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To report a typical case of Morvan syndrome with positive anti-leucine rich glioma-inactivated 1(LGI1) and contactin-associated protein 2 (CASPR2) antibodies in serum and cerebrospinal fluid. A 39-years-old female initially presented weakness of extremeties. The main symptoms included paroxysmal limb pain, wheezing, itching, muscle twitching, epilepsy, hypomnesia, dysphoria, apathy, intractable insomnia, salivation and sweating. Tests of electrolytes found hypokalemia (2.7-3.1 mmol/L) and hyponatremia (130-136 mmol/L). Arterial blood gas analysis showed hypoxemia (oxygen saturation 50%-70%). Total thyroxine (TT4) was elevated to 207 nmol/L with positive thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab). LGI1and CASPR2 antibodies (CBA method) were positive in both serum and cerebrospinal fluid, and the remaining antibodies related to autoimmune encephalitis and paraneoplastic syndrome were negative. Head MRI was almost normal, while mild abnormalities were found in electroencephalogram. Electromyography showed slightly increased voltage of left quadriceps motor unit potential. After treated with corticosteroids, IVIG and mycophenolate mofetil, the patient completely improved. Cognitive function scores recovered from MoCA/MMSE (16/24) to MoCA/MMSE (26/29). Positivity of LGI1/CASPR2 antibodies both in serum/cerebrospinal fluid are rarely seen in patients with Morvan syndrome. Steroids and immunosuppressants are suggested for treatment as early as possible.
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Encefalite , Epilepsia , Doença de Hashimoto , Adulto , Autoanticorpos , Feminino , HumanosRESUMO
To investigate the relationship between serum C-reactive protein (CRP) levels and work impairment in patients with ankylosing spondylitis (AS) based on real-world evidence. Outpatients with confirmed AS at Chinese PLA General Hospital were recruited consecutively by Smart-phone SpondyloArthritis Management System (SpAMS) from April 2016 to April 2018. The relationship between CRP and work productivity and activity impairment questionnaire (WPAI) were evaluated. Five hundred and fifty-one outpatients with AS in paid employment were recruited. The presenteeism, overall work impairment, and activity impairment rates increased by 1.4% (1.1%, 1.8%), 1.1% (0.5%, 1.6%), and 1.7% (1.3%, 2.1%), respectively, for every 10 mg/L increase in the CRP level (all P value<0.01). However, the CRP level was not associated with absenteeism after adjusting for covariates [0.5%(-0.4%, 1.0%),P>0.05]. There is a significant association between increased serum CRP levels at baseline and the previous 7-day work impairment in patients with AS. Higher CRP levels contribute to worse presenteeism, overall work impairment, and activity impairment rates, which suggests the necessity of monitoring CRP on treatment, and also indicates that anti-inflammatory therapy may be effective for improving work productivity.
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Espondilartrite , Espondilite Anquilosante , Proteína C-Reativa , China , Emprego , Humanos , Índice de Gravidade de Doença , Espondilite Anquilosante/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Objective: To investigate the relationship between high density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) and all-cause mortality in the elderly population. Methods: A total of 14 355 elderly persons aged ≥65 years, who participated in the annual physical examination in Kailuan Group in 2006 were included in this prospective cohort study. According to HDL-C level, the participants were divided into 4 groups: low-level group (HDL-C<1.30 mmol/L), intermediate-level group (1.30 mmol/L ≤HDL-C≤1.54 mmol/L), medium-high-level group (1.55 mmol/L ≤HDL-C≤1.80 mmol/L), high-level group (HDL-C≥1.81 mmol/L). Baseline data such as age, sex and blood lipid levels were collected and compared. Inpatient medical records and death information were obtained through the social security system, and CVD and all-cause mortality were analyzed. After adjusting for confounding factors, the medium-high-level group was used as the reference group. Cox proportional risk regression model was used to evaluate the impact of HDL-C on CVD and all-cause mortality events. The linear or nonlinear relationship between HDL-C level and CVD and all-cause mortality events was evaluated by restricted cubic spline regression model. Death competitive risk analysis was conducted, and sensitivity analysis was performed after excluding subjects with CVD or all-cause mortality within 1 year of follow-up and female participants. Results: The average age of this cohort was (71.5±5.5) years and follow-up time was (10.9±3.3) years. Compared with medium-high-level group, Cox proportional risk regression analysis showed that the HR (95%CI) of CVD and all-cause mortality in low-level group were 1.21 (1.06-1.38) (P<0.05) and 1.02 (0.95-1.11) (P>0.05), respectively; the HR (95%CI) of CVD events in high-level group was 1.17 (1.03-1.33) (P<0.05), and there was a marginal significant association with all-cause mortality, the HR (95%CI) was 1.07 (1.00-1.16) (0.05
0.1). Conclusions: In the elderly population, the risk of CVD is lowest when the HDL-C level is 1.55-1.80 mmol/L, either high or low HDL-C is a risk factor for CVD. High HDL-C tends to be related to increased risk of all-cause mortality and low HDL-C is not related to increased risk of all-cause mortality.
