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1.
J Gen Physiol ; 153(12)2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34647973

RESUMO

The ATP-binding cassette (ABC) transporter superfamily includes many proteins of clinical relevance, with genes expressed in all domains of life. Although most members use the energy of ATP binding and hydrolysis to accomplish the active import or export of various substrates across membranes, the cystic fibrosis transmembrane conductance regulator (CFTR) is the only known animal ABC transporter that functions primarily as an ion channel. Defects in CFTR, which is closely related to ABCC subfamily members that bear function as bona fide transporters, underlie the lethal genetic disease cystic fibrosis. This article seeks to integrate structural, functional, and genomic data to begin to answer the critical question of how the function of CFTR evolved to exhibit regulated channel activity. We highlight several examples wherein preexisting features in ABCC transporters were functionally leveraged as is, or altered by molecular evolution, to ultimately support channel function. This includes features that may underlie (1) construction of an anionic channel pore from an anionic substrate transport pathway, (2) establishment and tuning of phosphoregulation, and (3) optimization of channel function by specialized ligand-channel interactions. We also discuss how divergence and conservation may help elucidate the pharmacology of important CFTR modulators.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Trifosfato de Adenosina , Animais , Canais de Cloreto , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Evolução Molecular , Humanos
2.
In Vivo ; 35(6): 3165-3173, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697147

RESUMO

BACKGROUND/AIM: Chloride intracellular channel 4 (CLIC4) is associated with the progression of colorectal cancer (CRC). However, quantitative differences in CLIC4 expression in epithelial and stromal cells of normal mucosal tissue (NT), cancer adjacent to normal colorectal mucosal tissue (NAT), and CRC tissue remain unclear. MATERIALS AND METHODS: We investigated the number of CLIC4 high-expressing (CLIC4high) cells in colorectal tissue of CRC patients and healthy individuals. RESULTS: The number of CLIC4high cells in malignant epithelial cells at early cancerous lesions was significantly higher than that in NAT, but was significantly lower or tended to become low corresponding to the progression of colorectal carcinogenesis. Meanwhile, the number of CLIC4high cells in the stromal tissue remained low in NAT compared to late lesions. CONCLUSION: The number of CLIC4high cells is a useful predictor in determining the pathological condition in both malignant epithelial and stromal tissues of CRC patients.


Assuntos
Carcinogênese , Neoplasias Colorretais , Linhagem Celular Tumoral , Canais de Cloreto/genética , Neoplasias Colorretais/genética , Humanos
3.
Stem Cell Res ; 56: 102538, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34547705

RESUMO

Dent disease (DD) is a rare X-linked proximal tubulopathy associated with low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and phosphoruria, which may progress to chronic kidney disease (CKD). About 60% of cases are caused by the mutation in CLCN5 gene. Recently, we identified a mutation in the sequence of homodimer of CLCN5 gene in a patient with DD. The Peripheral Blood Mononuclear Cells (PBMCs) of the patient were obtained and a line of induced pluripotent stem cells (iPSCs) was successfully generated. The iPSC line will be useful for further study of the pathogenesis and drug screening for DD.


Assuntos
Doença de Dent , Células-Tronco Pluripotentes Induzidas , Canais de Cloreto/genética , Doença de Dent/genética , Hemizigoto , Humanos , Leucócitos Mononucleares , Mutação/genética
4.
Ecotoxicol Environ Saf ; 225: 112762, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34530263

RESUMO

A diet high in sodium chloride (NaCl) can affect renal function damage and increase urinary calcium excretion, leading to bone loss. in renal tubules, Na-Cl co-transporter (NCC) and chloride channel 5 (CLC-5) are involved in regulating urinary calcium excretion. In addition, some cytokines, such as Bone morphogenetic protein 7 (BMP-7) and 1α-hydroxylase, are synthesized by renal tubules, which target on bone and play important roles on bone metabolism. However, the specific mechanisms between NaCl and these ion channels or cytokines still need investigations from many aspects. This study, in culture normal rat renal tubular epithelial NRK-52E cells, showed that high concentrations of NaCl significantly inhibited the cell viability and increased the cell apoptosis. High concentration of NaCl reduce bone mineral density (BMD), as demonstrated by the significantly increased mRNA and protein levels of NCC and osteopontin (OPN), but decreased the levels of CLC-5, BMP-7, and 1α-hydroxylase. In addition, we found that ovariectomized (OVX) rats on a high-salt diet for 12 weeks had altered levels of these indices in the renal cortices. Moreover, the BMD in fourth and fifth lumbar vertebra (LV4 and 5) and femurs were significantly decreased and bone microstructure was destroyed of these rats. We also demonstrated that high concentration of NaCl enhanced the inhibition of these cytokines which is beneficial to increase BMD, induced by modulating ion channels NCC and CLC-5. In conclusion, our results indicate that high concentration of NaCl reduce BMD by regulating ion channels NCC and CLC-5.


