RESUMO
PURPOSE: Only few studies have analyzed the global distribution of anesthesia research. This study was designed to reveal the current global research status of anesthesiology. METHODS: Articles published between 1999 and 2018 in international journals in the field of anesthesiology were retrieved from the PubMed database. The top 20 ranked countries were identified. The gross domestic product (GDP) of each country was also retrieved to reveal the correlation between research outputs and the economy. The total outputs and outputs per 10 million inhabitants in each country were calculated and compared. To analyze the quality of publications among the top 10 ranked countries, the impact factor (IF), article influence score (AIS), and immediacy index (ImI) were calculated and analyzed. In addition, the keywords of publications were retrieved to conduct co-occurrence analysis in order to determine the research focus in anesthesiology. RESULTS: A total of 112,918 articles were published in 30 selected journals from 1999 to 2018. There was a positive correlation between research outputs and GDP of 10 countries (pâ¯< 0.001, râ¯= 0.825). The USA ranked 1st with 21,703 articles, followed by the UK (8393 articles) and Germany (6504 articles). Canada had the highest number of publications per 10 million inhabitants in 2018. The UK had the highest average IF (4.70), average AIS (1.16), and average ImI (1.64) among the 10 countries. The research highlights in the field of anesthesiology included "mechanism and management of pain", "cardiac anesthesia", "pediatric anesthesia and airway management", "analgesia" and "anesthetic agents". CONCLUSION: Regarding quantity trend, the output of global production in anesthesiology increased continuously as the number of articles from the high-output countries showed an increasing trend; however, there was still a gap between developing and developed countries in research quality. High-quality research should be encouraged in developing countries.
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Anestesia , Anestesiologia , Bibliometria , Criança , Alemanha , HumanosRESUMO
BACKGROUND AND AIM: Diabetes mellitus (DM) is a common complication of idiopathic chronic pancreatitis (ICP), which impairs the quality of life for patients. This study aimed to identify risk factors and develop nomogram for DM in ICP to help early diagnosis. METHODS: Idiopathic chronic pancreatitis patients admitted to our center from January 2000 to December 2013 were included. Cumulative rates of DM were calculated by Kaplan-Meier method. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. Based on training cohort, risk factors for DM were identified through Cox proportional hazards regression model, and nomogram was developed. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: Totally, 1633 patients with ICP were finally enrolled. The median follow-up duration was 9.8 years. DM was found in 26.3% (430/1633) of patients after the onset of CP. Adult at onset of ICP, biliary stricture at/before diagnosis of CP, steatorrhea at/before diagnosis of CP, and complex pathologic changes in main pancreatic duct were identified risk factors for DM development. The nomogram achieved good concordance indexes in the training and validation cohorts, respectively, with well-fitted calibration curves. CONCLUSIONS: Risk factors were identified, and nomogram was developed to determine the risk of DM in ICP patients. Patients with one or more of the risk factors including adult at onset of ICP, biliary stricture at/before diagnosis of CP, steatorrhea at/before diagnosis of CP, and complex pathologic changes in main pancreatic duct have higher incidence of DM.
