RESUMO
Hypermetabolism following severe burn injuries is associated with adipocyte dysfunction, elevated beige adipocyte formation, and increased energy expenditure. The resulting catabolism of adipose leads to detrimental sequelae such as fatty liver, increased risk of infections, sepsis, and even death. While the phenomenon of pathological white adipose tissue (WAT) browning is well-documented in cachexia and burn models, the molecular mechanisms are essentially unknown. Here, we report that adipose triglyceride lipase (ATGL) plays a central role in burn-induced WAT dysfunction and systemic outcomes. Targeting adipose-specific ATGL in a murine (AKO) model resulted in diminished browning, decreased circulating fatty acids, and mitigation of burn-induced hepatomegaly. To assess the clinical applicability of targeting ATGL, we demonstrate that the selective ATGL inhibitor atglistatin mimics the AKO results, suggesting a path forward for improving patient outcomes.
Assuntos
Aciltransferases/fisiologia , Adipócitos Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Queimaduras/complicações , Metabolismo Energético , Hepatomegalia/prevenção & controle , Lipólise , Adipócitos Bege/patologia , Tecido Adiposo Branco/patologia , Animais , Hepatomegalia/etiologia , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
OBJECTIVE: The aim of this retrospective study was to compare portal vein embolization (PVE) and radiologica simultaneous portohepatic vein embolization (RASPE) for future liver remnant (FLR) growth in terms of feasibility, safety, and efficacy. SUMMARY OF BACKGROUND DATA: After portal vein embolization (PVE), 15% of patients remain ineligible for hepatic resection due to insufficient hypertrophy of the FLR. RASPE has been proposed to induce FLR growth. MATERIALS AND METHODS: Between 2016 and 2018, 73 patients were included in the study. RASPE was proposed for patients with a ratio of FLR to total liver volume (FLR/TLV) of <25% (RASPE group). This group was compared to patients who underwent PVE for a FLR/TLV <30% (PVE group). Patients in the 2 groups were matched for age, sex, type of tumor, and number of chemotherapy treatments. FLR was assessed by computed tomography before and 4 weeks after the procedure. RESULTS: The technical success rate in both groups was 100%. Morbidity post-embolization, and the time between embolization and surgery were similar between the groups. In the PVE group, the FLR/TLV ratio before embolization was 31.03% (range: 18.33%-38.95%) versus 22.91% (range: 16.55-32.15) in the RASPE group (P < 0.0001). Four weeks after the procedure, the liver volume increased by 28.98% (range: 9.31%-61.23%) in the PVE group and by 61.18% (range: 23.18%-201.56%) in the RASPE group (P < 0.0001). Seven patients in the PVE group, but none in the RASPE group, had postoperative liver failure (P = 0.012). CONCLUSIONS: RASPE can be considered as "radiological associating liver partition and portal vein ligation for staged hepatectomy." RASPE induced safe and profound growth of the FLR and was more efficient than PVE. RASPE also allowed for extended hepatectomy with less risk of post-operative liver failure.
Assuntos
Embolização Terapêutica/métodos , Hepatectomia/métodos , Hepatomegalia/prevenção & controle , Neoplasias Hepáticas/cirurgia , Veia Porta/cirurgia , Cirurgia Assistida por Computador/métodos , Idoso , Distribuição de Qui-Quadrado , Estudos de Coortes , Intervalo Livre de Doença , Feminino , França , Hepatectomia/mortalidade , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Cuidados Pré-Operatórios/métodos , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Background and aims: TLR9 deletion protects against steatohepatitis due to choline-amino acid depletion and high-fat diet. We measured TLR9 in human non-alcoholic steatohepatitis (NASH) livers, and tested whether TLR9 mediates inflammatory recruitment in three murine models of non-alcoholic fatty liver disease (NAFLD). Methods: We assayed TLR mRNA in liver biopsies from bariatric surgery patients. Wild-type (Wt), appetite-dysregulated Alms1 mutant (foz/foz), Tlr9-/-, and Tlr9-/-foz/foz C57BL6/J mice and bone marrow (BM) chimeras were fed 0.2% cholesterol, high-fat, high sucrose (atherogenic[Ath]) diet or chow, and NAFLD activity score (NAS)/NASH pathology, macrophage/neutrophil infiltration, cytokines/chemokines, and cell death markers measured in livers. Results: Hepatic TLR9 and TLR4 mRNA were increased in human NASH but not simple steatosis, and in Ath-fed foz/foz mice with metabolic syndrome-related NASH. Ath-fed Tlr9-/- mice showed simple steatosis and less Th1 cytokines than Wt. Tlr9-/-foz/foz mice were obese and diabetic, but necroinflammatory changes were less severe than Tlr9+/+.foz/foz mice. TLR9-expressing myeloid cells were critical for Th1 cytokine production in BM chimeras. BM macrophages from Tlr9-/- mice showed M2 polarization, were resistant to M1 activation by necrotic hepatocytes/other pro-inflammatory triggers, and provoked less neutrophil chemotaxis than Wt Livers from Ath-fed Tlr9-/- mice appeared to exhibit more markers of necroptosis [receptor interacting protein kinase (RIP)-1, RIP-3, and mixed lineage kinase domain-like protein (MLKL)] than Wt, and â¼25% showed portal foci of mononuclear cells unrelated to NASH pathology. CONCLUSION: Our novel clinical data and studies in overnutrition models, including those with diabetes and metabolic syndrome, clarify TLR9 as a pro-inflammatory trigger in NASH. This response is mediated via M1-macrophages and neutrophil chemotaxis.
