Dataset Information

Gut-Sourced Vasoactive Intestinal Polypeptide Induced by the Activation of ?7 Nicotinic Acetylcholine Receptor Substantially Contributes to the Anti-inflammatory Effect of Sinomenine in Collagen-Induced Arthritis.

ABSTRACT: Sinomenine has long been used for the treatment of rheumatoid arthritis in China. However, its anti-inflammatory mechanism is still debatable because the in vitro minimal effective concentration (?250 ?M) is hardly reached in either synovium or serum after oral administration at a therapeutic dose. Recent findings suggest that the ?7 nicotinic acetylcholine receptor (?7nAChR) might mediate the inhibitory effect of sinomenine on macrophage activation, which attracts us to explore the anti-arthritis mechanism of sinomenine by taking neuroendocrine-inflammation axis into consideration. Here, we showed that orally administered sinomenine ameliorated the systemic inflammation of collagen-induced arthritis (CIA) rats, which was significantly diminished by either vagotomy or the antagonists of nicotinic acetylcholine receptors (especially the antagonist of ?7nAChR), but not by the antagonists of muscarinic receptor. Sinomenine might bind to ?7nAChR through interacting with the residues Tyr184 and Tyr191 in the pocket. In addition, the generation of vasoactive intestinal polypeptide (VIP) from the gut of CIA rats and cultured neuron-like cells was selectively enhanced by sinomenine through the activation of ?7nAChR-PI3K/Akt/mTOR pathway. The elevated levels of VIP in the serum and small intestine of rats were negatively correlated with the scores of joint destruction. The crucial role of VIP in the anti-arthritic effect of sinomenine was confirmed by using VIP hybrid, a non-specific antagonist of VIP receptor. Taken together, intestine-sourced VIP mediates the anti-arthritic effect of sinomenine, which is generated by the activation of ?7nAChR.

SUBMITTER: Yue M

PROVIDER: S-EPMC6028598 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Gut-Sourced Vasoactive Intestinal Polypeptide Induced by the Activation of α7 Nicotinic Acetylcholine Receptor Substantially Contributes to the Anti-inflammatory Effect of Sinomenine in Collagen-Induced Arthritis.

Yue MengFan M Zhang XinYu X Dou YanNong Y Wei ZhiFeng Z Tao Yu Y Xia YuFeng Y Dai Yue Y

Frontiers in pharmacology 20180626

Sinomenine has long been used for the treatment of rheumatoid arthritis in China. However, its anti-inflammatory mechanism is still debatable because the <i>in vitro</i> minimal effective concentration (≥250 μM) is hardly reached in either synovium or serum after oral administration at a therapeutic dose. Recent findings suggest that the α7 nicotinic acetylcholine receptor (α7nAChR) might mediate the inhibitory effect of sinomenine on macrophage activation, which attracts us to explore the anti- ...[more]

PMID: 29997506

Similar Datasets

Project description:PurposeThe α7 nicotinic acetylcholine receptor (nAChR) is widely expressed in the nervous system, including in the inner retinal neurons in all species studied to date. Although reductions in the expression of α7 nAChRs are thought to contribute to the memory and visual deficits reported in Alzheimer's disease (AD) and schizophrenia , the α7 nAChR knockout (KO) mouse is viable and has only slight visual dysfunction. The absence of a major phenotypic abnormality may be attributable to developmental mechanisms that serve to compensate for α7 nAChR loss. We hypothesized that the upregulation of genes encoding other nAChR subunits or muscarinic acetylcholine receptor (mAChR) subtypes during development partially accounts for the absence of major deficiencies in the α7 nAChR KO mouse. The purpose of this study was to determine whether the deletion of the α7 nAChR subunit in a mouse model resulted in changes in the regulation of other cholinergic receptors or other ion channels in an α7 nAChR KO mouse when compared to a wild-type (WT) mouse.MethodsTo examine gene expression changes, we employed a quantitative real-time polymerase chain reaction (qPCR) using whole retina RNA extracts as well as RNA extracted from selected regions of the retina. These extracts were collected using laser capture microdissection (LCM). The presence of acetylcholine receptor (AChR) subunit and subtype proteins was determined via western blotting. To determine any differences in the number and distribution of choline acetyltransferase (ChAT) amacrine cells, we employed wholemount and vertical immunohistochemistry (IHC) and cell counting. Additionally, in both WT and α7 nAChR KO mouse retinas, the distribution of the nAChR subunit and mAChR subtype proteins were determined via IHC for those KO mice that experienced mRNA changes.ResultsIn the whole retina, there was a statistically significant upregulation of α2, α9, α10, β4, nAChR subunit, and m1 and m4 mAChR subtype transcripts in the α7 nAChR KO mice. However, the retinal layers showed complex patterns of transcript expression. In the ganglion cell layer (GCL), m2 and m4 mAChR subtype transcripts were significantly upregulated, while β3 and β4 nAChR subunit transcripts were significantly downregulated. In the inner portion of the inner nuclear layer (iINL), α2, α9, β4, nAChR subunit, and m3 and m4 mAChR subtype transcripts were significantly downregulated. In the outer portion of the inner nuclear layer (oINL), β2, β4, and m4 AChR subunit transcripts were significantly upregulated. Western blot experiments confirmed the protein expression of α3-α5 and α9-containing nAChR subunits and m1-m2 mAChR subtypes in mouse retinas. IHC results supported many of the mRNA changes observed. Finally, this is the first report of α9 and α10 nAChR subunit expressions in the retina of any species.ConclusionsRather than a simple upregulation of a single AChR subunit or subtype, the absence of the α7 nAChR in the KO mice was associated with complex layer-specific changes in the expression of AChR subunits and subtypes.

Dataset Information

Gut-Sourced Vasoactive Intestinal Polypeptide Induced by the Activation of ?7 Nicotinic Acetylcholine Receptor Substantially Contributes to the Anti-inflammatory Effect of Sinomenine in Collagen-Induced Arthritis.

Publications

Gut-Sourced Vasoactive Intestinal Polypeptide Induced by the Activation of α7 Nicotinic Acetylcholine Receptor Substantially Contributes to the Anti-inflammatory Effect of Sinomenine in Collagen-Induced Arthritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets