RESUMEN
Caloric restriction activates sirtuin 1 (SIRT1) and induces a variety of metabolic effects that are beneficial for preventing age-related disease. The present study screened a commercially available used drug library to develop small molecule activators of SIRT1 as therapeutics for treatment of metabolic disorders. Using an in vitro fluorescence assay, the cancer therapeutic camptothecin increased SIRT1 enzymatic activity by 5.5-fold, indicating it to be a potent SIRT1 activator. Camptothecin also elevated the nicotinamide adenine dinucleotide (NAD)+/NADH ratio and increased SIRT1 protein levels in differentiated C2C12 myogenic cells. Treatment of C2C12 myotubes with camptothecin increased phosphorylation of AMP-dependent kinase (AMPK) and acetyl-coenzyme A carboxylase, caused nuclear translocation and deacetylation of forkhead box O1 (FoxO1), increased transcription and protein expression of adipose triglyceride lipase (ATGL), decreased the amount of intracellular oil droplets, and significantly increased ß-oxidation of fatty acids. These in vitro data were confirmed in vivo as camptothecin treatment of C57BL/6J mice reduced fat and plasma triglyceride levels. All of the above camptothecin-induced alterations were attenuated by the SIRT1-specific inhibitor nicotinamide and/or 6-[4-(2-piperidin-1-ylethoxy) phenyl]-3-pyridin-4-ylpyrazolo [1,5-a]pyrimidin (compound C). Thus, camptothecin activation of SIRT1 promotes lipid catabolism through AMPK/FoxO1/ATGL signaling.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Camptotecina/farmacología , Proteína Forkhead Box O1/metabolismo , Lipasa/metabolismo , Sirtuina 1/metabolismo , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Alzheimer's disease (AD) is characterized by extracellular deposition of amyloid plaques, which are predominantly composed of amyloid-ß (Aß) peptide derived from amyloid precursor protein (APP) cleavage. APP interacts with tropomyosin receptor kinase A, a neurotrophic receptor associated with gangliosides and mediating neuronal survival and differentiation through the extracellular signal-regulated protein kinase (ERK) pathway. The ganglioside Hp-s1's analogue Hp-s1A exerts neuritogenic activity; however, its effect on AD pathology remains unknown. To test the hypothesis that Hp-s1A is a potential candidate to treat AD, we established the AD-modeled cell line by expressing human Swedish and Indiana APP gene (APP-Swe/Ind) in N2a mouse neuroblastoma cells. The cells were treated with Hp-s1A or monosialoganglioside GM1 for comparison. The AD model cells expressing APP-Swe/Ind exhibited a significant reduction in viability, as well as neurite outgrowth rate, in comparison to the control cells expressing APP-695. APP C-terminal fragment-ß (CTFß) and Aß42 were increased in the AD cell lysates and the culture media, respectively. With the treatment of either Hp-s1A or GM1 at 1 µM, the AD model cells showed a significant increase in viability; however, only Hp-s1A reduced CTFß levels in these cells. Further analysis of the culture media revealed that Hp-s1A also reduced Aß42 production from AD model cells. The phosphorylation of ERK was elevated and the neurite outgrowth rate was restored with Hp-s1A treatment. In conclusion, the ganglioside analogue Hp-s1A inhibited amyloidogenic processing of APP and promoted neurotrophic activity and survival of AD model cells. Hp-s1A has great potential in AD therapeutic development.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Gangliósidos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Gangliósidos/metabolismo , Humanos , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/metabolismo , Presenilina-1/genéticaRESUMEN
Iron or oxygen regulates the stability of hypoxia inducible factor-1α (HIF-1α). We investigated whether ferrous glycinate would affect HIF-1α accumulation, aerobic glycolysis and mitochondrial energy metabolism in human A549 lung cancer cells. Incubation of A549 cells with ferrous glycinate decreased the protein levels of HIF-1α, which was abrogated by proteosome inhibitor, or prolyl hydroxylase inhibitor. The addition of ferrous glycinate decreased protein levels of glucose transporter-1, hexokinase-2, and lactate dehydrogenase A, and decreased pyruvate dehydrogenase kinase-1 (PDK-1) and pyruvate dehydrogenase (PDH) phosphorylation in A549 cells. Ferrous glycinate also increased the expression of the mitochondrial transcription factor A (TFAM), and the mitochondrial protein, cytochrome c oxidase (COX-IV). Silencing of HIF-1α expression mimicked the effects of ferrous glycinate on PDK-1, PDH, TFAM and COX-IV in A549 cells. Ferrous glycinate increased mitochondrial membrane potential and ATP production in A549 cells. These results suggest that ferrous glycinate may reverse Warburg effect through down regulating HIF-1α in A549 cells.
