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Introduction: This study aimed to analyze the effects of cannabis oil (cannabidiol:tetrahydrocannabinol [CBD:THC], 2:1 ratio) on the mechanisms involved in hepatic steatosis and oxidative stress in an experimental model of metabolic syndrome (MS) induced by a sucrose-rich diet (SRD). We hypothesized that noninvasive oral cannabis oil administration improves hepatic steatosis through a lower activity of lipogenic enzymes and an increase in carnitine palmitoyltransferase-1 (CPT-1) enzyme activity involved in the mitochondrial oxidation of fatty acids. Furthermore, cannabis oil ameliorates liver oxidative stress through the regulation of the main regulatory factors involved, nuclear factor erythroid 2 (NrF2) and nuclear factor-kB (NF-κB) p65. For testing this hypothesize, a relevant experimental model of MS was induced by feeding rats with a SRD for 3 weeks. Methods: Male Wistar rats were fed the following diets for 3 weeks: reference diet: standard commercial laboratory diet, SRD, and SRD + cannabis oil: noninvasive oral administration of 1 mg/kg body weight cannabis oil daily. The full-spectrum cannabis oil presents a total cannabinoid CBD:THC 2:1 ratio. Serum glucose, triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, uric acid, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (AP), N-arachidonoylethanolamine or anandamide and 2-arachidonoylglycerol endocannabinoids levels, thiobarbituric acid reactive substance (TBARS) levels, and non-enzymatic antioxidant capacity (ferric ion-reducing antioxidant power [FRAP]) were evaluated. In the liver tissue: histology, nonalcoholic fatty liver disease activity score (NAS), triglycerides and cholesterol content, lipogenic enzyme activities (fatty acid synthase, acetyl-CoA carboxylase, malic enzyme, and glucose-6-phosphate dehydrogenase), enzyme related to mitochondrial fatty acid oxidation (CPT-1), reactive oxygen species, TBARS, FRAP, glutathione, catalase, glutathione peroxidase, and glutathione reductase enzyme activities. 4-hydroxynonenal, NrF2, and NF-κB p65 levels were analyzed by immunohistochemistry. Results: The results showed that SRD-fed rats developed dyslipidemia, liver damage, hepatic steatosis (increase of key enzymes related to the novo fatty acid synthesis and decrease of key enzyme related to mitochondrial fatty acid oxidation), lipid peroxidation, and oxidative stress. Hepatic NrF2 expression was significantly decreased and NF-κB p65 expression was increased. Cannabis oil administration improved dyslipidemia, liver damage, hepatic steatosis, lipid peroxidation (improving enzymes involved in lipid metabolism), and oxidative stress. In the liver tissue, NrF2 expression increased, and NF-κB p65 expression was reduced. Conclusion: The present study revealed new aspects of liver damage and steatosis, lipid peroxidation, and oxidative stress in dyslipidemic insulin-resistant SRD-fed rats. We demonstrated new properties and molecular mechanisms of cannabis oil (CBD:THC, 2:1 ratio) on lipotoxicity and hepatic oxidative stress in an experimental model of MS.
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Genome instability is a feature of cancer cells, transcription being an important source of DNA damage. This is in large part associated with R-loops, which hamper replication, especially at head-on transcription-replication conflicts (TRCs). Here we show that TRCs trigger a DNA Damage Response (DDR) involving the chromatin network to prevent genome instability. Depletion of the key chromatin factors INO80, SMARCA5 and MTA2 results in TRCs, fork stalling and R-loop-mediated DNA damage which mostly accumulates at S/G2, while histone H3 Ser10 phosphorylation, a mark of chromatin compaction, is enriched at TRCs. Strikingly, TRC regions show increased mutagenesis in cancer cells with signatures of homologous recombination deficiency, transcription-coupled nucleotide excision repair (TC-NER) and of the AID/APOBEC cytidine deaminases, being predominant at head-on collisions. Thus, our results support that the chromatin network prevents R-loops and TRCs from genomic instability and mutagenic signatures frequently associated with cancer.
