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BACKGROUND: The aim of this study was to compare metabolic parameters, plasma Osteopontin (OPN) and Hepatocyte Growth Factor (HGF) levels between Sleeve Gastrectomy (SG) patients in their 6th post-operation month and healthy control patients. METHODS: Height, weight, Body Mass Index (BMI) and laboratory parameters of 58 SG patients aged 18â65 years (Group 1) and 46 healthy control patients (Group 2) were compared. In addition, preoperative and postoperative sixth-month BMI and laboratory parameters of the patients in Group 1 were compared. RESULTS: The mean age and gender distributions of the groups were similar (p > 0.05). Mean BMI was 28.9 kg/m2 in Group 1 and 27 kg/m2 in Group 2 (p < 0.01). While plasma HGF levels were similar between both groups, plasma OPN levels were higher in Group 2 (p < 0.001). Fasting plasma glucose, total cholesterol, triglyceride, fasting plasma insulin and insulin resistance values were higher in Group 1, while alanine aminotransferase and aspartate aminotransferase levels were higher in Group 2 (p < 0.05). There was a strong correlation between plasma HGF and OPN levels in Group 1, but not in Group 2 (Rho = 0.805, p < 0.001). CONCLUSION: OPN and HGF are promising biomarkers that can be used to better understand and detect problems related to obesity. The fact that patients in the early post-SG period had lower plasma OPN and similar plasma HGF compared to non-surgical patients of similar age and gender with higher BMI may be another favorable and previously unknown metabolic effect of SG.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Laparoscopia , Obesidade Mórbida , Humanos , Gastrectomia , Obesidade , Obesidade Mórbida/cirurgia , Osteopontina , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
Abstract Background: The aim of this study was to compare metabolic parameters, plasma Osteopontin (OPN) and Hepatocyte Growth Factor (HGF) levels between Sleeve Gastrectomy (SG) patients in their 6th post-operation month and healthy control patients. Methods: Height, weight, Body Mass Index (BMI) and laboratory parameters of 58 SG patients aged 18‒65 years (Group 1) and 46 healthy control patients (Group 2) were compared. In addition, preoperative and postoperative sixth-month BMI and laboratory parameters of the patients in Group 1 were compared. Results: The mean age and gender distributions of the groups were similar (p > 0.05). Mean BMI was 28.9 kg/m2 in Group 1 and 27 kg/m2 in Group 2 (p < 0.01). While plasma HGF levels were similar between both groups, plasma OPN levels were higher in Group 2 (p < 0.001). Fasting plasma glucose, total cholesterol, triglyceride, fasting plasma insulin and insulin resistance values were higher in Group 1, while alanine aminotransferase and aspartate aminotransferase levels were higher in Group 2 (p < 0.05). There was a strong correlation between plasma HGF and OPN levels in Group 1, but not in Group 2 (Rho = 0.805, p < 0.001). Conclusion: OPN and HGF are promising biomarkers that can be used to better understand and detect problems related to obesity. The fact that patients in the early post-SG period had lower plasma OPN and similar plasma HGF compared to non-surgical patients of similar age and gender with higher BMI may be another favorable and previously unknown metabolic effect of SG.
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Resumen Objetivo Determinar si los niveles plasmáticos de factor de crecimiento de hepatocitos podrían ayudar a realizar el diagnóstico diferencial en pacientes con dolor torácico prolongado y elevación de la troponina cardiaca, y evaluar su valor pronóstico de mortalidad al año en estos pacientes. Método: Estudio prospectivo observacional. Se incluyeron pacientes mayores de 18 años que acudieron a urgencias con dolor torácico agudo de más de 20 minutos y elevación de la troponina cardiaca, con seguimiento al año. Resultados Se incluyeron 303 pacientes, 103 (34%) con infarto de miocardio y 200 (66%) con otras enfermedades. Los niveles plasmáticos del factor de crecimiento de hepatocitos fueron superiores en el grupo sin infarto de miocardio: 329 pg/ml (rango intercuartílico [IQR]: 66-558) vs. 476 pg/ml (IQR: 264-908; p < 0.001). La mortalidad al año fue del 30.7%, superior en el grupo sin infarto de miocardio (36.5% vs. 19.4%; p = 0.002). Se encontró una fuerte asociación entre la mortalidad y los niveles elevados de factor de crecimiento de hepatocitos (650 pg/ml [344-1159] vs. 339 pg/ml [205-607]; p < 0.001). En el análisis multivariado se halló que los niveles de factor de crecimiento de hepatocitos, la edad y la escala GRACE son factores independientes de mortalidad al año en estos pacientes. Conclusiones En los pacientes con dolor torácico agudo prolongado y elevación de la troponina cardiaca, la determinación de los niveles del factor de crecimiento de hepatocitos no permite confirmar ni descartar la presencia de infarto agudo de miocardio. No obstante, podría ser un marcador pronóstico de mortalidad en estos pacientes, junto con la edad y la escala GRACE.