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Metabolismo Energético/efectos de los fármacos , Compuestos Ferrosos/farmacología , Glicina/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Subunidad alfa del Factor 1 Inducible por Hipoxia/deficiencia , Células A549 , Relación Dosis-Respuesta a Droga , Compuestos Ferrosos/química , Glicina/análogos & derivados , Glicina/química , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
OBJECTIVE: Advanced glycation end products (AGEs) are involved in the pathogenesis of Alzheimer's disease (AD). Specific AGEs and related autoantibodies may be early AD markers. Apolipoprotein A1 (ApoA1) and its post-translational modifications (PTMs) are associated with neurodegeneration and thus selected to test the hypothesis. METHODS: Serum samples from totally 64 AD or health control (HC) Taiwanese were analyzed. ApoA1 was isolated from the serum and examined through LC-MS/MS and PTM analyses. A specific AGE and its autoantibodies were determined using Western blotting or ELISA. RESULTS: Nε-(Carboxyethyl)lysine (CEL) modification, a kind of AGEs, was identified on ApoA1 peptide 141-QKVEPLR-147 (ApoA1141-147) from AD serum. Total CEL adducts and autoantibodies against CEL on ApoA1141-147 were significantly increased in AD samples. The area under the receiver operating characteristic curve was 0.965 for anti-CEL-ApoA1141-147 IgM. Mini Mental State Examination scores of the AD patients were positively correlated with anti-CEL-ApoA1141-147 IgM, suggesting that the IgM level is high in early AD pathology and decreased with disease progression. CONCLUSION: CEL modification was increased on AD serum proteins including ApoA1, leading to an elevated anti-CEL IgM in early disease state. Both CEL and anti-CEL IgM may serve as AD biomarkers.
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Enfermedad de Alzheimer/sangre , Apolipoproteína A-I/antagonistas & inhibidores , Autoanticuerpos/sangre , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Inmunoglobulina M/análisis , Procesamiento Proteico-Postraduccional , Regulación hacia Arriba , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Especificidad de Anticuerpos , Apolipoproteína A-I/sangre , Apolipoproteína A-I/química , Autoinmunidad , Biomarcadores/sangre , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Productos Finales de Glicación Avanzada/sangre , Productos Finales de Glicación Avanzada/química , Humanos , Lisina/análogos & derivados , Lisina/sangre , Lisina/química , Masculino , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/química , Escalas de Valoración Psiquiátrica , Curva ROC , TaiwánRESUMEN
Nε-(carboxymethyl) lysine (CML) plays causal roles in diabetic complications. In the present study, we investigated whether CML-induced HIF-1α accumulation and epithelial-mesenchymal transition (EMT) in HK-2 renal proximal tubular epithelial cells. Treatment with CML-BSA increased reactive oxygen species (ROS) production reduced the mitochondrial membrane potential and induced mitochondrial fragmentation. Pre-treatment of cells with antioxidant, α-lipoic acid, normalised the ROS production and restored the mitochondrial membrane potential. These changes were accompanied with morphological changes of epithelial mesenchymal transition. CML-BSA increased the protein level of hypoxia-inducible factor-1α (HIF-1α), and the EMT-associated transcription factor, TWIST. These effects were reversed by α-lipoic acid. CML-BSA increased the protein levels of mesenchymal-specific markers, including vimentin, α-smooth muscle actin, which were alleviated by pre-treatment with α-lipoic acid. Our data suggest that CML-BSA induces EMT through a ROS/HIF-1α/TWIST-dependent mechanism, and that α-lipoic acid may alleviate the CML-induced EMT in renal tubular cells.
Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Túbulos Renales Proximales/efectos de los fármacos , Lisina/análogos & derivados , Ácido Tióctico/farmacología , Células Cultivadas , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Túbulos Renales Proximales/metabolismo , Lisina/antagonistas & inhibidores , Lisina/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND/PURPOSE: Glucocorticoids (GC) are commonly used in rheumatoid arthritis (RA) patients which bears a risk of hepatitis B virus (HBV) reactivation. The purpose of this study was to investigate the risk of HBV-related mortality under long-term low-dose GCs in Taiwanese RA patients. METHODS: We retrospectively analyzed 45,423 RA patients using National Health Insurance Research Database from January 1999 to December 2011. Of them, 2204 patients had the diagnosis of HBV and were classified into four groups according to GCs regimens. Outcome comparison by Cox model analysis for liver-related mortality was performed. RESULTS: In this cohort, 90.5% were older than 40. One hundred and five patients had been treated with short-term large-dose GCs (Group A); 862 patients received GCs ≥20 mg/day for ≥3 days or a variable dose but did not meet Group C criteria (Group B); 689 