共查询到20条相似文献,搜索用时 31 毫秒
1.
Jiraporn Ousingsawat Raquel Centeio Rainer Schreiber Karl Kunzelmann 《International journal of molecular sciences》2022,23(6)
SLC26A9 is an epithelial anion transporter with a poorly defined function in airways. It is assumed to contribute to airway chloride secretion and airway surface hydration. However, immunohistochemistry showing precise localization of SLC26A9 in airways is missing. Some studies report localization near tight junctions, which is difficult to reconcile with a chloride secretory function of SLC26A9. We therefore performed immunocytochemistry of SLC26A9 in sections of human and porcine lungs. Obvious apical localization of SLC26A9 was detected in human and porcine superficial airway epithelia, whereas submucosal glands did not express SLC26A9. The anion transporter was located exclusively in ciliated epithelial cells. Highly differentiated BCi-NS1 human airway epithelial cells grown on permeable supports also expressed SLC26A9 in the apical membrane of ciliated epithelial cells. BCi-NS1 cells expressed the major Cl− transporting proteins CFTR, TMEM16A and SLC26A9 in about equal proportions and produced short-circuit currents activated by increases in intracellular cAMP or Ca2+. Both CFTR and SLC26A9 contribute to basal chloride currents in non-stimulated BCi-NS1 airway epithelia, with CFTR being the dominating Cl− conductance. In wtCFTR-expressing CFBE human airway epithelial cells, SLC26A9 was partially located in the plasma membrane, whereas CFBE cells expressing F508del-CFTR showed exclusive cytosolic localization of SLC26A9. Membrane localization of SLC26A9 and basal chloride currents were augmented by interleukin 13 in wild-type CFTR-expressing cells, but not in cells expressing the most common disease-causing mutant F508del-CFTR. The data suggest an upregulation of SLC26A9-dependent chloride secretion in asthma, but not in the presence of F508del-CFTR. 相似文献
2.
Valeria Capurro Valeria Tomati Elvira Sondo Mario Renda Anna Borrelli Cristina Pastorino Daniela Guidone Arianna Venturini Alessandro Giraudo Sine Mandrup Bertozzi Ilaria Musante Fabio Bertozzi Tiziano Bandiera Federico Zara Luis J. V. Galietta Nicoletta Pedemonte 《International journal of molecular sciences》2021,22(10)
Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties. 相似文献
3.
Sofia S. Ramalho Iris A. L. Silva Margarida D. Amaral Carlos M. Farinha 《International journal of molecular sciences》2022,23(1)
Most of the ~2100 CFTR variants so far reported are very rare and still uncharacterized regarding their cystic fibrosis (CF) disease liability. Since some may respond to currently approved modulators, characterizing their defect and response to these drugs is essential. Here we aimed characterizing the defect associated with four rare missense (likely Class II) CFTR variants and assess their rescue by corrector drugs. We produced CFBE cell lines stably expressing CFTR with W57G, R560S, H1079P and Q1100P, assessed their effect upon CFTR expression and maturation and their rescue by VX-661/VX-445 correctors. Results were validated by forskolin-induced swelling assay (FIS) using intestinal organoids from individuals bearing these variants. Finally, knock-down (KD) of genes previously shown to rescue F508del-CFTR was assessed on these mutants. Results show that all the variants preclude the production of mature CFTR, confirming them as Class II mutations. None of the variants responded to VX-661 but the combination rescued H1079P- and Q1100P-CFTR. The KD of factors that correct F508del-CFTR retention only marginally rescued R560S- and H1079P-CFTR. Overall, data evidence that Class II mutations induce distinct molecular defects that are neither rescued by the same corrector compounds nor recognized by the same cellular machinery, thus requiring personalized drug discovery initiatives. 相似文献
4.