Assuntos
Cromatina , Neoplasias , Humanos , Cromatina/genética , Replicação do DNA/genética , Transcrição Gênica , Mutagênese/genética , Dano ao DNA/genética , Instabilidade Genômica/genética , Neoplasias/genética , Neoplasias/prevenção & controle , Histona Desacetilases/genética , Proteínas Repressoras/genéticaRESUMO
The purposes of the present study were to analyze liver inflammation and endothelial dysfunction in an experimental model of metabolic syndrome (MS) induced by chronic administration of a sucrose-rich diet (SRD) and to evaluate the effects of chia seed as a therapeutic strategy. Male Wistar rats were fed with a reference diet (RD) for 6 months or a SRD for 3 months. Then, the latter group was randomly divided into two subgroups. One subgroup continued receiving the SRD for up to 6 months and the other was fed with a SRD where whole chia seed was incorporated as a source of dietary fat for the next 3 months (SRD + CHIA). Results showed that rats fed a SRD for a long period of time developed dyslipidemia, hyperglycemia, inflammation and endothelial dysfunction. Hepatic NAS, IL-1ß, NFκB p65, PAI-1, and F4-80 expression, as well as MPO activity were significantly increased and IL-10 expression was significantly decreased; this was accompanied by increased plasma IL-6 and TNF-α levels in rats fed a SRD. In addition, serum and liver nitric oxide (NO) levels and nitric oxide synthase (NOS) were significantly increased in the SRD group. In addition, a significant increase in hepatic iNOS expression and a positive correlation of this with liver NFκB p65 was found. We observed a significant increase in hepatic intercellular adhesion molecule (ICAM), and a negative correlation of this with liver Nrf2 was found. The administration of chia seed for 3 months reversed dyslipidemia, hyperglycemia, inflammation and endothelial dysfunction. In the liver tissue, NAS, IL-1ß, IL-10, NFκB p65, PAI-1, and F4-80 expression and MPO activity were normalized. Serum and liver NO and NOS levels and hepatic iNOS expression were decreased and this last one was associated with a decrease in liver NFκB p65 levels. Hepatic ICAM-1 was normalized and negatively correlated with liver NrF2 levels. This study showed new aspects of liver inflammation and endothelial dysfunction in dyslipidemic insulin resistant rats chronically fed with a sucrose-rich diet. In addition, we demonstrated new properties and molecular mechanisms associated with beneficial effects on inflammation and endothelial dysfunction of chia seed as a therapeutic strategy.
Assuntos
Dislipidemias , Hepatite , Hiperglicemia , Síndrome Metabólica , Salvia , Ratos , Masculino , Animais , Interleucina-10/metabolismo , Salvia hispanica , Fator 2 Relacionado a NF-E2/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Ratos Wistar , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Sementes/metabolismo , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Dislipidemias/metabolismo , Fígado/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Hepatite/metabolismo , Sacarose/metabolismo , Modelos Teóricos , Hiperglicemia/metabolismoRESUMO
The aim of this study was to analyze the liver injury and oxidative stress in an experimental model of Metabolic Syndrome (MS) induced by chronic administration of a sucrose-rich diet (SRD) and to evaluate the effects of chia seed as a therapeutic strategy. Male Wistar rats were fed with a reference diet (RD) -6 months- or a SRD -3 months. Then, the latter group was randomly divided into two subgroups. One subgroup continued receiving the SRD for up to 6 months and the other was fed with a SRD where whole chia seed was incorporated as a source of dietary fat for the next 3 months (SRD+CHIA). The results showed that rats fed with a SRD for a long period of time developed dyslipidemia, hyperglycemia, hepatic lipid accumulation, liver injury, hepatic lipid peroxidation and oxidative stress. Hepatic NrF2 expression was significantly decreased. In addition, a significant increase in hepatic NFκB p65 expression and a positive correlation of this with plasma TNFα levels were found. The administration of chia seed for 3 months reversed dyslipidemia, hyperglycemia, lipid accumulation, liver injury, lipid peroxidation and oxidative stress. In the liver tissue, NrF2 expression was normalized and NFκB p65 expression was decreased, the latter was associated with a decrease in plasma TNFα levels. The present study showed new aspects of liver damage, lipid peroxidation and oxidative stress in dyslipidemic insulin resistant rats chronically fed with a sucrose-rich diet. However, we demonstrated new properties and molecular mechanisms associated with the beneficial anti-oxidant effects of chia seed consumption.
