Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
1.
Int J Mol Sci ; 24(4)2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36835128

RESUMO

Omega-3 (ω-3) polyunsaturated fatty acids, including docosahexaenoic acid (DHA), are involved in numerous biological processes and have a range of health benefits. DHA is obtained through the action of elongases (ELOVLs) and desaturases, among which Elovl2 is the key enzyme involved in its synthesis, and can be further metabolized into several mediators that regulate the resolution of inflammation. Our group has recently reported that ELOVL2 deficient mice (Elovl2-/-) not only display reduced DHA levels in several tissues, but they also have higher pro-inflammatory responses in the brain, including the activation of innate immune cells such as macrophages. However, whether impaired synthesis of DHA affects cells of adaptive immunity, i.e., T lymphocytes, is unexplored. Here we show that Elovl2-/- mice have significantly higher lymphocytes in peripheral blood and that both CD8+ and CD4+ T cell subsets produce greater amounts of pro-inflammatory cytokines in both blood and spleen compared to wild type mice, with a higher percentage of cytotoxic CD8+ T cells (CTLs) as well as IFN-γ-producing Th1 and IL-17-producing Th17 CD4+ cells. Furthermore, we also found that DHA deficiency impacts the cross-talk between dendritic cells (DC) and T cells, inasmuch as mature DCs of Elovl2-/- mice bear higher expression of activation markers (CD80, CD86 and MHC-II) and enhance the polarization of Th1 and Th17 cells. Reintroducing DHA back into the diets of Elovl2-/- mice reversed the exacerbated immune responses observed in T cells. Hence, impairment of endogenous synthesis of DHA exacerbates T cell inflammatory responses, accounting for an important role of DHA in regulating adaptive immunity and in potentially counteracting T-cell-mediated chronic inflammation or autoimmunity.


Assuntos
Ácidos Docosa-Hexaenoicos , Inflamação , Animais , Camundongos , Linfócitos T CD4-Positivos/metabolismo , Citocinas , Ácidos Docosa-Hexaenoicos/metabolismo , Elongases de Ácidos Graxos , Inflamação/imunologia , Inflamação/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Linfócitos T CD8-Positivos/metabolismo
2.
Nutrients ; 14(3)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35276915

RESUMO

The fatty acid elongase elongation of very long-chain fatty acids protein 2 (ELOVL2) controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3, docosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn-6) in vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn-6 in liver mitochondrial membranes. Unexpectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation. The lipid peroxidation process was not involved in PUFAs reduction since malondialdehyde-lysine (MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrial respiratory chain proteins remained unchanged. Still, membrane remodeling was associated with the high voltage-dependent anion channel (VDAC) and adenine nucleotide translocase 2 (ANT2), a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mitochondrial function was impaired despite preserved content of the respiratory chain proteins and the absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coefficients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fatty acid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume and number of peroxisomes increased as revealed by transmission electron microscopy. In conclusion, the results imply that endogenous DHA production is vital for the normal function of mouse liver mitochondria and could be relevant not only for mice but also for human metabolism.


Assuntos
Mitocôndrias Hepáticas , Membranas Mitocondriais , Animais , Ácidos Graxos , Fígado , Camundongos , Mitocôndrias
3.
Lipids ; 57(3): 183-195, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35318678

RESUMO

1-O-Acylceramides (1-OACs) have a fatty acid esterified to the 1-hydroxyl of the sphingosine head group of the ceramide, and recently we identified these lipids as natural components of human and mouse epidermis. Here we show epidermal 1-OACs arise shortly before birth during the establishment of the water permeability barrier in mice. Fractionation of human epidermis indicates 1-OACs concentrate in the stratum corneum. During in vitro maturation into reconstructed human epidermis, human keratinocytes dramatically increase 1-OAC levels indicating they are one source of epidermal 1-OACs. In search of potential enzymes responsible for 1-OAC synthesis in vivo, we analyzed mutant mice with deficiencies of ceramide synthases (Cers2, Cers3, or Cers4), diacylglycerol acyltransferases (Dgat1 or Dgat2), elongase of very long fatty acids 3 (Elovl3), lecithin cholesterol acyltransferase (Lcat), stearoyl-CoA desaturase 1 (Scd1), or acidic ceramidase (Asah1). Overall levels of 1-OACs did not decrease in any mouse model. In Cers3 and Dgat2-deficient epidermis they even increased in correlation with deficient skin barrier function. Dagt2 deficiency reshapes 1-OAC synthesis with an increase in 1-OACs with N-linked non-hydroxylated fatty acids and a 60% decrease compared to control in levels of 1-OACs with N-linked hydroxylated palmitate. As none of the single enzyme deficiencies we examined resulted in a lack of 1-OACs, we conclude that either there is functional redundancy in forming 1-OAC and more than one enzyme is involved, and/or an unknown acyltransferase of the epidermis performs the final step of 1-OAC synthesis, the implications of which are discussed.