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Doenças Cardiovasculares , Idoso , HDL-Colesterol , Estudos de Coortes , Feminino , Humanos , Estudos Prospectivos , Fatores de RiscoRESUMO
In order to discuss the necessity of repeated renal arteriography in the treatment of severe bleeding after percutaneous nephrolithotomy, this study retrospectively analyzed the clinical data of patients with severe bleeding after percutaneous nephrolithotomy in the Department of Urology Surgery of the First Hospital of China Medical University from August 2010 to July 2020, summarily analyzing treatments, outcomes and follow-up results of 27 patients who were treated by renal arteriography more than twice. Of these 27 patients who underwent repeated renal arteriography, 23 of them were treated by two times, 4 by three times, all of whom were diagnosed as renal vascular injury. And 15 of them were diagnosed as pseudoaneurysm, 4 of them renal arteriovenous fistula, and 8 of them pseudoaneurysm combined with renal arteriovenous fistula. After clear diagnosis, all these patients were performed with renal artery embolization, after which the symptoms of hematuria and lumbar discomfort were relieved or disappeared immediately. These patients were followed up from 6 months to 5 years, without corresponding symptoms recurring and with the renal function equivalent to that before embolization. The results showed that repeated renal arteriography was of great significance in the treatment of patients with severe bleeding after percutaneous nephrolithotomy, helping to clarify the cause of bleeding and giving appropriate and timely treatment.
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Nefrolitotomia Percutânea , Nefrostomia Percutânea , Angiografia , Hemorragia , Humanos , Nefrolitotomia Percutânea/efeitos adversos , Estudos RetrospectivosRESUMO
Objective: Type 2 diabetes mellitus (T2DM) is a chronic condition resulting from insulin resistance and insufficient ß-cell secretion, leading to improper glycaemic regulation. Previous studies have found that excessive fat deposits in organs such as the liver and muscle can cause insulin resistance through lipotoxicity that affects ß-cell function. The relationships between fat deposits in pancreatic tissue, the function of ß-cells, the method of visceral fat evaluation and T2DM have been sought by researchers. This study aims to elucidate the role of pancreatic fat deposits in the development of T2DM using quantitative computed tomography (QCT), especially their effects on islet ß-cell function. Methods: We examined 106 subjects at the onset of T2DM who had undergone abdominal QCT. Estimated pancreatic fat and liver fat were quantified using QCT and calculated. We analysed the correlations with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores and other oral glucose tolerance test-derived parameters that reflect islet function. Furthermore, correlations of estimated pancreatic fat and liver fat with the area under the curve for insulin (AUCINS) and HOMA-IR were assessed with partial correlation analysis and demonstrated by scatter plots. Results: Associations were found between estimated liver fat and HOMA-IR, AUCINS, the modified ß-cell function index (MBCI) and Homeostatic Model Assessment ß (HOMA-ß). However, no significant differences existed between estimated pancreas fat and those parameters. Similarly, after adjustment for sex, age and body mass index, only estimated liver fat was correlated with HOMA-IR and AUCINS. Conclusions: This study suggests no significant correlation between pancreatic fat deposition and ß-cell dysfunction in the early stages of T2DM using QCT as a screening tool. The deposits of fat in the pancreas and the resulting lipotoxicity may play an important role in the late stage of islet cell function dysfunction as the course of T2DM progresses.
