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Discovery of alantolactone as a naturally occurring NLRP3 inhibitor to alleviate NLRP3‐driven inflammatory diseases in mice

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British Journal of Pharmacology
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Weifeng Li
Weifeng Li
Weifeng Li
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Haowen Xu
Haowen Xu
Haowen Xu
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Jingjing Shao
Jingjing Shao
Jingjing Shao
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Jiahao Chen
Jiahao Chen
Jiahao Chen
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Abstract and Figures

Background and Purpose The NLR family pyrin domain‐containing 3 (NLRP3) inflammasome is activated in many inflammatory conditions. So far, no low MW compounds inhibiting NLRP3 have entered clinical use. Identification of naturally occurring NLRP3 inhibitors may be beneficial to the design and development of compounds targeting NLRP3. Alantolactone is a phytochemical from a traditional Chinese medicinal plant with anti‐inflammatory activity, but its precise target remains unclear. Experimental Approach A bank of phytochemicals was screened for inhibitors of NLRP3‐driven production of IL‐1β in cultures of bone‐marrow‐derived macrophages from female C57BL/6 mice. Models of gouty arthritis and acute lung injury in male C57BL/6J mice were used to determine the in vivo effects of the most potent compound. Key Results Among the 150 compounds screened in vitro, alantolactone exhibited the highest inhibitory activity against LPS + ATP‐induced production of IL‐1β in macrophages, suppressing IL‐1β secretion, caspase‐1 activation and pyroptosis. Alantolactone directly bound to the NACHT domain of NLRP3 to inhibit activation and assembly of NLRP3 inflammasomes. Molecular simulation analysis suggested that Arg335 in NLRP3 was a critical residue for alantolactone binding, leading to suppression of NLRP3–NEK7 interaction. In vivo studies confirmed significant alleviation by alantolactone of two NLRP3‐driven inflammatory conditions, acute lung injury and gouty arthritis. Conclusion and Implications The phytochemical alantolactone inhibited activity of NLRP3 inflammasomes by directly targeting the NACHT domain of NLRP3. Alantolactone shows great potential in the treatment of NLRP3‐driven diseases and could lead to the development of novel NLRP3 inhibitors.
Alantolactone (ALA) inhibits NLRP3‐mediated pyroptosis in BMDMs. (a) BMDMs were primed with LPS for 3 h and stimulated with ATP for 0.5 h after treatment with 5‐μM compounds, from a bank of 150 natural products, for 0.5 h. ELISA was performed to measure the IL‐1β levels in the culture supernatant. (b) Structure of alantolactone. (c) CCK‐8 was used to assess the cytotoxicity of BMDMs treated with different doses of alantolactone for 24 h. (d–g) BMDMs were primed with LPS for 3 h and then treated with different doses of alantolactone for 0.5 h, and then stimulated with ATP for 0.5 h. Western blotting analysis was used to evaluate IL‐1β and caspase‐1 (p20) levels in culture supernatants and levels of pro‐IL‐1β, pro‐caspase‐1 and β‐actin in lysates (LYS) of BMDMs (d). ELISA was used to assess the levels of IL‐1β (e) and TNF‐α (f) in supernatants (SN) of BMDMs. (g) Western blotting analysis of GSDMD and cleaved‐GSDMD in lysates. (h) Assay of LDH release in the supernatant of LPS‐primed BMDMs treated with different doses of alantolactone for 0.5 h and then stimulated with ATP for 1 h. Data are presented as the mean ± SEM, n = 5. *P < 0.05, significantly different; ns, not significant, as indicated.