Assuntos
Epiderme , Água , Animais , Ceramidas , Ácidos Graxos , Queratinócitos , Camundongos , Permeabilidade , Esfingosina N-Aciltransferase
4.
FASEB J ; 34(2): 2024-2040, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31909582

RESUMO

Docosahexaenoic acid (DHA) is a ω-3 fatty acid typically obtained from the diet or endogenously synthesized through the action of elongases (ELOVLs) and desaturases. DHA is a key central nervous system constituent and the precursor of several molecules that regulate the resolution of inflammation. In the present study, we questioned whether the impaired synthesis of DHA affected neural plasticity and inflammatory status in the adult brain. To address this question, we investigated neural and inflammatory markers from mice deficient for ELOVL2 (Elovl2-/- ), the key enzyme in DHA synthesis. From our findings, Elovl2-/- mice showed an altered expression of markers involved in synaptic plasticity, learning, and memory formation such as Egr-1, Arc1, and BDNF specifically in the cerebral cortex, impacting behavioral functions only marginally. In parallel, we also found that DHA-deficient mice were characterized by an increased expression of pro-inflammatory molecules, namely TNF, IL-1ß, iNOS, caspase-1 as well as the activation and morphologic changes of microglia in the absence of any brain injury or disease. Reintroducing DHA in the diet of Elovl2-/- mice reversed such alterations in brain plasticity and inflammation. Hence, impairment of systemic DHA synthesis can modify the brain inflammatory and neural plasticity status, supporting the view that DHA is an essential fatty acid with an important role in keeping inflammation within its physiologic boundary and in shaping neuronal functions in the central nervous system.


Assuntos
Encéfalo/metabolismo , Ácidos Docosa-Hexaenoicos/biossíntese , Regulação da Expressão Gênica , Microglia/metabolismo , Plasticidade Neuronal , Animais , Biomarcadores/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Caspase 1/biossíntese , Caspase 1/genética , Ácidos Docosa-Hexaenoicos/genética , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Elongases de Ácidos Graxos/deficiência , Elongases de Ácidos Graxos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Camundongos , Camundongos Knockout , Microglia/patologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
5.
Nutrients ; 11(4)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991731

RESUMO

The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is implicated in theregulation of both lipid and carbohydrate metabolism. Thus, we questioned whether dietary DHAand low or high content of sucrose impact on metabolism in mice deficient for elongation of verylong-chain fatty acids 2 (ELOVL2), an enzyme involved in the endogenous DHA synthesis. Wefound that Elovl2 -/- mice fed a high-sucrose DHA-enriched diet followed by the high sucrose, highfat challenge significantly increased body weight. This diet affected the triglyceride rich lipoproteinfraction of plasma lipoproteins and changed the expression of several genes involved in lipidmetabolism in a white adipose tissue. Our findings suggest that lipogenesis in mammals issynergistically influenced by DHA dietary and sucrose content.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Sacarose Alimentar/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Lipogênese/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacos , Acetiltransferases/genética , Acetiltransferases/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Ácidos Docosa-Hexaenoicos/deficiência , Elongases de Ácidos Graxos , Lipogênese/genética , Lipoproteínas/sangue , Camundongos Knockout , Triglicerídeos/sangue
6.
Cell Mol Life Sci ; 74(15): 2815-2826, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28299384

