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1.
J Exp Med ; 217(5)2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32097463

RESUMO

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.

2.
Clin Med Res ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060044

RESUMO

BACKGROUND: Troponin values above the threshold established to diagnose acute myocardial infarction (AMI; >99th percentile) are commonly detected in patients with diagnoses other than AMI. The objective of this study is to compare inpatient mortality and 30-day readmission rate in patients with troponin I (TnI) above and below the 99th percentile in those with type 1 AMI and type 2 myocardial injury. METHODS: Between January 1st, 2016 through December 31st, 2016 there were 56,895 inpatient hospitalizations and of these, 14,326 (25.2%) patients received troponin testing. We evaluated mortality and readmissions in the entire cohort based on the primary discharge International Classification of Diseases, Tenth Edition (ICD-10) diagnosis and grouped into type 1 AMI versus other diagnoses comprising the type 2 AMI group (including ICD-10 codes for congestive heart failure (CHF), sepsis, and other). Among those with TnI drawn, we evaluated in-hospital mortality and 30-day readmissions based on troponin values > 99th percentile (>0.1 ng/ml). RESULTS: Among the entire cohort, the inpatient mortality rate was significantly higher in those with TnI testing (5.0%, 95% CI 4.6%-5.3%) compared to those without testing (0.7%, 95% CI 0.6%-0.7%, p<0.01). In the tested cohort 3,743 (26%) patients had troponin levels above the 99th percentile (>0.1 ng/ml) and 10,583 (74%) had troponin levels below the 99th percentile (<0.1 ng/ml). Comparing type 2 AMI with type 1 AMI and troponin testing, TnI values >0.1 ng/ml were associated with higher inpatient mortality (11.6% vs. 3.9%) and 30-day readmission rates (16.9% vs. 10.7%). CONCLUSIONS: A higher inpatient mortality and 30-day readmission rates were found in patients with type 2 AMI compared to type 1 AMI group.

3.
Proc (Bayl Univ Med Cent) ; 32(4): 498-501, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31656404

RESUMO

Hypertension management guidelines are influenced by clinical trials that utilize automated office blood pressure (BP) to measure BP. Many primary care clinics still use manual office BP, which has been shown to produce significantly higher BP values than automated office BP. In a primary care office, a manual BP was obtained by nursing staff using an aneroid sphygmomanometer. Initial BPs ≥120/80 mm Hg were repeated during the clinical encounter by the physician. A total of 1012 encounters were analyzed, with 1000 meeting inclusion criteria. The median difference between nurse and provider BP was 4 mm Hg in systolic BP and 2 mm Hg in diastolic BP (P < 0.0001), with the greatest difference seen in patients with initial BPs >150 mm Hg systolic (10 mm Hg; P < 0.0001). Repeating BP measurements resulted in 34% of patients being reclassified to a lower hypertension stage. Patients with stage 1 and 2 hypertension initially were reclassified as controlled (systolic BP <130 mm Hg) in 40% and 8% of encounters, respectively, with repeat measurements. In clinics that use manual office BP, repeating a manual BP by the physician may provide a better reflection of adherence to standard hypertension performance measures used in the primary care setting.

4.
Proc (Bayl Univ Med Cent) ; 32(4): 572-573, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31656424

RESUMO

Eustachian valve infective endocarditis is rare and mostly affects intravenous drug abusers and those with implanted medical devices or indwelling central venous catheters. The most commonly identified organism is Staphylococcus aureus. Treatment includes intravenous antibiotics for approximately 6 weeks. We present a case of Staphylococcus aureus Eustachian valve endocarditis in an individual without traditional risk factors.

5.
Proc (Bayl Univ Med Cent) ; 32(3): 385-386, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31384193

RESUMO

Cardiac lipomas are rare and usually benign tumors that often remain asymptomatic throughout one's lifetime. We report a case of a 60-year-old man with a cardiac lipoma diagnosed early in childhood. However, due to the lack of surgical expertise in rural India, the lipoma was not removed. After moving to the United States, he received irregular follow-up with serial chest x-ray and computed tomography, which demonstrated an enlarging lipomatous mass occupying the pericardial space. After remaining asymptomatic for more than 37 years, he presented to the hospital with dyspnea. He underwent a surgical resection but, unfortunately, given the extension of the mass into multiple critical portions of the heart, he ultimately died.