Assuntos
Cloretos , Cloreto de Sódio , Animais , Proteína Morfogenética Óssea 7 , Canais de Cloreto , Cloretos/toxicidade , Oxigenases de Função Mista , Ratos
5.
BMC Pediatr ; 21(1): 384, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479510

RESUMO

BACKGROUND: The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl-/H+ exchanger ClC-4 prominently expressed in brain. CASE PRESENTATION: We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. CONCLUSION: Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family.


Assuntos
Deficiência Intelectual , Retardo Mental Ligado ao Cromossomo X , Pré-Escolar , China , Canais de Cloreto/genética , Feminino , Genes Ligados ao Cromossomo X , Humanos , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
6.
J Physiol ; 599(21): 4741-4743, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34533833
7.
Nat Commun ; 12(1): 4893, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385445

RESUMO

The Tweety homologs (TTYHs) are members of a conserved family of eukaryotic membrane proteins that are abundant in the brain. The three human paralogs were assigned to function as anion channels that are either activated by Ca2+ or cell swelling. To uncover their unknown architecture and its relationship to function, we have determined the structures of human TTYH1-3 by cryo-electron microscopy. All structures display equivalent features of a dimeric membrane protein that contains five transmembrane segments and an extended extracellular domain. As none of the proteins shows attributes reminiscent of an anion channel, we revisited functional experiments and did not find any indication of ion conduction. Instead, we find density in an extended hydrophobic pocket contained in the extracellular domain that emerges from the lipid bilayer, which suggests a role of TTYH proteins in the interaction with lipid-like compounds residing in the membrane.


Assuntos
Canais de Cloreto/ultraestrutura , Microscopia Crioeletrônica/métodos , Proteínas de Membrana/ultraestrutura , Proteínas de Neoplasias/ultraestrutura , Canais de Cloreto/química , Canais de Cloreto/metabolismo , Humanos , Canais Iônicos/química , Canais Iônicos/metabolismo , Canais Iônicos/ultraestrutura , Bicamadas Lipídicas/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Modelos Moleculares , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Conformação Proteica
8.
In Vivo ; 35(5): 2711-2718, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410960

RESUMO

BACKGROUND/AIM: Colon cancer liver metastases with desmoplastic growth pattern (dGP) have a highly heterogeneous therapy response. The aim of the study was to evaluate the dGP liver metastasis molecular profile from a chemo-naive patient by mimicking metastatic process on an experimental chick embryo chorioallantoic membrane (CAM) model. MATERIALS AND METHODS: Three successive CAM passages of dGP human colorectal liver metastases were immunophenotyped for keratin (K) 8, and 20, CLIC1, VEGF, EGFR, CD34, podoplanin, Ki67, E-cadherin and vimentin. RESULTS: Metastatic cells gradually lost K20 while K8, E-cadherin and vimentin heterogeneously increased during passages. VEGF, CLIC 1, EGFR expression increased in metastatic cells especially at the tumor graft periphery. Scattered proliferating and non-proliferating podoplanin-positive tumor cells, lymphatic and blood vessels were heterogeneously detected in tumor xenografts depending on passage stage. CONCLUSION: By mimicking repetitive metastatic processes we proved that metastatic cells change their phenotype. This may explain why not all metastases have a similar response to therapy.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Animais , Embrião de Galinha , Canais de Cloreto , Membrana Corioalantoide , Neoplasias Colorretais/genética , Humanos , Neoplasias Hepáticas/genética , Fenótipo
9.
In Vivo ; 35(5): 2559-2567, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410943

