RESUMO
Pegmolesatide, a synthetic, polyethylene-glycolylated, peptide-based erythropoiesis-stimulating agent (ESA), has been recently approved in China. Pegmolesatide is derived from the structure of endogenous erythropoietin (EPO), a natural product in mammals. This study compared the in vitro effects and selectivity of pegmolesatide to those of recombinant EPO and carbamylated EPO (CEPO) through computer-aided analyses and biological tests. The findings indicate that pegmolesatide exhibited the same stimulating effect on erythropoiesis as EPO with fewer side effects than EPO and CEPO.
RESUMO
To investigate the role of glial cells in the regulation of glucoprivic responses in rats, a chemogenetic approach was used to activate astrocytes neighboring catecholamine (CA) neurons in the ventromedial medulla (VLM) where A1 and C1 CA cell groups overlap (A1/C1). Previous results indicate that activation of CA neurons in this region is necessary and sufficient for feeding and corticosterone release in response to glucoprivation. However, it is not known whether astrocyte neighbors of CA neurons contribute to glucoregulatory responses. Hence, we made nanoinjections of AAV5-GFAP-hM3D(Gq)-mCherry to selectively transfect astrocytes in the A1/C1 region with the excitatory designer receptor exclusively activated by designer drugs (DREADDs), hM3D(Gq). After allowing time for DREADD expression, we evaluated the rats for increased food intake and corticosterone release in response to low systemic doses of the antiglycolytic agent, 2-deoxy-d-glucose (2DG), alone and in combination with the hM3D(Gq) activator clozapine-n-oxide (CNO). We found that DREADD-transfected rats ate significantly more food when 2DG and CNO were coadministered than when either 2DG or CNO was injected alone. We also found that CNO significantly enhanced 2DG-induced FOS expression in the A1/C1 CA neurons, and that corticosterone release also was enhanced when CNO and 2DG were administered together. Importantly, CNO-induced activation of astrocytes in the absence of 2DG did not trigger food intake or corticosterone release. Our results indicate that during glucoprivation, activation of VLM astrocytes cells markedly increases the sensitivity or responsiveness of neighboring A1/C1 CA neurons to glucose deficit, suggesting a potentially important role for VLM astrocytes in glucoregulation.
Assuntos
Astrócitos , Corticosterona , Ratos , Animais , Astrócitos/metabolismo , Desoxiglucose/farmacologia , Ratos Sprague-Dawley , Bulbo/metabolismo , Glucose/metabolismo , Catecolaminas/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: G protein-coupled receptor 40 (GPR40) is a receptor for medium- and long-chain free fatty acids (FFAs). GPR40 activation improves type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and the complications of T2DM and MetS. Periodontitis, a common oral inflammatory disease initiated by periodontal pathogens, is another complication of T2DM and MetS. Since FFAs play a key role in the pathogenesis of MetS which exacerbates periodontal inflammation and GPR40 is a FFA receptor with anti-inflammatory properties, it is important to define the role of GPR40 in MetS-associated periodontitis. MATERIALS AND METHODS: We induced MetS and periodontitis by high-fat diet and periodontal injection of lipopolysaccharide (LPS), respectively, in wild-type and GPR40-deficient mice and determined alveolar bone loss and periodontal inflammation using micro-computed tomography, histology, and osteoclast staining. We also performed in vitro study to determine the role of GPR40 in the expression of proinflammatory genes. RESULTS: The primary outcome of the study is that GPR40 deficiency increased alveolar bone loss and enhanced osteoclastogenesis in control mice and the mice with both MetS and periodontitis. GPR40 deficiency also augmented periodontal inflammation in control mice and the mice with both MetS and periodontitis. Furthermore, GPR40 deficiency led to increased plasma lipids and insulin resistance in control mice but had no effect on the metabolic parameters in mice with MetS alone. For mice with both MetS and periodontitis, GPR40 deficiency increased insulin resistance. Finally, in vitro studies with macrophages showed that deficiency or inhibition of GPR40 upregulated proinflammatory genes while activation of GPR40 downregulated proinflammatory gene expression stimulated synergistically by LPS and palmitic acid. CONCLUSION: GPR40 deficiency worsens alveolar bone loss and periodontal inflammation in mice with both periodontitis and MetS, suggesting that GPR40 plays a favorable role in MetS-associated periodontitis. Furthermore, GPR40 deficiency or inhibition in macrophages further upregulated proinflammatory and pro-osteoclastogenic genes induced by LPS and palmitic acid, suggesting that GPR40 has anti-inflammatory and anti-osteoclastogenic properties.
