Compound K inhibits priming and mitochondria-associated activating signals of NLRP3 inflammasome in renal tubulointerstitial lesions

Hsu, Wan-Han; Hua, Kuo-Feng; Tuan, Li‐Heng; Tsai, Yu‐Ling; Chu, Lichieh Julie; Lee, Yu-Chieh; Wong, Wei-Ting; Lee, Sheau-Long; Lai, Jenn‐Haung; Chu, Chih‐Liang; Ho, Ling‐Jun; Chiu, Hsiao-Wen; Hsu, Yu‐Juei; Chen, Cheng‐Hsu; Ka, Shuk‐Man; Chen, Ann

doi:10.1093/ndt/gfz073

Cited by 20 publications

(13 citation statements)

References 42 publications

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“…We further demonstrated that F240B exerts in vivo anti-inflammatory activity in a mouse model of uric acid crystalinduced peritonitis, which is an NLRP3 inflammasome-associated disorder (33). As abnormal activation of the NLRP3 inflammasome leads to a broad range of inflammatory disorders, F240B has the potential to ameliorate NLRP3-associated diseases, including chronic kidney disease (34)(35)(36), inflammatory bowel disease (37) and neurodegenerative disorders (38). However, to assess the therapeutic potential of F240B, in vitro safety pharmacology studies and the in vitro and in vivo pharmacokinetics of F240B should be addressed.…”

Section: Discussionmentioning

confidence: 79%

A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction

Gan

et al. 2020

Front. Immunol.

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Conjugated polyenes are a class of widely occurring natural products with various biological functions. We previously identified 4-hydroxy auxarconjugatin B (4-HAB) as anti‐inflammatory agent with an IC50 of ~20 µM. In this study, we synthesized a new anti‐inflammatory 4-HAB analogue, F240B, which has an IC50 of less than 1 µM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibited NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome activation through autophagy induction. In a mechanistic study, F240B inhibited interleukin (IL)-1β (IL-1β) precursor expression, promoted degradation of NLRP3 and IL-1β, and reduced mitochondrial membrane integrity loss in an autophagy-dependent manner. Additionally, F240B inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation without affecting the interaction between NLRP3 and ASC or NIMA-related kinase 7 (NEK7) and double-stranded RNA-dependent kinase (PKR). Furthermore, F240B exerted in vivo anti-inflammatory activity by reducing the intraperitoneal influx of neutrophils and the levels of IL-1β, active caspase-1, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in lavage fluids in a mouse model of uric acid crystal-induced peritonitis. In conclusion, F240B attenuated the NLRP3 inflammasome through autophagy induction and can be developed as an anti-inflammatory agent in the future.

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Section: Discussionmentioning

confidence: 79%

A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction

Gan

et al. 2020

Front. Immunol.

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“…The results showed reduced production of pro-inflammatory cytokines and the prevention of leukocytes infiltration and fibrosis in the kidney. The positive outcomes were showcased by inhibiting NF-κB-associated priming, and by modulating STAT3 signaling and NLRP3 inflammasome activation ( Table 4 ) [ 112 ]. Likewise, another study showed the protecting effects of CK on accelerated and severe lupus nephritis by hindering activation of NLRP3 inflammasome [ 113 ].…”

Section: Health-promoting Activitiesmentioning

confidence: 99%

Ginsenoside Compound K: Insights into Recent Studies on Pharmacokinetics and Health-Promoting Activities

2020

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Ginseng (Panax ginseng) is an herb popular for its medicinal and health properties. Compound K (CK) is a secondary ginsenoside biotransformed from major ginsenosides. Compound K is more bioavailable and soluble than its parent ginsenosides and hence of immense importance. The review summarizes health-promoting in vitro and in vivo studies of CK between 2015 and 2020, including hepatoprotective, anti-inflammatory, anti-atherosclerosis, anti-diabetic, anti-cancer, neuroprotective, anti-aging/skin protective, and others. Clinical trial data are minimal and are primarily based on CK-rich fermented ginseng. Besides, numerous preclinical and clinical studies indicating the pharmacokinetic behavior of CK, its parent compound (Rb1), and processed ginseng extracts are also summarized. With the limited evidence available from animal and clinical studies, it can be stated that CK is safe and well-tolerated. However, lower water solubility, membrane permeability, and efflux significantly diminish the efficacy of CK and restrict its clinical application. We found that the use of nanocarriers and cyclodextrin for CK delivery could overcome these limitations as well as improve the health benefits associated with them. However, these derivatives have not been clinically evaluated, thus requiring a safety assessment for human therapy application. Future studies should be aimed at investigating clinical evidence of CK.

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“…Furthermore, it has been shown that NLRP3 can directly promote the TGF-β signal and activation of R-Smad independent of inflammasome (Wang et al, 2013), which offers new insights into the function and potential treatments of NLRP3 inflammasome in kidney disease. In addition, there are other potential treatment or drugs can reduce or inhibit tubular damage by interfering with the signal pathway of NLRP3 inflammasome; these include mitochondria target antioxidants, compound K, Neferine, allopurinol, and ghrelin (Ding et al, 2017;Foresto-Neto et al, 2018;Hsu et al, 2019;Ling et al, 2019).…”

Section: Inflammasomes In Chronic Kidney Diseasementioning

confidence: 99%

Role of Inflammasomes in Kidney Diseases via Both Canonical and Non-canonical Pathways

Xiang

Zhu

et al. 2020

Front. Cell Dev. Biol.

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Inflammasomes, multiprotein complex induced by harmful factors in the body, play a crucial role in innate immunity. Activation of inflammasomes lead to the activation of casepase-1 and then the secretion of inflammatory cytokines, including IL-1β and IL-18, subsequently leading to a type of cell death called pyroptosis. There are two types of signaling pathways involved in the process of inflammasome activation: the canonical and the non-canonical signaling pathway. The canonical signaling pathway is mainly dependent on casepase-1; the non-canonical signal pathway, which was recently discovered, is mainly dependent on caspase-11, but is also meditated by caspase-4, caspase-5, and caspase-8. Kidney inflammation is basically associated with inflammatory factor exudation and inflammatory cell infiltration. Several studies have showed that inflammasomes are closely related to kidney diseases, especially the NOD-, LRR-and pyrin domain-containing 3 (NLRP3) inflammasome, which play a role in regulating kidney inflammation and fibrosis. In this review, we focus on the relationship between inflammasomes and kidney diseases, especially the role of the NLRP3 inflammasome in different kinds of kidney disease via both canonical and non-canonical signal pathways.

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Compound K inhibits priming and mitochondria-associated activating signals of NLRP3 inflammasome in renal tubulointerstitial lesions

Cited by 20 publications

References 42 publications

A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction

A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction

Ginsenoside Compound K: Insights into Recent Studies on Pharmacokinetics and Health-Promoting Activities

Role of Inflammasomes in Kidney Diseases via Both Canonical and Non-canonical Pathways

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