Pharmacological potential of ginseng and ginsenosides in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by hepatic fat accumulation, while nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD characterized by hepatic inflammation, fibrosis, and liver injury, resulting in liver cirrhosis and hepatocellular carcinoma (HCC). Given the evidence that ginseng and its major bioactive components, ginsenosides, have potent anti-adipogenic, anti-inflammatory, anti-oxidative, and anti-fibrogenic effects, the pharmacological effect of ginseng and ginsenosides on NAFLD and NASH is noteworthy. Furthermore, numerous studies have successfully demonstrated the protective effect of ginseng on these diseases, as well as the underlying mechanisms in animal disease models and cells, such as hepatocytes and macrophages. This review discusses recent studies that explore the pharmacological roles of ginseng and ginsenosides in NAFLD and NASH and highlights their potential as agents to prevent and treat NAFLD, NASH, and liver diseases caused by hepatic steatosis and inflammation.

Maclurin inhibits caspase-11 non-canonical inflammasome in macrophages and ameliorates acute lethal sepsis in mice.

Maclurin is a natural phenolic compound isolated from Morus alba(white mulberry) andGarcinia mangostana (purple mangosteen) and has been reported to regulate cancer progression, oxidative stress, and melanogenesis. The regulatory role of maclurin, however, has never been demonstrated. This study investigated in vitro and in vivo anti-inflammatory roles of maclurin and the underlying mechanism in caspase-11 non-canonical inflammasome-stimulated inflammatory responses in macrophages and an animal model of acute lethal sepsis. Maclurin protected J774A.1 macrophages from LPS-induced cytotoxicity and suppressed caspase-11 non-canonical inflammasome-stimulated pyroptosis. Maclurin decreased the secretion and mRNA expression of pro-inflammatory cytokines and inflammatory mediators, such as IL-1ß, IL-18, TNF-α, IL-6, nitric oxide (NO), and inducible NO synthase (iNOS) in caspase-11 non-canonical inflammasome-stimulated J774A.1 macrophages. Mechanistic studies revealed that maclurin markedly suppressed the proteolytic activation of caspase-11 and gasdermin D (GSDMD) in caspase-11 non-canonical inflammasome-stimulated J774A.1 macrophages, while it did not inhibit caspase-11-mediated direct sensing of LPS. In vivo study revealed that maclurin ameliorated acute lethal sepsis in mice by increasing the survival rate and decreasing the serum levels of IL-1ß and IL-18 without significant toxicity. In conclusion, this study suggests that maclurin is a novel anti-inflammatory agent in inflammatory responses and against acute lethal sepsis via the inhibition of the caspase-11 non-canonical inflammasome in macrophages, which justifies its potential as an anti-inflammatory therapeutic agent in traditional medicine.

Roles of the Caspase-11 Non-Canonical Inflammasome in Rheumatic Diseases.

Inflammasomes are intracellular multiprotein complexes that activate inflammatory signaling pathways. Inflammasomes comprise two major classes: canonical inflammasomes, which were discovered first and are activated in response to a variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and non-canonical inflammasomes, which were discovered recently and are only activated in response to intracellular lipopolysaccharide (LPS). Although a larger number of studies have successfully demonstrated that canonical inflammasomes, particularly the NLRP3 inflammasome, play roles in various rheumatic diseases, including rheumatoid arthritis (RA), infectious arthritis (IR), gouty arthritis (GA), osteoarthritis (OA), systemic lupus erythematosus (SLE), psoriatic arthritis (PA), ankylosing spondylitis (AS), and Sjögren's syndrome (SjS), the regulatory roles of non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 non-canonical inflammasomes, in these diseases are still largely unknown. Interestingly, an increasing number of studies have reported possible roles for non-canonical inflammasomes in the pathogenesis of various mouse models of rheumatic disease. This review comprehensively summarizes and discusses recent emerging studies demonstrating the regulatory roles of non-canonical inflammasomes, particularly focusing on the caspase-11 non-canonical inflammasome, in the pathogenesis and progression of various types of rheumatic diseases and provides new insights into strategies for developing potential therapeutics to prevent and treat rheumatic diseases as well as associated diseases by targeting non-canonical inflammasomes.

Anti-inflammatory activity of calmodulin-lysine N-methyltransferase through suppressing the caspase-11 non-canonical inflammasome.

