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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.
Source publication
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...
Citations
... 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). ...
... 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]. ...
Background
Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with an increasing incidence, which can further develop into liver fibrosis and hepatocellular carcinoma at the end stage. Alantolactone (Ala), a sesquiterpene lactone isolated from Asteraceae, has shown anti-inflammatory effects in different models. However, the therapeutic effect of Ala on NAFLD is not clear.
Methods
C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD. After 16 weeks, Ala was administered by gavage to observe its effect on NAFLD. RNA sequencing of liver tissues was performed to investigate the mechanism. In vitro, mouse cell line AML-12 was pretreated with Ala to resist palmitic acid (PA)-induced inflammation, oxidative stress and fibrosis.
Results
Ala significantly inhibited inflammation, fibrosis and oxidative stress in HFD-induced mice, as well as PA-induced AML-12 cells. Mechanistic studies showed that the effect of Ala was related to the induction of Nrf2 and the inhibition of NF-κB. Taken together, these findings suggested that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress.
Conclusions
The study found that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress, suggesting that Ala is an effective therapy for NAFLD.
... Pyroptosis occurring in pulmonary macrophages plays a crucial role in acute lung injury, and this process can be principally triggered by inflammasome activation. 6 Inflammasomes are intracellular platforms containing cytosolic pattern recognition receptors, among which nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) is the most in-depth studied and clinically implicated one. 7,8 Purinergic CD39 functions as hydrolyzing ATP, the accumulation of which mediates NLRP3 activation and further controls the maturation of IL-1β and IL-18. ...
Purpose
Cytokine storm secondary lung injury (CSSLI) is the leading death cause in COVID-19 virus infection, and CD39-dominated purinergic brake drives NLRP3 inflammasome activation and pyroptosis, which plays a crucial role in the pathogenesis of CSSLI. Though electroacupuncture (EA) can alleviate lung injury caused by a variety of inducers, its effect on CSSLI and the underlying mechanism needs further investigation.
Methods
We established a widely recognized CSSLI mice model with CpG1826 (CpG), a TLR-9 agonist agent. Luminex liquid chip was employed to detect serum levels of 12 cytokines/chemokines to evaluate cytokine storm formation. H+E staining and transmission electron microscope were applied to examine pulmonary pathological injury and alveolar macrophage structure, respectively. IL-1β, IL-18, IL-1α, and HMGB-1 in BAL fluid were determined by ELISA kits. mRNA and protein levels of lung CD39 and NLRP3 were assessed by qRT-PCR and Western blotting. An in vitro model was also established by incubating PMA-differentiated THP-1 cells with serum samples obtained from relevant group of mice.
Results
Repeated CpG induced CSSLI together with the elevation of 11 cytokines/chemokines including GM-CSF, IL-16, IL-1α, MCP-1, IL-2, IL-10, CCL3, IL-1β, TNF-α, IL-6, and IL-17A, though not IFN-γ, which was reduced by EA pretreatment to a different extent. EA also alleviated lung injury and recovered lung macrophage structure. Moreover, CpG enhanced IL-1β and IL-18 level in BAL fluid, promoted NLRP3, while suppressing CD39 expression in lung, all of which were reversed by EA pretreatment. Of note, EA failed to further decrease BAL fluid IL-1β, IL-18, IL-1α, and HMGB-1 levels when A438079, a selective inhibitor of P2X7, was administered. However, both CD39 and NLRP3 are dispensable for EA decreasing multi-cytokine secretion in serum-incubated and CpG-stimulated THP-1 cells. Taken together, EA alleviated CSSLI in CpG-challenged mice by regulating the CD39-NLRP3 pathway in a P2X7-dependent way.
Conclusion
EA demonstrated potential to be applied in COVID-19 treatment.
