RESUMO
The high vulnerability of transgender (TG) persons to HIV infection and the difficulties associated with access to health services can lead to delays in the diagnosis and treatment of HIV infection, thus increasing the risk of transmission of HIV by this population. We performed a retrospective study to analyze the main characteristics of TG living with HIV infection in a hospital in Madrid, Spain and to identify issues related to lack of access to the health care system and combination antiretroviral therapy (cART). We analyzed 28 TG, of whom 22 (78.6%) were TG women. Median age was 28 years (interquartile range [IQR]: 29-45), 24 (85.7%) were Latin American (all of them without health insurance), and 12 (42.8%) were sex workers. Accessibility to the health system was more difficult for 22 (78.6%) of foreign-born TG people living with HIV, with a median delay to initiation of cART of six months (IQR: 2-24). These values were greater than those recorded for the control group comprising other people living with HIV (16.9% and one month, respectively). At the first access to health care in our hospital, CD4+ cell count and HIV viral load (VL) were worse in TG patients, with a median baseline CD4+ cell count below 350 cells/µl and a higher median HIV VL, both in naïve patients (28.6%) and in pre-treated patients whose therapy was interrupted owing to access-related issues (46.4%). These data show high vulnerability to HIV infection among TG and highlight that issues associated with access to health care can cause delays in the diagnosis and treatment of HIV infection. Based on our results, we think that the health care system should adapt to the sociodemographic, clinical, and behavioral characteristics of TG people living with HIV and develop specific, targeted preventive programs to address the vulnerability of this group.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Atenção à Saúde/organização & administração , Infecções por HIV/tratamento farmacológico , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Pessoas Transgênero/psicologia , Adulto , Estudos de Coortes , Feminino , Infecções por HIV/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , EspanhaAssuntos
Infecções por HIV/psicologia , Drogas Ilícitas/intoxicação , Metanfetamina/análogos & derivados , Metanfetamina/administração & dosagem , Metanfetamina/toxicidade , Adulto , Evolução Fatal , Infecções por HIV/complicações , Humanos , Masculino , Comportamento Sexual , Transtornos Relacionados ao Uso de Substâncias/complicaçõesRESUMO
Inflammation is typically associated with the development of fibrosis, cirrhosis and hepatocellular carcinoma. The key role of protein tyrosine phosphatase 1B (PTP1B) in inflammatory responses has focused this study in understanding its implication in liver fibrosis. Here we show that hepatic PTP1B mRNA expression increased after bile duct ligation (BDL), while BDL-induced liver fibrosis was markedly reduced in mice lacking Ptpn1 (PTP1B-/-) as assessed by decreased collagen deposition and α-smooth muscle actin (α-SMA) expression. PTP1B-/- mice also showed a significant increase in mRNA levels of key markers of monocytes recruitment (Cd68, Adgre1 and Ccl2) compared to their wild-type (PTP1B+/+) littermates at early stages of injury after BDL. Interestingly, the lack of PTP1B strongly increased the NADPH oxidase (NOX) subunits Nox1/Nox4 ratio and downregulated Cybb expression after BDL, revealing a pro-survival pattern of NADPH oxidase induction in response to liver injury. Chimeric mice generated by transplantation of PTP1B-/- bone marrow (BM) into irradiated PTP1B+/+ mice revealed similar hepatic expression profile of NOX subunits than PTP1B-/- mice while these animals did not show differences in infiltration of myeloid cells at 7 days post-BDL, suggesting that PTP1B deletion in other liver cells is necessary for boosting the early inflammatory response to the BDL. PTP1B-/- BM transplantation into PTP1B+/+ mice also led to a blockade of TGF-ß and α-SMA induction after BDL. In vitro experiments demonstrated that deficiency of PTP1B in hepatocytes protects against bile acid-induced apoptosis and abrogates hepatic stellate cells (HSC) activation, an effect ameliorated by NOX1 inhibition. In conclusion, our results have revealed that the lack of PTP1B switches NOX expression pattern in response to liver injury after BDL and reduces HSC activation and liver fibrosis.