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Dislipidemias , Hiperglicemia , Salvia , Animais , Dieta , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Hiperglicemia/metabolismo , Lipídeos , Fígado/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Salvia/metabolismo , Salvia hispanica , Sementes/metabolismo , Sacarose/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The effects of microcapsules containing brewer's spent grain (BSG) peptides were evaluated on a hypertensive/insulin-resistant rat model induced by a sucrose-rich diet (SRD) administration. Animals received for 100 days the control diet (CD), SRD, and CD and SRD diets supplemented with microencapsulated peptides (CD-P and SRD-P). During the experimental period, blood pressure was monitored. Glycemia, tissue glycogen content, nitric oxide, and the activity of enzymes related to hypertensive and diabetogenic mechanisms were determined. The consumption of SRD caused hypertensive and hyperglycemic effects compared to CD. However, the SRD-P group presented lower systolic pressure at the middle of ingestion, achieving similar values than the CD. The SRD-P rats decreased all enzymes' activities compared to the SRD reaching the values of CD, except for those of α-amylase in cecal content and DPP-IV in serum. It was possible to corroborate potential antihypertensive and antidiabetogenic in vivo effects of the microencapsulated BSG peptides. PRACTICAL APPLICATIONS: Brewer's spent grain (BSG) is the main waste obtained from brewing industry. Bioactive peptides obtained after an enzymatic hydrolysis of proteins with in vitro antihypertensive and antidiabetogenic activity have been described. However, to corroborate the action of these bioactive peptides, in vivo studies are necessary. In the present work, microcapsules containing bioactive peptides from BSG were administered on the rat model with induced hypertension and insulin-resistance, corroborating an in vivo antihypertensive and antidiabetogenic effects by inhibition of enzymes related with blood pressure regulation and glucose metabolism. This work demonstrated that microcapsules of BSG peptides could be included into functional foods formulations, or used as dietary supplement for improving health and the prevention of non-communicable diseases, adding value to the brewing process by-product.
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Anti-Hipertensivos , Hipertensão , Animais , Anti-Hipertensivos/farmacologia , Cápsulas/análise , Cápsulas/metabolismo , Grão Comestível/química , Grão Comestível/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Hipertensão/tratamento farmacológico , Insulina/metabolismo , Óxido Nítrico/metabolismo , Peptídeos/metabolismo , Ratos , Sacarose/análise , alfa-Amilases/metabolismoRESUMO
The aim of this study was to analyze the effects of Salvia hispanica L. (chia) seed upon metabolic pathways that play a key role in adipose tissue lipid handling which could be involved in visceral adiposity reduction developed in rats fed a sucrose-rich diet (SRD). Male Wistar rats were fed with a reference diet (RD) -6 months- or SRD-3 months. Then, the last group was randomly divided into two subgroups. One subgroup continued receiving the SRD up to 6 months and the other was fed with a SRD where whole chia seed was incorporated as the source of dietary fat for the next 3 months (SRD + CHIA). Results showed that chia seed in the SRD-fed rat reduced the abdominal and thoracic circumferences, carcass fat content, adipose tissue weights, and visceral adiposity index. This was accompanied by an improvement in insulin sensitivity and plasma lipid profile. In epididymal adipose tissue, the decreased fat cell triglyceride content was associated with a reduction in both, FAT/CD 36 plasma membrane levels and the fat synthesis enzyme activities. There were not changes in oxidative CPT enzyme activities. PKCß and the precursor and mature forms of SREBP-1 protein levels were decreased, while pAMPK was increased. Our findings suggest that chia seed supplementation can modulate essential pathways of lipid metabolism in adipose tissue, contributing to reduced visceral fat accumulation in SRD-fed rats.
