IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling / 中华医学杂志(英文版)

BACKGROUND@#Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.@*METHODS@#The yki -gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1 , Acly , and Fasn et al .@*RESULTS@#In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila . Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.@*CONCLUSION@#Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.

Impact of Kuntai Capsules on LIF, IGF-1 and EGF expression in the implantation window of endometrium in mice / Impacto de cápsulas de Kuntai en la expresión de LIF, IGF-1 y EGF en la ventana de implantación de endometrio en ratones

To investigate the influence of Kuntai capsules on the expression level of leukemia inhibitory factor (LIF), insulin-like growth factor-I (IGF-1)and epidermal growth factor (EGF) during the mouse's implantation window of superovulation period and controlled ovarian hyperstimulation period. 90 female mice were randomly divided into six groups in control, superovulation and controlled ovarian hyperstimulation (COH) conditions. The RNA expression of EGF, LIF and IGF-1 in the endometrium on the 4th day of pregnancy was detected, and the relative expression was compared. mRNA expression of these three factors in endometrium was significantly lower in superovulation and COH groups than control group (p<0.001). mRNA expression of these three factors in endometrium remained obviously lower in superovulation plus kuntai capsule group and COH plus kuntai capsule group than control group (p<0.01). mRNA expression of these three factors in endometrium was lower in control group than in the NS plus kuntai capsule group (p<0.05). Kuntai capsule cannot completely reverse the endometrial damages caused by superovulation and COH. Thus Kuntai capsule could partially improve a mouse's endometrial receptivity during the implantation window.

Para investigar la influencia de las cápsulas de Kuntai en el nivel de expresión del factor inhibidor de la leucemia (LIF), el factor de crecimiento similar a la insulina I (IGF-1) y el factor de crecimiento epidérmico (EGF) durante la ventana de implantación del ratón del período de superovulación y la hiperestimulación ovárica controlada período, se dividieron aleatoriamente 90 ratones hembra en seis grupos en condiciones de control, superovulación e hiperestimulación ovárica controlada (COH). Se detectó la expresión de ARN de EGF, LIF e IGF-1en el endometrio al cuarto día de embarazo, y se comparó la expresión relativa. La expresión de ARNm de estos tres factores en el endometrio fue significativamente menor en los grupos de superovulación y COH que en el grupo control (p<0,001). La expresión de ARNm de estos tres factores en el endometrio permaneció más baja en el grupo de cápsulas de superovulación más Kuntai y en el grupo de cápsulas de COH más Kuntai respecto del grupo control (p<0,01). La expresión de ARNm de estos tres factores en el endometrio fue menor en el grupo control que en el grupo de cápsula NS más Kuntai (p<0,05). La cápsula de Kuntai no pudo revertir completamente los daños endometriales causados por la superovulación y la COH. Por lo tanto, se sugiere que la cápsula de Kuntai podría mejorar parcialmente la receptividad endometrial de un ratón durante la ventana de implantación.

Obesity and Gastrointestinal Cancer-related Factor / 대한소화기학회지

Despite a higher incidence and less favorable outcome of malignant tumors in obese patients, much less recognized is the link between obesity and cancer. The mechanism of the association of obesity with carcinogenesis remains incompletely understood. Postulated mechanisms include insulin resistance, insulin-like growth factor signaling, chronic inflammation, immunomodulation, hyperglycemia-induced oxidative stress, and changes of intestinal microbiome. Insulin resistance leads to direct mitogenic and antiapoptotic signaling by insulin and the insulin-like growth factor axis. Obesity can be considered to be a state of chronic low-grade inflammation. In obesity, numerous proinflammatory cytokines are released from adipose tissue which may involve in carcinogenesis. Hyperglycemia in susceptible cells results in the overproduction of superoxide and this process is the key to initiating all damaging pathways related to diabetes. This hyperglycemia-induced oxidative stress could be one possible link among obesity, diabetes, and cancer development. The role of obesity-related changes in the intestinal microbiome in gastrointestinal carcinogenesis deserves further attention.

