scholarly journals NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling

2016 ◽  
Vol 130 (20) ◽  
pp. 1793-1806 ◽  
Author(s):  
Elisa Vivoli ◽  
Andrea Cappon ◽  
Stefano Milani ◽  
Benedetta Piombanti ◽  
Angela Provenzano ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Herbal Supplement ◽  
Tissue Inflammation ◽  
Murine Liver ◽  
Novel Target

Berberine is widely used as a herbal supplement for different hepatic abnormalities, In this study we identify inhibition of inflammasome activation, a potent pathway to amplify tissue inflammation, as a novel target of the action of berberine in the liver.

scholarly journals Epimedin B Through Enhancing NLRP3 Inflammasome Activation To Induces Idiosyncratic Hepatotoxicity

2021 ◽  
Author(s):  
Yuan Gao ◽  
Wei Shi ◽  
Can Tu ◽  
Guanyu Zhao ◽  
Guang Xu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Bone Fractures ◽  
Inflammasome Activation ◽  
Promoting Effect ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Nlrp3 Inflammasome Activation ◽  
Synergistic Induction ◽  
Induce Liver Injury

Abstract Background: The NLRP3 inflammasome plays a crucial role in the pathogenesis of various human diseases, also idiosyncratic drug-induced liver injury (IDILI). Epimedii Folium (EF) is commonly used for treating bone fractures, joint diseases and some chronic illness, but the EF also could induce IDILI. Several studies have confirmed that EF may induce liver injury by upregulating the activity of the NLRP3 inflammasome. However, the major active constituents of EF have not been well-studied. Results: In the present study, we showed that epimedin B, a major active ingredient of EF, induced the development of IDILI by promoting the activation of the NLRP3 inflammasome. Synergistic induction of mitochondrial reactive oxygen species was a crucial contributor to the promoting effect of epimedin B observed on nigericin- or ATP-induced NLRP3 inflammasome activation. Importantly, epimedin B induced liver injury in the LPS-mediated susceptibility mouse model of IDILI，while specifical NLRP3 inhibitor MCC950 pretreatment completely abrogated the Caspase-1 activation and IL-1β secretion then couldn't induce liver injury. Conclusions: Epimedin B specifically facilitated nigericin- or ATP-induced NLRP3 inflammasome activation and the development of IDILI, which is responsible for EF-induced liver injury. These findings suggest that epimedin B is one of the key constituents of liver injury caused by EF，the content of epimedin B in EF may be a risk factor for IDILI, especially in patients with diseases related to nigericin- or ATP-induced NLRP3 inflammasome activation.

scholarly journals Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2618
Author(s):  
Theresa Maria Holtmann ◽  
Maria Eugenia Inzaugarat ◽  
Jana Knorr ◽  
Lukas Geisler ◽  
Marten Schulz ◽  
...  
Keyword(s):  
Bile Acids ◽  
Liver Damage ◽  
Nlrp3 Inflammasome ◽  
Lithocholic Acid ◽  
Ex Vivo ◽  
Cell Types ◽  
Inflammasome Activation ◽  
Inflammatory Phenotype ◽  
Murine Liver ◽  
A Cell

Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.

scholarly journals Protective Role of Shiitake Mushroom-Derived Exosome-Like Nanoparticles in D-Galactosamine and Lipopolysaccharide-Induced Acute Liver Injury in Mice

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 477 ◽  
Author(s):  
Baolong Liu ◽  
Yizhu Lu ◽  
Xingyi Chen ◽  
Philma Glora Muthuraj ◽  
Xingzhi Li ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Acute Liver Injury ◽  
Therapeutic Potential ◽  
Disease Model ◽  
Protective Role ◽  
Therapeutic Interventions ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Shiitake Mushroom