Assuntos
Perda do Osso Alveolar , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Síndrome Metabólica , Periodontite , Camundongos , Animais , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Perda do Osso Alveolar/patologia , Diabetes Mellitus Tipo 2/complicações , Lipopolissacarídeos/efeitos adversos , Microtomografia por Raio-X , Periodontite/metabolismo , Inflamação , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Anti-Inflamatórios , Ácidos Graxos não Esterificados , Ácidos Palmíticos/efeitos adversosRESUMO
G-protein-coupled receptor 40 (GPR40) is highly expressed in pancreatic islets, and its activation increases glucose-stimulated insulin secretion from pancreas. Therefore, GPR40 is considered as a target for type 2 diabetes mellitus (T2DM). Since nonalcoholic fatty liver disease (NAFLD) is associated with T2DM and GPR40 is also expressed by hepatocytes and macrophages, it is important to understand the role of GPR40 in NAFLD. However, the role of GPR40 in NAFLD in animal models has not been well defined. In this study, we fed wild-type or GPR40 knockout C57BL/6 mice a high-fat diet (HFD) for 20 wk and then assessed the effect of GPR40 deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that an HFD increased body weight, glucose, insulin, insulin resistance, cholesterol, and alanine aminotransferase (ALT), and GPR40 deficiency did not mitigate the HFD-induced metabolic abnormalities. In contrast, we found that GPR40 deficiency was associated with increased body weight, insulin, insulin resistance, cholesterol, and ALT in control mice fed a low-fat diet (LFD). Surprisingly, histology and Oil Red O staining showed that GPR40 deficiency in LFD-fed mice was associated with steatosis. Immunohistochemical analysis showed that GPR40 deficiency also increased F4/80, a macrophage biomarker, in LFD-fed mice. Furthermore, results showed that GPR40 deficiency led to a robust upregulation of hepatic fatty acid translocase (FAT)/CD36 expression. Finally, our in vitro studies showed that GPR40 knockdown by siRNA or a GPR40 antagonist increased palmitic acid-induced FAT/CD36 mRNA in hepatocytes. Taken together, this study indicates that GPR40 plays an important role in homeostasis of hepatic metabolism and inflammation and inhibits nonalcoholic steatohepatitis by possible modulation of FAT/CD36 expression.
Assuntos
Antígenos CD36/biossíntese , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Animais , Peso Corporal , Antígenos CD36/genética , Dieta Hiperlipídica , Dislipidemias/genética , Fígado Gorduroso/patologia , Hepatite/metabolismo , Hepatite/patologia , Resistência à Insulina/genética , Fígado/patologia , Testes de Função Hepática , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Acoplados a Proteínas G/genética , Regulação para CimaRESUMO
Background and aim: The molecular signatures of lung adenocarcinoma (LUAD) are not well understood. Centromere protein F (CENPF) has been shown to promote oncogenesis in many cancers; however, its role in LUAD has not been illustrated. We explored the role of CENPF in LUAD. Methods: CENPF expression level was investigated in public online database firstly, the prognosis of CENPF in LUAD were also assessed by Kaplan-Meier analysis. Then quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed using 13 matched pairs of clinical LUAD tissue samples. Subsequently, the impact of CENPF expression on cell proliferation, cell cycle, apoptosis, colony formation was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), flow cytometric analysis and colony formation assay, respectively. Finally, experimental xenograft lung cancer model of nude mice armpit of right forelimb to determine the effect of CENPF on LUAD tumorigenesis. Results: CENPF mRNA expression was significantly elevated in LUAD tissues compared with adjacent non-tumor lung tissues in Gene Expression Profiling Interactive Analysis (GEPIA) (P < 0.001). Up-regulated CENPF was remarkably positively associated with pathological stage, relapse free survival (RFS) as well as overall survival (OS) of LUAD patients. Besides, CENPF knockdown greatly suppressed A549 cell proliferation, induced S phase arrest, promoted apoptosis and decreased colony numbers of LUAD cells. Furthermore, knockdown of CENPF significantly inhibited the tumor growth of the LUAD cells in an experimental xenograft lung cancer model of nude mice armpit of right forelimb. Conclusion: Taken together, these results demonstrated that CENPF may serve as a potential biomarker of prognostic relevance and a potential therapeutic target for LUAD.
Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Proteínas Cromossômicas não Histona/genética , Neoplasias Pulmonares/genética , Proteínas dos Microfilamentos/genética , Recidiva Local de Neoplasia/epidemiologia , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas Cromossômicas não Histona/análise , Proteínas Cromossômicas não Histona/metabolismo , Conjuntos de Dados como Assunto , Progressão da Doença , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Proteínas dos Microfilamentos/análise , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Leptin administration into the hindbrain, and specifically the nucleus of the solitary tract, increases phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor activation, in hypothalamic nuclei known to express leptin receptors. The ventromedial nucleus of the hypothalamus (VMH) shows the greatest response, with a threefold increase in pSTAT3. This experiment tested the importance of VMH leptin receptor-expressing neurons in mediating weight loss caused by fourth ventricle (4V) leptin infusion. Male Sprague-Dawley rats received bilateral VMH 75-nL injections of 260 ng/µL of leptin-conjugated saporin (Lep-Sap) or blank-saporin (Blk-Sap). After 23 days they were fitted with 4V infusion cannulas and 1 wk later adapted to housing in a calorimeter before they were infused with 0.9 µg leptin/day for 14 days. There was no effect of VMH Lep-Sap on weight gain or glucose clearance before leptin infusion. Leptin inhibited food intake and respiratory exchange ratio in Blk-Sap but not Lep-Sap rats. Leptin had no effect on energy expenditure or brown adipose tissue temperature of either group. Inguinal and epididymal fat were significantly reduced in leptin-treated Blk-Sap rats, but the response was greatly attenuated in Lep-Sap rats. VMH pSTAT3 was increased in leptin-treated Blk-Sap but not Lep-Sap rats. These results support the concept that leptin-induced weight loss results from an integrated response across different brain areas. They also support previous reports that VMH leptin receptors do not play a significant role in maintaining energy balance in basal conditions but limit weight gain during positive energy balance.
Assuntos
Quarto Ventrículo , Leptina/administração & dosagem , Leptina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores para Leptina/efeitos dos fármacos , Receptores para Leptina/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Redução de Peso/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/crescimento & desenvolvimento , Animais , Temperatura Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Glucose/metabolismo , Infusões Intraventriculares , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Saporinas/farmacologia , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
The aim of this study was to gain insight into the knowledge of, attitude toward, and practical experience with listeriosis among medical staff. In two hospitals in Fangshan, Beijing, 410 medical staff members were randomly selected using a random sampling method. Each selected staff member was invited to participate in a standardized questionnaire interview. In total, 397 valid questionnaires were collected. With regard to the staff members' general knowledge of listeriosis, they answered 65.96% of the items correctly. The knowledge scores among obstetricians and gynecologists were higher than those of other clinical doctors (p < 0.05); however, obstetricians and gynecologists were less knowledgeable about which drugs are effective against listeriosis than the other doctors (p = 0.007). The percentage of participants with a positive attitude about preventing listeriosis was 96.47%, the percentage with practice formation was 52.39%. The medical staff's mean score for knowledge of listeriosis was 4.61 ± 1.83. The mean score for attitude toward listeriosis was 9.71 ± 1.31. There was a significant association between attitude and knowledge of listeriosis (r = 0.221, p < 0.001). Medical staff obtained a mean score of 2.10 ± 1.07 for the practice formation. There was a significant association between practice formation and knowledge of listeriosis (r = 0.502, p < 0.001). The mean knowledge-attitude-practice (KAP) score for listeriosis among medical staff was 16.41 ± 3.19. The KAP scores were significantly correlated with age (r = 0.129, p = 0.011), occupation (r = -0.103, p = 0.041), department (r = -0.168, p = 0.001), and professional title (r = 0.166, p = 0.001). To improve medical outcomes and foodborne disease surveillance, medical staff should receive more training on listeriosis and the content of the training should be adjusted.
