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The p38 MAPK -MK2 signaling axis functions as an initiator of inflammation. Targeting the p38 MAPK -MK2 signaling axis represents a direct therapeutic intervention of inflammatory diseases. We described here a novel role of andrographolide (AG), a small-molecule ent-labdane natural compound, as an inhibitor of p38 MAPK -MK2 axis via MK2 degradation. AG was found to bind to the activation loop of MK2, located at the interface of the p38 MAPK -MK2 biomolecular complex. This interaction disrupted the complex formation and predisposed MK2 to proteasome-mediated degradation. We showed that AG induced MK2 degradation in a concentration- and time-dependent manner and exerted its anti-inflammatory effects by enhancing the mRNA-destabilizing activity of tristetraprolin, thereby inhibiting pro-inflammatory mediator production (e.g., TNF-α, MCP-1). Administration of AG via intratracheal (i.t.) route to mice induced MK2 downregulation in lung alveolar macrophages, but not lung tissues, and prevented macrophage activation. Our study also demonstrated that the anti-inflammatory effects achieved by AG via MK2 degradation were more durable and sustained than that achieved by the conventional MK2 kinase inhibitors (e.g., PF-3644022). Taken together, our findings illustrated a novel mode of action of AG by modulating the p38 MAPK -MK2 signaling axis and would pave the way for the development of a novel class of anti-inflammatory agents targeting MK2 for degradation by harnessing the privileged scaffold of AG., Competing Interests: Declaration of Competing Interest A patent application has been filed on the subject matter of this paper by Q.T.N.T., C.L.L.C. and W.S.F.W. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. Cumulative evidence has implicated renin-angiotensin system (RAS) in the pathogenesis of COPD. Alveolar macrophages (AMs) are the first line immune defense in the respiratory system and play a critical role in the lung homeostasis. This study aimed to investigate the role of AMs in contributing to the protective effects of angiotensin II type-2 receptor (AT2R) activation in cigarette smoke (CS)-induced COPD. The AM polarization, phagocytosis and metabolism, and the underlying biochemical mechanisms of compound 21 (C21), a selective and potent non-peptide small molecule AT2R agonist, were evaluated in a two-week CS-induced COPD mouse model. C21 restored AM phagocytosis ability, reversing CS-induced AM phagocytosis impairment. CS exposure polarized AMs towards M1 phenotype, whereas, C21 skewed the CS-exposed AMs towards M2 phenotype. C21 reprogrammed CS-exposed AM metabolism from a high glycolysis-driven process to support inflammation energy demand to a high mitochondrial respiration process to limit inflammation. Besides, C21 upregulated AT2R and Mas receptor levels in CS-exposed AMs, favoring the anti-inflammatory Ang II/AT2R axis and Ang 1-7/Mas axis in the RAS. C21 restored the normal levels of sirtuin 1 (SIRT1) and MAPK phosphatase 1 (MKP1) in CS-exposed AMs, leading to the reduction of phospho-p38, phospho-ERK and p65 subunit of NF-κB levels in CS-exposed AMs. We report here for the first time that AT2R agonist C21 acts by boosting the protective functions of AMs against CS-induced COPD, and our results support the development of AT2R agonist for the treatment of COPD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Covalent drugs with prolonged actions often show superior potency, yet integrated strategies for optimizing their structural and electronic features are lacking. Herein, we present our effort directed towards understanding the contribution of chemical reactivity to biological potency to rationally design new covalent inhibitors based on the ent-ladane andrographolide scaffold for anti-inflammatory action. Specifically, a series of andrographolide derivatives comprising various Michael acceptors was developed and their thiol reactivity was assayed under various chemical and biological conditions. The cell-based SAR studies permitted the assessment of the inhibitor efficacy in more complex systems, which were often limited in traditional covalent drug development using isolated proteins or peptides. Our in vitro study identified enone 17 as the most promising candidate which demonstrated potent anti-inflammatory activity and superior safety profiles as compared to the lead compound andrographolide. Its reversibility following a Michael addition reaction with biological thiols resulted in more predictable pharmacological responses. In addition, 17 exhibited good in vivo efficacy at doses as low as 0.3 mg/kg when tested in LPS-induced acute lung injury model. Given a good balance of chemical reactivity and biological potency, enone 17 potentially offers a new therapeutic option based on natural product chemistry for the management of inflammatory conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

In this study we report, for the first time, the synthesis of the natural product calcaratarin D via a stereo- and regio-selective aldol condensation with (S)-β-hydroxy-γ-butyrolactone as key steps. A concise synthetic route (under 10 steps) to a series of structurally related normal-labdane diterpenes was also developed and their anti-inflammatory activities were evaluated in an in vitro model of inflammation. The structure-activity relationships (SARs) pertaining to the labdane scaffold were elucidated and results suggest that an α-alkylidene-β-hydroxy-γ-butyrolactone system is necessary for potent activity in the labdanes. Our studies identified the natural product calcaratarin D (1) as a promising anti-inflammatory agent, which effectively modulates the production of pro-inflammatory mediators (e.g., TNF-α, IL-6, NO) at both transcriptional and translational levels. These inhibitory effects are likely to occur via the suppression of nuclear factor kappa B (NF-κB) activation by reducing the p65 nuclear translocation but not its phosphorylation or protein expression. Calcaratarin D exhibited significantly greater inhibition of NF-κB activation than andrographolide, a well-known NF-κB inhibitor from the labdane family, suggesting that a normal-configuration labdane ring or the absence of hydroxyl groups at C-3 and C-19 positions is favorable for potent NF-κB inhibition. We further investigated the effects of calcaratarin D on the upstream signalling pathways and found that the compound selectively suppressed the LPS-induced activation of PI3K/Akt pathway without affecting much of the MAPK (i.e., ERK, JNK, and p38) activation. These findings demonstrate that calcaratarin D exerts its anti-inflammatory effects via a selective Akt-NF-κB-mediated mechanism and potentially offers a new therapeutic strategy for the management of inflammatory diseases., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The search for new anti-inflammatory agents is challenging due to the complexity of the inflammatory process and its role in host defense. Over the past few decades, a significant body of evidence has emerged, supporting the prominent role of labdane diterpenoids in therapeutic interventions of various inflammatory diseases. The anti-inflammatory activity of labdane diterpenoids has been attributed mainly to the inhibition of nuclear factor-κB (NF-κB) activity, the modulation of arachidonic acid (AA) metabolism and the reduction of nitric oxide (NO) production. This article provides extensive coverage of naturally occurring labdane diterpenes, discovered between 1981 and 2016, which have been verified as NF-κB, NO, or AA modulators. Herein, we also discuss the role of Michael acceptor, a common structural feature present in most of the active labdane diterpenes, and its association with NF-κB signaling inhibition. In the cases where a sufficient amount of data exists, structure-activity relationship (SAR) studies and clinical studies performed on the anti-inflammatory labdane diterpenoids are also discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)