RESUMEN
The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP) levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.
Asunto(s)
Enfermedad de Alzheimer , Astrocitos , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Astrocitos/patología , Anciano , Masculino , Femenino , Anciano de 80 o más Años , Forma BB de la Creatina-Quinasa/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Creatina Quinasa/metabolismo , Proteínas tau/metabolismoRESUMEN
The nature of brain redox metabolism in health, aging, and disease remains to be fully established. Reversible oxidations, to disulfide bonds, of closely spaced (vicinal) protein thiols underlie the catalytic maintenance of redox homeostasis by redoxin enzymes, including thioredoxin peroxidases (peroxiredoxins), and have been implicated in redox buffering and regulation. We propose that non-peroxidase proteins containing vicinal thiols that are responsive to physiological redox perturbations may serve as intrinsic probes of brain redox metabolism. Using redox phenylarsine oxide (PAO)-affinity chromatography, we report that PAO-binding vicinal thiols on creatine kinase B and alpha-enolase from healthy rat brains were preferentially oxidized compared to other selected proteins, including neuron-specific (gamma) enolase, under conditions designed to trap in vivo protein thiol redox states. Moreover, measures of the extents of oxidations of vicinal thiols on total protein, and on creatine kinase B and alpha-enolase, showed that vicinal thiol-linked redox states were stable over the lifespan of rats and revealed a transient reductive shift in these redox couples following decapitation-induced global ischemia. Finally, formation of disulfide-linked complexes between peroxiredoxin-2 and brain proteins was demonstrated on redox blots, supporting a link between protein vicinal thiol redox states and the peroxidase activities of peroxiredoxins. The implications of these findings with respect to underappreciated aspects of brain redox metabolism in health, aging, and ischemia are discussed.
Asunto(s)
Envejecimiento , Isquemia Encefálica , Encéfalo , Oxidación-Reducción , Compuestos de Sulfhidrilo , Animales , Ratas , Envejecimiento/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Masculino , Fosfopiruvato Hidratasa/metabolismo , Arsenicales/metabolismo , Forma BB de la Creatina-Quinasa/metabolismo , Ratas Sprague-DawleyRESUMEN
20(S)-Protopanaxadiol (PPD) is one of the bioactive ingredients in ginseng and possesses neuroprotective properties. Brain-type creatine kinase (CK-BB) is an enzyme involved in brain energy homeostasis via the phosphocreatine-creatine kinase system. We previously identified PPD as directly bound to CK-BB and activated its activity in vitro. In this study, we explored the antidepressive effects of PPD that target CK-BB. First, we conducted time course studies on brain CK-BB, behaviors, and hippocampal structural plasticity responses to corticosterone (CORT) administration. Five weeks of CORT injection reduced CK-BB activity and protein levels and induced depression-like behaviors and hippocampal structural plasticity impairment. Next, a CK inhibitor and an adeno-associated virus-targeting CKB were used to diminish CK-BB activity or its expression in the brain. The loss of CK-BB in the brain led to depressive behaviors and morphological damage to spines in the hippocampus. Then, a polyclonal antibody against PPD was used to determine the distribution of PPD in the brain tissues. PPD was detected in the hippocampus and cortex and observed in astrocytes, neurons, and vascular endotheliocytes. Finally, different PPD doses were used in the chronic CORT-induced depression model. Treatment with a high dose of PPD significantly increased the activity and expression of CK-BB after long-term CORT injection. In addition, PPD alleviated the damage to depressive-like behaviors and structural plasticity induced by repeated CORT injection. Overall, our study revealed the critical role of CK-BB in mediating structural plasticity in CORT-induced depression and identified CK-BB as a therapeutic target for PPD, allowing us to treat stress-related mood disorders.
