Nicotine Activating α4β2 Nicotinic Acetylcholine Receptors to Suppress Neuroinflammation via JAK2-STAT3 Signaling Pathway in Ischemic Rats and Inflammatory Cells

Wang, Qi; Gou, Jinyu; Guo, Shenrui; Feng, Wei; Han, Tingting; Lai, Ruihe; Zhang, Dalong; Diao, Yun-Peng; Yin, Yilong

doi:10.1007/s12035-022-02797-4

Cited by 6 publications

(4 citation statements)

References 40 publications

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“…In vertebrates, 17 different subunits including α1-10, β1-4, δ, ε, γ have been identified for nicotinic receptors, which are grouped together as homopentamers or heteropentamers and form a large family of different types of receptors [46]. Subunits α4 and α7 also play a role in anti-inflammatory pathways and may be increased as protective factors during liver fibrosis [47,48]. α7nAChR are a family of ligand-dependent ion channels, which are composed of a homopentamer of five α7 subunits.…”

Section: Discussionmentioning

confidence: 99%

Nicotine promotes development of bile duct ligationinduced liver fibrosis by increasing expression of nicotinic acetylcholine receptors in rats

Hajiasgharzadeh,

Shahabi,

Karimi-Sales

et al. 2024

ceh

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Aim of the study: Liver fibrosis and cigarette smoking seem to be directly linked. Nicotine, as an agonist of nicotinic acetylcholine receptors (nAChRs), induces many downstream signaling pathways. The pathways through which nicotine affects the process of liver fibrosis have not been clarified. The present study aimed to investigate the nicotine-induced effects on fibrosis progression in cholestatic rats. Material and methods: First, the Wistar rats were subjected to sham or bile duct ligation (BDL) surgery. The rats were treated with low and high doses of nicotine (1 or 10 mg/kg) for three weeks. They were monitored for their body weights before and 21 days after BDL. Also, spleens were weighed to calculate the spleen/body weight ratio. Ductular proliferation and fibrosis were evaluated using hematoxylin and eosin (H&E) as well as Masson's trichrome staining. The mRNA expression of α4nAChR, α7nAChR, and fibrosis gene α-smooth muscle actin (α-SMA) was measured by real-time PCR. Results: The findings showed that nicotine promotes the development of BDL-induced liver fibrosis. The ratio of spleen/body weight was significantly affected by nicotine exposure. H&E and Masson's trichrome staining showed that the level of liver fibrosis was higher in the cholestatic BDL groups, and this effect was significantly augmented in the nicotine-treated rats. Also, α4nAChR, α7nAChR, and α-SMA expression was observed in the BDL rats and increased following nicotine treatment. Conclusions: The activation of nAChR triggers biliary proliferation and liver fibrosis. Studying the intracellular mechanism of nicotine and alteration in the expression of nicotinic receptors following nicotine exposure can be useful both in diagnosing nicotine-related diseases and finding new treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Nicotine promotes development of bile duct ligationinduced liver fibrosis by increasing expression of nicotinic acetylcholine receptors in rats

Hajiasgharzadeh,

Shahabi,

Karimi-Sales

et al. 2024

ceh

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“…The first pathway contained the transcription factors Sox2, Oct4, and Nanog, which are highly expressed in proliferative adult neurogenesis precursor cells in discrete brain regions (Suh et al, 2007;Bennett et al, 2009;Ahlfeld et al, 2017;Stevanovic et al, 2021) that are associated with Fos expression (Velazquez et al, 2015) and have been reported to be affected by nicotine (Brooks and Henderson, 2021). The second pathway was part of the immune response by JAK2-STAT3, which has been shown to be activated by nicotine through complex formation with Chrna7 or Crna4/ Chrnab2 to provide neuroprotective effects (Shaw et al, 2002;Wang et al, 2022). The third pathway brings up another very relevant transcription factor, MeCP2, which is mutated in the neurodevelopmental disorder Rett syndrome (Amir et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Hyperconnectivity of Two Separate Long-Range Cholinergic Systems Contributes to the Reorganization of the Brain Functional Connectivity during Nicotine Withdrawal in Male Mice