Claudio DAmore Christian Borgo Valentina Bosello Travain Mauro Salvi 《International journal of molecular sciences》2022,23(17)
Cystic fibrosis (CF) is caused by mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), an anion-selective plasma membrane channel that mainly regulates chloride transport in a variety of epithelia. More than 2000 mutations, most of which presumed to be disease-relevant, have been identified in the CFTR gene. The single CFTR mutation F508del (deletion of phenylalanine in position 508) is present in about 90% of global CF patients in at least one allele. F508del is responsible for the defective folding and processing of CFTR, failing to traffic to the plasma membrane and undergoing premature degradation via the ubiquitin–proteasome system. CFTR is subjected to different post-translational modifications (PTMs), and the possibility to modulate these PTMs has been suggested as a potential therapeutic strategy for the functional recovery of the disease-associated mutants. Recently, the PTM mapping of CFTR has identified some lysine residues that may undergo methylation or ubiquitination, suggesting a competition between these two PTMs. Our work hypothesis moves from the idea that favors methylation over ubiquitination, e.g., inhibiting demethylation could be a successful strategy for preventing the premature degradation of unstable CFTR mutants. Here, by using a siRNA library against all the human demethylases, we identified the enzymes whose downregulation increases F508del-CFTR stability and channel function. Our results show that KDM2A and KDM3B downregulation increases the stability of F508del-CFTR and boosts the functional rescue of the channel induced by CFTR correctors. 相似文献
5.
Lovato V Roesli C Ahlskog J Scheuermann J Neri D 《Protein engineering, design & selection : PEDS》2007,20(12):607-614
The homozygous deletion of the phenylalanine at position 508 (DeltaPhe508) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common CF-causing genetic defect. It has been proposed that the propensity of NBD1 to aggregate may lead to a lower display of the CFTR chloride channel to the cell membrane and to the disease, thus opening an avenue for the pharmacological development of CFTR folding correctors. Here, we show that a human monoclonal antibody fragment specific to the folded conformation of NBD1 inhibits the aggregation of NBD1 in vitro. However, in contrast to the previously published observations, we proved experimentally that NBD1 of wild-type and DeltaPhe508 version of CFTR display comparable propensities to aggregate in vitro and that the corresponding full-length CFTR protein reaches the cell membrane with comparable efficiency in mammalian cell expression systems. On the basis of our results, the 'folding defect' hypothesis seems unlikely to represent the causal mechanism for the pathogenesis of CF. A solid understanding of how the DeltaPhe508 deletion leads to the disease represents an absolute requirement for the development of effective drugs against CF. 相似文献
6.
Marco Pedrazzi Silvia Vercellone Elettra Barberis Michela Capraro Roberta De Tullio Federico Cresta Rosaria Casciaro Carlo Castellani Mauro Patrone Emilio Marengo Paola Lecca Paola Melotti Claudio Sorio Marcello Manfredi Monica Averna 《International journal of molecular sciences》2021,22(8)
The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from CF patients carrying residual function mutations and eligible for Ivacaftor therapy, and performed CFTR activity together with proteomic analyses through micro-LC–MS. Bioinformatic analyses of the results obtained revealed the downregulation of proteins belonging to the leukocyte transendothelial migration and regulation of actin cytoskeleton pathways when CFTR activity was rescued by VX770 treatment. In particular, we focused our attention on matrix metalloproteinase 9 (MMP9), because the high expression of this protease potentially contributes to parenchyma lung destruction and dysfunction in CF. Thus, the downregulation of MMP9 could represent one of the possible positive effects of VX770 in decreasing the disease progression, and a potential biomarker for the prediction of the efficacy of therapies targeting the defect of Cl− transport in CF. 相似文献
7.
