The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

Wang, Weijun; Zhang, Yaxing; Yang, Ling; Li, Hongliang

doi:10.1016/j.canlet.2016.06.004

Cited by 19 publications

(8 citation statements)

References 218 publications

(238 reference statements)

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“…As NAFLD is closely linked to a chronic inflammatory response, the expression levels of inflammatory mediators in the liver samples were measured. The levels of pro‐inflammatory cytokines [including IL‐1β , IL‐6, CCL2, CCL4, intercellular cell adhesion molecule‐1 (ICAM1) and TNF‐α] (Figure E) and innate immunity components [TLR4, TLR2, Cd14 , TRIF ‐ related adaptor molecule (TRAM), IL‐1 receptor‐associated kinase 4 (IRAK4) and TGF‐β activated kinase 1 (MAP3K7)‐binding protein 1 (TAB1)] (Wang et al ., ) (Figure F) were significantly higher in HFD‐treated mice than those in the control group, but the gene expression levels of these pro‐inflammatory cytokines and signalling molecules were markedly decreased by TUDCA.…”

Section: Resultsmentioning

confidence: 95%

Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non‐alcoholic fatty liver disease

Wang

Zhao

Gui

et al. 2018

British J Pharmacology

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147

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The gut-liver axis is associated with the progression of non-alcoholic fatty liver disease (NAFLD). Targeting the gut-liver axis and bile acid-based pharmaceuticals are potential therapies for NAFLD. The effect of tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD, on intestinal barrier function, intestinal inflammation, gut lipid transport and microbiota composition was analysed in a murine model of NAFLD. EXPERIMENTAL APPROACHThe NAFLD mouse model was established by feeding mice a high-fat diet (HFD) for 16 weeks. TUDCA was administered p.o. during the last 4 weeks. The expression levels of intestinal tight junction genes, lipid metabolic and inflammatory genes were determined by quantitative PCR. Tissue inflammation was evaluated by haematoxylin and eosin staining. The gut microbiota was analysed by 16S rRNA gene sequencing. KEY RESULTSTUDCA administration attenuated HFD-induced hepatic steatosis, inflammatory responses, obesity and insulin resistance in mice. Moreover, TUDCA attenuated gut inflammatory responses as manifested by decreased intestinal histopathology scores and inflammatory cytokine levels. In addition, TUDCA improved intestinal barrier function by increasing levels of tight junction molecules and the solid chemical barrier. The components involved in ileum lipid transport were also reduced by TUDCA administration in HFD-fed mice. Finally, the TUDCA-treated mice showed a different gut microbiota composition compared with that in HFD-fed mice but similar to that in normal chow diet-fed mice. CONCLUSIONS AND IMPLICATIONSTUDCA attenuates the progression of HFD-induced NAFLD in mice by ameliorating gut inflammation, improving intestinal barrier function, decreasing intestinal fat transport and modulating intestinal microbiota composition. Abbreviations ACOX1, peroxisomal acyl-CoA oxidase 1; ANOSIM, analysis of similarities; C3GNT, core 3β1,3-N-acetyl glucosaminyltransferase; CYP7a, cholesterol 7α-hydroxylase; ER, endoplasmic reticulum; FABP, fatty acid-binding protein; FATP4, fatty acid transport protein 4; FAR3, fatty acid receptor 3; H&E, haematoxylin and eosin; HFD, high-fat diet; HOMA-IR, homeostasis model assessment of the insulin resistance index; Iap, intestinal alkaline phosphatase; ICAM1, intercellular cell adhesion molecule-1; IPGTT, i.p. glucose tolerance test; IPITT, i.p. insulin tolerance test; Irak4, IL-1 receptor-associated kinase 4; JAM, junctional adhesion molecule; Lcad, long-chain acyl-CoA dehydrogenase; NAFLD, non-alcoholic fatty liver disease; NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic steatohepatitis; NCD, normal chow diet; OTU, operational taxonomic unit; PCoA, principal coordinates analysis; Tab1, TGF-β activated kinase 1 mitogen-activated protein kinase kinase kinase 7-binding protein 1; TC, total cholesterol; TEERs, transepithelial electrical resistances; TGs, triglycerides; TLR, toll-like receptor; Tram, toll or IL-1 receptor domain-containing adaptor inducing IFN-β-related adaptor molecule; TUDCA, tauroursodeoxycholic acid; UDCA...

