Mahuang Decoction Attenuates Airway Inflammation and Remodeling in Asthma via Suppression of the SP1/FGFR3/PI3K/AKT Axis

Wei, Li‐Na; Gou, Xulei; Su, Bao‐Ning; Han, Haiqiong; Guo, Tingting; Liu, Liang; Wang, Lei; Zhang, Lina; Chen, Weibin

doi:10.2147/dddt.s351264

Cited by 12 publications

(6 citation statements)

References 38 publications

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“…In addition to bronchodilation, ASMCs are also recognized as attractive anti-inflammatory targets for treating chronic asthma because they are known to release cytokines that play a key role in orchestrating and perpetuating airway inflammation 65 . For example, OVA-treated mice exhibit increased level of inflammatory cytokines including IL-4, IL-6 and TNF-α in the BALF, which can be inhibited by anti-inflammatory mahuang decoction, and patients with severe asthma have recently been approved to be treated by blocking antibodies against specific cytokines 66 , 67 . Consistent with these findings, our results demonstrated that FFA significantly attenuated the mRNA expression of inflammatory cytokines released from LPS-stimulated ASMCs, including IL-1β, IL-2, IL-6, IP-10, MCP-1, and TNF-α.…”

Section: Discussionmentioning

confidence: 99%

BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation

Ni,

Che,

et al. 2024

Theranostics

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Rationale: Bitter taste receptors (TAS2Rs) are abundantly expressed in airway smooth muscle cells (ASMCs), which have been recognized as promising targets for bitter agonists to initiate relaxation and thereby prevent excessive airway constriction as the main characteristic of asthma. However, due to the current lack of tested safe and potent agonists functioning at low effective concentrations, there has been no clinically approved TAS2R-based drug for bronchodilation in asthma therapy. This study thus aimed at exploring TAS2R agonists with bronchodilator potential by BitterDB database analysis and cell stiffness screening. Methods: Bitter compounds in the BitterDB database were retrieved and analyzed for their working subtype of TAS2R and effective concentration. Compounds activating TAS2R5, 10, and 14 at < 100 μM effective concentration were identified and subsequently screened by cell stiffness assay using optical magnetic twisting cytometry (OMTC) to identify the most potent to relax ASMCs. Then the compound identified was further characterized for efficacy on various aspects related to relaxation of ASMCs, incl. but not limited to traction force by Fourier transform traction force microscopy (FTTFM), [Ca 2+ ] i signaling by Fluo-4/AM intensity, cell migration by scratch wound healing, mRNA expression by qPCR, and protein expressing by ELISA. The compound identified was also compared to conventional β-agonist (isoproterenol and salbutamol) for efficacy in reducing cell stiffness of cultured ASMCs and airway resistance of ovalbumin-treated mice. Results: BitterDB analysis found 18 compounds activating TAS2R5, 10, and 14 at < 100 μM effective concentration. Cell stiffness screening of these compounds eventually identified flufenamic acid (FFA) as the most potent compound to rapidly reduce cell stiffness at 1 μM. The efficacy of FFA to relax ASMCs in vitro and abrogate airway resistance in vivo was equivalent to that of conventional β-agonists. The FFA-induced effect on ASMCs was mediated by TAS2R14 activation, endoplasmic reticulum Ca 2+ release, and large-conductance Ca 2+ -activated K + (BK Ca ) channel opening. FFA also attenuated lipopolysaccharide-induced inflammatory response in cultured ASMCs. Conclusions: FFA as a potent TAS2R14 agonist to relax ASMCs while suppressing cytokine release might be a favorite drug agent for further development of TAS2R-based novel dual functional medication for bronchodilation and anti-inflammation in asthma therapy.

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Section: Discussionmentioning

confidence: 99%

BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation

Ni,

Che,

et al. 2024

Theranostics

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“…Natural products exhibit the complex chemical backbone and the rich functionalization, making them unique biological activity and unique properties that cannot be replaced as lead compounds in pharmaceutical research [34][35][36][37]. Many antiasthmatic drugs derived from the herbal medicine, such as ephedrine and glycyrrhizic acid, have been used widely in the clinic for prevention and treatment of airway infammation and asthma [38][39][40][41]. Given the diversity of the compounds in the plant extract, network pharmacology technology was employed to fnd the potential active compounds in HHAE which may be responsible for its therapeutic efects against OVA-induced asthma.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Herba Houttuyniae Aqueous Extract against OVA-Induced Airway Hyperresponsiveness and Inflammation in Asthmatic Mice