Dr. Chandrima Sinha Prof. Weiqiang Zhang Dr. Chang Suk Moon Marcelo Actis Sunitha Yarlagadda Dr. Kavisha Arora Dr. Koryse Woodroofe Prof. John P. Clancy Dr. Songbai Lin Prof. Assem G. Ziady Prof. Raymond Frizzell Prof. Naoaki Fujii Prof. Anjaparavanda P. Naren 《Chembiochem : a European journal of chemical biology》2015,16(14):2017-2022
Cystic fibrosis (CF) is a lethal genetic disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel. F508del is the most prevalent mutation of the CFTR gene and encodes a protein defective in folding and processing. VX‐809 has been reported to facilitate the folding and trafficking of F508del‐CFTR and augment its channel function. The mechanism of action of VX‐809 has been poorly understood. In this study, we sought to answer a fundamental question underlying the mechanism of VX‐809: does it bind CFTR directly in order to exert its action? We synthesized two VX‐809 derivatives, ALK‐809 and SUL‐809, that possess an alkyne group and retain the rescue capacity of VX‐809. By using CuI‐catalyzed click chemistry, we provide evidence that the VX‐809 derivatives bind CFTR directly in vitro and in cells. Our findings will contribute to the elucidation of the mechanism of action of CFTR correctors and the design of more potent therapeutics to combat CF. 相似文献
8.
M Motiur Rahman Alip Borthakur Sheuli Afroz Subha Arthur Uma Sundaram 《International journal of molecular sciences》2021,22(8)
Electrolytes (NaCl) and fluid malabsorption cause diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption, mediated by Na+/H+ and Cl−/HCO3− exchanges on the intestinal villus cells brush border membrane (BBM), is inhibited in IBD. Arachidonic acid metabolites (AAMs) formed via cyclooxygenase (COX) or lipoxygenase (LOX) pathways are elevated in IBD. However, their effects on NaCl absorption are not known. We treated SAMP1/YitFc (SAMP1) mice, a model of spontaneous ileitis resembling human IBD, with Arachidonyl Trifluoro Methylketone (ATMK, AAM inhibitor), or with piroxicam or MK-886, to inhibit COX or LOX pathways, respectively. Cl−/HCO3− exchange, measured as DIDS-sensitive 36Cl uptake, was significantly inhibited in villus cells and BBM vesicles of SAMP1 mice compared to AKR/J controls, an effect reversed by ATMK. Piroxicam, but not MK-886, also reversed the inhibition. Kinetic studies showed that inhibition was secondary to altered Km with no effects on Vmax. Whole cell or BBM protein levels of Down-Regulated in Adenoma (SLC26A3) and putative anion transporter-1 (SLC26A6), the two key BBM Cl−/HCO3− exchangers, were unaltered. Thus, inhibition of villus cell Cl−/HCO3− exchange by COX pathway AAMs, such as prostaglandins, via reducing the affinity of the exchanger for Cl−, and thereby causing NaCl malabsorption, could significantly contribute to IBD-associated diarrhea. 相似文献
9.
Ines Pankonien Margarida C. Quaresma Cludia S. Rodrigues Margarida D. Amaral 《International journal of molecular sciences》2022,23(5)
The multi-organ disease cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, a cAMP regulated chloride (Cl−) and bicarbonate (HCO3−) ion channel expressed at the apical plasma membrane (PM) of epithelial cells. Reduced CFTR protein results in decreased Cl− secretion and excessive sodium reabsorption in epithelial cells, which consequently leads to epithelial dehydration and the accumulation of thick mucus within the affected organs, such as the lungs, pancreas, gastrointestinal (GI) tract, reproductive system and sweat glands. However, CFTR has been implicated in other functions besides transporting ions across epithelia. The rising number of references concerning its association to actin cytoskeleton organization, epithelial cell junctions and extracellular matrix (ECM) proteins suggests a role in the formation and maintenance of epithelial apical basolateral polarity. This review will focus on recent literature (the last 10 years) substantiating the role of CFTR in cell junction formation and actin cytoskeleton organization with its connection to the ECM. 相似文献
10.