Assuntos
Mediadores da Inflamação/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor Toll-Like 9/biossíntese , Regulação para Cima/fisiologia , Adiponectina/deficiência , Adulto , Animais , Cirurgia Bariátrica , Biópsia , Células Cultivadas , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Deleção de Genes , Hepatócitos/metabolismo , Hepatomegalia/prevenção & controle , Humanos , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Síndrome Metabólica/metabolismo , Erros Inatos do Metabolismo/prevenção & controle , Camundongos Knockout , Neutrófilos/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/prevenção & controle , RNA Mensageiro/genética , Receptor Toll-Like 9/deficiência , Receptor Toll-Like 9/genéticaRESUMO
Obesity is a known risk factor for the development of hepatic disease; obesity-induced fatty liver can lead to inflammation, steatosis, and cirrhosis and is associated with degeneration of the mitochondria. Lifestyle interventions such as physical activity may ameliorate this condition. The purpose of this study was to investigate regulation of mitochondrial and autophagy quality control in liver following Western diet-induced obesity and voluntary physical activity. Eight-week-old C57BL/6J mice were fed a Western diet (WD) or normal chow (NC, control) for 4 weeks; afterwards, groups were divided into voluntary wheel running (VWR) or sedentary (SED) conditions for an additional 4 weeks. WD-SED animals had a median histology score of 2, whereas WD-VWR was not different from NC groups (median score 1). There was no difference in mRNA of inflammatory markers Il6 and Tnfa in WD animals. WD animals had 50% lower mitochondrial content (COX IV and Cytochrome C proteins), 50% lower Pgc1a mRNA content, and reduced content of mitochondrial fusion and fission markers. Markers of autophagy were increased in VWR animals, regardless of obesity, as measured by 50% greater LC3-II/I ratio and 40% lower p62 protein content. BNIP3 protein content was 30% less in WD animals compared with NC animals, regardless of physical activity. Diet-induced obesity results in derangements in mitochondrial quality control that appear to occur prior to the onset of hepatic inflammation. Moderate physical activity appears to enhance basal autophagy in the liver; increased autophagy may provide protection from hepatic fat accumulation.
Assuntos
Autofagia , Fígado/patologia , Mitocôndrias Hepáticas/patologia , Atividade Motora , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/fisiopatologia , Regulação para Cima , Animais , Autofagossomos/imunologia , Autofagossomos/metabolismo , Autofagossomos/patologia , Biomarcadores/metabolismo , Dieta Ocidental/efeitos adversos , Regulação da Expressão Gênica , Hepatomegalia/etiologia , Hepatomegalia/prevenção & controle , Resistência à Insulina , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/fisiopatologia , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/imunologia , Mitocôndrias Hepáticas/metabolismo , Mitofagia , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Here we show that a mouse model of haploinsufficiency in the lipid and protein phosphatase and tensin homolog protein (PTEN(+/-)) exhibits hepatomegaly, increased liver lipogenic gene expression (SREBP-1C and PPARγ) and hepatic lesions analogous to human NAFLD. The livers of PTEN(+/-) mice also contained lower levels of retinoic acid (RA) than normal, similarly to human NAFLD patients. The RA signaling pathway thus offers a novel therapeutic target for the treatment of NAFLD although the impact of nutrition in this context is unclear. We therefore fed PTEN(+/-) mice for 36weeks a diet containing genetically engineered high-carotenoid corn (HCAR) to investigate its potential beneficial effects on the hepatic symptoms of NAFLD. The HCAR diet reduced hepatomegaly and promoted the repartitioning of fatty acids in the liver, away from triacylglycerol storage. At the molecular level, the HCAR diet clearly reduced lipogenic gene expression, boosted catabolism, and increased hepatic RA levels. These results set the stage for human trials to evaluate the use of high-carotenoid foods for the reduction or prevention of steatosis in NAFLD.
