A rapid administration of <scp>GW</scp>4064 inhibits the <scp>NLRP</scp>3 inflammasome activation independent of farnesoid X receptor agonism

Xie, Shujun; Guo, Chao; Chi, Zhexu; Huang, Bo; Wu, Yihua; Wang, Di; Xia, Dajing

doi:10.1002/1873-3468.12782

Cited by 17 publications

(15 citation statements)

References 48 publications

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“…It has been suggested that FXR involves in the regulation of cholestasis-associated sepsis, which can be mediated by the negative regulation of NACHT, leucin-rich-repeat (LRR), and pyrin (PYD) domains-containing protein 3 (NLRP3) inflammasome via the direct binding of FXR to NLRP3 and caspase 1 in macrophages [ 81 , 82 ]; thus, the FXR deficiency sensitized the mice to endotoxemia shock. Furthermore, the GW4064 inhibited the NLRP3 inflammasome activation independent of the FXR activation in macrophages [ 83 ]. These results suggest the potential roles of FXR agonism in the treatment of NLRP3-related diseases.…”

Section: Biological Roles Of Fxr In Various Organs and The Inter-omentioning

confidence: 99%

Update on FXR Biology: Promising Therapeutic Target?

Han

2018

IJMS

151

108

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Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addition, FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clinical and clinical investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biology in various organs and the gut–liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacological aspects of FXR modulation for rational therapeutic strategies and novel drug development.

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Section: Biological Roles Of Fxr In Various Organs and The Inter-omentioning

confidence: 99%

Update on FXR Biology: Promising Therapeutic Target?

Han

2018

IJMS

151

108

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“…Thus, these FXR agonists can be used to target NLRP3 inflammasome due to the negative effect of FXR activation on NLRP3 inflammasome and CASP1. For example, GW4064 is a molecular agonist for FXR and inhibits NLRP3 inflammasome in FXR-independent manner 388. GW4064 inhibits the oligomerization and ubiquitination of ASC, a critical step for NLRP3 inflammasome activation, and partially protects from the symptoms of NLRP3-dependent inflammatory diseases including sepsis in animal models.…”

Section: Future Perspectivementioning

confidence: 99%

Inflammasomes: Pandora’s box for sepsis

Kumar

2018

JIR

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Sepsis was known to ancient Greeks since the time of great physician Hippocrates (460–377 BC) without exact information regarding its pathogenesis. With time and medical advances, it is now considered as a condition associated with organ dysfunction occurring in the presence of systemic infection as a result of dysregulation of the immune response. Still with this advancement, we are struggling for the development of target-based therapeutic approach for the management of sepsis. The advancement in understanding the immune system and its working has led to novel discoveries in the last 50 years, including different pattern recognition receptors. Inflammasomes are also part of these novel discoveries in the field of immunology which are <20 years old in terms of their first identification. They serve as important cytosolic pattern recognition receptors required for recognizing cytosolic pathogens, and their pathogen-associated molecular patterns play an important role in the pathogenesis of sepsis. The activation of both canonical and non-canonical inflammasome signaling pathways is involved in mounting a proinflammatory immune response via regulating the generation of IL-1β, IL-18, IL-33 cytokines and pyroptosis. In addition to pathogens and their pathogen-associated molecular patterns, death/damage-associated molecular patterns and other proinflammatory molecules involved in the pathogenesis of sepsis affect inflammasomes and vice versa. Thus, the present review is mainly focused on the inflammasomes, their role in the regulation of immune response associated with sepsis, and their targeting as a novel therapeutic approach.

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“…If the levels of FXR expression are inappropriate, bile acid secretion and reabsorption disorders may occur, and bile will accumulate in the bile duct [21][22][23]. So cholesterol and bile pigments may accumulate in bile ducts, leading to the formation of stones.…”

Section: Discussionmentioning

confidence: 99%

FXR expression in a rat model of hilar cholangiocarcinoma

Zhang

Wang

2020

Preprint

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AIM: To develop a rat model of hilar cholangiocarcinoma and detect Farnesyl X receptor (FXR) expression in hilar cholangiocarcinoma tissues of this model, in order to provide a new method for the treatment of hilar cholangiocarcinoma. METHODS: Forty male Wistar rats (body weight, 185 ± 5 g) were randomly divided into two groups (n = 20 each) as follows: The control group was fed a standard diet, and the experimental group was injected by cholangiocarcinoma QBC939 cell suspension along the hilar bile duct into the bile duct bifurcation with microsyringe. Every day note the rats’ mental state, diet, and fur condition. At 4 weeks, one rat of the experimental group was sacrificed after it was administered anesthesia, and we recorded changes in hilar bile duct size, texture, and form. This procedure was repeated at 6 weeks. After 6 weeks, , hilar cholangiocarcinoma developed only in the experimental group, thereby establishing an experimental model for studying QBC939-induced hilar cholangiocarcinoma. Tumor formation was confirmed by pathological examination, and hilar bile duct tissues were harvested from both the groups. A real-time polymerase chain reaction assay and an immunohistochemical assay were used to analyze the expression of FXR in hilar cholangiocarcinoma and normal hilar bile duct tissues. RESULTS: From the second week, the rats in experimental group began to eat less, and their body mass decreased compared with controls. After 6 weeks, we detected hilar cholangiocarcinoma in 17 rats (85%) in the experimental group. In the experimental group with hilar cholangiocarcinoma, we found that the levels of total cholesterol, total bilirubin, and direct bilirubin were higher compared with those of the control group. Simultaneously, muddy stones emerged from the bile ducts of rats in the experimental group. The FXR /Gapdh mRNA ratio in hilar cholangiocarcinoma and normal hilar bile duct tissues differed markedly (16 and 35, respectively). Light microscopy revealed a granular pattern of FXR expression which reacted with the anti- FXR antibody. Each section was randomly divided into six regions, with 80 cells were observed in every region. Sections with >10% positive cells were designated positive, Sections with <10% positive cells were designated negative. Each group included 4,800 cells. In the experimental group, 1,196 cells (24.9%) were positive and 3,538 cells (73.7%) were positive in the control group, and this difference was statistically significant (χ2 = 10.35, P < 0.05). CONCLUSION: FXR expression significantly decreased in hilar cholangiocarcinoma of rats than in those of controls, suggesting that drugs targeting FXR may be a new strategy for hilar cholangiocarcinoma.

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A rapid administration of GW4064 inhibits the NLRP3 inflammasome activation independent of farnesoid X receptor agonism

Cited by 17 publications

References 48 publications

Update on FXR Biology: Promising Therapeutic Target?

Update on FXR Biology: Promising Therapeutic Target?

Inflammasomes: Pandora’s box for sepsis

FXR expression in a rat model of hilar cholangiocarcinoma

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A rapid administration of GW4064 inhibits the NLRP3 inflammasome activation independent of farnesoid X receptor agonism

Cited by 17 publications

References 48 publications

Update on FXR Biology: Promising Therapeutic Target?

Update on FXR Biology: Promising Therapeutic Target?

Inflammasomes: Pandora&rsquo;s box for sepsis

FXR expression in a rat model of hilar cholangiocarcinoma

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Product

Resources

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Inflammasomes: Pandora’s box for sepsis