6.
Proc (Bayl Univ Med Cent) ; 32(1): 34-36, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30956577

RESUMO

Adequate and reliable hemostasis following transcatheter aortic valve implantation (TAVI) is crucial. Closure devices have improved the amount of time required to achieve hemostasis following these procedures. We retrospectively looked at TAVI procedures that achieved adequate hemostasis after use of the Angio-Seal as an adjunctive measure following use of the Perclose ProGlide system. Sixteen cases (age range, 56-91 years) were identified between January 2016 and February 2018. Half had undergone transfemoral diagnostic angiography in the same vessel used for the TAVI delivery system within the prior 1 to 63 days. Five were receiving oral anticoagulants; six, aspirin; and two, dual-antiplatelet therapy. All had undergone computed tomography angiography for sizing of iliofemoral arteries, aorta, and the aortic valve prior to TAVI. No patient experienced any significant access site-related complications or ischemic leg symptoms, and there were no reports of late vascular or access site complications. Our case series suggests that adjunctive Angio-Seal systems may be a reliable alternative for incomplete hemostasis following Perclose ProGlide systems and can serve as a "bailout" procedure for incomplete postprocedural hemostasis.

7.
Neuron ; 100(4): 799-815.e7, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30344046

RESUMO

Alteration of tissue mechanical properties is a physical hallmark of solid tumors including gliomas. How tumor cells sense and regulate tissue mechanics is largely unknown. Here, we show that mechanosensitive ion channel Piezo regulates mitosis and tissue stiffness of Drosophila gliomas, but not non-transformed brains. PIEZO1 is overexpressed in aggressive human gliomas and its expression inversely correlates with patient survival. Deleting PIEZO1 suppresses the growth of glioblastoma stem cells, inhibits tumor development, and prolongs mouse survival. Focal mechanical force activates prominent PIEZO1-dependent currents from glioma cell processes, but not soma. PIEZO1 localizes at focal adhesions to activate integrin-FAK signaling, regulate extracellular matrix, and reinforce tissue stiffening. In turn, a stiffer mechanical microenvironment elevates PIEZO1 expression to promote glioma aggression. Therefore, glioma cells are mechanosensory in a PIEZO1-dependent manner, and targeting PIEZO1 represents a strategy to break the reciprocal, disease-aggravating feedforward circuit between tumor cell mechanotransduction and the aberrant tissue mechanics. VIDEO ABSTRACT.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Canais Iônicos/biossíntese , Mecanotransdução Celular/fisiologia , Adulto , Idoso , Animais , Animais Geneticamente Modificados , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Drosophila melanogaster , Feminino , Glioma/genética , Glioma/patologia , Humanos , Canais Iônicos/genética , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Microambiente Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Nature ; 553(7687): 222-227, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29323298

RESUMO

Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies. We have previously described gene fusions of FGFR3-TACC3 (F3-T3) in 3% of human glioblastoma cases. Subsequent studies have reported similar frequencies of F3-T3 in many other cancers, indicating that F3-T3 is a commonly occuring fusion across all tumour types. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown. Here we show that human tumours with F3-T3 fusions cluster within transcriptional subgroups that are characterized by the activation of mitochondrial functions. F3-T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. Phosphorylation of the phosphopeptide PIN4 is an intermediate step in the signalling pathway of the activation of mitochondrial metabolism. The F3-T3-PIN4 axis triggers the biogenesis of peroxisomes and the synthesis of new proteins. The anabolic response converges on the PGC1α coactivator through the production of intracellular reactive oxygen species, which enables mitochondrial respiration and tumour growth. These data illustrate the oncogenic circuit engaged by F3-T3 and show that F3-T3-positive tumours rely on mitochondrial respiration, highlighting this pathway as a therapeutic opportunity for the treatment of tumours with F3-T3 fusions. We also provide insights into the genetic alterations that initiate the chain of metabolic responses that drive mitochondrial metabolism in cancer.


Assuntos
Respiração Celular , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Peptidilprolil Isomerase de Interação com NIMA/química , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Biogênese de Organelas , Fosforilação Oxidativa/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Peroxissomos/efeitos dos fármacos , Peroxissomos/metabolismo , Fosforilação , Biossíntese de Proteínas , Espécies Reativas de Oxigênio/metabolismo , Receptores Estrogênicos/metabolismo , Transcrição Genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Proc (Bayl Univ Med Cent) ; 31(4): 496-498, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30948991

RESUMO

Valvular thrombosis is a known complication of bioprosthetic valve replacement that usually occurs within a year of implantation. Four-dimensional computed tomography is quickly becoming the gold standard to directly visualize thrombus. Current guidelines for prophylaxis include aspirin for all bioprosthetic valve replacements, dual antiplatelet therapy for aortic valves, and anticoagulation for mitral valves. However, new trials have suggested single-agent antiplatelet therapy or anticoagulation for treatment of bioprosthetic valve thrombosis. Three cases are presented that illustrate the use of anticoagulants and new techniques for detecting thrombosis on imaging.