Assuntos
Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , NADPH Oxidases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/deficiência , Animais , Apoptose/genética , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Linhagem Celular , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Imuno-Histoquímica , Células de Kupffer/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , NADPH Oxidases/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Non-alcoholic fatty liver disease (NAFLD) is associated with post-operative liver failure (PLF) and impaired liver regeneration. We investigated the effects of a glucagon-like peptide-1 (GLP-1) receptor agonist on NAFLD, PLF and liver regeneration in mice fed chow diet or methionine/choline-deficient diet (MCD) or high fat diet (HFD). Fc-GLP-1 decreased transaminases, reduced intrahepatic triglycerides (TG) and improved MCD-induced liver dysfuction. Macrophage/Kupffer cell-related markers were also reduced although Fc-GLP-1 increased expression of genes related to natural killer (NK), cytotoxic T lymphocytes and hepatic stellate cell (HSC) activation. After partial hepatectomy (PH), survival rates increased in mice receiving Fc-GLP-1 on chow or MCD diet. However, the benefit of Fc-GLP-1 on NASH-like features was attenuated 2 weeks post-PH and liver mass restoration was not improved. At this time-period, markers of NK cells and cytotoxic T lymphocytes were further elevated in Fc-GLP-1 treated mice. Increased HSC related gene expression in livers was observed together with decreased retinyl ester content and increased retinal and retinoic acid, reflecting HSC activation. Similar effects were found in mice fed HFD receiving Fc-GLP-1. Our results shed light on the differential effects of a long-acting GLP-1R agonist in improving NAFLD and PLF, but not enhancing liver regeneration in mice.
Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hepatectomia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Biomarcadores , Biópsia , Modelos Animais de Doenças , Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Imuno-Histoquímica , Mediadores da Inflamação , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Fígado/cirurgia , Regeneração Hepática , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
AIMS: Sirtuin 1 (SIRT1) is a key player in liver physiology and a therapeutic target against hepatic inflammation. We evaluated the role of SIRT1 in the proinflammatory context and oxidative stress during acetaminophen (APAP)-mediated hepatotoxicity. RESULTS: SIRT1 protein levels decreased in human and mouse livers following APAP overdose. SIRT1-Tg mice maintained higher levels of SIRT1 on APAP injection than wild-type mice and were protected against hepatotoxicity by modulation of antioxidant systems and restrained inflammatory responses, with decreased oxidative stress, proinflammatory cytokine messenger RNA levels, nuclear factor kappa B (NFκB) signaling, and cell death. Mouse hepatocytes stimulated with conditioned medium of APAP-treated macrophages (APAP-CM) showed decreased SIRT1 levels; an effect mimicked by interleukin (IL)1ß, an activator of NFκB. This negative modulation was abolished by neutralizing IL1ß in APAP-CM or silencing p65-NFκB in hepatocytes. APAP-CM of macrophages from SIRT1-Tg mice failed to downregulate SIRT1 protein levels in hepatocytes. In vivo administration of the NFκB inhibitor BAY 11-7082 preserved SIRT1 levels and protected from APAP-mediated hepatotoxicity. INNOVATION: Our work evidenced the unique role of SIRT1 in APAP hepatoprotection by targeting oxidative stress and inflammation. CONCLUSION: SIRT1 protein levels are downregulated by IL1ß/NFκB signaling in APAP hepatotoxicity, resulting in inflammation and oxidative stress. Thus, maintenance of SIRT1 during APAP overdose by inhibiting NFκB might be clinically relevant. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16:293-296, 2012) with the following serving as open reviewers: Rafael de Cabo, Joaquim Ros, Kalervo Hiltunen, and Neil Kaplowitz. Antioxid. Redox Signal. 28, 1187-1208.
Assuntos
Acetaminofen/toxicidade , Inflamação/induzido quimicamente , Fígado/efeitos dos fármacos , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Sirtuína 1/deficiênciaRESUMO
OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). METHODS: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2-7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. RESULTS: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. CONCLUSIONS: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Animais , Células Cultivadas , Colina/administração & dosagem , Dieta/efeitos adversos , Molécula de Adesão da Célula Epitelial/sangue , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Queratina-19/sangue , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Masculino , Metionina/administração & dosagem , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genéticaRESUMO
Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline-deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high-fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine-mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49. CONCLUSION: Dual-acting glucagon-like peptide-1/glucagon receptor agonists such as G49 represent a novel therapeutic approach for patients with NASH and particularly those requiring PH. (Hepatology 2017;65:950-968).
