RESUMEN
Eggs, an important part of a healthy daily diet, can protect chicken embryo development due to the shell barrier and various antibacterial components within the egg white. Our previous study demonstrated that Salmonella Pullorum, highly adapted to chickens, can survive in the egg white and, therefore, be passed to newly hatched chicks. However, the survival strategy of Salmonella Pullorum in antibacterial conditions remains unknown. The overall transcripts in the egg white showed a large-scale shift compared to LB broth. The expression of common response genes and pathways, such as those involved in iron uptake, biotin biosynthesis, and virulence, was significantly changed, consistent with the other transovarial transmission serovar Enteritidis. Notably, membrane stress response, amino acid metabolism, and carbohydrate metabolism were specifically affected. Additional upregulated functionally relevant genes (JI728_13095, JI728_13100, JI728_17960, JI728_10085, JI728_15605, and nhaA) as mutants confirmed the susceptible phenotype. Furthermore, fim deletion resulted in an increased survival capacity in the egg white, consistent with the downregulated expression. The second-round RNA-Seq analysis of the Δfim mutant in the egg white revealed significantly upregulated genes compared with the wild type in the egg white responsible for energy metabolism located on the hyc and hyp operons regulated by FhlA, indicating the Δfim mutant cannot receive enough oxygen and switched to fermentative growth due to its inability to attach to the albumen surface. Together, this study provides a first estimate of the global transcriptional response of Salmonella Pullorum under antibacterial egg white and highlights the new potential role of fim deletion in optimizing energy metabolism pathways that may assist vertical transmission. IMPORTANCE: Pullorum disease, causing serious embryo death and chick mortality, results in substantial economic losses worldwide due to transovarial transmission. Egg-borne outbreaks are frequently reported in many countries. The present study has filled the knowledge gap regarding how the specific chicken-adapted pathogen Salmonella Pullorum behaves within the challenging environment of egg white. The deletion of the fim fimbrial system can increase survival in the albumen, possibly by reprogramming metabolism-related gene products, which reveals a new adaptive strategy of pathogens. Moreover, the comparison, including previous research on Salmonella Enteritidis, capable of vertical transmission, aims to provide diversified data sets in the field and further help to implement reasonable and effective measures to improve both food safety and animal health.
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Pollos , Clara de Huevo , Metabolismo Energético , Metabolismo Energético/genética , Animales , Clara de Huevo/microbiología , Pollos/microbiología , Salmonelosis Animal/microbiología , Regulación Bacteriana de la Expresión Génica , Virulencia , Viabilidad Microbiana , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Enfermedades de las Aves de Corral/microbiologíaRESUMEN
Salmonellosis is one of the most common causes of diarrhea, affecting 1/10 of the global population. Salmonellosis outbreaks (SO) pose a severe threat to the healthcare systems of developing regions. To elucidate the patterns of SO in China, we conducted a systematic review and meta-analysis encompassing 1,134 reports across 74 years, involving 89,050 patients and 270 deaths. A rising trend of SO reports has been observed since the 1970s, with most outbreaks occurring east of the Hu line, especially in coastal and populated regions. It is estimated to have an overall attack rate of 36.66% (95% CI, 33.88-39.45%), and antimicrobial resistance towards quinolone (49.51%) and beta-lactam (73.76%) remains high. Furthermore, we developed an online website, the Chinese Salmonellosis Outbreak Database (CSOD), for visual presentation and data-sharing purposes. This study indicated that healthcare-associated SO required further attention, and our study served as a foundational step in pursuing outbreak intervention and prediction.
