RESUMEN
BACKGROUND: There is growing evidence that nonalcoholic fatty liver disease (NAFLD) is associated with perturbations in liver lipid metabolism. Liver phospholipid and fatty acid composition have been shown to be altered in NAFLD. However, detailed profiles of circulating lipids in the pathogenesis of NAFLD are lacking. OBJECTIVE: Therefore, the objective of the present study was to examine circulating lipids and potential mechanisms related to hepatic gene expression between liver biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH) and healthy subjects. SUBJECTS: Plasma phospholipid and fatty acid composition were determined in 31 healthy living liver donors as healthy controls (HC), 26 patients with simple hepatic steatosis (SS) and 20 with progressive NASH. Hepatic gene expression was analyzed by Illumina microarray in a subset of 22 HC, 16 SS and 14 NASH. RESULTS: Concentrations of phosphatidylethanolamine (PE) increased relative to disease progression, HCAsunto(s)
Ácidos Grasos/sangre
, Hígado/patología
, Enfermedad del Hígado Graso no Alcohólico/sangre
, Fosfolípidos/sangre
, Adulto
, Estudios Transversales
, Hígado Graso/sangre
, Hígado Graso/diagnóstico
, Hígado Graso/patología
, Femenino
, Voluntarios Sanos
, Humanos
, Masculino
, Persona de Mediana Edad
, Enfermedad del Hígado Graso no Alcohólico/diagnóstico
, Enfermedad del Hígado Graso no Alcohólico/patología
, Adulto Joven
RESUMEN
Body mass index (BMI) and mortality in old adults from the general population have been related in a U-shaped or J-shaped curve. However, limited information is available for elderly nursing home populations, particularly about specific cause of death. A systematic PubMed/EMBASE/CINAHL/SCOPUS search until 31 May 2014 without language restrictions was conducted. As no published study reported mortality in standard BMI groups (<18.5, 18.5-24.9, 25-29.9, ≥30 kg/m(2)), the most adjusted hazard ratios (HRs) according to a pre-defined list of covariates were obtained from authors and pooled by random-effect model across each BMI category. Out of 342 hits, 20 studies including 19,538 older nursing home residents with 5,223 deaths during a median of 2 years of follow-up were meta-analysed. Compared with normal weight, all-cause mortality HRs were 1.41 (95% CI = 1.26-1.58) for underweight, 0.85 (95% CI = 0.73-0.99) for overweight and 0.74 (95% CI = 0.57-0.96) for obesity. Underweight was a risk factor for higher mortality caused by infections (HR = 1.65 [95% CI = 1.13-2.40]). RR results corroborated primary HR results, with additionally lower infection-related mortality in overweight and obese than in normal-weight individuals. Like in the general population, underweight is a risk factor for mortality in old nursing home residents. However, uniquely, not only overweight but also obesity is protective, which has relevant nutritional goal implications in this population/setting.
Asunto(s)
Índice de Masa Corporal , Anciano Frágil/estadística & datos numéricos , Hogares para Ancianos/estadística & datos numéricos , Casas de Salud/estadística & datos numéricos , Sobrepeso/mortalidad , Delgadez/mortalidad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Fenómenos Fisiológicos de la Nutrición , Factores de RiesgoRESUMEN
Multiple myeloma (MM) is preceded by the asymptomatic pre-malignant state, monoclonal gammopathy of undetermined significance (MGUS). Although MGUS patients may remain stable for years, they are at increased risk of progressing to MM. A better understanding of the relevant molecular changes underlying the transition from an asymptomatic to symptomatic disease state is urgently needed. Our studies show for the first time that the CD147 molecule (extracellular matrix metalloproteinase inducer) may be having an important biological role in MM. We first demonstrate that CD147 is overexpressed in MM plasma cells (PCs) vs normal and pre-malignant PCs. Next, functional studies revealed that the natural CD147 ligand, cyclophilin B, stimulates MM cell growth. Moreover, when MM patient PCs displaying bimodal CD147 expression were separated into CD147(bright) and CD147(dim) populations and analyzed for proliferation potential, we discovered that CD147(bright) PCs displayed significantly higher levels of cell proliferation than did CD147(dim) PCs. Lastly, CD147-silencing significantly attenuated MM cell proliferation. Taken together, these data suggest that the CD147 molecule has a key role in MM cell proliferation and may serve as an attractive target for reducing the proliferative compartment of this disease.
