Phoenixin 14 inhibits ischemia/reperfusion-induced cytotoxicity in microglia.

The process of ischemia/reperfusion (IR) in ischemic stroke often leads to significant cell death and permanent neuronal damage. Safe and effective treatments are urgently needed to mitigate the damage caused by IR injury. The naturally occurring pleiotropic peptide phoenixin 14 (PNX-14) has recently come to light as a potential treatment for IR injury. In the present study, we examined the effects of PNX-14 on several key processes involved in ischemic injury, such as pro-inflammatory cytokine expression, oxidative stress, and the related cascade mediated through the toll-like receptor 4 (TLR4) pathway, using BV2 microglia exposed to oxygen-glucose deprivation and reoxygenation (OGD/R). Our results demonstrate an acute ability of PNX-14 to regulate the expression levels of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). PNX-14 also prevented oxidative stress by reducing the generation of reactive oxygen species (ROS) and increasing the level of the antioxidant glutathione (GSH). Importantly, PNX-14 inhibited high-mobility group box 1 (HMGB1)/TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway, by inhibiting the activation of TLR4 and preventing the nuclear translocation of p65 protein. We further confirmed the cerebroprotective effects of PNX-14 in an MCAO rat model, which resulted in reduced infarct volume and decreased microglia activation. Together, the results of this study implicate a possible protective role of PNX-14 against various aspects of IR injury in vitro.

El concepto darwiniano de la allostasis. Epigénesis / The Darwinian concept of allostasis. Epigenetic programming

El concepto de allostasis fué establecido a finales del siglo pasado como el conjunto de respuestas de los organismos vivos, regidas por el cerebro, para conservar su equilibrio interno y, por tanto, su supervivencia. Pero todo ello tiene resonancias Darwinianas . Cuestiones establecidas en el siglo XX. El axis HPA - hipotálamo -pituitaria-adrenal- es el más importante entre todos los sistemas movilizados por la allostasis. Y este axis se programa en periodo gestacional en los mamíferos. Cuando circunstancias de estrés maternal activan su axis HPA, grandes cantidades de glucocorticoides (GC) pasan al feto, y su axis HPA se programa de forma anómala, e irreversible en periodo adulto, además, se reduce el peso al nacimiento. Y todo ello es factor de riesgo de posibles patologías adultas (diabetes 2, cardiovasculares o hipertensión crónica). La causa es la reducción de receptores de glucocorticoides (GR) en el hipocampo, ya que ellos ejercen una acción tónica en la retroalimentación negativa del axis HPA. Sin embargo, se desconocía, en el siglo XX, por qué mecanismo los GC reducen la expresión de GR en hipocampo. Cuestiones establecidas en siglo XXI. Se eligen y exponen una serie de trabajos publicados en el siglo XXI sobre esta vertiente que nos han llevado al conocimiento de que la reducción en hipocampo de los GR se produce por un mecanismo epigenético. Sucintamente, se enumeran los principales mecanismos epigenéticos conocidos. Finalmente, se enuncian las grandes posibilidades terapéuticas que abren estos mecanismos epigenéticos para el futuro y para la posible explicación de procesos evolutivos

At the end of last Century the concept of allostasis was proposed as the group of responses from live beings, regulated by the brain, leading to maintain the organism balance and, therefore, to survival. But this concept has clear Darwinian significance. Questions established in the XX Century. The HPA (hypothalamus-pituitary-adrenal gland) axis is the most important among all regulatory systems triggered by allostasis, and it is programmed during the gestational period in mammals. Under a stressful situation the mother HPA axis operates secreting high amounts of glucocorticoids (GC) that get into the foetus affecting to the normal HPA programming; this abnormal development is irreversible in adulthood and will also reduce birth weight. Besides, it is a risk factor for possible adult pathologies such as diabetes mellitus type 2, cardiovascular disease or chronic hypertension. The reason is the decrease of glucocorticoid receptors (GR) in hippocampus, since they are crucial for the negative feedback of HPA axis. However, the mechanism by which GC reduce GR expression in hippocampus was unknown in the XX Century. Questions established in the XXI Century. A number of research articles published in the XXI Century reporting information about the epigenetic mechanism involved in the hippocampal reduction of GR are selected and presented. The main epigenetic mechanisms known up to date are also mentioned. Finally, the great therapeutic possibilities of the epigenetic mechanisms in the near future are enunciated as well as the possible explanation of evolutional processes

Expression levels of genes encoding melanin concentrating hormone (MCH) and MCH receptor change in taste aversion, but MCH injections do not alleviate aversive responses.

Melanin concentrating hormone (MCH) stimulates feeding driven by energy needs and reward and modifies anxiety behavior. Orexigenic peptides of similar characteristics, including nociceptin/orphanin FQ, Agouti-related protein and opioids, increase consumption also by reducing avoidance of potentially tainted food in animals displaying a conditioned taste aversion (CTA). Herein, using real-time PCR, we assessed whether expression levels of genes encoding MCH and its receptor, MCHR1, were affected in CTA in the rat. We also investigated whether injecting MCH intracerebroventricularly (ICV) during the acquisition and retrieval of LiCl-induced CTA, would alleviate aversive responses. MCHR1 gene was upregulated in the hypothalamus and brain stem of aversive animals, MCH mRNA was significantly higher in the hypothalamus, whereas a strong trend suggesting upregulation of MCH and MCHR1 genes was detected in the amygdala. Despite these expression changes associated with aversion, MCH injected prior to the induction of CTA with LiCl as well as later, during the CTA retrieval upon subsequent presentations of the aversive tastant, did not reduce the magnitude of CTA. We conclude that MCH and its receptor form an orexigenic system whose expression is affected in CTA. This altered MCH expression may contribute to tastant-targeted hypophagia in CTA. However, changing the MCH tone in the brain by exogenous peptide was insufficient to prevent the onset or facilitate extinction of LiCl-induced CTA. This designates MCH as one of many accessory molecules associated with shaping an aversive response, but not a critical one for LiCl-dependent CTA to occur.

