Protectin Conjugates in Tissue Regeneration 1 Inhibits Macrophage Pyroptosis by Restricting NLRP3 Inflammasome Assembly to Mitigate Sepsis via the cAMP-PKA Pathway.

Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel anti-inflammatory and proresolving lipid mediator biosynthesized from docosahexaenoic acid. Excessive activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome and consequent pyroptosis are involved in diverse inflammatory diseases. However, how PCTR1 affects NLRP3 inflammasome activation and pyroptosis are still unclear. Here, we demonstrated that PCTR1 inhibited NLRP3 inflammasome activation and pyroptosis. These results show that PCTR1 dose-dependently inhibited gasdermin D cleavage in lipopolysaccharide (LPS)-primed murine primary macrophages upon nigericin stimulation. Additionally, PCTR1 treatment after LPS priming inhibited caspase-1 activation and subsequent mature interleukin-1ß release independent of the nuclear factor-kappa B pathway. PCTR1 exerted its inhibitory effects by blocking NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC) interaction and ASC oligomerization, thereby restricting NLRP3 inflammasome assembly. However, the inhibitory effect of PCTR1 could be reversed by KH7 and H89, which are the inhibitors of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway. Moreover, PCTR1 treatment alleviated lung tissue damage and improved mouse survival in LPS-induced sepsis. Our study unveils the molecular mechanism of negative regulation of NLRP3 inflammasome activation and pyroptosis by a novel lipid mediator and suggests that PCTR1 may serve as a potential treatment option for NLRP3-inflammasome driven diseases.

[Correlation analysis between HPLC fingerprint of astragali radix extracts and antifatigue effect].

OBJECTIVE: To study the correlation analysis between the HPLC fingerprints of Astragali Radix extracts and the antifatigue effects. METHODS: Three types of extracts of Astragali Radix were obtained and arranged by uniform design for HPLC fingerprint analysis and the antifatigue effect experiment. The correlation analysis between the HPLC fingerprints of Astragali Radix extracts and the antifatigue effects were carried out with orthogonal signal correction-partial least squares (OSC- PLS) method. RESULTS: The antifatigue activity could be strengthened by chromatographic peaks in the fingerprints of flavonoids and other kinds of ingredients (including saponins), but could be weakened by Astragalus polysaccharides in Astragali Radix. Among total variables, there were 36 variables (including 35 peaks and a variable of Astragalus polysaccharides) that had important contribution to "fingerprint-efficacy" model. CONCLUSION: OSC-PLS can remove uncorrelated information between fingerprint and efficacy, simplify the structure of model and improve the interpretative ability of model, and could be a reference method to investigate chromatographic fingerprint-efficacy relationship of complex system of traditional Chinese medicine.