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1.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(6): 686-690, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32684213

RESUMO

OBJECTIVE: To investigate the level and changing trend of microparticles (MPs) in super-elderly infected patients, and explore its early warning effect on infection. METHODS: The infected patients ≥ 85 years old admitted to the Second Medical Center of Chinese PLA General Hospital from December 2018 to March 2019 were selected as the observation group, and the healthy volunteers ≥ 85 years old in the same period were selected as the control group. Venous blood samples were collected at the 2nd hour, the 2nd day and the 7th day after fever, and the inflammatory markers such as white blood cell count (WBC), neutrophil percentage (NEUT), C-reactive protein (CRP) and procalcitonin (PCT) were measured. The levels of MPs were determined by flow cytometry. Annexin V labeled CD11b positive MPs (Annexin V+/CD11b+ MPs) represented leukocyte microparticles (LMPs), and Annexin V labeled CD66b positive MPs (Annexin V+/CD66b+ MPs) represented neutrophil microparticle (NMPs). The differences of each index at different time points between the two groups were compared, and the predictive value of each index to the infection of elderly patients was analyzed by receiver operating characteristic (ROC) curve. RESULTS: A total of 38 subjects were enrolled, including 28 cases in the observation group and 10 cases in the control group. The levels of LMPs and NMPs in the observation group increased to the peak at the 2nd hour after fever, and were significantly higher than those in the control group [LMPs (cells/µL): 55.0 (28.8, 197.2) vs. 19.0 (13.5, 28.3), NMPs (cells/µL): 226.5 (123.3, 516.5) vs. 26.5 (22.0, 48.8), both P < 0.01]. With the control of the disease, LMPs and NMPs decreased gradually. The NMPs on the 2nd day was significantly lower than that at the 2nd hour of fever [cells/µL: 106.0 (40.0, 309.0) vs. 226.5 (123.3, 516.5), P < 0.05], and the LMPs and NMPs on the 7th day were significantly lower than those on the 2nd day [LMPs (cells/µL): 17.0 (12.5, 43.8) vs. 42.0 (13.0, 117.0), NMPs (cells/µL): 30.0 (15.8, 62.0) vs. 106.0 (40.0, 309.0), both P < 0.05]. There was no significant difference in the levels of LMPs and NMPs between the two groups on the 7th day. Among the inflammatory markers, the NEUT in the observation group was significantly higher than that in the control group at the 2nd hour of fever (0.70±0.09 vs. 0.59±0.04, P < 0.01), but there was no significant difference in WBC, CRP and PCT between the two groups. On the 2nd day, the inflammatory markers in the observation group reached the peak and were significantly higher than those in the control group [WBC (×109/L): 9.33±2.44 vs. 6.37±1.28, NEUT: 0.78±0.08 vs. 0.57±0.04, CRP (mg/L): 5.67±2.99 vs. 0.33±0.18, PCT (µg/L): 0.80±0.67 vs. 0.07±0.03, all P < 0.01]. On the 7th day, the inflammatory markers in the observation group decreased significantly, and there was no significant difference between the observation group and the control group. ROC curve analysis showed that the area under ROC curve (AUC) and 95% confidence interval (95%CI) of LMPs and NMPs on the day of fever were higher than those of WBC, NEUT, CRP and PCT [0.888 (0.763-1.000), 0.973 (0.931-1.000) vs. 0.679 (0.346-0.811), 0.829 (0.700-0.958), 0.607 (0.404-0.811), 0.554 (0.358-0.749)]. CONCLUSIONS: LMPs and NMPs are significantly increased in the early stage of fever, which can predict the incidence of infection in the super-elderly patients.