Alantolactone (ALA) inhibits NLRP3‐mediated pyroptosis in BMDMs. (a) BMDMs were primed with LPS for 3 h and stimulated with ATP for 0.5 h after treatment with 5‐μM compounds, from a bank of 150 natural products, for 0.5 h. ELISA was performed to measure the IL‐1β levels in the culture supernatant. (b) Structure of alantolactone. (c) CCK‐8 was used to assess the cytotoxicity of BMDMs treated with different doses of alantolactone for 24 h. (d–g) BMDMs were primed with LPS for 3 h and then treated with different doses of alantolactone for 0.5 h, and then stimulated with ATP for 0.5 h. Western blotting analysis was used to evaluate IL‐1β and caspase‐1 (p20) levels in culture supernatants and levels of pro‐IL‐1β, pro‐caspase‐1 and β‐actin in lysates (LYS) of BMDMs (d). ELISA was used to assess the levels of IL‐1β (e) and TNF‐α (f) in supernatants (SN) of BMDMs. (g) Western blotting analysis of GSDMD and cleaved‐GSDMD in lysates. (h) Assay of LDH release in the supernatant of LPS‐primed BMDMs treated with different doses of alantolactone for 0.5 h and then stimulated with ATP for 1 h. Data are presented as the mean ± SEM, n = 5. *P < 0.05, significantly different; ns, not significant, as indicated.
… 
Alantolactone (ALA) specifically suppresses NLRP3 inflammasome activation. (a, b) BMDMs were treated with different doses of alantolactone before or after LPS challenge. After treatment, the cells were stimulated with ATP for 0.5 h. Western blotting analysis was used to evaluate IL‐1β and p20 levels in supernatants (SN) and levels of pro‐IL‐1β, pro‐caspase‐1 and β‐actin in lysates (LYS) of BMDMs (a). ELISA of IL‐1β in supernatants (b). (c) Fluorescence analysis of LPS‐primed BMDMs treated with alantolactone for 0.5 h and stimulated with ATP for 0.5 h, followed by staining with MitoSOX, MitoTracker and DAPI. (d) Detection of chloride efflux in LPS‐primed BMDMs treated with alantolactone (2 μM) for 0.5 h and stimulated with ATP at different time points. (e, f) LPS‐primed BMDMs treated with alantolactone (2 μM) and then stimulated with poly(dA:dT). Western blotting analysis of IL‐1β and p20 in supernatants (e). ELISA of IL‐1β in culture supernatants (f). Data are presented as the mean ± SEM, n = 5. *P < 0.05, significantly different; ns, not significant, as indicated.; ns, not significant.
Alantolactone (ALA) specifically suppresses NLRP3 inflammasome activation. (a, b) BMDMs were treated with different doses of alantolactone before or after LPS challenge. After treatment, the cells were stimulated with ATP for 0.5 h. Western blotting analysis was used to evaluate IL‐1β and p20 levels in supernatants (SN) and levels of pro‐IL‐1β, pro‐caspase‐1 and β‐actin in lysates (LYS) of BMDMs (a). ELISA of IL‐1β in supernatants (b). (c) Fluorescence analysis of LPS‐primed BMDMs treated with alantolactone for 0.5 h and stimulated with ATP for 0.5 h, followed by staining with MitoSOX, MitoTracker and DAPI. (d) Detection of chloride efflux in LPS‐primed BMDMs treated with alantolactone (2 μM) for 0.5 h and stimulated with ATP at different time points. (e, f) LPS‐primed BMDMs treated with alantolactone (2 μM) and then stimulated with poly(dA:dT). Western blotting analysis of IL‐1β and p20 in supernatants (e). ELISA of IL‐1β in culture supernatants (f). Data are presented as the mean ± SEM, n = 5. *P < 0.05, significantly different; ns, not significant, as indicated.; ns, not significant.