Paola Fossa Matteo Uggeri Alessandro Orro Chiara Urbinati Alessandro Rondina Maria Milanesi Nicoletta Pedemonte Emanuela Pesce Rita Padoan Robert C. Ford Xin Meng Marco Rusnati Pasqualina DUrsi 《International journal of molecular sciences》2022,23(20)
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. 相似文献
11.
Daria Ponomareva Elena Petukhova Piotr Bregestovski 《International journal of molecular sciences》2021,22(24)
Optosensorics is the direction of research possessing the possibility of non-invasive monitoring of the concentration of intracellular ions or activity of intracellular components using specific biosensors. In recent years, genetically encoded proteins have been used as effective optosensory means. These probes possess fluorophore groups capable of changing fluorescence when interacting with certain ions or molecules. For monitoring of intracellular concentrations of chloride ([Cl−]i) and hydrogen ([H+] i) the construct, called ClopHensor, which consists of a H+- and Cl−-sensitive variant of the enhanced green fluorescent protein (E2GFP) fused with a monomeric red fluorescent protein (mDsRed) has been proposed. We recently developed a line of transgenic mice expressing ClopHensor in neurons and obtained the map of its expression in different areas of the brain. The purpose of this study was to examine the effectiveness of transgenic mice expressing ClopHensor for estimation of [H+]i and [Cl−]i concentrations in neurons of brain slices. We performed simultaneous monitoring of [H+]i and [Cl−]i under different experimental conditions including changing of external concentrations of ions (Ca2+, Cl−, K+, Na+) and synaptic stimulation of Shaffer’s collaterals of hippocampal slices. The results obtained illuminate different pathways of regulation of Cl− and pH equilibrium in neurons and demonstrate that transgenic mice expressing ClopHensor represent a reliable tool for non-invasive simultaneous monitoring of intracellular Cl− and pH. 相似文献
12.
Targeting of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein with a Technetium‐99m Imaging Probe
下载免费PDF全文
![点击此处可从《ChemMedChem》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Vera F. C. Ferreira Dr. Bruno L. Oliveira João D. Santos Dr. João D. G. Correia Prof. Dr. Carlos M. Farinha Dr. Filipa Mendes 《ChemMedChem》2018,13(14):1469-1478
Cystic fibrosis (CF) is caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to almost total absence of CFTR at the plasma membrane, a defect potentially corrected via drug‐based therapies. Herein, we report the first proof‐of‐principle study of a noninvasive imaging probe able to detect CFTR at the plasma membrane. We radiolabeled the CFTR inhibitor, CFTRinh‐172a, with technetium‐99m via a pyrazolyl‐diamine chelating unit, yielding a novel 99mTc(CO)3 complex. A non‐radioactive surrogate showed that the structural modifications introduced in the inhibitor did not affect its activity. The radioactive complex was able to detect plasma membrane CFTR, shown by its significantly higher uptake in wild‐type versus mutated cells. Furthermore, assessment of F508del CFTR pharmacological correction in human cells using the radioactive complex revealed differences in corrector versus control uptake, recapitulating the biochemical correction observed for the protein. 相似文献
13.
Asma Chinigarzadeh Nor Fadila Kasim Sekaran Muniandy Normadiah M. Kassim Naguib Salleh 《International journal of molecular sciences》2014,15(1):958-976
Genistein has been reported to stimulate luminal HCO3− secretion. We hypothesized that genistein mediates this effect via SLC26A6 and SLC4A4 (NBCe1) transporters. Our study aimed to: investigate changes in uterine fluid pH, Na+ and HCO3− concentration and expression of uterine SLC26A6 and NBCe1 under genistein effect. Ovariectomized adult female rats received 25, 50 and 100 mg/kg/day genistein for a week with and without ICI 182780. A day after the last injection, in vivo uterine perfusion was performed to collect uterine fluid for Na+, HCO3− and pH determination. The animals were then sacrificed and uteri were removed for mRNA and protein expression analyses. SLC26A6 and NBCe1-A and NBCe1-B distribution were visualized by immunohistochemistry (IHC). Genistein at 50 and 100 mg/kg/day stimulates uterine fluid pH, Na+ and HCO3− concentration increase. Genistein at 100 mg/kg/day up-regulates the expression of SLC26A6 and SLC4A4 mRNA, which were reduced following concomitant ICI 182780 administration. In parallel, SLC26A6 and NBCe1-B protein expression were also increased following high dose genistein treatment and were localized mainly at the apical membrane of the luminal epithelia. SLC26A6 and NBCe1-B up-regulation by genistein could be responsible for the observed increase in the uterine fluid pH, Na+ and HCO3− concentration under this condition. 相似文献
14.