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Diabetes Mellitus/etiologia , Nomogramas , Pancreatite Crônica/complicações , Idade de Início , Ductos Biliares/patologia , Constrição Patológica , Humanos , Ductos Pancreáticos/patologia , Fatores de Risco , EsteatorreiaRESUMO
CD97 belongs to the adhesion GPCR family characterized by a long ECD linked to the 7TM via a GPCR proteolytic site (GPS) and plays important roles in modulating cell migration and invasion. CD97 (EGF1-5) is a splicing variant of CD97 that recognizes a specific ligand chondroitin sulfate on cell membranes and the extracellular matrix. The aim of this study was to elucidate the extracellular molecular basis of the CD97 EGF1-5 isoform in protein expression, auto-proteolysis and cell adhesion, including epidermal growth factor (EGF)-like domain, GPCR autoproteolysis-inducing (GAIN) domain, as well as GPS mutagenesis and N-glycosylation. Both wild-type (WT) CD97-ECD and its truncated, GPS mutated, PNGase F-deglycosylated, and N-glycosylation site mutated forms were expressed and purified. The auto-proteolysis of the proteins was analyzed with Western blotting and SDS-PAGE. Small angle X-ray scattering (SAXS) and molecular modeling were used to determine a structural profile of the properly expressed receptor. Potential N-glycosylation sites were identified using MS and were modulated with PNGase F digestion and glyco-site mutations. A flow cytometry-based HeLa cell attachment assay was used for all aforementioned CD97 variants to elucidate the molecular basis of CD97-HeLa interactions. A unique concentration-dependent GPS auto-proteolysis was observed in CD97 EGF1-5 isoform with the highest concentration (4 mg/mL) per sample was self-cleaved much faster than the lower concentration (0.1 mg/mL), supporting an intermolecular mechanism of auto-proteolysis that is distinct to the reported intramolecular mechanism for other CD97 isoforms. N-glycosylation affected the auto-proteolysis of CD97 EGF1-5 isoform in a similar way as the other previously reported CD97 isoforms. SAXS data for WT and deglycosylated CD97ECD revealed a spatula-like shape with GAIN and EGF domains constituting the body and handle, respectively. Structural modeling indicated a potential interaction between the GAIN and EGF5 domains accounting for the absence of expression of the GAIN domain itself, although EGF5-GAIN was expressed similarly in the wild-type protein. For HeLa cell adhesion, the GAIN-truncated forms showed dramatically reduced binding affinity. The PNGase F-deglycosylated and GPS mutated forms also exhibited reduced HeLa attachment compared with WT CD97. However, neither N-glycosylation mutagenesis nor auto-proteolysis inhibition caused by N-glycosylation mutagenesis affected CD97-HeLa cell interactions. A comparison of the HeLa binding affinities of PNGase F-digested, GPS-mutated and N-glycosylation-mutated CD97 samples revealed diverse findings, suggesting that the functions of CD97 ECD were complex, and various technologies for function validation should be utilized to avoid single-approach bias when investigating N-glycosylation and auto-proteolysis of CD97. A unique mechanism of concentration-dependent auto-proteolysis of the CD97 EGF1-5 isoform was characterized, suggesting an intermolecular mechanism that is distinct from that of other previously reported CD97 isoforms. The EGF5 and GAIN domains are likely associated with each other as CD97 expression and SAXS data revealed a potential interaction between the two domains. Finally, the GAIN and EGF domains are also important for CD97-HeLa adhesion, whereas N-glycosylation of the CD97 GAIN domain and GPS auto-proteolysis are not required for HeLa cell attachment.
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Antígenos CD/metabolismo , Adesão Celular/fisiologia , Proteólise , Antígenos CD/genética , Glicosilação , Células HeLa , Humanos , Modelos Estruturais , Mutagênese , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo , Isoformas de Proteínas/metabolismo , Receptores Acoplados a Proteínas GRESUMO
Acute pancreatitis (AP) is a common digestive disease encountered in Emergency Departments that carries a heavy socioeconomic burden. This study was conducted to determine the global status of AP research. Articles related to AP published in 1999 to 2018 were retrieved from the Web of Science (WOS) database and the 20 highest-output countries or regions were determined based on the total number of publications. Correlation analysis of AP research output and the gross domestic product (GDP) of each country or region was conducted. The quantity and quality of research of these 20 highest-output countries were compared to the total output, outputs per capita, and average impact factor (IF). All annual data were analyzed using time-trend analysis. A keyword co-occurrence analysis was conducted to determine the highlights in AP research. In total, 17,698 publications were retrieved, and 16,461 papers (93.0%) of them were from the 20 highest-output countries. A significantly positive correlation was identified between AP research output and the GDP (R = 0.973, P < .001). The 5 highest-output countries were the USA (24.9%), China (12.3%), Germany (7.5%), Japan (6.7%), and the UK (6.1%). Finland ranked 1st in the number of publication per capita, the USA had the highest accumulated IF (25,432.758) and total citations (104,592), Switzerland had the highest average IF (6.723), and Netherland had the highest average citations (51.90). Genetic research and AP-related hyperglycemia were research highlights. Analysis of the global output of research of AP research showed signs of growth. Research output was positively correlated with GDP. For the most productive countries, research quality was stable. Although developing countries lagged behind in output per capita and quality, great progress has been made in the past 2 decades.