RESUMO

BACKGROUND/AIM: Chloride intracellular channel protein 1 (CLIC1) activates inflammasomes in rheumatoid (RA) and psoriatic (PsA) arthritis. We studied CLIC1 expression in RA and PsA patients' skin with vasculitis and its variability depending on the therapy used. MATERIALS AND METHODS: CLIC1 immunoexpression was evaluated in the vascular (CLIC1-V) and stromal (CLIC1-S) compartments of the RA and PsA skin biopsies of patients treated with methotrexate (MTX), leflunomid (LFN), corticotherapy (CT), or biological therapies. RESULTS: MTX significantly reduced CLIC1-S expression (p=0.016), whereas LFN decreased CLIC1-V (p<0.001). LFN therapy duration also correlated with CLIC1-V (p<0.001). CT decreased CLIC1-S expression (p=0.006). CLIC1-S expression persisted in skin biopsies despite of erythrocyte sedimentation rate (ESR, p=0.018) and C reactive protein (CRP, p=0.0026) normalisation. For PsA, CLIC1-S expression significantly related to MTX (p<0.022). Both CLIC1-S (p<0.001) and CLIC1-V (p=0.007) decreased by biological therapies in RA. CONCLUSION: CLIC1 expression is strongly influenced by the therapy used. Our data strongly support the extensive evaluation of CLIC1 in RA as a potential marker of inflammation and tool to predict therapy response.


Assuntos
Artrite Psoriásica , Artrite Reumatoide , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Biópsia , Canais de Cloreto , Humanos , Metotrexato , Pele
10.
J Physiol ; 599(20): 4625-4642, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34411298

RESUMO

Opening of the cystic fibrosis transmembrane conductance regulator (CFTR) channel is coupled to the motion of its two nucleotide-binding domains: they form a heterodimer sandwiching two functionally distinct ATP-binding sites (sites 1 and 2). While active ATP hydrolysis in site 2 triggers rapid channel closure, the functional role of stable ATP binding in the catalysis-incompetent (or degenerate) site 1, a feature conserved in many other ATP-binding cassette (ABC) transporter proteins, remains elusive. Here, we found that CFTR loses its prompt responsiveness to ATP after the channel is devoid of ATP for tens to hundreds of seconds. Mutants with weakened ATP binding in site 1 and the most prevalent disease-causing mutation, F508del, are more vulnerable to ATP depletion. In contrast, strengthening ligand binding in site 1 with N6 -(2-phenylethyl)-ATP, a high-affinity ATP analogue, or abolishing ATP hydrolysis in site 2 by the mutation D1370N, helps sustain a durable function of the otherwise unstable mutant channels. Thus, tight binding of ATP in the degenerate ATP-binding site is crucial to the functional stability of CFTR. Small molecules targeting site 1 may bear therapeutic potential to overcome the membrane instability of F508del-CFTR. KEY POINTS: During evolution, many ATP-binding cassette transporters - including the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, whose dysfunction causes cystic fibrosis (CF) - lose the ability to hydrolyse ATP in one of the two ATP-binding sites. Here we show that tight ATP binding at this degenerate site in CFTR is central for maintaining the stable, robust function of normal CFTR. We also demonstrate that membrane instability of the most common CF-causing mutant, F508del-CFTR, can be rescued by strengthening ATP binding at CFTR's degenerate site. Our data thus explain an evolutionary puzzle and offer a potential therapeutic strategy for CF.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Trifosfato de Adenosina , Sítios de Ligação , Canais de Cloreto , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos
11.
PLoS One ; 16(7): e0254251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234379

RESUMO

Pentameric ligand-gated ion channels (pLGICs) activated by the inhibitory neurotransmitter γ-aminobutyric acid (GABA) are expressed widely in both vertebrate and invertebrate species. One of the best characterised insect GABA-gated chloride channels is RDL, an abbreviation of 'resistance to dieldrin', that was originally identified by genetic screening in Drosophila melanogaster. Here we have cloned the analogous gene from the bumblebee Bombus terrestris audax (BtRDL) and examined its pharmacological properties by functional expression in Xenopus oocytes. Somewhat unexpectedly, the sensitivity of BtRDL to GABA, as measured by its apparent affinity (EC50), was influenced by heterologous expression conditions. This phenomenon was observed in response to alterations in the amount of cRNA injected; the length of time that oocytes were incubated before functional analysis; and by the presence or absence of a 3' untranslated region. In contrast, similar changes in expression conditions were not associated with changes in apparent affinity with RDL cloned from D. melanogaster (DmRDL). Changes in apparent affinity with BtRDL were also observed following co-expression of a chaperone protein (NACHO). Similar changes in apparent affinity were observed with an allosteric agonist (propofol) and a non-competitive antagonist (picrotoxinin), indicating that expression-depended changes are not restricted to the orthosteric agonist binding site. Interestingly, instances of expression-dependent changes in apparent affinity have been reported previously for vertebrate glycine receptors, which are also members of the pLGIC super-family. Our observations with BtRDL are consistent with previous data obtained with vertebrate glycine receptors and indicates that agonist and antagonist apparent affinity can be influenced by the level of functional expression in a variety of pLGICs.