Assuntos
Infecções/diagnóstico , Idoso , Proteína C-Reativa , Calcitonina , Peptídeo Relacionado com Gene de Calcitonina , Humanos , Pró-Calcitonina , Prognóstico , Precursores de Proteínas , Curva ROC , Estudos Retrospectivos
2.
Cochrane Database Syst Rev ; 6: CD008482, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32497260

RESUMO

BACKGROUND: Malabsorption and deficiency of fat-soluble vitamins K may occur in cystic fibrosis, a genetic disorder affecting multiple organs. Vitamin K is known to play an important role in both blood coagulation and bone formation, hence the role of supplementation of vitamin K in this category needs to be reviewed. This is an updated version of the review. OBJECTIVES: To assess the effects of vitamin K supplementation in people with cystic fibrosis and to investigate the hypotheses that vitamin K will decrease deficiency-related coagulopathy, increase bone mineral density, decrease risk of fractures and improve quality of life in people with CF. Also to determine the optimal dose and route of administration of vitamin K for people with CF (for both routine and therapeutic use). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 12 August 2019. SELECTION CRITERIA: Randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. The quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: Three trials (total 70 participants, aged 8 to 46 years) assessed as having a moderate risk of bias were included. One trial compared vitamin K to placebo, a second to no supplementation and the third compared two doses of vitamin K. No trial in either comparison reported our primary outcomes of coagulation and quality of life or the secondary outcomes of nutritional parameters and adverse events. Vitamin K versus control Two trials compared vitamin K to control, but data were not available for analysis. One 12-month trial (n = 38) compared 10 mg vitamin K daily or placebo in a parallel design and one trial (n = 18) was of cross-over design with no washout period and compared 5 mg vitamin K/week for four-weeks to no supplementation for four-weeks. Only the 12-month trial reported on the primary outcome of bone formation; we are very uncertain whether vitamin K supplementation has any effect on bone mineral density at the femoral hip or lumbar spine (very low-quality evidence). Both trials reported an increase in serum vitamin K levels and a decrease in undercarboxylated osteocalcin levels. The cross-over trial also reported that levels of proteins induced by vitamin K absence (PIVKA) showed a decrease and a return to normal following supplementation, but due to the very low-quality evidence we are not certain that this is due to the intervention. High-dose versus low-dose vitamin K One parallel trial (n = 14) compared 1 mg vitamin K/day to 5 mg vitamin K/day for four weeks. The trial did report that there did not appear to be any difference in serum undercarboxylated osteocalcin or vitamin K levels (very low-quality evidence). While the trial reported that serum vitamin K levels improved with supplementation, there was no difference between the high-dose and low-dose groups. AUTHORS' CONCLUSIONS: There is very low-quality evidence of any effect of vitamin K in people with cystic fibrosis. While there is no evidence of harm, until better evidence is available the ongoing recommendations by national CF guidelines should be followed.


Assuntos
Fibrose Cística/sangue , Osteogênese/efeitos dos fármacos , Deficiência de Vitamina K/tratamento farmacológico , Vitamina K/administração & dosagem , Vitaminas/administração & dosagem , Adolescente , Adulto , Biomarcadores/sangue , Coagulação Sanguínea/efeitos dos fármacos , Densidade Óssea , Criança , Fibrose Cística/complicações , Suplementos Nutricionais , Fraturas Ósseas/prevenção & controle , Humanos , Pessoa de Meia-Idade , Osteocalcina/sangue , Precursores de Proteínas/sangue , Protrombina , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina K/sangue , Deficiência de Vitamina K/complicações
3.
Mol Pharmacol ; 98(2): 96-108, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32487735

RESUMO

In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, >20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors, proenkephalin, prodynorphin, and proopiomelanocortin, by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides binds to all three of the opioid receptor types (µ, δ, or κ), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in the brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been used to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e., to excised tissue) or in vivo (in animals), using antagonists of opioid receptors to infer endogenous peptide activity, and genetic knockout of opioid peptide precursors. Collectively, these studies add to our current understanding of the function of endogenous opioids, especially when similar results are found using different approaches. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENT: Activation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects, including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.


