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Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer's disease (AD) risk; however, the underlying mechanisms are not fully understood. Here, it is found that the injection of chondroitinase ABC (ChABC), mimicking ECM remodeling, into the medial prefrontal cortex (mPFC) reversed short-term memory loss and reduced amyloid-beta (Aß) deposition in 5xFAD mice. ECM remodeling also reactivated astrocytes, reduced the levels of aggrecan in Aß plaques, and enhanced astrocyte recruitment to surrounding plaques. Importantly, ECM remodeling enhanced the autophagy-lysosome pathway in astrocytes, thereby mediating Aß clearance and alleviating AD pathology. ECM remodeling also promoted Aß plaque phagocytosis by astrocytes by activating the astrocytic phagocytosis receptor MERTK and promoting astrocytic vesicle circulation. The study identified a cellular mechanism in which ECM remodeling activates the astrocytic autophagy-lysosomal pathway and alleviates AD pathology. Targeting ECM remodeling may represent a potential therapeutic strategy for AD and serve as a reference for the treatment of this disease.
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Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disease, characterized by dysregulated immune response. HDAC3 is reported to be an epigenetic brake in inflammation, playing critical roles in macrophages. However, its role in IBD is unclear. In our study, we found HDAC3 was upregulated in CX3CR1-positive cells in the mucosa from IBD mice. Conditional knockout (cKO) of Hdac3 in CX3CR1 positive cells attenuated the disease severity of Dextran Sulfate Sodium (DSS)-induced colitis. In addition, inhibition of HDAC3 with RGFP966 could also alleviate the DSS-induced tissue injury and inflammation in IBD. The RNA sequencing results revealed that Hdac3 cKO restrained DSS-induced upregulation of genes in the pathways of cytokine-cytokine receptor interaction, complement and coagulation cascades, chemokine signaling, and extracellular matrix receptor interaction. We also identified that Guanylate-Binding Protein 5 (GBP5) was transcriptionally regulated by HDAC3 in monocytes by RNA sequencing. Inhibition of HDAC3 resulted in decreased transcriptional activity of interferon-gamma-induced expression of GBP5 in CX3CR1-positive cells, such as macrophages and microglia. Overexpression of HDAC3 upregulated the transcriptional activity of GBP5 reporter. Lastly, conditional knockout of Hdac3 in macrophages (Hdac3 mKO) attenuated the disease severity of DSS-induced colitis. In conclusion, inhibition of HDAC3 in macrophages could ameliorate the disease severity and inflammatory response in colitis by regulating GBP5-NLRP3 axis, identifying a new therapeutic avenue for the treatment of colitis.
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Colite , Sulfato de Dextrana , Histona Desacetilases , Macrófagos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais , Animais , Sulfato de Dextrana/toxicidade , Sulfato de Dextrana/efeitos adversos , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Camundongos , Macrófagos/metabolismo , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Colite/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/antagonistas & inibidores , Modelos Animais de Doenças , Receptor 1 de Quimiocina CX3C/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Camundongos Endogâmicos C57BL , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Acrilamidas , FenilenodiaminasRESUMO
Oligodendrocyte progenitor cells (OPCs) differentiate into myelin-producing cells and modulate neuronal activity. Defects in OPC development are associated with neurological diseases. N6-methyladenosine (m6A) contributes to neural development; however, the mechanism by which m6A regulates OPC development remains unclear. Here, we demonstrate that PRRC2B is an m6A reader that regulates OPC development and myelination. Nestin-Cre-mediated Prrc2b deletion affects neural stem cell self-renewal and glial differentiation. Moreover, the oligodendroglia lineage-specific deletion of Prrc2b reduces the numbers of OPCs and oligodendrocytes, causing hypomyelination and impaired motor coordination. Integrative methylated RNA immunoprecipitation sequencing, RNA sequencing, and RNA immunoprecipitation sequencing analyses identify Sox2 as the target of PRRC2B. Notably, PRRC2B, displaying separate and cooperative functions with PRRC2A, stabilizes mRNA by binding to m6A motifs in the coding sequence and 3' UTR of Sox2. In summary, we identify the posttranscriptional regulation of PRRC2B in OPC development, extending the understanding of PRRC2 family proteins and providing a therapeutic target for myelin-related disorders.