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Brotes de Enfermedades , Infecciones por Salmonella , Humanos , China/epidemiología , Infecciones por Salmonella/epidemiología , Infecciones por Salmonella/microbiología , Antibacterianos/farmacología , Farmacorresistencia BacterianaRESUMEN
Infectious disease outbreaks transcend the medical and public health realms, triggering widespread panic and impeding socio-economic development. Considering that self-limiting diarrhoea of sporadic cases is usually underreported, the Salmonella outbreak (SO) study offers a unique opportunity for source tracing, spatiotemporal correlation, and outbreak prediction. To summarize the pattern of SO and estimate observational epidemiological indicators, 1,134 qualitative reports screened from 1949 to 2023 were included in the systematic review dataset, which contained a 506-study meta-analysis dataset. In addition to the dataset comprising over 50 columns with a total of 46,494 entries eligible for inclusion in systematic reviews or input into prediction models, we also provide initial literature collection datasets and datasets containing socio-economic and climate information for relevant regions. This study has a broad impact on advancing knowledge regarding epidemic trends and prevention priorities in diverse salmonellosis outbreaks and guiding rational policy-making or predictive modeling to mitigate the infringement upon the right to life imposed by significant epidemics.
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Brotes de Enfermedades , Intoxicación Alimentaria por Salmonella , Infecciones por Salmonella , Humanos , China/epidemiología , Recolección de Datos , Salmonella , Intoxicación Alimentaria por Salmonella/epidemiología , Infecciones por Salmonella/epidemiología , Revisiones Sistemáticas como Asunto , Metaanálisis como AsuntoRESUMEN
BACKGROUND: The triglyceride glucose-body mass index (TyG-BMI) has been considered a surrogate marker for assessing insulin resistance. We aimed to correlate the TyG-BMI, triglyceride glucose combined with body mass index, with femoral neck bone mineral density (FN BMD) in non-diabetic elderly men. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) database, totally, 1182 eligible men aged ≥ 50 years without diabetes were included in the current study. Smoothed curves were obtained by a two-piecewise linear regression model and the threshold effects were explored by using a smoothing function. RESULTS: TyG-BMI was positive related with and FN BMD with or without adjustment for confounders. However, no typical dose-dependent positive association between TyG-BMI and FN BMD was observed across the TyG-BMI tertiles, indicating a non-linear association. Further analysis by the weighted two-piecewise linear regression model and recursive algorithm suggested that per SD increase in TyG-BMI increased FN BMD by 0.266 gm/cm2 when TyG-BMI lower than 168.20. However, when TyG-BMI is higher than 168.20, FN BMD only increased 0.046 gm/cm2 for per SD increase of TyG-BMI after fully adjustment (OR = 11.258, 95%CI: 6.034, 16.481). Moreover, subgroup analyses showed that higher TyG-BMI levels were related to elevated FN BMD in all groups, suggesting the consistency of the positive association within these stratas. CONCLUSIONS: This study demonstrated that TyG-BMI is positively associated with FN BMD in a nonlinear fashion among elderly men without diabetes, which may be a reliable marker for the early identification of individuals with lower FN BMD.
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Diabetes Mellitus , Cuello Femoral , Anciano , Masculino , Humanos , Índice de Masa Corporal , Encuestas Nutricionales , Glucosa , TriglicéridosRESUMEN
Background: Serum triglyceride (TG) was an important biomarker for nonalcoholic fatty liver disease (NAFLD), and the association between TG and incident type 2 diabetes mellitus is still under debate with some studies suggesting that elevated TG increase the risk of incident T2DM while others indicative of a negative relationship. These controversial findings may be partially due to the inclusion of the participants with NAFLD. The association between TG and incident type 2 diabetes mellitus in people with NAFLD remained unclear. Therefore, this study aimed to characterize the relationship between the baseline TG levels and incident type 2 diabetes mellitus in a male Japanese cohort with NAFLD. Methods: A total of 1221 males with NAFLD were enrolled from the Nagala (NAFLD in the Gifu Area Longitudinal analysis) study conducted from 2004 to 2015. Cox proportional hazards models were performed to examine the relationship between baseline TG concentration and incident type 2 diabetes mellitus. A two-piecewise linear regression model was explored to evaluate the threshold effect of the baseline TG levels on type 2 diabetes mellitus incidence by using a smoothing function. Results: During a median follow-up of 6.05 years, 39 males with NAFLD at baseline developed type 2 diabetes mellitus. The risk of incident type 2 diabetes mellitus was significantly associated with baseline TG concentration in males with NAFLD after fully adjustment for confounders, with per 10 mg/dl elevation in TG levels increasing the risk of incident diabetes by 8.5% (HR=1.085, CI=1.039-1.132; P<0.001). However, no typical dose-dependent positive association between type 2 diabetes mellitus incidence and the TG levels was observed across the TG tertiles. Interestingly, a U-shaped association between TG concentration and risk of incident type 2 diabetes mellitus was revealed by the two-piecewise linear regression analysis. Baseline TG concentration lower than the threshold values (TG <53mg/dl) were negatively associated with risk of incident type 2 diabetes mellitus. With each 10mg/dl increase in baseline TG levels, the risk of incident type 2 diabetes mellitus decreased by nearly 59% (HR=0.413, 95% CI=0.220-0.778). In contrast, when TG levels were higher than the threshold values (TG>53mg/dl), the risk of incident diabetes increased 9.1% with every 10mg TG elevation (HR=1.091, 95% CI=1.046-1.137). Conclusions: A U-shaped relationship was observed between baseline TG levels and incident type 2 diabetes mellitus in a male normoglycemic Japanese population with NAFLD, although extrapolation of the finding to other populations should be made with caution.