Assuntos
Peptídeo 1 Semelhante ao Glucagon/antagonistas & inibidores , Regeneração Hepática/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores de Glucagon/antagonistas & inibidores , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Imuno-Histoquímica , Peroxidação de Lipídeos , Regeneração Hepática/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Distribuição Aleatória , Receptores de Glucagon/administração & dosagem , Resultado do TratamentoRESUMO
A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25µM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB). Instead, C18 enhanced and prolonged nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased the expression of its target genes including hemeoxigenase 1 (HO1). C25 efficiently inhibited LPS-mediated phosphorylation of JNK, p38 and ERK, without affecting NFκB or Nrf2 signaling pathways. Both compounds reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1ß (IL1ß) proform, reflecting their ability to target the inflammasome. C25 also counteracted LPS effects on iNOS expression and pro-inflammatory cytokines mRNA levels in Bv-2 microglial cells. The anti-inflammatory effect of both compounds was also assessed in human macrophages. Our results suggest that triterpenoids C18 and C25 possess anti-inflammatory effects, which may be therapeutically relevant for diseases linked to inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Caspase 1/metabolismo , Linhagem Celular , Indução Enzimática , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , RNA Mensageiro/genéticaRESUMO
Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) ß/δ deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARß/δ-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2α and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARß/δ and activation of the HRI-eIF2α-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , PPAR delta/metabolismo , PPAR beta/metabolismo , eIF-2 Quinase/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/fisiologia , Fatores de Crescimento de Fibroblastos/genética , Immunoblotting , Masculino , Camundongos , Camundongos Knockout , PPAR delta/deficiência , PPAR delta/genética , PPAR beta/deficiência , PPAR beta/genética , Fosforilação/genética , Fosforilação/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , eIF-2 Quinase/genéticaRESUMO
Excess of saturated free fatty acids, such as palmitic acid (PA), in hepatocytes has been implicated in nonalcoholic fatty liver disease. α-Lipoic acid (LA) is an antioxidant that protects against oxidative stress conditions. We have investigated the effects of LA in the early activation of oxidative and endoplasmic reticulum stress, lipid accumulation, and Nrf2-mediated antioxidant defenses in hepatocytes treated with PA or in rats fed a high-fat diet. In primary human hepatocytes, a lipotoxic concentration of PA triggered endoplasmic reticulum stress, induced the apoptotic transcription factor CHOP, and increased the percentage of apoptotic cells. Cotreatment with LA prevented these effects. Similar results were found in mouse hepatocytes in which LA attenuated PA-mediated activation of caspase 3 and reduced lipid accumulation by decreasing PA uptake and increasing fatty acid oxidation and lipophagy, thereby preventing lipoapoptosis. Moreover, LA augmented the proliferation capacity of hepatocytes after PA challenge. Antioxidant effects of LA ameliorated reactive oxygen species production and endoplasmic reticulum stress and protected against mitochondrial apoptosis in hepatocytes treated with PA. Cotreatment with PA and LA induced an early nuclear translocation of Nrf2 and activated antioxidant enzymes, whereas reduction of Nrf2 by siRNA abolished the benefit of LA on PA-induced lipoapoptosis. Importantly, posttreatment with LA reversed the established damage induced by PA in hepatocytes, as well as preventing obesity-induced oxidative stress and lipoapoptosis in rat liver. In conclusion, our work has revealed that in hepatocytes, Nrf2 is an essential early player in the rescue of oxidative stress by LA leading to protection against PA-mediated lipoapoptosis.
Assuntos
Antioxidantes/farmacologia , Apoptose , Hepatócitos/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Ácido Tióctico/farmacologia , Transporte Ativo do Núcleo Celular , Animais , Elementos de Resposta Antioxidante , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Humanos , Masculino , Potencial da Membrana Mitocondrial , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Ácido Palmítico/farmacologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
The excess of saturated free fatty acids, such as palmitic acid, that induces lipotoxicity in hepatocytes, has been implicated in the development of non-alcoholic fatty liver disease also associated with insulin resistance. By contrast, oleic acid, a monounsaturated fatty acid, attenuates the effects of palmitic acid. We evaluated whether palmitic acid is directly associated with both insulin resistance and lipoapoptosis in mouse and human hepatocytes and the impact of oleic acid in the molecular mechanisms that mediate both processes. In human and mouse hepatocytes palmitic acid at a lipotoxic concentration triggered early activation of endoplasmic reticulum (ER) stress-related kinases, induced the apoptotic transcription factor CHOP, activated caspase 3 and increased the percentage of apoptotic cells. These effects concurred with decreased IR/IRS1/Akt insulin pathway. Oleic acid suppressed the toxic effects of palmitic acid on ER stress activation, lipoapoptosis and insulin resistance. Besides, oleic acid suppressed palmitic acid-induced activation of S6K1. This protection was mimicked by pharmacological or genetic inhibition of S6K1 in hepatocytes. In conclusion, this is the first study highlighting the activation of S6K1 by palmitic acid as a common and novel mechanism by which its inhibition by oleic acid prevents ER stress, lipoapoptosis and insulin resistance in hepatocytes.