Assuntos
Carotenoides/farmacologia , Alimentos Geneticamente Modificados , Haploinsuficiência , Hepatomegalia/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , PTEN Fosfo-Hidrolase/genética , Zea mays , Ração Animal , Animais , Feminino , Hepatomegalia/genética , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Camundongos , Camundongos Mutantes , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR gama/genética , PPAR gama/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
OBJECTIVE: To determine the safety, feasibility, and efficacy of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in a single high-volume hepatobiliary center. BACKGROUND: The ALPPS approach allows achieving resectability of liver malignancies by a rapid and large future liver remnant (FLR) hypertrophy. However, this proposal has been associated with high morbidity and mortality rates. METHODS: This was a single-cohort, prospective, observational study [NCT02164292]. Between June 2011 and April 2014, patients with liver malignancies considered unresectable due to an insufficient FLR who underwent ALPPS were included. RESULTS: Thirty patients were treated. Median age was 58.6 years (range = 35-81) and 19 patients were males (63%). In a median of 6 days (range = 4-67), the median FLR hypertrophy was 89.7% (range = 21-287). Twenty-nine patients completed the second stage (97% feasibility). Morbidity according to the Dindo-Clavien classification was 53% (grade ≥IIIa 43% and grade ≥IIIb 31%). The mortality rate was 6.6%. Total parenchymal transection was identified as an independent risk factor for complications (P = 0.049). There was not significant difference in terms of FLR hypertrophy between total or partial parenchymal transection (P = 0.45). Median hospital stay was 16 days (range = 11-62). The overall and disease-free survival at 1 year was 78% and 67% and at 2 years was 63% and 40%, respectively. CONCLUSIONS: This prospective study on the largest reported single-center experience shows that ALPPS has acceptable morbidity and mortality, together with a high oncological feasibility and hypertrophic efficacy. Partial parenchymal transection seems to reduce morbidity without negatively impacting FLR hypertrophy.
Assuntos
Hepatectomia/métodos , Ligadura/métodos , Neoplasias Hepáticas/cirurgia , Veia Porta/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Seguimentos , Hepatectomia/efeitos adversos , Hepatomegalia/epidemiologia , Hepatomegalia/etiologia , Hepatomegalia/prevenção & controle , Humanos , Laparoscopia , Tempo de Internação/estatística & dados numéricos , Fígado/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Tamanho do Órgão , Segurança do Paciente , Estudos Prospectivos , Reoperação , Taxa de Sobrevida , Resultado do Tratamento , Procedimentos Cirúrgicos VascularesRESUMO
Single-incision surgery in the morbidly obese patient has not been widely adopted, but remains a popular choice amongst patients. In the bariatric patient, it presents its own surgical challenges with hepatomegaly and increased abdominal adiposity. Here, we present our experience of 275 single-incision laparoscopic gastric bands.Between June 2009 and April 2013, 275 obese patients underwent single-incision laparoscopic adjustable gastric banding through a single incision using a multichannel single port and via a pars flaccida approach. Prospective data collection was undertaken including operating time, additional ports and additional procedures undertaken.In this series, median operative time was 60 (range 34-170) min. An additional port was placed in 15 patients (5%), including two conversions to four-port technique (0.7%). Of these patients (n = 15), the majority were male (p < 0.0001). Reasons for additional port placement included bleeding and anatomical abnormalities. Additional port placement occurred more often within the first 50 cases (5/50, 10% vs 10/225, 4%). An umbilical incision resulted in more wound-related complications than a transverse incision in the upper abdomen (p < 0.001). There were no 30-day mortality and minimal morbidity with two wound infections resulting in band removal.Single-incision laparoscopic adjustable gastric banding can be performed safely with minimal morbidity in the morbidly obese patient, and our technique has a high rate of success for all BMIs. Following 275 single-incision band insertions additional port placements were more commonly required in male patients, BMI >45 and earlier in the learning curve.