Fulminant hepatic failure (FHF) is a rare, life-threatening liver disease with a poor prognosis. Administration of D-galactosamine (GalN) and lipopolysaccharide (LPS) triggers acute liver injury in mice, simulating many clinical features of FHF in humans; therefore, this disease model is often used to investigate potential therapeutic interventions to treat FHF. Recently, suppression of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome, was shown to alleviate the severity of GalN/LPS-induced liver damage in mice. Therefore, the goal of this study was to find dietary exosome-like nanoparticles (ELNs) with therapeutic potential in curbing FHF by suppressing the NLRP3 inflammasome. Seven commonly consumed mushrooms were used to extract ELNs. These mushrooms were found to contain ELNs composed of RNAs, proteins, and lipids. Among these mushroom-derived ELNs, only shiitake mushroom-derived ELNs (S-ELNs) substantially inhibited NLRP3 inflammasome activation by preventing inflammasome formation in primary macrophages. S-ELNs also suppressed the secretion of interleukin (IL)-6, as well as both protein and mRNA levels of the Il1b gene. Remarkably, pre-treatment with S-ELNs protected mice from GalN/LPS-induced acute liver injury. Therefore, S-ELNs, identified as potent new inhibitors of the NLRP3 inflammasome, represent a promising class of agents with the potential to combat FHF.

scholarly journals Irisin Contributes to the Hepatoprotection of Dexmedetomidine during Intestinal Ischemia/Reperfusion

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Xin Fan ◽  
Juan Du ◽  
Mao-Hua Wang ◽  
Jia-Man Li ◽  
Bo Yang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Neutralizing Antibody ◽  
Inflammasome Activation ◽  
High Morbidity ◽  
Antibody Treatment ◽  
Sod Activity ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia/reperfusion (I/R), which is associated with high morbidity and mortality, is also accompanied with abnormal energy metabolism and liver injury. Irisin, a novel exercise-induced hormone, can regulate adipose browning and thermogenesis. The following study investigated the potential role of dexmedetomidine in liver injury during intestinal I/R in rats. Adult male Sprague–Dawley rats underwent occlusion of the superior mesenteric artery for 90 min followed by 2 h of reperfusion. Dexmedetomidine or irisin-neutralizing antibody was intravenously administered for 1 h before surgery. The results demonstrated that severe intestine and liver injuries occurred during intestinal I/R as evidenced by pathological scores and an apparent increase in serum diamine oxidase (DAO), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels. In addition, the hepatic irisin, cleaved caspase-3, Bax, and NLRP3 inflammasome components (including NLRP3, ASC, and caspase-1), protein expressions, apoptotic index, reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 6 levels increased; however, the serum irisin level and hepatic Bcl-2 protein expression and superoxide dismutase (SOD) activity decreased after intestinal I/R. Interestingly, dexmedetomidine could reduce the above listed changes and increase the irisin levels in plasma and the liver in I/R rats. Dexmedetomidine-mediated protective effects on liver injury and NLRP3 inflammasome activation during intestinal I/R were partially abrogated via irisin-neutralizing antibody treatment. The results suggest that irisin might contribute to the hepatoprotection of dexmedetomidine during intestinal ischemia/reperfusion.

scholarly journals Icarisid I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity

2020 ◽  
Author(s):  
Yuan Gao ◽  
Guang Xu ◽  
Li Ma ◽  
Wei Shi ◽  
Zhilei Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Bone Fractures ◽  
Reactive Oxygen ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Hepatocyte Apoptosis ◽  
Specific Stimulus ◽  
Nlrp3 Inflammasome Activation

Abstract Background Epimedii Folium(EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI. Methods Mouse were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo. Results Icariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mice model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation. Conclusions Our study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI.

scholarly journals Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity

2020 ◽  
Author(s):  
Yuan Gao ◽  
Zhaofang Bai ◽  
Xiaohe Xiao ◽  
guang Xu ◽  
ming Niu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Bone Fractures ◽  
Reactive Oxygen ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Hepatocyte Apoptosis ◽  
Specific Stimulus ◽  
Nlrp3 Inflammasome Activation

Abstract Background: Epimedii Folium(EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI.Methods: Mouse were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo.Results: Icariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mice model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation.Conclusions: Our study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI.

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