Assuntos
Doenças Transmitidas por Alimentos/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Listeriose/prevenção & controle , Corpo Clínico , Adulto , Idoso , Pequim , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto JovemRESUMO
Catecholamine (CA) neurons within the A1 and C1 cell groups in the ventrolateral medulla (VLM) potently increase food intake when activated by glucose deficit. In contrast, CA neurons in the A2 cell group of the dorsomedial medulla are required for reduction of food intake by cholecystokinin (CCK), a peptide that promotes satiation. Thus dorsal and ventral medullary CA neurons are activated by divergent metabolic conditions and mediate opposing behavioral responses. Acute glucose deficit is a life-threatening condition, and increased feeding is a key response that facilitates survival of this emergency. Thus, during glucose deficit, responses to satiation signals, like CCK, must be suppressed to ensure glucorestoration. Here we test the hypothesis that activation of VLM CA neurons inhibits dorsomedial CA neurons that participate in satiation. We found that glucose deficit produced by the antiglycolytic glucose analog, 2-deoxy-d-glucose, attenuated reduction of food intake by CCK. Moreover, glucose deficit increased c-Fos expression by A1 and C1 neurons while reducing CCK-induced c-Fos expression in A2 neurons. We also selectively activated A1/C1 neurons in TH-Cre+ transgenic rats in which A1/C1 neurons were transfected with a Cre-dependent designer receptor exclusively activated by a designer drug (DREADD). Selective activation of A1/C1 neurons using the DREADD agonist, clozapine- N-oxide, attenuated reduction of food intake by CCK and prevented CCK-induced c-Fos expression in A2 CA neurons, even under normoglycemic conditions. Results support the hypothesis that activation of ventral CA neurons attenuates satiety by inhibiting dorsal medullary A2 CA neurons. This mechanism may ensure that satiation does not terminate feeding before restoration of normoglycemia.
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Catecolaminas/metabolismo , Colecistocinina/farmacologia , Clozapina/análogos & derivados , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Glucose/deficiência , Bulbo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Clozapina/farmacologia , Desoxiglucose/farmacologia , Feminino , Integrases/genética , Integrases/metabolismo , Masculino , Bulbo/citologia , Bulbo/metabolismo , Neurônios/metabolismo , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Transgênicos , Resposta de Saciedade/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Both increased and decreased fatty acid (FA) availability contribute to control of food intake. For example, it is well documented that intestinal FA reduces feeding by triggering enterondocrine secretion of satietogenic peptides, such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). In contrast, mechanisms by which decreased FA availability increase feeding are not well understood. Over the past three decades substantial research related to FA availability and increased feeding has involved use of the orexigenic compound mercaptoacetate (MA). Because MA reportedly inhibits FA oxidation, it has been assumed that reduced FA oxidation accounts for the orexigenic action of MA. Recently, however, we demonstrated that MA antagonizes G protein-coupled receptor 40 (GPR40), a membrane receptor for long and medium chain FA. We also demonstrated that, by antagonizing GPR40, MA inhibits GLP-1 secretion and attenuates vagal afferent activation by FA. Because both vagal afferent activation and GLP-1 inhibit food intake, we postulated that inhibition of GPR40 by MA might underlie the orexigenic action of MA. We tested this hypothesis using male and female GPR40 knockout (KO) and wild-type (WT) mice. Using several testing protocols, we found that MA increased feeding in WT, but not GPR40 KO mice, and that GPR40 KO mice gained more weight than WT on a high-fat diet. Metabolic monitoring after MA or saline injection in the absence of food did not reveal significant differences in respiratory quotient or energy expenditure between treatment groups or genotypes. These results support the hypothesis that MA stimulates food intake by blocking FA effects on GPR40.
