Matrine modulates HSC70 levels and rescues ΔF508‐CFTR

Basile, Anna; Pascale, Maria; Franceschelli, Silvia; Nieddu, Erika; Mazzei, Marco T.; Fossa, Paola; Turco, Maria Caterina; Mazzei, Mauro

doi:10.1002/jcp.24028

Cited by 15 publications

(11 citation statements)

References 53 publications

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“…An intensive investigation into the pharmacology and clinical applications of matrine has been ongoing in China for the past decade [2,3,4,5,6]. Matrine has been widely used for the treatment of chronic hepatitis B and chronic hepatitis C since 1998 and has recently been reported to have anti-tumor activities with potential as an adjunct therapy for cancers [5,7,8,9,10,11].…”

Section: Introductionmentioning

confidence: 99%

Matrine Inhibits Mouse Sperm Function by Reducing Sperm [Ca2+]i and Phospho-ERK1/2

Luo

Zou²,

He³

et al. 2015

Cell Physiol Biochem

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Background: Matrine is a bioactive alkaloid that has a variety of pharmacological effects and is widely used in Chinese medicine. However, its effects on male reproduction are not well known. In this study, we aimed to investigate the in vitro toxicity of matrine on mature mouse sperm. Methods: Mouse cauda epididymal sperm were exposed to matrine (10-200 µM) in vitro. The viability, motility, capacitation, acrosome reaction and fertilization ability of the mouse sperm were examined. Furthermore, the intracellular calcium concentration ([Ca²⁺]_i), calcium (Catsper) and potassium (Ksper) currents, and phosphorylation of extracellular signal regulated kinases 1/2 (p-ERK1/2) of the sperm were analyzed. Results: After exposure to 100 µM or more of matrine, mouse cauda epididymal sperm exhibited a significant reduction in total motility, progressive motility, linear velocity and acrosome reaction rate induced by Ca²⁺ ionophore A23187. As a result, the fertilization ability of mouse sperm was remarkably decreased by matrine. Our data further demonstrated that matrine significantly reduced sperm [Ca²⁺]_i and [Ca²⁺]_i-related p-ERK1/2; however, both the CatSper and KSper currents, which are thought to interactively regulate Ca²⁺ influx in sperm, were not affected by matrine. Conclusion: Our findings indicate that matrine inhibits mouse sperm function by reducing sperm [Ca²⁺]_i and suppressing the phosphorylation of ERK1/2.

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Section: Introductionmentioning

confidence: 99%

Matrine Inhibits Mouse Sperm Function by Reducing Sperm [Ca2+]i and Phospho-ERK1/2

Luo

Zou²,

He³

et al. 2015

Cell Physiol Biochem

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“…Moreover, their mechanism of action is still unclear. For instance, some of them could bind to CFTR itself , while others could act favorably on the complex system of proteins (namely, molecular chaperones, phosphodiesterases, kinases, and PARPs), helping in the folding and trafficking of F508del‐CFTR .…”

Section: Introductionmentioning

confidence: 99%

Phenylhydrazones as Correctors of a Mutant Cystic Fibrosis Transmembrane Conductance Regulator

Nieddu

Pollarolo

Mazzei

et al. 2015

Archiv der Pharmazie

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The phenylhydrazone RDR-1 is endowed with moderate activity as F508del-CFTR corrector; nevertheless, its simple structure enables stimulating developments in this class of correctors. Therefore, we synthesized a number of phenylhydrazones 3 by reacting phenylhydrazine derivatives 1 with furfural derivatives 2. By the same reaction, also the pyridine derivatives 4, the thiophene derivatives 5, and the hydrazides 6 and 7 were prepared. All compounds were tested as F508del-CFTR correctors in the cystic fibrosis (CF) bronchial epithelial cell line CFBE41o-, using corr-4a and VX-809 as controls. Some of the tested compounds emerged as interesting F508del-CFTR correctors at 20 μM (3c) and 2 μM (5d). 3c and 5d administered together with VX-809 produced a satisfactory additivity of action. When the structure of 5d was overlapped with RDR-1 and five other established correctors, a shared central design was clearly visible. This fact may be of interest in the search for new F508del-CFTR correctors.

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“…Matrine decreases Hsc70 levels in human alveolar epithelial cells in vitro, promoting F508del-CFTR binding to chaperone, BAG3, which promotes translocation to the membrane [88]. …”

Section: Cftr Modulatorsmentioning

confidence: 99%

Therapeutic Options for Hydrating Airway Mucus in Cystic Fibrosis

Tildy

Rogers

2015

Pharmacology

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Background: In cystic fibrosis (CF), genetic mutations in the CF transmembrane conductance regulator (CFTR) gene cause reduced chloride efflux from ciliated airway epithelial cells. This results in a reduction in periciliary liquid (PCL) depth of the airway surface liquid due to associated reduced water efflux. PCL layer dehydration reduces mucociliary clearance (MCC), leading to airway obstruction (reduced airflow and inflammation due to pathogen invasion) with mucus plug formation. Summary: Rehydrating mucus increases MCC. Mucus hydration can be achieved by direct hydration (administering osmotic agents to set up an osmotic gradient), using CFTR modulators to correct dysfunctional CFTR, or it can be achieved pharmacologically (targeting other ion channels on airway epithelial cells). Key Messages: The molecular mechanisms of several therapies are discussed in the context of pre-clinical and clinical trial studies. Currently, only the osmotic agent 7% hypertonic saline and the CFTR ‘potentiator' VX-770 (ivacaftor) are used clinically to hydrate mucus. Emerging therapies include the osmotic agent mannitol (Bronchitol), the intracellular Ca²⁺-raising agent Moli1901/lancovutide, the CFTR potentiator sildenafil [phosphodiesterase type 5 (PDE5) inhibitor] and the CFTR ‘corrector' VX-809 (lumacaftor). Other CFTR correctors (e.g. ‘chemical chaperones') are also showing pre-clinical promise.

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Matrine modulates HSC70 levels and rescues ΔF508‐CFTR

Cited by 15 publications

References 53 publications

Matrine Inhibits Mouse Sperm Function by Reducing Sperm [Ca2+]i and Phospho-ERK1/2

Matrine Inhibits Mouse Sperm Function by Reducing Sperm [Ca2+]i and Phospho-ERK1/2

Phenylhydrazones as Correctors of a Mutant Cystic Fibrosis Transmembrane Conductance Regulator

Therapeutic Options for Hydrating Airway Mucus in Cystic Fibrosis

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