lps-atp-induced-death-pma-differentiated-thp-1-macrophages-its

LPS and ATP-induced Death of PMA-differentiated THP-1 Macrophages and its Validation

Cell death is a fundamental process in all living organisms. The protocol establishes a lipopolysaccharide (LPS) and adenosine triphosphate (ATP)-induced ...

Chengdu University of Traditional Chinese Medicine

The assembly of inflammasomes drives caspase-1 activation, which further promotes proinflammatory cytokine secretion and downstream pyroptosis. The discovery of novel caspase-1 inhibitors is pivotal to developing new therapeutic means for inflammasome-involved diseases. In our present study, sennoside A (Sen A), a popular ingredient in multiple weight-loss medicines and dietary supplements, is found to potently inhibit the enzymatic activity of caspase-1 . Sen A considerably decreased IL-1β production in macrophages stimulated by LPS plus ATP, nigericin or MSU as well as poly(dA:dT) transfection, and remedied ROS-involved pyroptosis  caspase-1 inhibition. Mechanistically, Sen A not only suppressed the assembly of both NLRP3 and AIM2 inflammasome but also affected the priming process of NLRP3 inflammasome by blocking NF-κB signaling. Sen A significantly ameliorated the pathophysiological effect in LPS-, MSU- and carrageenan-challenged rodent models by suppressing inflammasome activation. Furthermore, P2X7 was indispensable for Sen A inhibiting NLRP3 inflammasome since it failed to further decrease IL-1β and IL-18 production in LPS plus ATP-stimulated BMDMs that were transfected with P2X7 siRNA. Sen A also restrained the large pore-forming functionalities of the P2X7R as verified by the YO-PRO-1 uptake assay. Taken together, Sen A inactivates caspase-1 to inhibit NLRP3 and AIM2 inflammasome-involved inflammation in a P2X7-dependent manner, making it an attractive candidate as a caspase-1 small-molecular inhibitor.

Sennoside A is a novel inhibitor targeting caspase-1.

Coronavirus disease (COVID-19) has spread worldwide and its effects have been more devastating than any other infectious disease. Importantly, patients with severe COVID-19 show conspicuous increases in cytokines, including interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, IL-8, tumor necrosis factor (TNF)-α, IL-1, IL-18, and IL-17, with characteristics of the cytokine storm (CS). Although recently studied cytokine inhibitors are considered as potent and targeted approaches, once an immunological complication like CS happens, anti-viral or anti-inflammation based monotherapy alone is not enough. Interestingly, certain isoquinoline alkaloids in  Franch. (CCFIAs) exerted a multitude of biological activities such as anti-inflammatory, antioxidant, antibacterial, and immunomodulatory etc, revealing a great potential for calming CS. Therefore, in this timeline review, we report and compare the effects of CCFIAs to attenuate the exacerbation of inflammatory responses by modulating signaling pathways like NF-ĸB, mitogen-activated protein kinase, JAK/STAT, and NLRP3. In addition, we also discuss the role of berberine (BBR) in two different triggers of CS, namely sepsis and viral infections, as well as its clinical applications. These evidence provide a rationale for considering CCFIAs as therapeutic agents against inflammatory CS and this suggestion requires further validation with clinical studies.

Cytokine storm-calming property of the isoquinoline alkaloids in  Franch.

Sepsis-induced acute respiratory distress syndrome (ARDS) has high morbidity and mortality, and it has three major pathogeneses, namely alveolar-capillary barrier destruction, elevated gut permeability, and reduced neutrophil extracellular traps (NETS), all of which are pyroptosis-involved. Due to limitations of current agents like adverse reaction superposition, inevitable drug resistance, and relatively heavier financial burden, naturally extracted small-molecule compounds have a broad market even though chemically modified drugs have straightforward efficacy. Despite increased understanding of the molecular biology and mechanism underlying sepsis-induced ARDS, there are no specific reviews concerning how small molecules from dietary plants alleviate sepsis-induced acute lung injury (ALI) via regulating pyroptotic cell death. Herein, we traced and reviewed the molecular underpinnings of sepsis-induced ALI with a focus on small-molecule compounds from dietary plants, the top three categories of which are respectively flavonoids and flavone, terpenoids, and polyphenol and phenolic acids, and how they rescued septic ALI by restraining pyroptosis.

Sepsis-Induced Acute Lung Injury Is Alleviated by Small Molecules from Dietary Plants via Pyroptosis Modulation.

A drug pair is a fundamental aspect of traditional Chinese medicine prescriptions. Scutellaria baicalensis Georgi and Coptis chinensis Franch, commonly used as an herb couple (SBCC), are representative heat-clearing and dampness-drying drugs. They possess functions such as clearing heat, drying dampness, purging fire, and detoxifying. These herbs are used in both traditional and modern medicine for treating inflammation.

The Scutellaria-Coptis herb couple and its active small-molecule ingredient wogonoside alleviate cytokine storm by regulating the CD39/NLRP3/GSDMD signaling pathway.

Yuejia Lan

State Key Laboratory of Southwestern Chinese Medicine Resources

Chengdu University of Traditional Chinese Medicine

LPS and ATP-induced Death of PMA-differentiated THP-1 Macrophages and its Validation

Yuejia Lan

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Chengdu University of Traditional Chinese Medicine

LPS and ATP-induced Death of PMA-differentiated THP-1 Macrophages and its Validation

State Key Laboratory of Southwestern Chinese Medicine Resources