Denatonium inhibits growth and induces apoptosis of airway epithelial cells through mitochondrial signaling pathways

Wen, Xiaoxing; Zhou, Jian; Zhang, Dan; Li, Jing; Wang, Qin; Feng, Na; Zhu, Hangyu; Song, Yuanlin; Li, Huayin; Bai, Chunxue

doi:10.1186/s12931-015-0183-9

Cited by 23 publications

(16 citation statements)

References 29 publications

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“…Our data on the inhibitory effect of the majority of the tested bitter avonoids on the proliferation of BECs are consistent with that of the canonical bitter tastant denatonium, as previously reported by Wen et al [5]. Additionally, these bitter avonoids exhibited inhibitory effect on the proliferation of BECs at a dose of a few hundred micromoles, which falls within the dosage level for the bitter tastant to be used to relax ASMCs [25].…”

Section: Discussionsupporting

confidence: 91%

“…We rst analyzed the effect of denatonium on the proliferation of 16HBE14o-cells by cell counting (Figures S1A) and ATP luminescent assay ( Figures S1B). The result shows that denatonium inhibited the proliferation and decreased cell activity of the epithelial cells, which con rmed the data reported by Wen et al [5]. To explore bitter tastant that is not only useful for relaxation of ASMCs but also unharmful for proliferation of BECs, we rst focused on six bitter avonoids that are commonly used in both food and TCM and also known to alleviate asthma symptoms (Table S1).…”

Section: Naringin Promoted the Proliferation Of 16hbe14o-cellssupporting

confidence: 82%

“…However, a recent study has reported that the canonical bitter substance such as denatonium can induce apoptosis of BECs [5]. Since BECs form the rst-line physical barrier in the bronchial airways to protect them from harmful insults of inhaled pathogens and pollutants such as airborne particulates, the healthy integrity of BECs plays a vital role in maintaining the airway health [6][7][8], and otherwise the accumulation of BECs damage may lead to asthma-associated pathologies including airway in ammation, airway hyper-responsiveness and airway narrowing.…”

Section: Introductionmentioning

confidence: 99%

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Naringin as a natural bitter tastant promotes proliferation of cultured human bronchial epithelial cells via activation of TAS2R signaling

Luo

et al. 2020

Preprint

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Bitter tastants can activate bitter taste receptors (TAS2Rs) and thus initiate the relaxation of airway smooth muscle cells, which have great potential in the development of novel asthma therapy. However, recent study shows that canonical bitter substance denatonium induces apoptosis of bronchial epithelial cells (BECs), indicating the toxic effect of bitter tastants on airways. Considering the diversity of bitter tastants in nature and TAS2Rs expressed in airway cells, it is thus necessary to carefully evaluate the bitter tastant for its effect on the proliferation of BECs, if aimed to treat airway disease. Here we first screened a group of bitter flavonoids, including apignenin, hespretin, kaempferol, naringenin, naringin and quercetin which are commonly used in food and traditional medicine, and then quantitatively evaluated the effects of this group of bitter flavonoids on the proliferation of BECs (i.e. 16HBE14o- cells) cultured in vitro. The results show that five of the six tested bitter tastants inhibited, but only naringin promoted the proliferation of 16HBE14o- BECs in vitro at the dose of a few hundred micromoles. Furthermore, the naringin-promoted cell proliferation was associated with enhanced cell cycle progression, mRNA expression of cyclin E, and evoked calcium signaling/ERK signaling. Inhibition of the TAS2R signaling pathways with specific blockers attenuated the naringin-enhanced cell proliferation, cyclin E expression and calcium signaling/ERK activation. Taken together, these findings indicate that although many bitter flavonoids may inhibit the proliferation of BECs, naringin emerges as one of the kind that promotes the proliferation of BECs via cell cycle progression and TAS2R-activated intracellular signaling. Only such bitter tastant proven to be unharmful to the epithelial structure and function could be further developed as safe and effective TAS2Rs-based bronchodilator in asthma therapy.