patients were continuously treated with low-dose (<20 mg/day) GCs for ≥3 months for at least one session (Group C); and 548 patients had never been exposed to GCs (Group D). Two hundred and sixty-one patients had been exposed to antiviral agents, which was significantly higher in Group C. Fifty-eight patients (2.63%) died of acute hepatic failure, while no statistically significant difference between each groups (p = 0.074). Groups C and D comparison by two-sample test showed that long-term low-dose GC treatment was not associated with liver-related death after adjusting for malignancy. CONCLUSION: Long-term low-dose GC treatment was not associated with liver-related mortality in RA with concomitant HBV patients probably due to commonly applied antiviral therapy by rheumatologists.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/mortalidad , Glucocorticoides/administración & dosificación , Hepatitis B/mortalidad , Activación Viral/efectos de los fármacos , Adulto , Anciano , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Antivirales/uso terapéutico , Artritis Reumatoide/virología , Femenino , Glucocorticoides/efectos adversos , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/fisiología , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , TaiwánRESUMEN
PURPOSE: Most of the existing studies on postcoital bleeding (PCB) in Western countries. To date, no study has focused on the various PCB-related comorbidities in Taiwan women. This work aims to analyze and compare the presence or absence of PCB among Taiwanese women with gynecological comorbidity. METHODS: This study is a population-based retrospective cohort investigation. Outpatients with PCB after the index date were considered. A total of 2377 female patients with PCB (ICD-9 626.7) were identified using a nationwide outpatient sample from 2001 to 2010. For comparison, 7131 cases were randomly matched with the study group in terms of gender and age. RESULTS: The PCB incidence rate was 39-59 cases/100,000 Taiwanese women, with mean age (±SD) of 36.74 ± 10.79 years, median age of 36 years, and mode age of 29 years. Women with PCB exhibited 1.47-fold risk of cervical dysplasia and 1.59-fold risk for malignant neoplasm of cervix. Young women with PCB showed high risk of cervical cancer. The most common benign diseases among PCB- related comorbidities were cervical erosion and ectropion (20.66%), followed by vaginitis and vulvovaginitis (19.18%). Comparison between PCB and non-PCB groups indicated several significant high-risk comorbidities including cervical polyps, cervical erosion, leukoplakia of cervix, intrauterine contraceptive device, cervicitis, vaginitis, menopause, dyspareunia, and vulvodynia. CONCLUSIONS: This study provides evidence that PCB-related comorbidities manifested benign diseases (51.58%), lower genital tract infection (46.11%), and cervical cancer (2.31%). Thus, healthcare providers must ensure that appropriate routine screening tests and counseling are given to women with PCB.
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Disfunciones Sexuales Fisiológicas/epidemiología , Adulto , Anciano , Comorbilidad , Femenino , Humanos , Seguro de Salud , Dispositivos Intrauterinos/efectos adversos , Menopausia , Persona de Mediana Edad , Pólipos/epidemiología , Pólipos/patología , Infecciones del Sistema Genital/epidemiología , Infecciones del Sistema Genital/patología , Estudios Retrospectivos , Taiwán , Enfermedades del Cuello del Útero/epidemiología , Enfermedades del Cuello del Útero/patología , Displasia del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , Cervicitis Uterina/epidemiología , Cervicitis Uterina/patologíaRESUMEN
Corrosive injury results from the intake of corrosive-acid-based chemicals. However, this phenomenon is limited to a small number of cases and cannot be extrapolated to the epidemiology of corrosive injuries in actual situations. This study focuses on the annual incidence of corrosive injury and its connection to gender, risk factors, and in-hospital mortality. All patients with corrosive injury (ICD-9 947.0-947.3) were identified using a nationwide inpatient sample from 1996 until 2010. Chi-squared tests and multivariate logistic regression were used to examine risk factors of gender differences and in-hospital mortality of corrosive injury. Young adults comprised the majority of patients (71.2%), and mean age was 44.6 ± 20.9 years. Women showed a higher incidence rate of corrosive injuries, age, suicide, psychiatric disorder, and systemic complications compared with men (p < 0.001). The present study demonstrated that age (OR = 10.93; 95% CI 5.37-22.27), systemic complications (OR = 5.43; 95% CI 4.61-6.41), malignant neoplasms (OR = 2.23; 95% CI 1.37-3.62), gastrointestinal complications (OR = 2.02; 95% CI 1.63-2.51), chronic disease (OR = 1.30; 95% CI 1.08-1.56), and suicide (OR = 1.23; 95% CI 1.05-1.44) were strongly associated with in-hospital mortality. Educational programs may be helpful for reducing the incidence of ingestion of corrosive chemicals.