Assuntos
Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Tioglicolatos/farmacologia , Animais , Ácidos Graxos/metabolismo , Comportamento Alimentar/fisiologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores Acoplados a Proteínas G/genética , Aumento de PesoRESUMO
Mercaptoacetate (MA) is an orexigenic agent reported to block fatty acid (FA) oxidation. Recently, however, we reported evidence from isolated nodose ganglion neurons that MA antagonizes the G protein-coupled long- and medium-chain FA receptor GPR40. GPR40 mediates FA-induced secretion of the satietogenic incretin peptide glucagon-like peptide 1 (GLP-1), by enteroendocrine L cells, as well as FA-induced enhancement of glucose-stimulated insulin secretion. Our results in cultured nodose neurons suggest that MA would also block GPR40 in enteroendocrine cells controlling GLP-1 secretion. If so, this would suggest an alternative mechanism by which MA increases food intake. We tested the hypothesis that MA blocks FA-induced GLP-1 secretion in vitro using cultured STC-1 cells (a murine enteroendocrine cell line) and in vivo in adult male rats. In vitro, MA blocked the increase in both cytosolic Ca(2+)and GLP-1 release stimulated by FAs and also reduced (but less effectively) the response of STC-1 cells to grifolic acid, a partial agonist of the GPR120 FA receptor. In vivo, MA reduced GLP-1 secretion following olive oil gavage while also increasing glucose and decreasing insulin levels. The carnitine palmatoyltransferase 1 antagonist etomoxir did not alter these responses. Results indicate that MA's actions, including its orexigenic effect, are mediated by GPR40 (and possibly GPR120) receptor antagonism and not by blockade of fat oxidation, as previously believed. Analysis of MA's interaction with GPR40 may facilitate understanding of the multiple functions of this receptor and the manner in which FAs participate in the control of hunger and satiety.
Assuntos
Depressores do Apetite/farmacologia , Células Enteroendócrinas/efeitos dos fármacos , Ácidos Graxos/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Azeite de Oliva/administração & dosagem , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Tioglicolatos/farmacologia , Animais , Regulação do Apetite/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Células Enteroendócrinas/metabolismo , Ácidos Graxos/metabolismo , Insulina/sangue , Masculino , Azeite de Oliva/metabolismo , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Fatores de TempoRESUMO
Both lateral hypothalamic orexinergic neurons and hindbrain catecholaminergic neurons contribute to control of feeding behavior. Orexin fibers and terminals are present in close proximity to hindbrain catecholaminergic neurons, and fourth ventricular (4V) orexin injections that increase food intake also increase c-Fos expression in hindbrain catecholamine neurons, suggesting that orexin neurons may stimulate feeding by activating catecholamine neurons. Here we examine that hypothesis in more detail. We found that 4V injection of orexin-A (0.5 nmol/rat) produced widespread activation of c-Fos in hindbrain catecholamine cell groups. In the A1 and C1 cell groups in the ventrolateral medulla, where most c-Fos-positive neurons were also dopamine ß hydroxylase (DBH) positive, direct injections of a lower dose (67 pmol/200 nl) of orexin-A also increased food intake in intact rats. Then, with the use of the retrogradely transported immunotoxin, anti-DBH conjugated to saporin (DSAP), which targets and destroys DBH-expressing catecholamine neurons, we examined the hypothesis that catecholamine neurons are required for orexin-induced feeding. Rats given paraventricular hypothalamic injections of DSAP, or unconjugated saporin (SAP) as control, were implanted with 4V or lateral ventricular (LV) cannulas and tested for feeding in response to ventricular injection of orexin-A (0.5 nmol/rat). Both LV and 4V orexin-A stimulated feeding in SAP controls, but DSAP abolished these responses. These results reveal for the first time that catecholamine neurons are required for feeding induced by injection of orexin-A into either LV or 4V.