Obesity and Colorectal Cancer / 대한소화기학회지

Obesity worldwide is constantly increasing. Obesity acts as an independent significant risk factor for malignant tumors of various organs including colorectal cancer. Visceral adipose tissue is physiologically more important than subcutaneous adipose tissue. The relative risk of colorectal cancer of obese patients is about 1.5 times higher than the normal-weight individuals, and obesity is also associated with premalignant colorectal adenoma. The colorectal cancer incidence of obese patients has gender-specific and site-specific characteristics that it is higher in men than women and in the colon than rectum. Obesity acts as a risk factor of colorectal carcinogenesis by several mechanisms. Isulin, insulin-like growth factor, leptin, adiponectin, microbiome, and cytokines of chronic inflammation etc. have been understood as its potential mechanisms. In addition, obesity in patients with colorectal cancer negatively affects the disease progression and response of chemotherapy. Although the evidence is not clear yet, there are some reports that weight loss as well as life-modification such as dietary change and physical activity can reduce the risk of colorectal cancer. It is very important knowledge in the point that obesity is a potentially modifiable risk factor that can alter the incidence and outcome of the colorectal cancer.

Obesity and Pancreatic Diseases / 대한소화기학회지

Obesity is defined as BMI (calculated as weight in kg divided by height in m2) more than 30, and overweight is defined as BMI of 25-29.9. Obesity has been considered as a risk factor for pancreatic diseases, including pancreatitis and pancreatic cancer. Severe acute pancreatitis is significantly more frequent in obese patients. Furthermore, obese patients develop systemic and local complications of acute pancreatitis more frequently. The underlying mechanisms are increased inflammation and necrosis from increased amount of intra- and peri-pancreatic fat. In addition, obesity is a poor prognostic factor in acute pancreatitis, and overweight before disease onset appears to be a risk factor for chronic pancreatitis. Overweight and/or obesity are associated with greater risk of pancreatic cancer and younger age of onset. Physical activity appears to decrease the risk of pancreatic cancer, especially among those who are overweight. Long-standing diabetes increases the risk of pancreatic cancer. The pathogenic mechanism is that obesity and physical inactivity increase insulin resistance. In a state of hypersinulinemia, increased circulating level of insulin-like growth factor-1 induces cellular proliferation of pancreatic cancer. Obesity is associated with negative prognostic factor and increased mortality in pancreatic cancer. However, there are controversies regarding the effects of obesity on long-term post-operative results in the patient with pancreatic cancer.

Fatores hepatotróficos e regeneraçäo hepática. Parte I: o papel dos hormônios / Hepatotrophic factors and liver regeneration. Part I: the role of hormones

No complexo processo de proliferaçäo celular, os hormônios agem de diferentes maneiras ao atingirem seus receptores nos tecidos-alvo. Os principais fatores ligados ao crescimento hepático säo HGF, TGF-alpha, IL-6, TNF-alpha, norepinefrina, EGF e insulina. O GH estimula tanto o fígado a produzir fatores de crescimento, como a expressäo genética do HGF e a síntese de DNA. Hormônios tireoideanos aumentam a capacidade proliferativa dos hepatócitos. A insulina age sinergicamente com GH e glucagon. Näo tem potencial mitogênico primário mas intensifica o estímulo regenerativo iniciado pela epinefrina e norepinefrina. Esta amplifica os sinais mitogênicos do EGF e HGF, induz a secreçäo de EGF e antagoniza os efeitos inibitórios do TGF-beta 1. O glucagon isoladamente näo produz efeitos mas provavelmente participa na síntese de DNA e da resposta homeostásica pela qual a glicemia é mantida estável durante a regeneraçäo. Também há indícios de açäo hepatotrófica da gastrina.