Asunto(s)
Antidepresivos , Corticosterona , Forma BB de la Creatina-Quinasa , Depresión , Sapogeninas , Animales , Humanos , Masculino , Ratones , Ratas , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Forma BB de la Creatina-Quinasa/metabolismo , Forma BB de la Creatina-Quinasa/genética , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Panax/química , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Ratas Sprague-Dawley , Sapogeninas/farmacologíaRESUMEN
That uncoupling protein 1 (UCP1) is the sole mediator of adipocyte thermogenesis is a conventional viewpoint that has primarily been inferred from the attenuation of the thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue. To mitigate these potentially confounding ancillary changes, we constructed mice with inducible adipocyte-selective Ucp1 disruption. We find that, although germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with the inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase b (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold intolerance. Following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature brown adipocytes that coordinately restore UCP1 and CKB expression. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy-through UCP1 and CKB-to promote cold-induced energy dissipation.
Asunto(s)
Adipocitos Marrones , Tejido Adiposo Pardo , Animales , Ratones , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/metabolismo , Termogénesis , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Forma BB de la Creatina-Quinasa/metabolismoRESUMEN
Brain-type Creatine kinase (CK-BB), which has a high affinity for Aluminum (Al), and its abnormality is closely related to neurodegenerative diseases. In this study, the comparative effect of Al speciation on the bioactivity of CK-BB has been studied by the inhibition kinetics method, molecular docking, cellular experiment, and mouse model study. Results showed that the half-inhibitory concentration of AlCl3 was 0.67 mM, while Al(mal)3 was 3.81 mM. Fluorescence spectra showed that Al(mal)3 had a more substantial effect on the endogenous fluorescence of CK-BB than AlCl3. Molecular docking showed that AlCl3 was closer to the active site of CK-BB. C6 cells were used to explore the enzyme activity and intracellular distribution of CK-BB by AlCl3 or Al(mal)3. AlCl3 treatment may directly affect CK-BB activity and cause insufficient local ATP supply in cells which affected the formation of F-actin and cell morphology. The change in the hydrophobicity of CK-BB induced by Al(mal)3 affected the movement of CK-BB, which subsequently activated thecytochrome C (Cyt C)/Caspase 9/Caspase 3 pathway. Similar results have been found in vivo experiments. This study demonstrated that interaction between Al and CK-BB might be related to the process of Al-induced energy metabolism disorders, in which the Al speciation revealed differentiated toxicity mechanisms.
Asunto(s)
Aluminio , Forma BB de la Creatina-Quinasa , Animales , Ratones , Simulación del Acoplamiento Molecular , Aluminio/toxicidad , Forma BB de la Creatina-Quinasa/química , Forma BB de la Creatina-Quinasa/metabolismo , Cinética , Encéfalo/metabolismoRESUMEN
Epithelial-mesenchymal transition (EMT) contributes to tumor invasion, metastasis and drug resistance. AKT activation is key in a number of cellular processes. While many positive regulators for either EMT or AKT activation have been reported, few negative regulators are established. Through kinase cDNA screen, we identified brain-type creatine kinase (CKB or BCK) as a potent suppressor for both. As a ubiquitously expressed kinase in normal tissues, CKB is significantly downregulated in several solid cancer types. Lower CKB expression is significantly associated with worse prognosis. Phenotypically, CKB overexpression suppresses, while its silencing promotes, EMT and cell migration, xenograft tumor growth and metastasis of prostate cancer cells. AKT activation is one of the most prominent signaling events upon CKB silencing in prostate cancer cells, which is in line with prostate cancer TCGA data. EMT enhanced by CKB silencing is abolished by AKT inhibition. Mechanistically, CKB interacts with AKT and sequestrates it from activation by mTOR. We further elucidated that an 84aa fragment at C-terminus of CKB protein interacts with AKT's PH domain. Ectopic expression of the 84aa CKB fragment inhibits AKT activation, EMT and cell proliferation. Interestingly, molecular dynamics simulation on crystal structures of AKT and CKB independently demonstrates that AKT's PH domain and CKB's 84aa fragment establish their major interaction interface. In summary, we have discovered CKB as a negative regulator of EMT and AKT activation, revealing a new mode of their regulation . We have also demonstrated that CKB downregulation is a poor prognosticator, which is sufficient to promote prostate cancer progression.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Forma BB de la Creatina-Quinasa/farmacología , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/prevención & control , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease1. Thermogenesis by adipocytes can counteract obesity and metabolic diseases2,3. In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP-purportedly via a phosphorylation cycle4-to drive thermogenic respiration. However, the proteins that control this futile creatine cycle are unknown. Here we show that creatine kinase B (CKB) is indispensable for thermogenesis resulting from the futile creatine cycle, during which it traffics to mitochondria using an internal mitochondrial targeting sequence. CKB is powerfully induced by thermogenic stimuli in both mouse and human adipocytes. Adipocyte-selective inactivation of Ckb in mice diminishes thermogenic capacity, increases predisposition to obesity, and disrupts glucose homeostasis. CKB is therefore a key effector of the futile creatine cycle.