Assuntos
Catecolaminas/metabolismo , Ventrículos Cerebrais/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Fibras Nervosas/efeitos dos fármacos , Neuropeptídeos/administração & dosagem , Rombencéfalo/efeitos dos fármacos , Animais , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/imunologia , Ventrículos Cerebrais/metabolismo , Dopamina beta-Hidroxilase/imunologia , Dopamina beta-Hidroxilase/metabolismo , Imunotoxinas/administração & dosagem , Injeções Intraventriculares , Masculino , Fibras Nervosas/imunologia , Fibras Nervosas/metabolismo , Orexinas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Rombencéfalo/citologia , Rombencéfalo/imunologia , Rombencéfalo/metabolismo , Proteínas Inativadoras de Ribossomos Tipo 1/administração & dosagem , SaporinasRESUMO
BACKGROUND & AIMS: The aim of this randomized comparative trial (RCT) is to compare partial hepatectomy (PH) with transcatheter arterial chemoembolization (TACE) to treat patients with resectable multiple hepatocellular carcinoma (RMHCC) outside of Milan Criteria. METHODS: This RCT was conducted on 173 patients with RMHCC outside of Milan Criteria (a solitary tumor up to 5 cm or multiple tumors up to 3 in number and up to 3 cm for each tumor) who were treated in our centre from November 2008 to September 2010. The patients were randomly assigned to the PH group or the TACE group. The primary outcome measure was overall survival (OS) from the date of treatment. A multivariate Cox proportional hazards regression analysis was performed to assess the prognostic risk factors associated with OS. RESULTS: The 1-, 2-, and 3-year OS rates were 76.1%, 63.5%, and 51.5%, respectively, for the PH group compared with 51.8%, 34.8%, and 18.1%, respectively, for the TACE group (Log-rank test, χ(2)=24.246, p<0.001). Multivariate Cox proportional hazards regression analysis revealed the type of treatment (hazard ratio, 0.434; 95% CI, 0.293 to 0.644, p<0.001), number of tumor (hazard ratio, 1.758; 95% CI, 1.213 to 2.548, p=0.003) and gender (hazard ratio, 0.451; 95% CI, 0.236 to 0.862, p=0.016) were significant independent risk factors associated with OS. CONCLUSIONS: PH provided better OS for patients with RMHCC outside of Milan Criteria than conventional TACE. The number of tumor and gender were also independent risk factors associated with OS for RMHCC.
Assuntos
Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Hepatectomia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/terapia , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias Primárias Múltiplas/terapia , Adulto , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica/efeitos adversos , Feminino , Hepatectomia/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/mortalidade , Guias de Prática Clínica como Assunto , Prognóstico , Fatores de Risco , Resultado do TratamentoRESUMO
Previous work has shown that hindbrain catecholamine neurons are required components of the brain's glucoregulatory circuitry. However, the mechanisms and circuitry underlying their glucoregulatory functions are poorly understood. Here we examined three drugs, glucosamine (GcA), phloridzin (Phl) and 5-thio-d-glucose (5TG), that stimulate food intake but interfere in different ways with cellular glucose utilization or transport. We examined feeding and blood glucose responses to each drug in male rats previously injected into the hypothalamic paraventricular nucleus with anti-dopamine-ß-hydroxylase conjugated to saporin (DSAP), a retrogradely transported immunotoxin that selectively lesions noradrenergic and adrenergic neurons, or with unconjugated saporin (SAP) control. Our major findings were 1) that GcA, Phl, and 5TG all stimulated feeding in SAP controls whether injected into the lateral or fourth ventricle (LV or 4V), 2) that each drug's potency was similar for both LV and 4V injections, 3) that neither LV or 4V injection of these drugs evoked feeding in DSAP-lesioned rats, and 4) that only 5TG, which blocks glycolysis, stimulated a blood glucose response. The antagonist of the MEK/ERK signaling cascade, U0126, attenuated GcA-induced feeding, but not Phl- or 5TG-induced feeding. Thus GcA, Phl, and 5TG, although differing in mechanism and possibly activating different neural populations, stimulate feeding in a catecholamine-dependent manner. Although results do not exclude the possibility that catecholamine neurons possess glucose-sensing mechanisms responsive to all of these agents, currently available evidence favors the possibility that the feeding effects result from convergent neural circuits in which catecholamine neurons are a required component.
Assuntos
Catecolaminas/metabolismo , Ingestão de Alimentos/fisiologia , Glucose/metabolismo , Neurônios/metabolismo , Rombencéfalo/metabolismo , Animais , Ingestão de Alimentos/efeitos dos fármacos , Glucosamina/farmacologia , Glucose/análogos & derivados , Glucose/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Florizina/farmacologia , Ratos , Ratos Sprague-Dawley , Rombencéfalo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
ß-mercaptoacetate (MA) is a drug known to block mitochondrial oxidation of medium- and long-chain fatty acids (FAs) and to stimulate feeding. Because MA-induced feeding is vagally dependent, it has been assumed that the feeding response is mediated by MA's antimetabolic action at a peripheral, vagally innervated site. However, MA's site of action has not yet been identified. Therefore, we used fluorescent calcium measurements in isolated neurons from rat nodose ganglia to determine whether MA has direct effects on vagal sensory neurons. We found that MA alone did not alter cytosolic calcium concentrations in nodose neurons. However, MA (60 µM to 6 mM) significantly decreased calcium responses to both linoleic acid (LA; 10 µM) and caprylic acid (C8; 10 µM) in all neurons responsive to LA and C8. GW9508 (40 µM), an agonist of the FA receptor, G protein-coupled receptor 40 (GPR40), also increased calcium levels almost exclusively in FA-responsive neurons. MA significantly inhibited this response to GW9508. MA did not inhibit calcium responses to serotonin, high K(+), or capsaicin, which do not utilize GPRs, or to CCK, which acts on a different GPR. GPR40 was detected in nodose ganglia by RT-PCR. Results suggest that FAs directly activate vagal sensory neurons via GPR40 and that MA antagonizes this effect. Thus, we propose that MA's nonmetabolic actions on GPR40 membrane receptors, expressed by multiple peripheral tissues in addition to the vagus nerve, may contribute to or mediate MA-induced stimulation of feeding.