Assuntos
Gastroplastia , Hepatomegalia/etiologia , Laparoscopia , Obesidade Mórbida/cirurgia , Complicações Pós-Operatórias/cirurgia , Adolescente , Adulto , Idoso , Estudos de Viabilidade , Feminino , Gastroplastia/métodos , Hepatomegalia/prevenção & controle , Humanos , Laparoscopia/métodos , Curva de Aprendizado , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Dor Pós-Operatória , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Resultado do TratamentoRESUMO
IMPORTANCE: Portal vein embolization improves the safety of liver resection by increasing the size of residual liver, but the embolization may increase tumor growth during the waiting period before definitive hepatectomy. OBJECTIVE: To determine whether the administration of chemotherapy mitigates tumor growth after portal vein embolization (PVE) performed before major hepatectomy for metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Review of prospectively collected data at Memorial-Sloan Kettering Cancer Center was conducted. The database included patients subjected to PVE before major hepatectomy for metastatic colorectal cancer. MAIN OUTCOMES AND MEASURES: Lesions in both the embolized and nonembolized lobes of the liver before and 1 month after PVE were measured and Response Evaluation Criteria in Solid Tumors were applied to assess disease status. Assessment of survival was based on receipt of post-PVE chemotherapy and then stratified by subsequent resectability. RESULTS: Two hundred eight tumors were measured in 64 patients; 53 tumors were in patients undergoing post-PVE chemotherapy. Approximately one-third of the lesions progressed after PVE when no chemotherapy was administered. This did not differ significantly according to whether tumors were ipsilateral or contralateral to the PVE. When chemotherapy was administered, there was a significantly lower rate of progression (18.9%, P = .03). In long-term follow-up, treatment with post-PVE chemotherapy was also independently associated with improved survival (P < .006). CONCLUSIONS AND RELEVANCE: Chemotherapy does not retard growth of the liver after PVE and may prevent cancer progression. Thus, the combination of PVE and chemotherapy may enhance both oncologic and operative safety.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Embolização Terapêutica/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Terapia Neoadjuvante/métodos , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Estudos de Coortes , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Terapia Combinada , Feminino , Seguimentos , Hepatectomia/métodos , Hepatomegalia/prevenção & controle , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Veia Porta , Cuidados Pré-Operatórios/métodos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Taxa de Sobrevida , Resultado do Tratamento , Carga TumoralRESUMO
BACKGROUND AND AIM: The clinical usefulness of portal vein embolization (PVE) for Klatskin tumor is not well established. The authors explored the change in liver volume and function before and after major hepatectomy and evaluated the effect of PVE. METHODS: Thirty-three consecutive patients who underwent right hepatectomy with an initial future liver remnant (FLR) ≤ 30% for Klatskin tumors at Seoul National University Hospital were included. RESULTS: Eleven patients underwent PVE, and eight patients received right trisectionectomy. PVE induced a mean FLR increase of 19.3% after a mean of 15.8 days. At postoperative month 1, liver volume and liver hypertrophy ratio was comparable between PVE and no-PVE group. For patients with an initial FLR ≤ 20%, postoperative liver hypertrophy rate of PVE group was comparable to no-PVE group. Liver function tests were not affected by PVE or the initial FLR. Postoperative liver hypertrophy ratio was negatively correlated with the initial FLR (hypertrophy ratio (%) = 326.7-0.4×initial FLR (ml), P = 0.001). There was no severe PVE-related morbidity, and postoperative morbidity rate was comparable in PVE and no-PVE group. CONCLUSION: The postoperative liver hypertrophy ratio, final liver volume, or liver function tests were not affected by PVE. Postoperative liver hypertrophy was related to the initial FLR.
Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Embolização Terapêutica , Hepatectomia , Ducto Hepático Comum , Tumor de Klatskin/cirurgia , Veia Porta , Cuidados Pré-Operatórios/métodos , Idoso , Feminino , Hepatectomia/métodos , Hepatomegalia/epidemiologia , Hepatomegalia/etiologia , Hepatomegalia/prevenção & controle , Humanos , Modelos Lineares , Fígado/crescimento & desenvolvimento , Fígado/cirurgia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Resultado do TratamentoRESUMO
Chronic ibuprofen (0.4 g/kg intraperitoneally, once daily for 4 weeks) evidenced a series of pathologies, not previously reported in ibuprofen-dosed rats, namely hepatic encephalopathy, gastric lesions, hepatomegaly, increased AST and ALT serum values with prolonged sedation/unconsciousness, and weight loss. In particular, ibuprofen toxicity was brain edema, particularly in the cerebellum, with the white matter being more affected than in gray matter. In addition, damaged and red neurons, in the absence of anti-inflammatory reaction was observed, particularly in the cerebral cortex and cerebellar nuclei, but was also present although to a lesser extent in the hippocampus, dentate nucleus and Purkinje cells. An anti-ulcer peptide shown to have no toxicity, the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, 10 µg, 10 ng/kg) inhibited the pathology seen with ibuprofen (i) when given intraperitoneally, immediately after ibuprofen daily or (ii) when given in drinking water (0.16 µg, 0.16 ng/ml). Counteracted were all adverse effects, such as hepatic encephalopathy, the gastric lesions, hepatomegaly, increased liver serum values. In addition, BPC 157 treated rats showed no behavioral disturbances and maintained normal weight gain. Thus, apart from efficacy in inflammatory bowel disease and various wound treatments, BPC 157 was also effective when given after ibuprofen.