Asunto(s)
Tejido Adiposo/metabolismo , Forma BB de la Creatina-Quinasa/metabolismo , Creatina/metabolismo , Termogénesis , Adipocitos/metabolismo , Tejido Adiposo/citología , Tejido Adiposo/enzimología , Animales , Forma BB de la Creatina-Quinasa/deficiencia , Forma BB de la Creatina-Quinasa/genética , AMP Cíclico/metabolismo , Metabolismo Energético/genética , Femenino , Glucosa/metabolismo , Homeostasis , Humanos , Masculino , Ratones , Mitocondrias/metabolismo , Obesidad/enzimología , Obesidad/genética , Obesidad/metabolismo , Transducción de SeñalRESUMEN
Silver nanoparticles (AgNPs) are widely applied in various aspects of life. However, recent studies reported their potential toxicity both on environment and human health. The present study aimed to unravel the underlying molecular mechanisms involved in AgNPs-induced brain toxicity. Moreover, chemopreventive effect of tranilast, an analogue of tryptophan metabolite and a mast cell membrane stabilizer was evaluated. Thirty Sprague Dawley rats were enrolled equally into Normal control group, AgNPs-intoxicated group (50 mg/kg, 3 times/week) and tranilast (300 mg/kg, 3 times/week)+AgNPs group. AgNPs administration triggered brain oxidative stress as depicted by reduced Nrf-2 expression, decreased TAC and GSH as well as upregulated brain lipid peroxidation. The apparent brain oxidative damage was accompanied by elevated levels of inflammatory cytokines (IL-1ß, IL-6 and TNF-α). Moreover, brain levels of TLR4, NLRP3 and caspase-1 were up-regulated. Additionally, histological study indicated marked cellular injury in cerebrum and cerebellum specimens. This was concomitant with elevated serum CK activity and CK-BB level. On the other hand, tanilast administration remarkably alleviated AgNPs-induced brain toxicity. The present study shed the light on implication of TLR4/NLRP3 axis and NrF2 in AgNPs-induced brain toxicity. In addition, it explored the potential protective effect of tranilast on AgNPs-induced brain injury via antioxidant and anti-inflammatory efficacies.
Asunto(s)
Cerebro/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fármacos Neuroprotectores/farmacología , Compuestos de Plata/toxicidad , Receptor Toll-Like 4/metabolismo , ortoaminobenzoatos/farmacología , Animales , Caspasa 1/metabolismo , Cerebro/metabolismo , Cerebro/patología , Creatina Quinasa/sangre , Forma BB de la Creatina-Quinasa/sangre , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Increasing evidence indicates that the enzyme creatine kinase (CK) is intimately involved in microvascular contractility. The mitochondrial isoenzyme catalyses phosphocreatine synthesis from ATP, while cytoplasmic CK, predominantly the BB isoenzyme in vascular tissue, is tightly bound near myosin ATPase, where it favours ATP production from phosphocreatine to metabolically support vascular contractility. However, the effect of CK gene inactivation on microvascular function is hitherto unknown. We studied functional and structural parameters of mesenteric resistance arteries isolated from 5 adult male mice lacking cytoplasmic BB-CK and ubiquitous mitochondrial CK (CK-/-) vs 6 sex/age-matched controls. Using a Mulvany Halpern myograph, we assessed the acute maximum contractile force with 125 mM K+ and 10-5 M norepinephrine, and the effect of two inhibitors, dinitrofluorobenzene, which inhibits phosphotransfer enzymes (0.1 µM), and the specific adenylate kinase inhibitor P1, P5-di(adenosine 5') pentaphosphate (10-6 to 10-5 M). WT and CK-/- did not significantly differ in media thickness, vascular elasticity parameters, or acute maximum contractile force. CK-/- arteries displayed greater reduction in contractility after dinitrofluorobenzene 38%; vs 14% in WT; and after AK inhibition, 14% vs 5.5% in WT, and displayed abnormal mitochondria, with a partial loss of the inner membrane. Thus, CK-/- mice display a surprisingly mild phenotype in vascular dysfunction. However, the mitochondrial abnormalities and greater effect of inhibitors on contractility may reflect a compromised energy metabolism. In CK-/- mice, compensatory mechanisms salvage energy metabolism, as described for other CK knock-out models.
