Korean Red Ginseng aqueous extract improves markers of mucociliary clearance by stimulating chloride secretion

Cho, Do‐Yeon; Skinner, Daniel; Zhang, Shaoyan; Lazrak, Ahmed; Lim, Dong Woo; Weeks, Christopher G.; Banks, Catherine; Han, Chang Kyun; Kim, Si-Kwan; Tearney, Guillermo J.; Matalon, Sadis; Rowe, Steven M.; Woodworth, Bradford A.

doi:10.1016/j.jgr.2019.09.001

Cited by 5 publications

(5 citation statements)

References 44 publications

(32 reference statements)

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“…Irrespective of the mechanisms underlying hypoxia-mediated CFTR dysfunction, the confirmation of pronounced dysfunction strongly suggests activating CFTR with several Cl − secretagogues and CFTR modulators that are currently available is a worthy strategy. 37,46,47,[50][51][52][53][54][55] Additionally, methods to oxygenate the sinuses and the underlying mucosa using surgical strategies and/or oxygen-generating biomaterials are reasonable approaches to mitigate the impact of hypoxia. 56 As we have noted previously, ROS scavengers like glutathione could play a role in mitigating the early impact of obstruction-induced hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…The identification of an acquired CFTR dysfunction (as demonstrated indirectly by surface pH and directly by SPD measurements) validates the model as uniquely suited to evaluate interventions designed to treat or overcome hypoxia‐induced anion transport defects and improve MCT. Irrespective of the mechanisms underlying hypoxia‐mediated CFTR dysfunction, the confirmation of pronounced dysfunction strongly suggests activating CFTR with several Cl − secretagogues and CFTR modulators that are currently available is a worthy strategy 37,46,47,50–55 . Additionally, methods to oxygenate the sinuses and the underlying mucosa using surgical strategies and/or oxygen‐generating biomaterials are reasonable approaches to mitigate the impact of hypoxia 56 .…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis

Cho,

Zhang,

Norwood

et al. 2023

Int Forum Allergy Rhinol

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IntroductionHypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo.MethodsCystic fibrosis bronchoepithelial cells expressing wild‐type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time‐dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole‐cell and cell‐attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro‐optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF‐1α, pH, sinus potential difference (SPD), and MCT were determined.ResultsUssing chamber (p < 0.05), whole‐cell (p < 0.001), and single channel patch‐clamp (p < 0.0001) showed significant inhibition of Cl− currents in hypoxic cells. Cytoplasmic free radicals showed time‐dependent elevation peaking at 4 h (p < 0.0001). Airway surface liquid (p < 0.0001), periciliary liquid (p < 0.001), and MCT (p < 0.01) were diminished. Co‐incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p < 0.0001), increased HIF1α mRNA (p < 0.05), reduced pH (p < 0.01), and decreased MCT (p < 0.001). SPD measurements demonstrated markedly diminished transepithelial Cl− transport (p < 0.0001).ConclusionHypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis

Cho,

Zhang,

Norwood

et al. 2023

Int Forum Allergy Rhinol

Self Cite

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“…In addition, a recent study showed that Korean red ginseng aqueous extract is capable of increasing chloride secretion in nasal epithelium (wild and mutant CFTR) via TMEM16A-mediated current. 143 Cinnamaldehyde (CA) derived from cinnamon cortex may affect a variety of cellular pathways. Huang et al 144 showed that CA can activate calcium-activated chloride channels (TMEM16A channels) in the cell, and may represent a potential novel treatment for patients with CF.…”

Section: Other Medicinal Natural Compounds (Herbs)mentioning

confidence: 99%

“…Therefore, it has been suggested that these three natural compounds might represent novel therapeutic agents with which to treat patients with CF. In addition, a recent study showed that Korean red ginseng aqueous extract is capable of increasing chloride secretion in nasal epithelium (wild and mutant CFTR) via TMEM16A‐mediated current 143 …”

Section: Herbal Medicinementioning

confidence: 99%

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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“…The recent development of small molecule CFTR modulators that improve folding, trafficking and gating and thereby restore function to the most common F508del mutation, but also a spectrum of rare CFTR mutations, enables a personalized approach to CF therapy (9)(10)(11)(12)(13)(14)(15)(16). However, despite the established link between the underlying ion transport defect, ASL depletion and mucociliary dysfunction in the pathogenesis of CF lung disease, studies on the effects of CFTR modulators and other ion channel modulators on ASL regulation remain limited (14,(17)(18)(19)(20). With a growing number of pharmacologic and genetic approaches becoming available to restore CFTR function in the airway epithelium, quantitative assessment of ASL dysregulation and response to therapy may facilitate preclinical development of novel drugs and precision medicine for individual patients with CF (8).…”

Section: Introductionmentioning

confidence: 99%

Reflection confocal microscopy for quantitative assessment of airway surface liquid dysregulation and pharmacological rescue in cystic fibrosis under near-physiological conditions

Agircan,

Lampe,

Scheuermann

et al. 2024

Preprint

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Proper regulation of airway surface liquid (ASL) is essential for effective mucociliary clearance (MCC) in healthy airways, and ASL depletion due to deficient cystic fibrosis transmembrane conductance regulator (CFTR)-mediated anion/fluid secretion plays an important role in the pathogenesis of mucociliary dysfunction and chronic muco-obstructive lung disease in patients with cystic fibrosis (CF). The current standard for quantitative measurements of ASL height is confocal fluorescence microscopy that has the disadvantage that it requires apical addition of volume for fluorescent staining, and hence perturbation of the ASL. Therefore, our aim was to develop a method that enables studies of ASL regulation under unperturbed conditions using reflected light by confocal microscopy of primary airway epithelial cultures grown at air-liquid interface (ALI). After apical volume addition to primary tracheal mouse cultures, confocal reflection microscopy yielded comparable ASL height as confocal fluorescence microscopy on cultures of wild-type mice, and was sensitive to detect ASL depletion on cultures of βENaC-Tg mice. Under unperturbed conditions, ASL determined by confocal reflection microscopy was significantly higher in wild-type and βENaC-Tg mice compared to values obtained by confocal fluorescence microscopy. Studies in normal and CF primary human airway epithelial cultures showed that confocal reflection microscopy was sensitive to detect effects of low temperature rescue and pharmacological modulation including improvement of CFTR function by VX-809 and VX-770 in cultures from CF patients with the F508del mutation. Our results support confocal reflection microscopy as a novel sensitive technique for quantitative studies of ASL regulation and response to therapeutic intervention under unperturbed near-physiological conditions in healthy and CF airways.

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Korean Red Ginseng aqueous extract improves markers of mucociliary clearance by stimulating chloride secretion

Cited by 5 publications

References 44 publications

Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis

Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis

Therapeutic potential of phytochemicals for cystic fibrosis

Reflection confocal microscopy for quantitative assessment of airway surface liquid dysregulation and pharmacological rescue in cystic fibrosis under near-physiological conditions

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