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Triglicéridos , Estudios de Cohortes , Incidencia , Factores de RiesgoRESUMEN
IMPORTANCE: Antimicrobial resistance (AMR) has become a significant global challenge, with an estimated 10 million deaths annually by 2050. The emergence of AMR is mainly attributed to mobile genetic elements (MGEs or mobilomes), which accelerate wide dissemination among pathogens. The interaction between mobilomes and AMR genes (or resistomes) in Salmonella, a primary cause of diarrheal diseases that results in over 90 million cases annually, remains poorly understood. The available fragmented or incomplete genomes remain a significant limitation in investigating the relationship between AMR and MGEs. Here, we collected the most extensive closed Salmonella genomes (n = 1,817) from various sources across 58 countries. Notably, our results demonstrate that resistome transmission between Salmonella lineages follows a specific pattern of MGEs and is influenced by external drivers, including certain socioeconomic factors. Therefore, targeted interventions are urgently needed to mitigate the catastrophic consequences of Salmonella AMR.
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Farmacorresistencia Bacteriana , Salmonella , Salmonella/efectos de los fármacos , Salmonella/genéticaRESUMEN
BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.
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Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada , Glucemia , Hipoglucemiantes/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Método Doble Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: Limited data show that changes in fasting plasma glucose (FPG changes) are related to the incidence of type 2 diabetes (T2D). We aimed to correlate FPG changes with incident diabetes and evaluate FPG changes as a marker to screen participants at high risk of T2D in China. METHODS: A total of 116,816 individuals were followed during a median follow-up of 3.10 years by secondary analysis in a nondiabetic Chinese cohort. The turning points were derived from a receiver operating characteristic curve. Hazard ratios (HRs) were evaluated by Cox proportional hazards models. RESULTS: A total of 2669 cases of T2D were identified (788 women and 1881 men). The age-standardized incidence of diabetes was 12.87 per 1000 person-years (women: 11.04; men: 14.69). A nonlinear relationship between FPG changes and incident diabetes is shown by the fitting curves. The curves were categorized into three stages by two turning points (-0.04 and 1.25 mmol/L) and conformed to the hook-like pattern: an initial decrease (stage-1), then a transient sharp elevation (stage-2), followed by a slow increase (stage-3). HRs per SD of FPG changes on incident diabetes varied with stage: stage-1: 0.16 (0.12, 0.23), stage-2: 0.20 (0.15, 0.28) and stage-3: 0.22 (0.16, 0.31). Compared with stage-1, the HR in stage-3 was significantly higher at 28.05 (23.99, 32.79), while the increase in stage-2 was slight at 2.16 (1.79, 2.61), and the HR in stage-3 rose to 30.09 (25.02, 36.19). CONCLUSIONS: FPG changes had a strong correlation with the incidence of T2D and was a steady indicator that was used to distinguish the participants at high risk of diabetes.