Asunto(s)
Basigina/fisiología , Proliferación Celular , Mieloma Múltiple/patología , Basigina/administración & dosificación , Basigina/genética , Línea Celular Tumoral , Ciclofilinas/farmacología , ADN/biosíntesis , Regulación Neoplásica de la Expresión Génica , Humanos , Mieloma Múltiple/químicaRESUMEN
DNA double-strand breaks (DSBs) are deleterious lesions that can lead to chromosomal anomalies, genomic instability and cancer. The histone protein H2AX has an important role in the DNA damage response (DDR) and the presence of phospho-H2AX (γH2AX) nuclear foci is the hallmark of DSBs. We hypothesize that ongoing DNA damage provides a mechanism by which chromosomal abnormalities and intratumor heterogeneity are acquired in malignant plasma cells (PCs) in patients with multiple myeloma (MM). Therefore, we assessed PCs from patients with the premalignant condition, monoclonal gammopathy of undetermined significance (MGUS) and MM, as well as human MM cell lines (HMCLs) for evidence of DSBs. γH2AX foci were detected in 2/5 MGUS samples, 37/40 MM samples and 6/6 HMCLs. Notably, the DSB response protein 53BP1 colocalized with γH2AX in both MM patient samples and HMCLs. Treatment with wortmannin decreased phosphorylation of H2AX and suggests phosphoinositide (PI) 3-kinases and/or PI3-kinase-like family members underlie the presence of γH2AX foci in MM cells. Taken together, these data imply that ongoing DNA damage intensifies across the disease spectrum of MGUS to MM and may provide a mechanism whereby clonal evolution occurs in the monoclonal gammopathies.
Asunto(s)
Daño del ADN , Histonas/metabolismo , Mieloma Múltiple/genética , Proteínas de la Ataxia Telangiectasia Mutada , Ciclo Celular , Proteínas de Ciclo Celular/fisiología , Línea Celular Tumoral , Núcleo Celular/química , Genes p53 , Histonas/análisis , Humanos , Mieloma Múltiple/metabolismo , Mutación , Fosfatidilinositol 3-Quinasas/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Proteínas Serina-Treonina Quinasas/fisiologíaRESUMEN
BACKGROUND: Hepatitis C virus (HCV) is the most common indication for liver transplantation, but HCV recurrence is frequent after 1 year and is associated with increased morbidity and mortality. Oxidative stress (OxS) is involved in the pathogenesis of HCV, but little is known about its presence prior to disease recurrence. AIM: To determine if at 6 months HCV-positive liver recipients (HCV-OLT) without recurrence were oxidatively stressed. METHODS: 33 HCV-OLTs, 12 controls, and 39 HCV-positive nontransplant patients (HCV-NTs). OxS was assessed by using commercial kits to measure liver lipid peroxidation (LPO) and antioxidant potential (AOP). Plasma vitamin E, retinol (HPLC), and vitamin C (spectrophotometry) were assessed. We collected Anthropometry and 3-day food records. We performed analysis by the Kruskal-Wallis test expressing data as mean values +/- standard errors of the mean. RESULT: Waist-hip ratio was higher in both HCV-OLTs and HCV-NTs compared to the controls. HCV-OLTs showed higher hepatic LPO (mumol malondialdehyde/g tissue) versus controls (1.4 +/- 0.20 vs 0.54 +/- 0.10; P = .010) and compared to HCV-NTs (0.98 +/- 0.17; P = .030). No significant differences were found among the groups regarding hepatic AOP. However, lower plasma AOP (micromols UEA) were observed in HCV-OLTs (0.07 +/- 0.008) versus controls (0.17 +/- .040; P = .021) or HCV-NTs (0.08 +/- 0.009; P = .015) versus controls. Plasma gamma-tocopherol was higher in HCV-OLTs and HCV-NTs compared to controls (P = .001). We observed lower vitamin A intake in HCV-OLTs compared with the other two groups (P = .001). CONCLUSIONS: HCV-OLTs without disease recurrence are oxidatively stressed compared with control and HCV-NTs. Future research is needed to determine the impact of this increased oxidative stress on HCV disease recurrence.