Assuntos
Peptídeos Opioides/genética , Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Animais , Encéfalo/metabolismo , Carboxipeptidase H/metabolismo , Encefalinas/química , Encefalinas/genética , Humanos , Pró-Opiomelanocortina/química , Pró-Opiomelanocortina/genética , Pró-Proteína Convertases/metabolismo , Precursores de Proteínas/química , Precursores de Proteínas/genética
4.
Eur J Endocrinol ; 183(2): R29-R40, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32580146

RESUMO

For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine-vasopressin (AVP) is normally produced but not recognized by the kidney with an inability to concentrate urine despite elevated plasma concentrations of AVP. Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter's syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter's syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.


Assuntos
Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/fisiopatologia , Desidratação/prevenção & controle , Diabetes Insípido Nefrogênico/terapia , Feminino , Triagem de Portadores Genéticos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Testes Genéticos , Humanos , Hipernatremia , Recém-Nascido , Glomérulos Renais/fisiopatologia , Masculino , Mutação , Neurofisinas/sangue , Neurofisinas/fisiologia , Concentração Osmolar , Gravidez , Diagnóstico Pré-Natal , Precursores de Proteínas/sangue , Precursores de Proteínas/fisiologia , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/fisiologia , Vasopressinas/sangue , Vasopressinas/fisiologia
5.
Gan To Kagaku Ryoho ; 47(2): 319-321, 2020 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-32381975

RESUMO

We report a case of a 75-year-old man with a-fetoprotein(AFP)-producing gastric cancer accompanied by multiple large liver metastases. The patient underwent a total gastrectomy for gastric cancer(p-T3N3H0P0M0, fStage ⅢB). The patient then underwent chemotherapy(TS-1 80m g/day)following the radical operation. However, 5 months after the radical operation, he presented with multiple large liver tumors, which were subsequently biopsied. Based on immunohistochemical examination, the liver tumors were negative for AFP protein, but were similar to hepatoid adenocarcinoma, and no fibrosis was observed in the background liver. Therefore, we diagnosed the tumors as liver metastases of AFP producing gastric cancer and metachronous liver metastasis. The patient underwent transcatheter arterial chemoembolization(TACE). TACE decreased the AFP and PIVKA-Ⅱ levels and reduced the multiple huge liver metastases. Due to the increase in AFP and the multiple liver metastases, despite intensive hepatic infusion chemotherapy, he died 5 months after admission.


Assuntos
Quimioembolização Terapêutica , Neoplasias Hepáticas , Neoplasias Gástricas , Idoso , Biomarcadores , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Masculino , Precursores de Proteínas , Protrombina , alfa-Fetoproteínas
6.
Nature ; 580(7803): 376-380, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32296182

RESUMO

Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut-brain communication pathways and mechanisms remain poorly understood1-12. Here we show that, in mice, neurons in the parabrachial nucleus that express the prodynorphin gene (hereafter, PBPdyn neurons) monitor the intake of both fluids and solids, using mechanosensory signals that arise from the upper digestive tract. Most individual PBPdyn neurons are activated by ingestion as well as the stimulation of the mouth and stomach, which indicates the representation of integrated sensory signals across distinct parts of the digestive tract. PBPdyn neurons are anatomically connected to the digestive periphery via cranial and spinal pathways; we show that, among these pathways, the vagus nerve conveys stomach-distension signals to PBPdyn neurons. Upon receipt of these signals, these neurons produce aversive and sustained appetite-suppressing signals, which discourages the initiation of feeding and drinking (fully recapitulating the symptoms of gastric distension) in part via signalling to the paraventricular hypothalamus. By contrast, inhibiting the same population of PBPdyn neurons induces overconsumption only if a drive for ingestion exists, which confirms that these neurons mediate negative feedback signalling. Our findings reveal a neural mechanism that underlies the mechanosensory monitoring of ingestion and negative feedback control of intake behaviours upon distension of the digestive tract.