Calmodulin (CaM)-lysine N-methyltransferase (CAMKMT) is a novel methyltransferase that catalyzes lysine trimethylation in CaM. However, its specific roles in inflammatory responses and diseases remain unclear. In this study, we investigated the effects of CAMKMT on caspase-11 non-canonical inflammasomes. CAMKMT expression levels were significantly decreased during inflammatory responses activated by caspase-11 non-canonical inflammasome in macrophages. Moreover, CaM lysine trimethylation was markedly inhibited, but no change was observed in CaM expression during these inflammatory responses in macrophages. Activation of the CaM downstream effectors, CaM-dependent proteinkinase kinase 2 and CaM-dependent proteinkinase type IV, was also inhibited during inflammatory responses activated by caspase-11 non-canonical inflammasome in macrophages. Notably, forced expression of CAMKMT restrained caspase-11 non-canonical inflammasome activation via inhibiting proteolytic activation of caspase-11 and gasdermin D (GSDMD), which in turn suppressed pyroptosis and the release of interleukin (IL)-1ß and IL-18 in macrophages. Finally, an in vivo study revealed that CAMKMT ameliorated lipopolysaccharide (LPS)-stimulated acute lethal sepsis in mice by increasing the survival rate and reducing the serum levels of IL-1 ß. These findings suggest CAMKMT as a novel methyltransferase that plays an anti-inflammatory role through restraining caspase-11 non-canonical inflammasome in macrophages.

Inflammation, Inflammatory Diseases, and Inflammasomes.

Inflammation represents the innate immune response of the body tissues against invading microbes and cellular danger signals, and, in this way, it is beneficial [...].

Regulatory Roles of Flavonoids in Caspase-11 Non-Canonical Inflammasome-Mediated Inflammatory Responses and Diseases.

Inflammasomes are multiprotein complexes that activate inflammatory responses by inducing pyroptosis and secretion of pro-inflammatory cytokines. Along with many previous studies on inflammatory responses and diseases induced by canonical inflammasomes, an increasing number of studies have demonstrated that non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 inflammasomes, are emerging key players in inflammatory responses and various diseases. Flavonoids are natural bioactive compounds found in plants, fruits, vegetables, and teas and have pharmacological properties in a wide range of human diseases. Many studies have successfully demonstrated that flavonoids play an anti-inflammatory role and ameliorate many inflammatory diseases by inhibiting canonical inflammasomes. Others have demonstrated the anti-inflammatory roles of flavonoids in inflammatory responses and various diseases, with a new mechanism by which flavonoids inhibit non-canonical inflammasomes. This review discusses recent studies that have investigated the anti-inflammatory roles and pharmacological properties of flavonoids in inflammatory responses and diseases induced by non-canonical inflammasomes and further provides insight into developing flavonoid-based therapeutics as potential nutraceuticals against human inflammatory diseases.

Anti-inflammatory role of Artemisia argyi methanol extract by targeting the caspase-11 non-canonical inflammasome in macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia argyi possesses pharmacological activities against various immunopathological conditions associated with inflammation. AIM OF THE STUDY: This study explored the inhibitory role of Artemisia argyi methanol extract (Aa-ME) in inflammatory responses and the underlying mechanism in macrophages. MATERIALS AND METHODS: Caspase-11 non-canonical inflammasome was activated in J774A.1 macrophage by Pam3CSK4 treatment and lipopolysaccharide (LPS) transfection. Aa-ME-mediated in vitro anti-inflammatory action was examined using MTT assay, lactate dehydrogenase (LDH) activity assay, enzyme-linked immunosorbent assay (ELISA), nitric oxide (NO) generation assay, and quantitative real-time polymerase chain reaction (qPCR). Aa-ME-mediated in vivo anti-inflammatory action was examined in LPS-stimulated lethal septic mice. RESULTS: Aa-ME inhibited caspase-11 non-canonical inflammasome-stimulated pyroptosis and the secretion of IL-1ß and IL-18 in J774A.1 macrophages. Aa-ME also inhibited NO generation by downregulating inducible NO synthase (iNOS) expression in LPS-primed and caspase-11 non-canonical inflammasome-triggered J774A.1 cells. The mechanism study revealed Aa-ME suppressed the auto-proteolytic activation of caspase-11 and gasdermin D (GSDMD) in J774A.1 cells and also interfered with caspase-11-mediated direct recognition of LPS. Moreover, Aa-ME alleviated LPS-induced lethal sepsis in mice by increasing their survival rate without significant toxicity. CONCLUSION: These results suggest a novel mechanism by which Aa-ME alleviates inflammatory responses by deactivating caspase-11 non-canonical inflammasome in macrophages.