Ariadna Delgado-Bermúdez Marc Yeste Sergi Bonet Elisabeth Pinart 《International journal of molecular sciences》2022,23(11)
Alkalinization of sperm cytosol is essential for plasma membrane hyperpolarization, hyperactivation of motility, and acrosomal exocytosis during sperm capacitation in mammals. The plasma membrane of sperm cells contains different ion channels implicated in the increase of internal pH (pHi) by favoring either bicarbonate entrance or proton efflux. Bicarbonate transporters belong to the solute carrier families 4 (SLC4) and 26 (SLC26) and are currently grouped into Na+/HCO3− transporters and Cl−/HCO3− exchangers. Na+/HCO3− transporters are reported to be essential for the initial and fast entrance of HCO3− that triggers sperm capacitation, whereas Cl−/HCO3− exchangers are responsible for the sustained HCO3− entrance which orchestrates the sequence of changes associated with sperm capacitation. Proton efflux is required for the fast alkalinization of capacitated sperm cells and the activation of pH-dependent proteins; according to the species, this transport can be mediated by Na+/H+ exchangers (NHE) belonging to the SLC9 family and/or voltage-gated proton channels (HVCN1). Herein, we discuss the involvement of each of these channels in sperm capacitation and the acrosome reaction. 相似文献
15.
Elvira Sondo Federico Cresta Cristina Pastorino Valeria Tomati Valeria Capurro Emanuela Pesce Mariateresa Lena Michele Iacomino Ave Maria Baffico Domenico Coviello Tiziano Bandiera Federico Zara Luis J. V. Galietta Renata Bocciardi Carlo Castellani Nicoletta Pedemonte 《International journal of molecular sciences》2022,23(6)
Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators. 相似文献
16.
Ly Thi Thanh Le Lukasz Kotula Kadambot H. M. Siddique Timothy D. Colmer 《International journal of molecular sciences》2021,22(4)
Grain legumes are important crops, but they are salt sensitive. This research dissected the responses of four (sub)tropical grain legumes to ionic components (Na+ and/or Cl−) of salt stress. Soybean, mungbean, cowpea, and common bean were subjected to NaCl, Na+ salts (without Cl−), Cl− salts (without Na+), and a “high cation” negative control for 57 days. Growth, leaf gas exchange, and tissue ion concentrations were assessed at different growing stages. For soybean, NaCl and Na+ salts impaired seed dry mass (30% of control), more so than Cl− salts (60% of control). All treatments impaired mungbean growth, with NaCl and Cl− salt treatments affecting seed dry mass the most (2% of control). For cowpea, NaCl had the greatest adverse impact on seed dry mass (20% of control), while Na+ salts and Cl− salts had similar intermediate effects (~45% of control). For common bean, NaCl had the greatest adverse effect on seed dry mass (4% of control), while Na+ salts and Cl− salts impaired seed dry mass to a lesser extent (~45% of control). NaCl and Na+ salts (without Cl−) affected the photosynthesis (Pn) of soybean more than Cl− salts (without Na+) (50% of control), while the reverse was true for mungbean. Na+ salts (without Cl−), Cl− salts (without Na+), and NaCl had similar adverse effects on Pn of cowpea and common bean (~70% of control). In conclusion, salt sensitivity is predominantly determined by Na+ toxicity in soybean, Cl− toxicity in mungbean, and both Na+ and Cl− toxicity in cowpea and common bean. 相似文献
17.