RESUMEN
Denervation-mediated skeletal muscle atrophy results from the loss of electric stimulation and leads to protein degradation, which is critically regulated by the well-confirmed transcriptional co-activator peroxisome proliferator co-activator 1 alpha (PGC-1α). No adequate treatments of muscle wasting are available. Pyrroloquinoline quinone (PQQ), a naturally occurring antioxidant component with multiple functions including mitochondrial modulation, demonstrates the ability to protect against muscle dysfunction. However, it remains unclear whether PQQ enhances PGC-1α activation and resists skeletal muscle atrophy in mice subjected to a denervation operation. This work investigates the expression of PGC-1α and mitochondrial function in the skeletal muscle of denervated mice administered PQQ. The C57BL6/J mouse was subjected to a hindlimb sciatic axotomy. A PQQ-containing ALZET® osmotic pump (equivalent to 4.5 mg/day/kg b.w.) was implanted subcutaneously into the right lower abdomen of the mouse. In the time course study, the mouse was sacrificed and the gastrocnemius muscle was prepared for further myopathological staining, energy metabolism analysis, western blotting, and real-time quantitative PCR studies. We observed that PQQ administration abolished the denervation-induced decrease in muscle mass and reduced mitochondrial activities, as evidenced by the reduced fiber size and the decreased expression of cytochrome c oxidase and NADH-tetrazolium reductase. Bioenergetic analysis demonstrated that PQQ reprogrammed the denervation-induced increase in the mitochondrial oxygen consumption rate (OCR) and led to an increase in the extracellular acidification rate (ECAR), a measurement of the glycolytic metabolism. The protein levels of PGC-1α and the electron transport chain (ETC) complexes were also increased by treatment with PQQ. Furthermore, PQQ administration highly enhanced the expression of oxidative fibers and maintained the type II glycolytic fibers. This pre-clinical in vivo study suggests that PQQ may provide a potent therapeutic benefit for the treatment of denervation-induced atrophy by activating PGC-1α and maintaining the mitochondrial ETC complex in skeletal muscles.
Asunto(s)
Mitocondrias/metabolismo , Músculo Esquelético/efectos de los fármacos , Cofactor PQQ/farmacología , Factores de Transcripción/metabolismo , Animales , Desnervación , Transporte de Electrón , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/inervación , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Fosforilación Oxidativa , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gammaRESUMEN
Nε-(carboxymethyl) lysine-conjugated bovine serum albumin (CML-BSA) is a major component of advanced glycation end products (AGEs). We hypothesised that AGEs reduce insulin secretion from pancreatic ß-cells by damaging mitochondrial functions and inducing mitophagy. Mitochondrial morphology and the occurrence of autophagy were examined in pancreatic islets of diabetic db/db mice and in the cultured CML-BSA-treated insulinoma cell line RIN-m5F. In addition, the effects of α-lipoic acid (ALA) on mitochondria in AGE-damaged tissues were evaluated. The diabetic db/db mouse exhibited an increase in the number of autophagosomes in damaged mitochondria and receptor for AGEs (RAGE). Treatment of db/db mice with ALA for 12 wk increased the number of mitochondria with well-organized cristae and fewer autophagosomes. Treatment of RIN-m5F cells with CML-BSA increased the level of RAGE protein and autophagosome formation, caused mitochondrial dysfunction, and decreased insulin secretion. CML-BSA also reduced mitochondrial membrane potential and ATP production, increased ROS and lipid peroxide production, and caused mitochondrial DNA deletions. Elevated fission protein dynamin-related protein 1 (Drp1) level and mitochondrial fragmentation demonstrated the unbalance of mitochondrial fusion and fission in CML-BSA-treated cells. Additionally, increased levels of Parkin and PTEN-induced putative kinase 1 protein suggest that fragmented mitochondria were associated with increased mitophagic activity, and ALA attenuated the CML-BSA-induced mitophage formation. Our study demonstrated that CML-BSA induced mitochondrial dysfunction and mitophagy in pancreatic ß-cells. The findings from this study suggest that increased concentration of AGEs may damage ß-cells and reduce insulin secretion.
