and Issue: 121, P. 155083 - 155083

Published: Sept. 13, 2023

Language: Английский

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Smouldering Lesion in MS: Microglia, Lymphocytes and Pathobiochemical Mechanisms

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12631 - 12631

Published: Aug. 10, 2023

Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). Immune cell infiltration can lead to permanent activation macrophages microglia in parenchyma, resulting demyelination neurodegeneration. Thus, neurodegeneration that begins with acute lymphocytic inflammation may progress inflammation. This thought underlie development so-called smouldering lesions. These lesions evolve from inflammatory are associated continuous low-grade over many years. Their presence poor prognosis promotes transition progressive MS, which later manifest clinically as MS when exceeds upper limit functional compensation. In lesions, only moderate activity, a toxic environment clearly identifiable contributes degeneration neurons, axons, oligodendrocytes and, thus, clinical progression. addition cells immune system, oxidative stress mitochondrial damage, hypoxia caused by energy deficit iron accumulation play role this process. classical mediators, contains high concentrations oxidants ions, well excitatory neurotransmitter glutamate. review, we will discuss how these pathobiochemical markers mechanisms, alone or combination, neuronal, axonal, glial death ultimately process neuroinflammation neurodegeneration, then concepts conclusions emerge findings. Understanding would be important gain better insight into relationship between classification pathomechanism MS.

Language: Английский

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Human iPSC-derived glia models for the study of neuroinflammation

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Oct. 10, 2023

Abstract Neuroinflammation is a complex biological process that plays significant role in various brain disorders. Microglia and astrocytes are the key cell types involved inflammatory responses central nervous system. results increased levels of secreted factors, such as cytokines, chemokines, reactive oxygen species. To model neuroinflammation vitro, human induced pluripotent stem (iPSC)-based models have been utilized, including monocultures, transfer conditioned media between types, co-culturing multiple neural organoids, xenotransplantation cells into mouse brain. induce neuroinflammatory several stimuli established can either microglia, astrocytes, or both. Here, we describe critically evaluate different iPSC be used to study highlight how has measured these cultures.

Language: Английский

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Predicting blood–brain barrier permeability of molecules with a large language model and machine learning

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 9, 2024

Abstract Predicting the blood–brain barrier (BBB) permeability of small-molecule compounds using a novel artificial intelligence platform is necessary for drug discovery. Machine learning and large language model on (AI) tools improve accuracy shorten time new development. The primary goal this research to develop computing models deep architectures capable predicting whether molecules can permeate human (BBB). in silico (computational) vitro (experimental) results were validated by Natural Products Research Laboratories (NPRL) at China Medical University Hospital (CMUH). transformer-based MegaMolBART was used as simplified molecular input line entry system (SMILES) encoder with an XGBoost classifier method check if molecule could cross through BBB. We Morgan or Circular fingerprints apply algorithm set atomic invariants baseline also compare results. BBB assessed three-dimensional (3D) spheroids (human brain microvascular endothelial cells, vascular pericytes, astrocytes). Using multiple databases, final transformer achieved area under receiver operating characteristic curve 0.88 held-out test dataset. Temozolomide (TMZ) 21 randomly selected permeable (Pred scores = 1, indicating BBB-permeable) from NPRL penetrated spheroid cells. No evidence suggests that ferulic acid five BBB-impermeable < 1.29423E−05, which designate pass BBB) cells Our validation experiments indicated prediction permeation accurate. Transformer-based like MegaMolBART, leveraging SMILES representations molecules, show great promise applications These have potential accelerate development targeted treatments disorders central nervous system.

Language: Английский

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Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson’s disease

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: March 30, 2024

Abstract Neuroinflammation is one of the core pathological features Parkinson’s disease (PD). Innate immune cells play a crucial role in progression PD. Microglia, major innate brain, exhibit memory effects and are recognized as key regulators neuroinflammatory responses. Persistent modifications microglia provoked by first stimuli pivotal for memory, resulting an enhanced or suppressed response to second stimuli, which known training tolerance, respectively. In this study, LPS was used establish vitro vivo models memory. Microglia-specific Hif-1α knockout mice were further employed elucidate regulatory HIF-1α MPTP-induced PD pathology. Our results showed that different paradigms could induce tolerance nigrostriatal pathway mice. We found lasting month protected dopaminergic system mice, whereas effect limited. Deficiency impeded formation exerted protective MPTP-intoxicated suppressing neuroinflammation. Therefore, essential microglial can promote neuroinflammation associated with

Language: Английский

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Mitochondrial stress: a key role of neuroinflammation in stroke

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Feb. 6, 2024

Abstract Stroke is a clinical syndrome characterized by an acute, focal neurological deficit, primarily caused the occlusion or rupture of cerebral blood vessels. In stroke, neuroinflammation emerges as pivotal event contributing to neuronal cell death. The occurrence and progression entail intricate processes, prominently featuring mitochondrial dysfunction adaptive responses. Mitochondria, double membrane-bound organelle are recognized “energy workshop” body. Brain particularly vulnerable disturbances due its high energy demands from mitochondria-related production. interplay between mitochondria plays significant role in pathogenesis stroke. biological pathological consequences resulting stress have substantial implications for function. Mitochondrial serves mechanism aimed at mitigating induced import misfolded proteins, which occurs response This involves reduction protein accumulation overall synthesis. influence on state stroke underscored capacity interact with neuroinflammation. impact varies according severity. Moderate can bolster cellular defenses, enabling cells better withstand detrimental stressors. contrast, sustained excessive detrimentally affects tissue integrity. relationship depends degree present. Understanding instrumental excavating novel treatment review aims provide evaluation cross-talk within context We aim reveal how environment

Language: Английский

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Neurodegenerative Diseases: Unraveling the Heterogeneity of Astrocytes

Cells, Journal Year: 2024, Volume and Issue: 13(11), P. 921 - 921

Published: May 27, 2024

The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality central nervous system (CNS). Astrocytes are vital orchestrating neuronal development by releasing synaptogenic molecules eliminating excessive synapses. They also modulate excitability contribute to CNS homeostasis, promoting survival clearance neurotransmitters, transporting metabolites, secreting trophic factors. highly heterogeneous respond injuries diseases through process known as reactive astrogliosis, which can both inflammation its resolution. Recent evidence has revealed remarkable alterations transcriptomes response several diseases, identifying at least two distinct phenotypes called A1 or neurotoxic A2 neuroprotective astrocytes. However, due vast heterogeneity these it is limited classify them into only phenotypes. This review explores various physiological pathophysiological roles, potential markers, pathways that might be activated different astrocytic Furthermore, we discuss main neurodegenerative identify therapeutic strategies. Understanding underlying mechanisms differentiation imbalance population will allow identification specific biomarkers timely approaches diseases.

Language: Английский

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Emerging roles of astrocytes as immune effectors in the central nervous system

Trends in Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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