Usefulness of insulin-like growth factor binding protein-3 levels to determine acromegaly activity and effectiveness of transsphenoidal pituitary surgery

Background. Several series reported in the literature concerning the results of the treatment of acromegaly have difficult to evaluated because the indicators are inaccurate Methods. We investigated the usefulness of insulin. Like growth factor binding protein-3 (IGFBP) levels to determine disease activity after surgical treatment of acromegaly in 13 patients with confirmed somatotroph adenoma. Results. Before surgery, all 13 non-treated patients had levated serum levels of IGFBP-3 as well as total and free IGF-I. In addition, there was no overlap with the normal controls (p < 0.001). IGFBP-3 levels correlated significantly (0.91, p < 0.001) with GH suppressibility by glucose after surgery. Conclusions. These data confirm that IGFBP-3 is a better indicator of acromegalic activity than either total or free IGF-i. There was a high correlation with GH suppressibility by glucose after surgery; both free and total IGF-I could be considered sensitive markers only for diagnosis of active acromegaly but not for efficacy of surgery

Correlación entre factor de crecimiento insulínico tipo 1 (IGF-1), citoquinas proinflamatorias y activación neurohumoral en pacientes con isuficiencia cardíaca crónica avanzada / Correlation of insulin like growth factor (IGF-1), cytokines and neurohumoral activation in patiens with advanced congestive heart failure

Hemos demostrado previamente que la actividad del eje hormona de crecimiento (GH) y su mediador activo, el factor de crecimiento insulínico tipo 1 (IGF-1) se encuentra disminuido en pacientes (pts) con insuficiencia cardíaca crónica (ICC). Por otra parte, se ha reportado que otras moléculas biológicamente activas, las citoquinas, se encuentran aumentadas en pts con ICC avanzada. Es posible que estas alteraciones neurohumorales contribuyan al compromiso del estado general y a un mayor deterioro de la función ventricular izquierda en estos pts. El objetivo del presente estudio fue evaluar si existe correlación entre la actividad del eje GH-IGF- 1, niveles de citoquinas proinflamatorias como el factor de necrosis tumoral (TNF) e interleuquína 6 (IL-6), y noradrenalina en reposo y ejercicio (NAD rep-NAD ex) en pts con ICC avanzada. Se estudiaron en forma prospectiva 10 pts con ICC por cardiopatía dilatada o isquémica. Se determinó consumo de 02 máximo (V02 max), Fracción de eyección (FE) radiolisotópica y niveles sóricos de GH e IGF- 1 (técnica IRMA), catecolaminas plasmáticas en reposo y en ejercicio máximo (NAD replex) (técnica RIA) y TNF e IL-6 (técnica ELISA). El análisis estadístico se realizó mediante regresión lineal Los resultados se expresaron como promedio k desviación estándar. La FE promedio del grupo fue de 17 por ciento ñ 4 por ciento y el V02 máx promedio de 15,9 ñ 3,9 ml/kg/min. LA GH fue de 3,4 ñ 4,55 ng/ml; IGF- 1 de 177,1 ñ 69,4 ng/ml, NAD rep 612,9 ñ 407,3 pg/ml y NAD ex de 4250 ñ 2620 pg/ml. El TNF del grupo fue de 1,2 ñ 1,4 pg/ml y la IL-6 de 4,4 ñ 3,55 pg/ml. Hubo correlación estadísticamente significativa entre el Logaritmo (log) IGF- 1 y Log NADex (r=-0, 66 p=0, 03 ), Log IGF- 1 y Log TNF(r=-0, 65p=0, 04)e IL-6 y NADex (r=0, 781 p=0,0l). Nuestro estudio demuestra por primera vez una correlación entre el aumento de la actividad simpática (NAD ex) y la menor actividad del eje GH-IGF- 1 en pts con ICC avanzada. Al mismo tiempo, confirma que también existe una correlación entre la actividad simpática exagerada y el aumento de citoquinas proinflamatorias en pts con ICC avanzada

Fatores insulinóides e suas proteínas ligantes: importância e influência sobre a funçäo ovariana: atualizaçäo / Insulin growth factors and their binding proteins: importance and influence over the ovarian function: an update