Asunto(s)
Arteriolas/metabolismo , Arteriolas/fisiología , Forma BB de la Creatina-Quinasa/deficiencia , Forma Mitocondrial de la Creatina-Quinasa/deficiencia , Vasoconstricción/fisiología , Animales , Dinitrofluorobenceno/administración & dosificación , Fosfatos de Dinucleósidos/administración & dosificación , Isoenzimas/metabolismo , Masculino , Ratones , Ratones Noqueados , Norepinefrina/administración & dosificaciónRESUMEN
OBJECTIVES: To find suitable biomarkers for diagnosis of prostate cancer (PC) in serum and saliva; also, to evaluate the diagnostic efficacy of saliva in patients with PC. METHODS: This case-control study included 20 patients with PC and 20 patients with benign prostatic hyperplasia (BPH). Blood and saliva were collected from the participants and centrifuged. Serum and supernatant saliva were used for biochemical analysis. We evaluated serum and salivary levels of urea, creatinine, prostate-specific antigen (PSA), creatine kinase BB (CK-BB), zinc, ß-2 microglobulin (B2M), and melatonin. Also, we used Mann-Whitney U testing, Spearman correlation coefficients, and receiver operating characteristic (ROC) analysis to evaluate the data. RESULTS: Serum and salivary concentrations of urea, creatinine, PSA, CK-BB, zinc, and B2M were significantly higher in patients with PC, compared with the BPH group (P <.05). However, serum and salivary concentrations of melatonin were significantly lower in patients with PC, compared with BPH group (P <.05). In both groups, salivary concentrations of all markers were lower (P <.05), compared with those values in serum. We observed positive correlation between serum and salivary concentrations of all markers studied (P <.05). CONCLUSION: From the data, we conclude that investigation using saliva specimens is a noninvasive, simple, and effective tool for screening of biochemical parameters.
