ReferenceID 4496
Restoration of HDAC2 and Nrf2 by andrographolide overcomes corticosteroid resistance in chronic obstructive pulmonary disease
Br J Pharmacol
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 cortico
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- Reference Id
- 4496
- Evidence Id
- 21086
- Core Evidence Id
- 21086
- Source Reference Id
- 2271
- Herb2 Reference Id
- HBREF003068
- Subject Paper Key
- HBIN016019_32335896
- Pubmed Id
- 32335896
- Doi
- 10.1111/bph.15080
- Paper Title
- Restoration of HDAC2 and Nrf2 by andrographolide overcomes corticosteroid resistance in chronic obstructive pulmonary disease
- Paper 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.
- Journal
- Br J Pharmacol
- Publish Year
- 2020
- Experiment Subject
- mouse; human; patient; cse-exposed u937 cells; human monocytic u937 cells; u937 cells
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Chronic Obstructive Pulmonary Disease; Acute Lung Injury
- Paper Title Cn
- Paper Title En
- Restoration of HDAC2 and Nrf2 by andrographolide overcomes corticosteroid resistance in chronic obstructive pulmonary disease
- Bilingual Status
- semi_complete