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Pesquisa Biomédica , Pancreatite , Doença Aguda , Bibliometria , Alemanha , Humanos , Pancreatite/epidemiologiaRESUMO
PURPOSE: Endoscopic retrograde cholangiopancreatography (ERCP) has been used in clinical practice for over 50 years. This study aims to investigate the current state of research in the field of ERCP. METHODS: Web of Science database was searched using the term "ERCP" for articles published between 1994 and 2018. The total number of articles from the top 20 countries with the most published articles was determined. The top 5 countries were compared in terms of output per capita, number of articles published in top journals, cumulative impact factor (IF), and average IF. All annual data were subjected to time-trend analysis. The frequently used terms in the titles and abstracts of all articles were retrieved to conduct co-occurrence analysis to determine the research focus of ERCP. RESULTS: A total of 9960 articles on ERCP were published between 1994 and 2018, of which 8778 articles were from the top 20 producing countries. There was a significant positive correlation between the output and GDP of each country (R = 0.870, P = .001). The United States of America (USA), Japan, Germany, Italy, and China were the top 5 producing countries with 3190 (32.0%), 868 (8.7%), 658 (6.6%), 512 (5.1%) and 488 (4.9%) articles published, respectively. The USA, Japan, Italy, and China were trending upwards in the total outputs and outputs per capita, while Germany were trending downwards. For average IF, Germany had a downwards trend, while the other 4 countries remained stable. Overall, the USA had the highest output per capita (97.5/10 million) and the highest average IF (6.454). China had the lowest output per capita (3.5/10 million) and average IF (3.125). The ERCP procedures for sphincter of Oddi dysfunction, the combination of ERCP, and laparoscopic cholecystectomy have been the research focus of ERCP. CONCLUSIONS: Except for Germany, research on ERCP will continue to increase in the top-producing countries. The outputs per capita and quality of articles from developed countries are higher than those from developing countries.
Assuntos
Pesquisa Biomédica , Colangiopancreatografia Retrógrada Endoscópica , Bibliometria , Alemanha , Humanos , Publicações , Estados UnidosRESUMO
BACKGROUND: There is huge shortage of ERCP practitioners (ERCPists) in China, and ERCP training is urgently needed. ChangHai Advanced eNdoscopy Courses for ERCP (CHANCE) is a 4-month program for ERCP training since 2004. This study evaluated the efficiency of this short-term training model, and reported on the ERCP careers of the trainees following completion of the CHANCE program. METHODS: This study was a retrospective investigation included all the CHANCE trainees from Jan 2004 to Dec 2014. Questionnaires were sent to all trainees. The career competence percentage, ERCP careers and predictive factors of career competence were investigated and analyzed. RESULTS: A total of 413 trainees participated in the CHANCE program over 11 years covered by the survey and 258 questionnaires were valid for the study. The mean (SD) age of the trainees was 35.36 (4.17), and the male to female ratio was 4.4:1. The average follow-up time was 7.77 (3.44) years. A total of 173 (67.1%) trainees had achieved career competence. In terms of ERCP careers, the mean annual ERCP volume was 120.60 (96.67), with a complication percentage of 8.2%. Hospital qualification, compliance with follow-up learning guidance, participating academic activity, and practitioner type were identified predictive factors of career competence. CONCLUSIONS: As a short-term training program, the CHANCE achieved an acceptable career competence percentage, providing endoscopists more chances to learn ERCP and giving them appropriate training guidance for career competence. This training mode is worth promoting in developing countries with shortage of ERCPists.
Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Competência Clínica , Endoscopia Gastrointestinal , Feminino , Humanos , Masculino , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Steatorrhea, a sign of severe pancreatic exocrine insufficiency (PEI), is related to consequences caused by pancreatitis. This study aimed to identify predictors and to construct a nomogram for steatorrhea in idiopathic chronic pancreatitis (ICP). METHODS: ICP patients admitted to our hospital from January 2000 to December 2013 were enrolled in this retrospective-prospective cohort study and randomly assigned to the training and validation cohorts. The cumulative rate of steatorrhea was calculated. A Cox proportional hazard regression model was used to identify predictors for steatorrhea and construct the nomogram. Internal and external validation of the nomogram was then performed. RESULTS: There were 1633 ICP patients enrolled, with a median follow-up duration of 9.8 years and 20.8% (339/1633) of patients developed steatorrhea following onset of ICP. Steatorrhea was observed in 93, 115, and 133 patients at 1, 3, and 5 years following diagnosis of CP, with a cumulative rate of 6.5% (95% confidence interval [CI] 5.1%-7.9%), 8.0% (95% CI 6.2%-9.8%), and 9.3% (95% CI 6.6%-12.0%), respectively. Male sex (hazard ratio [HR] 2.479, P < 0.001), diabetes mellitus at/before diagnosis of ICP (HR 2.274, P = 0.003), and aged less than 18 years at onset of ICP (HR 0.095, P < 0.001) were identified risk factors for steatorrhea. Initial manifestations were associated with development of steatorrhea. The nomogram was proven to have good concordance indexes. CONCLUSIONS: We identified predictors and developed a nomogram for predicting steatorrhea in ICP. It was recommended that high-risk populations be followed up closely, which might contribute to the early diagnosis and treatment of PEI.
Assuntos
Insuficiência Pancreática Exócrina , Pancreatite Crônica , Esteatorreia , Insuficiência Pancreática Exócrina/etiologia , Análise Fatorial , Feminino , Humanos , Masculino , Nomogramas , Pancreatite Crônica/complicações , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Esteatorreia/complicaçõesRESUMO
BACKGROUND: Accumulating evidence has shown the important role of the inflammatory process in the pathophysiology of mental disorders. However, the relative levels of inflammatory markers in patients with panic disorder (PD) have rarely been evaluated. The aim of the present study was to conduct a systematic review to determine the correlation of peripheral C-reactive protein (CRP) and inflammatory cytokine profiles with PD. METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched for quantitative research studies published up to July 31, 2021 that measured peripheral levels of CRP and inflammatory cytokines in people with PD compared with controls. Meta-analysis using a random-effects model was performed for the levels of CRP and inflammatory cytokines with data from three or more studies. RESULTS: Fourteen identified studies met the inclusion criteria. In total, 18 cytokines were evaluated. Markers that were reported in more than 3 studies were included in this meta-analysis. The results showed that peripheral levels of CRP, IL-6, IL-2 and TNF-α were significantly higher in PD patients than in healthy controls, while there was no significant difference in peripheral levels of IL-1ß, IL-10 and IFN-γ between groups. Notably, the relevant studies involving IL-6, IL-1ß, IL-10 and IFN-γ in PD patients were highly heterogeneous. Similar to meta-analyses of other inflammatory factors in mental disorders, our meta-analysis also reflected differences in participant medication use, comorbid anxiety or depression, sampling methods and detection methods. Eight inflammatory cytokines were reported in only one study, and their expression levels were higher, lower, or unchanged compared with those in healthy controls. CONCLUSION: There is preliminary evidence to suggest a significant inflammatory response in PD patients, but the role of inflammatory markers in PD remains unclear. Studying inflammatory markers in PD will help to clarify the etiology and pathophysiological mechanisms of the disorder.