RESUMO

Docosahexaenoic acid (DHA) is an omega-3 fatty acid obtained from the diet or synthesized from alpha-linolenic acid through the action of fatty acid elongases (ELOVL) and desaturases. DHA plays important roles in the central nervous system as well as in peripheral organs and is the precursor of several molecules that regulate resolution of inflammation. In the present study, we questioned whether impaired synthesis of DHA affected macrophage plasticity and polarization both in vitro and in vivo models. For this we investigated the activation status and inflammatory response of bone marrow-derived M1 and M2 macrophages obtained from mice deficient of Elovl2 (Elovl2-/-), a key enzyme for DHA synthesis in mammals. Although both wild type and Elovl2-/- mice were able to generate efficient M1 and M2 macrophages, M1 cells derived from Elovl2-/- mice showed an increased expression of key markers (iNOS, CD86 and MARCO) and cytokines (IL-6, IL-12 and IL-23). However, M2 macrophages exhibited upregulated M1-like markers like CD80, CD86 and IL-6, concomitantly with a downregulation of their signature marker CD206. These effects were counteracted in cells obtained from DHA-supplemented animals. Finally, white adipose tissue of Elovl2-/- mice presented an M1-like pro-inflammatory phenotype. Hence, impairment of systemic DHA synthesis delineates an alteration of M1/M2 macrophages both in vitro and in vivo, with M1 being hyperactive and more pro-inflammatory while M2 less protective, supporting the view that DHA has a key role in controlling the balance between pro- and anti-inflammatory processes.


Assuntos
Ácidos Docosa-Hexaenoicos/imunologia , Inflamação/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/imunologia , Animais , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , Interleucina-12/imunologia , Interleucina-23/imunologia , Interleucina-6/imunologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/imunologia
7.
J Lipid Res ; 58(1): 111-123, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27864326

RESUMO

The molecular details relevant to dietary supplementation of the omega-3 fatty acid DHA in mothers as well as in their offspring are not clear. The PUFA elongase, elongation of very long-chain fatty acid (ELOVL)2, is a critical enzyme in the formation of DHA in mammals. In order to address the question regarding the origin of DHA during perinatal life, we have used DHA-deficient Elovl2-ablated mice as a model system to analyze the maternal impact on the DHA level in their offspring of various genotypes. Elovl2-/- mothers maintained on control diet had significantly lower systemic levels of DHA compared with the Elovl2+/- and Elovl2+/+ mothers. Dietary DHA administration during the pregnancy and lactation periods led to increased DHA accretion in maternal tissues and serum of all genotypes. The proportion of DHA in the liver and serum of the Elovl2-/- offspring was significantly lower than in the Elovl2+/+ offspring. Remarkably, the DHA level in the Elovl2+/- offspring nursed by DHA-free-fed Elovl2-/- mothers was almost as high as in +/+ pups delivered by +/+ mothers, suggesting that endogenous synthesis in the offspring can compensate for maternal DHA deficiency. Maternal DHA supplementation had a strong impact on offspring hepatic gene expression, especially of the fatty acid transporter, Mfsd2a, suggesting a dynamic interplay between DHA synthesis and DHA uptake in the control of systemic levels in the offspring.


Assuntos
Acetiltransferases/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Acetiltransferases/metabolismo , Animais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Elongases de Ácidos Graxos , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Fígado/patologia , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Gravidez , Simportadores
8.
PLoS One ; 11(10): e0164241, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27788154

RESUMO

Endocrine therapy is the first-line targeted adjuvant therapy for hormone-sensitive breast cancer. In view of the potential anticancer property of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) together with chemotherapy in estrogen receptor alpha (ERα) positive mammary tumors, we have explored the regulation by estradiol of the fatty acid desaturation and elongation enzymes involved in DHA synthesis in the human breast cancer cell line MCF7, which expresses ERα but not ERß. We demonstrate a robust up-regulation in the expression of the fatty acid elongases Elovl2 and Elovl5 upon estradiol stimulation in MCF7 cells, which was sustained for more than 24 hours. Exposure with the ER inhibitor tamoxifen abolished specifically the Elovl2 but not the Elovl5 expression. Similarly, knock-down of ERα eliminated almost fully the Elovl2 but not the Elovl5 expression. Furthermore, ERα binds to one specific ERE within the Elovl2 enhancer in a ligand dependent manner. The involvement of ERα in the control of especially Elovl2, which plays a crucial role in DHA synthesis, may have potential implications in the treatment of breast cancer.