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Section: Resultsmentioning

confidence: 95%

Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non‐alcoholic fatty liver disease

Wang

Zhao

Gui

et al. 2018

British J Pharmacology

Self Cite

147

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“…The abundant blood supply and unique sinusoid microstructure place the liver at the frontline in immune responses, and its profound functions provide a significant barrier in the development of immune responses . The blood supplied to the liver is enriched in pathogen‐associated molecular patterns (PAMPs), microbe‐associated molecular patterns (MAMPs), and the danger‐associated molecular patterns (DAMPs) . Microbiota dysbiosis and intestinal permeation disorders, which are always a feature of MetS, induce plentiful gut‐derived products translocated into portal circulation, provoking the immune responses and chronic inflammation in the liver via PAMPs.…”

Section: Pathogenesismentioning

confidence: 99%

“…Furthermore, TLR9 is also implicated as a sensor of free genomic double‐stranded DNA (dsDNA) released during the apoptosis, a cell death process . TLRs can also located on the endosome and they can regulate the downstream molecules including interferon regulatory factors (IRFs) and NF‐κB via MyD88‐ and TRIF‐dependent pathway …”

Section: Pathogenesismentioning

confidence: 99%

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

et al. 2018

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Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease which affects ≈25% of the adult population worldwide, placing a tremendous burden on human health. The disease spectrum ranges from simple steatosis to steatohepatitis, fibrosis, and ultimately, cirrhosis and carcinoma, which are becoming leading reasons for liver transplantation. NAFLD is a complex multifactorial disease involving myriad genetic, metabolic, and environmental factors; it is closely associated with insulin resistance, metabolic syndrome, obesity, diabetes, and many other diseases. Over the past few decades, countless studies focusing on the investigation of noninvasive diagnosis, pathogenesis, and therapeutics have revealed different aspects of the mechanism and progression of NAFLD. However, effective pharmaceuticals are still in development. Here, the current epidemiology, diagnosis, animal models, pathogenesis, and treatment strategies for NAFLD are comprehensively reviewed, emphasizing the outstanding breakthroughs in the above fields and promising medications in and beyond phase II.

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“…Notably, dysregulation of inflammasome activation can contribute to a multitude of inflammatory diseases, as well as to auto-immune disorders, cardiometabolic diseases, microbiome homeostasis, cancer, neurological disorders and more. The substantive role of NLRs in disease has been reviewed extensively so is not the focus of this article (see topical reviews: [ 7 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Due to the significance of NLRs in disease and their characterization as critical drug targets to modulate inflammation, the biochemical and structural interrogation of NLRs has emerged as an area of vigorous investigation.…”

Section: The Nlr Inflammasomesmentioning

confidence: 99%

ATP-Binding and Hydrolysis in Inflammasome Activation

2020

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The prototypical model for NOD-like receptor (NLR) inflammasome assembly includesnucleotide-dependent activation of the NLR downstream of pathogen- or danger-associatedmolecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomericplatforms that lie upstream of inflammatory responses associated with innate immunity. Asmembers of the STAND ATPases, the NLRs are generally thought to share a similar model of ATPdependentactivation and effect. However, recent observations have challenged this paradigm toreveal novel and complex biochemical processes to discern NLRs from other STAND proteins. Inthis review, we highlight past findings that identify the regulatory importance of conserved ATPbindingand hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explorerecent breakthroughs that generate connections between NLR protein structure and function.Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectiveson the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations ofNLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctionsin nucleotide-binding domain topology with occupancy of ATP or ADP that are in turndisseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATPbindingand hydrolysis properties of NACHT domains in different NLRs integrate with signalingmodules and binding partners to control innate immune responses at the molecular level.

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The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

Cited by 19 publications

References 218 publications

Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non‐alcoholic fatty liver disease

Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non‐alcoholic fatty liver disease

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

ATP-Binding and Hydrolysis in Inflammasome Activation

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