Assuntos
Ácidos Graxos/farmacologia , Gânglio Nodoso/efeitos dos fármacos , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Tioglicolatos/farmacologia , Animais , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Caprilatos/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ácido Linoleico/farmacologia , Masculino , Gânglio Nodoso/citologia , Gânglio Nodoso/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) with tumor thrombus (TT) in hepatic vein, inferior vena cava (IVC), and right atrium (RA) portends a poor prognosis because of intravascular extension leading to rapid distal metastases. En bloc resection of cavoatrial TT without the use of cardiopulmonary bypass (CPB) is challenging. We describe a new method of vascular occlusion for thrombus entering into the RA without the need for CPB as shown in echocardiography. METHODS AND RESULTS: Retrospective analysis was carried out in 1 HCC patient, who had undergone hepatectomy with TT extension into IVC and RA. The infrahepatic IVC was occluded with vascular tape and the right atrial appendage was controlled with a Satinsky clamp proximal to the TT. The IVC wall was incised under direct vision from the infrahepatic IVC cranially. The tumor and thrombus were then removed en bloc under direct vision. Thus, cavoatrial thrombectomy was performed under total hepatic vascular exclusion without the use of CPB. He survived for 6 months and died of tumor recurrence. CONCLUSIONS: Using this technique, advanced HCC with cavoatrial TT can be resected safely without CPB and thereby avoid dislodgement of TT and air embolism.
Assuntos
Carcinoma Hepatocelular/patologia , Procedimentos Cirúrgicos Cardíacos/métodos , Átrios do Coração/cirurgia , Cardiopatias/cirurgia , Neoplasias Hepáticas/patologia , Trombectomia/métodos , Veia Cava Inferior/cirurgia , Trombose Venosa/cirurgia , Idoso , Carcinoma Hepatocelular/cirurgia , Ponte Cardiopulmonar , Evolução Fatal , Átrios do Coração/patologia , Cardiopatias/patologia , Hepatectomia , Humanos , Neoplasias Hepáticas/cirurgia , Imageamento por Ressonância Magnética , Masculino , Invasividade Neoplásica , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/patologia , Trombose Venosa/patologiaRESUMO
Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.
Assuntos
Comportamento Alimentar , Hipotálamo , Neurônios , Neuropeptídeo Y , Ratos Sprague-Dawley , Animais , Feminino , Masculino , Ratos , Desoxiglucose/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Glucose/metabolismo , Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melaninas/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/farmacologia , Neuropeptídeos/metabolismo , Orexinas/metabolismo , Hormônios Hipofisários/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/genética , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas/farmacologiaRESUMO
Previously, we investigated the role of neuropeptide Y and leptin-sensitive networks in the mediobasal hypothalamus in sleep and feeding and found profound homeostatic and circadian deficits with an intact suprachiasmatic nucleus. We propose that the arcuate nuclei (Arc) are required for the integration of homeostatic circadian systems, including temperature and activity. We tested this hypothesis using saporin toxin conjugated to leptin (Lep-SAP) injected into Arc in rats. Lep-SAP rats became obese and hyperphagic and progressed through a dynamic phase to a static phase of growth. Circadian rhythms were examined over 49 days during the static phase. Rats were maintained on a 12:12-h light-dark (LD) schedule for 13 days and, thereafter, maintained in continuous dark (DD). After the first 13 days of DD, food was restricted to 4 h/day for 10 days. We found that the activity of Lep-SAP rats was arrhythmic in DD, but that food anticipatory activity was, nevertheless, entrainable to the restricted feeding schedule, and the entrained rhythm persisted during the subsequent 3-day fast in DD. Thus, for activity, the circuitry for the light-entrainable oscillator, but not for the food-entrainable oscillator, was disabled by the Arc lesion. In contrast, temperature remained rhythmic in DD in the Lep-SAP rats and did not entrain to restricted feeding. We conclude that the leptin-sensitive network that includes the Arc is required for entrainment of activity by photic cues and entrainment of temperature by food, but is not required for entrainment of activity by food or temperature by photic cues.