Asunto(s)
Hepatitis C/cirugía , Trasplante de Hígado/fisiología , Estrés Oxidativo/fisiología , Antioxidantes/metabolismo , Ácido Ascórbico/sangre , Estatura , Índice de Masa Corporal , Peso Corporal , Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus/epidemiología , Femenino , Hepatitis C/metabolismo , Hepatitis C/fisiopatología , Humanos , Peróxidos Lipídicos/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia , Vitamina A/sangre , Vitamina E/sangre , Relación Cintura-CaderaRESUMEN
BACKGROUND: Hepatitis C virus (HCV) reinfection after liver transplantation is universal and progresses to cirrhosis in 10% to 30% of patients. Several risk factors are associated with progression. Oxidative stress may be involved because it has a role in the pathogenesis of HCV. OBJECTIVE: To determine whether HCV liver recipients with disease recurrence are more oxidatively stressed than those with no recurrence. METHODS: Measurements were performed at 12 months posttransplantation, and in a subgroup of patients at 6 months. Liver lipid peroxidation (LPO), antioxidant potential, plasma vitamin E, retinol, and vitamin C were measured. Demographic data, pretransplantation viral load, anthropometry, and 3-day food records were also obtained. Data were log-transformed; analysis was performed using the independent t test, Pearson correlation, and multivariate regression analysis. RESULTS: Recipients of HCV livers with recurrence (n = 21) had higher liver LPO (mean [SEM] micromoles of malondialdehyde per gram of liver tissue, 1.66 [0.28]) vs those with no recurrence (n = 16; 0.88 [0.13]) (P = .02). A significant relationship was found between liver LPO and HCV recurrence, and this significance continued when accounting for pretransplantation viral load and donor age. Six patients with recurrence and 11 with no recurrence also had measurements obtained at 6 months posttransplantation. Those with recurrence at 12 months had significantly higher hepatic LPO at 6 months (1.86 [0.62]) compared with those with no recurrence (0.75 [0.14]) (P = .04). CONCLUSIONS: Recipients of HCV livers with recurrence are more oxidatively stressed at 6 and 12 months compared with those with no recurrence. Accounting for viral load and donor age, oxidative stress was independently associated with recurrence. More research is needed to confirm this association.
Asunto(s)
Antioxidantes/metabolismo , Hepatitis C/cirugía , Peroxidación de Lípido , Trasplante de Hígado/fisiología , Adolescente , Adulto , Anciano , Aspartato Aminotransferasas/sangre , Biopsia , Femenino , Hepatitis C/patología , Humanos , Inflamación/patología , Cirrosis Hepática/patología , Masculino , Micronutrientes/metabolismo , Persona de Mediana Edad , Necrosis , Estrés Oxidativo , Selección de Paciente , Recurrencia , Carga ViralRESUMEN
Survival after lung transplantation is limited by bronchiolitis obliterans syndrome (BOS). Oxidative stress (OxS) can be associated with BOS due to chronic inflammation. The type of fat and antioxidant intakes may also contribute to OxS. Our aim was to compare OxS and nutritional intakes in non-BOS versus various stages of BOS. Fifty-eight lung recipients with versus without BOS were prospectively classified as: non-BOS; BOS Op-1 (mild), and BOS 2-3 (severe). We measured nutritional intake and plasma vitamins A, C, and E. Among a subgroup of 37 patients, OxS was assessed by measuring lipid peroxidation (LPO micromol/L MDA) and oxidized glutathione (GSSG) in bronchoalveolar lavage BAL fluid (BALF). One-way analysis of variance was used to compare groups. Results are reported as mean values +/- standard errors of the mean. There was no significant difference in demographic features on time posttransplant among groups. Although there were comparable cell counts in BALF, severe BOS patients showed significantly higher BALF LPO concentrations when compared with milder stage of BOS or with non-BOS (P = .001, for both). Severe BOS recipients also displayed higher BALF GSSG concentrations compared to milder stage of BOS (P = .001) or non-BOS (P = .007). In conclusion, patients with severe BOS were more oxidatively stressed compared with mild and non-BOS recipients.