Korean Red Ginseng Saponins Play an Anti-Inflammatory Role by Targeting Caspase-11 Non-Canonical Inflammasome in Macrophages.

We previously reported that Korean red ginseng (KRG) exerts an anti-inflammatory role through inhibiting caspase-11 non-canonical inflammasome in macrophages; however, the components responsible for the anti-inflammatory role remained unclear. This study explored the anti-inflammatory activity of the KRG saponin fraction (KRGSF) in caspase-11 non-canonical inflammasome-activated macrophages. KRGSF inhibited pyroptosis, pro-inflammatory cytokine secretion, and inflammatory mediator production in caspase-11 non-canonical inflammasome-activated J774A.1 cells. A mechanism study revealed that KRGSF-induced anti-inflammatory action was mediated via suppressing the proteolytic activation of caspase-11 and gasdermin D (GSDMD) in caspase-11 non-canonical inflammasome-activated J774A.1 cells. Moreover, KRGSF increased the survival of lethal septic mice. Taken together, these results reveal KRGSF-mediated anti-inflammatory action with a novel mechanism, by inhibiting caspase-11 non-canonical inflammasome in macrophages.

Syk promotes phagocytosis by inducing reactive oxygen species generation and suppressing SOCS1 in macrophage-mediated inflammatory responses.

OBJECTIVE: Inflammation, a vital innate immune response against infection and injury, is mediated by macrophages. Spleen tyrosine kinase (Syk) regulates inflammatory responses in macrophages; however, its role and underlying mechanisms are uncertain. MATERIALS AND METHODS: In this study, overexpression and knockout (KO) cell preparations, phagocytosis analysis, confocal microscopy, reactive oxygen species (ROS) determination, mRNA analysis, and immunoprecipitation/western blotting analyses were used to investigate the role of Syk in phagocytosis and its underlying mechanisms in macrophages during inflammatory responses. RESULTS: Syk inhibition by Syk KO, Syk-specific small interfering RNA (siSyk), and a selective Syk inhibitor (piceatannol) significantly reduced the phagocytic activity of RAW264.7 cells. Syk inhibition also decreased cytochrome c generation by inhibiting ROS-generating enzymes in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and ROS scavenging suppressed the phagocytic activity of RAW264.7 cells. LPS induced the tyrosine nitration (N-Tyr) of suppressor of cytokine signaling 1 (SOCS1) through Syk-induced ROS generation in RAW264.7 cells. On the other hand, ROS scavenging suppressed the N-Tyr of SOCS1 and phagocytosis. Moreover, SOCS1 overexpression decreased phagocytic activity, and SOCS1 inhibition increased the phagocytic activity of RAW264.7 cells. CONCLUSION: These results suggest that Syk plays a critical role in the phagocytic activity of macrophages by inducing ROS generation and suppressing SOCS1 through SOCS1 nitration during inflammatory responses.

A novel mechanism of Korean Red Ginseng-mediated anti-inflammatory action via targeting caspase-11 non-canonical inflammasome in macrophages.

