Norisoboldine, a natural aryl hydrocarbon receptor agonist, alleviates TNBS-induced colitis in mice, by inhibiting the activation of NLRP3 inflammasome

Lv, Qi; Wang, Kai; Qiao, Simiao; Dai, Yue; Wei, Zhifeng

doi:10.1016/s1875-5364(18)30044-x

Cited by 24 publications

(22 citation statements)

References 51 publications

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“…Studies also reveal that NOR promotes T reg cell differentiation from naïve T-cells in-vitro and increased its immunosuppressive effects on T eff cells through inducing apoptotic events and inhibiting T h 1 and T h 17 differentiation [170,171]. In the context of IBD, NOR has also been demonstrated to reduce NLRP3, ASC and caspase-1 expression in TNBS-induced mice, which could imply that NOR has inhibitory effects on NLRP3 inflammasome activation through an AhR pathway [169]. The study further found a link between NOR and Nrf2, a nuclear transcriptional factor of Cap'n' Collar family that can inhibit NLRP3 priming [172], as the mechanism for NOR-induced inhibition of NLRP3 inflammasome activation; where NOR up-regulated the expression of Nrf2 but down-regulated the production of ROS signals in THP-1 cells [169].…”

Section: Therapeutic Potential Of Ahr As a Natural Nlrp3 Inflammasomementioning

confidence: 98%

“…Norisoboldine (NOR) is the primary isoquinoline alkaloid constituent of Radix Linderae; the dry root of Lindera aggregata (Sims) Kosterm (L. strychnifolia Vill), which is commonly used in Chinese medicine in treating a variety of ailments, which include constipation, polyuria, dyspepsia, acute and chronic colitis, chest and abdominal pain and rheumatism palsy [168,169]. NOR has been shown to be a natural AhR ligand by Qi et al through its up-regulation of CYP1A1 expression, promotion of AhR nuclear translocation after dissociation of the AhR/Hsp90 complex and transcriptional activity of AhR/ARNT via DNA binding to the XRE region in THP-1 cells [169]. Studies also reveal that NOR promotes T reg cell differentiation from naïve T-cells in-vitro and increased its immunosuppressive effects on T eff cells through inducing apoptotic events and inhibiting T h 1 and T h 17 differentiation [170,171].…”

Section: Therapeutic Potential Of Ahr As a Natural Nlrp3 Inflammasomementioning

confidence: 99%

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Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?

2020

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Inflammation is a hallmark in many forms of cancer; with colitis-associated colorectal cancer (CAC) being a progressive intestinal inflammation due to inflammatory bowel disease (IBD). While this is an exemplification of the negatives of inflammation, it is just as crucial to have some degree of the inflammatory process to maintain a healthy immune system. A pivotal component in the maintenance of such intestinal homeostasis is the innate immunity component, inflammasomes. Inflammasomes are large, cytosolic protein complexes formed following stimulation of microbial and stress signals that lead to the expression of pro-inflammatory cytokines. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been extensively studied in part due to its strong association with colitis and CAC. The aryl hydrocarbon receptor (AhR) has recently been acknowledged for its connection to the immune system aside from its role as an environmental sensor. AhR has been described to play a role in the inhibition of the NLRP3 inflammasome activation pathway. This review will summarise the signalling pathways of both the NLRP3 inflammasome and AhR; as well as new-found links between these two signalling pathways in intestinal immunity and some potential therapeutic agents that have been found to take advantage of this link in the treatment of colitis and CAC.

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Section: Therapeutic Potential Of Ahr As a Natural Nlrp3 Inflammasomementioning

confidence: 98%

Section: Therapeutic Potential Of Ahr As a Natural Nlrp3 Inflammasomementioning

confidence: 99%

Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?