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Diabetes Mellitus/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Lisina/análogos & derivados , Dinámicas Mitocondriales , Mitofagia , Animales , Antioxidantes/metabolismo , Antioxidantes/uso terapéutico , Biomarcadores/metabolismo , Línea Celular Tumoral , Diabetes Mellitus/dietoterapia , Diabetes Mellitus/patología , Suplementos Dietéticos , Regulación hacia Abajo/efectos de los fármacos , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Productos Finales de Glicación Avanzada/farmacología , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/ultraestructura , Lisina/antagonistas & inhibidores , Lisina/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Dinámicas Mitocondriales/efectos de los fármacos , Mitofagia/efectos de los fármacos , Oxidantes/antagonistas & inhibidores , Oxidantes/farmacología , Fagosomas/efectos de los fármacos , Fagosomas/metabolismo , Fagosomas/ultraestructura , Ratas , Receptor para Productos Finales de Glicación Avanzada/agonistas , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Albúmina Sérica Bovina/antagonistas & inhibidores , Albúmina Sérica Bovina/farmacología , Ácido Tióctico/metabolismo , Ácido Tióctico/uso terapéuticoRESUMEN
INTRODUCTION: Most of the existing studies on dyspareunia only focus on qualitative observations. These measurement tools may not reflect the actual situation of dyspareunia in Taiwan. AIM: This study aimed to estimate the incidence of dyspareunia in Taiwan and investigate dyspareunia-associated comorbidities using the National Health Insurance Research Database (NHIRD). METHODS: This study is a population-based retrospective cohort investigation. MAIN OUTCOME MEASURES: We analyzed the 2004-2010 claims data on dyspareunia from the NHIRD. Dyspareunia was identified by outpatient visits using International Classification of Diseases, Ninth Revision, Clinical Modification (diagnosis code 6250). Patients who visited as outpatients with dyspareunia after the index date were considered to have comorbidities associated with dyspareunia medical conditions. The index events included vaginal disorders, vulvar disorders, uterine and ovarian factors, female genital organ and menstrual cycle disorders, menopause, and relative abdominopelvic organ disorders. The incidence of dyspareunia among different age groups was determined. The location and areas significantly related to the physical gynecology or relative pelvic organ causing the disease were also analyzed. RESULTS: A total of 978 females of different ages had experienced dyspareunia. The incidence of dyspareunia was higher among individuals aged 30-34 years. The findings of this study indicated that dyspareunia was comorbid with menopause, pelvic floor dysfunction, and most gynecological infections. In particular, the more common physical causes of dyspareunia were introitus and vaginal infections (19.95%), menopause (16.80%), female genital organ and menstrual cycle disorders (15.22%), and female pelvic organ infections (13.65%). CONCLUSIONS: This study posits that women of all ages (20-70 years) experience painful sexual intercourse. This large-scale nationwide claims-based study showed that menopause and pelvic infection disorder were dyspareunia-related comorbidities. Moreover, gynecological infections and pelvic floor dysfunctions were associated with dyspareunia.
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Dispareunia/epidemiología , Adulto , Anciano , Comorbilidad , Dispareunia/diagnóstico , Femenino , Enfermedades de los Genitales Femeninos/epidemiología , Humanos , Incidencia , Revisión de Utilización de Seguros/estadística & datos numéricos , Menopausia , Persona de Mediana Edad , Diafragma Pélvico/fisiopatología , Estudios Retrospectivos , Taiwán/epidemiología , Vagina/fisiopatología , Adulto JovenRESUMEN
BACKGROUND/PURPOSE: Interferon (IFN) is able to induce significant psychiatric side effects in chronic hepatitis C (CHC) patients, whereas the risk of nonpsychotic mental disorder (NPMD) development in antiviral-treated mentally healthy CHC patients remains obscure. We used a population-based study to assess the risk of NPMD development in patients who had undergone antiviral treatment compared with untreated chronic hepatitis C virus (HCV)-infected and nonalcoholic fatty liver disease (NAFLD) patients. METHODS: Data were retrieved from Taiwan's National Health Insurance Research Database cohort consisting of 1 million individuals for a longitudinal analysis. A total of 313 mentally healthy CHC patients who received IFN-based antiviral therapy were recruited and compared with those without antiviral therapy and NAFLD patients. The Chi-square test was used to obtain the hazard ratio and 95% confidence interval. RESULTS: Among the 313 CHC patients receiving pegylated interferon/ribavirin therapy, 62 patients (19.8%) were associated with NPMD. In the comparison cohort, composed of 313 age- and sex-matched CHC patients not receiving antiviral therapy, 70 patients (22.4%) were associated with NPMD. The Chi-square analysis revealed that antiviral therapy was not significantly associated with NPMD. The diagnosis of HCV-infected hepatitis was independently associated with NPMD when compared with NAFLD. The hazard ratio was 1.67 (95% confidence interval, 1.11-2.52; p = 0.018). Furthermore, generalized anxiety disorder was specifically higher in HCV-infected patients than those with NAFLD. CONCLUSION: Patients with HCV infection are at high risk of developing NPMD with or without IFN-based therapy.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Trastornos Mentales/epidemiología , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Adulto , Distribución de Chi-Cuadrado , Bases de Datos Factuales , Quimioterapia Combinada , Femenino , Humanos , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud , Escalas de Valoración Psiquiátrica , Ribavirina/uso terapéutico , Factores de Riesgo , TaiwánRESUMEN
Healthcare professionals have a high risk of needlestick and sharps injuries (NSIs), which have a high potential for disease transmission. Ambulatory care follow up is essential, but is usually overlooked. This study aimed to investigate the annual and cumulative (age-, sex-, and subtype-specific) incidences of ambulatory care visits after NSIs. This study was also designed to evaluate the incidences of blood-borne diseases associated with NSIs among Taiwanese health professionals in Taiwan between 2004 and 2010. Data were obtained from the National Health Insurance Research Database, which contains anonymized records representing approximately 99% of the Taiwan population. A total of 4443 nurse healthcare workers (NHCWs) and 3138 non-nurse healthcare workers (NNHCWs), including physicians, medical technologists, and other health professionals were included in this longitudinal study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The Mantel-Haenszel method was used to adjust for sex, age, and type of affiliation. Results showed that the annual incidence of ambulatory care visits of NHCWs increased from 0.7% in 2004 to 1.9% in 2010; this incidence was significantly higher than that of NNHCWs (from 0.3% in 2004 to 0.5% in 2010) in any yearly comparison (p < 0.05). The sex-adjusted 7-year cumulative incidence rate was 3.23 (95% CI = 1.23-8.45) in males and 3.92 (95% CI = 2.70-5.69) in females (p < 0.05). The age-adjusted 7-year cumulative incidence rate was 2.74 (95% CI = 1.99-3.77) and 2.14 (95% CI = 1.49-3.07) in subjects ≤ 30 and ≥31 years old, respectively (p < 0.0005). The affiliation-adjusted 7-year cumulative incidence rate was 1.89 (95% CI = 1.21-2.94) in medical centers and 3.33 (95% CI = 2.51-4.41) in nonmedical centers (p < 0.01). In conclusion, NSIs increased steadily from 2004 to 2010 in Taiwan with NHCWs having higher NSIs incidences than NNHCWs. A routine ambulatory care visit after NSIs can prevent blood-borne transmission, especially for NHCWs. Educational programs may be helpful for reducing the incidence of NSIs and increasing ambulatory care visit ratios after NSIs.