Asunto(s)
Biomarcadores/metabolismo , Hiperplasia Prostática/diagnóstico , Neoplasias de la Próstata/diagnóstico , Saliva/metabolismo , Estudios de Casos y Controles , Forma BB de la Creatina-Quinasa/metabolismo , Creatinina/metabolismo , Regulación hacia Abajo , Humanos , Irán , Masculino , Melatonina/metabolismo , Persona de Mediana Edad , Antígeno Prostático Específico/metabolismo , Suero/metabolismo , Regulación hacia Arriba , Urea/metabolismo , Microglobulina beta-2/metabolismoRESUMEN
Some studies have demonstrated that the implantation rate of fresh transfer cycles is lower in the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol than in the GnRH agonist (GnRH-a) protocol during in vitro fertilization (IVF). This effect may be related to endometrial receptivity. However, the mechanisms are unclear. Here, endometrial tissues obtained from the mid-secretory phase of patients treated with GnRH-a or GnRH-ant protocols and from patients on their natural cycle were assessed. Endometrial expression of B-type creatine kinase (CKB), which plays important roles in the implantation phase, was significantly reduced in the GnRH-ant group. At the same time, expression of the endometrial receptivity marker HOXA10 was considerably reduced in the GnRH-ant group. GnRH-ant exposure in endometrial epithelial cells (EECs) in vitro decreased CKB expression and ATP generation and blocked polymerization of actin. Furthermore, in vitro GnRH-ant-exposed Ishikawa cells showed enhanced F-actin depolymerization, and these effects were rescued by CKB overexpression. Similar effects were observed after CKB knockdown, and these effects were rescued by CKB overexpression. Moreover, cell migration was decreased in CKB-knockdown Ishikawa cells compared with that in control cells, and this effect was also rescued by CKB overexpression. Overall, these findings showed that GnRH-ant affected CKB expression in EECs, resulting in cytoskeletal damage and migration failure. These results provide insight into the roles and molecular mechanisms of GnRH-ant treatment in the endometrium.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Forma BB de la Creatina-Quinasa/metabolismo , Endometrio/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/farmacología , Línea Celular Tumoral , Implantación del Embrión/efectos de los fármacos , Endometrio/citología , Endometrio/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Pamoato de Triptorelina/farmacologíaRESUMEN
BACKGROUND: Idiopathic achalasia is an uncommon esophageal motor disorder. The disease involves interaction between inflammatory and autoimmune responses. However, the antigens related to the disease are still unknown. AIM: To identify the possible antigen targets in muscle biopsies from lower esophageal sphincter (LES) of achalasia patients. METHODS: Esophageal biopsies of patients with type I and type II achalasia and esophagogastric junction outflow obstruction (EGJOO) were analyzed. Lower esophageal sphincter muscle biopsy from a Healthy organ Donor (HD) was included as control for two-dimensional gel electrophoresis. Immunoblotting of muscle from LES lysate with sera of type I, type II achalasia, or type III achalasia, sera of EGJOO and sera of healthy subjects (HS) was performed. The target proteins of the serum were identified by mass spectrometry Matrix-assited laser desorption/ionization time-of-flight (MALDI-TOF). KEY RESULTS: The proteomic map of muscle from LES tissue lysates of type I, and type II achalasia, EGJOO, and HD were analyzed and divided into three important regions. We found a difference in the concentration of certain spots. Further, we observed the serum reactivity of type I achalasia and type II achalasia against 45 and 25 kDa bands of type I achalasia tissue. Serum of type III achalasia and EGJOO mainly recognized 25 kDa band. Bands correspond to triosephosphate isomerase (TPI) (25 kDa), carbonic anhydrase (CA) (25 kDa) and creatinine kinase-brain (CKB) isoform (45 kDa). CONCLUSIONS AND INFERENCES: We identify three antigen targets, TPI, CA, and CKB isoform, which are recognized by sera from patients with achalasia.
Asunto(s)
Antígenos/inmunología , Anhidrasas Carbónicas/inmunología , Forma BB de la Creatina-Quinasa/inmunología , Acalasia del Esófago/inmunología , Triosa-Fosfato Isomerasa/inmunología , Adulto , Anciano , Acalasia del Esófago/sangre , Esfínter Esofágico Inferior/inmunología , Esfínter Esofágico Inferior/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteómica , Adulto JovenRESUMEN
Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), which reduces levels of misfolded proteins. However, if ER homeostasis is not restored and the UPR remains chronically activated, cells undergo apoptosis. The UPR regulator, PKR-like endoplasmic reticulum kinase (PERK), plays an important role in promoting cell death when persistently activated; however, the underlying mechanisms are poorly understood. Here, we profiled the microRNA (miRNA) transcriptome in human cells exposed to ER stress and identified miRNAs that are selectively induced by PERK signaling. We found that expression of a PERK-induced miRNA, miR-483, promotes apoptosis in human cells. miR-483 induction was mediated by a transcription factor downstream of PERK, activating transcription factor 4 (ATF4), but not by the CHOP transcription factor. We identified the creatine kinase brain-type (CKB) gene, encoding an enzyme that maintains cellular ATP reserves through phosphocreatine production, as being repressed during the UPR and targeted by miR-483. We found that ER stress, selective PERK activation, and CKB knockdown all decrease cellular ATP levels, leading to increased vulnerability to ER stress-induced cell death. Our findings identify miR-483 as a downstream target of the PERK branch of the UPR. We propose that disruption of cellular ATP homeostasis through miR-483-mediated CKB silencing promotes ER stress-induced apoptosis.