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Salvia , Adipócitos , Tecido Adiposo , Animais , Dieta , Masculino , Ratos , Ratos Wistar , Sementes , SacaroseRESUMO
The aim of this study was to analyze blood coagulation, endothelial dysfunction and liver fibrosis in an experimental model of Metabolic Syndrome (MS) induced by chronic administration of a sucrose-rich diet (SRD) and to evaluate the effects of chia seed as a therapeutic strategy. Male Wistar rats were fed with a reference diet (RD) - 6 months - or a SRD - 3 months. Then, the last group was randomly divided into two subgroups. One subgroup continued receiving the SRD for up to 6 months and the other was fed with a SRD where whole chia seed was incorporated as the source of dietary fat for the next 3 months (SRD + CHIA). Results showed that rats fed a SRD for a long period of time develop dyslipidemia, visceral adiposity, insulin resistance, and a hypercoagulable and hypofibrinolytic basal state. Hepatic VCAM-1 (main adhesion molecules involved in endothelial dysfunction) expression was significantly increased. In addition, the SRD group presented hepatic steatosis, a significant increase in interstitial collagen deposition and hydroxyproline content. Liver TGF-ß1 (a key cytokine involved in fibrogenesis) levels increased and a negative correlation with PPARα protein mass levels was found. The administration of chia seed for 3 months reversed dyslipidemia, visceral adiposity and insulin resistance. Platelet count, coagulation parameters and plasma fibrinogen levels were normalized. In the liver tissue, VCAM-1 expression, steatosis, interstitial collagen deposition and the hydroxyproline content decreased. TGF-ß1 expression was decreased and this was associated with an increase in the PPARα protein levels. The present study showed new aspects in the progression from liver steatosis to fibrosis in dyslipidemic insulin-resistant rats chronically fed a sucrose-rich diet. Chia seed supplementation could be used as a functional food and a potential dietary strategy to prevent or ameliorate disorders related to atherothrombotic cardiovascular events and NASH.
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Anticoagulantes/farmacologia , Hipolipemiantes/farmacologia , Extratos Vegetais/farmacologia , Salvia hispanica , Animais , Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Açúcares da Dieta , Modelos Animais de Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/tratamento farmacológico , Alimento Funcional , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , SementesRESUMO
Tigecycline (TGC), a glycylcycline, has expanded activity against Gram-positive and Gram-negative, anaerobic, and atypical bacteria. Two phase 3 studies were conducted. Hospitalized patients with community-acquired pneumonia (CAP) were randomized to intravenous (IV) TGC (100 mg followed by 50 mg bid) or IV levofloxacin (LEV) (500 mg bid). In 1 study, patients could be switched to oral LEV after at least 3 days intravenously. The coprimary efficacy end points were as follows: clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC). The secondary end points were as follows: microbiologic efficacy and susceptibility to TGC for CAP bacteria. Safety evaluations were included. Eight hundred ninety-one were patients screened: 846 mITT (TGC 424, LEV 422), 574 CE (TGC 282, LEV 292). Most patients had Fine Pneumonia Severity Index II to IV (80.7% TGC, 74.4% LEV, mITT). At TOC (CE), TGC cured 253/282 patients (89.7%) and LEV cured 252/292 patients (86.3%); the absolute difference of TGC-LEV was 3.4% (95% confidence interval [CI], -2.2 to 9.1, noninferior [P < 0.001]). In c-mITT, TGC cured 319/394 patients (81.0%) and LEV cured 321/403 patients (79.7%); the absolute difference of TGC-LEV was 1.3% (95% CI -4.5 to 7.1, noninferior [P < 0.001]). The drug-related adverse events (AEs) of nausea (20.8% TGC versus 6.6% LEV) and vomiting (13.2% TGC versus 3.3% LEV) were significantly higher in TGC; elevated alanine aminotransferase (2.8% TGC versus 7.3% LEV) and aspartate aminotransferase (2.6% TGC versus 6.9% LEV) were significantly higher in LEV. Discontinuations for AEs were low (TGC, 26 patients [6.1%]; LEV, 34 patients [8.1%]). TGC appeared safe and achieved cure rates similar to LEV in hospitalized patients with CAP.