Assuntos
Ingestão de Alimentos , Retroalimentação , Neurônios/fisiologia , Animais , Encefalinas/genética , Encefalinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Trato Gastrointestinal Superior/fisiologia
7.
Nat Commun ; 11(1): 1662, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245955

RESUMO

The proteasome is an essential protein-degradation machinery in eukaryotic cells that controls protein turnover and thereby the biogenesis and function of cell organelles. Chloroplasts import thousands of nuclear-encoded precursor proteins from the cytosol, suggesting that the bulk of plastid proteins is transiently exposed to the cytosolic proteasome complex. Therefore, there is a cytosolic equilibrium between chloroplast precursor protein import and proteasomal degradation. We show here that a shift in this equilibrium, induced by mild genetic proteasome impairment, results in elevated precursor protein abundance in the cytosol and significantly increased accumulation of functional photosynthetic complexes in protein import-deficient chloroplasts. Importantly, a proteasome lid mutant shows improved photosynthetic performance, even in the absence of an import defect, signifying that functional precursors are continuously degraded. Hence, turnover of plastid precursors in the cytosol represents a mechanism to constrain thylakoid membrane assembly and photosynthetic electron transport.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Cloroplastos/metabolismo , Complexo de Proteínas do Centro de Reação Fotossintética/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Proteínas de Cloroplastos/metabolismo , Citosol/metabolismo , Mutação , Fotossíntese , Plantas Geneticamente Modificadas , Complexo de Endopeptidases do Proteassoma/metabolismo , Precursores de Proteínas/metabolismo , Proteólise , Estresse Fisiológico
9.
Chem Biol Interact ; 323: 109063, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32224134

RESUMO

Exposure to TiO2 NPs induces several cellular alterations after NPs uptake including disruption of cytoskeleton that is crucial for lung physiology but is not considered as a footprint of cell damage. We aimed to investigate cytoskeleton disturbances and the impact on cell migration induced by an acute TiO2 NPs exposure (24 h) and the recovery capability after 6 days of NPs-free treatment, which allowed investigating if cytoskeleton damage was reversible. Exposure to TiO2 NPs (10 µg/cm2) for 24 h induced a decrease 20.2% and 25.1% in tubulin and actin polymerization. Exposure to TiO2 NPs (10 µg/cm2) for 24 h followed by 6 days of NPs-free had a decrease of 26.6% and 21.3% in tubulin and actin polymerization, respectively. The sustained exposure for 7 days to 1 µg/cm2 and 10 µg/cm2 induced a decrease of 22.4% and 30.7% of tubulin polymerization respectively, and 28.7% and 46.2% in actin polymerization. In addition, 24 h followed 6 days of NPs-free exposure of TiO2 NPs (1 µg/cm2 and 10 µg/cm2) decreased cell migration 40.7% and 59.2%, respectively. Cells exposed (10 µg/cm2) for 7 days had a decrease of 65.5% in cell migration. Ki67, protein surfactant B (SFTPB) and matrix metalloprotease 2 (MMP2) were analyzed as genes related to lung epithelial function. The results showed a 20% of Ki67 upregulation in cells exposed for 24 h to 10 µg/cm2 TiO2 NPs while a downregulation of 20% and 25.8% in cells exposed to 1 µg/cm2 and 10 µg/cm2 for 24 h followed by 6 days of NPs-free exposure. Exposure to 1 µg/cm2 and 10 µg/cm2 for 24 h and 7 days upregulates SFTPB expression in 53% and 59% respectively, MMP2 expression remain unchanged. In conclusion, exposure of TiO2 NPs affected cytoskeleton of lung epithelial cells irreversibly but this damage was not cumulative.


Assuntos
Citoesqueleto/patologia , Células Epiteliais/patologia , Pulmão/patologia , Nanopartículas/toxicidade , Titânio/toxicidade , Células A549 , Actinas/metabolismo , Movimento Celular/efeitos dos fármacos , Tamanho Celular , Sobrevivência Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Endocitose , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/ultraestrutura , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Antígeno Ki-67/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Nanopartículas/ultraestrutura , Polimerização , Precursores de Proteínas/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , Tubulina (Proteína)/metabolismo
10.
J Cancer Res Clin Oncol ; 146(4): 897-907, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146565

RESUMO

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. MATERIALS AND METHODS: The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. RESULTS: Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. CONCLUSION: Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.