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Section: Discussionsupporting

confidence: 91%

Section: Naringin Promoted the Proliferation Of 16hbe14o-cellssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Naringin as a natural bitter tastant promotes proliferation of cultured human bronchial epithelial cells via activation of TAS2R signaling

Luo

et al. 2020

Preprint

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“…The present results indicated that cowanin induced apoptosis via the mitochondrial pathway. As Bcl-2 is an antiapoptotic protein which binds with Bax and Bak to protect mitochondrial damage, the present results demonstrated that cowanin treatment decreased Bcl-2, leading to mitochondrial dysfunction and apoptosis (42).…”

Section: Discussionsupporting

confidence: 52%

p38 inhibitor inhibits the apoptosis of cowanin-treated human colorectal adenocarcinoma cells

et al. 2018

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Colorectal cancer, which is the third most common type of cancer diagnosed in both men and women, is the leading cause of cancer-related deaths worldwide. Cowanin is a pure compound extracted from Garcinia cowa Roxb., a tree species present in Thailand, Malaysia and Myanmar. The crude extract has been demonstrated to have antitumor activity, inflammation induction, antibacterial activity, anti-inflammatory activity and antimalarial activity. In the present study, the effects of cowanin on apoptosis induction and on the apoptosis-related and mitogen-activated protein kinase (MAPK) pathways were investigated in the LoVo human colorectal cancer cell line. The cytotoxicity of cowanin in LoVo cells was determined by MTT assay. Hoechst 33342 and JC‑1 staining were used to determine nuclear morphological changes and mitochondrial membrane potential, respectively. The expression levels of BCL2 apoptosis regulator (Bcl‑2) family, MAPK and AKT serine/threonine kinase 1 (Akt) pathway proteins following cowanin treatment were determined by western blot analysis. The results demonstrated that cowanin inhibited cell proliferation and induced cell death via the apoptosis pathway. Cowanin treatment increased BCL2 associated X (Bax) and decreased Bcl‑2 expression. In addition, cowanin activated caspase‑9, -7 and poly-ADP-ribose-polymerase expression. Furthermore, cowanin decreased the levels of phosphorylated extracellular signal-regulated kinase (p‑ERK), p‑Akt, p‑3‑phosphoinositide‑dependent protein kinase‑1, while it increased p‑p38 expression, thus resulting in the induction of apoptosis. In conclusion, cowanin inhibited cell proliferation and induced apoptosis of LoVo cells via the MAPK and Akt signaling pathways. Notably, inhibition of p38 by using a p38 inhibitor (SB203580) prevented the cowanin-induced apoptosis in LoVo cells. These results suggested that cowanin may be a potential candidate for the treatment of colorectal cancer and provided important information on the molecular mechanisms underlying its antitumor activity.

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“…Indeed, many anticancer agents used in clinical therapy intervene with apoptotic signaling, either with the intrinsic or the extrinsic pathway [9,10].…”

Section: Introductionmentioning

confidence: 99%

Ethylacetate extract from Tetrastigma hemsleyanum induces apoptosis via the mitochondrial caspase-dependent intrinsic pathway in HepG2 cells

et al. 2015

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Ethylacetate extract of Tetrastigma hemsleyanum (EET) has a potent antitumor activity in vitro and in vivo. However, the molecular mechanism underlying EET-induced apoptosis remains elusive. As part of our continuing studies, we investigated the apoptosis mechanism of HepG2 cells exposed to different concentrations of EET in vitro. Confocal laser scanning was used to detect the apoptotic morphological changes. Flow cytometer and inverted fluorescence microscope were used to detect the mitochondrial membrane potential and cytosolic Ca(2+) level. Western blotting analysis was used to evaluate the expression of the apoptosis-related proteins. Annexin V/PI staining was used to investigate cell apoptosis. Spectrophotometry was used to detect the activity of caspase family. The results showed that distinct apoptotic morphological changes occurred in HepG2 cells treated by EET. EET caused collapse of mitochondrial membrane potential, elevation of cytosolic Ca(2+) level, and evoked release of cytochrome c from mitochondria in a concentration-dependent manner. The apoptosis was accompanied by a significant activation of caspase-3, caspase-9, and the cleavage of poly (ADP-ribose) polymerase, but there was no significant change in either the activity or the expression level of caspase-8. Furthermore, EET-induced apoptosis could be inhibited by caspase-9 inhibitor Z-LEHD-FMK but not by caspase-8 inhibitor Z-IETD-FMK. Taken together, these overall results demonstrated that EET-induced apoptosis of HepG2 cells was mediated by the mitochondrial caspase-dependent intrinsic pathway rather than the death receptor/caspase-8-mediated signaling route.

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Denatonium inhibits growth and induces apoptosis of airway epithelial cells through mitochondrial signaling pathways

Cited by 23 publications

References 29 publications

Naringin as a natural bitter tastant promotes proliferation of cultured human bronchial epithelial cells via activation of TAS2R signaling

Naringin as a natural bitter tastant promotes proliferation of cultured human bronchial epithelial cells via activation of TAS2R signaling

p38 inhibitor inhibits the apoptosis of cowanin-treated human colorectal adenocarcinoma cells

Ethylacetate extract from Tetrastigma hemsleyanum induces apoptosis via the mitochondrial caspase-dependent intrinsic pathway in HepG2 cells

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