… 
Alantolactone (ALA) inhibits the NLRP3‐dependent ASC oligomerization and the interaction between NEK7 and NLRP3. (a) Western blotting analysis of ASC oligomerization in 0.5% Triton X‐100 (pellets) of LPS‐primed BMDMs treated with or without alantolactone for 0.5 h and stimulated with ATP for 0.5 h. (b) An endogenous immunoprecipitation (co‐IP) with ASC antibody was performed in LPS‐primed BMDMs treated with or without alantolactone for 0.5 h and stimulated with ATP for 0.5 h. (c) An endogenous co‐IP with NEK7 antibody was performed in LPS‐primed BMDMs treated with or without alantolactone for 0.5 h and stimulated with ATP for 0.5 h. (d) Co‐IP with HA antibody and western blotting analysis to assess the NLRP3–NEK7 interaction in HEK‐293T cells transfected with the high expression plasmid and treated with alantolactone (2 μM) for 16 h. (e) Co‐IP with HA antibody and western blotting analysis to assess the NLRP3–ASC interaction in HEK‐293T cells transfected with the high expression plasmid and treated with alantolactone (2 μM) for 16 h. Data are presented as the mean ± SEM, n = 5. *P < 0.05, significantly different; ns, not significant, as indicated.
Alantolactone (ALA) inhibits the NLRP3‐dependent ASC oligomerization and the interaction between NEK7 and NLRP3. (a) Western blotting analysis of ASC oligomerization in 0.5% Triton X‐100 (pellets) of LPS‐primed BMDMs treated with or without alantolactone for 0.5 h and stimulated with ATP for 0.5 h. (b) An endogenous immunoprecipitation (co‐IP) with ASC antibody was performed in LPS‐primed BMDMs treated with or without alantolactone for 0.5 h and stimulated with ATP for 0.5 h. (c) An endogenous co‐IP with NEK7 antibody was performed in LPS‐primed BMDMs treated with or without alantolactone for 0.5 h and stimulated with ATP for 0.5 h. (d) Co‐IP with HA antibody and western blotting analysis to assess the NLRP3–NEK7 interaction in HEK‐293T cells transfected with the high expression plasmid and treated with alantolactone (2 μM) for 16 h. (e) Co‐IP with HA antibody and western blotting analysis to assess the NLRP3–ASC interaction in HEK‐293T cells transfected with the high expression plasmid and treated with alantolactone (2 μM) for 16 h. Data are presented as the mean ± SEM, n = 5. *P < 0.05, significantly different; ns, not significant, as indicated.
… 
Alantolactone (ALA) binds to the NACHT domain of NLRP3. (a) DARTS assay of NLRP3, ASC and NEK7 in LPS‐primed BMDMs. (b) DARTS assay of Flag‐NLRP3 in transfected HEK‐293T cells. (c) DARTS assay of purified His‐NLRP3 protein. (d–f) DARTS assay of Flag‐NLRP3‐LRR (d), Flag‐NLRP3‐NACHT (e) and Flag‐NLRP3‐PYD (f) in the cell lysates of HEK‐293T cells transfected with high expression plasmids. The DARTS assay was performed five times (n = 5). Representative images are shown. (g) Binding affinity of alantolactone with rhNLRP3‐NACHT was determined using a BLI assay.
Alantolactone (ALA) binds to the NACHT domain of NLRP3. (a) DARTS assay of NLRP3, ASC and NEK7 in LPS‐primed BMDMs. (b) DARTS assay of Flag‐NLRP3 in transfected HEK‐293T cells. (c) DARTS assay of purified His‐NLRP3 protein. (d–f) DARTS assay of Flag‐NLRP3‐LRR (d), Flag‐NLRP3‐NACHT (e) and Flag‐NLRP3‐PYD (f) in the cell lysates of HEK‐293T cells transfected with high expression plasmids. The DARTS assay was performed five times (n = 5). Representative images are shown. (g) Binding affinity of alantolactone with rhNLRP3‐NACHT was determined using a BLI assay.
… 
Alantolactone (ALA) may interact with Arg335 of NLRP3 and has no effect on its ATPase activity. (a) Molecular docking analysis of alantolactone binding to NLRP3. Alantolactone (sticks model) in the binding site of the NACHT domain (cartoon, PDB ID: 6NPY). (b) Pose view of the interaction between alantolactone and NLRP3 in the molecular docking model. (c) ATPase activity assay for endogenous NLRP3 proteins in the presence of different concentrations of alantolactone. Data are presented as the mean ± SEM, n = 6. ns, not significant, as indicated.