2020

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“…Mechanism of action studies showed that this alkaloid prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints in adjuvant-induced arthritic rats, as a substrate of P-glycoprotein (P-gp). [270][271][272] The antiarthritic mechanism involved inhibition of inflammatory synovial hyperplasia by promoting the release of cytochrome C and regulating the expression of Bax and Bcl-2 proteins via a mitochondrial-dependent pathway, 273 as well as prevention of synovial angiogenesis by moderating the Notch1 pathway-related endothelial tip cell phenotype. 274,275 Tong et al 276 suggested that norisoboldine induced the generation of intestinal Treg cells by the activation of AhR (aryl hydrocarbon receptor) as well as promoted Treg differentiation and then reduced the development of colitis by regulating AhR/ glycolysis axis and subsequent NAD + /SIRT1/SUV39H1/H3K9me3 signaling pathway.…”

Section: Anti-inflammatory and Immunosuppressive Activitiesmentioning

confidence: 99%

“…272,278 Finally, the compound inhibited activation of the NLRP3 inflammasome by regulating the AhR/Nrf2/ ROS signaling pathway and thereby improved the TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colitis in mice. 270 NF-κB plays an important role in inflammation, sepsis and immunity. 279 Hence, great attention has been focused on compounds that produce inhibitory effects on the NF-κB pathway.…”

Section: Anti-inflammatory and Immunosuppressive Activitiesmentioning

confidence: 99%

Biologically active isoquinoline alkaloids covering 2014–2018

Shang

Yang

Morris‐Natschke

et al. 2020

Medicinal Research Reviews

116

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Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014-2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti-inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids.

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“…Therefore, the expression levels of CYP1A may be a marker of AhR activation. AhR ligands, such as FICZ and ITE, have been shown to attenuate experimental colitis and restore the Th17 /Treg cell balance by inhibiting Th17 cell differentiation and promoting Treg cell formation (13,14). A previous study demonstrated that ITE could inhibit T cell-mediated immunity by acting on the DCs (15).…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Ameliorates Experimental Colitis by Modulating the Tolerogenic Dendritic and Regulatory T Cell Formation

Cui

Wang

et al. 2020

Preprint

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Background Intestinal immune dysfunction is involved in the onset of Crohn's disease (CD). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor widely expressed in various immune cells, including DCs. Although AhR plays an important role in immune tolerance, its role in the DCs is unclear. The purpose of this study was to investigate whether the activation of AhR can induce tolerogenic DCs (tolDCs) and the differentiation of regulatory T (Treg) cells, as well as ameliorate experimental colitis. Methods Bone marrow derived DCs were incubated with or without FICZ(100 nM) which was a kind of AhR for 12 hours, subsequently the cells were stimulated to mature. Scanning electron microscope (SEM) was used to observe dendritic formation on DC surface. Proliferation of T lymphocytes was evaluated by proliferation experiment. The expression of surface markers in DCs were detected by flow cytometry and the gene expression levels of cytokines were measured using RT-qPCR. The levels of cytokines in cell supernatants were determined by ELISA. The expression of cytochrome P450 1A1(CYP1A1) and forkhead box P3 (Foxp3) were measured by Western blotting. TolDCs were transferred to murine colitis model and the intestinal inflammation were evaluated. T-helper (Th) 17 cells and Treg in spleens and mesenteric lymph nodes (MLNs) were analyzed by flow cytometry. Results AhR activation in the DCs resulted in a lower expression of surface markers such as CD80, CD83, CD86, and pro-inflammatory cytokine production, and higher anti-inflammatory production (IL-1β, IL-23, and IL-12) compared to the control DCs. The surface dendrites in DCs were significantly reduced following AhR activation by FICZ. Such DCs with FICZ-mediated activation of AhR, namely tolDCs, inhibited CD4+ T cell proliferation and promoted Treg cell differentiation. Adoptive transfer of tolDCs to a TNBS-induced colitis mouse model significantly alleviated the severity of inflammation by decreasing the frequency of Th17 cells and increasing the frequency of Treg cells. Conclusions Activation of AhR in the DCs could induce tolDCs, and the transplantation of tolDCs may help in relieving intestinal inflammation and maintaining the Th17/Treg differentiation balance. Thus, our data suggest that AhR may be a potential therapeutic target for CD.

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Norisoboldine, a natural aryl hydrocarbon receptor agonist, alleviates TNBS-induced colitis in mice, by inhibiting the activation of NLRP3 inflammasome

Cited by 24 publications

References 51 publications

Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?

Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?

Biologically active isoquinoline alkaloids covering 2014–2018

Aryl Hydrocarbon Receptor Activation Ameliorates Experimental Colitis by Modulating the Tolerogenic Dendritic and Regulatory T Cell Formation

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