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1.
Biochem Pharmacol ; 222: 116050, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38354960

RESUMO

The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca2+ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca2+ influx and cytoskeletal remodelling. The increase in intracellular Ca2+ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca2+ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.


Assuntos
Glucocorticoides , Proteínas Serina-Treonina Quinases , Humanos , Glucocorticoides/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor 4 Toll-Like/metabolismo , Macrófagos/metabolismo , Apoptose , Inflamação , Dexametasona/farmacologia , Cálcio/metabolismo , Proteína ORAI1/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Canais Iônicos/genética
2.
Brain Behav ; 13(9): e3136, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37366640

RESUMO

BACKGROUND: The brain is a highly mechanosensitive organ, and changes in the mechanical properties of brain tissue influence many physiological and pathological processes. Piezo type mechanosensitive ion channel component 1 (Piezo1), a protein found in metazoans, is highly expressed in the brain and involved in sensing changes of the mechanical microenvironment. Numerous studies have shown that Piezo1-mediated mechanotransduction is closely related to glial cell activation and neuronal function. However, the precise role of Piezo1 in the brain requires further elucidation. OBJECTIVE: This review first discusses the roles of Piezo1-mediated mechanotransduction in regulating the functions of a variety of brain cells, and then briefly assesses the impact of Piezo1-mediated mechanotransduction on the progression of brain dysfunctional disorders. CONCLUSIONS: Mechanical signaling contributes significantly to brain function. Piezo1-mediated mechanotransduction regulates processes such as neuronal differentiation, cell migration, axon guidance, neural regeneration, and oligodendrocyte axon myelination. Additionally, Piezo1-mediated mechanotransduction plays significant roles in normal aging and brain injury, as well as the development of various brain diseases, including demyelinating diseases, Alzheimer's disease, and brain tumors. Investigating the pathophysiological mechanisms through which Piezo1-mediated mechanotransduction affects brain function will give us a novel entry point for the diagnosis and treatment of numerous brain diseases.


Assuntos
Encéfalo , Mecanotransdução Celular , Humanos , Axônios , Encéfalo/metabolismo , Neoplasias Encefálicas , Neurônios , Microambiente Tumoral
3.
J Neuroinflammation ; 20(1): 113, 2023 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-37170230

RESUMO

Postoperative delirium (POD) is a frequent and debilitating complication, especially amongst high risk procedures, such as orthopedic surgery. This kind of neurocognitive disorder negatively affects cognitive domains, such as memory, awareness, attention, and concentration after surgery; however, its pathophysiology remains unknown. Multiple lines of evidence supporting the occurrence of inflammatory events have come forward from studies in human patients' brain and bio-fluids (CSF and serum), as well as in animal models for POD. ß-arrestins are downstream molecules of guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). As versatile proteins, they regulate numerous pathophysiological processes of inflammatory diseases by scaffolding with inflammation-linked partners. Here we report that ß-arrestin1, one type of ß-arrestins, decreases significantly in the reactive astrocytes of a mouse model for POD. Using ß-arrestin1 knockout (KO) mice, we find aggravating effect of ß-arrestin1 deficiency on the cognitive dysfunctions and inflammatory phenotype of astrocytes in POD model mice. We conduct the in vitro experiments to investigate the regulatory roles of ß-arrestin1 and demonstrate that ß-arrestin1 in astrocytes interacts with the dynamin-related protein 1 (Drp1) to regulate mitochondrial fusion/fission process. ß-arrestin1 deletion cancels the combination of ß-arrestin1 and cellular Drp1, thus promoting the translocation of Drp1 to mitochondrial membrane to provoke the mitochondrial fragments and the subsequent mitochondrial malfunctions. Using ß-arrestin1-biased agonist, cognitive dysfunctions of POD mice and pathogenic activation of astrocytes in the POD-linked brain region are reduced. We, therefore, conclude that ß-arrestin1 is a promising target for the understanding of POD pathology and development of POD therapeutics.