Carrette

Kimbrough

Davoudian

et al. 2023

eNeuro

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Chronic nicotine results in dependence with withdrawal symptoms upon discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity, however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene FOS during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity they were organized into two anticorrelated networks that were separated into basal forebrain projecting and brainstem-thalamic projecting cholinergic regions, validating a long-standing hypothesis of the organization of the brain cholinergic systems. Moreover, baseline (without nicotine) expression ofChrna2,Chrna3,Chrna10, andChrndmRNA of each brain region correlated with withdrawal-induced changes in FOS expression. Finally, by mining the Allen Brain mRNA expression database, we were able to identify 1755 gene candidates and three pathways (Sox2-Oct4-Nanog, JAK-STAT, and MeCP2-GABA) that may contribute to nicotine withdrawal-induced FOS expression. These results identify the dual contribution of the basal forebrain and brainstem-thalamic cholinergic systems to whole-brain functional connectivity during withdrawal; and identify nicotinic receptors and novel cellular pathways that may be critical for the transition to nicotine dependence.Significance StatementDiscontinuation of nicotine use in dependent users is associated with increased whole-brain activation and functional connectivity and leads to withdrawal symptoms. Here we investigated the contribution of the nicotinic cholinergic receptors and main cholinergic projecting brain areas in the whole-brain changes associated with withdrawal. This not only allowed us to visualize and confirm the previously described duality of the cholinergic brain system using this novel methodology, but also identify nicotinic receptors together with 1751 other genes that contribute, and could thus be targets for treatments against, nicotine withdrawal and dependence.

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“…However, the therapeutic use of JAK inhibitors is still under investigation, and their molecular mechanisms are not yet clear ( 47 ). The JAK2-STAT3 signaling pathway is reportedly involved in cognitive improvement ( 48 ), and the SOCS1/JAK2/STAT3 axis has been shown to regulate early brain injury induced by subarachnoid hemorrhage through inflammatory responses ( 49 ). De novo JAK2 and MAPK7 mutations closely associated with ASD have been identified using whole-exome sequencing in Chinese children and adolescent trio samples ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of genomic and immune infiltration patterns in autism spectrum disorder

Wei¹,

Guo²,

Wu³

et al. 2022

Ann Transl Med

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Background: Autism spectrum disorder (ASD) is a specific type of pervasive developmental disorder, and most studies suggest that the onset of autism may be related to genetic and immune factors. The etiology of autism and the underlying molecular events need to be further addressed. Methods:The ASD-related dataset GSE18123 was downloaded from the Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) was used to screen for Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that may be associated with autism. The top 5,000 genes with an absolute median difference were obtained, and a co-expression network was constructed using weighted correlation network analysis (WGCNA). In addition, GO and KEGG enrichment analyses were performed for genes in the modules most closely related to ASD. Hub genes were found in the significant modules, and the expression values and receiver operating characteristic (ROC) curves of the hub genes were analyzed and validated. Immune cell infiltration in ASD was calculated using the CIBERSORT algorithm, and the relationship between hub genes and immune cells was analyzed. Finally, GSEA was used to explore the potential pathways of hub genes affecting ASD. Results:The 5,000 DEGs were divided into eight significant modules by WGCNA. The green module was most significantly associated with ASD, and two hub genes [fatty acid-binding protein 2 (FABP2) and Janus kinase 2 (JAK2)] were found. Immune cell infiltration showed that resting dendritic cells and monocytes differed significantly in ASD and healthy individuals. FABP2 was significantly associated with memory B cells and CD8 T cells. JAK2 was significantly associated with monocytes, CD4 activated memory T cells, CD4 resting memory T cells, activated dendritic cells, gamma delta T cells, regulatory T cells (Tregs), CD8 T cells, and naïve CD4 T cells. FABP2 and JAK2 were found to affect multiple pathways of immunity.Conclusions: FABP2 and JAK2 may influence the immune microenvironment of ASD by regulating immune cells and immune-related pathways and are candidate molecular markers for the development of ASD.

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Nicotine Activating α4β2 Nicotinic Acetylcholine Receptors to Suppress Neuroinflammation via JAK2-STAT3 Signaling Pathway in Ischemic Rats and Inflammatory Cells

Cited by 6 publications

References 40 publications

Nicotine promotes development of bile duct ligationinduced liver fibrosis by increasing expression of nicotinic acetylcholine receptors in rats

Nicotine promotes development of bile duct ligationinduced liver fibrosis by increasing expression of nicotinic acetylcholine receptors in rats

Hyperconnectivity of Two Separate Long-Range Cholinergic Systems Contributes to the Reorganization of the Brain Functional Connectivity during Nicotine Withdrawal in Male Mice

Bioinformatics analysis of genomic and immune infiltration patterns in autism spectrum disorder

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