Activation of TMEM16A by natural product canthaxanthin promotes gastrointestinal contraction

Ji, Qing; Shi, Sai; Guo, Shuai; Ye, Zhan; Zhang, Hailin; Chen, Yafei; An, Hailong

doi:10.1096/fj.202000443rr

Cited by 12 publications

(12 citation statements)

References 51 publications

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“…All chemicals and organic solvents were purchased from Aladdin or MACKLIN. PDPP was synthesized according previous studies . Amphiphilic material was purchased from Ananti Polar Lipids, Inc. Rabbit polyclonal antibodies specific for MEK1/2, p-MEK1/2, ERK1/2, cyclin D1 were obtained from Proteintech (Wuhan, China).…”

Section: Methodsmentioning

confidence: 99%

“…PDPP was synthesized according previous studies. 13 Amphiphilic material was purchased from Ananti Polar Lipids, Inc. Rabbit polyclonal antibodies specific for MEK1/2, p-MEK1/2, ERK1/2, cyclin D1 were obtained from Proteintech (Wuhan, China). p-ERK1/2 and GAPDH were obtained from Signalway Antibody.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…They have been reported to inhibit TMEM16A with acceptable biosafety. However, off-target effects of inhibitors as well as biotoxicity in normal tissues are major concerns due to the wide expression of TMEM16A in many normal tissues, including epithelia, vascular smooth muscle cells, and nociceptive neurons . Therefore, there is an urgent need to screen and identify effective biocompatible inhibitors, clarify the mode of interaction between inhibitors and TMEM16A anion channels, and develop systems to regulate the inhibition in target sites for efficacious cancer ablation.…”

Section: Introductionmentioning

confidence: 99%

“…After four cycles of heating and natural cooling processes, CPNs-PC showed only inconspicuous changes (Figure 3e), and the photothermal conversion efficiency of CNPs-PC was 43.7% under laser irradiation (Figure S4f). 13 To assess the photothermal triggering release ability of CNPs-PC, the concentration of PC released from CNPs-PC at different temperatures was examined. We found that the concentration was markedly increased at the phasetransition temperature of DPPC (41 °C) for a release rate of approximately 43.4%, demonstrating a controllable drug release ability (Figure S4b).…”

Section: ■ Introductionmentioning

confidence: 99%

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Near-Infrared Light-Responsive Nanoinhibitors for Tumor Suppression through Targeting and Regulating Anion Channels

Shi

Gao

et al. 2022

ACS Appl. Mater. Interfaces

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The gated state of anion channels is involved in the regulation of proliferation and migration of tumors. Specific regulators are urgently needed for efficacious cancer ablation. For this purpose, it is essential to understand the molecular mechanisms of interaction between the regulators and anion channels and apply this knowledge to regulate anion channels. Transmembrane 16A (TMEM16A) is the molecular basis of the calcium-activated chloride channels. It is an anion channel activated by Ca2+, and the inhibition of TMEM16A is associated with a decrease in tumorigenesis. Herein, we characterized a natural compound procyanidin (PC) as an efficacious and selective inhibitor of TMEM16A with an IC50 of 10.6 ± 0.6 μM. Our research revealed the precise sites (D383, R535, and E624) of electrostatic interactions between PC and TMEM16A. Near-infrared (NIR)-light-responsive photothermal conjugated polymer nanoparticles encapsulating PC (CPNs-PC) were established to remotely target and regulate the TMEM16A anion channel. Upon NIR irradiation, CPNs-PC downregulated the signaling pathway downstream of TMEM16A and arrested the cell cycle progression of cancer cells and improved the bioavailability of PC. The tumor inhibition ratio of CPNs-PC was superior to PC by 13.4%. Our findings enabled the development of a strategy to accurately and remotely regulate anion channels to promote tumor regression using NIR-light-responsive conjugated polymer nanoparticles containing specific inhibitors of TMEM16A.

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Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Near-Infrared Light-Responsive Nanoinhibitors for Tumor Suppression through Targeting and Regulating Anion Channels

Shi

Gao

et al. 2022

ACS Appl. Mater. Interfaces

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“…These compounds include ginsenoside Rb1, 186 , 187 resveratrol, 188 chitooligosaccharide 186 and canthaxanthin. 189 Cinnamaldehyde is another natural compound that activates TMEM16A, but it does so by increasing Ca 2+ concentration. 190 These molecules may have therapeutic value for gastrointestinal disorders, such as hypomotility and constipation, as they demonstrated to increase ileum contractions in guinea pigs.…”

Section: Modulation Of Alternative (Non-cftr) Channels/transportersmentioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.

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Therapeutic potential of phytochemicals for cystic fibrosis

et al. 2023

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The aim of this review was to review and discuss various phytochemicals that exhibit beneficial effects on mutated membrane channels, and hence, improve transmembrane conductance. These therapeutic phytochemicals may have the potential to decrease mortality and morbidity of CF patients. Four databases were searched using keywords. Relevant studies were identified, and related articles were separated. Google Scholar, as well as gray literature (i.e., information that is not produced by commercial publishers), were also checked for related articles to locate/identify additional studies. The relevant databases were searched a second time to ensure that recent studies were included. In conclusion, while curcumin, genistein, and resveratrol have demonstrated effectiveness in this regard, it should be emphasized that coumarins, quercetin, and other herbal medicines also have beneficial effects on transporter function, transmembrane conductivity, and overall channel activity. Additional in vitro and in vivo studies should be conducted on mutant CFTR to unequivocally define the mechanism by which phytochemicals alter transmembrane channel function/activity, since the results of the studies evaluated in this review have a high degree of heterogenicity and discrepancy. Finally, continued research be undertaken to clearly define the mechanism(s) of action and the therapeutic effects that therapeutic phytochemicals have on the symptoms observed in CF patients in an effort to reduce mortality and morbidity.

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Activation of TMEM16A by natural product canthaxanthin promotes gastrointestinal contraction

Cited by 12 publications

References 51 publications

Near-Infrared Light-Responsive Nanoinhibitors for Tumor Suppression through Targeting and Regulating Anion Channels

Near-Infrared Light-Responsive Nanoinhibitors for Tumor Suppression through Targeting and Regulating Anion Channels

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Therapeutic potential of phytochemicals for cystic fibrosis

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