Acute liver failure (ALF) is a serious clinical disorder with high fatality rates. Mahuang decoction (MHD), a well-known traditional Chinese medicine, has multiple pharmacological effects, such as anti-inflammation, anti-allergy, anti-asthma, and anti-hyperglycemia. In this study, we investigated the protective effect of MHD against ALF. In the lipopolysaccharide and D-galactosamine (LPS/D-GalN)-induced ALF mouse model, the elevated activities of the serum alanine and aspartate transaminases as well as the liver pathological damage were markedly alleviated by MHD. Subsequently, a metabolomics study based on the ultrahigh performance liquid chromatograph coupled with Q Exactive Orbitrap mass spectrometry was carried to clarify the therapeutic mechanisms of MHD against ALF. A total of 36 metabolites contributing to LPS/D-GalN-induced ALF were identified in the serum samples, among which the abnormalities of 27 metabolites were ameliorated by MHD. The analysis of metabolic pathways revealed that the therapeutic effects of MHD are likely due to the modulation of the metabolic disorders of tricarboxylic acid (TCA) cycle, retinol metabolism, tryptophan metabolism, arginine and proline metabolism, nicotinate and nicotinamide metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan synthesis, as well as cysteine and methionine metabolism. This study demonstrated for the first time that MHD exerted an obvious protective effect against ALF mainly through the regulation of TCA cycle and amino acid metabolism, highlighting the importance of metabolomics to investigate the drug-targeted metabolic pathways.
Ethnopharmacological relevance Houpo Mahuang Decoction (HPMHD is one of the classic traditional Chinese prescriptions that has been used in the treatment of asthma. The therapeutic effects and mechanism of HPMHD in aggravated asthma remain to be explored, especially from the perspective of metabolomics and Transient Receptor Potential Vanilloid-1 (TRPV1)/Ca 2+ /Tight junction (TJ) regulation. Aim of the study To investigate the therapeutic and metabolic regulatory effects and the underlying mechanism of HPMHD in asthmatic rats. Materials and methods The asthmatic rats were administered with the corresponding HPMHD (at dosages of 5.54, 11.07, 22.14 mg/kg). Then inflammatory cells in peripheral blood and bronchoalveolar lavage fluid (BALF) were counted, the levels of interleukin (IL)-4 and IL-13 in BALF were measured, and the changes in enhanced pause (Penh) and pathological damage of lung tissues were also detected to evaluate the protective effects of HPMHD. The serum metabolic profile of HPMHD in asthmatic rats was explored using Ultra-High-Performance Liquid Chromatography-mass spectrometer (UHPLC-MS), and the regulatory effects on TRPV1 and TJs of HPMHD in asthmatic rats were detected by Western blotting analysis. In vitro , 16HBE cells were stimulated with IL-4 plus SO 2 derivatives and then administered HPMHD. The intracellular Ca 2+ regulated by TRPV1, and the expression levels of TRPV1 and TJ proteins (TJs) were then detected by calcium imaging and Western blotting. The effects were verified by inhibition of TRPV1 and in short hairpin RNA (shRNA)-mediated TRPV1 silencing cells. Results HPMHD significantly attenuated the airway inflammation of asthmatic rats, and reduced the levels of inflammatory cells in peripheral blood and BALF as well as the levels of IL-4 plus IL-13 in BALF. In addition, the airway hyperresponsiveness and lung pathological damage were alleviated. Serum metabolomic analysis showed that 31 metabolites were differentially expressed among the normal saline-, model-, and HPMHD-treated rats. Pathway enrichment analysis showed that the metabolites were involved in 45 pathways, among which, TJs regulation-relevant pathway was associated with the Ca 2+ concentration change mediated by the TRP Vanilloid channel. In vivo and in vitro experiments indicated that HPMHD reduced the concentration of intracellular Ca 2+ via suppressing the expression and activation of TRPV1, increased the expression of ZO-1, Occludin , and Claudin-3, and protected the integrity of TJs. Conclusion The current study indicates that HPMHD alleviates rat asthma and participates in the regulation of serum metabolism. The anti-asthma effects of HPMHD might be related to the protection of TJs by inhibiting the intracellular Ca 2+ concentration via TRPV1.
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