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Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Levofloxacino , Minociclina/análogos & derivados , Ofloxacino/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Feminino , Infecções por Bactérias Gram-Negativas , Infecções por Haemophilus/tratamento farmacológico , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Minociclina/administração & dosagem , Minociclina/efeitos adversos , Minociclina/uso terapêutico , Ofloxacino/administração & dosagem , Ofloxacino/efeitos adversos , Infecções Pneumocócicas/tratamento farmacológico , Tigeciclina , Resultado do TratamentoRESUMO
OBJECTIVES: In our hospital, a continuous intervention program aimed at optimizing the quality of antibiotic use was introduced by late 1999 and antibiotic consumption was a major outcome for assessment. However, healthcare conditions have been subject to change over the last five years, and a pronounced economic crisis in 2002 affected the availability of antibiotics. Therefore, we hypothesized that the consumption of these drugs could be a suitable indirect marker of the crisis. DESIGN: We performed segmented regression analysis between different periods. Variations in antibiotic consumption during periods corresponding to the four-phase intervention program (from 1999 to the first six months of 2001) were assumed to be 'intervention-induced', while those observed during the crisis period were considered as 'situation-enforced'. RESULTS: Whereas the intervention-induced (desirable) decrease of total antibiotic and carbapenem consumption proved to correlate with a decreased crude mortality rate during the control period prior to the crisis (R2, 0.82 and 0.91, respectively), the crisis-induced (undesirable) decrease in total antibiotic and carbapenem consumption correlated with an increased mortality during this phase (R2, 0.80 and 0.75, respectively). CONCLUSIONS: Our results illustrate that a reduction in antibiotic consumption does not always represent a favorable outcome from an intervention program on prescribing practice. Moreover, it may be a sensitive indirect marker of a deficient healthcare condition leading to an increase in in-hospital mortality.
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Antibacterianos/administração & dosagem , Infecção Hospitalar/tratamento farmacológico , Uso de Medicamentos/estatística & dados numéricos , Distribuição de Qui-Quadrado , Infecção Hospitalar/mortalidade , Humanos , Modelos Lineares , Avaliação de Resultados em Cuidados de Saúde , Padrões de Prática Médica , Estatísticas não ParamétricasRESUMO
Several findings from Argentina provide compelling evidence of the need for more rational use of antimicrobial agents. Thus, a multidisciplinary antimicrobial treatment committee for the development of a hospital-wide intervention program was formed to optimize the quality of antibiotic use in hospitals. Four successive steps were developed during 6-month periods: baseline data collection, introduction of a prescription form, education, and prescribing control. Sustained reduction of drug consumption was shown during the study (R2=0.6885; P=.01). Total cost savings was 913,236 US dollars. To estimate the consumption of cefepime and aminopenicillin-sulbactam in relation to that of the third-generation cephalosporins, 2 indices were calculated: Icfp and Iams, respectively. Decreasing resistance to ceftriaxone by Proteus mirabilis and Enterobacter cloacae proved to be associated with increasing Icfp. Decreasing rates of methicillin-resistant Staphylococcus aureus were related to increasing Iams. The present study indicates that a systematic program performed by a multidisciplinary team is a cost-effective strategy for optimizing antibiotic prescribing.