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Diabetes Mellitus Tipo 2 , Ayuno , Glucemia , Estudios de Cohortes , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Incidencia , Masculino , Factores de RiesgoRESUMEN
RESULTS: Prolonged exposure to palmitate increased the expression of ACE and AngII type 1 receptor (ATR1) and decreased the ACE2 expression, which was partly offset by berberine. In ob/ob mice, berberine increased in tolerance to glucose, improved abnormal ß-cell and α-cell distributions, upregulated ACE2 expression, and decreased autophagosomes and the expression of LC3 and SQSTM1/p62. Autophagosomes and expression of LC3 and SQSTM1/p62 were increased in ACE2KO mice. CONCLUSIONS: We demonstrated that berberine may improve the pancreatic islet function by regulating local RAS-mediated autophagy under metabolic stress.
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Berberina , Islotes Pancreáticos , Animales , Autofagia , Berberina/metabolismo , Berberina/farmacología , Islotes Pancreáticos/metabolismo , Ratones , Ratones Noqueados , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-Angiotensina , Estrés FisiológicoRESUMEN
AIMS: The aim was to systematically review the efficacy and safety of sodium-glucose cotransporter inhibitor (SGLT2i) as an adjunct to insulin at different follow-up durations in randomized, double-blind clinical trials in patients with type 1 diabetes. METHODS: We conducted a search on Medline, Embase, and the Cochrane Library for relevant studies published before May 2020. According to the duration of follow-up, the subgroup analysis included four periods: 1-4, 12-18, 24-26, and 52 weeks. In the five trials included both 24-26 and 52 weeks of follow-up, we compared the efficacy by the placebo-subtracted difference and changes in SGLT2i groups. RESULTS: Fifteen trials including 7109 participants were analyzed. The combination of SGLT2i and insulin improved hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), daily insulin dose, body weight, and blood pressure, which varied greatly by different follow-ups. Compared with %HbA1c at 24-26 weeks, placebo-subtracted differences and changes in the SGLT2i groups slightly increased. SGLT2i plus insulin treatment showed no difference in the occurrence of urinary tract infections (UTIs), hypoglycemia, or severe hypoglycemia but increased the risk of genital tract infections (GTIs) in a duration-dependent manner. SGLT2i treatment was associated with a significantly higher rate of ketone-related SAEs and diabetic ketoacidosis (DKA) at 52 weeks. CONCLUSION: SGLT2i as an add-on therapy to insulin improved glycemic control and body weight and decreased the required dose of insulin without increasing the risk of hypoglycemia. However, after 6 months the benefits of SGLT2is on glycemic control may weaken and the risks of GTIs and DKA increased.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Insulina/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/epidemiología , Cetoacidosis Diabética/sangre , Cetoacidosis Diabética/inducido químicamente , Cetoacidosis Diabética/epidemiología , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversosRESUMEN
The aim of this study was to evaluate the clinical efficacy of N-acetylcysteine (NAC) in the treatment of ST segment elevation myocardial infarction (STEMI).PubMed, EMBASE, Cochrane Library, and Web of Science were searched systematically from the establishment of the database to June 2020. Two researchers independently completed literature screening and data extraction and conducted a meta-analysis.Nine articles including 1419 patients were enrolled. Meta-analysis showed that all-cause mortality [RR = 0.56, 95%CI (0.33, 0.93), P = 0.02], occurrence of major adverse cardiovascular events (MACE) [RR = 0.63, 95%CI (0.47, 0.85), P = 0.002], and myocardial enzyme hs-TnT level [SMD = -0.42, 95%CI (-0.71, -0.13), P = 0.005] were significantly lower in patients with STEMI treated with NAC than those in the control group. There was no significant difference between the NAC group and the control group in new congestive heart failure [RR = 0.94, 95%CI (0.48, 1.82), P = 0.84], ejection fraction [MD = 2.00, 95%CI (-0.59, 4.60), P = 0.13], and CK-MB [SMD = -0.18, 95%CI (-0.47, 0.11), P = 0.23]. There was no significant difference in the occurrence of adverse reactions between the NAC group and the control group [RR = 1.04, 95%CI (0.57-1.89), P = 0.90].NAC can reduce the all-cause mortality and MACE cases of STEMI.