10.
Curr Vasc Pharmacol ; 14(5): 409-414, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27456102

RESUMO

BACKGROUND: Chronic kidney disease (CKD) accounts for a significant proportion of the morbidity and mortality in the United States. CKD is defined as glomerular filtration rate (GFR) <60ml/min/1.73m2 or clear evidence of renal damage from biopsy. All-cause cardiovascular risk increases with decreasing GFR. Clinically, detection of CKD is through changes in creatinine clearance which estimates GFR, an indicator of kidney function. We reviewed conventional and nonconventional cardiovascular risk factors associated with CKD. Clinically, we reviewed the status of statins as a treatment option for CKD-induced dyslipidemia. OBJECTIVE: CKD has dramatic consequences on cardiovascular risk profile due to a complex pathophysiologic response to declining kidney function. In this review, we explored new, more accurate methods of detecting decreasing kidney function, discerned risk factors for the development of cardiovascular events, and examined the controversial use of statins for renoprotection. RESULTS: Detection of declining renal function by monitoring creatinine has been the clinical gold standard, but it substantially fluctuates with muscle mass, sex, and ethnicity. Newer methods using cystatin C have been at the forefront as the next substance that will be used for detection of CKD. Traditional and non-traditional risk factors contribute to the cardiovascular risk profile of patients with declining renal function. Statins, along with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB)s, have been used for renoprotection, but evidence shows only modest benefits in non-dialysis patients. CONCLUSION: Cardio-renal interaction involves multiple risk factors that contribute significantly to the CKD-induced development of accelerated atherosclerosis, an inflammatory state that causes cardiovascular events.


Assuntos
Doenças Cardiovasculares/epidemiologia , Dislipidemias/epidemiologia , Taxa de Filtração Glomerular , Rim/fisiopatologia , Insuficiência Renal Crônica/epidemiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Rim/efeitos dos fármacos , Testes de Função Renal , Valor Preditivo dos Testes , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
11.
Pol J Radiol ; 81: 233-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27279924

RESUMO

BACKGROUND: Myxomatous mitral valve with prolapse are classically seen with abnormal leaflet apposition during contraction of the heart. Hemodynamic disorders can result from eccentric mitral regurgitation usually caused by chordae tendinae rupture or papillary muscle dysfunction. Echocardiography is the gold standard for evaluation of leaflet flail and prolapse due to high sensitivity and specificity. Though most mitral valve prolapse are asymptomatic those that cause severe regurgitation need emergent surgical intervention to prevent disease progression. CASE REPORT: We report a 54 year old Hispanic male who presented with progressively worsening dyspnea and palpitations. Initial evaluation was significant for atrial fibrillation on electrocardiogram with subsequent echocardiography revealing myxomatous mitral valve with prolapse. Following surgical repair of the mitral valve, the dyspnea and palpitations resolved. CONCLUSIONS: Mitral valve prolapse is a common valvular abnormality but the pathogenic cause of myxomatous valves has not been elucidated. Several theories describe multiple superfamilies of proteins to be involved in the process. Proper identification of these severe mitral regurgitation due to these disease valves will help relieve symptomatic mitral valve prolapse patients.

12.
Pol J Radiol ; 80: 529-31, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26688703

RESUMO

BACKGROUND: Absence of the left circumflex artery (LCX) is an extremely rare congenital anomaly of the coronary circulation. While some coronary circulation anomalies are associated with significant complications, including sudden cardiac death and premature atherosclerosis, absence of the LCX is largely considered benign, though it has been associated with exertional chest pain, which may mimic acute coronary syndrome. Diagnosis is made when heart catheterization is performed in the work up for acute coronary syndrome or when computed tomography coronary angiography is performed during evaluation of coronary artery disease. CASE REPORT: We report a 55 year old female who presented with non-exertional chest pain in the setting of an emotional stressor. The initial work up was only significant for elevated troponins, and subsequent left heart catheterization revealed findings consistent with congenital absence of the LCX. No significant stenosis was appreciated, and no intervention was performed. Following catheterization, the patient's troponins began to trend down, and her chest pain resolved. CONCLUSIONS: Congenitally absent LCX is a rare entity detected when work up is performed to rule out acute coronary syndrome in patients presenting with exertional chest pain. This is the first reported case of chest pain unrelated to physical activity reported in a patient with an absent LCX. There is no specific treatment for an absent LCX; however, proper identification of this anomaly and differentiation from complete occlusion of the LCX is important in making an accurate diagnosis of myocardial ischemia and for choosing the best intervention when ischemia is present.