Asunto(s)
Adenosina Trifosfato/metabolismo , MicroARNs/metabolismo , Respuesta de Proteína Desplegada , eIF-2 Quinasa/metabolismo , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Apoptosis , Forma BB de la Creatina-Quinasa/genética , Forma BB de la Creatina-Quinasa/metabolismo , Células HEK293 , Células HeLa , Homeostasis , Humanos , MicroARNs/genética , eIF-2 Quinasa/genéticaRESUMEN
OBJECTIVE: To evaluate the effect of high-dose vitamin C on cardiac reperfusion injury and plasma levels of creatine kinase-muscle/brain (CK-MB), troponin I, and lactate dehydrogenase (LDH) in patients undergoing coronary artery bypass grafting (CABG). METHODS: This is a double-blind randomized clinical trial study. Fifty patients (50-80 years old) who had CABG surgery were selected. The intervention group received 5 g of intravenous vitamin C before anesthesia induction and 5 g of vitamin C in cardioplegic solution. The control group received the same amount of placebo (normal saline). Arterial blood samples were taken to determine the serum levels of CK-MB, troponin I, and LDH enzymes. Left ventricular ejection fraction was measured and hemodynamic parameters were recorded at intervals. RESULTS: High doses of vitamin C in the treatment group led to improvement of ventricular function (ejection fraction [EF]) and low Intensive Care Unit (ICU) stay. The cardiac enzymes level in the vitamin C group was lower than in the control group. These changes were not significant between the groups in different time intervals (anesthesia induction, end of bypass, 6 h after surgery, and 24 h after surgery) for CK-MB, LDH, and troponin I. Hemodynamic parameters, hematocrit, potassium, urinary output, blood transfusion, arrhythmia, and inotropic support showed no significant difference between the groups. CONCLUSION: Vitamin C has significantly improved the patients' ventricular function (EF) 72 h after surgery and reduced the length of ICU stay. No significant changes in cardiac biomarkers, including CK-MB, troponin I, and LDH, were seen over time in each group. IRCT CODE: IRCT2016053019470N33.
Asunto(s)
Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Puente de Arteria Coronaria/métodos , Daño por Reperfusión Miocárdica/prevención & control , Anciano , Anciano de 80 o más Años , Arritmias Cardíacas/prevención & control , Biomarcadores/sangre , Forma BB de la Creatina-Quinasa/sangre , Forma MM de la Creatina-Quinasa/sangre , Método Doble Ciego , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Unidades de Cuidados Intensivos , L-Lactato Deshidrogenasa/sangre , Masculino , Persona de Mediana Edad , Daño por Reperfusión Miocárdica/sangre , Reproducibilidad de los Resultados , Estadísticas no Paramétricas , Factores de Tiempo , Resultado del Tratamiento , Troponina I/sangre , Función Ventricular/efectos de los fármacosRESUMEN
Abstract Objective: To evaluate the effect of high-dose vitamin C on cardiac reperfusion injury and plasma levels of creatine kinase-muscle/brain (CK-MB), troponin I, and lactate dehydrogenase (LDH) in patients undergoing coronary artery bypass grafting (CABG). Methods: This is a double-blind randomized clinical trial study. Fifty patients (50-80 years old) who had CABG surgery were selected. The intervention group received 5 g of intravenous vitamin C before anesthesia induction and 5 g of vitamin C in cardioplegic solution. The control group received the same amount of placebo (normal saline). Arterial blood samples were taken to determine the serum levels of CK-MB, troponin I, and LDH enzymes. Left ventricular ejection fraction was measured and hemodynamic parameters were