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Atención Ambulatoria/estadística & datos numéricos , Personal de Salud/estadística & datos numéricos , Encuestas Epidemiológicas/estadística & datos numéricos , Lesiones por Pinchazo de Aguja/epidemiología , Adulto , Factores de Edad , Enfermedades Transmisibles/etiología , Demografía , Femenino , Humanos , Incidencia , Masculino , Lesiones por Pinchazo de Aguja/complicaciones , Enfermeras y Enfermeros/estadística & datos numéricos , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
AIM: To investigate the effects of punicalagin, a polyphenol isolated from Punica granatum, on human U87MG glioma cells in vitro. METHODS: The viability of human U87MG glioma cells was evaluated using MTT assay. Cell cycle was detected with flow cytometry analysis. The levels of Bcl-2, cleaved caspase-9, cleaved poly(ADP-ribose) polymerase (PARP), phosphor-AMPK and phosphor-p27 at Thr198 were measured using immunoblot analyses. Caspase-3 activity was determined with spectrophotometer. To determine autophagy, LC3 cleavage and punctate patterns were examined. RESULTS: Punicalagin (1-30 µg/mL) dose-dependently inhibited the cell viability in association with increased cyclin E level and decreased cyclin B and cyclin A levels. The treatment also induced apoptosis as shown by the cleavage of PARP, activation of caspase-9, and increase of caspase-3 activity in the cells. However, pretreatment of the cells with the pan-caspase inhibitor z-DEVD-fmk (50 µmol/L) did not completely prevent the cell death. On the other hand, punicalagin treatment increased LC3-II cleavage and caused GFP-LC3-II-stained punctate pattern in the cells. Suppressing autophagy of cells with chloroquine (1-10 µmol/L) dose-dependently alleviated the cell death caused by punicalagin. Punicalagin (1-30 µg/mL) also increased the levels phosphor-AMPK and phosphor-p27 at Thr198 in the cells, which were correlated with the induction of autophagic cell death. CONCLUSION: Punicalagin induces human U87MG glioma cell death through both apoptotic and autophagic pathways.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Glioma/tratamiento farmacológico , Taninos Hidrolizables/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Glioma/patología , Humanos , Taninos Hidrolizables/administración & dosificación , Taninos Hidrolizables/aislamiento & purificación , Lythraceae/química , FosforilaciónRESUMEN
BACKGROUND: A shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis is the biochemical hallmark of malignant cancer cells. METHODS: In the present study, we demonstrated that Nodal stimulated the expression of glycolytic enzymes and decreased reliance on mitochondrial oxidative phosphorylation in human glioma cancer cells. The shift in glucose metabolism was mediated by induction of the hypoxia-inducible factor (HIF). RESULTS: Nodal protein expression was shown to be correlated with expression levels of glucose transporter (Glut)-1, hexokinase (HK)-II, pyruvate dehydrogenase kinase (PDK)-1, the phosphorylation level of pyruvate dehydrogenase (PDH), glucose uptake, and lactate accumulation in human glioma cells. These effects were inversely correlated with mitochondrial oxygen consumption and ATP production. Knockdown of Nodal expression with specific small hairpin RNA reduced Glut-1, HK-II, and PDK-1 expressions and PDH phosphorylation. Nodal knockdown also reduced glucose uptake and lactate generation, which in turn increased mitochondrial membrane potential (Ψ), O2 utilization, and ATP synthesis. The ectopic expression of Nodal in low-expressing Nodal glioma cells resulted in the opposite results compared with those of Nodal knockdown glioma cells. Treatment of cells with recombinant Nodal increased HIF-1 expression, and this effect was regulated at the transcriptional level. Blockage of the Nodal receptor by a pharmacological inhibitor or Nodal knockdown in U87MG cells decreased HIF-1α expression. Furthermore, HIF-1α knockdown in U87MG cells decreased Glut-1, HK-II, and PDK-1 expressions and PDH phosphorylation, which were similar to results in Nodal knockdown cells. CONCLUSION: Taken together, these results suggest that Nodal affects energy metabolism through HIF-1α.