Assuntos
Antiulcerosos/farmacologia , Encefalopatia Hepática/prevenção & controle , Hepatomegalia/prevenção & controle , Ibuprofeno/efeitos adversos , Peptídeos/farmacologia , Gastropatias/prevenção & controle , Estômago/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antiulcerosos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Lesões Encefálicas/induzido quimicamente , Mucosa Gástrica/metabolismo , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/patologia , Hepatomegalia/induzido quimicamente , Hepatomegalia/patologia , Ibuprofeno/antagonistas & inibidores , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Dados de Sequência Molecular , Tamanho do Órgão/efeitos dos fármacos , Peptídeos/efeitos adversos , Peptídeos/química , Ratos , Ratos Wistar , Estômago/lesões , Estômago/patologia , Gastropatias/induzido quimicamente , Gastropatias/patologiaRESUMO
UNLABELLED: Transient hepatomegaly often accompanies acute bacterial infections. Reversible, dose-dependent hepatomegaly also occurs when animals are given intravenous infusions of bacterial lipopolysaccharide (LPS). We found that recovery from LPS-induced hepatomegaly requires a host enzyme, acyloxyacyl hydrolase (AOAH), that inactivates LPS. When we challenged Aoah(-/-) mice with low doses of LPS or gram-negative bacteria, their livers remained enlarged (as much as 80% above normal) many weeks longer than did the livers of Aoah(+/+) animals. When compared with livers from LPS-primed Aoah(+/+) mice, LPS-primed Aoah(-/-) livers had (1) more numerous and larger Kupffer cells, (2) intrasinusoidal leukocyte aggregates and activated sinusoidal endothelial cells, and (3) sustained production of interleukin (IL)-10 and messenger RNAs (mRNAs) for tumor necrosis factor (TNF), IL-10, and IRAK-M. Depleting Kupffer cells decreased the liver enlargement by ≈40%, whereas depletion of neutrophils, dendritic cells, natural killer (NK) cells, NK-T cells, or B cells had no effect. Pretreatment with dexamethasone almost completely prevented prolonged hepatomegaly in Aoah(-/-) mice, whereas neutralizing TNF or interleukin-1ß was only partially effective. In contrast, an antagonistic antibody to the IL-10 receptor increased LPS-induced hepatomegaly by as much as 50%. CONCLUSION: our findings suggest that persistently active LPS induces Kupffer cells to elaborate mediators that promote the accumulation of leukocytes within enlarged sinusoids. Large increases in IL-10 and several other modulatory molecules are unable to prevent prolonged hepatomegaly in mice that cannot inactivate LPS. The striking findings in this mouse model should encourage studies to find out how AOAH contributes to human liver physiology and disease.
Assuntos
Hepatomegalia/etiologia , Lipopolissacarídeos/toxicidade , Animais , Hidrolases de Éster Carboxílico/fisiologia , Proliferação de Células , Citocinas/análise , Citocinas/fisiologia , Células Endoteliais/fisiologia , Hepatomegalia/prevenção & controle , Células de Kupffer/fisiologia , Antígeno 96 de Linfócito/fisiologia , Camundongos , Óxido Nítrico Sintase/fisiologia , Receptor 4 Toll-Like/fisiologiaRESUMO
Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease in industrialized countries. Thus, the discovery of food components that would ameliorate NAFLD is of interest. Various mushrooms have been used in folk medicine for the treatment of lifestyle diseases in eastern countries and several compounds that modulate immune system, lower blood lipid levels, inhibit tumor and viral action have been isolated from them. In this study, we tested whether feeding Panellus serotinus (Mukitake) to db/db mice protects them from hepatic injury. After 4 weeks of feeding, hepatomegaly, hepatic triglyceride accumulation and elevated hepatic injury markers in serum were markedly alleviated in Mukitake-fed db/db mice compared with control mice. These effects were partly attributable to the enhancement of lipolytic enzyme activity and the suppression of lipogenic enzyme activities due to the Mukitake diet. The severe hyperinsulinemia in control db/db mice tended to attenuate in Mukitake-fed mice due to an enhanced production of adiponectin, which improves insulin sensitivity. Moreover, production of monocyte chemoattractant protein 1 (MCP1), an inflammatory cytokine, was markedly suppressed by the Mukitake diet. In addition, water-soluble extracts of Mukitake powder showed an inhibitory effect on inhibitor of kappaB (IkappaB) kinase (IKK) beta, whose activation is required for nuclear factor kappaB (NFkappaB)-mediated inflammatory response. We speculate that the development and progression of NAFLD was prevented by the reduction of MCP1 production through the interference in the IKKbeta-NFkappaB signaling pathway in Mukitake-fed db/db mice.