Assuntos
Acetiltransferases/genética , Acetiltransferases/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor alfa de Estrogênio/deficiência , Receptor alfa de Estrogênio/genética , Elongases de Ácidos Graxos , Ácidos Graxos Insaturados/biossíntese , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Células MCF-7 , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Elementos de Resposta/efeitos dos fármacos , Elementos de Resposta/genética , Tamoxifeno/farmacologia
9.
Sci Transl Med ; 8(353): 353ra111, 2016 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-27559094

RESUMO

Resolution of inflammation is a finely regulated process mediated by specialized proresolving lipid mediators (SPMs), including docosahexaenoic acid (DHA)-derived resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. We report that D-series resolvins (resolvin D1 and resolvin D2) and maresin 1 modulate adaptive immune responses in human peripheral blood lymphocytes. These lipid mediators reduce cytokine production by activated CD8(+) T cells and CD4(+) T helper 1 (TH1) and TH17 cells but do not modulate T cell inhibitory receptors or abrogate their capacity to proliferate. Moreover, these SPMs prevented naïve CD4(+) T cell differentiation into TH1 and TH17 by down-regulating their signature transcription factors, T-bet and Rorc, in a mechanism mediated by the GPR32 and ALX/FPR2 receptors; they concomitantly enhanced de novo generation and function of Foxp3(+) regulatory T (Treg) cells via the GPR32 receptor. These results were also supported in vivo in a mouse deficient for DHA synthesis (Elovl2(-/-)) that showed an increase in TH1/TH17 cells and a decrease in Treg cells compared to wild-type mice. Additionally, either DHA supplementation in Elovl2(-/-) mice or in vivo administration of resolvin D1 significantly reduced cytokine production upon specific stimulation of T cells. These findings demonstrate actions of specific SPMs on adaptive immunity and provide a new avenue for SPM-based approaches to modulate chronic inflammation.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Acetiltransferases/deficiência , Acetiltransferases/genética , Imunidade Adaptativa , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular , Elongases de Ácidos Graxos , Humanos , Inflamação/terapia , Mediadores da Inflamação/metabolismo , Interleucina-2/biossíntese , Metabolismo dos Lipídeos , Ativação Linfocitária , Camundongos , Camundongos Knockout , Receptores de Formil Peptídeo/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Lipoxinas/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/citologia
10.
Neuroepidemiology ; 45(1): 20-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26201267

RESUMO

BACKGROUND: With an increasing and aging population, there is a global demand for improving the primary prevention strategies aimed at reducing traumatic brain injuries (TBIs). The objective of the present epidemiological study was to evaluate the pattern of TBI in Sweden over a 24 years period (1987-2010). METHODS: The Swedish Hospital Discharge Register was used, where in-patient care with a main diagnosis of TBI according to ICD9/10 was included. External factors, age and gender distribution was evaluated. RESULTS: A decreasing number of annual incidence was observed, that is, from 230 to 156 per 100,000 inhabitants. A steady decrease of concussion was observed while other intracranial injuries increased especially traumatic subdural hemorrhage and subarachnoid hemorrhage. The study identified 3 groups of patients - young, adults and elderly. The highest incidence and the largest increase of incidence were seen in the oldest age group (85+ years) while the population under 65 years had a decreasing incidence of TBI. The most frequent etiology was fall accidents (57%) with a relative constant trend over the study period. CONCLUSIONS: More effort should be focused on different strategies for different age groups, especially the elderly group. A well-planned strategy for primary prevention guidelines for different age groups will have the chance to further reduce not only the health-care costs but also complications among elderly care.