Assuntos
Canais de Cloreto/antagonistas & inibidores , Canais de Cloreto/metabolismo , Drosophila melanogaster/metabolismo , Ácido gama-Aminobutírico/metabolismo , Regiões 3' não Traduzidas/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Abelhas/metabolismo , Agonistas dos Canais de Cloreto/farmacologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Feminino , Picrotoxina/análogos & derivados , Picrotoxina/farmacologia , Propofol/farmacologia , Receptores de Glicina/metabolismo , Xenopus laevis/metabolismo
12.
Kidney Int ; 100(2): 269-272, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34294205

RESUMO

Hypertension is the leading risk factor for the development of heart diseases and stroke. Many hypertensive patients experience undesirable side effects to conventional antihypertensive pharmacotherapy. Cil et al. documented the antihypertensive profile of a novel molecule, TMinh-23 (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide), in the spontaneously hypertensive rat model of systemic hypertension. They showed that this agent reduces blood pressure by inhibiting transmembrane member 16A-encoded calcium-activated chloride channels in vascular myocytes from resistance arteries. If validated, TMinh-23 could become a useful clinical tool.


Assuntos
Anti-Hipertensivos , Canais de Cloreto , Anoctamina-1 , Anti-Hipertensivos/uso terapêutico , Artérias , Canais de Cloreto/genética , Humanos
13.
J Phys Chem B ; 125(29): 7975-7984, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34260231

RESUMO

Canonical descriptions of multistep biomolecular transformations generally follow a single-pathway viewpoint, with a series of transitions through intermediates converting reactants to products or repeating a conformational cycle. However, mounting evidence suggests that more complexity and pathway heterogeneity are mechanistically relevant due to the statistical distribution of multiple interconnected rate processes. Making sense of such pathway complexity remains a significant challenge. To better understand the role and relevance of pathway heterogeneity, we herein probe the chemical reaction network of a Cl-/H+ antiporter, ClC-ec1, and analyze reaction pathways using multiscale kinetic modeling (MKM). This approach allows us to describe the nature of the competing pathways and how they change as a function of pH. We reveal that although pH-dependent Cl-/H+ transport rates are largely regulated by the charge state of amino acid E148, the charge state of E203 determines relative contributions from coexisting pathways and can shift the flux pH-dependence. The selection of pathways via E203 explains how ionizable mutations (D/H/K/R) would impact the ClC-ec1 bioactivity from a kinetic perspective and lends further support to the indispensability of an internal glutamate in ClC antiporters. Our results demonstrate how quantifying the kinetic selection of competing pathways under varying conditions leads to a deeper understanding of the Cl-/H+ exchange mechanism and can suggest new approaches for mechanistic control.


Assuntos
Antiporters , Ácido Glutâmico , Antiporters/metabolismo , Canais de Cloreto/metabolismo , Cloretos/metabolismo , Concentração de Íons de Hidrogênio , Cinética
14.
BMC Genomics ; 22(1): 517, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233613

RESUMO

OBJECTIVE: To prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT). METHODS: We applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analyses were done for participants of European and East Asian ancestries, separately. RESULTS: We identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; PSMR = 4.15 × 10- 12), PTGDS (ILMN_1664464; PSMR = 6.88 × 10- 9) and C9orf142 (ILMN_1761138; PSMR = 8.09 × 10- 9) were the top three genes using the CAGE eQTL data, and RP11-458F8.4 (ENSG00000273142.1; PSMR = 5.89 × 10- 9), LCNL1 (ENSG00000214402.6; PSMR = 5.67 × 10- 8), and PTGDS (ENSG00000107317.7; PSMR = 1.92 × 10- 7) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing. CONCLUSION: We identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.