Uma avalanche de conhecimentos referentes aos fatores insulinóides de crescimento e de suas proteínas ligantes vem sendo publicada nos últimos anos. Sabe-se hoje que estes fatores, assim como suas proteínas, têm um papel importantíssimo na regulaçäo da funçäo folicular dos ovários, atuando como verdadeiras segundas gonadotrofinas. Conhece-se dois fatores insulinóides de crescimento (I e II) e seis proteínas ligantes (1 a 6). Identificados inicialmente como somatomedinas, os fatores de crescimento insulinóides atuam em diferentes regiöes do organismo, possuindo duas funçöes básicas: estímulo ao crescimento e açäo insulino-símile, através de efeitos endócrinos, par crinos e autócrinos. O controle da açäo destes fatores é feito principalmente pela ligaçäo às suas proteínas ligantes, tanto no soro, como nos tecidos. Ligado principalmente às proteínas 1 e 3, estes hormônios induzem a alteraçöes locais e teciduais no ovário e trabalham favoravelmente no sentido da seleçäo, recrutamento folicular, na ovulaçäo e no bom desempenho da fase lútea. Pouco se sabe sobre as açöes do fator insulinóide do tipo II nas gônadas. Na síndrome dos ovários policísticos vem sendo reportada uma diminuiçäo importante dos níveis da proteína ligante-1, o que levaria a um aumento secundário dos níveis do fator insulinóide do tipo I que, por sua vez, atuando sobre as células da teca e do estroma do ovário, incrementariam a atresia folicular pelo hiperandrogenismo local resultante. Tais conhecimentos ajudam a explicar e conhecer com muita profundidada a fisiologia do ciclo ovariano e suas repercussöes endócrinas secundárias.

Sistema hormona del crecimiento-efector y su rol en el crecimiento infantil / Growth-effector hormone system and it role in children growth

La consulta por retraso del crecimiento es muy frecuente en pediatría. En la última década se han efectuado importantes avances en la comprensión de los mecanismos hormonales que regulan el crecimiento infantil. Este artículo tiene por objeto hacer una actualización sobre el sistema hormona de crecimiento (GH) -efector. Se revisan los mecanismos de control hipotalámico de la secreción de GH (factor liberador de GH y somatotastina), secreción hipofisiaria de GH, la proteína ligadora de GH (GHBP), el receptor de GH y sus efectores periféricos (IGFs e IGFBPS). Se analizan las repercusiones clínicas de las alteraciones de cada uno de estos componentes, que pueden conducir a una falla en el crecimiento durante la infancia

Discrepancies between biossayable somatomedin activity and somatomedin C levels in acromegalic patients

En publicaciones previas se han descripto niveles elevados de actividad biológica de somatomedinas en pacientes acromegálicos. Utilizando un bioensayo que mide la incorporación de 35S a cartílagos pelvianos de embriones de pollo encontramos niveles normales de actividad de somatomedina en los 11 pacientes acromegálicos estudiados. Midiendo somatomedina C (Sm-C) por radioinmunoensayo en la misma muestra de 9 de esos pacientes, se encontraron niveles normales en sólo 2 de ellos. En total, de 12 pacientes acromegálicos en los que se dosó Sm-C sólo esos 2 tuvieron valores normales, el resto estuvieron por encima de 2 desvíos standard de la media normal (controles normales 1,410ñ0,269, acromegálicos 6,030 ñ3,350, U/ml, xñDS, p<0,001). Los valores normales de bioactividad de somatomedinas no pueden ser debidos a tratamientos previos ya que 13 de los 14 pacientes acromegálicos eran vírgenes de tratamiento. Tampoco se los puede adjudicar a niveles bajos de hormona de crecimiento (GH) ya que 10 de ellos tuvieron niveles altos de GH. El hallazgo de valores normales de actividad biológica de somatomedinas podría deberse a la presencia de inhibidores séricos; sin embargo, experimentos de mezcla de suero humano normal con el suero de pacientes acromegálicos revelaron la presencia de inhibidores en sólo 1 de los 8 pacientes estudiados. Utilizando este mismo bioensayo se encontraron valores bajos de actividad de somatomedina en niños con déficit de hormona de crecimiento 11. Por lo tanto, este bioensayo parece detectar mejor aquellas somatomedinas que disminuyen en situaciones de déficit de hormona de crecimiento pero que no aumentan frente a situaciones de exceso de hormona de crecimiento. Este es el comportamiento descripto para la somatomedina conocida como factor de crecimiento insulino-símil II (IGF II). Sería entonces posible que los valores normales de actividad biológica de somatomedinas encontrados en pacientes acromegálicos se deban a que el bioensayo empleado tenga mayor sensibilidad para el IGF II que para la Sm-C