RESUMO
BACKGROUND: There are no reports on global research status of gastroenterology and hepatology (GI). This study was conducted to reveal the current global research status and trends in GI. METHODS: Articles published during 2009 to 2018 in international GI journals were retrieved from the PubMed database. The top 20 countries by output were determined. The gross domestic product (GDP) of each country was also retrieved to figure out the correlation between outputs in GI and economy. The 5 highest-ranking countries were compared in the number of total articles, articles per capita, articles published in top journals, the accumulated impact factor (IF), and average IF. Total articles and articles per capita of the 5 countries were conducted time-trend analysis. The frequently-used terms in titles and abstracts of articles published in 2009 and 2018 were retrieved to conduct co-occurrence analysis to figure out the change of research highlights in GI. RESULTS: A total of 120,267 articles were included, of which 116,485 articles were from 20 highest-output countries. There was a positive correlation between output and GDP (râ=â0.921, Pâ<â.001). The USA, Japan, China, Italy, and the UK were the 5 highest-ranking countries. The USA was the largest contributor with 26,215 articles, accounting for 17.4% of the total, but with no significant increasing trend (Pâ=â.122). Other 4 countries all showed increasing trends (all Pâ<â.001). For articles per capita, Italy ranked 1st among the 5 countries with 1591.0 articles per 10 million. The USA showed a decreasing trend (Pâ=â.026), other 4 countries all showed increasing trends (all Pâ<â.001). The UK had the highest average IF (6.685). For change of research highlights, it is more inclined to research of endoscopy, inflammatory bowel diseases, and nonalcoholic fatty liver disease. CONCLUSION: It is delightful that the global research output in GI field would be continuingly increased as the major highest-output countries showed increasing trends. However, the developing countries fell behind both in quantity and quality when compared with developed countries.
Assuntos
Bibliometria , Pesquisa Biomédica/estatística & dados numéricos , Gastroenterologia/estatística & dados numéricos , Países Desenvolvidos/estatística & dados numéricos , Gastroenterologia/classificação , Humanos , Hepatopatias/terapiaRESUMO
OBJECTIVE: The aim of the study was to investigate the global research levels in chronic pancreatitis (CP) fields. METHODS: The term "chronic pancreatitis" was used to retrieve articles published between 2009 and 2018 from the Web of Science database. The 15 highest-output countries' gross domestic product was retrieved to analyze the correlation between output and economic development. The 5 top-ranking countries were compared in quantity and quality. The frequently used terms of all articles were retrieved to conduct co-occurrence analysis to reveal research highlights for CP. RESULTS: There were 6094 articles included and 6007 articles were from 15 highest-output countries. There was a positive correlation between output and gross domestic product (r = 0.928, P < 0.001). The United States, China, and Japan had increasing trends in total output (P = 0.022, P < 0.001, and P = 0.021, respectively). China and Japan had increasing trends in output per capita (P < 0.001 and P = 0.023). However, in average impact factor, all 5 countries did not show increasing trends (all P > 0.05). For research highlights, mass lesion and autoimmune pancreatitis were the notable aspects. CONCLUSIONS: The global output for CP will continue increasing and research quality will be stable.