Assuntos
Glaucoma de Ângulo Aberto , Análise da Randomização Mendeliana , Canais de Cloreto , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/genética , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
15.
Biomed Pharmacother ; 139: 111615, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243598

RESUMO

BACKGROUND: Severe acidosis deteriorates cardiac injury. Rat coronary arteries (RCAs) are unusually hypercontractive to extracellular (o) acidosis (EA). TMEM16A-encoded anoctamin 1 (ANO1), a Ca2+-activated chloride channel (CaCC), plays an important role in regulating coronary arterial tension. PURPOSE: We tested the possibility that the activation of CaCCs in the arterial smooth muscle cell (ASMC) contributes to EA-induced RCA constriction. METHODS: ANO1 expression was detected with immunofluorescence staining and Western blot. TMEM16A mRNA was assessed with quantitative Real-Time PCR. Cl- currents and membrane potentials were quantified with a patch clamp. The vascular tension was recorded with a myograph. Intracellular (i) level of Cl- and Ca2+ was measured with fluorescent molecular probes. RESULTS: ANO1 was expressed in all tested arterial myocytes, but was much more abundant in RCA ASMCs as compared with ASMCs isolated from rat cerebral basilar, intrarenal and mesenteric arteries. EA reduced [Cl-]i levels, augmented CaCC currents exclusively in RCA ASMCs and depolarized RCA ASMCs to a greater extent. Cl- deprivation, which depleted [Cl-]i by incubating the arteries or their ASMCs in Cl--free bath solution, decreased EA-induced [Cl-]i reduction, diminished EA-induced CaCC augmentation and time-dependently depressed EA-induced RCA constriction. Inhibitor studies showed that these EA-induced effects including RCA constriction, CaCC current augmentation, [Cl-]i reduction and/or [Ca2+]i elevation were depressed by various Cl- channel blockers, [Ca2+]i release inhibitors and L-type voltage-gated Ca2+ channel inhibitor nifedipine. ANO1 antibody attenuated all observed changes induced by EA in RCA ASMCs. CONCLUSION: The greater activity of RCA ASMC CaCCs complicated with an enhanced Ca2+ mobilization from both [Ca2+]i release and [Ca2+]o influx plays a pivotal role in the distinctive hypercontractility of RCAs to acidosis. Translation of these findings to human beings may lead to a new conception in our understanding and treating cardiac complications in severe acidosis.


Assuntos
Acidose/metabolismo , Anoctamina-1/metabolismo , Vasos Coronários/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Vasoconstrição/fisiologia , Acidose/tratamento farmacológico , Animais , Cálcio/metabolismo , Canais de Cloreto/metabolismo , Cloretos/metabolismo , Vasos Coronários/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nifedipino/farmacologia , Técnicas de Patch-Clamp/métodos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos
16.
Pediatr Cardiol ; 42(7): 1459-1477, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34327543

RESUMO

Abnormal congenital aorto-cardiac communications (CACC) are a heterogeneous constellation of anomalies that provide an abnormal connection between the aorta and other cardiac chambers or structures, including the atria, ventricles, the main pulmonary artery, and the coronary sinus. The current terminology of CACC has significant errors and shortcomings including inconsistent and interchangeable use of terms of fistula and tunnel and lack of an inclusive classification with practical information on therapeutic management. The aims of this study were threefold: firstly, to perform a concise narrative review of congenital pathologic connections between the aortic root and cardiac chambers which include rupture of congenital sinus of Valsalva aneurysm, aorto-left ventricular and less commonly right ventricular tunnels, coronary cameral fistulas, and aorto-atrial communications; secondly, to investigate the differentiating features of the so-called aorta right atrial tunnel (ARAT), with and without coronary artery take-off from the tunnel, and coronary cameral fistula (CCF) by applying a differential diagnostic assistance toolbox to two groups of patients with ARAT and CCF; and lastly, to propose a practical and inclusive anatomic-therapeutic classification for CACCs. The two main cornerstones of the proposed classification are the type of the connector between the aorta and cardiac chamber (hole versus passage) and the nature of the connecting passage ( anatomic versus extra-anatomic). We classified CACCs into three types. Depending on the intramural versus extramural course of the extra-anatomic connecting passage, type 3 is further subdivided into type 3A and type 3B.