Abstract Objective To determine if plasma levels of hepatocyte growth factor could help in the differential diagnosis of patients with prolonged chest pain and elevated cardiac troponin; and to evaluate its prognostic value for one-year mortality in these patients. Method A prospective observational study. Patients over the age of 18 who were seen in the emergency room for acute chest pain lasting longer than 20 minutes and elevated cardiac troponin were included, with follow up after one year. Results We included 303 patients, 103 (34%) with myocardial infarction and 200 (66%) with other diseases. Plasma levels of hepatocyte growth factor were higher in the group without myocardial infarction: 329 pg/ml (IQR: 166-558) vs. 476 pg/ml (IQR: 264-908; p < 0.001). One-year mortality was 30.7%, higher in the group without myocardial infarction (36.5% vs. 19.4%; p = 0.002). We found a strong association between mortality and elevated levels of hepatocyte growth factor (650 pg/ml [344-1,159] vs. 339 pg/ml [205-607]; p < 0.001). Multivariate analysis showed that levels of hepatocyte growth factor, age and the GRACE scale are independent factors for one-year mortality in these patients. Conclusions In patients with prolonged acute chest pain and elevated cardiac troponin, hepatocyte growth factor levels do not confirm or rule out acute myocardial infarction, although they may be a prognostic marker for mortality in these patients, along with age and the GRACE scale.
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Wound scarring remains a major challenge for plastic surgeons. Transforming growth factor (TGF)-β plays a key role in the process of scar formation. Previous studies have demonstrated that truncated TGF-β type II receptor (t-TGF-βRII) is unable to continue signal transduction but is still capable of binding to TGF-β, thereby blocking the TGF-β signaling pathway. Hepatocyte growth factor (HGF) is a multifunctional growth factor that promotes tissue regeneration and wound healing. Theoretically, the combination of HGF and t-TGF-βRII would be expected to exert a synergistic effect on promoting wound healing and reducing collagen formation. In the present study, lentivirus-mediated transfection of the two genes (t-TGF-βRII/HGF) into fibroblasts in vitro and in a rat model in vivo was used. The results demonstrated that the expression of t-TGF-βRII and HGF in NIH-3T3 cells was successfully induced. The expression of both molecules significantly reduced collagen I and III expression, and also inhibited fibroblast proliferation. Furthermore, histological examination and scar quantification revealed less scarring in the experimental wound in a rat model. Moreover, on macroscopic inspection, the experimental wound exhibited less visible scarring compared with the control. Therefore, the present study demonstrated that the combination gene therapy of t-TGF-βRII and HGF promoted wound healing, with less scarring and more epithelial tissue formation, not only by suppressing the overgrowth of collagen due to its antifibrotic effect, but also by promoting tissue regeneration.