Assuntos
Lesões Encefálicas/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Hospitais/estatística & dados numéricos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Suécia , Adulto Jovem
11.
J Lipid Res ; 55(4): 718-28, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24489111

RESUMO

The potential role of endogenously synthesized PUFAs is a highly overlooked area. Elongation of very long-chain fatty acids (ELOVLs) in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2(-/-) mice displayed substantially decreased levels of 22:6(n-3), DHA, and 22:5(n-6), docosapentaenoic acid (DPA) n-6, and an accumulation of 22:5(n-3) and 22:4(n-6) in both liver and serum, showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24-carbon precursors for DHA and DPAn-6 formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol-regulatory element binding protein 1c (SREBP-1c), as well as its downstream target genes. Surprisingly, the Elovl2(-/-) mice were resistant to hepatic steatosis and diet-induced weight gain, implying that hepatic DHA synthesis via ELOVL2, in addition to controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP-1c-independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA.


Assuntos
Acetiltransferases/genética , Ácidos Docosa-Hexaenoicos/sangue , Acetiltransferases/metabolismo , Animais , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Elongases de Ácidos Graxos , Fígado Gorduroso/enzimologia , Homeostase , Lipogênese/genética , Fígado/enzimologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Transcrição Gênica , Ativação Transcricional , Triglicerídeos/metabolismo
12.
Arch Surg ; 147(4): 359-65, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22508781

RESUMO

OBJECTIVE: To investigate the incidence and risk factors for small-bowel obstruction (SBO) after certain surgical procedures. DESIGN: A population-based retrospective register study. SETTING: Small-bowel obstruction causes considerable patient suffering. Risk factors for SBO have been identified, but the effect of surgical technique (open vs laparoscopic) on the incidence of SBO has not been fully elucidated. PATIENTS: The Inpatient Register held by the Swedish National Board of Health and Welfare was used. The hospital discharge diagnoses and registered performed surgical procedures identified data for cholecystectomy, hysterectomy, salpingo-oophorectomy, bowel resection, anterior resection, abdominoperineal resection, rectopexy, appendectomy, and bariatric surgery performed from January 1, 2002, through December 31, 2004. Data on demographic characteristics, comorbidity, previous abdominal surgery, and death were collected. MAIN OUTCOME MEASURES: Episodes of hospital stay and surgery for SBO within 5 years after the index surgery. RESULTS: A total of 108,141 patients were included. The incidence of SBO ranged from 0.4% to 13.9%. Multivariate analysis revealed age, previous surgery, comorbidity, and surgical technique to be risk factors for SBO. Laparoscopy exceeded other risk factors in reduction of the risk of SBO for most of the surgical procedures. CONCLUSIONS: Open surgery seems to increase the risk of SBO at least 4 times compared with laparoscopy for most of the abdominal surgical procedures studied. Other factors such as age, previous abdominal surgery, and comorbidity are also of importance.


Assuntos
Obstrução Intestinal/etiologia , Intestino Delgado , Laparoscopia/efeitos adversos , Adulto , Idoso , Distribuição de Qui-Quadrado , Comorbidade , Feminino , Humanos , Incidência , Obstrução Intestinal/epidemiologia , Tempo de Internação/estatística & dados numéricos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Suécia/epidemiologia
13.
Work ; 41 Suppl 1: 3216-22, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22317207

RESUMO

Learning from incidents is important for improving safety. Many companies spend a great deal of time and money on such learning procedures. The objectives of this paper are to present some early results from a project aimed at revealing weaknesses in the procedures for learning from incidents and to discuss improvements in these procedures, especially in chemical process industries. The empirical base comes from a project assessing organizational learning and the effectiveness of the different steps of the learning cycle for safety and studying relations between safety-specific transformational leadership, safety climate, trust, safety-related behavior and learning from incidents. The results point at common weaknesses in the organizational learning, both in the horizontal learning (geographical spread) and in vertical learning (double-loop learning). Furthermore, the effectiveness in the different steps of the learning cycle is low due to insufficient information in incident reports, very shallow analyses of reports, decisions that focus at solving the problem only at the place where the incident took place, late implementations and weak solutions. Strong correlations with learning from incidents were found for all safety climate variables as well as for safety-related behaviors and trust. The relationships were very strong for trust, safety knowledge, safety participation and safety compliance.


