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Tag: JNK (Page 1 of 3)

Estrogens prevent the hypothalamus-periphery crosstalk induced by olanzapine intraperitoneal treatment in female mice: effects on brown/beige adipose tissues and liver

Vítor Ferreira, Cintia Folgueira, Ángela Montes-San Lorenzo, Andrea Rodríguez-López, Eva Gonzalez-Iglesias, Pablo Zubiaur, Francisco Abad-Santos, Guadalupe Sabio, Patricia Rada & Ángela M Valverde.

Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS).

Olanzapine reduces body weight exclusively in ovariectomized mice (Image: Cintia Folgueira).

Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17β-estradiol (E2) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E2 prevented OLA-induced phospho-JNK in hypothalamic neurons.

These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.

Stress-activated kinases signaling pathways in cancer development

Leticia Herrera-Melle, María Crespo, Magdalena Leiva & Guadalupe Sabio.

Cancer is a large group of diseases characterized by abnormal cell growth that can lead to metastasis. It is the second leading cause of death worldwide, and its incidence is expected to rise over the next decades. Stress-activated protein kinases (SAPK) are important players in its regulation. Several studies have tried to unravel their role; however, their pro-tumorigenic or anti-tumorigenic properties are sometimes controversial.

JNK control of tumor microenvironment
JNK control of tumor microenvironment.

In this review, we will discuss the main roles of the different SAPK in the control of tumor development through essential processes such as cell proliferation, apoptosis or invasiveness. We will also show the latest discoveries regarding the contribution of SAPK in shaping tumor microenvironment through the regulation of organ crosstalk and immune cell response during cancer progression.

All these studies are relevant examples of how SAPK offer new therapeutic avenues for cancer patients that may help increase their survival.

Descubierto un mecanismo que controla la aparición del cáncer de hígado

Es un tumor silencioso. No avisa ni advierte de su presencia. Cuando se detecta suele ser ya demasiado tarde, porque el diagnóstico coincide con la colonización de otros órganos. La temida metástasis. Es el colangiocarcinoma, el segundo cáncer de hígado más común y uno de los más agresivos y con peor pronóstico de toda la amplia familia de tumores. Y es, también, uno de los grandes olvidados, porque la ciencia apenas ha descubierto nuevos tratamientos y ni tan siquiera lo conoce demasiado. Ha sido poco estudiado a nivel molecular, un vacío que ahora empieza a llenarse en parte con un descubrimiento realizado por investigadores del Centro Nacional de Investigaciones Cardiovasculares (CNIC), que han descubierto un mecanismo molecular que controla su aparición. El trabajo acaba de publicarse en la revista PNAS.

De izquierda a derecha: Alfonso Mora, Elena Rodríguez, Guadalupe Sabio, Alejandro Rosell, Cintia Folgueira y Luis Leiva-Vega.
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