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Células Precursoras de Oligodendrócitos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Oligodendroglia/metabolismo , Bainha de Mielina/metabolismo , Neurogênese , Diferenciação Celular/genéticaRESUMO
BACKGROUND: Damage in the ischemic core and penumbra after stroke affects patient prognosis. Microglia immediately respond to ischemic insult and initiate immune inflammation, playing an important role in the cellular injury after stroke. However, the microglial heterogeneity and the mechanisms involved remain unclear. METHODS: We first performed single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) on middle cerebral artery occlusion (MCAO) mice from three time points to determine stroke-associated microglial subclusters and their spatial distributions. Furthermore, the expression of microglial subcluster-specific marker genes and the localization of different microglial subclusters were verified on MCAO mice through RNAscope and immunofluorescence. Gene set variation analysis (GSVA) was performed to reveal functional characteristics of microglia sub-clusters. Additionally, ingenuity pathway analysis (IPA) was used to explore upstream regulators of microglial subclusters, which was confirmed by immunofluorescence, RT-qPCR, shRNA-mediated knockdown, and targeted metabolomics. Finally, the infarct size, neurological deficits, and neuronal apoptosis were evaluated in MCAO mice after manipulation of specific microglial subcluster. RESULTS: We discovered stroke-associated microglial subclusters in the brains of MCAO mice. We also identified novel marker genes of these microglial subclusters and defined these cells as ischemic core-associated (ICAM) and ischemic penumbra-associated (IPAM) microglia, according to their spatial distribution. ICAM, induced by damage-associated molecular patterns, are probably fueled by glycolysis, and exhibit increased pro-inflammatory cytokines and chemokines production. BACH1 is a key transcription factor driving ICAM generation. In contrast, glucocorticoids, which are enriched in the penumbra, likely trigger IPAM formation, which are presumably powered by the citrate cycle and oxidative phosphorylation and are characterized by moderate pro-inflammatory responses, inflammation-alleviating metabolic features, and myelinotrophic properties. CONCLUSIONS: ICAM could induce excessive neuroinflammation, aggravating brain injury, whereas IPAM probably exhibit neuroprotective features, which could be essential for the homeostasis and survival of cells in the penumbra. Our findings provide a biological basis for targeting specific microglial subclusters as a potential therapeutic strategy for ischemic stroke.
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Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Camundongos , Humanos , Microglia/metabolismo , Acidente Vascular Cerebral/genética , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Inflamação/genética , Inflamação/metabolismoRESUMO
INTRODUCTION: Depression is considered a prodromal state of Alzheimer's disease (AD), yet the underlying mechanism(s) by which depression increases the risk of AD are not known. METHODS: Single-nucleotide polymorphism (SNP) analysis was used to determine the CALHM2 variants in AD patients. Cellular and molecular experiments were conducted to investigate the function of CALHM2 V136G mutation. We generated a new genetically engineered Calhm2 V136G mouse model and performed behavioral tests with these mice. RESULTS: CALHM2 V136G mutation (rs232660) is significantly associated with AD. V136G mutation resulted in loss of the CALHM2 ATP-release function in astrocytes and impaired synaptic plasticity. Mice homozygous for the Calhm2 V136G allele displayed depressive-like behaviors that were rescued by administration of exogenous ATP. Moreover, Calhm2 V136G mutation predisposed mice to cognitive decline in old age. DISCUSSION: CALHM2 dysfunction is a biologically relevant mechanism that may contribute to the observed clinical correlation between depression and AD.
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Microglia-mediated neuroinflammation is involved in various neurological diseases, including ischemic stroke, but the endogenous mechanisms preventing unstrained inflammation is still unclear. The anti-inflammatory role of transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) in macrophages and microglia has previously been identified. However, the endogenous mechanisms that how NR4A1 restricts unstrained inflammation remain elusive. Here, we observed that NR4A1 is up-regulated in the cytoplasm of activated microglia and localizes to processing bodies (P-bodies). In addition, we found that cytoplasmic NR4A1 functions as an RNA-binding protein (RBP) that directly binds and destabilizes Tnf mRNA in an N6-methyladenosine (m6A)-dependent manner. Remarkably, conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens outcomes in a mouse model of ischemic stroke, in which case NR4A1 expression is significantly induced in the cytoplasm of microglia. Thus, our study illustrates a novel mechanism that NR4A1 posttranscriptionally regulates Tnf expression in microglia and determines stroke outcomes.
