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

Abstract

Background and Purpose Corticosteroid resistance poses a major barrier to an effective anti‐inflammatory therapy for chronic obstructive pulmonary disease (COPD). The present study aimed to investigate potential corticosteroid re‐sensitization actions of andrographolide, a bioactive molecule from the herb Andrographis paniculata, in COPD models, particularly in peripheral blood mononuclear cells (PBMCs) from COPD patients. Experimental Approach Corticosteroid sensitivity in PBMCs collected from COPD patients, or in human monocytic U937 cells exposed to cigarette smoke extract (CSE), was determined by measuring LPS‐induced IL‐8 production, in the presence and absence of andrographolide. The mechanisms of corticosteroid re‐sensitization action of andrographolide were evaluated in a mouse cigarette smoke (CS)‐induced acute lung injury model. Key Results Impaired inhibition of IL‐8 production by dexamethasone was detected in PBMCs from COPD patients and in CSE‐exposed U937 cells, together with reduced levels of nuclear factor erythroid 2‐related factor 2 (Nrf2) and histone deacetylase‐2 (HDAC2). In both PBMCs and CSE‐exposed U937 cells, andrographolide restored dexamethasone inhibition of IL‐8 production, accompanied by the up‐regulation of Nrf2 and HDAC2 levels. In the U937 cells, andrographolide was able to block CSE‐induced Akt and reduce the level of c‐Jun. Besides, andrographolide also augmented dexamethasone actions on lowering total and neutrophil counts, cytokine levels, and oxidative damage markers in bronchoalveolar lavage fluid from CS‐exposed mice. Conclusion and Implications We report here for the first time a novel corticosteroid re‐sensitization property of andrographolide in human PBMCs and provide mechanistic evidence to support clinical evaluation of andrographolide in reversing steroid resistance in COPD.

Andrographolide and its fluorescent derivative inhibit the main proteases of 2019-nCoV and SARS-CoV through covalent linkage

“…Accumulating evidences from clinical studies indicate that Andrographis paniculata extract and andrographolide reduce symptoms in patients with HIV, upper respiratory infection, ulcerative colitis or rheumatoid arthritis with considerable safety [ 10 , [27] , [28] , [29] , [30] ]. Furthermore, experimental data from preclinical studies demonstrated the diverse pharmacological mechanisms of A. paniculata and andrographolide, including those in anti-inflammation, antiviral activity, hepatoprotection, anti-pulmonary fibrosis, and cardiopretection [ 10 , 12 , [31] , [32] , [33] ] Particularly, their safety profile in clinical uses are well accepted and andrographolide up to 30 μM did not cause cytotoxicity on human peripheral blood mononuclear cells (PBMC) [ 10 , 34 ].…”

Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

“…Inhibition of the PI3K/Akt/p70S6K signaling pathway restores nuclear HDAC2 expression and activity. Increasing nuclear Nrf2 levels also enhances HDAC2 levels, indicating HDAC2 and Nrf2 involvement in restoring corticoid sensitivity in COPD [194].…”

Novel drug delivery systems targeting oxidative stress in chronic obstructive pulmonary disease: a review

“…Data from clinical and basic research have identified the protective effects of Nrf2 on COPD. For instance, Nrf2 restored corticosteroid sensitivity of peripheral blood mononuclear cells from COPD patients and, human monocytic U937 cells exposed to cigarette smoke extract [ 35 ]. Recent findings on the mechanisms of Nrf2-mediated lung protection in COPD have been reviewed by Barnes [ 36 ].…”