+2
Alantolactone (ALA) may interact with Arg335 of NLRP3 and has no effect on its ATPase activity. (a) Molecular docking analysis of alantolactone binding to NLRP3. Alantolactone (sticks model) in the binding site of the NACHT domain (cartoon, PDB ID: 6NPY). (b) Pose view of the interaction between alantolactone and NLRP3 in the molecular docking model. (c) ATPase activity assay for endogenous NLRP3 proteins in the presence of different concentrations of alantolactone. Data are presented as the mean ± SEM, n = 6. ns, not significant, as indicated.
… 
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RESEARCH ARTICLE
Discovery of alantolactone as a naturally occurring NLRP3
inhibitor to alleviate NLRP3-driven inflammatory diseases in
mice
Weifeng Li
1
| Haowen Xu
1,2
| Jingjing Shao
1,2
| Jiahao Chen
1
| Yimin Lin
1
|
Zhiwei Zheng
1
| Yi Wang
1
| Wu Luo
1,3
| Guang Liang
1,2
1
Chemical Biology Research Center, School of
Pharmaceutical Sciences, Wenzhou Medical
University, Wenzhou, Zhejiang, China
2
School of Pharmaceutical Sciences, Hangzhou
Medical College, Hangzhou, Zhejiang, China
3
Medical Research Center, The First Affiliated
Hospital of Wenzhou Medical University,
Wenzhou, Zhejiang, China
Correspondence
Professor Guang Liang, PhD, Chemical Biology
Research Center, School of Pharmaceutical
Sciences, Wenzhou Medical University,
Wenzhou, Zhejiang 325035, China.
Email: wzmcliangguang@163.com
Wu Luo, PhD, Medical Research Center, The
First Affiliated Hospital of Wenzhou Medical
University, Wenzhou, Zhejiang 325000, China.
Email: wuluo@wmu.edu.cn
Funding information
National Natural Science Foundation of China,
Grant/Award Numbers: 21961142009,
82000793; Natural Science Foundation of
Zhejiang Province, Grant/Award Number:
LY22H070004; Zhejiang Provincial Key
Scientific Project, Grant/Award Number:
2021C03041
Background and Purpose: The NLR family pyrin domain-containing 3 (NLRP3)
inflammasome is activated in many inflammatory conditions. So far, no low MW com-
pounds inhibiting NLRP3 have entered clinical use. Identification of naturally occur-
ring NLRP3 inhibitors may be beneficial to the design and development of
compounds targeting NLRP3. Alantolactone is a phytochemical from a traditional
Chinese medicinal plant with anti-inflammatory activity, but its precise target remains
unclear.
Experimental Approach: A bank of phytochemicals was screened for inhibitors of
NLRP3-driven production of IL-1βin cultures of bone-marrow-derived macrophages
from female C57BL/6 mice. Models of gouty arthritis and acute lung injury in male
C57BL/6J mice were used to determine the in vivo effects of the most potent
compound.
Key Results: Among the 150 compounds screened in vitro, alantolactone exhibited
the highest inhibitory activity against LPS +ATP-induced production of IL-1βin mac-
rophages, suppressing IL-1βsecretion, caspase-1 activation and pyroptosis. Alanto-
lactone directly bound to the NACHT domain of NLRP3 to inhibit activation and
assembly of NLRP3 inflammasomes. Molecular simulation analysis suggested that
Arg335 in NLRP3 was a critical residue for alantolactone binding, leading to suppres-
sion of NLRP3–NEK7 interaction. In vivo studies confirmed significant alleviation by
alantolactone of two NLRP3-driven inflammatory conditions, acute lung injury and
gouty arthritis.
Conclusion and Implications: The phytochemical alantolactone inhibited activity of
NLRP3 inflammasomes by directly targeting the NACHT domain of NLRP3. Alanto-
lactone shows great potential in the treatment of NLRP3-driven diseases and could
lead to the development of novel NLRP3 inhibitors.