Assuntos
Carcinoma Ductal Pancreático/genética , DNA Tumoral Circulante/genética , Metilação de DNA , Genes Supressores de Tumor , Neoplasias Pancreáticas/genética , Proteína C-Reativa/genética , Carcinoma Ductal Pancreático/sangue , Estudos de Casos e Controles , Diferenciação Celular/genética , DNA Tumoral Circulante/sangue , Encefalinas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Osteonectina/genética , Neoplasias Pancreáticas/sangue , Pancreatite Crônica/sangue , Pancreatite Crônica/genética , Regiões Promotoras Genéticas , Precursores de Proteínas/genética , Ubiquitina Tiolesterase/genética
11.
Gene ; 742: 144583, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32184167

RESUMO

BACKGROUND: Studies showed that increased let-7b-5p microRNA during repeated electroacupuncture (EA) treatment was associated the formation of EA tolerance, which manifested as gradually decreased nociceptive threshold. Proenkephalin (PENK) is the precursor of enkephalin which is a pivot neuropeptide responsible for the decreased nociceptive threshold in EA. The aim of this study was to evaluate the relationship between let-7b-5p and PENK in EA tolerance. METHODS: The target gene of let-7b-5p microRNA was determined through the dual-luciferase reporter assay in cortical neurons. Seventy-two Sprague Dawley rats received a combination of EA and intracerebroventricular injection of microRNA (let-7b-5p agomir, antagomir or their controls). The nociceptive thresholds were assessed with radiant heat tail-flick method. PENK and let-7b-5p were measured with Western Blot and qPCR, respectively, after administration of let-7b-5p agomir, antagomir, and their controls at day 1, 4 and 7. RESULTS: Let-7b-5p targeted the 3' untranslated region of Penk1. The nociceptive thresholds in Let-7b-5p agomir + EA group were decreased (p < 0.05) compared with those in Let-7b-5p antagomir + EA group at day 1 to 7. Compared with Let-7b-5p agomir + EA group, the expression level of PENK in Let-7b-5p antagomir + EA group was increased at days 1, 4, and 7 (p < 0.05) CONCLUSION: Let-7b-5p may be a new potential target for decreasing the EA tolerance effect and facilitating the application of EA in treating chronic nociception of patients.


Assuntos
Eletroacupuntura , Encefalinas/genética , MicroRNAs/metabolismo , Dor Nociceptiva/terapia , Precursores de Proteínas/genética , Animais , Antagomirs/administração & dosagem , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Injeções Intraventriculares , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/diagnóstico , Dor Nociceptiva/genética , Dor Nociceptiva/imunologia , Limiar da Dor/efeitos dos fármacos , Ratos
12.
Invest Ophthalmol Vis Sci ; 61(2): 48, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32106291

