Hesperetin from Root Extract of Clerodendrum petasites S. Moore Inhibits SARS-CoV-2 Spike Protein S1 Subunit-Induced NLRP3 Inflammasome in A549 Lung Cells via Modulation of the Akt/MAPK/AP-1 Pathway

Arjsri, Punnida; Srisawad, Kamonwan; Mapoung, Sariya; Semmarath, Warathit; Thippraphan, Pilaiporn; Umsumarng, Sonthaya; Yodkeeree, Supachai; Limtrakul, Pornngarm

doi:10.3390/ijms231810346

Cited by 13 publications

(14 citation statements)

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“…The health benefits of these anthocyanins should be confirmed in COVID-19 patients. Hesperetin from root extract of Clerodendrum petasites S. Moore decreased SARS-CoV-2 S1induced expression of NLRP3, ASC and caspase-1 through counteraction with the protein kinase B (Akt)/MAPK/activator protein-1 (AP-1) pathway (96). Hesperetin markedly attenuated the production of proinflammatory cytokines including IL-1b and IL-8.…”

Section: Therapeutic Potential Of Inflammasome-targeting Intervention...mentioning

confidence: 99%

Inflammasomes: a rising star on the horizon of COVID-19 pathophysiology

Wang

Chang

et al. 2023

Front. Immunol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a contagious respiratory virus that is the cause of the coronavirus disease 2019 (COVID-19) pandemic which has posed a serious threat to public health. COVID-19 is characterized by a wide spectrum of clinical manifestations, ranging from asymptomatic infection to mild cold-like symptoms, severe pneumonia or even death. Inflammasomes are supramolecular signaling platforms that assemble in response to danger or microbial signals. Upon activation, inflammasomes mediate innate immune defense by favoring the release of proinflammatory cytokines and triggering pyroptotic cell death. Nevertheless, abnormalities in inflammasome functioning can result in a variety of human diseases such as autoimmune disorders and cancer. A growing body of evidence has showed that SARS-CoV-2 infection can induce inflammasome assembly. Dysregulated inflammasome activation and consequent cytokine burst have been associated with COVID-19 severity, alluding to the implication of inflammasomes in COVID-19 pathophysiology. Accordingly, an improved understanding of inflammasome-mediated inflammatory cascades in COVID-19 is essential to uncover the immunological mechanisms of COVID-19 pathology and identify effective therapeutic approaches for this devastating disease. In this review, we summarize the most recent findings on the interplay between SARS-CoV-2 and inflammasomes and the contribution of activated inflammasomes to COVID-19 progression. We dissect the mechanisms involving the inflammasome machinery in COVID-19 immunopathogenesis. In addition, we provide an overview of inflammasome-targeted therapies or antagonists that have potential clinical utility in COVID-19 treatment.

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Section: Therapeutic Potential Of Inflammasome-targeting Intervention...mentioning

confidence: 99%

Inflammasomes: a rising star on the horizon of COVID-19 pathophysiology

Wang

Chang

et al. 2023

Front. Immunol.

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“…However, citrus flavonoids are readily available from natural plant sources. On the one hand, citrus flavonoids are abundant in a wide range of plants such as fatted olive (8.0%), immature oranges (14.0%), fatted soybean (17.2%), and Clerodendrum petasites S. Moore (11.2%) (Table ). On the other hand, up to 15 million tons of citrus waste are generated globally each year, containing a large amount of citrus flavonoids (13.2%) (Table ).…”

Section: Results and Discussionmentioning

confidence: 99%

Citrus Flavonoid Hesperetin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Reduces Their Cytotoxicity: In Vitro and In Vivo Studies

Wang,

Qu,

Cui

et al. 2023

J. Agric. Food Chem.

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Misfolding and subsequent fibrillogenesis of α-synuclein (αSN) significantly influence the development of Parkinson’s disease (PD). This study reports the inhibitory effect of citrus flavonoid hesperetin (Hst) on αSN fibrillation. Based on thioflavin T fluorometry and atomic force microscopy studies, Hst inhibited αSN fibrillation by interfering with initial nucleation and slowing the elongation rate. Furthermore, the inhibitory effect was concentration-dependent with a half-maximal inhibitory concentration of 24.4 μM. Cytotoxicity experiments showed that 100 μM Hst significantly reduced the cytotoxicity of αSN aggregates and maintained 98.4% cell activity. In addition, Hst disassembled the preprepared αSN fibrils into smaller and less-toxic aggregates. Excitingly, supplementation with 100 μM Hst inhibited the accumulation of 36.3% αSN in NL5901 and restored the amyloid-induced reduction in NL5901 lipid abundance, extending the mean lifespan of NL5901 to 23 d. These findings could support the use of Hst as a dietary supplement to regulate αSN fibrillation and prevent the development of PD.

