Ginsenoside metabolite 20(S)-protopanaxatriol from Panax ginseng attenuates inflammation-mediated NLRP3 inflammasome activation

Jiang, Jun; Sun, Xiao; Akther, Mahbuba; Lian, Mei-Lan; Quan, Lin-Hu; Koppula, Sushruta; Han, Jun-Hyuk; Kopalli, Spandana Rajendra; Kang, Tae-Bong; Lee, Kwang-Ho

doi:10.1016/j.jep.2020.112564

Cited by 31 publications

(13 citation statements)

References 14 publications

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“…In this study, we further found that KM potently inhibited IL-1β production and neutrophil influx in MSU peritonitis. Interestingly, all the above-mentioned diseases are accompanied by abnormal activation of the NLRP3 inflammasome (Xu et al, 2016;Guo et al, 2018;Mi et al, 2018;Zhang et al, 2018;Xu et al, 2019;Jiang et al, 2020). Our results support the theory that the aberrant NLRP3 activation is involved in a range of both acute and chronic inflammatory conditions and linked with the development of many diseases, and it is feasible to treat these diseases by modulating NLRP3 inflammasome activation (Mangan et al, 2018).…”

Section: Discussionsupporting

confidence: 82%

“…These results indicate that the pretreatment of BMDMs with KM inhibits the transcriptional upregulation of NLRP3 and pro-IL-1β by interfering with NF-κB activity. ASC is critical for the assembly and subsequent activation of the NLRP3 inflammasome by yielding ASC dimers and/or oligomers that localize to a detergent-insoluble fraction in the cells (Zhou et al, 2011;Jiang et al, 2020). Immunofluorescence and immunoblotting analyses confirmed that treatment with LPS plus ATP resulted in the formation of ASC specks and oligomerization, and these effects were significantly reduced in the presence of KM.…”

Section: Discussionmentioning

confidence: 83%

“…Because KM inhibited IL-1β production upon NLRP3 inflammasome activation in vitro, we further examined the activity of KM in vivo. A mouse model of MSU-induced peritonitis characterized by massive neutrophil influx and IL-1β production was established to define the suppressive effects of KM on the NLRP3 inflammasome in vivo (Martinon et al, 2006;Jiang et al, 2020). Peritoneal exudate cells were collected, and the MSU-induced recruitment of inflammatory cells was analyzed by flow cytometry.…”

Section: Km Attenuates Il-1β Production In Msu-induced Peritonitismentioning

confidence: 99%

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Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

Luo

Xiong

et al. 2021

Front. Pharmacol.

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Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 83%

Section: Km Attenuates Il-1β Production In Msu-induced Peritonitismentioning

confidence: 99%

See 1 more Smart Citation

Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

Luo

Xiong

et al. 2021

Front. Pharmacol.

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“…Glaucocalyxin A is a bioactive ent-kauranoid diterpenoid derived from herbal medicine that can alleviate LPS-induced septic shock and the inflammatory response by inhibiting NLRP3 inflammasome activation ( 71 ). The ginsenoside metabolite protopanaxatriol can play a therapeutic role in inflammatory disorders by inhibiting inflammation-mediated activation of the NLRP3 inflammasome, ASC oligomerization, and IL-1β secretion ( 72 ). Myricetin inhibits NLRP3 inflammasome assembly by promoting non-reactive oxygen species (ROS)-dependent NLRP3 ubiquitination and reducing ROS-dependent ASC ubiquitination; this blocks the interaction between ASC and NLRP3, inhibits ASC aggregation, and alleviates the sepsis-induced inflammatory response ( 73 ).…”

Section: The Relationship Between Pyroptosis and Sepsismentioning

confidence: 99%

The Role and Mechanism of Pyroptosis and Potential Therapeutic Targets in Sepsis: A Review

et al. 2021

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Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Recently was been found that pyroptosis is a unique form of proinflammatory programmed death, that is different from apoptosis. A growing number of studies have investigated pyroptosis and its relationship with sepsis, including the mechanisms, role, and relevant targets of pyroptosis in sepsis. While moderate pyroptosis in sepsis can control pathogen infection, excessive pyroptosis can lead to a dysregulated host immune response and even organ dysfunction. This review provides an overview of the mechanisms and potential therapeutic targets underlying pyroptosis in sepsis identified in recent decades, looking forward to the future direction of treatment for sepsis.

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“…Ginsenoside PPT is one of the terminal metabolites commonly detected in human circulation after ingestion of ginseng [121]. Jiang et al reported that PPT suppressed activation of the NLRP3 inflammasome, but not AIM2 or NLRC4 inflammasome, in LPS-primed peritoneal macrophages [117]. PPT blocked ASC oligomerization and subsequent caspase-1 autocleavage and IL-1β release upon NLRP3 inflammasome activation by nigericin, ATP, or silica, but it had no impact on the protein levels of NLRP3, ASC, or caspase-1.…”

Section: Ginsenosidesmentioning

confidence: 99%

Anti-NLRP3 Inflammasome Natural Compounds: An Update

Liu

2021

Biomedicines

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The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex that recognizes various danger or stress signals from pathogens, the host, and the environment, leading to activation of caspase-1 and inducing inflammatory responses. This pro-inflammatory protein complex plays critical roles in pathogenesis of a wide range of diseases including neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Therefore, intensive efforts have been devoted to understanding its activation mechanisms and to searching for its specific inhibitors. Approximately forty natural compounds with anti-NLRP3 inflammasome properties have been identified. Here, we provide an update about new natural compounds that have been identified within the last three years to inhibit the NLRP3 inflammasome and offer an overview of the underlying molecular mechanisms of their anti-NLRP3 inflammasome activities.

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Ginsenoside metabolite 20(S)-protopanaxatriol from Panax ginseng attenuates inflammation-mediated NLRP3 inflammasome activation

Cited by 31 publications

References 14 publications

Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

The Role and Mechanism of Pyroptosis and Potential Therapeutic Targets in Sepsis: A Review

Anti-NLRP3 Inflammasome Natural Compounds: An Update

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