Assuntos
Pesquisa Biomédica/tendências , Gastroenterologia/tendências , Pancreatite Crônica , Publicações Periódicas como Assunto/tendências , Animais , Bibliometria , Humanos , Fator de Impacto de Revistas , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/terapiaRESUMO
Bimodal classification of idiopathic chronic pancreatitis (ICP) into early-onset (<35 years) and late-onset (>35 years) ICP was proposed in 1994 based on a study of 66 patients. However, bimodal distribution wasn't sufficiently demonstrated. Our objective was to examine the validity and relevance of the age-based bimodal classification of ICP. We analyzed the distribution of age at onset of ICP in our cohort of 1633 patients admitted to our center from January 2000 to December 2013. Classify ICP patients into early-onset ICP(a) and late-onset ICP(a) according to different cut-off values (cut-off value, a = 15, 25, 35, 45, 55, 65 years old) for age at onset. Compare clinical characteristics of early-onset ICP(a) and late-onset ICP(a). We found slightly right skewed distribution of age at onset for ICP in our cohort. There were differences between early-onset and late-onset ICP with respect to basic clinical characteristics and development of key clinical events regardless of the cut off age at onset i.e. 15, 25, 35, 45 or even higher. The validity of the bimodal classification of early-onset and late-onset ICP could not be established in our large patient cohort and therefore such a classification needs to be reconsidered.
Assuntos
Pancreatite Crônica/classificação , Adolescente , Adulto , Idade de Início , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite Crônica/patologia , Reprodutibilidade dos Testes , Adulto JovemRESUMO
OBJECTIVE: The study concerns identifying risk factors and developing nomogram for pancreatic pseudocyst (PPC) in idiopathic chronic pancreatitis (ICP) to facilitate early diagnosis. METHODS: From January 2000 to December 2013, ICP patients admitted to our center were enrolled. Cumulative incidence of PPC was determined by Kaplan-Meier method. Patients were randomized into training group and validation group in a 2:1 ratio. Risk factors of PPC were determined through Cox proportional hazards regression model based on training cohort. The nomogram was constructed according to risk factors. RESULTS: Totally, 1633 ICP patients were included with a median follow-up duration of 9.8 years. Pancreatic pseudocyst was observed in 14.7% (240/1633) of patients after ICP onset. The cumulative incidences of PPC were 8.2%, 10.4%, and 12.9% at 3, 5, and 10 years after ICP onset, respectively. Male sex, smoking history, history of severe acute pancreatitis, and chronic pain at/before diagnosis of ICP and complex pathologic changes in main pancreatic duct were recognized as risk factors of PPC development. The nomogram constructed with these risk factors achieved good concordance indexes. CONCLUSIONS: Risk for PPC could be estimated through the nomogram. High-risk patients were suggested to be followed up closely to help early diagnosis of PPC.
Assuntos
Nomogramas , Pseudocisto Pancreático/diagnóstico , Pancreatite Crônica/diagnóstico , Medição de Risco/estatística & dados numéricos , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pseudocisto Pancreático/etiologia , Pancreatite Crônica/complicações , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Medição de Risco/métodos , Fatores de RiscoRESUMO
The His-x-Asp (HxD) motif is one of the most conserved structural components of the catalytic core of protein kinases; however, the functional role of the conserved histidine is unclear. Here we report that replacement of the HxD-histidine with Arginine or Phenylalanine in Aurora A abolishes both the catalytic activity and auto-phosphorylation, whereas the Histidine-to-tyrosine impairs the catalytic activity without affecting its auto-phosphorylation. Comparisons of the crystal structures of wild-type (WT) and mutant Aurora A demonstrate that the impairment of the kinase activity is accounted for by (1) disruption of the regulatory spine in the His-to-Arg mutant, and (2) change in the geometry of backbones of the Asp-Phe-Gly (DFG) motif and the DFG-1 residue in the His-to-Tyr mutant. In addition, bioinformatics analyses show that the HxD-histidine is a mutational hotspot in tumor tissues. Moreover, the H174R mutation of the HxD-histidine, in the tumor suppressor LKB1 abrogates the inhibition of anchorage-independent growth of A549 cells by WT LKB1. Based on these data, we propose that the HxD-histidine is involved in a conserved inflexible organization of the catalytic core that is required for the kinase activity. Mutation of the HxD-histidine may also be involved in the pathogenesis of some diseases including cancer.