Assuntos
Retículo Endoplasmático/efeitos dos fármacos , Resistência à Insulina , Ácido Palmítico/toxicidade , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Animais , Células Cultivadas , Inibidores Enzimáticos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Lipídeos/toxicidade , Camundongos , Ácido Oleico/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genéticaRESUMO
SCOPE: Mice with deletion of insulin receptor substrate (IRS) 2 develop hyperglycaemia, impaired hepatic insulin signaling and elevated gluconeogenesis. Protein tyrosine phosphatase 1B (PTP1B) inhibition by resveratrol improves peripheral insulin sensitivity of these mice. Although resveratrol activates Sirtuin1 (Sirt1), the mechanisms underlying its beneficial effects are not totally elucidated. In this study, we have investigated whether Sirt1 mediates the effects of resveratrol in controlling insulin resistance in diabetic mice. METHODS AND RESULTS: We attempted to ameliorate peripheral insulin resistance in two diabetic models, Irs2-deficient (Irs2(-/-)) mice and streptozotocin (STZ)-injected mice by resveratrol treatment or Sirt1 overexpression. Resveratrol improved systemic insulin sensitivity of Irs2-deficient mice. Irs2-deficient mice are characterized by high levels of PTP1B expression in liver and muscle. Interestingly, resveratrol decreased PTP1B in both tissues, thereby restoring IRS1-mediated insulin signaling. Moreover, resveratrol also restored insulin sensitivity and hepatic insulin signaling in STZ-diabetic mice. In contrast, moderate overexpression of Sirt1 neither normalized PTP1B levels nor restored insulin signaling in Irs2-deficient mice or STZ-diabetic mice. CONCLUSION: Resveratrol improves peripheral insulin signaling independently of Sirt1 in diabetic mice in association with the inhibition of PTP1B and, therefore, this polyphenol could be an effective adjuvant for the treatment of diabetes.
Assuntos
Antioxidantes/uso terapêutico , Diabetes Mellitus Tipo 2/dietoterapia , Suplementos Nutricionais , Resistência à Insulina , Músculo Esquelético/metabolismo , Sirtuína 1/metabolismo , Estilbenos/uso terapêutico , Animais , Cruzamentos Genéticos , Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Hipoglicemiantes/uso terapêutico , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Músculo Esquelético/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Resveratrol , Sirtuína 1/genéticaRESUMO
Chronic low grade inflammation in adipose tissue during obesity is associated with an impairment of the insulin signaling cascade. In this study, we have evaluated the impact of palmitate or oleate overload of macrophage/Kupffer cells in triggering stress-mediated signaling pathways, in lipoapoptosis, and in the cross-talk with insulin signaling in hepatocytes. RAW 264.7 macrophages or Kupffer cells were stimulated with oleate or palmitate, and levels of M1/M2 polarization markers and the lipidomic profile of eicosanoids were analyzed. Whereas proinflammatory cytokines and total eicosanoids were elevated in macrophages/Kupffer cells stimulated with palmitate, enhanced arginase 1 and lower leukotriene B4 (LTB4) levels were detected in macrophages stimulated with oleate. When hepatocytes were pretreated with conditioned medium (CM) from RAW 264.7 or Kupffer cells loaded with palmitate (CM-P), phosphorylation of stress kinases and endoplasmic reticulum stress signaling was increased, insulin signaling was impaired, and lipoapoptosis was detected. Conversely, enhanced insulin receptor-mediated signaling and reduced levels of the phosphatases protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homolog (PTEN) were found in hepatocytes treated with CM from macrophages stimulated with oleate (CM-O). Supplementation of CM-O with LTB4 suppressed insulin sensitization and increased PTP1B and PTEN. Furthermore, LTB4 decreased insulin receptor tyrosine phosphorylation in hepatocytes, activated the NFκB pathway, and up-regulated PTP1B and PTEN, these effects being mediated by LTB4 receptor BTL1. In conclusion, oleate and palmitate elicit an opposite cross-talk between macrophages/Kupffer cells and hepatocytes. Whereas CM-P interferes at the early steps of insulin signaling, CM-O increases insulin sensitization, possibly by reducing LTB4.