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Animais , Coelhos , Ratos , Transfecção , Colágeno/metabolismo , Cicatriz/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Cicatriz/patologia , Ratos Sprague-Dawley , Modelos Animais , Proliferação de CélulasRESUMO
The hepatocyte growth factor (HGF)/c-met pathway, which mainly consists of HGF activator (HGFA) and its substrate HGF, protects various types of cells via anti-apoptotic and anti-inflammatory signals. Thrombin is the main physiological activator of such plasmatic pathway, and increased plasma concentrations of HGF have been considered as a molecular marker for some pathological conditions, such as disseminated intravascular coagulation. Since thrombin generation is often linked to tissue injury, and these events are common during snake venom-induced consumption coagulopathies (VICC), our goals were to examine whether Bothrops jararaca venom (Bjv), which induces VICC in vivo: (i) activates the HGF/c-met pathway in vivo and (ii) cleaves zymogen forms of HGFA and HGF (proHGFA and proHGF, respectively) in vitro. Two experimental groups (n = 6, each) of male adult Wistar rats were subcutaneously injected with 500?µL of 0.9% NaCl solution (control) or sub-lethal doses (1.6 mg/kg) of Bjv. Three hours after envenomation, whole blood samples were collected from the carotid arteries to evaluate relevant coagulation parameters using rotational thromboelastometry and fibrinogen level (colorimetric assay). Additionally, the plasma concentration of HGF was assayed (ELISA). Thromboelastometric assays showed that blood clotting and fibrin polymerization were severely impaired 3 h after Bjv injection. Total plasma HGF concentrations were almost 6-fold higher in the Bjv-injected group (410.0 ± 91) compared with control values (68 ± 18 pg/mL, p < 0.05). Western blotting assay showed that Bjv processed proHGFA and proHGF, generating bands resembling those generated by thrombin and kallikrein, respectively. In contrast to the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF), the metalloprotease inhibitor ethylenediaminetetraacetic acid disodium salt (Na2-EDTA) strongly reduced the ability of Bjv to process proHGFA and generated one active band similar to that of thrombin. Since Bjv contains prothrombin and factor X activators, increased intravascular thrombin formation might partly explain the increased HGF levels after bothropic envenomation. In conclusion, these findings suggest that snake venom metalloproteases may be determinant for elevation of plasma levels of HGF in rats experimentally envenomated with Bjv.
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In obesity, insulin resistance (IR) and diabetes, there are proteins and hormones that may lead to the discovery of promising biomarkers and treatments for these metabolic disorders. For example, these molecules may impair the insulin signaling pathway or provide protection against IR. Thus, identifying proteins that are upregulated in IR states is relevant to the diagnosis and treatment of the associated disorders. It is becoming clear that hepatocyte growth factor (HGF) is an important component of the pathophysiology of IR, with increased levels in most common IR conditions, including obesity. HGF has a role in the metabolic flux of glucose in different insulin sensitive cell types; plays a key role in ß-cell homeostasis; and is capable of modulating the inflammatory response. In this review, we discuss how, and to what extent HGF contributes to IR and diabetes pathophysiology, as well as its role in cancer which is more prevalent in obesity and diabetes. Based on the current literature and knowledge, it is clear that HGF plays a central role in these metabolic disorders. Thus, HGF levels could be employed as a biomarker for disease status/progression, and HGF/c-Met signaling pathway modulators could effectively regulate IR and treat diabetes.
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Acute kidney injury is mostly reversible, and hepatocyte growth factor (HGF) has a relevant role in the tissue repair. MicroRNA (miR)-26a is an endogenous modulator of HGF. The role of miR-26a in the kidney repair process was evaluated in Wistar rats submitted to an acute kidney injury model of rhabdomyolysis induced by glycerol (6 mL/kg). Animals were evaluated 3, 12, 48, 96, and 120 hours after glycerol injection. Serum creatinine (SCr) and gene expression of HGF, c-met, signal transducer and activator of transcription 3 (STAT3), and miR-26a were estimated. Also, tubular NK52E cells were transfected with anti-miR26a and stimulated with Fe3+ for 24 hours to mimic the effects of myoglobin in vitro. SCr was highest after 48 hours. After 96 hours, SCr started to decrease, characterizing the recovery phase, with normalization after 120 hours. HGF expression increased during the onset phase (3 hours), with a low relationship with miR-26a. In contrast, in the recovery phase, the increase in miR-26a was coincident with HGF messenger RNA suppression, suggesting that in the recovery phase, miR-26a may have a role in HGF modulation. Fe3+ induced cellular death after 3 hours and proliferation after 24 hours. There was no correlation between miR-26a and STAT3 during the death phase; however, during the proliferation phase, an increase in STAT3 was paralleled with a decrease in miR-26a. miR-26a silencing induced increases in cell viability and the phosphorylated form of STAT3 protein expression in cells receiving Fe3+ . In conclusion, miR-26a may have a key role in modulating HGF levels after its proliferative effects have been triggered.