Arianna Venturini Anna Borrelli Ilaria Musante Paolo Scudieri Valeria Capurro Mario Renda Nicoletta Pedemonte Luis J. V. Galietta 《International journal of molecular sciences》2021,22(21)
Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations. We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. We found that the extent of rescue and sensitivity to the various agents is largely dependent on the type of mutation, with W1282X and R553X being the mutations most and least sensitive to pharmacological treatments, respectively. In particular, W1282X-CFTR was highly responsive to NMD suppression by SMG1i but also required treatment with VX-445 corrector to show function. In contrast, G542X-CFTR required treatment with readthrough agents and VX-809. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation. 相似文献
18.
19.
Chung-Chieh Hung Chieh-Hsin Lin Hsien-Yuan Lane 《International journal of molecular sciences》2021,22(18)
Glutamate, a crucial excitatory neurotransmitter, plays a major role in the modulation of schizophrenia’s pathogenesis. New drug developments for schizophrenia have been prompted by the hypoglutamatergic hypothesis of schizophrenia. The cystine/glutamate antiporter system xc− is related to glutamate-release regulation. Patients with schizophrenia were recently discovered to exhibit downregulation of xc− subunits—the solute carrier (SLC) family 3 member 2 and the SLC family 7 member 11. We searched for relevant studies from 1980, when Bannai and Kitamura first identified the protein subunit system xc− in lung fibroblasts, with the aim of compiling the biological, functional, and pharmacological characteristics of antiporter xc−, which consists of several subunits. Some of them can significantly stimulate the human brain through the glutamate pathway. Initially, extracellular cysteine activates neuronal xc−, causing glutamate efflux. Next, excitatory amino acid transporters enhance the unidirectional transportation of glutamate and sodium. These two biochemical pathways are also crucial to the production of glutathione, a protective agent for neural and glial cells and astrocytes. Investigation of the expression of system xc− genes in the peripheral white blood cells of patients with schizophrenia can facilitate better understanding of the mental disorder and future development of novel biomarkers and treatments for schizophrenia. In addition, the findings further support the hypoglutamatergic hypothesis of schizophrenia. 相似文献
20.
Dongkyu Jeon Ikhyun Jun Ho K. Lee Jinhong Park Bo-Rahm Kim Kunhi Ryu Hongchul Yoon Tae-im Kim Wan Namkung 《International journal of molecular sciences》2022,23(9)
Cystic fibrosis transmembrane conductance regulator (CFTR) is highly expressed on the ocular epithelium and plays a pivotal role in the fluid secretion driven by chloride transport. Dry eye disease is one of the most common diseases with limited therapeutic options. In this study, a high-throughput screening was performed to identify novel CFTR activators capable of inducing chloride secretion on the ocular surface. The screening of 50,000 small molecules revealed three novel CFTR activators. Among them, the most potent CFTR activator, Cact-3 (7-(3,4-dimethoxyphenyl)-N-(4-ethoxyphenyl)pyrazolo [1,5-α]pyrimidine-2-carboxamide), produced large and sustained Cl− currents in WT-CFTR-expressing FRT cells with no alterations of ANO1 and hERG channel activity. The application of Cact-3 strongly activated CFTR in the ocular epithelia of mice and it also significantly increased CFTR-mediated Cl− transport in a primary cultured human conjunctival epithelium. Cact-3 strongly stimulated tear secretion in normal mice. In addition, Cact-3 significantly reduced ocular surface damage and the expression of proinflammatory factors, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in an experimental mouse model of dry eye disease. These results suggest that Cact-3, a novel CFTR activator, may be a potential development candidate for the treatment of dry eye disease. 相似文献