Assuntos
Agaricales , Quimiocina CCL2/metabolismo , Fígado Gorduroso/prevenção & controle , Adiponectina/sangue , Agaricales/química , Animais , Biomarcadores/sangue , Quimiocina CCL2/sangue , Misturas Complexas/isolamento & purificação , Fígado Gorduroso/sangue , Fígado Gorduroso/dietoterapia , Hepatomegalia/prevenção & controle , Hiperinsulinismo/prevenção & controle , Quinase I-kappa B/antagonistas & inibidores , Resistência à Insulina , Lipogênese , Lipólise , Fígado/química , Fígado/enzimologia , Masculino , Medicina Tradicional do Leste Asiático , Camundongos , Camundongos Endogâmicos C57BL , Pós/administração & dosagem , Pós/química , Triglicerídeos/análise , Aumento de PesoRESUMO
We focused on over-dose insulin (250 IU/kg i.p.) induced gastric ulcers and then on other disturbances that were concomitantly induced in rats, seizures (eventually fatal), severely damaged neurons in cerebral cortex and hippocampus, hepatomegaly, fatty liver, increased AST, ALT and amylase serum values, breakdown of liver glycogen with profound hypoglycemia and calcification development. Calcium deposits were present in the blood vessel walls, hepatocytes surrounding blood vessels and sometimes even in parenchyma of the liver mainly as linear and only occasionally as granular accumulation. As an antidote after insulin, we applied the stable gastric pentadecapeptide BPC 157 (10 microg/kg) given (i) intraperitoneally or (ii) intragastrically immediately after insulin. Controls received simultaneously an equivolume of saline (5 ml/kg). Those rats that survived till the 180 minutes after over-dose application were further assessed. Interestingly, pentadecapeptide BPC 157, as an antiulcer peptide, may besides stomach ulcer consistently counteract all insulin disturbances and fatal outcome. BPC 157 rats showed no fatal outcome, they were mostly without hypoglycemic seizures with apparently higher blood glucose levels (glycogen was still present in hepatocytes), less liver pathology (i.e., normal liver weight, less fatty liver), decreased ALT, AST and amylase serum values, markedly less damaged neurons in brain and they only occasionally had small gastric lesions. BPC 157 rats exhibited mostly only dot-like calcium presentation. In conclusion, the success of BPC 157 therapy may indicate a likely role of BPC 157 in insulin controlling and BPC 157 may influence one or more causative process(es) after excessive insulin application.
Assuntos
Antiulcerosos/uso terapêutico , Antídotos/uso terapêutico , Hipoglicemia/prevenção & controle , Hipoglicemiantes/toxicidade , Insulina/toxicidade , Fragmentos de Peptídeos/uso terapêutico , Proteínas/uso terapêutico , Úlcera Gástrica/prevenção & controle , Animais , Antiulcerosos/administração & dosagem , Antídotos/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Calcinose/induzido quimicamente , Calcinose/prevenção & controle , Overdose de Drogas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Glicogênio/metabolismo , Hepatomegalia/induzido quimicamente , Hepatomegalia/patologia , Hepatomegalia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/complicações , Hipoglicemia/mortalidade , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Fragmentos de Peptídeos/administração & dosagem , Proteínas/administração & dosagem , Ratos , Ratos Wistar , Convulsões/etiologia , Convulsões/prevenção & controle , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologiaRESUMO
OBJECTIVE: The objective of this study was to test the hypothesis that hepatomegaly in burned children can be attenuated or reversed by blocking lipolysis and reducing free fatty acids delivered to the liver. SUMMARY BACKGROUND DATA: Accelerated lipolysis in severely burned children has been shown to play an important role in the accumulation of hepatic TGs. Severely burned children who survive 10 days or more after injury commonly have enlarged livers often twice or more normal size for their sex, age, and weight. METHODS: Ninety-eight children, 2 to 18 years of age, with burns covering more than 40% of their body surface and who received either propranolol (beta-adrenergic blockade) or placebo were studied. Liver weights were measured by ultrasonic scanning. Body composition changes were identified by dual-image x-ray absorptiometry and validated by whole-body potassium-40 scintillation counting. Discarded abdominal cutaneous adipose tissue was collected before and after propranolol or placebo for microarray analysis. RESULTS: In 80% of severely burned children studied not receiving propranolol, liver sizes increased by 100% or more while 86% of burned children receiving propranolol showed a decrease or no change in liver size over the same period of time after injury. Gene expression patterns of adipose tissue after propranolol treatment showed that all of the identified genes related to lipid metabolism were down-regulated. CONCLUSIONS: Data reported here support the hypothesis that beta-adrenergic blockade can reduce delivery of fatty acids to the liver and hepatic congestion commonly found in severely burned children by inhibiting lipolysis and reducing hepatic blood flow.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Queimaduras/tratamento farmacológico , Hepatomegalia/prevenção & controle , Propranolol/uso terapêutico , Queimaduras/complicações , Queimaduras/terapia , Criança , Nutrição Enteral , Feminino , Hepatomegalia/etiologia , Humanos , Masculino , Transplante de Pele , Procedimentos Cirúrgicos Operatórios , Resultado do TratamentoRESUMO
Evaluating regression of morbidity associated with parasitic infections is an important component of community-based control programmes. We performed an intervention against Schistosoma mansoni infection, focusing on hepatosplenomegaly in the absence of periportal fibrosis, in a cohort of 67 Kenyan children aged 7-18 years from Makueni District, selected on the basis of hepatosplenomegaly detected by ultrasonography. Clinical and ultrasound examinations were conducted annually for three years after treatment, and the source of infection (a river) was regularly treated with molluscicide, thereby severely reducing exposure to schistosomiasis. Malaria transmission was uninterrupted. The prevalence of hard spleens, and the magnitude of clinically assessed splenomegaly along the mid-axillary and mid-clavicular lines decreased monotonically over time, independently of age, whereas clinically measured hepatomegaly along the mid-sternal line and the prevalence of firm livers decreased in an age-specific manner, being more pronounced amongst children aged 14 years or older at enrolment. Ultrasound data were less informative, and did not concur with clinical observations. These results demonstrate that praziquantel treatment reduces hepatosplenomegaly in the absence of exposure to S. mansoni, even with continuing exposure to malaria. The lack of complete resolution of hepatosplenomegaly in most children suggests, among other things, a residual organomegaly attributable to malaria.