recorded at intervals. Results: High doses of vitamin C in the treatment group led to improvement of ventricular function (ejection fraction [EF]) and low Intensive Care Unit (ICU) stay. The cardiac enzymes level in the vitamin C group was lower than in the control group. These changes were not significant between the groups in different time intervals (anesthesia induction, end of bypass, 6 h after surgery, and 24 h after surgery) for CK-MB, LDH, and troponin I. Hemodynamic parameters, hematocrit, potassium, urinary output, blood transfusion, arrhythmia, and inotropic support showed no significant difference between the groups. Conclusion: Vitamin C has significantly improved the patients' ventricular function (EF) 72 h after surgery and reduced the length of ICU stay. No significant changes in cardiac biomarkers, including CK-MB, troponin I, and LDH, were seen over time in each group. IRCT code: IRCT2016053019470N33
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Ácido Ascórbico/administración & dosificación , Daño por Reperfusión Miocárdica/prevención & control , Puente de Arteria Coronaria/métodos , Antioxidantes/administración & dosificación , Arritmias Cardíacas/prevención & control , Factores de Tiempo , Biomarcadores/sangre , Daño por Reperfusión Miocárdica/sangre , Método Doble Ciego , Reproducibilidad de los Resultados , Función Ventricular/efectos de los fármacos , Resultado del Tratamiento , Estadísticas no Paramétricas , Troponina I/sangre , Forma BB de la Creatina-Quinasa/sangre , Forma MM de la Creatina-Quinasa/sangre , Hemodinámica/efectos de los fármacos , Unidades de Cuidados Intensivos , L-Lactato Deshidrogenasa/sangreRESUMEN
The main difference between the primary structures of human and mouse tau can be found at the N-terminal end of the protein. Residues 17 to 28 in human tau are not present in the mouse form of the molecule. Here we tested the capacity of these human tau residues to bind to specific proteins. Several proteins were observed to bind to these residues. Among those that showed the greatest binding were three related to energetic processes: enolase, glyceraldehyde 3 phosphate dehydrogenase and creatine kinase B. The latter did not bind to tau from brain extracts taken from patients with Alzheimer's disease (AD). This lack of binding could be due to the modification of CKB by oxidation in AD.
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Enfermedad de Alzheimer/metabolismo , Proteínas tau/química , Proteínas tau/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Animales , Sitios de Unión , Forma BB de la Creatina-Quinasa/metabolismo , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Fosfopiruvato Hidratasa/metabolismo , Unión Proteica , Ratas , Alineación de SecuenciaRESUMEN
Odor transduction in the cilia of olfactory sensory neurons involves several ATP-requiring enzymes. ATP is generated by glycolysis in the ciliary lumen, using glucose incorporated from surrounding mucus, and by oxidative phosphorylation in the dendrite. During prolonged stimulation, the cilia maintain ATP levels along their length, by unknown means. We used immunochemistry, RT-PCR, and immunoblotting to explore possible underlying mechanisms. We found the ATP-shuttles, adenylate and creatine kinases, capable of equilibrating ATP. We also investigated how glucose delivered by blood vessels in the olfactory mucosa reaches the mucus. We detected, in sustentacular and Bowman's gland cells, the crucial enzyme in glucose secretion glucose-6-phosphatase, implicating both cell types as putative glucose pathways. We propose a model accounting for both processes.
