Article
Pharmacology & Pharmacy
Jia Liu, Allison P. Berg, Yiting Wang, Walailak Jantarajit, Katy J. Sutcliffe, Edward B. Stevens, Lishuang Cao, Marko J. Pregel, David N. Sheppard
Summary: This study investigates the action of a new CFTR potentiator, CP-628006, and compares it with the marketed CFTR potentiator ivacaftor. CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Cell Biology
Alessandra Ghigo, Alessandra Murabito, Valentina Sala, Anna Rita Pisano, Serena Bertolini, Ambra Gianotti, Emanuela Caci, Alessio Montresor, Aiswarya Premchandar, Flora Pirozzi, Kai Ren, Angela Della Sala, Marco Mergiotti, Wito Richter, Eyleen de Poel, Michaela Matthey, Sara Caldrer, Rosa A. Cardone, Federica Civiletti, Andrea Costamagna, Nancy L. Quinney, Cosmin Butnarasu, Sonja Visentin, Maria Rosaria Ruggiero, Simona Baroni, Simonetta Geninatti Crich, Damien Ramel, Muriel Laffargue, Carlo G. Tocchetti, Renzo Levi, Marco Conti, Xiao-Yun Lu, Paola Melotti, Claudio Sorio, Virginia De Rose, Fabrizio Facchinetti, Vito Fanelli, Daniela Wenzel, Bernd K. Fleischmann, Marcus A. Mall, Jeffrey Beekman, Carlo Laudanna, Martina Gentzsch, Gergely L. Lukacs, Nicoletta Pedemonte, Emilio Hirsch
Summary: This study identifies PI3Kγ as a critical regulator of the cAMP signaling microdomain activated by β(2)-ARs. By using a PI3Kγ mimetic peptide (PI3Kγ MP) to displace the PKA pool anchored by PI3Kγ, cAMP can be safely increased in the lungs, leading to airway smooth muscle relaxation and reduced inflammation.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Roberta Bongiorno, Alessandra Ludovico, Oscar Moran, Debora Baroni
Summary: Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by loss of function variants of CFTR. Small-molecule modulators, potentiators and correctors, have been developed to rescue defective F508del CFTR. Kaftrio, a next-generation triple-combination drug, has shown to be a life-changing therapeutic for CF patients worldwide. The study investigated the activity of VX445 on mutant F508del CFTR to reveal its mechanism of action.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Jesper Levring, Daniel S. Terry, Zeliha Kilic, Gabriel Fitzgerald, Scott Blanchard, Jue Chen
Summary: The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes. Alterations in CFTR cause cystic fibrosis, a fatal disease without a cure. In this study, the authors investigate the structure and function of CFTR, specifically focusing on the dimerization of its nucleotide-binding domains (NBDs) and the allosteric gating mechanism that regulates chloride conductance. They also explore the effects of disease-causing substitutions on NBD dimerization and propose implications for potential clinical therapies.
Article
Multidisciplinary Sciences
Parameet Kumar, Dharmendra Kumar Soni, Chaitali Sen, Mads B. Larsen, Krystyna Mazan-Mamczarz, Yulan Piao, Supriyo De, Myriam Gorospe, Raymond A. Frizzell, Roopa Biswas
Summary: SFPQ expression is reduced in CF lung epithelial cells, but overexpression can increase F508del-CFTR expression and rescue function by modulating cellular signaling pathways. This study is the first to report on the role of SFPQ in regulating the expression and function of F508del-CFTR in CF lung disease, providing insights into potential epigenetic therapeutic targets.
SCIENTIFIC REPORTS
(2021)
Article
Biotechnology & Applied Microbiology
Nika V. Petrova, Nataliya Y. Kashirskaya, Tatyana A. Vasilyeva, Natalia V. Balinova, Andrey V. Marakhonov, Elena I. Kondratyeva, Elena K. Zhekaite, Anna Y. Voronkova, Sergey I. Kutsev, Rena A. Zinchenko
Summary: Cystic fibrosis (CF) is an autosomal recessive disease caused by genetic variants within the CFTR gene. Variants located on the same chromosome can affect disease severity or treatment response. The prevalence of complex alleles in Russian CF patients and their genetic background have just started being studied. The study found that the frequency of complex alleles associated with F508del was at least 6.6% in Russian CF patients.