Assuntos
Domínio Catalítico , Sequência Conservada , Histidina/metabolismo , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Motivos de Aminoácidos , Arginina/genética , Aurora Quinase A/química , Aurora Quinase A/genética , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Mutação/genética , Conformação Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Relação Estrutura-Atividade , Tirosina/genética , Difração de Raios XRESUMO
Considerable studies indicate huperzine A is a promising natural product to suppress neuronal damages induced by ß-amyloid (Aß), a key pathogenic event in the Alzheimer's disease (AD). As an extension, the present study for the first time explored whether the beneficial profiles of huperzine A against oligomeric Aß(42) induced neurotoxicity are associated with the accumulation and detrimental function of intraneuronal/mitochondrial Aß, on the basis of the emerging evidence that intracellular Aß is more relevant to AD progression as compared with extracellular Aß. Huperzine A treatment was shown to significantly attenuate the neurotoxicity of oligomeric Aß(42), as demonstrated by increased neuronal viability. Interestingly, our results proved that exogenous Aß(42) could accumulate intraneuronally in a dose- and time-dependent manner, while huperzine A treatment markedly reduced the level of intracellular Aß(42). Moreover, huperzine A treatment rescued mitochondrial dysfunction induced by oligomeric Aß(42), including adenosine triphosphate (ATP) reduction, reactive oxygen species (ROS) overproduction and membrane potential depolarization. Further study demonstrated that huperzine A also significantly reduced the level of Aß(42) in the mitochondria-enriched subcellular fractions, as well as the Aß(42) fluorescent signals colocalized with mitochondrial marker. This study indicates that interfering intracellular Aß especially mitochondrial Aß accumulation, together with ameliorating Aß-associated mitochondrial dysfunction, may contribute to the protective effects of huperzine A against Aß neurotoxicity. Above results may shed more light on the pharmacological mechanisms of huperzine A and provide important clues for discovering novel therapeutic strategies for AD.
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Alcaloides/farmacologia , Peptídeos beta-Amiloides/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Mitocôndrias/patologia , Neurônios/patologia , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.
Assuntos
Arsênio/metabolismo , Arsenicais/metabolismo , Arsenicais/farmacologia , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Óxidos/metabolismo , Óxidos/farmacologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Trióxido de Arsênio , Linhagem Celular , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutação , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/genética , Oxazinas/metabolismo , Proteína da Leucemia Promielocítica , Conformação Proteica , Multimerização Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores do Ácido Retinoico/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Receptor alfa de Ácido Retinoico , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Fatores de Transcrição/química , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Ubiquitinação , Dedos de ZincoRESUMO
Pond aquaculture has existed in China for thousands of years, which has not only contributed great economic value, but also presented cultural value for human beings. With the development and upgrading of Chinese economy and culture, these values will be highlighted further. To evaluate the cultural service value of pond aquaculture ecosystem would provide a scientific base to the policy-making to avoid or reduce the wrong design-making or avoid the policy-malfunction, and also, to promote the development of aquaculture and related recreational fishing industry, increase the added value of aquaculture and the income of fish-farmers, and promote the economic development of rural area. Based on the survey data from the aquaculture ponds in the water conservation area of Dianshan Lake in Qingpu District of Shanghai and the related statistical data, the cultural service value including recreational value and existence value of the aquaculture pond ecosystem in the area was estimated by means of travel cost method (TCM) and contingent valuation method (CVM). The total cultural service value of this ecosystem was about 213 million Yuan x a(-1) or 231296. 69 Yuan x hm(-2) x a(-1), being 5. 25 times of the market value of aquaculture products, among which, recreational value was about 189 million Yuan x a(-1), and existence value was about 24 million Yuan x a(-1). It was suggested that in the construction of new rural areas of Shanghai, sufficient attention should be paid on the full play of the cultural service value of aquaculture pond ecosystem.