Background: Korean Red Ginseng (KRG) was reported to play an anti-inflammatory role, however, previous studies largely focused on the effects of KRG on priming step, the inflammation-preparing step, and the anti-inflammatory effect of KRG on triggering, the inflammation-activating step has been poorly understood. This study demonstrated anti-inflammatory role of KRG in caspase-11 non-canonical inflammasome activation in macrophages during triggering of inflammatory responses. Methods: Caspase-11 non-canonical inflammasome-activated J774A.1 macrophages were established by priming with Pam3CSK4 and triggering with lipopolysaccharide (LPS). Cell viability and pyroptosis were examined by MTT and lactate dehydrogenase (LDH) assays. Nitric oxide (NO)-inhibitory effect of KRG was assessed using a NO production assay. Expression and proteolytic cleavage of proteins were examined by Western blotting analysis. In vivo anti-inflammatory action of KRG was evaluated with the LPS-injected sepsis model in mice. Results: KRG reduced LPS-stimulated NO production in J774A.1 cells and suppressed pyroptosis and IL-1ß secretion in caspase-11 non-canonical inflammasome-activated J774A.1 cells. Mechanistic studies demonstrated that KRG suppressed the direct interaction between LPS and caspase-11 and inhibited proteolytic processing of both caspase-11 and gasdermin D in caspase-11 non-canonical inflammasome-activated J774A.1 cells. Furthermore, KRG significantly ameliorated LPS-mediated lethal septic shock in mice. Conclusion: The results demonstrate a novel mechanism of KRG-mediated anti-inflammatory action that operates through targeting the caspase-11 non-canonical inflammasome at triggering step of macrophage-mediated inflammatory response.

Editorial of Special Issue "Roles of Inflammasomes and Methyltransferases in Inflammation".

Inflammation is the first line of defense against pathogens and cellular dangers [...].

Regulatory Roles of Caspase-11 Non-Canonical Inflammasome in Inflammatory Liver Diseases.

An inflammatory response consists of two consecutive steps: priming and triggering, to prepare and activate inflammatory responses, respectively. The cardinal feature of the triggering step is the activation of intracellular protein complexes called inflammasomes, which provide a platform for the activation of inflammatory signaling pathways. Despite many studies demonstrating the regulatory roles of canonical inflammasomes in inflammatory liver diseases, the roles of newly discovered non-canonical inflammasomes in inflammatory liver diseases are still largely unknown. Recent studies have reported the regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory liver diseases, providing strong evidence that the caspase-11 non-canonical inflammasome may play key roles in the pathogenesis of inflammatory liver diseases. This review comprehensively discusses the emerging roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory liver diseases, focusing on non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and inflammatory liver injuries and its underlying mechanisms. This review highlights the current knowledge on the regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory liver diseases, providing new insights into the development of potential therapeutics to prevent and treat inflammatory liver diseases by targeting the caspase-11 non-canonical inflammasome.

Korean Red Ginseng saponin fraction exerts anti-inflammatory effects by targeting the NF-κB and AP-1 pathways.

Background: Although ginsenosides and saponins in Korea red ginseng (KRG) shows various pharmacological roles, their roles in the inflammatory response are little known. This study investigated the anti-inflammatory role of ginsenosides identified from KRG saponin fraction (RGSF) and the potential mechanism in macrophages. Methods: The ginsenoside composition of RGSF was identified by high-performance liquid chromatography (HPLC) analysis. An anti-inflammatory effect of RGSF and its mechanisms were studied using nitric oxide (NO) and prostaglandin E2 (PGE2) production assays, mRNA expression analyses of inflammatory genes and cytokines, luciferase reporter gene assays of transcription factors, and Western blot analyses of inflammatory signaling pathways using the lipopolysaccharide (LPS)-treated RAW264.7 cells. Results: HPLC analysis identified the types and amounts of various panaxadiol ginsenosides in RGSF. RGSF reduced the generation of inflammatory molecules and mRNA levels of inflammatory enzymes and cytokines in LPS-treated RAW264.7 cells. Additionally, RGSF inhibited the signaling pathways of NF-κB and AP-1 by suppressing both transcriptional factors and signaling molecules in LPS-treated RAW264.7 cells. Conclusion: RGSF contains ginsenosides that have anti-inflammatory action via restraining the NF-κB and AP-1 signaling pathways in macrophages during inflammatory responses.

Dual roles of the caspase-11 non-canonical inflammasome in inflammatory bowel disease.

Inflammation is a two-step process comprising the first priming step that prepares inflammatory responses and the second triggering step that activates inflammatory responses. The key feature of the triggering step is the activation of inflammasomes and intracellular inflammatory protein complexes that provide molecular platforms to activate inflammatory signal transduction cascades. Although canonical inflammasomes have been well demonstrated to be actively involved in numerous human diseases, the roles of the recently identified non-canonical inflammasomes are largely unknown. However, recent studies have demonstrated the emerging roles of the caspase-11 non-canonical inflammasome in various human inflammatory diseases, ultimately providing strong evidence that the caspase-11 non-canonical inflammasome is a key player in the pathogenesis of various human diseases. Here, we comprehensively reviewed the regulatory roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory bowel disease (IBD) and its underlying mechanisms. Overall, this review highlights the current understanding of the regulatory roles of the caspase-11 non-canonical inflammasome in IBD and may provide insight into new strategies for preventing and treating IBD and caspase-11 non-canonical inflammasome-driven diseases.