KEYWORDS
acute lung injury, alantolactone, gouty arthritis, macrophage, NLRP3 inflammasome
Abbreviations: AIM2, absent in melanoma 2; ALI, acute lung injury; Alum, aluminium potassium sulfate dodecahydrate; ASC, apoptosis-associated speck-like protein containing a CARD; BLI, bio-
layer interferometry; GSDMD, gasdermin D; NEK7, never in mitosis A-related kinase-7; NLR, nucleotide-oligomerization domain-like receptor; NLRC4, NLR family CARD domain containing 4;
NLRP3, NLR family pyrin domain-containing 3; p20, cleavage product of caspase-1.
Weifeng Li and Haowen Xu made equal contributions to this work.
Received: 21 September 2022 Revised: 14 December 2022 Accepted: 13 January 2023
DOI: 10.1111/bph.16036
1634 © 2023 British Pharmacological Society. Br J Pharmacol. 2023;180:1634–1647.wileyonlinelibrary.com/journal/bph
... By targeting the NLRP3/GSDMD/caspase-1 axis, it suppressed macrophage pyroptosis and effectively alleviated IgG-IC-induced ALI (98). Alantolactone inhibits the activation and assembly of nlrP3 inflammasomes, lPS-aTP-induced il-1β secretion and caspase-1 activation in macrophages by binding directly to the nacHT domain of NLRP; it also reduces macrophage pyroptosis (99). α-linolenic acid can alleviate neT-induced aM pyroptosis and ali/ardS by mediating pyrin inflammasome activation (100). ...
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... First of all, we have yet to further investigate the target of Ala. Recent study has shown that Ala inhibits NLRP3 inflammasome activity by directly targeting the NACHT domain of NLRP3 [33]. In addition, Ala plays an anti-inflammatory role in LPS-stimulated RAW 264.7 cells by inhibiting NF-κB activation and MAPKs phosphorylation through down-regulating MyD88 signaling pathway [34]. ...
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Osteoarthritis (OA), which is identified by chronic pain, impacts the quality of life. Cartilage degradation and inflammation are the most relevant aspects involved in its development. Signal transducer and activator of transcription 3(STAT3), a member of the STATs protein family, is associated with inflammation. Alantolactone (ALT), a sesquiterpene lactone compound, can selectively suppress the phosphorylation of STAT3. However, the pharmacological effect of ALT on OA is still imprecise. In this study, IL-1β (10 ng/ml) was applied to cartilage chondrocytes, which were treated with different concentrations of Alantolactone for 24 h. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2(COX2), matrix metalloproteinases (MMPs) and thrombospondin motifs-5 (ADAMTS5) were detected by western blot. Protein expression of Collagen Ⅱ was observed by western blot, safranin O staining and immunofluorescence. Manifestation of autophagy related proteins such as autophagy-related gene-5 (ATG5), P62, LC3Ⅱ/Ⅰ and PI3K/AKT/mTOR-related signaling molecules were measured by western blot and autophagic flux monitored by confocal microscopy. Expression of STAT3 and NF-κB-related signaling molecules were evaluated by western blot and immunofluorescence. In vivo, 2 mg/kg ALT or equal bulk of vehicle was engaged in the destabilization of medial meniscus (DMM) mouse models by intra-articular injection, the degree of cartilage destruction was classified by Safranin O/Fast green staining. Our findings reported that the enhance of inflammatory factors containing iNOS, COX2, MMPs and ADAMTS5 induced by IL-1β could be ameliorated by ALT. Additionally, the diminish of Collagen Ⅱ and autophagy which was stimulated by IL-1β could be alleviated by ALT. Mechanistically, STAT3, NF-κB and PI3K/AKT/mTOR signal pathways might be involved in the effect of ALT on IL-1β-induced mouse chondrocytes. In vivo, ALT protected cartilage in the DMM mouse model. Overall, this study illustrated that ALT attenuated IL-1β-induced inflammatory responses, relieved cartilage degeneration and promoted impaired autophagy via restraining of STAT3 and NF-κB signal pathways, implying its auspicious therapeutical effect for OA.