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AVC Isquêmico , Acidente Vascular Cerebral , Animais , Camundongos , Fatores de Transcrição , Microglia , Inflamação , RNA MensageiroRESUMO
High altitude exposure leads to various cognitive impairments. The cerebral vasculature system plays an integral role in hypoxia-induced cognitive defects by reducing oxygen and nutrition supply to the brain. RNA N6-methyladenosine (m6A) is susceptible to modification and regulates gene expression in response to environmental changes, including hypoxia. However, the biological significance of m6A in endothelial cell performance under hypoxic conditions is unknown. Using m6A-seq, RNA immunoprcipitation-seq, and transcriptomic co-analysis, the molecular mechanism of vascular system remodeling under acute hypoxia is investigated. A novel m6A reader protein, proline-rich coiled-coil 2B (PRRC2B), exists in endothelial cells. PRRC2B knockdown promoted hypoxia-induced endothelial cell migration by regulating alternative splicing of the alpha 1 chain of collagen type XII in an m6A-dependent manner and the decay of matrix metallopeptidase domain 14 and ADAM metallopeptidase domain 19 mRNA in an m6A-independent manner. In addition, conditional knockout of PRRC2B in endothelial cells promotes hypoxia-induced vascular remodeling and cerebral blood flow redistribution, thus alleviating hypoxia-induced cognitive decline. Therefore, PRRC2B is integral in the hypoxia-induced vascular remodeling process as a novel RNA-binding protein. These findings provide a new potential therapeutic target for hypoxia-induced cognitive decline.
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Células Endoteliais , Remodelação Vascular , Camundongos , Animais , RNA , Hipóxia , MetaloproteasesRESUMO
Endothelial dysfunction plays a crucial role in the pathogenesis of vascular disease. Long noncoding RNA (lncRNA) and microRNA (miRNA) play important roles in various cellular processes and are involved in several vascular endothelial cells (VECs) biological processes, including cell growth, migration, autophagy, and apoptosis. The functions of plasmacytoma variant translocation 1 (PVT1) in VECs have been progressively investigated in recent years, mainly with regard to proliferation and migration of endothelial cells (ECs). However, the mechanism underlying the regulation of autophagy and apoptosis in human umbilical vein endothelial cells (HUVEC) by PVT1 remains unclear. The present study showed that PVT1 knockdown accelerated apoptosis induced by oxygen and glucose deprivation (OGD) through suppression of cellular autophagy. Bioinformatic prediction of PVT1 target miRNAs revealed that PVT1 interacts with miR-15b-5p and miR-424-5p. The study further showed that miR-15b-5p and miR-424-5p inhibit the functions of autophagy related 14 (ATG14) and suppress cellular autophagy. The results showed that PVT1 can function as a competing endogenous RNA (ceRNA) of miR-15b-5p and miR-424-5p and promote cellular autophagy by competitive binding, which down-regulates apoptosis. The results showed that PVT1 can function as a competing endogenous RNA (ceRNA) of miR-15b-5p and miR-424-5p and promote cellular autophagy through competitive binding, which down-regulates apoptosis. The study provides insight into a novel therapeutic target that may be explored in the future for the treatment of cardiovascular disease.
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MicroRNAs , RNA Longo não Codificante , Humanos , Células Endoteliais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Autofagia/genética , Proliferação de Células/genética , Apoptose/genética , Hipóxia , RNA Longo não Codificante/metabolismo , Proteínas Relacionadas à Autofagia , Proteínas Adaptadoras de Transporte VesicularRESUMO
Major depressive disorder is a frequent and debilitating psychiatric disease. We have shown in some of the acute animal models of major depressive disorder (tail suspension test and forced swim test) that depression-like behavior can be aggravated in mice by the microinjection into the medial prefrontal cortex of the P2X7R agonistic adenosine 5'-triphosphate or its structural analog dibenzoyl-ATP, and these effects can be reversed by the P2X7R antagonistic JNJ-47965567. When measuring tail suspension test, the prolongation of immobility time by the P2YR agonist adenosine 5'-[ß-thio]diphosphate and the reduction of the adenosine 5'-(γ-thio)triphosphate effect by P2Y1R (MRS 2179) or P2Y12R (PSB 0739) antagonists, but not by JNJ-47965567, all suggest the involvement of P2YRs. In order to elucidate the localization of the modulatory P2X7Rs in the brain, we recorded current responses to dibenzoyl-ATP in layer V astrocytes and pyramidal neurons of medial prefrontal cortex brain slices by the whole-cell patch-clamp procedure; the current amplitudes were not altered in preparations taken from tail suspension test or foot shock-treated mice. The release of adenosine 5'-triphosphate was decreased by foot shock, although not by tail suspension test both in the hippocampus and PFC. In conclusion, we suggest, that in the medial prefrontal cortex, acute stressful stimuli cause supersensitivity of P2X7Rs facilitating the learned helplessness reaction.