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Acetilcisteína/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Acetilcisteína/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Estudios de Casos y Controles , Forma MB de la Creatina-Quinasa/metabolismo , Femenino , Depuradores de Radicales Libres/administración & dosificación , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/metabolismo , Infarto del Miocardio/mortalidad , Infarto del Miocardio/fisiopatología , Intervención Coronaria Percutánea/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Infarto del Miocardio con Elevación del ST/mortalidad , Volumen Sistólico , Resultado del Tratamiento , Troponina T/metabolismoRESUMEN
OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve ß cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1-7 (A1-7), in reducing ß cell dedifferentiation during metabolic stress. METHODS: First, a lineage-tracing experiment was performed to track ß cells in mice fed a high-fat diet (HFD). Second, the ACE2/A1-7 axis was evaluated in the HFD mouse model. Intraperitoneal glucose tolerance tests (IPGTTs) and intraperitoneal insulin tolerance tests (IPITTs) were conducted. Phenotypic changes in ß cells were detected by immunohistochemistry and quantitative real-time PCR. Pancreatic sections were immunostained for vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Finally, the effects of the ACE2/A1-7 axis were explored in isolated mouse islets exposed to different concentrations of glucose. Glucose-stimulated insulin release and levels of insulin mRNA and OCT4 mRNA were measured. RESULTS: Pancreatic ß cell dedifferentiation occurred both in vitro and in vivo in response to metabolic stress and was accompanied by ACE2 reduction. HFD-induced insulin resistance and glucose intolerance were exacerbated in ACE2-knockout (ACE2KO) mice but were alleviated by exogenous A1-7 in C57BL/6J mice. Approximately 20% of ß cells were dedifferentiated in ACE2KO mice fed a standard rodent chow diet (SD). A higher percentage of dedifferentiated ß cells was detected in ACE2KO mice than in wild-type (WT) mice under HFD conditions. In contrast, the administration of A1-7 alleviated HFD-induced ß cell dedifferentiation in C57BL/6J mice. Moreover, the exogenous injection of A1-7 improved microcirculation in islets and decreased the production of iNOS in islets of C57BL/6J mice fed an HFD. Additionally, ACE2 was found to be mainly expressed in α cells of mice, while Mas, the receptor of A1-7, was distributed in ß cells. CONCLUSIONS: Overall, this study is the first to demonstrate that the ACE2/A1-7/Mas axis may be one of the intra-islet paracrine mechanisms of communication between α and ß cells. Enhancing the ACE2/A1-7 axis exerts a protective effect by ameliorating ß cell dedifferentiation, and this effect might be partially mediated through improvements in islet microcirculation and suppression of islet iNOS.
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Angiotensina I/fisiología , Desdiferenciación Celular , Células Secretoras de Insulina/citología , Fragmentos de Péptidos/fisiología , Peptidil-Dipeptidasa A/fisiología , Enzima Convertidora de Angiotensina 2 , Animales , Linaje de la Célula , Dieta Alta en Grasa , Intolerancia a la Glucosa/etiología , Insulina/genética , Insulina/metabolismo , Resistencia a la Insulina , Secreción de Insulina , Células Secretoras de Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Aumento de PesoRESUMEN
The number of pro-α cells is known to increase in response to ß cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by ß cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on ß cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the ß cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of ß cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing ß cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.
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Dieta Alta en Grasa , Péptido 1 Similar al Glucagón/metabolismo , Células Secretoras de Glucagón/citología , Células Secretoras de Insulina/metabolismo , Palmitatos/farmacología , Acetilcisteína/farmacología , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Proteínas de Homeodominio/antagonistas & inhibidores , Inflamación/patología , Liraglutida/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/fisiología , Fragmentos de Péptidos/farmacología , Proproteína Convertasa 1/biosíntesis , Proproteína Convertasa 1/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiología , Transactivadores/antagonistas & inhibidores , Factor de Transcripción ReIA/biosíntesisRESUMEN
Radioresistant cells have been shown to correlate with poor outcome after radiotherapy. Here, we found that human telomerase reverse transcriptase promoter (hTERTp) had lower activity in laryngeal squamous carcinomas cells than in radioresistant variant cells. Combining radiotherapy with plasmid phTERTp-HRP, in which expression of enzyme horseradish peroxidase (HRP) controlled by hTERTp, resulted in increased apoptosis and necrosis of tumor cells after prodrug indole-3-acetic acid (IAA; converted by HRP into a cytotoxin) incubation. Volume and wet weight of xenograft tumor were reduced more in the combination groups. These data suggest that hTERTp has potential use in targeted cancer gene therapy, especially for radioresistant tumors. Combining radiotherapy with hTERTp-HRP/IAA may overcome radioresistance in laryngeal squamous carcinomas cells and amplify the killing effect in targeted cancer cells.
