PHYTOMEDICINE
·
2021
·
IF 5.34
Kai Ni,Jia Guo,Bing Bu,Yan Pan,Jingjing Li,Lei Liu,Mingzhi Luo,Linhong Deng
Background Bitter tastants can activate bitter taste receptors (TAS2Rs) and thus initiate relaxation of airway smooth muscle cells (ASMCs), which have great potential in the development of novel bronchodilator drugs for asthma therapy. However, the canonical bitter substance, denatonium is known to induce apoptosis of airway epithelial cells (AECs), indicating that other bitter tastants may also impair the epithelial integrity to prevent hazardous particulate matters such as coronaviruses . Therefore, any bitter tastants intended for treating airway disease should be carefully evaluated for potential toxicity to AECs. Hypothesis/Purpose Considering the vast diversity of bitter tastants in nature and different types of TAS2Rs expressed in airway cells , we hypothesized that there must be some natural bitter tastants to be not only potent in inducing relaxation of ASMCs but also unharmful to AECs. Study design and methods Here we evaluated a group of bitter flavonoids that are derived from fruits and commonly used in traditional herbal medicine , including apigenin , hesperetin , kaempferol , naringenin , quercetin , and naringin , for their effects on the proliferation of human airway epithelial-like (16HBE14o-, BEAS-2B, and A549) cells cultured in vitro . Cell proliferation and associated signaling pathways were assessed by cell counting, ATP assay, cell cycling assay, quantitative RT-PCR, Fluo-4 labeling, and fluorescence resonance energy transfer , respectively. Results The results show that five of the six tested bitter tastants inhibited, but only naringin promoted the proliferation of the 16HBE14o-, BEAS-2B, and A549 cells at the dose of a few hundred micromoles. Furthermore, the naringin-promoted proliferation of the 16HBE14o- cells was associated with enhanced cell cycle progression , mRNA expression of cyclin E , and evoked calcium signaling/ERK signaling, which were all attenuated by inhibition of the TAS2R signaling pathways with specific blockers. Conclusion These findings indicate that although the majority of the bitter flavonoids may inhibit the proliferation of AECs, naringin emerged as one to promote the proliferation of AECs via cell cycle progression and TAS2R-activated intracellular signaling . It suggests that naringin and not a few other bitter tastants can be proven with nontoxicity to the airway epithelial structure and function, which provides further confidence in the development of safe and effective TAS2R-based bronchodilators for asthma therapy.
研究领域:
药理学
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呼吸病学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2020
·Vol. 43
·期 7
·1027-1034
·
IF 1.863
Mingzhi Luo,Peili Yu,Kai Ni,Yang Jin,Lei Liu,Jingjing Li,Yan Pan,Linhong Deng
Excessive contraction of airway smooth muscle cells (ASMCs) is a hallmark feature of asthma. Intriguing, the activation of bitter taste receptor (TAS2R) in ASMCs can relax ASMCs. However, there is a lack of potent TAS2R agonists that can be used in asthma therapies since those tested agonists cannot relax ASMCs at the dose below a few hundred micromolar. Considering that sanguinarine (SA) is a bitter substance often used in small doses for the treatment of asthma in folk medicine, the present study was to determine the rapid relaxation effect of SA on ASMCs and to reveal the underlying mechanisms associated with TAS2R signaling. Here, cell stiffness, traction force, calcium signaling, cAMP levels, and the mRNA expression were evaluated by using optical magnetic twisting cytometry, traction force microscopy, Fluo-4/AM labeling, enzyme-linked immunosorbent assay (ELISA), and quantitative (q)RT-PCR, respectively. We found that 0.5 µM SA immediately decreased cell stiffness and traction force, which is comparable with the effect of 5 µM isoproterenol. In addition, 0.5 µM SA immediately increased intracellular free calcium concentration ([Ca2+]i) and decreased the mRNA expression of contractile proteins such as calponin and α-smooth muscle actin after the treatment for 24 h. Furthermore, SA-mediated decrease in cell stiffness/traction force and increase in [Ca2+]i were significantly blunted by inhibiting the TAS2Rs signaling. These findings establish the rapid relaxation effect of SA at low concentration (<1 µM) on cultured ASMCs depending on TAS2R signaling, indicating that SA might be developed as a useful bronchodilator in asthma therapy.
研究领域:
药理学
·
呼吸医学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2020
·
IF 3.263
Guanyin Yuan,Yang Jing,Ting Wang,Vitor S. Fernandes,Wenkuan Xin
Bitter taste receptors (Tas2rs), the members of the G-protein-coupled receptors, mediate the bitter taste and express in extra-oral tissues. Previous studies have shown that Tas2r mRNAs are expressed in the whole heart and cultured cardiomyocytes of neonatal rats. This study aimed to determine the expression of Tas2rs and their function in the adult rat hearts by using RT-qPCR techniques, Langendorff-perfused isolated hearts, and isolated sinoatrial (SA) nodes. The data presented here revealed the mRNA expression of Tas2rs and their coupled G-protein subunits in the SA node and left ventricle of adult rat hearts. Tas2r agonists, quinine and chloroquine , decreased the heart rate and increased the RR interval and QRS duration in Langendorff-perfused isolated rat hearts; they reduced the spontaneous beating rate of isolated SA nodes with pEC 50 values of 4.907 ± 0.045 and 4.968 ± 0.030, respectively. The blockade of Tas2r108 with abscisic acid , the inhibition of phosphodiesterases (PDEs) with 3-isobutyl-1-methylxanthine (IBMX), or the selective inhibition of PDE3 and PDE4 with a cocktail of cilostamide and rolipram , attenuated the negative chronotropic effects of quinine and chloroquine on the SA node. Furthermore, quinine and chloroquine suppressed the tachycardia effect of isoprenaline on the SA node and shifted the concentration-response curve of isoprenaline rightward. In summary, we provided a few lines of evidence that Tas2r agonists, quinine and chloroquine, decreased the heart rate by prolonging ventricular depolarization, and by attenuating the SA node pace in a PDE-dependent manner; they can counteract with β -adrenergic receptor activation and eliminate isoprenaline-induced tachycardia.
研究领域:
心脏病学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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