13.
Proc (Bayl Univ Med Cent) ; 28(3): 350-2, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26130886

RESUMO

Pulmonary veno-occlusive disease (PVOD) represents a rare form of precapillary pulmonary arterial hypertension. We present a young patient hospitalized with progressive dyspnea, with initial workup suggestive of pulmonary hypertension and unexplained noncardiogenic pulmonary edema. His subsequent clinical course was consistent with the diagnosis of PVOD.

14.
Clin Anat ; 28(7): 844-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25708184

RESUMO

The lacrimal artery is classically described as a branch of the ophthalmic artery supplied by the internal carotid. In this study, 25 orbits were dissected to identify variations in glandular branching and to compare them to previously published accounts. The glandular branching patterns of the lacrimal artery fall into two categories, those that branch (56%) and those that do not branch (44%). We found the medial and lateral glandular branches to be equal in diameter with a divergence of 2.67-40.58 mm proximal to the gland parenchyma. The long glandular branches run alongside the superolateral aspect of the orbit. The lateral branch runs lateral to the lateral rectus muscle. The medial branch runs superomedial to the lateral rectus muscle and lateral to the superior rectus muscle. In relation to the lacrimal gland, the medial branch enters the superior aspect of the gland parenchyma and the lateral branch enters its inferior aspect. The average branch lengths were 17.88 mm (medial) and 13.51 mm (lateral) as measured with a Mitutoyo Absolute 1/100 mm caliper. We could not confirm the existence of a third branch supplying the lacrimal gland, as posited by other authors. The key finding in this study is that the lacrimal gland is predominantly supplied by two significant arterial branches, both of which must be identified during procedures involving the lateral orbit.


Assuntos
Aparelho Lacrimal/irrigação sanguínea , Artéria Oftálmica/anatomia & histologia , Órbita/anatomia & histologia , Idoso , Idoso de 80 Anos ou mais , Cadáver , Fossa Craniana Média/anatomia & histologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Proc (Bayl Univ Med Cent) ; 28(1): 72-4, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25552807

RESUMO

Cryoglobulinemic vasculitis is a small vessel vasculitis that has been associated with chronic infections and autoimmune, lymphoproliferative, and neoplastic disorders. When no significant etiological factors are identified, it is called essential mixed cryoglobulinemia. A detailed and thorough laboratory investigation is required to exclude all possible causes of cryoglobulin formation. Although cryoglobulin testing is simple, careful temperature regulation is needed to avoid false-negative results. Consensus diagnosis should be developed and implemented for appropriate cryoglobulin detection and accurate clinical diagnosis for cryoglobulinemic vasculitis. Here we present an interesting, first-ever case report of a 54-year-old Hispanic-American woman with essential mixed cryoglobulinemia presenting with significant digital necrosis in association with membranous nephropathy.

16.
Clin Anat ; 27(8): 1174-7, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25092807

RESUMO

Parasympathetic stimulation of the lacrimal gland is responsible for tear production, and this innervation originates from fibers conveyed in the facial nerve. After synapse in the pterygopalatine ganglion, postsynaptic parasympathetic fibers travel within the zygomatic and zygomaticotemporal nerves (ZTN) into the orbit. As described in most anatomy texts, ZTN communicates with the lacrimal nerve (LN) posterior to the gland and then secretomotor fibers enter the gland. This study was performed to gain a better understanding of the innervation of the lacrimal gland. Seventeen cadaver heads were bisected for a total of 34 sides, which then underwent dissection of the superolateral orbital region to observe the course for the LN and ZTN. Three variations of the course of the LN and ZTN were found. In 20 (60.6%) dissections it was documented that the ZTN entered directly into the lacrimal gland with no communication with the LN. In 12 (36.4%) of the bisected heads, ZTN had both a direct connection into the gland and a communicating branch with the LN. In only one (3.0%) bisected head, ZTN communicated with the LN before entering the gland as it is commonly described in anatomy texts. Our study reveals that the ZTN usually takes a different course than is classically described in most anatomy textbooks. A greater understanding of the typical course these nerves take may help surgeons identify them more easily and avoid damaging them.