Asunto(s)
Bronquiolitis Obliterante/fisiopatología , Bronquiolitis Obliterante/cirugía , Enfermedades Pulmonares/fisiopatología , Trasplante de Pulmón/fisiología , Estado Nutricional , Estrés Oxidativo , Líquido del Lavado Bronquioalveolar/química , Estudios Transversales , Estudios de Seguimiento , Glutatión/análisis , Disulfuro de Glutatión/análisis , Rechazo de Injerto , Humanos , Peróxidos Lipídicos/análisis , Trasplante de Pulmón/mortalidad , Estudios Retrospectivos , Tocoferoles/análisis , Vitamina A/análisis , Vitaminas/administración & dosificación , Vitaminas/metabolismoRESUMEN
Survivin is a member of the inhibitor of apoptosis protein (IAP) family and functions both as an apoptosis inhibitor and a regulator of cell division. Survivin overexpression is common in many human tumors and correlates with survival in large cell non-Hodgkin's lymphoma. To evaluate this molecule as a potential therapeutic target in large-cell lymphoma, we evaluated the effect of survivin inhibition both in vitro and in vivo. Using an antisense oligonucleotide (ASO) approach, cell growth was significantly inhibited in the DoHH2, RL and HT lymphoma cell lines. In a lymphoma xenograft model, the development of tumors as well as the growth of established tumors was inhibited in the survivin ASO-treated mice compared to controls. To assess the efficacy of the survivin ASO in combination with other biological agents, we combined the survivin ASO with an anti-CD20 monoclonal antibody, rituximab. The effect of survivin ASO and rituximab in combination was additive in vitro. In vivo, however, suppression of tumor growth with the combination was not significantly superior to controls. We conclude that inhibition of survivin expression is an attractive therapeutic strategy in aggressive non-Hodgkin's lymphomas, and that combining survivin ASO with rituximab may enhance the efficacy of this approach.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Linfoma no Hodgkin/patología , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Caspasa 3 , Caspasas/metabolismo , División Celular/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Apoptosis , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/prevención & control , Ratones , Ratones SCID , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Neoplasias , Oligonucleótidos Antisentido/farmacología , Survivin , Células Tumorales CultivadasRESUMEN
OBJECTIVE: We investigated whether ingestion of polyphenols from fruit juices or a fruit-vegetable-concentrate affects lymphocyte proliferation and apoptosis in human immunodeficiency virus (HIV)-seropositive (HIV(+)) and HIV-seronegative (HIV(-)) subjects. DESIGN: Randomized, prospective pilot intervention study. SETTING: University of Bonn, Department of General Internal Medicine. SUBJECTS: A total of 23 HIV(+) subjects from the HIV outpatient clinic, 18 HIV(-) controls. INTERVENTIONS: Subjects ingested either 1 l of fruit juice or 30 ml of fruit-vegetable-concentrate daily for 16 weeks in addition to their regular diet. Lymphocyte proliferation and apoptosis were investigated in peripheral blood mononuclear cells at baseline, during 16-weeks of intervention, and after a 6-week washout. Proliferation was assessed by (3)H-thymidine incorporation and apoptosis by nuclear content as measured by flow cytometry. RESULTS: Supplementation of fruit juices increased phytohemagglutinin-induced lymphocyte proliferation (mitotic index) in HIV(+) patients from 18+/-16 to 40+/-34 (P=0.004) and in healthy controls from 27+/-16 to 51+/-21 (P=0.016). Apoptosis was not affected in HIV(+) patients, but rose in healthy controls from 9+/-10 to 34+/-11 (apoptotic index; P=0.001). Intervention with concentrate did not significantly alter proliferation and apoptosis in HIV(+) and HIV(-) subjects. CONCLUSIONS: Even though apoptosis did not change in HIV(+) subjects, ingestion of polyphenol-rich fruit juices might be favorable to HIV(+) patients due to enhanced proliferation, which could restore disturbances in T-cell homeostasis. In healthy controls, increased lymphocyte proliferation during juice consumption was counterbalanced by increased apoptosis.