Assuntos
Cardiopatias Congênitas , Aorta , Canais de Cloreto , Átrios do Coração , Ventrículos do Coração/diagnóstico por imagem , Humanos
18.
PLoS One ; 16(7): e0246224, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228751

RESUMO

Chloride intracellular channels (CLICs) are a unique family of evolutionarily conserved metamorphic proteins, switching between stable conformations based on redox conditions. CLICs have been implicated in a wide variety biological processes including ion channel activity, apoptosis, membrane trafficking, and enzymatic oxidoreductase activity. Understanding the molecular mechanisms by which CLICs engage in these activities is an area of active research. Here, the sole Drosophila melanogaster ortholog, Clic, was targeted for RNAi knockdown to identify genes and biological processes associated with Clic expression. Clic knockdown had a substantial impact on global transcription, altering expression of over 7% of transcribed Drosophila genes. Overrepresentation analysis of differentially expressed genes identified enrichment of Gene Ontology terms including Cytoplasmic Translation, Oxidation-Reduction Process, Heme Binding, Membrane, Cell Junction, and Nucleolus. The top term, Cytoplasmic Translation, was enriched almost exclusively with downregulated genes. Drosophila Clic and vertebrate ortholog Clic4 have previously been tied to ethanol sensitivity and ethanol-regulated expression. Clic knockdown-responsive genes from the present study were found to overlap significantly with gene sets from 4 independently published studies related to ethanol exposure and sensitivity in Drosophila. Bioinformatic analysis of genes shared between these studies revealed an enrichment of genes related to amino acid metabolism, protein processing, oxidation-reduction processes, and lipid particles among others. To determine whether the modulation of ethanol sensitivity by Clic may be related to co-regulated oxidation-reduction processes, we evaluated the effect of hyperoxia on ethanol sedation in Clic knockdown flies. Consistent with previous findings, Clic knockdown reduced acute ethanol sedation sensitivity in flies housed under normoxia. However, this effect was reversed by exposure to hyperoxia, suggesting a common set of molecular-genetic mechanism may modulate each of these processes. This study suggests that Drosophila Clic has a major influence on regulation of oxidative stress signaling and that this function overlaps with the molecular mechanisms of acute ethanol sensitivity in the fly.


Assuntos
Canais de Cloreto/deficiência , Canais de Cloreto/genética , Cloretos/metabolismo , Drosophila melanogaster/citologia , Etanol/farmacologia , Perfilação da Expressão Gênica , Espaço Intracelular/metabolismo , Animais , Drosophila melanogaster/metabolismo , Técnicas de Silenciamento de Genes , Espaço Intracelular/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
19.
J Biosci ; 462021.
Artigo em Inglês | MEDLINE | ID: mdl-34148879

RESUMO

To promote diligent analysis of the progression of a disease, it is important to identify interesting biomarkers for the disease. Biclustering has already been established as an effective technique to help identify such biomarkers of high biological significance. Although in the recent past, a good number of biclustering techniques have been introduced, most of them fail to perform consistently across multiple domains or datasets. To choose a single biclustering technique that can help the accomplishment of such a critical task for multiple diseases with high precision is extremely difficult. Hence, in this study, we considered several biclustering techniques and accepted those techniques and their results which are found significant from enrichment perspective for subsequent analysis. Based on biclustering results, we constructed biological networks and carried out a topological, pathway and causal analysis on the modules extracted from the networks. Our multiobjective study enabled us to identify several biomarkers for esophageal squamous cell carcinoma (ESCC) such as IFNGR1, CLIC1, CDK4, and COPS5, after applying a ranking scheme.


Assuntos
Complexo do Signalossomo COP9/genética , Canais de Cloreto/genética , Quinase 4 Dependente de Ciclina/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Neoplasias/genética , Peptídeo Hidrolases/genética , Receptores de Interferon/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Complexo do Signalossomo COP9/metabolismo , Canais de Cloreto/metabolismo , Análise por Conglomerados , Biologia Computacional/métodos , Quinase 4 Dependente de Ciclina/metabolismo , Conjuntos de Dados como Assunto , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Anotação de Sequência Molecular , Proteínas de Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Peptídeo Hidrolases/metabolismo , Receptores de Interferon/metabolismo
20.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067708

RESUMO

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.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Pirrolidinas/farmacologia , Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Células Epiteliais/metabolismo , Humanos , Indóis/farmacologia , Dobramento de Proteína/efeitos dos fármacos , Pirazóis/metabolismo , Piridinas/metabolismo , Pirrolidinas/metabolismo , Quinolinas/farmacologia
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