Assuntos
Indústria Química , Aprendizagem Baseada em Problemas , Gestão da Segurança , Tomada de Decisões , Humanos , Liderança , Cultura Organizacional , Comportamento de Redução do Risco , Inquéritos e Questionários , Suécia , Confiança
14.
J Lipid Res ; 52(2): 245-55, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21106902

RESUMO

ELOVL2 is a member of the mammalian microsomal ELOVL fatty acid enzyme family, involved in the elongation of very long-chain fatty acids including PUFAs required for various cellular functions in mammals. Here, we used ELOVL2-ablated (Elovl2(-/-)) mice to show that the PUFAs with 24-30 carbon atoms of the ω-6 family in testis are indispensable for normal sperm formation and fertility in male mice. The lack of Elovl2 was associated with a complete arrest of spermatogenesis, with seminiferous tubules displaying only spermatogonia and primary spermatocytes without further germinal cells. Furthermore, based on acyl-CoA profiling, heterozygous Elovl2(+/-) male mice exhibited haploinsufficiency, with reduced levels of C28:5 and C30:5n-6 PUFAs, which gave rise to impaired formation and function of haploid spermatides. These new insights reveal a novel mechanism involving ELOVL2-derived PUFAs in mammals and previously unrecognized roles for C28 and C30 n-6 PUFAs in male fertility. In accordance with the function suggested for ELOVL2, the Elovl2(-/-) mice show distorted levels of serum C20 and C22 PUFAs from both the n-3 and the n-6 series. However, dietary supplementation with C22:6n-3 could not restore male fertility to Elovl2(+/-) mice, suggesting that the changes in n-6 fatty acid composition seen in the testis of the Elovl2(+/-) mice, cannot be compensated by increased C22:6n-3 content.


Assuntos
Acetiltransferases/fisiologia , Ácidos Graxos Insaturados/metabolismo , Acetiltransferases/deficiência , Animais , Gorduras Insaturadas na Dieta/farmacologia , Elongases de Ácidos Graxos , Ácidos Graxos Insaturados/biossíntese , Feminino , Fertilidade/fisiologia , Masculino , Camundongos , Maturação do Esperma , Espermatogênese/fisiologia , Testículo
15.
FASEB J ; 24(11): 4366-77, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20605947

RESUMO

Although saturated and monounsaturated very-long-chain fatty acids (VLCFAs) have long been associated with undesirable effects on health, including obesity, heart failure, and atherosclerosis, the physiological role of endogenous synthesis is largely unknown. The fatty acid elongase ELOVL3 is involved in the synthesis of C20-C24 saturated and monounsaturated VLCFAs mainly in liver, brown and white adipose tissue, and triglyceride-rich glands such as the sebaceous and meibomian glands. Here we show that ablation of ELOVL3 leads to reduced adiponectin levels, constrained expansion of adipose tissue, and resistance against diet-induced obesity, a situation that is more exaggerated in female mice. Both female and male knockout mice show reduced hepatic lipogenic gene expression and triglyceride content, a situation that is associated with reduced de novo fatty acid synthesis and uptake. As a consequence, the VLDL-triglyceride level in serum is significantly reduced. Remarkably, despite increased energy expenditure, markedly reduced serum levels of leptin, and increased expression of orexigenic peptides in the hypothalamus, the Elovl3(-/-) mice do not compensate by increased food intake. Thus, these results reveal that C20-C22 saturated and monounsaturated VLCFAs produced by ELOVL3 are indispensable for appropriate synthesis of liver triglycerides, fatty acid uptake, and storage in adipose tissue.


Assuntos
Acetiltransferases/genética , Acetiltransferases/metabolismo , Dieta , Obesidade/enzimologia , Adipocinas/metabolismo , Adiponectina/sangue , Tecido Adiposo/metabolismo , Animais , Metabolismo Basal/genética , Células Cultivadas , Ingestão de Alimentos/genética , Elongases de Ácidos Graxos , Feminino , Regulação Enzimológica da Expressão Gênica , Lipogênese/genética , Lipoproteínas VLDL/biossíntese , Lipoproteínas VLDL/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Fatores Sexuais , Triglicerídeos/biossíntese , Triglicerídeos/sangue
16.
Prog Lipid Res ; 49(2): 186-99, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20018209