Yang

Lai²,

Wang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Herba Houttuyniae is the well-knownfood-medicine herb with the special taste and smell. It is also widely used in south China for prevention of various chronic pulmonary inflammatory diseases including asthma. However, the active ingredients and therapeutic mechanism of this herb remain obscure. In this study, network pharmacology technology was employed to investigate the effects of Herba Houttuyniae aqueous extract (HHAE) on OVA-induced airway hyperresponsiveness and inflammation. The results showed that six compounds (isoramanone, kaempferol, 1-methyl-2-nonacosyl-4-quinolone, C09747, spinasterol, and quercetin) were found to be mainly responsible for the therapeutic effects of the herb, which totally regulated the expressions of 168 asthma-related proteins. All those targets involved in the signal transduction of the prolactin signaling pathway, central carbon metabolism in cancer, EGFR tyrosine kinase inhibitor resistance, endocrine resistance, and VEGF signaling pathway. The in vivo experiment also revealed that orally administrated with HHAE alleviated airway hyperresponsiveness and inflammation in OVA-induced asthmatic mice. It significantly decreased the counts of neutrophils, eosinophils, and lymphocytes as well as the levels of IL-1β, IL-4, IL-6, and IL-13 in BALF of asthmatic mice. Mechanically, HHAE downregulated both the mRNA and protein expressions of p38 MAPK, PI3K, AKT, and VEGF in the lung tissues of asthmatic mice. Therefore, HHAE improved OVA-induced airway hyperresponsiveness and inflammation in mice and could be a potential supplement for asthma treatment.

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“…Accumulating evidence suggests the key role of the PI3K/Akt pathway in the immune response and remodelling in the airways, contributing to the pathological changes of asthma (Wei et al. 2022 ). In this respect, it has been reported that inhibiting the PI3K/Akt pathway by Akt dephosphorylation could reduce the expression of hypoxia-inducing factor HIF-α and vascular endothelial growth factor VEGF, thereby reducing the permeability of respiratory mucosa, inhibiting respiratory oedema and contraction, and reducing airway remodelling in asthma (Dahlin et al.…”

Section: Introductionmentioning

confidence: 99%

Loke zupa decoction attenuates bronchial EMT-mediated airway remodelling in chronic asthma through the PI3K-Akt/HIF-1α signaling pathway

Liu,

Li,

Han

et al. 2023

Pharmaceutical Biology

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Context Loke zupa decoction (Lok) is a well-established classic Chinese folk remedy for asthma. Objective We sought to investigate the effect and mechanism of Lok on asthma airway remodelling and provide novel insights for the prevention and treatment of asthma. Materials and methods For in vitro experiments, BEAS-2B cells were assigned into six groups: Control, TGF-β1 (10 μM), TGF-β1 + Lok-20, TGF-β1 + Lok-40, TGF-β1 + Lok-80 μg/mL and TGF-β1 + SB431542 (5 μM). CCK8 and wound healing assays were performed. For in vivo experiments, 60 female BALB/c mice were randomly divided into 5 groups: Control, model, Lok-4.55, Lok-9.1, and DEX group. Lok was administrated by gavage during the challenge stage for 8 consecutive weeks (4.55 and 9.1 g/kg/day). We investigated airway inflammation and airway remodelling in the lungs and verified the activation status of EMT-related markers and the PI3K-Akt/HIF-1α signalling pathway. Results In vitro , Lok efficiently inhibited TGF-β1-induced BEAS-2B cell proliferation ability (cell viability 165% vs. 105%) and migration (migration areas 85% vs. 35%) without affecting their normal growth (IC50 274.2 µg/mL at 48 h). In vivo , Lok effectively protected mice from asthma, as evidenced by decreased histological damage and level of cytokines in BALF (IL-4, IL-13 and TGF-β1) by 17%–77%. Mechanistic research revealed that Lok reduced the levels of EMT-related molecules and significantly downregulated the PI3K-Akt/HIF-1α signalling pathway. Discussion and conclusions Our findings provide novel insights into the protective effect of Lok on asthma and the underlying mechanisms, providing a theoretical basis and potential treatment possibilities for this patient population.

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Mahuang Decoction Attenuates Airway Inflammation and Remodeling in Asthma via Suppression of the SP1/FGFR3/PI3K/AKT Axis

Cited by 12 publications

References 38 publications

BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation

BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation

Protective Effects of Herba Houttuyniae Aqueous Extract against OVA-Induced Airway Hyperresponsiveness and Inflammation in Asthmatic Mice

Loke zupa decoction attenuates bronchial EMT-mediated airway remodelling in chronic asthma through the PI3K-Akt/HIF-1α signaling pathway

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