RESUMO

Purpose: Anti-vascular endothelial growth factor (VEGF) therapy for neovascular AMD (nvAMD) obtains a variable outcome. We performed a genome-wide association study for anti-VEGF treatment response in nvAMD to identify variants potentially underlying such a variable outcome. Methods: Israeli patients with nvAMD who underwent anti-VEGF treatment (n = 187) were genotyped on a whole exome chip containing approximately 500,000 variants. Genotyping was correlated with delta visual acuity (deltaVA) between baseline and after three injections of anti-VEGF. Top principal components, age, and baseline VA were included in the analysis. Two lead associated variants were genotyped in an independent validation set of patients with nvAMD (n = 108). Results: Linear regression analysis on 5,353,842 variants revealed five exonic variants with an association P value of less than 6 × 10-5. The top variant in the gene VWA3A (P = 1.77 × 10-6) was tested in the validation cohort. The minor allele of the VWA3A variant was associated with worse response to treatment (P = 0.02). The average deltaVA of discovery plus validation was -0.214 logMAR (≈ a gain of 10.7 Early Treatment Diabetic Retinopathy Study letters) for homozygote for the major allele, 0.172 logMAR for heterozygotes (≈ a loss of 8.6 Early Treatment Diabetic Retinopathy Study letters), and 0.21 logMAR for homozygote for the minor allele (≈ a loss of 10.5 Early Treatment Diabetic Retinopathy Study letters). Minor allele carriers had a higher frequency of macular hemorrhage at baseline. Conclusions: An VWA3A gene variant was associated with worse response to anti-VEGF treatment in Israeli patients with nvAMD. The VWA3A protein is a precursor of the multimeric von Willebrand factor which is involved in blood coagulation, a system previously associated with nvAMD.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide , Precursores de Proteínas/genética , Degeneração Macular Exsudativa , Idoso , Idoso de 80 Anos ou mais , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/genética , Feminino , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Acuidade Visual , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/genética , Fator de von Willebrand/genética
13.
Mol Cell ; 77(3): 656-668.e5, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004469

RESUMO

Class B G protein-coupled receptors (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gs-bound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/ultraestrutura , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/ultraestrutura , Sequência de Aminoácidos , Microscopia Crioeletrônica/métodos , Encefalinas , Humanos , Ligantes , Modelos Moleculares , Peptídeos , Precursores de Proteínas , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Acoplados a Proteínas-G/ultraestrutura , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Transdução de Sinais
14.
Rev Soc Bras Med Trop ; 53: e20190418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049203

RESUMO

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a serious pulmonary circulation disease caused by several etiologies, including schistosomiasis. The present study retrospectively evaluated the clinical and hemodynamic characteristics of patients with schistosomal PAH (PAH-Sch) compared to those of non-Sch PAH patients (non-Sch PAH). METHODS: Patients treated at the Pronto-Socorro Cardiológico de Pernambuco and diagnosed by right cardiac catheterization were divided into PAH-Sch and non-Sch PAH groups. Their socio-demographic and clinical characteristics, N-terminal-pro B-type natriuretic peptide (NT-proBNP), and echocardiography and hemodynamic parameters were retrospectively reviewed. RESULTS: Among the included 98 patients (mean age, 45 ± 14 years; 68 women [69.4%]), we found 56 PAH-Sch and 42 non-Sch PAH. The age distribution was heterogeneous in the PAH-Sch group, with patients predominantly ranging from 50-59 (p <0.004). Dyspnea was the most common symptom, reported by 92 patients (93.8%), and commonly present for over two years prior to diagnosis. Clinical symptoms were similar in both groups, with no differences in functional class, pulmonary artery systolic pressure (p = 0.102), 6-minute walk test score (p = 0.234), NT-proBNP serum levels (p = 0.081), or hemodynamic parameters. CONCLUSIONS: Patients with PAH-Sch present clinical, laboratory, and hemodynamic profiles similar to those with PAH resulting from other etiologies of poor prognosis. PAH is an important manifestation of schistosomiasis in endemic regions that is often diagnosed late.


Assuntos
Fator Natriurético Atrial/sangue , Precursores de Proteínas/sangue , Hipertensão Arterial Pulmonar/etiologia , Esquistossomose/complicações , Adulto , Idoso , Biomarcadores/sangue , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/sangue , Estudos Retrospectivos , Fatores Socioeconômicos
15.
Clin Appl Thromb Hemost ; 26: 1076029619895318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31973568

RESUMO

OBJECTIVE: The aim of this study was to confirm previous observations that proenkephalin A (PENK-A) may serve as prognostic marker in the setting of acute ischemic stroke in a large stroke cohort. METHODS: The plasma concentration of PENK-A was measured within 72 hours of symptom onset in 320 consecutively enrolled patients with stroke. The primary outcome measures were unfavorable functional outcome (modified Rankin Scale score 0-2 vs 3-6) and mortality within 90 days. Logistic and cox proportional regression analyses were fitted to estimate odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs), respectively, for the association between PENK-A and the primary outcome measures. RESULTS: After adjusting for demographic and vascular risk factors, PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (HR: 1.02, 95% CI: 0.14-7.33). CONCLUSION: Among patients with acute stroke, PENK-A does not serve as an independent prognostic marker in this external validation cohort.