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Metabolismo Energético , Glioma/metabolismo , Glioma/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mitocondrias/metabolismo , Proteína Nodal/metabolismo , Adenosina Trifosfato/metabolismo , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glucosa/metabolismo , Glucólisis , Humanos , Hipoxia/metabolismo , Hipoxia/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ácido Láctico/metabolismo , Luciferasas/metabolismo , Potencial de la Membrana Mitocondrial , Proteína Nodal/antagonistas & inhibidores , Proteína Nodal/genética , Consumo de Oxígeno , ARN Interferente Pequeño/genética , Células Tumorales CultivadasRESUMEN
Monacolin K is the secondary metabolite isolated from Monascus spp. It is the natural form of lovastatin, which is clinically used to reduce the synthesis of cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase. In the present study, monacolin K increased protein expression of SIRT1 and phosphorylation level of AMP-activated protein kinase (AMPK) in HepG2 cells. Through activation of SIRT1/AMPK pathway, monacolin K increased phosphorylation of acetyl CoA carboxylase and caused nuclear translocation of forkhead box O1. The western blotting results showed that monacolin K increased expression of adipose triglyceride lipase but decreased abundances of fatty acid synthase (FAS) and sterol regulatory element-binding protein 1 (SREBP1). Monacolin K also decreased the intracellular accumulation of lipids as demonstrated by Oil Red O staining. In addition, the immunostaining showed that monacolin K prevented the nuclear translocation of SREBP1, indicating the association with down-regulation of FAS. All the demonstrated effects of monacolin K were counteracted by nicotinamide or compound C, the inhibitors of SIRT1 or AMPK. In summary, monacolin K reduces the lipid content through SIRT1/AMPK pathway in HepG2 cells, which promotes catabolism and inhibits anabolism of lipid.
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Proteínas Quinasas Activadas por AMP/metabolismo , Anticolesterolemiantes/farmacología , Metabolismo de los Lípidos/fisiología , Lovastatina/farmacología , Transducción de Señal/fisiología , Sirtuina 1/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Musculoskeletal disorders (MSDs) represent the leading causes of occupational injuries among nursing staff. This population-based study was designed to assess the incidence and age-specific incidence of MSDs among a Taiwanese nurse cohort compared with non-nurses. DESCRIPTION: Data from the Taiwan National Health Insurance Research Database were used to identify MSDs in the study population. A total of 3914 nurses with a diagnosis of MSD were included, together with 11,744 non-nurses as a comparison group. The comparison subjects were randomly selected at a ratio of 3:1 relative to the nurse population and were matched by gender and age. The incidence of MSDs was calculated for the study group, with nurse-to-reference risk ratios presented as odds ratios with 95% confidence intervals (CIs). During the period 2004-2010, 3004 MSDs occurred among the nurses (76.24%) and 7779 (65.79%) in the non-nurses. The annual incidence of MSDs for the nurses increased from 28.35% in 2006 to 33.65% in 2010. The nurse-to-reference risk ratio was 1.27 (95% CI 1.19-1.35) in 2004 and 1.46 (1.37-1.55) in 2010. Herniation of intervertebral disc, lumbago, rotator cuff syndrome, medial epicondylitis, trigger finger and carpal tunnel syndrome were the most common problems. CONCLUSIONS: Nurses are at higher risk of MSDs and the trend is increasing. Incorrect work-related posture/movement, psychological issues and the rolling shift system may be the major causes of MSDs among nurses in Taiwan.
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Enfermedades Musculoesqueléticas/epidemiología , Enfermeras y Enfermeros , Traumatismos Ocupacionales/epidemiología , Vigilancia de la Población , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Enfermedades Musculoesqueléticas/diagnóstico , Traumatismos Ocupacionales/diagnóstico , Vigilancia de la Población/métodos , Factores de Riesgo , Taiwán/epidemiología , Adulto JovenRESUMEN
Non-alcoholic fatty liver disease can be attributed to the imbalance between lipogenesis and lipolysis in the liver. Alpha-lipoic acid has been shown to activate the 5'-AMP-activated protein kinase (AMPK) signalling pathway and to effectively inhibit the lipogenesis pathway in liver. However, whether alpha-lipoic acid stimulates lipolysis remains unclear. Recently, adipose triglyceride lipase (ATGL) was shown to be responsible for triacylglycerol hydrolase activity in cells. In the present study, we established a fatty liver cell model by incubating HepG2 cells in a high glucose (30mM glucose) and high fat (0.1mM palmitate) medium. We found that the activation of the AMPK signalling pathway induced ATGL protein expression and enhanced lipid hydrolysis. Similarly, treatment of the fatty liver cell model with alpha-lipoic acid reduced intracellular lipid accumulation in HepG2 cells, increased AMPK phosphorylation, and induced ATGL expression. We showed that insulin phosphorylates the transcription factor forkhead box O1 (FOXO1), which regulates ATGL expression and inhibits FOXO1 translocation into the nucleus. In contrast, alpha-lipoic acid dephosphorylated FOXO1 and reversed the nuclear exclusion of FOXO1. These data suggest that alpha-lipoic acid can effectively ameliorate intracellular lipid accumulation and induce ATGL expression through the FOXO1/ATGL pathway in liver cells. Thus, alpha-lipoic acid may be a potential therapeutic agent for treating fatty liver disease.