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Tecido Adiposo/diagnóstico por imagem , Diabetes Mellitus Tipo 2/diagnóstico , Células Secretoras de Insulina/patologia , Pâncreas/diagnóstico por imagem , Tecido Adiposo/patologia , Adulto , Glicemia/genética , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Resistência à Insulina/genética , Células Secretoras de Insulina/metabolismo , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Tomografia Computadorizada de EmissãoRESUMO
Presently, nonalcoholic fatty liver disease has become the most common pathogenic factor of chronic liver disease worldwide that can lead to the occurrence of hepatocellular carcinoma (HCC). Lipid metabolism in cancer cells is closely related to tumorgenesis, invasion and metastasis, and thus acts as one of the hallmark of cancer cells. Lipolipomics is an important branch of metabolomics, which has been adapted recently in the study of HCC for analysis of the structure and function of lipid components by chromatography and mass spectrometry. Fatty acids, glycerides, glycerophospholipids, sphingolipids, and sterol are significantly different in HCC tissues or serum. Therefore, it contributes to the diagnosis, determination of prognosis, mechanistic study and targeted therapy of HCC.
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Carcinoma Hepatocelular/diagnóstico , Lipídeos/análise , Neoplasias Hepáticas/diagnóstico , Metabolômica , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Humanos , Espectrometria de MassasRESUMO
The article "Fas/FasL induces myocardial cell apoptosis in myocardial ischemia-reperfusion rat model", by X.-M. Liu, Z.-M. Yang, X.-K. Liu, published in Eur Rev Med Pharmacol Sci 2017; 21 (12): 2913-2918- PMID: 28682425 has been retracted by the Editor in Chief. Following some concerns raised on PubPeer (link: https://pubpeer.com/publications/29CE1A59A8180E414855FA3871BCAC), the Editor in Chief has started an investigation to assess the validity of the results as well as possible figure manipulation. The authors were informed about the journal's investigation but remained unresponsive and have not provided the manuscript's raw data. The journal's investigation revealed a figure overlap between panels 10 U/mL and 100 U/mL in Figure 1. Consequently, the Editor in Chief mistrusts the results presented and has decided to retract the article. This article has been retracted. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/12953.
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Objective: To assess the efficacy of neoadjuvant treatment with PD-1 (programmed cell death protein 1) inhibitors combined with paclitaxel (albumin-conjugated) and cisplatin (TP regimen) for locally advanced hypopharyngeal squamous cell carcinoma and laryngeal organ function preservation. Methods: Data of 53 patients, including 51 males and 2 females, aged 38-70 years old, who were diagnosed with locally advanced hypopharyngeal squamous carcinoma confirmed by histology and enhanced CT at the Cancer Prevention and Control Center of Sun Yat-sen University during the initial treatment from January 1, 2019 to January 15, 2023, were retrospectively analyzed. All patients received neoadjuvant therapy with PD-1 inhibitors combined with albumin-bound paclitaxel (260 mg/m2) and cisplatin (60 mg/m2) for 3 to 4 cycles. The main outcome measures were larynx dysfunction-free survival (LDFS), overall survival (OS), and progression-free survival (PFS). Survival curves were plotted using the Kaplan-Meier method, and Cox multifactorial analysis was further performed if Cox univariate analysis was statistically significant. Results: The overall efficiency was 90.6% (48/53). The 1-year and 2-year LDFS rates were 83.8% (95%CI: 74.0% to 94.8%) and 50.3% (95%CI: 22.1% to 91.6%), the 1-year and 2-year OS rates were 95.2% (95%CI: 88.9% to 100.0%) and 58.2% (95%CI: 25.6% to 81.8%), and the 1-year and 2-year PFS rates were 83.9% (95%CI: 74.2% to 94.9%) and 53.5% (95%CI: 32.1% to 89.1%). Adverse events associated with the neoadjuvant therapy were mainly myelosuppression (45.3%), gastrointestinal reactions (37.7%) and hypothyroidism (20.8%). Conclusion: The neoadjuvant treatment of locally advanced hypopharyngeal squamous cell carcinoma using PD-1 inhibitors combined with paclitaxel and cisplatin can provide with a higher survival rate with a improved laryngeal organ function preservation rate.
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Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Neoplasias Hipofaríngeas , Terapia Neoadjuvante , Paclitaxel , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Cisplatino/uso terapêutico , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , Adulto , Idoso , Neoplasias Hipofaríngeas/terapia , Neoplasias Hipofaríngeas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Albuminas/uso terapêutico , Albuminas/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
A scheme to improve the bandwidth of slow light using cascaded vertical-cavity surface-emitting lasers (VCSELs) is proposed and experimentally demonstrated. In the scheme, a proper adjustment on the gain peaks of two cascaded VCSELs enables the generation of the desired composite gain spectrum, which has flat-top gain and delay profiles with enhanced peak values. By employing the improved gain and delay profiles in a slow light system, a large delay can be achieved within a wider bandwidth. In the experiment, by using two cascaded VCSELs, a tunable slow light up to 135 ps for a 5 Gbits/s pseudorandom binary sequence is demonstrated with relatively low signal distortion.