Assuntos
Arrestinas , Delírio do Despertar , Humanos , Camundongos , Animais , Arrestinas/genética , Dinâmica Mitocondrial , Astrócitos/metabolismo , beta-Arrestinas/metabolismo , Dinaminas/metabolismo , Camundongos Knockout
4.
Cell Biosci ; 12(1): 106, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35831869

RESUMO

The importance of neuroglia in maintaining normal brain function under physiological and pathological conditions has been supported by growing evidence in recent years. The most important issues regarding glial metabolism and function include the cooperation between glial populations and neurons, morphological and functional changes in pathological states, and the role in the onset and progression of neurodegenerative diseases. Although lipid accumulation and further lipid droplet production in neurodegenerative disease brain models have been observed for a long time, the dynamic development of brain lipid droplet research in recent years suggests its role in the development and progression of neurodegenerative diseases was previously underestimated. First recognized as organelles of lipid storage, lipid droplets (LDs) have emerged as an important organelle in metabolic diseases, inflammation, and host defense. Dynamic changes in lipid metabolism within neurons and glial cells resulting in lipid accumulation and lipid droplet formation are present in brain models of various neurodegenerative diseases, yet their role in the brain remains largely unexplored. This paper first reviews the metabolism and accumulation of several major lipids in the brain and discusses the regulation of lipid accumulation in different types of brain cells. We explore the potential role of intracellular lipid accumulation in the pathogenesis of neurodegeneration, starting from lipid metabolism and LDs biogenesis in glial cells, and discuss several pathological factors that promote lipid droplet formation, mainly focusing on oxidative stress, energy metabolism and glial cell-neuron coupling, which are closely related to the etiology and progression of neurodegenerative diseases. Finally, the directions and challenges of intracellular lipid metabolism in glial cells in neurodegeneration are discussed.

5.
Front Immunol ; 13: 836494, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35392078

RESUMO

Evidence suggests that the accumulation of lipid drots (LDs) accelerates damage to mitochondria and increases the release of inflammatory factors. These have been implicated as a mechanism underlying neurodegenerative diseases or tumors and aging-related diseases such as postoperative cognitive dysfunction (POCD), nevertheless, accumulation of lipid droplets has not been extensively studied in the central nervous system (CNS). Here, we found that after surgery, there was activation of astrocytes and lipid accumulation in the hippocampus. However, cannabinoid receptor type II (CB2R) activation significantly reduced lipid accumulation in astrocytes and change the expression of genes related to lipid metabolism. CB2R reduces the release of the inflammatory factors interleukin-1 beta (IL-1ß) and interleukin 6 (IL-6) in peripheral serum and simultaneously improves cognitive ability in mice with POCD. Further research on mechanisms indicates that CB2R activation promotes the nuclear entry of the bHLH-leucine zipper transcription factor, the transcription factor EB (TFEB), and which is a master transcription factor of the autophagy-lysosomal pathway, also reduces TFEB-S211 phosphorylation. When CB2R promotes TFEB into the nucleus, TFEB binds at two sites within promoter region of PGC1α, promoting PGC1α transcription and accelerating downstream lipid metabolism. The aforementioned process leads to autophagy activation and decreases cellular lipid content. This study uncovers a new mechanism allowing CB2R to regulate lipid metabolism and inflammation in POCD.


Assuntos
Astrócitos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Complicações Cognitivas Pós-Operatórias , Receptor CB2 de Canabinoide , Animais , Astrócitos/metabolismo , Autofagia/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fatores de Transcrição/metabolismo
6.
BMC Infect Dis ; 22(1): 353, 2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35397512

RESUMO

BACKGROUND: The incidence of sparganosis, especially intracranial live sparganosis is very low in China. Due to the lack of typical clinical manifestations, it is difficult to make a clear preoperative diagnosis of the disease, which often leads to delays the disease and serious consequences. CASE PRESENTATION: A 23-year-old man presented with a 17-year history of intermittent seizures and right extremity numbness and weakness. Magnetic resonance imaging (MRI) showed patchy, nodular and line-like enhancement. Enzyme-linked immunosorbent assay (ELISA) detected positive antibodies to Spirometra mansoni in peripheral blood and cerebrospinal fluid (CSF). In addition, during the operation, an ivory-colored live sparganosis was removed under the precise positioning of neuronavigation, and the patient was diagnosed with cerebral sparganosis. The patient began praziquantel and sodium valproate treatment after the operation, and was followed up for 3 months. There was no recurrence of epilepsy, and the weakness and numbness of the right limb improved. CONCLUSION: Nonspecific clinical manifestations often make the diagnosis of cerebral sparganosis difficult, and a comprehensive diagnosis should be made based on epidemiological history, clinical manifestations, ELISA results and imaging findings. Surgery is the preferred method for the treatment of cerebral sparganosis, and more satisfactory results can be achieved under the precise positioning of neuronavigation.