Assuntos
Encefalinas/sangue , Precursores de Proteínas/sangue , Acidente Vascular Cerebral/diagnóstico , Idoso , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/mortalidade , Estudos de Coortes , Humanos , Razão de Chances , Prognóstico , Análise de Regressão , Acidente Vascular Cerebral/mortalidade
16.
Clinics (Sao Paulo) ; 75: e1448, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994614

RESUMO

OBJECTIVES: The purpose of this study was to evaluate the relationship between the serum levels of calcitonin gene-related peptide (CGRP) and the prognosis of pediatric patients with severe pneumonia. METHODS: Children diagnosed with severe pneumonia (n=76) were stratified into the survival (n=58) and non-survival groups (n=18) according to their 28-day survival status and into the non-risk (n=51), risk (n=17) and high-risk (n=8) categories based on the pediatric critical illness score (PCIS). Demographic data and laboratory results were collected. Serum CGRP levels were determined by enzyme-linked immunosorbent assay (ELISA). A receiver operating characteristic (ROC) curve was generated to determine the cutoff score for high CGRP levels. RESULTS: Serum CGRP levels were significantly higher in the survival group than in the non-survival group and were significantly higher in the non-risk group than in the risk and high-risk groups. The ROC curve for the prognostic potential of CGRP yielded a significant area under the curve (AUC) value with considerable sensitivity and specificity. CONCLUSION: Our findings show that CGRP downregulation might be a diagnostic marker that predicts the prognosis and survival of children with severe pneumonia.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/genética , Pneumonia/sangue , Precursores de Proteínas/sangue , Vasodilatadores/metabolismo , Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Criança , Estado Terminal , Feminino , Humanos , Masculino , Pneumonia/mortalidade , Prognóstico , Curva ROC , Análise de Sobrevida
17.
Diabetes ; 69(4): 670-680, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31896552

RESUMO

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)-mediated ß-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human ß-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of ß-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in ß-cell destruction processes and as a potential target for the treatment of autoimmune T1D.


Assuntos
Aminopeptidases/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Precursores de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Aminopeptidases/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/genética , Células HEK293 , Humanos , Inflamação/genética , Inflamação/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/imunologia , Interferon gama/farmacologia , Interleucina-1beta/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Proteínas Serina-Treonina Quinases/genética , Regulação para Cima
18.
Biochem Soc Trans ; 48(1): 71-82, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31922184

RESUMO

Chloroplasts are photosynthetic plant organelles descended from a bacterial ancestor. The vast majority of chloroplast proteins are synthesized in the cytosol and then imported into the chloroplast post-translationally. Translocation complexes exist in the organelle's outer and inner envelope membranes (termed TOC and TIC, respectively) to facilitate protein import. These systems recognize chloroplast precursor proteins and mediate their import in an energy-dependent manner. However, many unanswered questions remain regarding mechanistic details of the import process and the participation and functions of individual components; for example, the cytosolic events that mediate protein delivery to chloroplasts, the composition of the TIC apparatus, and the nature of the protein import motor all require resolution. The flux of proteins through TOC and TIC varies greatly throughout development and in response to specific environmental cues. The import process is, therefore, tightly regulated, and it has emerged that the ubiquitin-proteasome system (UPS) plays a key role in this regard, acting at several different steps in the process. The UPS is involved in: the selective degradation of transcription factors that co-ordinate the expression of chloroplast precursor proteins; the removal of unimported chloroplast precursor proteins in the cytosol; the inhibition of chloroplast biogenesis pre-germination; and the reconfiguration of the TOC apparatus in response to developmental and environmental signals in a process termed chloroplast-associated protein degradation. In this review, we highlight recent advances in our understanding of protein import into chloroplasts and how this process is regulated by the UPS.