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Aim: Metformin is a first-line therapy for the treatment of Type 2 diabetes mellitus (T2DM), due to its inhibition of hepatic gluconeogenesis. Wingless family member 5a (Wnt5a) was significantly decreased in newly diagnosed T2DM patients and regulates secretion of ß cells through the Wnt/calcium signalling cascades. This study aims to investigate how metformin works on glucose-lowering effects in diabetes and whether the mechanism underlying it is associated with Wnt5a. Methods: A total of 144 participants were enrolled in this study. Serum Wnt5a levels were measured by an enzyme-linked immunosorbent assay (ELISA). The demographic and clinical parameters were evaluated in normal weight, overweight and obese new-onset T2DM subjects grouped. Results: Wnt5a was increased in overweight T2DM patients and obese T2DM patients compared with the levels in normal Body Mass Index (BMI) T2DM. The level of Wnt5a gradually increased after 3 and 6 months of metformin treatment. Among the three groups, the most significant improvement in blood glucose was observed in the obese type 2 diabetic patients, and the improvement showed a significant correlation with Wnt5a protein after patients received metformin treatment. Pearson correlation showed that there was a significant relationship between â³2hOGTT and Wnt5a. After further adjusting for sex and age, a significant association existed only between Wnt5a and 2-h oral glucose tolerance test(2hOGTT), and this association was negative. Conclusion: Our results indicate that Wnt5a may play a role in the mechanism by which metformin improves blood glucose in patients with type 2 diabetes.
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Objective: Previous studies have found that wnt5a promotes ß-cell insulin secretion and reduced concentrations in patients with type 2 diabetes. GLP-1RA (Glucagon-like peptide-1 receptor agonists) can regulate insulin secretion. However, the evidence that GLP-1RA affect insulin secretion through the Wnt5a is inconclusive. Therefore, this study aimed to evaluate the effect of GLP-1 RA on wnt5a levels in patients with type 2 diabetes. Methods: A total of 56 onset diabetics were selected our study, 29 of them were treated by GLP-1RAs (1.2mg subcutaneous injection once a day, liraglutide, Novo Nordisk), the rest (27 case) treated by Metformin (0.5 g twice a day, Glucophage, Merck). Individuals who were using medications to manage platelet (Aspirin) and cholesterol (Statins) were enrolled and continued treatment throughout the study. Results: Our study found that the waist circumference and insulin secretion index in the GLP-1RA intervention group were significantly increased, and the insulin resistance index was lower than that of the control group. More interestingly, the serum Wnt5a protein level increased dramatically after the GLP-1RA intervention, and the level of Secreted frizzled-related protein 5 (Sfrp5) decreased compared with the control group. Multivariate linear regression analysis showed that the change of HOMA-ß (Homeostasis model assessment- ß) was significantly correlated with the changes of Wnt5a and Sfrp5, and the change of Wnt5a protein was positively correlated with HOMA-ß. Conclusion: Our results confirmed that GLP-1RA may improve HOMA-ß in patients with type 2 diabetes by affecting the level of Wnt5a protein.
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Many efforts have been made to improve the neuron integration efficiency on neuromorphic chips, such as using emerging memory devices and shrinking CMOS technology nodes. However, in the fully connected (FC) neuromorphic core, increasing the number of neurons will lead to a square increase in synapse & dendrite costs and a high-slope linear increase in soma costs, resulting in an explosive growth of core hardware costs. We propose a co-designed neuromorphic core (SRCcore) based on the quantized spiking neural network (SNN) technology and compact chip design methodology. The cost of the neuron/synapse module in SRCcore weakly depends on the neuron number, which effectively relieves the growth pressure of the core area caused by increasing the neuron number. In the proposed BICS chip based on SRCcore, although the neuron/synapse module implements 1â¼16 times of neurons and 1â¼66 times of synapses, it only costs an area of 1.79 × 107 F2, which is 7.9%â¼38.6% of that in previous works. Based on the weight quantization strategy matched with SRCcore, quantized SNNs achieve 0.05%â¼2.19% higher accuracy than previous works, thus supporting the design and application of SRCcore. Finally, a cross-modeling application is demonstrated based on the chip. We hope this work will accelerate the development of cortical-scale neuromorphic systems.