Article
Biochemistry & Molecular Biology
Stella Prins, Valentina Corradi, David N. N. Sheppard, D. Peter Tieleman, Paola Vergani
Summary: Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) protein has a significant impact on membrane proximity and ion-channel function. Mutagenesis scan of intracellular loop 4 (ICL4) reveals that second-site mutations, such as R1070W, F1068M, and F1074M, can partially rescue F508del defects. Molecular dynamics simulations highlight the importance of flexibility and aromatic sidechains at the ICL4/NBD1 interface in F508del-induced dysfunction.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Zhi Wei Zeng, Paul Linsdell, Regis Pomes
Summary: The recent atomistic structures of the CFTR Cl- channel provide insights into the molecular understanding of cystic fibrosis. Molecular dynamics simulations show that under a strong electric field, the protein spontaneously transitions from a closed state to an open state, allowing Cl- ions to translocate through the narrow pore bottleneck. The observed pathway of Cl- ions is consistent with the locations of mutations that affect CFTR channel function.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Respiratory System
Guido Veit, Christian Vaccarin, Gergely L. Lukacs
Summary: The study found that the combination therapy of VX-445 and VX-770 has significant therapeutic effects on CF patients with the F508del mutation, improving CFTR channel currents. VX-445 has a unique potentiator activity that can enhance the effect of VX-770, especially beneficial for CF patients with G551D and other dual potentiator responsive mutations.
JOURNAL OF CYSTIC FIBROSIS
(2021)
Article
Biochemistry & Molecular Biology
Christian Borgo, Claudio D'Amore, Valeria Capurro, Valeria Tomati, Elvira Sondo, Federico Cresta, Carlo Castellani, Nicoletta Pedemonte, Mauro Salvi
Summary: The advent of Trikafta has revolutionized the treatment of cystic fibrosis patients with the most common misfolding mutation, F508del-CFTR. However, there is still room for improvement in its efficacy, especially in rare CFTR mutations. By targeting the misfolding detection machinery, the combination of Trikafta with a drug like TAK-243 shows promising results in improving CFTR function, including in rare CF-causing mutations.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Respiratory System
Edward F. McKone, Emily A. DiMango, Sivagurunathan Sutharsan, Tara Lynn Barto, Daniel Campbell, Neil Ahluwalia, Mark Higgins, Caroline A. Owen, Elizabeth Tullis
Summary: The Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants >12 years of age with F/gating genotypes. However, TEZ/IVA was generally safe and well tolerated, consistent with previous studies.
JOURNAL OF CYSTIC FIBROSIS
(2021)
Article
Cell Biology
Eijaz Ahmed Bhat, Nasreena Sajjad, Saeed Banawas, Johra Khan
Summary: CALHMs, particularly CALHM1, play crucial roles in neuronal functioning and have been associated with pathologies like Alzheimer's disease. Recent Cryo-EM research on CALHM5 has provided insights into its structure and potential functional properties.
MOLECULAR AND CELLULAR BIOCHEMISTRY
(2021)
Article
Cell Biology
Lasti Erfinanda, Lin Zou, Birgitt Gutbier, Laura Kneller, Sarah Weidenfeld, Laura Michalick, Disi Lei, Katrin Reppe, Luiz Gustavo Teixeira Alves, Bill Schneider, Qi Zhang, Caihong Li, Diana Fatykhova, Paul Schneider, Wolfgang Liedtke, Eisei Sohara, Timothy J. Mitchell, Achim D. Gruber, Andreas Hocke, Stefan Hippenstiel, Norbert Suttorp, Andrea Olschewski, Marcus A. Mall, Martin Witzenrath, Wolfgang M. Kuebler
Summary: Pneumonia-induced loss of CFTR leads to lung edema through alterations in chloride and calcium ion concentrations. Modulation of CFTR and WNK1 can decrease endothelial permeability. The use of CFTR potentiators can prevent lung CFTR loss and associated symptoms.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Multidisciplinary Sciences
Nurunisa Akyuz, K. Domenica Karavitaki, Bifeng Pan, Panos Tamvakologos, Kelly P. Brock, Yaqiao Li, Debora S. Marks, David P. Corey
Summary: This study investigated the effects of 12 mutations on the mechanical gating of transduction currents in native hair cells of Tmc1/2-null mice expressing virally introduced TMC1 variants. The results showed that mutations within the pore-lining TM4 and TM6 helices modified gating, reducing force sensitivity or changing the open probability of the channels.