There has been abundant research on the variety of programmed cell death pathways. Apoptosis, pyroptosis, and necroptosis under the action of the caspase family are essential for the innate immune response. Caspases are classified into inflammatory caspase-1/4/5/11, apoptotic caspase-3/6/7, and caspase-2/8/9/10. Although necroptosis is not caspase-dependent to transmit cell death signals, it can cross-link with pyroptosis and apoptosis signals under the regulation of caspase-8. An increasing number of studies have reiterated the involvement of the caspase family in acute lung injuries caused by bacterial and viral infections, blood transfusion, and ventilation, which is influenced by noxious stimuli that activate or inhibit caspase engagement pathways, leading to subsequent lung injury. This article reviews the role of caspases implicated in diverse programmed cell death mechanisms in acute lung injury and the status of research on relevant inhibitors against essential target proteins of the described cell death mechanisms. The findings of this review may help in delineating novel therapeutic targets for acute lung injury.
Gout is a systemic metabolic disorder caused by elevated uric acid (UA) levels, affecting over 1% of the population. The most common complication of gout is gouty arthritis (GA), characterized by swelling, pain or tenderness in peripheral joints or bursae, which can lead to the formation of tophi. At present, western medicines like colchicine, febuxostat and allopurinol are the primary treatment strategy to alleviate pain and prevent flare-ups in patients with GA, but they have significant side effects and increased mortality risks. Traditional Chinese medicine (TCM) has been utilized for thousands of years for the prevention and treatment of GA, demonstrating effective control over serum UA (SUA) levels with fewer side effects. Herein we summarized a total of 541 studies published from 2000 to 2023 in sources including PubMed, Web of Science, the Cochrane Library and Embase, highlighting the therapeutic potential of TCM in treating gout and GA, particularly in combination with modern medical strategies. This review focuses on TCM formulas, Chinese herbal extracts, and active compounds derived from TCM, providing an overview of recent clinical application and the pharmacological research based on animal models and cellular systems. Particularly, the current review categorized the clinical and experimental evidence into the strategies for improving hyperuricemia, decreasing the sudden onset of acute GA and retarding chronic GA progression, supplied further coherent reference and enlightenment for clinicians, investigators of natural product chemistry, researchers in TCM and pharmacology. We hope this article will inspire the development of novel formulas and molecular entities for the treatment of gout and GA.
The food industry has been focusing on food bioactive compounds with multiple physiological and immunological properties that benefit human health. These bioactive compounds, including polyphenols, flavonoids, and terpenoids, have great potential to limit inflammatory responses especially NLRP3 inflammasome activation, which is a key innate immune platform for inflammation. Current studies have revealed numerous food bioactive compounds with promising activities for unraveling immune metabolic disorders and excessive inflammatory responses by directly and indirectly regulating the NLRP3 inflammasome activation. This review explores the food hazards, including microbial and abiotic factors, that may trigger NLRP3-mediated illnesses and inflammation. It also highlights bioactive compounds in food that can suppress NLRP3 inflammasome activation through various mechanisms, linking its activation and inhibition to different pathways. Especially, this review provided further insight into NLRP3-related targets where food bioactive compounds can interact to block the NLRP3 inflammasome activation process, as well as mechanisms on how these compounds facilitate inactivation processes.
Alantolactone, a sesquiterpene lactone, is isolated from the traditional Chinese medicinal herb Inula helenium L. (Asteraceae). Alantolactone is known as its wide spectrum of biological effects, including antimicrobial, antifungal, antiviral, anthelmintic activities, anti‐inflammatory activities, and antiproliferative effects on several cancer cell lines. Thus, it has received extensive attention causing in‐depth research in medicinal chemistry and numerous undescribed alantolactone derivatives have been synthesized through different strategies. Herein, recent advances in diverse bioactivities and mechanism of alantolactone including its derivatives were summarized.
Isoalantolactone (ISA) is a sesquiterpene lactone that could be isolated from Inula helenium as well as many other herbal plants belonging to Asteraceae. Over the past 2 decades, lots of researches have been made on ISA, which owns multiple pharmacological effects, such as antimicrobial, anticancer, anti-inflammatory, neuroprotective, antidepressant-like activity, as well as others. The anticancer effects of ISA involve proliferation inhibition, ROS overproduction, apoptosis induction and cell cycle arrest. Through inhibiting NF-κB signaling, ISA exerts its anti-inflammatory effects which are involved in the neuroprotection of ISA. This review hackled the reported pharmacological effects of ISA and associated mechanisms, providing an update on understanding its potential in drug development.