Assuntos
Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Insulina/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ácido Oleico/farmacologia , Palmitatos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Meios de Cultura Livres de Soro , Citocinas/metabolismo , Eicosanoides/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Leucotrieno B4/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Proteínas Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismoRESUMO
PURPOSE: Mice with deletion of insulin receptor substrate (IRS) 2 develop type 2 diabetes and photoreceptor degeneration. Loss of protein tyrosine phosphatase 1B (PTP1B) in diabetic IRS2(-/-) mice restores insulin sensitivity and normalizes glucose homeostasis. Since insulin-like growth factor (IGF)-IR promotes survival of photoreceptors and is a substrate of PTP1B, we investigated IGF-IR-mediated survival signaling and visual function in PTP1B(-/-) and double mutant IRS2(-/-)/PTP1B(-/-) mice. METHODS: IGF-IR-mediated Akt signaling was evaluated in IGF-I-stimulated retinal explants. Histologic and electroretinogram analysis was performed in wild-type (WT), IRS2(-/-), PTP1B(-/-), and the double mutant IRS2(-/-)/PTP1B(-/-) mice. RESULTS: IGF-I stimulated the tyrosine phosphorylation of its receptor and Akt activation in retinal explants of WT mice. In PTP1B(-/-) retinal explants, these responses were enhanced. Conversely, in retinas from IRS2(-/-) mice, expression of PTP1B was increased, coincident with decreased IGF-I-mediated Akt serine 473 phosphorylation. PTP1B deletion in IRS2(-/-) mice also enhanced IGF-IR tyrosine phosphorylation but, unexpectedly, did not rescue Akt activation in response to IGF-I. One potential explanation is that PTEN was increased in retinas of IRS2(-/-) and IRS2(-/-)/PTP1B(-/-) mice. Histologic evaluation revealed alterations in various structures of the retina in IRS2(-/-) and IRS2(-/-)/PTP1B(-/-) mice, specifically in the outer nuclear layer (ONL) and retinal outer segments (ROS). Electroretinogram (ERG) analysis confirmed that PTP1B deficiency did not restore visual function in IRS2(-/-) mice. CONCLUSIONS: Although loss of PTP1B enhances tyrosine phosphorylation of the IGF-IR in retinal explants of IRS2(-/-) mice, Akt activation remains defective owing to elevated PTEN levels and, thus, structural and functional visual defects persist in this model.
Assuntos
Proteínas Substratos do Receptor de Insulina/deficiência , Fator de Crescimento Insulin-Like I/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/fisiologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptor IGF Tipo 1/metabolismo , Doenças Retinianas/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/deficiência , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Type 2 diabetes mellitus (T2DM) is a rapidly expanding public epidemic and frequently results in severe vascular complications. In an attempt to find anti-diabetic agents, we report herein on the isolation, structural elucidation and bioactivity of nine friedelane-type triterpenes (1-9) and twenty two known ones (10-31) from the root barks of Celastrus vulcanicola and Maytenus jelskii. Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques. Two compounds from this series (1 and 3) exhibited increased insulin-mediated signalling, which suggests these friedelane triterpenes have potential therapeutic use in insulin resistant states.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Resistência à Insulina , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/uso terapêutico , Celastrus/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Maytenus/química , Modelos Moleculares , Conformação Molecular , Casca de Planta/química , Raízes de Plantas/química , Estereoisomerismo , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/uso terapêuticoRESUMO
Entre los factores nutricionales, el aporte de calcio parece el más importante para alcanzar un nivel óptimo de masa ósea; en este sentido, la vitamina D desempeña un rol importante en la absorción intestinal del calcio y en la regulación de la homeostasia del calcio
Assuntos
Humanos , Cálcio da Dieta , Vitamina D , BolíviaRESUMO
Como la tos serve para eliminar el moco, es necesario usar la imaginación e intuición que ayuden a disolver el catarro. Existen algunas reglas muy útiles para su aplicación, antes de recurrir al uso de medicamentos; a no ser que hayan sido recetados por el médico
Assuntos
Humanos , Tosse , Prevenção Primária , BolíviaRESUMO
La práctica médica diaria en nuestro medio permitió verificar resultados citados en este artículo, por lo que se ha resuelto efectuar una revisión bibliográfica, sobre todo referente a la detección de la diabetes en mujeres embarazadas. Contiene además datos generales sobre causales y complicaciones en el binomio madre niño que deben ser conocidas para optimizar el tratamiento de esta enfermedad durante la gestación y el periodo neonatal imnediato
Assuntos
Humanos , Gravidez , Gravidez em Diabéticas/história , BolíviaRESUMO
Esta sección está dedicada a los múltiples problemas que confrontan los adolescentes y que podría servir de guía a padres y educadores en sus conductas frente a esta edad de transición. Si bien no existen publicaciones especializadas ni populares que enfoquen la problemática de nuestros jóvenes, en el presente artículo se señalan características del perfil social y síquico del adolescente y éstas pautas iniciales servirán para abrir un espacio de discusión sobre el tema y para plantear enfoques concretos y prácticos de ayuda y orientación a los adolescentes