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“…In this study, we employed the cellular model of Spike S1-induced inflammation directly against A549 epithelial cells as representative of the inflammatory responses upon the SARS-CoV-2 spike protein induction. This model has also been used in other research studies and in our previously published studies (29, [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Luteolin-rich fraction from Perilla frutescens seed meal inhibits spike glycoprotein S1 of SARS-CoV-2-induced NLRP3 inflammasome lung cell inflammation via regulation of JAK1/STAT3 pathway: A potential anti-inflammatory compound against inflammation-induced long-COVID

et al. 2023

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ObjectiveThe multi-systemic inflammation as a result of COVID-19 can persevere long after the initial symptoms of the illness have subsided. These effects are referred to as Long-COVID. Our research focused on the contribution of the Spike protein S1 subunit of SARS-CoV-2 (Spike S1) on the lung inflammation mediated by NLRP3 inflammasome machinery and the cytokine releases, interleukin 6 (IL-6), IL-1beta, and IL-18, in lung epithelial cells. This study has attempted to identify the naturally- occurring agents that act against inflammation-related long-COVID. The seed meal of Perilla frutescens (P. frutescens), which contains two major dietary polyphenols (rosmarinic acid and luteolin), has been reported to exhibit anti-inflammation activities. Therefore, we have established the ethyl acetate fraction of P. frutescens seed meal (PFEA) and determined its anti-inflammatory effects on Spike S1 exposure in A549 lung cells.MethodsPFEA was established using solvent-partitioned extraction. Rosmarinic acid (Ra) and luteolin (Lu) in PFEA were identified using the HPLC technique. The inhibitory effects of PFEA and its active compounds against Spike S1-induced inflammatory response in A549 cells were determined by RT-PCR and ELISA. The mechanistic study of anti-inflammatory properties of PFEA and Lu were determined using western blot technique.ResultsPFEA was found to contain Ra (388.70 ± 11.12 mg/g extract) and Lu (248.82 ± 12.34 mg/g extract) as its major polyphenols. Accordingly, A549 lung cells were pre-treated with PFEA (12.5-100 μg/mL) and its two major compounds (2.5-20 μg/mL) prior to the Spike S1 exposure at 100 ng/mL. PFEA dose-dependently exhibited anti-inflammatory properties upon Spike S1-exposed A549 cells through IL-6, IL-1β, IL-18, and NLRP3 gene suppressions, as well as IL-6, IL-1β, and IL-18 cytokine releases with statistical significance (p < 0.05). Importantly, Lu possesses superior anti-inflammatory properties when compared with Ra (p < 0.01). Mechanistically, PFEA and Lu effectively attenuated a Spike S1-induced inflammatory response through downregulation of the JAK1/STAT3-inflammasome-dependent inflammatory pathway as evidenced by the downregulation of NLRP3, ASC, and cleaved-caspase-1 of the NLRP3 inflammasome components and by modulating the phosphorylation of JAK1 and STAT3 proteins (p < 0.05).ConclusionThe findings suggested that luteolin and PFEA can modulate the signaling cascades that regulate Spike S1-induced lung inflammation during the incidence of Long-COVID. Consequently, luteolin and P. frutescens may be introduced as potential candidates in the preventive therapeutic strategy for inflammation-related post-acute sequelae of COVID-19.

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Hesperetin from Root Extract of Clerodendrum petasites S. Moore Inhibits SARS-CoV-2 Spike Protein S1 Subunit-Induced NLRP3 Inflammasome in A549 Lung Cells via Modulation of the Akt/MAPK/AP-1 Pathway

Cited by 13 publications

References 68 publications

Inflammasomes: a rising star on the horizon of COVID-19 pathophysiology

Inflammasomes: a rising star on the horizon of COVID-19 pathophysiology

Citrus Flavonoid Hesperetin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Reduces Their Cytotoxicity: In Vitro and In Vivo Studies

Luteolin-rich fraction from Perilla frutescens seed meal inhibits spike glycoprotein S1 of SARS-CoV-2-induced NLRP3 inflammasome lung cell inflammation via regulation of JAK1/STAT3 pathway: A potential anti-inflammatory compound against inflammation-induced long-COVID

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