Assuntos
Esparganose , Spirometra , Adulto , Animais , Humanos , Hipestesia/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Praziquantel/uso terapêutico , Esparganose/diagnóstico , Esparganose/tratamento farmacológico , Esparganose/cirurgia , Adulto Jovem
7.
Front Immunol ; 13: 816149, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154133

RESUMO

Mechanical damage is one of the predisposing factors of inflammation, and it runs through the entire inflammatory pathological process. Repeated or persistent damaging mechanical irritation leads to chronic inflammatory diseases. The mechanism of how mechanical forces induce inflammation is not fully understood. Piezo1 is a newly discovered mechanically sensitive ion channel. The Piezo1 channel opens in response to mechanical stimuli, transducing mechanical signals into an inflammatory cascade in the cell leading to tissue inflammation. A large amount of evidence shows that Piezo1 plays a vital role in the occurrence and progression of chronic inflammatory diseases. This mini-review briefly presents new evidence that Piezo1 responds to different mechanical stresses to trigger inflammation in various tissues. The discovery of Piezo1 provides new insights for the treatment of chronic inflammatory diseases related to mechanical stress. Inhibiting the transduction of damaging mechanical signals into inflammatory signals can inhibit inflammation and improve the outcome of inflammation at an early stage. The pharmacology of Piezo1 has shown bright prospects. The development of tissue-specific Piezo1 drugs for clinical use may be a new target for treating chronic inflammation.


Assuntos
Inflamação , Canais Iônicos , Animais , Doença Crônica , Humanos , Estresse Mecânico
8.
Front Mol Neurosci ; 14: 729273, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34658786

RESUMO

Astrocytes are the major glial cells in the brain, which play a supporting role in the energy and nutritional supply of neurons. They were initially regarded as passive space-filling cells, but the latest progress in the study of the development and function of astrocytes highlights their active roles in regulating synaptic transmission, formation, and plasticity. In the concept of "tripartite synapse," the bidirectional influence between astrocytes and neurons, in addition to their steady-state and supporting function, suggests that any negative changes in the structure or function of astrocytes will affect the activity of neurons, leading to neurodevelopmental disorders. The role of astrocytes in the pathophysiology of various neurological and psychiatric disorders caused by synaptic defects is increasingly appreciated. Understanding the roles of astrocytes in regulating synaptic development and the plasticity of neural circuits could help provide new treatments for these diseases.

9.
Front Aging Neurosci ; 13: 738686, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616289

RESUMO

The intracellular energy state will alter under the influence of physiological or pathological stimuli. In response to this change, cells usually mobilize various molecules and their mechanisms to promote the stability of the intracellular energy status. Mitochondria are the main source of ATP. Previous studies have found that the function of mitochondria is impaired in aging, neurodegenerative diseases, and metabolic diseases, and the damaged mitochondria bring lower ATP production, which further worsens the progression of the disease. Silent information regulator-1 (SIRT1) is a multipotent molecule that participates in the regulation of important biological processes in cells, including cellular metabolism, cell senescence, and inflammation. In this review, we mainly discuss that promoting the expression and activity of SIRT1 contributes to alleviating the energy stress produced by physiological and pathological conditions. The review also discusses the mechanism of precise regulation of SIRT1 expression and activity in various dimensions. Finally, according to the characteristics of this mechanism in promoting the recovery of mitochondrial function, the relationship between current pharmacological preparations and aging, neurodegenerative diseases, metabolic diseases, and other diseases was analyzed.