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Carcinoma de Células Escamosas/terapia , Terapia Genética/métodos , Neoplasias Laríngeas/terapia , Radioterapia/métodos , Telomerasa/genética , Animales , Apoptosis/fisiología , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Terapia Combinada , Femenino , Genes Transgénicos Suicidas/genética , Humanos , Etiquetado Corte-Fin in Situ , Ratones , Ratones Desnudos , Regiones Promotoras Genéticas , Tolerancia a Radiación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Human telomerase reverse transcriptase (hTERT) promoter has been proposed in cancer-targeted gene therapy. However, this promoter has not been strong enough to achieve therapeutic levels of transgene expression. We favor the hypothesis that telomerase may participate in the process of DNA repair and that the up-regulation of hTERT promoter activity may be a reaction to DNA damage. In previous investigations, we tested an 'indirected-activator' strategy that utilizes radiation to increase the activity of the hTERT promoter. The purpose of the present study was to implement a strategy using cisplatin to enhance hTERT promoter activity. The results indicate that, in human uterine cervical cancer (HeLa) cells exposed to 5 µg/ml cisplatin, the hTERT promoter had 3.1-fold increased activity compared to untreated cells. In addition, the combination of cisplatin and hTERT promoter-mediated horseradish peroxidase/indole-3-acetic acid gene-directed enzyme prodrug therapy induced cell cycle arrest at the S phase and apoptosis leading to a more significant reduction in cell viability. These findings suggest that hTERT promoter-mediated gene therapy is improved when combined with cisplatin.
RESUMEN
OBJECTIVE: To explore the therapeutic efficiency of human telomerase reverse transcriptase promoter (hTERTp) mediated horseradish peroxidase (HRP) catalyzed effects of indole-3-acetic (IAA) on laryngeal squamous cell carcinoma with different radiosensitivity in vivo. METHODS: Human laryngeal squamous cell carcinoma Hep-2 and Hep-2R cells were transplanted into nude mice. After growing to about 30 approximately 50 mm3, the tumor-bearing mice were randomly divided into eight groups: Hep-2 line: combined group (A), gene group (B), radiation group (C) and blank group (D); Hep-2R line: combined group (AR), gene group (BR), radiation group (CR) and blank group (DR). The phTERTp-HRP was delivered by intratumoral injection and the IAA by intraperitoneal injection, combined with 2 Gy daily radiation to a total dose of 30 Gy. The tumor volume was recorded. The cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The expression of HRP protein was detected by AP immunohistochemisty. RESULTS: The tumor growth of combined groups was attenuated significantly and the tumor volume of Hep-2R blank group was the largest. The inhibition rate of each group was: A: 54.8%, B: 10.0%, C: 31.9%; AR: 52.7%, BR: 24.8%, CR: 17.0%. In the combined groups, necrosis and apoptosis of tumor cells were observed under the light microscope and the apoptotic index [A (16.6 +/- 1.3)% vs. AR (17.6 +/- 1.3)%] of tumor cells was highest (P < 0.05). The HRP protein expression of BR (33.3 +/- 8.9)% was higher than that of B (21.9 +/- 5.7)%, which was directly up-regulated in the tumors (45.0% vs. 54.8%, P < 0.05) after radiation. CONCLUSION: In the Hep-2- and Hep-2R-transplantation tumors in nude mice, hTERTp can be induced by radiation and enhance the expression of horseradish peroxidase (HRP) gene according to telomerase activity. hTERTp-HRP/IAA system, which has synergistic effects with radiation and inhibits the tumor growth by induction of apoptosis and necrosis, may be a new gene-radiation strategy for the treatment of laryngeal carcinoma.