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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Introduction and Other Protein Targets
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The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified ‘Other protein targets’ which fall outside of the subsequent categorisation, there are six areas of focus: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes
Article
Full-text available
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15542. Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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Alantolactone alleviates collagen-induced arthritis and inhibits Th17 cell differentiation through modulation of STAT3 signalling
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  • Jan 2021
Context Alantolactone, the bioactive component in Inula helenium L. (Asteraceae), exhibits multiple biological effects. Objective We aimed to determine the anti-inflammatory effect of alantolactone in a collagen-induced arthritis (CIA) mouse model and its immunomodulatory effects on Th17 differentiation. Materials and methods A CIA mouse model was established with DBA/1 mice randomly divided into four groups (n = 6): healthy, vehicle and two alantolactone-treated groups (25 or 50 mg/kg), followed by oral administration of alantolactone to mice for 21 consecutive days after arthritis onset. The severity of CIA was evaluated by an arthritic scoring system and histopathological examination. Levels of cytokines and anti-CII antibodies as well as percentages of splenic Th17 and Th17 differentiation with or without alantolactone treatments (0.62, 1.2 or 2.5 μM) were detected with ELISA and flow cytometry, respectively. Western blot analysis was used to evaluate intracellular signalling in alantolactone-treated spleen cells. Results In CIA mice, alantolactone at 50 mg/kg attenuated RA symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion and levels of the proinflammatory cytokines TNF-α, IL-6 and IL-17A, but not IL-10 in paw tissues. Alantolactone also reduced the number of splenic Th17 cells and the capability of naïve CD4⁺ T cells to differentiate into the Th17 subset by downregulating STAT3/RORγt signalling by as early as 24 h of treatment. Discussion and conclusions Alantolactone possesses an anti-inflammatory effect that suppresses murine CIA by inhibiting Th17 cell differentiation, suggesting alantolactone is an adjunctive therapeutic candidate to treat rheumatoid arthritis.
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Alantolactone: A sesquiterpene lactone with diverse pharmacological effects
Article
  • Oct 2021
Alantolactone (Ala) is a sesquiterpene lactone that can be isolated from many herbal plants belonging to Asteraceae. Besides the antimicrobial activities against bacteria, fungi and viruses, Ala has also demonstrated significant anti‐inflammatory effects in various models by inhibiting NF‐κB and MAPKs to decrease the pro‐inflammatory cytokines such as IL‐1β, IL‐6 and TNF‐α. The antitumor effects of Ala have been demonstrated in vitro and in vivo via inducing intrinsic apoptosis, oxidative stress, ER stress, cell cycle arrest and inhibiting autophagy and STAT3 phosphorylation, which are also involved in its combination or synergy with other antitumor drugs. Ala also has neuroprotective activity through attenuating oxidative stress and inflammation, besides its modulation of glucose and lipid metabolism. This review summarizes the recent advances of the pharmacological effects of Ala, including anti‐inflammatory, antitumor, antimicrobial, neuroprotective activities, as well as the underlying mechanisms. Ala might be employed as a potential lead to develop drugs for multiple diseases. Alantolactone can be isolated from Inula helenium, Inula racemose, Inula royleana, Saussurea costus, Carpesium macrocephalum, Chrysanthemum indicum, Globba schomburgkii, Stevia lucida, and Telekia speciosa. Alantolactone has significant antitumor, anti‐inflammatory, antifungal, antiviral, antibacterial, insecticidal, neuroprotective and glycolipid‐regulating activities.
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NLRP3 inflammasome in cancer and metabolic diseases
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  • Mar 2021
The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1β or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome–mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway. The NLRP3 inflammasome is a central operator in inflammation. Sharma and Kanneganti review the varied roles played by the NLRP3 inflammasome in cancer and metabolic diseases.
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