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Injúria Renal Aguda/genética , Glicerol/efeitos adversos , Fator de Crescimento de Hepatócito/genética , MicroRNAs/genética , Fator de Transcrição STAT3/genética , Injúria Renal Aguda/sangue , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Animais , Linhagem Celular , Creatinina/sangue , Modelos Animais de Doenças , Regulação da Expressão Gênica , Fator de Crescimento de Hepatócito/metabolismo , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos , Ratos Wistar , Rabdomiólise/induzido quimicamente , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
INTRODUCTION AND AIM: Hepatocyte growth factor (HGF) has been shown to ameliorate liver inflammation and fibrosis; however, the mechanism underlying its effects in non-alcoholic steatohepatitis (NASH) is unclear. This study aimed to analyse the relationship between the JAK2-STAT3 signalling pathway and the ameliorating effect of HGF on NASH. MATERIAL AND METHODS: Mice were fed a high-fat diet (HFD) for 16 weeks, and then plasma and hepatic tissues were collected. Histological and clinical chemistry assays were performed to assess liver disease. The mRNA and protein levels of JAK2, STAT3, and c-Met were assessed by real-time PCR and western blotting, respectively. RESULTS: Serum ALT, AST, and TG levels were increased in NASH mice. Histological analysis showed different degrees of steatosis, inflammatory infiltrates, and fibrosis in HFD animals. Exogenous administration of recombinant human (rh) HGF via the tail vein for 14 days markedly decreased ALT and AST to levels lower than those in the control group. Compared with the levels in HFD mice, c-Met, p-c-Met, JAK2, p-JAK2, and p-STAT3 levels were increased in mice that were administered HGF (P < 0.05). Furthermore, silencing of HGF or blocking of its receptor c-Met affected JAK2 and STAT3 protein phosphorylation. CONCLUSIONS: Excess HGF highly probable improved NASH liver function. Combined with its ligand, c-Met, HGF may promote the phosphorylation of JAK2-STAT3 and inhibit inflammation in NASH. Therefore, it may be potentially useful treatment for NASH.
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Anti-Inflamatórios/farmacologia , Fator de Crescimento de Hepatócito/farmacologia , Janus Quinase 2/metabolismo , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Citocinas/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Mediadores da Inflamação/sangue , Janus Quinase 2/genética , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos BALB C , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Fosforilação , Receptores Proteína Tirosina Quinases/genética , Fator de Transcrição STAT3/genética , Triglicerídeos/sangueRESUMO
Angiotensin II (Ang II) plays an important role in cardiomyocyte hypertrophy. The combined effect of hepatocyte growth factor (HGF) and Ang II on cardiomyocytes is unknown. The present study was designed to determine the effect of HGF on cardiomyocyte hypertrophy and to explore the combined effect of HGF and Ang II on cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from neonatal rat hearts and cultured in vitro. Cells were treated with Ang II (1 µM) alone, HGF (10 ng/mL) alone, and Ang II (1 µM) plus HGF (10 ng/mL) for 24, 48, and 72 h. The amount of [³H]-leucine incorporation was then measured to evaluate protein synthesis. The mRNA levels of β-myosin heavy chain and atrial natriuretic factor were determined by real-time PCR to evaluate the presence of fetal phenotypes of gene expression. The cell size of cardiomyocytes was also studied. Ang II (1 µM) increased cardiomyocyte hypertrophy. Similar to Ang II, treatment with 1 µM HGF promoted cardiomyocyte hypertrophy. Moreover, the combination of 1 µM Ang II and 10 ng/mL HGF clearly induced a combined pro-hypertrophy effect on cardiomyocytes. The present study demonstrates for the first time a novel, combined effect of HGF and Ang II in promoting cardiomyocyte hypertrophy.