Asunto(s)
Antioxidantes/administración & dosificación , Apoptosis , Frutas/química , Seropositividad para VIH/sangre , Verduras/química , Vitaminas/administración & dosificación , Adulto , Antirretrovirales/uso terapéutico , Bebidas/análisis , Recuento de Linfocito CD4 , Registros de Dieta , Femenino , Flavonoides/administración & dosificación , Flavonoides/análisis , Alemania , Seropositividad para VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Fenoles/administración & dosificación , Proyectos Piloto , Polifenoles , TiempoRESUMEN
Interleukin 6 (IL-6) is known to play an important role in the biology of the malignant plasma cells in multiple myeloma. In an effort to better understand IL-6 stimulated myeloma cell growth, we have performed gene expression profiling to identify IL-6 early response genes. Using the KAS-6/1 IL-6-dependent human myeloma cell line, IL-6 stimulation dramatically induced expression of monocyte chemoattractant protein-1 (MCP-1) mRNA. To verify this result, we used reverse transcriptase PCR and RNAse protection assays and demonstrated using both assays that MCP-1 is indeed an IL-6 responsive gene in a variety of IL-6-responsive myeloma cell lines. Moreover, we also demonstrated IL-6 stimulated MCP-1 secretion by the myeloma cell lines as well as by fresh patient tumor cells. Lastly, we present evidence that fresh patient tumor cells express mRNA for the MCP-1 receptor, CCR2, as do myeloma cell lines along with a second MCP-1 receptor, CCR11. Although MM cell chemotaxis in response to MCP-1 was only minimal, we were able to demonstrate that MCP-1 stimulated activation of MAPK. Because of the important role that this chemokine plays in both angiogenesis and bone homeostasis, and the ability of MCP-1 to activate myeloma cells, these results suggest a new mechanism by which IL-6 may contribute to disease pathogenesis.
Asunto(s)
Quimiocina CCL2/genética , Interleucina-6/fisiología , Mieloma Múltiple/metabolismo , Secuencia de Bases , Cartilla de ADN , ADN Complementario , Activación Enzimática , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To investigate whether antioxidant polyphenols from fruit juices or a fruit-vegetable-concentrate increase the plasma antioxidant capacity in HIV-infected and healthy subjects. DESIGN: Twenty-three HIV-seropositive and 18 seronegative adults were randomized to ingest either 1 l of fruit juice or 30 ml fruit-vegetable-concentrate per day over 16 weeks in addition to their normal Western diet. METHODS: Plasma antioxidant capacity was determined as Trolox equivalent antioxidant capacity (TEAC) at baseline, after 1 and 16 weeks of intervention, and after a 6 week washout. RESULTS: There was no difference in plasma antioxidant capacity between HIV-infected and healthy subjects at baseline (P=0.1). After 16 weeks of intervention TEAC increased in HIV-positive subjects with both types of polyphenol supplementation (juice, 1.38+/-0.07 to 1.42+/-0.04 mM, P=0.034; concentrate, 1.40+/-0.09 to 1.46+/-0.08 mM, P=0.025). TEAC was not altered by either type of supplementation in HIV-seronegative subjects. CONCLUSION: Plasma antioxidant capacity can be increased by long-term ingestion of polyphenols from fruit juices or fruit-vegetable-concentrate in HIV-seropositive but not in HIV-seronegative subjects. SPONSORSHIP: This study was supported by a grant and Cellagon aurum from HG Berner GmbH, Altenholz, and fruit juices from Eckes Granini GmbH & Co. KG, Nieder-Olm.