RESUMO

In mammalian cells, elongases and desaturases play critical roles in regulating the length and degree of unsaturation of fatty acids and thereby their functions and metabolic fates. In the past decade, a great deal has been learnt about these enzymes and the first part of this review summarizes our current knowledge concerning these enzymes. More recently, several transgenic mouse models lacking either an elongase (Elovl3(-/-), Elovl4(-/-), Elovl5(-/-), Elovl6(-/-)) or a desaturase (Scd-1(-/-), Scd-2(-/-), Fads2(-/-)) have been developed and the second part of this review focuses on the insights gained from studies with these mice, as well as from investigations on cell cultures.


Assuntos
Acetiltransferases/fisiologia , Ácidos Graxos Dessaturases/fisiologia , Ácidos Graxos/metabolismo , Acetiltransferases/genética , Acetiltransferases/metabolismo , Animais , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos , Ácidos Graxos/biossíntese , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos
17.
Stroke ; 40(8): 2691-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19498188

RESUMO

BACKGROUND AND PURPOSE: Stroke incidence rates were unchanged whereas fatality rates declined during the period 1971 to 1987 in Gothenburg (Göteborg), Sweden. For the period 1987 to 2006, we now report on trends in stroke incidence and mortality with concurrent risk factor trends in the same population. Since 1976 the incidence of myocardial infarction decreased by 50%. METHODS: Through the National Hospital Discharge Register linked with the Cause of Death Register, 12 904 males and 15 250 females with first strokes were detected for the period 1987 to 2006. Cardiovascular risk factor data were available for random population samples of men and women aged 50 years from 1963 to 2003. RESULTS: Incidence and mortality rates for all-stroke were unchanged. Rates for subarachnoid hemorrhage declined for the age group 45 to 54 in men, but not significantly in any other age group of men or women. Mortality rates of intracerebral hemorrhage declined for women aged 65 to 74, with no significant changes in any other age group. Ischemic stroke incidence did not change, but mortality increased for men and women aged 75 and older, whereas mortality declined for the age group 20 to 44 for men. In the general population there were significant reductions in smoking, total cholesterol, and blood pressure levels in both men and women, whereas diabetes prevalence, body weight, and BMI increased among both sexes, and triglycerides increased in men. CONCLUSIONS: Contrary to myocardial infarction, stroke incidence and mortality did not change. Monitoring of cardiovascular risk factors in the community is important.


Assuntos
Doenças Cardiovasculares/mortalidade , Acidente Vascular Cerebral/mortalidade , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Taxa de Sobrevida/tendências , Suécia/epidemiologia , Adulto Jovem
18.
Neuroepidemiology ; 32(3): 217-28, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19174611

RESUMO

BACKGROUND: To define the epidemiological pattern of nerve injuries and traumatic amputations in Sweden, 1998-2006, and investigate possible targets for emerging neural engineering and neuroprosthetic technologies. METHODS: The Swedish Hospital Discharge Register was used as the information base, including data from all public inpatient care, excluding outpatient data. ICD-10 codes were used to classify nerve injuries and traumatic amputations of high incidence levels or inpatient care time. Selected codes, causative factors, age and gender distribution were discussed in detail, and potential targets for tailored solutions were identified. RESULTS: Incidence rate was determined as 13.9 for nerve injuries and 5.21 for amputations per 100,000 person-years. The majority of injuries occurred at the wrist and hand levels, although it could be concluded that these are often minor injuries requiring less than a week of hospitalization. The single most care-consuming nerve injury was brachial plexus injury, constituting on average 68 injuries and 960 hospital days annually. When minor amputations of fingers and toes were disregarded, the most frequent site of amputation was between the knee and ankle (24 patients/year). CONCLUSIONS: Based on an analysis of incidence and care time, we find that brachial plexus injuries and lower leg amputations should be the primary targets of new technologies.