Assuntos
Núcleo Arqueado do Hipotálamo/fisiologia , Ritmo Circadiano/fisiologia , Privação de Alimentos/fisiologia , Leptina/farmacologia , Atividade Motora/fisiologia , Neurônios/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Supraquiasmático/fisiologiaRESUMO
BACKGROUND: The aim of this study was to compare the results of surgical resection with three-dimensional conformal radiotherapy (3D-CRT) in the treatment of resectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Transarterial chemoembolization (TACE) was given to both groups of patients when possible. METHODS: A retrospective study of 371 patients with resectable HCC with PVTT was conducted in two tertiary referral centers. The treatment of choice for these patients in one center was surgical resection. In the other center it was 3D-CRT. In the radiotherapy group (RG, n = 185), patients received 3D-CRT to the tumor and PVTT for a total radiation dose of 30-52 Gy (median 40 Gy). In the surgical group (SG, n = 186), patients underwent surgical resection. TACE was applied after surgery or 3D-CRT and then was repeated every 4-6 weeks if the patient tolerated the treatment. RESULTS: The median survival was 12.3 months for RG and 10.0 months for SG. The 1-, 2-, and 3-year overall survivals were 51.6, 28.4, and 19.9 %, respectively, for RG and 40.1, 17.0, and 13.6 %, respectively, for SG (p = 0.029). Stepwise multivariate analysis showed that the extent of PVTT and mode of treatment were independent risk factors of overall survival. The most common cause of death after treatment was liver failure as a consequence of progressive intrahepatic disease. CONCLUSIONS: 3D-CRT gave better survival than surgical resection for HCC with PVTT.
Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Veia Porta/patologia , Trombose/patologia , Trombose/terapia , Quimioembolização Terapêutica , Terapia Combinada , Feminino , Hepatectomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Radioterapia Conformacional , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
We propose a scheme for realizing electromagnetically induced grating via the giant Kerr nonlinearity in a coherently driven four-level system with spontaneously generated coherence. In the presence of spontaneously generated coherence, Kerr nonlinearity can be enhanced with vanishing linear absorption. Thus, with a standing-wave coupling field, one can achieve a pure absorption grating, which leads the probe field to gather the zero-order direction when the detuning of the coupling field is on resonance. Moreover, we can obtain a pure phase grating, which diffracts a weak probe light into the first-order direction and the second-order direction when the detuning of the coupling field is off resonance.
RESUMO
BACKGROUND: Metastatic liver melanoma is a rare event in the Chinese population with extremely poor prognosis. Any treatment that controls a metastatic hepatic lesion potentially prolongs survival. This study aimed to evaluate the survival of patients with isolated liver metastases from uveal melanoma treated with partial hepatectomy or non-surgical management and to find the best therapeutic modality for these patients. METHODS: From January 1996 to September 2008, eight patients with liver metastases secondary to uveal melanoma were admitted to our hospital. Five patients underwent partial hepatectomy and 3 received other treatments (TACE, RFA, PEI). Their medical records were reviewed and overall survival was analyzed. RESULTS: The patients comprised 3 men and 5 women, with a median age of 44 years. Six patients presented with liver metastases at the time the primary tumor was diagnosed. The interval from the diagnosis of uveal melanoma to liver metastasis in the remaining 2 patients was 9.5 and 32.5 months, respectively. The median survival after the treatment of liver metastasis was 11.5 and 7.5 months in the surgical and non-surgical groups, respectively. There was no procedure-related mortality in the whole study cohort. CONCLUSIONS: Partial hepatectomy or other therapies were safe and feasible for isolated liver metastases from uveal melanoma. Aggressive treatment with multidisciplinary modalities may result in prolonged survival.