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Redes Neurais de Computação , Neurônios , Neurônios/fisiologia , Computadores , Sinapses , TecnologiaRESUMO
OBJECTIVE: microRNAs (miRNAs) abnormal expression was proved to regulate the bladder cancer (BC) development. Here, we aimed to investigate the role of miR-335 played in BC. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to examine the miR-335 and CRKL (CT10 regulator of kinase-like protein) expression level in BC. Methyl thiazolyl tetrazolium (MTT) and RT-qPCR were used to examine cell viability of BC cells. Cell transwell assay was used to assess the migratory ability of BC cells. The direct target of miR-335 in BC was verified by luciferase reporter assay. RESULTS: The results showed that the expression of miR-335 and CRKL in normal and adjacent tissues showed no significant differences. Whereas, miR-335 expression in BC was significantly lower and CRKL expression was observably higher than normal. CRKL was verified as a specific target of miR-335 in BC cells and the relationship between CRKL and miR-335 expression was negatively correlated in BC tissues. Furthermore, CRKL siRNA group in BC cells remarkably inhibited cell proliferation and migration. MiR-335 mimic in BC cells remarkably curbed cell proliferation and migration and CRKL could reverse the proliferative and migratory ability of BC cells regulated by miR-335. CONCLUSIONS: miR-335 could suppress BC cell proliferation and migration by upregulating of CRKL.
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Proteínas Adaptadoras de Transdução de Sinal/genética , MicroRNAs/genética , Regulação para Cima , Neoplasias da Bexiga Urinária/patologia , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Gradação de Tumores , Neoplasias da Bexiga Urinária/genéticaRESUMO
BACKGROUND: Emerging evidence suggests that T2DM is attributable to the dysfunction of ß-cells and the activation of islet stellate cells (ISCs). The wingless-type MMTV integration site family member 5a (Wnt5a)/frizzled 5 (Fzd5) signalling pathway might take part in this process. Our study is aimed at defining the status of ISCs during ß-cell insulin secretion homeostasis by determining the role of the Wnt5a protein in the regulation of insulin production. We examined the effects of the status of ISCs on ß-cell insulin secretion in normoglycemic db/m and hyperglycaemic db/db mice. METHODS: iTRAQ protein screening and RNA interference were used to determine novel ISC-derived secretory products that may use other mechanisms to influence the function of islets. RESULTS: We showed a significant reduction in insulin secretion by ß-cells in vitro when they were cocultured with db/db ISCs compared to when they were cocultured with ISCs isolated from normoglycemic db/m mice; in addition, both Wnt5a and its receptor Fzd5 were more highly expressed by quiescent ISCs than by activated db/db ISCs. Treatment with exogenous Wnt5a increased the secretion of insulin in association with the deactivation of ISCs. CONCLUSION: Our observations revealed that the Wnt5a protein is a key effector of ISC-mediated improvement in islet function.
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[This corrects the article DOI: 10.1155/2019/7870109.].
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BACKGROUND: Obesity is strongly associated with insulin resistance and elevated plasma glucose levels. The rs9356744 polymorphism in the CDKAL1 gene is associated with body mass index (BMI) only in East Asians. Here, we examined the effect of the rs9356744 polymorphism on glucose-related traits and prediabetes in Chinese adults. METHODS: A total of 2 357 participants were enrolled from the Cardiometabolic Risk in Chinese (CRC) Study, including 499 persons with prediabetes, 204 persons with type 2 diabetes, and 1 654 normoglycemic controls. The rs9356744 polymorphism in CDKAL1 was genotyped and analyzed in all participants. RESULTS: Despite the positive relationship between obesity and glucose traits, the T allele of rs9356744, which is associated with a predisposition to obesity, was correlated with lower levels of 2-h oral glucose tolerance test (OGTT) plasma glucose (2hPG) (ß=- 0.2104 and P=0.0233), glycated hemoglobin (HbA1c) (ß=- 0.0551 and P=0.0298) and higher levels of homeostasis model of assessment ß-cell function (HOMA-B) (ß=5.282 and P=0.0424). After further adjustment for BMI, the levels of HOMA-B maintained a similar increased trend across rs9356744 genotype (ß=3.277 and P=0.1958). In stratified analyses, the associations of rs9356744 with 2hPG and HbA1c were significant for individuals with a low BMI. Moreover, an antagonism action of BMI and rs9356744 on 2hPG (P for interaction=0.0055) was observed. In addition, we found a protective effect of rs9356744 on prediabetes. CONCLUSIONS: The CDKAL1 rs9356744 T allele associated with a predisposition to obesity showed a protective effect on HbA1c, 2hPG, and prediabetes. BMI was mediator of the association between the genetic variant and HbA1c, 2hPG, and prediabetes.