Assuntos
Antibacterianos/economia , Redução de Custos , Prescrições de Medicamentos , Farmacorresistência Bacteriana , Infecção Hospitalar/mortalidade , Uso de Medicamentos/economia , Hospitalização , Hospitais , Humanos , Unidades de Terapia Intensiva , Testes de Sensibilidade Microbiana , Padrões de Prática Médica , Estatística como AssuntoRESUMO
Nutritional insults during pregnancy and lactation (P + L) are often associated with offspring health risks. We investigated the effect of maternal exposure to a sucrose-rich diet (SRD) during P + L on glucose and lipid metabolism of adult offspring regardless of post-weaning diet. Dams were fed an SRD or a control diet (CD) during P + L. After weaning, male offspring from SRD and CD dams were divided into two groups and fed a CD or SRD until 150 days old forming CD-CD, CD-SRD, SRD-SRD and SRD-CD groups. Offspring where SRD was fed at any period of life showed: (1) increased adipose tissue weight without changes in the final body weight; (2) dyslipidemia as a result of increased very low density lipoprotein triglyceride secretion rate and decreased triglyceride clearance; (3) hepatic steatosis associated with increased activity of key enzymes involved in liver de novo lipogenesis and significant decrease of the activity of mitochondrial fatty acid oxidation enzyme. These results were more pronounced in CD-SRD and SRD-SRD groups. (4) Hyperglycemia without changes in insulin levels, plus a deterioration of intravenous glucose tolerance and intraperitoneal insulin tolerance test. We hypothesized that SRD during P + L could be associated with a programming effect on glucose homeostasis and hepatic lipid metabolism that predispose offspring to develop later-life insulin resistance and metabolic disorders, regardless of post-natal diet.
Assuntos
Sacarose Alimentar/efeitos adversos , Desenvolvimento Fetal , Glucose/metabolismo , Lipogênese , Fígado/metabolismo , Troca Materno-Fetal , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Tecido Adiposo/metabolismo , Animais , Sacarose Alimentar/metabolismo , Feminino , Homeostase , Humanos , Lactação , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos WistarRESUMO
Introducción: el acúmulo de lípidos en el músculo esquelético se encuentra estrechamente vinculado con el desarrollo de la resistencia insulínica. Esta última cumple un rol patogénico central en el desarrollo de numerosos desórdenes metabólicos incluidos en el síndrome metabólico. Objetivos: analizar algunas vías metabólicas implicadas en el acúmulo de lípidos en el músculo esquelético y su asociación con la resistencia insulínica en un modelo experimental que mimetiza el fenotipo del síndrome metabólico humano. Materiales y métodos: ratas macho Wistar recibieron una dieta control (DC) o una dieta rica en sacarosa (DRS) durante seis meses. Al final del período experimental se analizó en músculo esquelético gastrocnemio: contenido de triglicéridos (TG), acil-CoA de cadena larga y diacilglicerol, actividad enzimática carnitina palmitoil transferasa muscular (M-CPT1, M-CPT2 y M-CPT total) y masa proteica del PPARα, AMPK y AMPKp. Se determinaron los niveles séricos de TG, AGNE, glucosa, insulina, TNFα y adiponectina. La sensibilidad insulínica se midió por la técnica clamp euglucémica-hiperinsulinémica. Resultados: en los animales alimentados con DRS la dislipemia, hiperglucemia moderada, insensibilidad insulínica e incremento del contenido de especies lipídicas en el músculo esquelético se acompañaron de una disminución en la actividad enzimática M-CPT1 y M-CPT total, y un descenso de la masa proteica del PPARα. Además se observó una reducción de la masa proteica de la AMPKp, la cual se correlacionó con bajos niveles de adiponectina y elevados niveles de TNFα séricos. Conclusiones: los resultados aportan nuevos datos sobre algunos mecanismos involucrados en el desarrollo de la lipotoxicidad en el músculo esquelético en ratas dislipémicas insulinorresistentes
Introduction: the skeletal muscle lipid accumulation is closely linked to the development of insulin resistance. The latter plays a central pathogenic role in the development of numerous metabolic disorders included in the metabolic syndrome. Objectives: to analyze some metabolic pathways involved in the skeletal muscle lipid accumulation and its association with insulin resistance in an experimental model that mimics the phenotype of the human metabolic syndrome. Materials and methods: male Wistar rats received a control diet (CD) or a sucrose rich diet (SRD) for six months. At the end of the experimental period, in gastrocnemius skeletal muscle were analyzed: triglyceride (TG), long chain acyl-CoA and diacylglycerol (DAG) contents, muscle carnitine palmitoyl transferase enzymes activities (M-CPT1, M-CPT2 and total M-CPT) and protein mass levels of PPARα, AMPK and AMPKp. Serum levels of TG, AGNE, glucose and insulin, TNFα and adiponectin were determined. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp technique. Results: in SRD fed animals, dyslipidemia, moderate hyperglycemia, insulin insensitivity and the increased content of lipid species in the skeletal muscle were accompanied by a decrease in the enzymes activities of both M-CPT1 and total M-CPT and protein mass levels of PPARα. In addition, a reduction in the protein mass levels of AMPKp was observed, which was correlated with low serum levels of adiponectin and high levels of TNFα. Conclusions: the results provide new data on some mechanisms involved in the development of lipotoxicity in skeletal muscle in insulin resistant dyslipidemic rats
Assuntos
Resistência à Insulina , Síndrome Metabólica , Diabetes Mellitus Tipo 2RESUMO
An increased availability of plasma free fatty acids (FFA) seems to play a role in the early stages of experimental type 1 diabetes mellitus induced in C57BL/6J mice by multiple low doses of streptozotoxin (mld-STZ). We analyzed the temporal changes of: (1) plasma and skeletal muscle lipids and their relationship with glucose metabolism; (2) triglyceride (Tg) concentration in isolated islets; (3) intraperitoneal glucose tolerance test; and (4) insulin secretion patterns when the three mutually interactive glucose signaling pathways were activated. Animals were killed by cervical dislocation at days 4, 6, 7, 8, 9 and 12 post first injection of mld-STZ. Compared with control mice, we observed: (1) at day 6, a significant increase of plasma FFA and both muscle and islet Tg content and a significant decrease of muscle pyruvate dehydrogenase activity. These parameters further deteriorated with time. (2) plasma Tg, glucose and insulin levels and glucose tolerance test were significantly different only after day 8. (3) an increase in both phases of the glucose plus palmitate-stimulated insulin secretion was observed at day 4. This effect progressively decreased since day 7 up to day 9. Moreover, an inhibitory action of cerulenin over glucose plus palmitate-stimulated insulin secretion was observed between days 6 and 9. Taken together these results suggest that early alteration in carbohydrate and lipid metabolism could represent a "metabolic window" which would develop between days 6 and 8. Afterwards, subsequent immunological alterations, apoptosis and necrosis induced the destruction of ß cells and would mask the results mentioned above.
Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Transtornos do Metabolismo dos Lipídeos/etiologia , Estreptozocina/administração & dosagem , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Autoimunidade/fisiologia , Peso Corporal/fisiologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Relação Dose-Resposta a Droga , Epididimo , Insulina/sangue , Transtornos do Metabolismo dos Lipídeos/sangue , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Transtornos do Metabolismo dos Lipídeos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/metabolismo , Tamanho do Órgão , Fatores de TempoRESUMO
Tigecycline exhibits potent in vitro activity against many community-acquired pneumonia (CAP) pathogens, including antibiotic-resistant ones. Its spectrum of activity and ability to penetrate lung tissue suggest it may be effective for hospitalized CAP patients. Hospitalized CAP patients (n=418) were randomized to receive intravenous (i.v.) tigecycline or levofloxacin. Patients could be switched to oral levofloxacin after receiving 6 or more doses of i.v. study medication. Therapy duration was 7 to 14 days. Coprimary efficacy end points were clinical responses in the clinically evaluable (CE: tigecycline, n=138; levofloxacin, n=156) and clinical modified intent-to-treat (c-mITT: tigecycline, n=191; levofloxacin, n=203) populations at test-of-cure (TOC). Safety was assessed in the mITT population (tigecycline, n=208; levofloxacin, n=210). Cure rates in tigecycline and levofloxacin groups were comparable in CE (90.6% versus 87.2%, respectively) and c-mITT (78% versus 77.8%, respectively) populations at TOC. Nausea and vomiting occurred in significantly more tigecycline-treated patients; elevated alanine aminotransferase and aspartate aminotransferase levels were reported in significantly more levofloxacin-treated patients. There were no significant differences in hospital length of stay, median duration of i.v. or oral antibiotic treatments, hospital readmissions, or number of patients switched to oral levofloxacin. Tigecycline was safe, effective, and noninferior to levofloxacin in hospitalized patients with CAP.