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Adenosina Trifosfato/metabolismo , Cilios/metabolismo , Glucosa-6-Fosfatasa/metabolismo , Glucosa/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , Adenilato Quinasa/genética , Adenilato Quinasa/metabolismo , Animales , Transporte Biológico , Membrana Celular/metabolismo , Membrana Celular/ultraestructura , Cerebelo/citología , Cerebelo/metabolismo , Cilios/ultraestructura , Forma BB de la Creatina-Quinasa/genética , Forma BB de la Creatina-Quinasa/metabolismo , Expresión Génica , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Glucosa-6-Fosfatasa/genética , Glucólisis , Masculino , Microsomas/metabolismo , Microsomas/ultraestructura , Neuronas Receptoras Olfatorias/citología , Fosforilación Oxidativa , Ratas , Ratas Sprague-Dawley , Técnicas de Cultivo de TejidosAsunto(s)
Forma BB de la Creatina-Quinasa/sangre , Forma MB de la Creatina-Quinasa/sangre , Mieloma Múltiple/diagnóstico , Anciano , Alquilantes/uso terapéutico , Autoanticuerpos/inmunología , Forma BB de la Creatina-Quinasa/inmunología , Forma MB de la Creatina-Quinasa/inmunología , Femenino , Humanos , Inmunoelectroforesis , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunofenotipificación , Mieloma Múltiple/tratamiento farmacológicoRESUMEN
Arsenic trioxide (As2O3) is utilized for treating patients suffering from hematological malignancies particularly acute promyelocytic leukemia. Unfortunately, the extensive application of this chemotherapeutic agent has been limited due to its adverse effects such as cardiotoxicity. Ellagic acid, as a phenolic compound, has shown to exert antioxidant, anti-inflammatory, antifibrotic, and antiatherogenic properties. It is also capable of protecting against drug toxicity. In this study, we evaluated whether ellagic acid can protect against As2O3-induced heart injury in rats. Thirty-two male Wistar rats were randomly divided into four treatment groups, that is, control (0.2 mL of normal saline, intraperitoneally (ip)), As2O3 (5 mg/kg, ip), As2O3 plus ellagic acid, and ellagic acid (30 mg/kg, orally) groups. The drugs were administered daily for 10 days and pretreatment with ellagic acid was performed 1 h prior to As2O3 injection. Cardiotoxicity was characterized by electrocardiological, biochemical, and histopathological evaluations. Our results showed that ellagic acid pretreatment significantly ameliorated As2O3-induced increase in glutathione peroxidase activity and malondialdehyde concentration ( p < 0.05 and p < 0.001, respectively) and also diminished QTc prolongation ( p < 0.0001) and cardiac tissue damages. Pretreatment with ellagic acid also lowered the increased troponin I ( p < 0.0001) and creatine kinase isoenzyme MB ( p < 0.01) levels in response to As2O3. In conclusion, results of this study demonstrated that ellagic acid has beneficial cardioprotective effects against As2O3 toxicity. It is suggested that the protective effects were mediated by antioxidant properties of ellagic acid.
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Antioxidantes/farmacología , Arritmias Cardíacas/prevención & control , Arsenicales , Cardiomiopatías/prevención & control , Ácido Elágico/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Óxidos , Animales , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Trióxido de Arsénico , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiotoxicidad , Forma BB de la Creatina-Quinasa/sangre , Citoprotección , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Sistema de Conducción Cardíaco/metabolismo , Sistema de Conducción Cardíaco/fisiopatología , Masculino , Malondialdehído/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Wistar , Troponina I/sangreRESUMEN
EDITOR'S NOTE: This article by Dr. Günter Scheuerbrandt is a fascinating personal account and historical narrative of the birth and development of a screening program for Duchenne Muscular Dystrophy in Germany, beginning 40 years ago. As the author notes, approval of an institutional review board or ethics committee was not required for this type of scientific investigation in one's field at the time this program was begun, but we have removed all personal data from any of the materials presented in here in order to conform to current concepts of ethical publication. This article is about the screening of 528,410, mostly 4-6-week-old, boys in Germany between 1977 and 2011 for high levels of creatine kinase (CK) to identify those with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). During these 34 years of infant screening, 147 boys with confirmed, probable, and possible DMD (incidence 1:3,600 male births) and 33 boys with confirmed, probable, and possible BMD (incidence 1:15,500 male births) were found. Research reports about DMD were sent to families and pediatricians participating in the screening, and, on request, to families and scientists everywhere. It is hoped that screening programs used as the basis for future therapies will be able to modify the natural history of boys with DMD. New dystrophin mutations will continue to occur, necessitating screening and early therapy. Abstract Submitted for Presentation at the 10th International Society for Neonatal Screening-Asia Pacific Regional Meeting, August 2017, Ulaanbataar, Mongolia. Muscle Nerve 57: 185-188, 2018.