10.
Front Aging Neurosci ; 13: 691230, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349634

RESUMO

Neurodegenerative diseases are a class of slow-progressing terminal illnesses characterized by neuronal lesions, such as multiple sclerosis [MS, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)]. Their incidence increases with age, and the associated burden on families and society will become increasingly more prominent with aging of the general population. In recent years, there is growing studies have shown that lactosylceramide (LacCer) plays a crucial role in the progression of neurodegeneration, although these diseases have different pathogenic mechanisms and etiological characteristics. Based on latest research progress, this study expounds the pathogenic role of LacCer in driving central nervous system (CNS) inflammation, as well as the role of membrane microstructure domain (lipid rafts) and metabolite gangliosides, and discusses in detail their links with the pathogenesis of neurodegenerative diseases, with a view to providing new strategies and ideas for the study of pathological mechanisms and drug development for neurodegenerative diseases in the future.

11.
Front Pharmacol ; 12: 646265, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079457

RESUMO

Background: Surgery and anesthesia-induced perioperative neurocognitive disorder (PND) are closely related to NOD-like receptors (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome microglia inflammatory response. Inhibiting the occurrence of neuroinflammation is an important treatment method to improve postoperative delirium. Fewer NLRP3-targeting molecules are currently available in the clinic to reduce the incidence of postoperative delirium. Dexmedetomidine (DEX), an α2 adrenergic receptor agonist has been shown to have antioxidant and anti-inflammatory activities. The present study showed that DEX reduced the production of cleaved caspase1 (CASP1) and destroyed the NLRP3-PYD And CARD Domain Containing (PYCARD)-CASP1 complex assembly, thereby reducing the secretion of IL-1ß interleukin beta (IL-1ß). DEX promoted the autophagy process of microglia and reduced NLRP3 expression. More interestingly, it promoted the ubiquitination and degradation of NLRP3. Thus, this study demonstrated that DEX reduced NLRP3-mediated inflammation through the activation of the ubiquitin-autophagy pathway. This study provided a new mechanism for treating PND using DEX. Methods: C57BL/6 mice were pre-administered DEX 3 days in advance, and an abdominal exploration model was used to establish a perioperative neurocognitive disorder model. The anti-inflammatory effect of DEX was explored in vivo by detecting NLRP3-CASP1/IL-1ß protein expression and behavioral testing. Primary microglia were stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in vitro, the expression of CASP1 and IL-1ß was detected in the supernatant of cells, and the expression of autophagy-related proteins microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) and sequestosome 1 (SQSTM1) was examined in the cytoplasm. Meanwhile, Co-immunoprecipitation (Co-IP) was used to detect NLRP3 protein ubiquitination so as to clarify the new mechanism underlying the anti-inflammatory effect of DEX. Results: Pre-administration of DEX reduced the protein expression of NLRP3, CASP1, and IL-1ß in the hippocampus of mice induced by surgery and also improved the impairment of learning and memory ability. At the same time, DEX also effectively relieved the decrease in spine density of the hippocampal brain induced by surgery. DEX decreased the cleaved CASP1 expression, blocked the assembly of NLRP3-PYCARD-CASP1 complex, and also reduced the secretion of mature IL-1ß in vitro. Mechanically, it accelerated the degradation of NLRP3 inflammasome via the autophagy-ubiquitin pathway and reduced the green fluorescent protein/red fluorescent protein MAP1LC3B ratio, which was comparable to the effect when using the autophagy activator rapamycin (Rapa). Furthermore, it increased the ubiquitination of NLRP3 after LPS plus ATP stimulated microglia. Conclusion: DEX attenuated the hippocampal brain inflammation by promoting NLRP3 inflammasome degradation via the autophagy-ubiquitin pathway, thus improving cognitive impairment in mice.

12.
Front Neurosci ; 15: 654785, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912006

RESUMO

In neurodegenerative diseases, neurodegeneration has been related to several mitochondrial dynamics imbalances such as excessive fragmentation of mitochondria, impaired mitophagy, and blocked mitochondria mitochondrial transport in axons. Mitochondria are dynamic organelles, and essential for energy conversion, neuron survival, and cell death. As mitochondrial dynamics have a significant influence on homeostasis, in this review, we mainly discuss the role of mitochondrial dynamics in several neurodegenerative diseases. There is evidence that several mitochondrial dynamics-associated proteins, as well as related pathways, have roles in the pathological process of neurodegenerative diseases with an impact on mitochondrial functions and metabolism. However, specific pathological mechanisms need to be better understood in order to propose new therapeutic strategies targeting mitochondrial dynamics that have shown promise in recent studies.

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