Potential benefits of ginseng against COVID-19 by targeting inflammasomes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogenic virus that causes coronavirus disease 2019 (COVID-19), with major symptoms including hyper-inflammation and cytokine storm, which consequently impairs the respiratory system and multiple organs, or even cause death. SARS-CoV-2 activates inflammasomes and inflammasome-mediated inflammatory signaling pathways, which are key determinants of hyperinflammation and cytokine storm in COVID-19 patients. Additionally, SARS-CoV-2 inhibits inflammasome activation to evade the host's antiviral immunity. Therefore, regulating inflammasome initiation has received increasing attention as a preventive measure in COVID-19 patients. Ginseng and its major active constituents, ginsenosides and saponins, improve the immune system and exert anti-inflammatory effects by targeting inflammasome stimulation. Therefore, this review discussed the potential preventive and therapeutic roles of ginseng in COVID-19 based on its regulatory role in inflammasome initiation and the host's antiviral immunity.

Editorial of Special Issue "Inflammasomes and Inflammation".

Although inflammation is a host-protective mechanism from infection and cellular danger signals, chronic inflammation is a major risk factor for various human diseases [...].

Functional Interplay between Methyltransferases and Inflammasomes in Inflammatory Responses and Diseases.

An inflammasome is an intracellular protein complex that is activated in response to a pathogenic infection and cellular damage. It triggers inflammatory responses by promoting inflammatory cell death (called pyroptosis) and the secretion of pro-inflammatory cytokines, interleukin (IL)-1ß and IL-18. Many types of inflammasomes have been identified and demonstrated to play a central role in inducing inflammatory responses, leading to the onset and progression of numerous inflammatory diseases. Methylation is a biological process by which methyl groups are transferred from methyl donors to proteins, nucleic acids, and other cellular molecules. Methylation plays critical roles in various biological functions by modulating gene expression, protein activity, protein localization, and molecular stability, and aberrant regulation of methylation causes deleterious outcomes in various human diseases. Methylation is a key determinant of inflammatory responses and diseases. This review highlights the current understanding of the functional relationship between inflammasome regulation and methylation of cellular molecules in inflammatory responses and diseases.

14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS: Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS: Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS: This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

New mechanisms of ginseng saponin-mediated anti-inflammatory action via targeting canonical inflammasome signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is an ethnopharmacological herbal plant in Asian countries, particularly in Korea, China, and Japan. Ginseng saponins, including ginsenosides, are major active components in ginseng and have been demonstrated to have numerous pharmacological effects on various human diseases. AIM OF THE REVIEW: Many previous studies investigating the anti-inflammatory effect of ginseng saponins have mostly focused on the 'priming' step rather than the 'triggering' step. This review aims to discuss the studies investigating an inhibitory role of ginseng saponins in inflammasome activation of the triggering step. MATERIALS AND METHODS: The literature was explored using the search strings, such as "ginseng saponins and inflammasomes" and "ginsenosides and inflammasomes" in several resources, such as PubMed, Google Scholar, and Scopus databases. RESULTS: Various ginseng saponins of Panax ginseng, Panax japonicas, and Panax quinquefolius alleviated inflammatory responses and diseases by inhibiting the nucleotide-binding oligomerization domain-like receptor (NLR) P3 (NLRP3) inflammasome activation. Also, ginseng saponin, Rg1 of Panax ginseng alleviated neuroinflammation and diseases by inhibiting NLRP1 inflammasome activation. Finally, ginseng saponins, Rh1 and Rg3 in Korea red ginseng (KRG) of Panax ginseng ameliorated sepsis by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. CONCLUSION: The studies discussed in this review provide insight into the new paradigm of the ginseng saponins as the promising anti-inflammatory agents that could be ethnopharmacologically used to prevent and treat inflammatory and inflammation-induced disorders via targeting inflammasomes.