Assuntos
Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Levofloxacino , Minociclina/análogos & derivados , Ofloxacino/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Método Duplo-Cego , Feminino , Haemophilus influenzae , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Minociclina/administração & dosagem , Minociclina/efeitos adversos , Minociclina/uso terapêutico , Moraxella catarrhalis , Análise Multivariada , Ofloxacino/administração & dosagem , Ofloxacino/efeitos adversos , Streptococcus pneumoniae , Tigeciclina , Resultado do TratamentoRESUMO
OBJECTIVES: Antibiograms are often taken into account to define a rational selection of an empirical antimicrobial therapy for treating patients with hospital-acquired infections. In this study, we performed a paired comparison between the antibiogram constructed with laboratory-based data and that formed with data subjected to prior clinical validation. METHODS: Between 2003 and 2005, the laboratory of microbiology printed in duplicate every individual susceptibility report corresponding to hospitalized patients and the copy was sent to the department of infection control. Every individual report was assessed in real time at the bedside of the patient by a multidisciplinary team for clinical significance and appropriateness of the specimen, as well as for the type, source and origin of the infection. Cumulative resistance rates were estimated in parallel at the laboratory with the whole data, and at the infection control department with data subjected to prior clinical validation. These rates were designated as 'laboratory-based' and 'clinically based', respectively. RESULTS: A total of 2305 individual susceptibility reports were assessed. Only 1429 (62.0%) were considered as clinically significant by the multidisciplinary team. Escherichia coli, Enterobacter cloacae, Citrobacter freundii group, Klebsiella species and Proteus mirabilis resistant to broad-spectrum cephalosporins, as well as methicillin-resistant Staphylococcus aureus, were significantly more frequent in the clinically based rates (P < or = 0.03). CONCLUSIONS: Laboratory-based data underestimate the frequency of several major resistant organisms in patients with hospital-acquired infection. Previous clinical validation of the individual susceptibility reports seems to be a suitable strategy to get more reliable data.
Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana , HumanosRESUMO
We have previously observed a significant reduction of ceftriaxone resistance in Proteus mirabilis associated with an increase in the use of cefepime, along with a decrease in the consumption of broad-spectrum cephalosporins (CEP). However, we did not observe such a reduction with Klebsiella pneumoniae. Therefore, we sought to determine whether replacement of CEP by piperacillin-tazobactam might be useful in reducing sustained high rates of CEP resistance by this organism. We used a 6-month "before and after model"; during the second (intervention) period, most prescriptions of CEP were changed to piperacillin-tazobactam at the pharmacy. No additional barrier precautions were undertaken. During intervention, consumption of ceftazidime decreased from 17.73 to 1.14 defined daily doses (DDD) per 1,000 patient-days (P < 0.0001), whereas that of piperacillin-tazobactam increased from 0 to 30.57 DDD per 1,000 patient-days (P < 0.0001). The levels of resistance to CEP by K. pneumoniae and P. mirabilis decreased from 68.4 and 57.9% to 37.5 and 29.4%, respectively (P < 0.05). We conclude that replacement of ceftazidime by piperacillin-tazobactam might be a suitable strategy to decrease endemic CEP resistance by K. pneumoniae and P. mirabilis, even where there are high bacterial resistance rates and irrespective of any additional precautions for controlling nosocomial infection.