Assuntos
Amputação Traumática/epidemiologia , Traumatismos dos Nervos Periféricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amputação Traumática/diagnóstico , Amputação Traumática/prevenção & controle , Criança , Pré-Escolar , Feminino , Traumatismos da Mão/diagnóstico , Traumatismos da Mão/epidemiologia , Traumatismos da Mão/prevenção & controle , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/prevenção & controle , Sistema de Registros , Suécia/epidemiologia , Adulto Jovem
19.
Endocrinology ; 149(6): 3158-66, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18292190

RESUMO

The Elovl3 gene belongs to the Elovl gene family, which encodes for enzymes involved in the elongation of very long chain fatty acids. The recognized role for the enzyme is to control the elongation of saturated and monounsaturated fatty acids up to 24 carbons in length. Elovl3 was originally identified as a highly expressed gene in brown adipose tissue on cold exposure. Here we show that hepatic Elovl3 mRNA expression follows a distinct diurnal rhythm exclusively in mature male mice, with a sharp increase early in the morning Zeitgeber time (ZT) 20, peaks around ZT2, and is back to basal level at the end of the light period at ZT10. In female mice and sexually immature male mice, the Elovl3 expression was constantly low. Fasting and refeeding mice with chow or high-fat diet did not alter the Elovl3 mRNA levels. However, animals that were exclusively fed during the day for 9 d displayed an inverted expression profile. In addition, we show that Elovl3 expression is transcriptionally controlled and significantly induced by the exposure of the synthetic glucocorticoid dexamethasone. Taken together, these data suggest that Elovl3 expression in mouse liver is under strict diurnal control by circulating steroid hormones such as glucocorticoids and androgens. Finally, Elovl3 expression was found to be elevated in peroxisomal transporter ATP-binding cassette, subfamily D(ALD), member 2 ablated mice and suppressed in ATP-binding cassette subfamily D(ALD) member 2 overexpressing mice, implying a tight cross talk between very long chain fatty acid synthesis and peroxisomal fatty acid oxidation.


Assuntos
Androgênios/farmacologia , Ritmo Circadiano/fisiologia , Glucocorticoides/farmacologia , Fígado/metabolismo , Proteínas de Membrana/genética , Acetiltransferases , Animais , Elongases de Ácidos Graxos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Fígado/efeitos dos fármacos , Masculino , Proteínas de Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , PPAR alfa/farmacologia , Transcrição Gênica
20.
Am J Physiol Endocrinol Metab ; 293(5): E1159-68, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17726147

RESUMO

The Elovl3 gene, which putatively encodes for a protein involved in the elongation of saturated and monounsaturated fatty acids in the C20-C24 range, is expressed in murine liver, skin, and brown adipose tissue (BAT). In BAT, Elovl3 is dramatically upregulated during tissue activation in response to cold exposure, and functional data imply that ELOVL3 is a critical enzyme for lipid accumulation in brown adipocytes during the early phase of tissue recruitment. The activation of BAT is controlled by sympathetic nerve activity and norepinephrine release. By using primary cultures of brown adipocytes, we show here that the induced Elovl3 gene expression is synergistically regulated by norepinephrine and the peroxisome proliferator-activated receptor (PPAR) gamma ligand rosiglitazone. In addition, the potency of rosiglitazone to induce Elovl3 expression was several orders of magnitude higher than for the PPARalpha and PPARdelta ligands WY-14643 and L-165041, respectively. The maximal increase in mRNA level by norepinephrine and rosiglitazone is achieved by induced transcription as well as increased mRNA stability, and the whole process requires novel protein synthesis. We conclude that norepinehrine and PPARgamma, despite having different roles in brown adipocyte activation and differentiation, cooperate in expanding the intracellular lipid pool by synergistically stimulating Elovl3 expression.


Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Proteínas de Membrana/biossíntese , Norepinefrina/farmacologia , PPAR gama/fisiologia , Proliferadores de Peroxissomos/farmacologia , Tiazolidinedionas/farmacologia , Acetiltransferases , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Cicloeximida/farmacologia , Dactinomicina/farmacologia , Sinergismo Farmacológico , Elongases de Ácidos Graxos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Proteínas de Membrana/genética , Camundongos , Norepinefrina/antagonistas & inibidores , Fenoxiacetatos/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Pirimidinas/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona , Tiazolidinedionas/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...