Assuntos
Cloroplastos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Transporte Proteico/fisiologia , Ubiquitina/metabolismo , Proteínas de Cloroplastos/metabolismo , Citosol/metabolismo , Organelas/metabolismo , Fotossíntese , Proteínas de Plantas/metabolismo , Plantas/anatomia & histologia , Plantas/metabolismo , Precursores de Proteínas/metabolismo , Proteólise
19.
Anesth Analg ; 130(1): 248-257, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166231

RESUMO

BACKGROUND: Persistent use of prescription opioids beyond the period of surgical recovery is a large part of a public health problem linked to the current opioid crisis in the United States. However, few studies have been conducted to examine whether morphine reward is influenced by acute pain and injury. METHODS: In a mouse model of incisional injury and minor trauma, animals underwent conditioning, extinction, and drug-primed reinstatement with morphine to examine the rewarding properties of morphine in the presence of acute incisional injury and drug-induced relapse, respectively. In addition, we sought to determine whether these behaviors were influenced by kappa opioid receptor signaling and measured expression of prodynorphin messenger RNA in the nucleus accumbens and medial prefrontal cortex after conditioning and before reinstatement with morphine and incisional injury. RESULTS: In the presence of incisional injury, we observed enhancement of morphine reward with morphine-conditioned place preference but attenuated morphine-primed reinstatement to reward. This adaptation was not present in animals conditioned 12 days after incisional injury when nociceptive sensitization had resolved; however, they showed enhancement of morphine-primed reinstatement. Prodynorphin expression was greatly enhanced in the nucleus accumbens and medial prefrontal cortex of mice with incisional injury and morphine conditioning and remained elevated up to drug-primed reinstatement. These changes were not observed in mice conditioned 12 days after incisional injury. Further, kappa opioid receptor blockade with norbinaltorphimine before reinstatement reversed the attenuation induced by injury. CONCLUSIONS: These findings suggest enhancement of morphine reward as a result of incisional injury but paradoxically a protective adaptation with incisional injury from drug-induced relapse resulting from kappa opioid receptor activation in the reward circuitry. Remote injury conferred no such protection and appeared to enhance reinstatement.


Assuntos
Dor Aguda/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/agonistas , Recompensa , Ferimentos Penetrantes/tratamento farmacológico , Dor Aguda/metabolismo , Dor Aguda/fisiopatologia , Dor Aguda/psicologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Encefalinas/genética , Encefalinas/metabolismo , Extinção Psicológica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Limiar da Dor/efeitos dos fármacos , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Ferimentos Penetrantes/metabolismo , Ferimentos Penetrantes/fisiopatologia , Ferimentos Penetrantes/psicologia
20.
J Anal Toxicol ; 44(2): 173-179, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-31287544

RESUMO

Botulinum neurotoxins (BoNTs) are a family of protein toxins consisting of seven known serotypes (BoNT/A-BoNT/G) and multiple subtypes within the serotypes, and all of which cause the disease botulism-a disease of great public health concern. Accurate detection of BoNTs in human clinical samples is therefore an important public health goal. To achieve this goal, our laboratory developed a mass spectrometry-based assay detecting the presence of BoNT via its enzymatic activity on a peptide substrate. Recently, publications reported the use of new peptide substrates to detect BoNT/A and /B with improved results over other peptide substrates. However, the authors did not provide results of their peptide substrate on multiple subtypes of BoNT. In this work, we describe the results of testing the new substrates with multiple BoNT/A and /B subtypes and find that the substrates cannot detect many subtypes of BoNT/A and /B.


Assuntos
Toxinas Botulínicas/análise , Bioensaio , Toxinas Botulínicas Tipo A , Botulismo , Encefalinas , Humanos , Limite de Detecção , Espectrometria de Massas , Peptídeos , Precursores de Proteínas
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