Asunto(s)
Antioxidantes/metabolismo , Flavonoides , Frutas/química , Seronegatividad para VIH/fisiología , Seropositividad para VIH/metabolismo , Verduras/química , Adulto , Femenino , Humanos , Cinética , Masculino , Persona de Mediana Edad , Fenoles , Polímeros , PolifenolesRESUMEN
Insulin-like growth factors (IGF-I, IGF-II) have long been recognized as important mitogens in many types of malignancies. Because the role of IGFs in growth control of myeloma cells has not been extensively examined, we have used a panel of IL-6-responsive myeloma cell lines to address this issue. Initial studies demonstrated that IGF-I and IGF-II significantly enhanced DNA synthesis by each of the four cell lines, even when assayed in the absence of IL-6. The specificity of the IGF response was confirmed using an IGF-I receptor Ab, and additional studies demonstrated that IGF responsiveness did not result from induction of autocrine IL-6 expression. When IL-6 responsiveness was assayed, three of four cell lines synthesized DNA in response to IL-6 alone; however, the magnitude of responsiveness was greatly enhanced by addition of IGFs. Similar results were obtained when proliferation and cell cycle progression were analyzed. By contrast, the KP-6 cell line was responsive to IL-6 only when IGF was present. Finally, we analyzed the effects of IGF-I on normal B lymphocytes. IGF, however, did not stimulate B cell DNA synthesis, suggesting that IGF responsiveness may represent a key difference between normal and malignant B cells. In summary, these studies suggest that IGFs may play an important role in multiple myeloma by virtue of their ability to directly stimulate tumor cell growth as well as modulate the magnitude of IL-6-driven growth.
Asunto(s)
Factor II del Crecimiento Similar a la Insulina/farmacología , Factor I del Crecimiento Similar a la Insulina/farmacología , Interleucina-6/metabolismo , Mieloma Múltiple/patología , División Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Mieloma Múltiple/metabolismo , Células Tumorales CultivadasRESUMEN
Although IFN-alpha is commonly used as maintenance treatment for multiple myeloma patients, its effectiveness is varied. In this study, we have used a panel of IL-6 responsive myeloma cell lines that vary remarkably in responsiveness to IFN-alpha. Three cell lines were growth arrested by IFN-alpha; however, IFN-alpha significantly stimulated growth of the fourth cell line, KAS-6/1. Our studies have focused on elucidating the mechanism of differential IFN-alpha responsiveness. First, we have shown that IFN-alpha-stimulated growth of the KAS-6/1 cells did not result from induction of autocrine IL-6 expression. Second, analysis of Stats 1, 2, and 3 and IFN regulatory factor-1 (IRF-1) and IRF-2 activation failed to reveal differences between the IFN-alpha growth-arrested or growth-stimulated cells. Third, although IFN-alpha treatment of the IFN-alpha growth-inhibited cell lines reduced IL-6 receptor (IL-6R) expression, IFN-alpha also reduced KAS-6/1 IL-6R expression. Finally, although IFN-alpha treatment reduced IL-6R numbers on each cell line, analysis of Stat protein activation revealed that the receptors were still functional. We conclude that myeloma cell responsiveness to IFN-alpha is heterogeneous and that mechanisms of IFN-alpha-mediated growth inhibition other than IL-6R downregulation must exist in myeloma. Identification of these mechanisms may allow development of agents that are more universally effective than IFN-alpha.