Assuntos
Nervo Facial/anatomia & histologia , Gânglios Parassimpáticos/anatomia & histologia , Aparelho Lacrimal/inervação , Fibras Parassimpáticas Pós-Ganglionares/anatomia & histologia , Idoso , Idoso de 80 Anos ou mais , Cadáver , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Nervoso Parassimpático/anatomia & histologia
17.
Cell Mol Neurobiol ; 33(1): 31-46, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22865002

RESUMO

To survive, neurons and other eukaryotic cells must rapidly repair (seal) plasmalemmal damage. Such repair occurs by an accumulation of intracellular vesicles at or near the plasmalemmal disruption. Diacylglycerol (DAG)-dependent and cAMP-dependent proteins are involved in many vesicle trafficking pathways. Although recent studies have implicated the signaling molecule cAMP in sealing, no study has investigated how DAG and DAG-dependent proteins affect sealing. By means of dye exclusion to assess Ca(2+)-dependent vesicle-mediated sealing of transected neurites of individually identifiable rat hippocampal B104 cells, we now report that, compared to non-treated controls, sealing probabilities and rates are increased by DAG and cAMP analogs that activate PKC and Munc13-1 and PKA. Sealing is decreased by inhibiting DAG-activated novel protein kinase C isozymes η (nPKCη) and θ (nPKCθ) and Munc13-1, the PKC effector myristoylated alanine rich PKC substrate (MARCKS) or phospholipase C (PLC). DAG-increased sealing is prevented by inhibiting MARCKS or protein kinase A (PKA). Sealing probability is further decreased by simultaneously inhibiting nPKCη, nPKCθ, and PKA. Extracellular Ca(2+), DAG, or cAMP analogs do not affect this decrease in sealing. These and other data suggest that DAG increases sealing through MARCKS and that nPKCη, nPKCθ, and PKA are all required to seal plasmalemmal damage in B104 and likely all eukaryotic cells.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Diglicerídeos/metabolismo , Neuritos/metabolismo , Proteína Quinase C/fisiologia , Transdução de Sinais/fisiologia , Animais , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diglicerídeos/fisiologia , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos
18.
Dev Neurobiol ; 72(11): 1399-414, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22076955

RESUMO

Plasmalemmal repair (sealing) is necessary for survival of damaged eukaryotic cells. Ca(2+) influx through plasmalemmal disruptions activates pathways that initiate sealing, which is commonly assessed by exclusion of extracellular dye. These sealing pathways include PKA, Epac, and cytosolic oxidation. In this article, we investigate whether PKA, Epac, and/or cytosolic oxidation, activate specific proteins required to produce a plasmalemmal seal. We report that toxin cleavage of proteins required for neurotransmitter release (SNAP-25), inhibition of Golgi trafficking (with Brefeldin A: Bref A) or inhibition of N-ethylmaleimide sensitive factor (NSF) all decrease sealing of rat B104 hippocampal cells with transected neuritis in vitro. Epac, but not PKA or cytosolic oxidation, partly overcomes the decrease in sealing produced by cleavage of SNAP-25. PKA and increased cytosolic oxidation, but not Epac, can partly overcome the decrease in sealing due to Bref A. PKA, Epac, and/or cytosolic oxidation cannot overcome NSF inhibition. Substances that affect plasmalemmal sealing of B104 neurites in vitro have similar effects on plasmalemmal sealing in rat sciatic axons ex vivo. From these and other data, we propose a model of plasmalemmal sealing having three redundant, evolutionarily conserved, parallel pathways that all converge on NSF.


Assuntos
Axônios/fisiologia , Membrana Celular/fisiologia , Regeneração Nervosa/fisiologia , Transdução de Sinais/fisiologia , Animais , Axotomia , Cálcio/fisiologia , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Citosol/fisiologia , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Hipocampo/fisiologia , Técnicas In Vitro , Proteínas Sensíveis a N-Etilmaleimida/fisiologia , Neuritos/fisiologia , Oxirredução , Ratos , Nervo Isquiático/fisiologia , Proteína 25 Associada a Sinaptossoma/fisiologia
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