Melanin-concentrating hormone (MCH) reverts the behavioral effects induced by inescapable stress.

The aim of this work was to investigate if MCH modifies the feeding and freezing responses in rats exposed to stressful stimuli. We used a basic version of contextual fear, where one group of rats were placed in a novel environment and two different groups were exposed to footshock paradigms, one of them escapable and the other one inescapable. At the end of each treatment, freezing and feeding were measured. Only the animals exposed to inescapable footshock paradigm showed significant increase in the food intake and freezing behavior in comparison to the control animals. The MCH administration (intra-hippocampal or intra-amygdaline) reverted these effects elicited by inescapable footshock. Results presented in this paper lead us to the assumption that the anxiolytic effect of the peptide is responsible for the reversion of the IS effects.

Hypothalamic-pituitary function and growth in children with intracranial lesions.

Intracranial lesions may affect hypothalamic-pituitary (HP) function and growth in several ways, depending on the location of the lesion within this area, the presence or absence of secondary hydrocephalus, and/or treatment of the lesion by surgery and/or radiotherapy. The lesion may cause a deficiency of HP hormones or, conversely, activation of the HP-gonadal axis leading to precocious puberty. Growth hormone (GH) deficiency is the most frequent endocrine abnormality that results from the lesions of the HP area. There has been progress in diagnosis, patterns of replacement therapy and the administration of biosynthetic GH in association with gonadotropin-releasing hormone analogues in precocious puberty. The major problem in these patients is the dramatic increase in their weight, which frequently occurs after surgery and increases their psychosocial and physical disabilities. It may be due to the hyperinsulinism caused by the lesion. This hyperinsulinism may be the factor that replaces GH in stimulating growth factor production and leads to normal growth in some of the patients.

Hypothalamic hormones: from neuroendocrinology to cancer therapy.

The discovery of hypothalamic hormones, especially LH-RH and somatostatin has led to practical clinical use of their analogs in the field of cancer treatment. Bombesin/GRP antagonists can be also considered for the development of new methods for treatment of various tumors. The understanding of functions of these peptide hormones and the availability of their synthetic analogs should permit the clinicians to treat a variety of cancers more successfully than in the past.

Infertilidade masculina: diagnóstico, classificaçäo e tratamento das oligozoospermias de causa endócrina / Male infertility: diagnosis, classification and treatment of oligospermias of endocrine cause

O autor com base nas provas dinâmicas de funçäo hormonal faz uma classificaçäo das oligozoospermias de causa endócrina e, baseado na mesma, um resumo das possibilidades de tratamento hormonal dessas oligozoospermias

Long-term growth hormone responses to nonspecific hypothalamic hormones in acromegalic patients.

Nonspecific hypothalamic hormones such as thyrotropin-releasing hormone or luteinizing hormone-releasing hormone, or both, elicited abnormal growth hormone responses in 73 of 108 (67.6%) acromegalic patients. After transsphenoidal adenomectomy, the provocative tests using these hormones were repeated in 26 patients with abnormal preoperative growth hormone responses to study variations in these responses during a 1-8-year observation period (average duration, 4 years). After surgery, 7 of the 26 patients regained normal basal growth hormone levels (less than 5 ng/mL) and manifested normal responses to the hypothalamic hormones. During the postoperative observation period, their basal growth hormone levels remained normal as did their responses to provocation with hypothalamic hormones, confirming that the adenoma had been completely resected. Eight other patients demonstrated normal growth hormone levels after surgery; however, they continued to have abnormal responses to provocation with hypothalamic hormones, suggesting the presence of residual adenomatous tissue in the gland. These patients manifested no marked increase in basal or peak growth hormone levels during the follow-up period (from less than 1 to less than 7.5 years) and they were all in clinical remission without any other treatment. Only one incompletely adenomectomized patient who had received no additional treatment experienced regrowth of the tumor. The main factor affecting the surgical results appears to be the preoperative basal growth hormone level, because abnormal growth hormone secretion ceased in all patients who had manifested preoperative levels below 45 ng/mL. Technical refinements of the operative procedure are another important factor in the postoperative outcome. Peritumoral tissue resection after simple selective adenomectomy is mandatory for better surgical results. Our studies indicate that fairly good results can be obtained without risk of the recurrence of the tumor or regrowth, when postoperative growth hormone levels are below 5 ng/mL and that the results are not affected by the postoperative growth hormone responses to provocation with hypothalamic hormones.

[Use and misuse of hormones in female reproductive disorders]. / Die gebruik en misbruik van hormone in geslagskundige gevalle.

The correct use of hormones in genesiological cases is discussed with indications for their use, dosage levels and duration of treatment under the following groups, viz. hypothalamic hormones, hypophyseal hormones, other gonadotrophins, steroids, combinations of the foregoing and prostaglandins. The more important dangers associated with hormone therapy are then briefly discussed with a few examples of the more common and hazardous abuses.