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Transtorno Depressivo Maior , Receptores Purinérgicos P2X7 , Camundongos , Animais , Depressão , Córtex Pré-Frontal , Trifosfato de Adenosina , Adenosina , Modelos Animais de DoençasRESUMO
Background: Neuroinflammation is involved in the development of Parkinson's disease (PD). Calhm2 plays an important role in the development of microglial inflammation, but whether Calhm2 is involved in PD and its regulatory mechanisms are unclear. Methods: To study the role of Calhm2 in the development of PD, we utilized conventional Calhm2 knockout mice, microglial Calhm2 knockout mice and neuronal Calhm2 knockout mice, and established the MPTP-induced PD mice model. Moreover, a series of methods including behavioral test, immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, western blot, mass spectrometry analysis and co-immunoprecipitation were utilized to study the regulatory mechanisms. Results: We found that both conventional Calhm2 knockout and microglial Calhm2 knockout significantly reduced dopaminergic neuronal loss, and decreased microglial numbers, thereby improving locomotor performance in PD model mice. Mechanistically, we found that Calhm2 interacted with EFhd2 and regulated downstream STAT3 signaling in microglia. Knockdown of Calhm2 or EFhd2 both inhibited downstream STAT3 signaling and inflammatory cytokine levels in microglia. Conclusion: We demonstrate the important role of Calhm2 in microglial activation and the pathology of PD, thus providing a potential therapeutic target for microglia-mediated neuroinflammation-related diseases.
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Canais de Cálcio , Doença de Parkinson Secundária , Animais , Camundongos , Proteínas de Ligação ao Cálcio , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Doenças Neuroinflamatórias , Transdução de Sinais , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Canais de Cálcio/genéticaRESUMO
Background: Major depression is one of the most common psychiatric disorders worldwide, inflicting suffering, significant reduction in life span, and financial burdens on families and society. Mounting evidence implicates that exposure to chronic stress can induce the dysregulation of the immune system, and the activation of brain-resident innate immune cells, microglia, leading to depression-like symptoms. However, the specific mechanisms need to be further elucidated. Method: Animal models of depression were established by chronic restraint stress (CRS), and depression-like behavior was assessed by sucrose preference test (SPT), open field test (OFT), tail suspension test (TST) and forced swimming test (FST). Microglial activation was visualized by immunofluorescent and immunohistochemical staining, and microglial morphological changes were further analyzed by skeleton analysis. The levels of inflammatory cytokines were detected by western blotting and qPCR. Result: Microglial Dlg1 knockout ameliorates CRS-induced mice depression-like behavior. In contrast to the effect of Dlg1 in the LPS-induced mouse model, Dlg1 knockout had little effect on microglial density, but significantly decreased the number of activated microglia and reversed microglia morphological changes in mice challenged with CRS. Moreover, the upregulation of inflammatory cytokines following CRS exposure was partially reversed by Dlg1 deletion. Conclusion: Our study provides the evidence that Dlg1 ablation in microglia remarkedly reverses microglial activation and depression-like behavior in mice exposed to CRS, implicating a potential target for the treatment of clinical depression.
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The three sets of symptoms associated with schizophrenia-positive, negative, and cognitive-are burdensome and have serious effects on public health, which affects up to 1% of the population. It is now commonly believed that in addition to the traditional dopaminergic mesolimbic pathway, the etiology of schizophrenia also includes neuronal networks, such as glutamate, GABA, serotonin, BDNF, oxidative stress, inflammation and the immune system. Small noncoding RNA molecules called microRNAs (miRNAs) have come to light as possible participants in the pathophysiology of schizophrenia in recent years by having an impact on these systems. These small RNAs regulate the stability and translation of hundreds of target transcripts, which has an impact on the entire gene network. There may be improved approaches to treat and diagnose schizophrenia if it is understood how these changes in miRNAs alter the critical related signaling pathways that drive the development and progression of the illness.
