Consuming Genistein Improves Survival Rates in the Absence of Laxative in ΔF508-CF Female Mice

Lord, Ryan; Fairbourn, Nathan; Mylavarapu, Charisma; Dbeis, Ammer; Bowman, Taylor; Chandrashekar, Archana; Banayat, Tatum; Hodges, Craig A.; Al‐Nakkash, Layla

doi:10.3390/nu10101418

Cited by 9 publications

(9 citation statements)

References 54 publications

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“…103 In addition, an early study proved that genistein activates CFTR-mediated chloride ion secretion in the murine trachea and distal colon, which may explain the improvement of intestinal relative symptoms in the previous study. 103,104 A clinical trial was initiated in 2003 to evaluate the effectiveness of a combination of genistein and phenylbutyrate in treating CF patients with the Delta F508 mutation. However, the trial halted in 2008 since the results were unconclusive and unsatisfactory.…”

Section: ■ Cystic Fibrosismentioning

confidence: 88%

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants

Han,

Li,

Zhu

et al. 2024

ACS Pharmacol. Transl. Sci.

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Cystic fibrosis (CF) is a genetic disorder arising from variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to multiple organ system defects. CFTR tool compounds are molecules that can modify the activity of the CFTR channel. Especially, patients that are currently not able to benefit from approved CFTR modulators, such as patients with rare CFTR variants, benefit from further research in discovering novel tools to modulate CFTR. This Review explores the development and classification of CFTR tool compounds, including CFTR blockers (CFTRinh-172, GlyH-101), potentiators (VRT-532, Genistein), correctors (VRT-325, Corr-4a), and other approved and unapproved modulators, with detailed descriptions and discussions for each compound. The challenges and future directions in targeting rare variants and optimizing drug delivery, and the potential synergistic effects in combination therapies are outlined. CFTR modulation holds promise not only for CF treatment but also for generating CF models that contribute to CF research and potentially treating other diseases such as secretory diarrhea. Therefore, continued research on CFTR tool compounds is critical.

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Section: ■ Cystic Fibrosismentioning

confidence: 88%

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants

Han,

Li,

Zhu

et al. 2024

ACS Pharmacol. Transl. Sci.

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“…It is well-known that the incidence of obstructive episodes (always lethal) in cftr −/− mice is very high during weaning [ 31 ], with 90% of cftr −/− mice dead by day 30 unless preventive measures are taken [ 14 ], and decreases in adulthood. Previous studies that aimed at pharmacological prevention of obstructive episodes in cftr −/− mice have, therefore, administered the pharmaceutical agent to mice aged 3–6 weeks [ 32 ] and 20 days [ 33 ], respectively. For our study, the mice had to tolerate twice daily gavage and preferably not loose body weight due to this procedure; we therefore chose the age range of 9–13 weeks.…”

Section: Discussionmentioning

confidence: 99%

The NHE3 Inhibitor Tenapanor Prevents Intestinal Obstructions in CFTR-Deleted Mice

Tan¹,

Kini²,

Römermann³

et al. 2022

IJMS

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Mutations in the CFTR chloride channel result in intestinal obstructive episodes in cystic fibrosis (CF) patients and in CF animal models. In this study, we explored the possibility of reducing the frequency of obstructive episodes in cftr−/− mice through the oral application of a gut-selective NHE3 inhibitor tenapanor and searched for the underlying mechanisms involved. Sex- and age-matched cftr+/+ and cftr−/− mice were orally gavaged twice daily with 30 mg kg− 1 tenapanor or vehicle for a period of 21 days. Body weight and stool water content was assessed daily and gastrointestinal transit time (GTT) once weekly. The mice were sacrificed when an intestinal obstruction was suspected or after 21 days, and stool and tissues were collected for further analysis. Twenty-one day tenapanor application resulted in a significant increase in stool water content and stool alkalinity and a significant decrease in GTT in cftr+/+ and cftr−/− mice. Tenapanor significantly reduced obstructive episodes to 8% compared to 46% in vehicle-treated cftr−/− mice and prevented mucosal inflammation. A decrease in cryptal hyperproliferation, mucus accumulation, and mucosal mast cell number was also observed in tenapanor- compared to vehicle-treated, unobstructed cftr−/− mice. Overall, oral tenapanor application prevented obstructive episodes in CFTR-deficient mice and was safe in cftr+/+ and cftr−/− mice. These results suggest that tenapanor may be a safe and affordable adjunctive therapy in cystic fibrosis patients to alleviate constipation and prevent recurrent DIOS.

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“…Moreover, they may have a positive effect on glucose metabolism [ 64 , 65 ]. Fatty acids, vitamins (A, D, E, K and B12) [ 26 , 27 , 28 , 29 , 66 , 67 ], flaxseed [ 68 ], caffeic acid phenethyl ester [ 69 ], furocoumarins [ 70 ], curcumin, resveratrol, genistein [ 63 , 71 , 72 , 73 ] and rutin/quercetin [ 74 , 75 ] are endowed with antioxidant potential that may compensate the oxidative stress caused by the increased production of ROS during chronic pulmonary infections. They can reduce airway inflammation and/or increase survival in animal models and/or in cystic fibrosis patients.…”

Section: Discussionmentioning

confidence: 99%

Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing

Fossa

Uggeri

Orro

et al. 2022

IJMS

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Cystic fibrosis is a hereditary disease mainly caused by the deletion of the Phe 508 (F508del) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. Cystic fibrosis remains a potentially fatal disease, but it has become treatable as a chronic condition due to some CFTR-rescuing drugs that, when used in combination, increase in their therapeutic effect due to a synergic action. Also, dietary supplementation of natural compounds in combination with approved drugs could represent a promising strategy to further alleviate cystic fibrosis symptoms. On these bases, we screened by in silico drug repositioning 846 small synthetic or natural compounds from the AIFA database to evaluate their capacity to interact with the highly druggable lumacaftor binding site of F508del-CFTR. Among the identified hits, nicotinamide (NAM) was predicted to accommodate into the lumacaftor binding region of F508del-CFTR without competing against the drug but rather stabilizing its binding. The effective capacity of NAM to bind F508del-CFTR in a lumacaftor-uncompetitive manner was then validated experimentally by surface plasmon resonance analysis. Finally, the capacity of NAM to synergize with lumacaftor increasing its CFTR-rescuing activity was demonstrated in cell-based assays. This study suggests the possible identification of natural small molecules devoid of side effects and endowed with the capacity to synergize with drugs currently employed for the treatment of cystic fibrosis, which hopefully will increase the therapeutic efficacy with lower doses.

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Consuming Genistein Improves Survival Rates in the Absence of Laxative in ΔF508-CF Female Mice

Cited by 9 publications

References 54 publications

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants

The NHE3 Inhibitor Tenapanor Prevents Intestinal Obstructions in CFTR-Deleted Mice

Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing

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