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Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Estado Pré-Diabético/sangue , Estado Pré-Diabético/genética , tRNA Metiltransferases/genética , Adulto , Idoso , Índice de Massa Corporal , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Fatores de ProteçãoRESUMO
OBJECTIVE: Myocardium ischemia reperfusion is easy to induce myocardial injury. Fas/FasL is an important signaling pathway mediating cell apoptosis. This study aims to analyze the cell apoptosis and Fas/FasL expression in myocardial cell ischemia reperfusion rat model. MATERIALS AND METHODS: Coronary artery ligation method was used to establish myocardial ischemia reperfusion model. Rats were grouped according to different ischemia and reperfusion time: Group A, myocardial ischemia for 30 min and reperfusion for 24 h; Group B, myocardial ischemia for 30 min and reperfusion for 48 h; Group C, myocardial ischemia for 1 h and reperfusion for 24 h. Myocardial injury indicators were tested. Myocardial cell apoptosis was detected by transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay. Fas and FasL mRNA and protein expressions were evaluated by Real-time PCR (RT-PCR) and Western blot. RESULTS: Creatine kinase (CK), lactic dehydrogenase (LDH), and malondialdehyde (MDA) significantly elevated, while superoxide dismutase (SOD) obviously declined in the experimental group compared with control and blank group (p<0.05). CK, LDH, and MDA gradually upregulated, whereas SOD was reduced in experimental groups following the time extension of ischemia and reperfusion (p<0.05). Apoptosis cell number was markedly higher in the experimental group compared with control and blank group (p<0.05). Apoptosis cell number gradually increased in the experimental groups following ischemia and reperfusion time extension (p<0.05). Fas/FasL mRNA and protein markedly upregulated in the experimental group compared with control and blank group (p<0.05). Fas/FasL mRNA and protein expressions enhanced in experimental groups following the time extension of ischemia and reperfusion (p<0.05). CONCLUSIONS: Fas/FasL induces myocardial cell apoptosis in the process of myocardium ischemia reperfusion in rat model.
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Apoptose , Proteína Ligante Fas/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Receptor fas/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
The carcinogenic tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), both methylates and pyridyloxobutylates DNA. O6-Methylguanine (O6-mG) persistence has been correlated to NNK-induced lung tumor formation in A/J mice. The pyridyloxobutylation pathway enhances the tumorigenicity of the methylation pathway. In this paper we test the hypothesis that DNA pyridyloxobutylation increases O6-mG persistence by inhibiting the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Pyridyloxobutylated DNA was generated by reacting calf thymus DNA with the model pyridyloxobutylating agent 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) in the presence of esterase. The alkylated DNA inhibited the ability of partially purified rat liver AGT to repair O6-mG when it was incubated with AGT prior to the addition of 3H-methylated DNA. The extent of inhibition was dependent on the amount of NNKOAc reacted with DNA. The ability of NNKOAc-treated DNA to inhibit AGT was destroyed when the DNA was subjected to neutral thermal hydrolysis. Approximately 1 pmol of AGT was inhibited for every 25 to 50 pmol of 4-hydroxy-1-(3-pyridyl)-1-butanone- releasing adducts present in NNKOAc-treated DNA. The inhibitory activity of this alkylated DNA was relatively stable under physiological conditions (pH 7.4, 37 degrees C). Only 13% of the AGT reactive activity was lost after 7 days. When pyridyloxobutylated DNA was incubated simultaneously with 3H-methylated DNA and AGT, a significant reduction in [3H]methyl transfer to AGT was observed. The levels of reduction were similar to those observed when unlabeled methylated DNA containing comparable levels of O6-mG was substituted for NNKOAc-treated DNA. Based on these results, a cocarcinogenic role for pyridyloxobutylation in NNK-induced lung tumorigenesis is proposed in which pyridyloxobutyl DNA adduct(s) compete with O6-mG for reaction with AGT resulting in sustained levels of O6-mG. These enhanced levels then increase the probability of tumor induction by NNK.