Assuntos
Anti-Helmínticos/uso terapêutico , Hepatomegalia/epidemiologia , Praziquantel/uso terapêutico , Esquistossomose mansoni/tratamento farmacológico , Esplenomegalia/epidemiologia , Adolescente , Distribuição por Idade , Criança , Estudos de Coortes , Feminino , Hepatomegalia/prevenção & controle , Humanos , Quênia/epidemiologia , Fígado/diagnóstico por imagem , Fígado/parasitologia , Masculino , Contagem de Ovos de Parasitas/métodos , Prevalência , Esquistossomose mansoni/epidemiologia , Baço/diagnóstico por imagem , Baço/parasitologia , Esplenomegalia/prevenção & controle , Resultado do Tratamento , UltrassonografiaAssuntos
Proteínas de Ligação ao Cálcio/deficiência , Hepatomegalia/complicações , Hipoglicemia/complicações , Cetose/complicações , Transportadores de Ânions Orgânicos/deficiência , Acidose Láctica/complicações , Acidose Láctica/prevenção & controle , Pré-Escolar , Citrulina/análise , Feminino , Teste de Tolerância a Glucose , Hepatomegalia/prevenção & controle , Humanos , Hipoglicemia/prevenção & controle , Lactente , Proteínas de Membrana Transportadoras/genética , Proteínas de Transporte da Membrana Mitocondrial , Proteínas Mitocondriais/genética , Mutação , Irmãos , Amido/uso terapêuticoRESUMO
We investigated the potential of chronic administration of an oral daily dose (10 mg/kg) of the dietary flavonoid quercetin to prevent hypertension and oxidative stress induced by deoxycorticosterone acetate (DOCA)-salt in rats. We have compared its effects to those produced by the well-known anti-hypertensive drug verapamil, administered orally (20 mg/kg/day). Quercetin and verapamil treatments reduced systolic blood pressure of DOCA-salt rats in approximately 67.6 and 63.3% respectively, producing no effect in control animals. Both drugs reduced significantly hepatic and renal hypertrophy induced by DOCA-salt administration, while only quercetin prevented cardiac hypertrophy. Decreased endothelium-dependent relaxation to acetylcholine of aortic rings from DOCA-salt-treated rats was improved by quercetin, but verapamil only enhanced it in the presence of superoxide dismutase (SOD) plus catalase. Increased plasma and heart thiobarbituric acid reactive substances (TBARS) and total glutathione (GSH) levels in liver and heart, decreased liver glutathione peroxidase (GPX) and liver and kidney glutathione transferase (GST) activities were observed in DOCA-salt-treated rats compared to the control animals. The antihypertensive effect of quercetin was accompanied by normalisation of plasma TBARS values, improvement of the antioxidant defences system in heart and liver, restoring total GSH levels in both organs and altered liver GST and GPX activities, and improving kidney GST activity. Verapamil treatment only restored GSH levels in heart, having no effect on other alterations induced by DOCA-salt chronic administration in the antioxidant defences analysed. In conclusion, quercetin shows both antihypertensive and antioxidant properties in this model of mineralocorticoid hypertension, while verapamil exhibits only antihypertensive effects.
Assuntos
Hipertensão/tratamento farmacológico , Quercetina/administração & dosagem , Vasodilatadores/administração & dosagem , Verapamil/administração & dosagem , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/prevenção & controle , Catalase/sangue , Desoxicorticosterona/administração & dosagem , Glutationa/análise , Glutationa Peroxidase/análise , Glutationa Transferase/análise , Hepatomegalia/prevenção & controle , Hipertensão/sangue , Hipertensão/induzido quimicamente , Rim/química , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/química , Masculino , Miocárdio/química , Oxirredução , Ratos , Ratos Wistar , Superóxido Dismutase/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
We investigated the effects of vinyl chloride monomer exposure on the liver of 86 workers by measuring beta-glucuronidase, arylsulfatase A, adenosine deaminase, 5'-nucleotidase and routine liver function enzymes in the sera of the workers. In 21 of them, three or more of these parameters were raised, with a significant decrease in the level of blood glutathione and a significant increase in the enzyme activity level of glutathione S-transferase. Of these 21 workers, 14 had fatty liver infiltration, 8 of whom were also suffering from liver enlargement. Also, 4 workers had liver enlargement without fatty infiltration and 3 had enlarged spleens. The study highlights the need for vigilance in environmental monitoring and medical surveillance of workers exposed to this chemical.