Article
Biochemistry & Molecular Biology
Paul Linsdell, Christina L. Irving, Elizabeth A. Cowley, Yassine El Hiani
Summary: Positively charged amino acid side-chains are important for anion binding and permeation through the CFTR chloride channel. The lysine residue K95 and arginine residue R134 within the pore play crucial roles in anion binding and conductance properties. Despite the importance of specific positive charges, it is the overall number of charges rather than their exact locations that control pore function.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Respiratory System
Bertrand Kleizen, John F. Hunt, Isabelle Callebaut, Tzyh-Chang Hwang, Isabelle Sermet-Gaudelus, Sylvia Hafkemeyer, David N. Sheppard
JOURNAL OF CYSTIC FIBROSIS
(2020)
Article
Biochemistry & Molecular Biology
Walailak Jantarajit, Kannikar Wongdee, Kornkamon Lertsuwan, Jarinthorn Teerapornpuntakit, Ratchaneevan Aeimlapa, Jirawan Thongbunchoo, Bartholomew S. J. Harvey, David N. Sheppard, Narattaphol Charoenphandhu
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2020)
Article
Respiratory System
Samuel J. Bose, Georg Krainer, Demi R. S. Ng, Mathias Schenkel, Hideki Shishido, Jae Seok Yoon, Peter M. Haggie, Michael Schlierf, David N. Sheppard, William R. Skach
JOURNAL OF CYSTIC FIBROSIS
(2020)
Editorial Material
Neurosciences
Alexandre Hinzpeter, Isabelle Sermet-Gaudelus, David N. Sheppard
JOURNAL OF PHYSIOLOGY-LONDON
(2020)
Article
Nutrition & Dietetics
Fittree Hayeeawaema, Santad Wichienchot, Pissared Khuituan
Article
Multidisciplinary Sciences
Saranya Peerakietkhajorn, Nilobon Jeanmard, Papatsorn Chuenpanitkit, K-DA Sakena, Kanrawee Bannob, Pissared Khuituan
Article
Food Science & Technology
Sakena K-da, Saranya Peerakietkhajorn, Brenda Siringoringo, Paradorn Muangnil, Santad Wichienchot, Pissared Khuituan
JOURNAL OF FUNCTIONAL FOODS
(2020)
Article
Physiology
Mayuree Rodrat, Walailak Jantarajit, Demi R. S. Ng, Bartholomew S. J. Harvey, Jia Liu, William J. Wilkinson, Narattaphol Charoenphandhu, David N. Sheppard
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2020)
Article
Multidisciplinary Sciences
Pissared Khuituan, Chotika Nhaemchei, Sakda Pradab, Sakena K-da, Nipaporn Konthapakdee
Summary: The research found that fluoxetine has different effects on the contraction amplitudes of duodenal and proximal colonic tissue, with higher concentrations of fluoxetine reducing the contraction amplitude in proximal colonic tissue. Additionally, the mechanism inhibiting the effect of fluoxetine is likely mediated mainly via 5-HT3 receptors and muscarinic signaling.
Article
Pharmacology & Pharmacy
Rattanaporn Sengkhim, Saranya Peerakietkhajorn, Nilobon Jeanmard, Supattra Pongparadon, Pissared Khuituan, Thanvarin Thitiphatphuvanon, Piyaporn Surinlert, Chittipong Tipbunjong
Summary: The study demonstrates that pretreatment with SPE reduces ROS production in human colon cells, has no toxic effects on mice, and shows positive effects on defecation.
TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH
(2021)
Article
Nutrition & Dietetics
Pissared Khuituan, Nawiya Huipao, Nilobon Jeanmard, Sitthiwach Thantongsakul, Warittha Promjun, Suwarat Chuthong, Chittipong Tipbunjong, Saranya Peerakietkhajorn
Summary: This study found that the extract from Sargassum plagiophyllum has effects on gastrointestinal function and gut microbiota, and can prevent constipation.
Article
Chemistry, Applied
Nantaporn Promdam, Pissared Khuituan, Pharkphoom Panichayupakaranant
Summary: Standardized [6]-gingerol extracts were prepared using alternative green solvents and showed significant inhibitory effects on mouse ileal contractions and lower esophageal sphincter contractions, indicating their potential as nutraceuticals for alleviating nausea and vomiting.
Article
Tropical Medicine
Brenda Siringoringo, Nawiya Huipao, Chittipong Tipbunjong, Jongdee Nopparat, Santad Wichienchot, Albert M. Hutapea, Pissared Khuituan
Summary: The study found that GFO has anti-inflammatory properties and can improve colonic epithelial barrier dysfunction in colitis mice. Additionally, GFO can regulate the expression of tight junction proteins that are crucial for colonic barrier function.
ASIAN PACIFIC JOURNAL OF TROPICAL BIOMEDICINE
(2021)
Meeting Abstract
Pediatrics
K. S. Raraigh, K. C. Paul, J. L. Goralski, E. N. Worthington, A. Faino, S. Sciortino, Y. Wang, M. A. Aksit, H. Ling, D. L. Osorio, F. M. Onchiri, S. Patel, C. Merlo, K. Montemayor, R. Gibson, N. E. West, D. N. Sheppard, N. Sharma, G. R. Cutting
PEDIATRIC PULMONOLOGY
(2020)
Article
Chemistry, Multidisciplinary
Hongyu Li, Hennie Valkenier, Abigail G. Thorne, Christopher M. Dias, James A. Cooper, Marion Kieffer, Nathalie Busschaert, Philip A. Gale, David N. Sheppard, Anthony P. Davis