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MicroRNAs , Esquizofrenia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Esquizofrenia/tratamento farmacológico , Biomarcadores , Transdução de Sinais , Redes Reguladoras de GenesRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and currently there are no available treatments. Alongside the conventional Aß and tau hypotheses, neuroinflammation and metabolism disruption have also been regarded as crucial hallmarks of AD. In this study, a novel Chinese formula Nao Tan Qing (NTQ) was developed and shown to improve AD. In vivo experiments showed that NTQ significantly mitigated cognitive impairment, Aß burden and neuroinflammation in a transgenic AD mouse model (5×FAD). Network pharmacology results revealed that the active components of NTQ could target inflammatory and metabolic pathways. In addition, hippocampal transcriptomics suggested that NTQ regulated signaling pathways related to inflammation and lipid metabolism. Consistently, serum metabolomics further indicated that NTQ could modulate glycolipid metabolism. In summary, a combination of systems pharmacology analysis and biological validation study demonstrates that NTQ could alleviate behavioral abnormality and pathological alterations of AD by targeting glycolipid metabolism and neuroinflammation, and is accordingly a potential therapeutic agent for AD.
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Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/metabolismo , Doenças Neuroinflamatórias , Farmacologia em Rede , Camundongos Transgênicos , Modelos Animais de Doenças , Metabolismo dos Lipídeos , Glicolipídeos/uso terapêutico , Peptídeos beta-Amiloides/metabolismoRESUMO
Microglial cells consume adenosine triphosphate (ATP) during phagocytosis to clear neurotoxic ß-amyloid in Alzheimer's disease (AD). However, the contribution of energy metabolism to microglial function in AD remains unclear. Here, we demonstrate that hexokinase 2 (HK2) is elevated in microglia from an AD mouse model (5xFAD) and AD patients. Genetic deletion or pharmacological inhibition of HK2 significantly promotes microglial phagocytosis, lowers the amyloid plaque burden and attenuates cognitive impairment in male AD mice. Notably, the ATP level is dramatically increased in HK2-deficient or inactive microglia, which can be attributed to a marked upregulation in lipoprotein lipase (LPL) expression and subsequent increase in lipid metabolism. We further show that two downstream metabolites of HK2, glucose-6-phosphate and fructose-6-phosphate, can reverse HK2-deficiency-induced upregulation of LPL, thus supporting ATP production and microglial phagocytosis. Our findings uncover a crucial role for HK2 in phagocytosis through regulation of microglial energy metabolism, suggesting a potential therapeutic strategy for AD by targeting HK2.
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Doença de Alzheimer , Microglia , Animais , Camundongos , Masculino , Microglia/metabolismo , Lipase Lipoproteica/metabolismo , Lipase Lipoproteica/uso terapêutico , Hexoquinase/genética , Hexoquinase/metabolismo , Hexoquinase/uso terapêutico , Metabolismo dos Lipídeos , Trifosfato de Adenosina/metabolismo , Glucose-6-Fosfato/metabolismo , Glucose-6-Fosfato/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismoRESUMO
N6-methyladenosine (m6A) modification regulates RNA translation, splicing, transport, localization, and stability at the post-transcriptional level. The m6A modification has been reported to have a wide range of effects on the nervous system, including neurogenesis, cerebellar development, learning, cognition, and memory, as well as the occurrence and development of neurological disorders. In this review, we aim to summarize the findings on the role and regulatory mechanism of m6A modification in the nervous system, to reveal the molecular mechanisms of neurodevelopmental processes, and to promote targeted therapy for nervous system-related diseases.
