Proteomics analysis of Pro-inflammatory Cytokine-stimulated human lung fibroblasts and bronchial epithelial cells

Ph.DDOCTOR OF PHILOSOPH

Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action

10.1016/j.bcp.2017.03.024BIOCHEMICAL PHARMACOLOGY13971-8

Dexamethasone protects against Aspergillus fumigatus-induced severe asthma via modulating pulmonary immunometabolism

Severe asthma is a difficult-to-treat chronic airway inflammatory disease requiring systemic corticosteroids to achieve asthma control. It has recently been shown that drugs targeting immunometabolism have elicited anti-inflammatory effects. The purpose of this study was to investigate potential immunometabolic modulatory actions of systemic dexamethasone (Dex) in an Aspergillus fumigatus (Af)-induced severe asthma model. Mice were repeatedly exposed to the Af aeroallergen before systemic treatment with Dex. Simultaneous measurements of airway inflammation, real-time glycolytic and oxidative phosphorylation (OXPHOS) activities, expression levels of key metabolic enzymes, and amounts of metabolites were studied in lung tissues, and in primary alveolar macrophages (AMs) and eosinophils. Dex markedly reduced Af-induced eosinophilic airway inflammation, which was coupled with an overall reduction in lung glycolysis, glutaminolysis, and fatty acid synthesis. The anti-inflammatory effects of Dex may stem from its immunometabolic actions by downregulating key metabolic enzymes including pyruvate dehydrogenase kinase, glutaminase, and fatty acid synthase. Substantial suppression of eosinophilic airway inflammation by Dex coincided with a specific escalation of mitochondrial proton leak in primary lung eosinophils. Besides, while our findings confirmed that inflammation corresponds with an upregulation of glycolysis, it was accompanied with an unexpectedly stable or elevated OXPHOS in the lungs and activated immune cells, respectively. Our findings reveal that the anti-inflammatory effects of Dex in severe asthma are associated with downregulation of pyruvate dehydrogenase kinase, glutaminase, and fatty acid synthase, and the augmentation of mitochondrial proton leak in lung eosinophils. These enzymes and biological processes may be valuable targets for therapeutic interventions against severe asthma

Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases

10.1016/j.coph.2017.12.002CURRENT OPINION IN PHARMACOLOGY40Sep-1

Restoration of HDAC2 and Nrf2 by andrographolide overcomes corticosteroid resistance in chronic obstructive pulmonary disease

10.1111/bph.15080BRITISH JOURNAL OF PHARMACOLOGY177163662-367

ISM1 suppresses LPS-induced acute lung injury and post-injury lung fibrosis in mice

10.1186/s10020-022-00500-wMOLECULAR MEDICINE28

Ribosomal Protein S3 Gene Silencing Protects Against Cigarette Smoke-Induced Acute Lung Injury

Chronic obstructive pulmonary disease (COPD) is estimated to be the third leading cause of death by 2030. Transcription factor NF-κB may play a critical role in COPD pathogenesis. Ribosomal protein S3 (RPS3), a 40S ribosomal protein essential for executing protein translation, has recently been found to interact with the NF-κB p65 subunit and promote p65 DNA-binding activity. We sought to study whether RPS3 gene silencing could protect against cigarette-smoke (CS)-induced acute lung injury in a mouse model. Effects of an intratracheal RPS3 siRNA in CS-induced lung injury were determined by measuring bronchoalveolar lavage (BAL) fluid cell counts, levels of inflammatory and oxidative damage markers, and NF-κB translocation. Lung RPS3 level was found to be upregulated for the first time with CS exposure, and RPS3 siRNA blocked CS-induced neutrophil counts in BAL fluid. RPS3 siRNA suppressed CS-induced lung inflammatory mediator and oxidative damage marker levels, as well as nuclear p65 accumulation and transcriptional activation. RPS3 siRNA was able to disrupt CS extract (CSE)-induced NF-κB activation in an NF-κB reporter gene assay. We report for the first time that RPS3 gene silencing ameliorated CS-induced acute lung injury, probably via interruption of the NF-κB activity, postulating that RPS3 is a novel therapeutic target for COPD. Keywords: ribosomal protein S3, chronic obstructive pulmonary disease, NF-KB, siRNA, cigarette smok

Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy

The p38MAPK-MK2 signaling axis functions as an initiator of inflammation. Targeting the p38MAPK-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 p38MAPK-MK2 axis via MK2 degradation. AG was found to bind to the activation loop of MK2, located at the interface of the p38MAPK-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 p38MAPK-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