Assuntos
Carcinógenos , Fígado Gorduroso/induzido quimicamente , Hepatomegalia/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Esplenomegalia/induzido quimicamente , Cloreto de Vinil/intoxicação , 5'-Nucleotidase/sangue , Adenosina Desaminase/sangue , Adulto , Estudos de Casos e Controles , Cerebrosídeo Sulfatase/sangue , Egito , Monitoramento Ambiental , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/enzimologia , Fígado Gorduroso/prevenção & controle , Glucuronidase/sangue , Glutationa Transferase/sangue , Hepatomegalia/diagnóstico , Hepatomegalia/enzimologia , Hepatomegalia/prevenção & controle , Humanos , Testes de Função Hepática , Masculino , Avaliação das Necessidades , Doenças Profissionais/diagnóstico , Doenças Profissionais/enzimologia , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/análise , Saúde Ocupacional , Esplenomegalia/diagnóstico , Esplenomegalia/enzimologia , Esplenomegalia/prevenção & controleRESUMO
The specific treatment of schistosomiasis has been thought to prevent or revert severe forms of the disease, since 1957. Starting in 1977, prospective and controlled studies performed in different endemic areas of Brazil were able to confirm such facts. The new drugs, of high efficacy and well tolerated--Oxamniquine and Praziquantel--can actually prevent and cure the severe forms of some patients, contributing to change the morbidity pattern of the disease, thus being considered as important weapons in its control. Analysis of the principal Brazilian articles on the subject is presented.
Assuntos
Oxamniquine/uso terapêutico , Praziquantel/uso terapêutico , Esquistossomose mansoni/tratamento farmacológico , Adolescente , Brasil/epidemiologia , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Seguimentos , Hepatomegalia/parasitologia , Hepatomegalia/prevenção & controle , Humanos , Masculino , Moluscocidas , Prevalência , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos , Recidiva , Esquistossomose mansoni/epidemiologia , Esquistossomose mansoni/prevenção & controle , Esplenectomia , Esplenomegalia/parasitologia , Esplenomegalia/prevenção & controle , Esplenomegalia/cirurgiaRESUMO
Susceptible rat strains develop hepatobiliary injury following the surgical creation of self-filling blind loops that cause small bowel bacterial overgrowth. Luminal bacteria or their cell wall polymers were implicated in the pathogenesis of the lesions because sham-operated rats and rats with self-emptying blind loops, having only slightly increased bacterial counts, did not develop hepatic injury. In this study, antibiotics with different spectra of activities were continuously administered starting 1 day or 22 days after surgery to determine which intestinal flora may be responsible for the development of hepatic injury in rats with small bowel bacterial overgrowth. Four weeks following surgery, Lewis rats with self-filling blind loops receiving no antibiotics had elevated liver histology scores (8.2 +/- 1.3 vs. 0.7 +/- 0.4) and plasma aspartate aminotransferase levels (269 +/- 171 vs. 84 +/- 24) compared with sham-operated rats, P less than 0.001. Oral gentamicin as well as oral and intraperitoneal polymyxin B, which binds endotoxin, did not prevent hepatic injury in rats with self-filling blind loops. However, oral metronidazole and tetracycline therapy continuously administered beginning 1 day after surgery diminished hepatic injury (histology score 3.0 +/- 1.8, 2.9 +/- 1.1; aspartate aminotransferase 87 +/- 25, 98 +/- 34; respectively P less than 0.001 compared with self-filling blind loops receiving no antibiotics). Metronidazole also protected Wistar rats that require 12 weeks to develop hepatic injury following experimentally induced small bowel bacterial overgrowth compared with rats with self-filling blind loops that received no antibiotic treatment (histology score 10.4 +/- 1.3 vs. 0.7 +/- 1.1, and aspartate aminotransferase 273 +/- 239 vs. 76 +/- 20, P less than 0.001). When rats started metronidazole therapy 22 days after self-filling blind loop surgery, elevated aspartate aminotransferase values decreased to normal during the next 77 days and final histology scores were normal. All rats with self-filling blind loops had negative peritoneal, liver, spleen, and blood cultures but approximately 75% of mesenteric lymph node cultures were positive irrespective of antibiotic treatment. Because Bacteroides species have been implicated in causing vitamin B12 and disaccharidase deficiencies in rats with self-filling blind loops, we documented the presence or absence of these organisms from blind loops using selective culture techniques. Metronidazole and tetracycline eliminated Bacteroides sp. from blind loops, but polymyxin B and gentamicin did not.(ABSTRACT TRUNCATED AT 400 WORDS)