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Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Lipasa/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Ácido Tióctico/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Activación Enzimática/efectos de los fármacos , Hígado Graso/tratamiento farmacológico , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/metabolismo , Glucosa/metabolismo , Células Hep G2 , Humanos , Insulina/farmacología , Enfermedad del Hígado Graso no Alcohólico , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sirtuina 1/metabolismo , Ácido Tióctico/uso terapéuticoRESUMEN
Fenofibrate, a fibric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate may activate peroxisome proliferator-activated receptor (PPAR)α and regulate the transcription of several genes, the underlying mechanisms are poorly understood. In this study, we demonstrated that incubation of C2C12 myotubes with fenofibrate increased adipose triglyceride lipase (ATGL) expression and suppressed fatty acid synthase (FAS) level, thereby decreasing intracellular triglyceride accumulation when cells were incubated at high-glucose condition. Fenofibrate increased the phosphorylation of AMP-activated protein kinase (AMPK), which subsequently increased fatty acid ß-oxidation. AMPK phosphorylation was reduced by pretreatment with GW9662 (a PPARα inhibitor), suggesting that AMPK may be a downstream effector of PPARα. Pretreatment with compound C (an AMPK inhibitor) or GW9662 blocked fenofibrate-induced ATGL expression and the lipid-lowering effect. Our results suggest that AMPK is as an upstream regulator of ATGL. With further exploration, we demonstrated that fenofibrate stimulated FoxO1 translocation from the cytosol to nuclei by immunefluorescence assay, chromatin immuneprecipitation assay, and reporter assay. Furthermore, oral administration of fenofibrate ameliorated the body weight, visceral fat and serum biochemical indexes in db/db mice. Taken together, our results suggest that the lipid-lowering effect of fenofibrate was achieved by activating PPARα and AMPK signaling pathway that resulted in increasing ATGL expression, lipolysis, and fatty acid ß-oxidation.
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Proteínas Quinasas Activadas por AMP/fisiología , Fenofibrato/farmacología , Factores de Transcripción Forkhead/fisiología , Hipolipemiantes/farmacología , Lipasa/fisiología , Metabolismo de los Lípidos , Fibras Musculares Esqueléticas/metabolismo , PPAR alfa/fisiología , Acetil-CoA Carboxilasa/metabolismo , Animales , Línea Celular , Núcleo Celular/metabolismo , Citosol/metabolismo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/metabolismo , Lipasa/genética , Masculino , Ratones , Fosforilación , Regiones Promotoras Genéticas , Unión Proteica , Transporte de Proteínas , Transducción de SeñalRESUMEN
Although many clinical trials have showed that metformin improves non-alcoholic fatty liver disease, which is a common liver disease associated with hepatic enzyme abnormalities, an animal model is required to investigate the effects of altered gene expression and post-translational processing (proteins) in mediating the observed responses. Laying hens appear to develop fatty livers, as in the case in human beings, when ingesting energy in excess of maintenance, and they can be used as an animal model for observing hepatic steatosis. The aim of this study was to investigate whether metformin could improve the non-alcoholic fatty liver of laying hens and to examine the possible mechanisms of lipid-lowering effects. Forty-eight Leghorn laying hens of Hy-Line variety W-36 - 44 weeks with 64.8% hen-day egg production - were randomly assigned into 4 treatments, each receiving 0, 10, 30, or 100mg of metformin with saline per kg body weight by daily wing vein injection. Results showed that, compared with the control, significant decreases existed in the laying rates; plasma triglyceride, cholesterol, and insulin levels; body weights; abdominal fat weights; hepatic lipid contents; and hepatic fatty acid synthase expression of layers receiving 30 or 100mg per kg body weight, whereas significant increases in their hepatic 5'adenosine monophosphate-activated protein kinase, acyl-CoA carboxylase phosphorylation, adipose triglyceride lipase, and carnitine palmitoyl transferase-1 expression were observed. These data suggest that metformin could reduce lipid deposits in the liver and that the laying hen is a valuable animal model for studying hepatic steatosis.