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BACKGROUND: DJ-1 is an antioxidant protein known to regulate mast cell-mediated allergic response, but its role in airway eosinophilic interactions and allergic inflammation is not known. OBJECTIVE: The aim of this study was to investigate the role of DJ-1 in airway eosinophilic inflammation in vitro and in vivo. METHODS: Ovalbumin-induced airway allergic inflammation was established in mice. ELISA was adopted to analyze DJ-1 and cytokine levels in mouse bronchoalveolar lavage fluid. Transcriptional profiling of mouse lung tissues was conducted by single-cell RNA-sequencing technology. The role of DJ-1 in the differentiation of airway progenitor cells into goblet cells was examined by organoid cultures, immunofluorescence staining, quantitative PCR, and cell transplantation in normal, DJ-1 knockout (KO), or conditional DJ-1 KO mice. RESULTS: This study observed that DJ-1 was increased in the lung tissues of ovalbumin-sensitized and challenged mice. DJ-1 KO mice exhibited reduced airway eosinophil infiltration and goblet cell differentiation. Mechanistically, we discovered that eosinophil-club cell interactions are reduced in the absence of DJ-1. Organoid cultures indicated that eosinophils impair the proliferative potential of club cells. Intratracheal transplantation of DJ-1-deficient eosinophils suppresses airway goblet cell differentiation. Loss of DJ-1 inhibits the metabolism of arachidonic acid into cysteinyl leukotrienes in eosinophils while these secreted metabolites promote airway goblet cell fate in organoid cultures and in vivo. CONCLUSIONS: DJ-1-mediated interactions between airway epithelial progenitor cells and immune cells are essential in controlling airway goblet cell metaplasia and eosinophilia. Blockade of the DJ-1 pathway is protective against airway allergic inflammation.
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Eosinofilia , Eosinófilos , Camundongos , Animais , Ovalbumina , Inflamação , Líquido da Lavagem Broncoalveolar , Pulmão , Camundongos Knockout , Comunicação Celular , Células-Tronco , Camundongos Endogâmicos BALB CRESUMO
Exportin 1 (XPO1) is an important transport receptor that mediates the nuclear export of various proteins and RNA. KPT-8602 is a second-generation inhibitor of XPO1, demonstrating the lowest level of side effects, and is currently in clinical trials for the treatment of cancers. Previous studies suggest that several first-generation inhibitors of XPO1 demonstrate anti-inflammation activities, indicating the application of this drug in inflammation-related diseases. In this study, our results suggested the potent anti-inflammatory effect of KPT-8602 in vitro and in vivo. KPT-8602 inhibited the activation of the NF-κB pathway by blocking the phosphorylation and degradation of IκBα, and the priming of NLRP3. Importantly, the administration of KPT-8602 attenuated both lipopolysaccharide (LPS)-induced peripheral inflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroinflammation in vivo. In addition, the tissue damage was also ameliorated by KPT-8602, indicating that KPT-8602 could be used as a novel potential therapeutic agent for the treatment of inflammasome-related diseases such as Parkinson's disease, through the regulation of the NF-κB signaling pathway and the NLRP3 inflammasome.
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Background: Non-motor symptoms, including sleep disorders and depression, are common in Parkinson's disease (PD). The purpose of our study is to explore the effect of sleep disorders, including the probable rapid eye movement (REM) sleep behavior disorder (pRBD) and the daytime sleepiness, on depressive symptoms in patients with early and prodromal PD. Methods: A total of 683 participants who obtained from the Parkinson Progression Markers Initiative (PPMI) were included, consisting of 423 individuals with early PD, 64 individuals with prodromal PD, and 196 healthy controls (HCs), who were followed up to 5 years from baseline. Multiple linear regression models and linear mixed-effects models were conducted to explore the relationship between sleep disorders and depression at baseline and longitudinally, respectively. Multiple linear regression models were used to further investigate the association between the change rates of daytime sleepiness score and depression-related score. Mediation analyses were also performed. Results: At baseline analysis, individuals with early and prodromal PD, who had higher RBD screening questionnaire (RBDSQ) score, or who were considered as pRBD, or who manifested specific behaviors of RBD (things falling down when sleep or disturbance of sleep), showed significantly the higher score of depression-related questionnaires. Our 5-year follow-up study showed that sleep disorders, including pRBD and daytime sleepiness, were associated with the increased depressive-related score in individuals with early and prodromal PD. Interestingly, we also found that the increased possibilities of daytime sleepiness were associated with depressive-related score. Finally, mediation analysis demonstrated that the relationship between RBD and depressive symptoms was partially mediated by autonomic symptoms, such as postural hypertension, salivation, dysphagia, and constipation. Conclusion: Our study shows that sleep disorders, including pRBD and daytime sleepiness, are associated with depression at baseline and longitudinally, which is partially mediated by the autonomic dysfunction in early and prodromal PD, with an implication that sleep management is of great value for disease surveillance.