The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder in which inflammation and oxidative stress play key etiopathological role. The pathology of PD brain is characterized by inclusions of aggregated α-synuclein (α-SYN) in the cytoplasmic region of neurons. Clinical evidence suggests that stimulation of pro-inflammatory cytokines leads to neuroinflammation in the affected brain regions. Upon neuroinflammation, the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway, and other transcription factors such as nuclear factor κB (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), mammalian target of rapamycin (mTOR), and toll-like receptors (TLRs) are upregulated and induce the microglial activation, contributing to PD via dopaminergic neuron autophagy. Aberrant activation or phosphorylation of the components of JAK/STAT signaling pathway has been implicated in increased transcription of the inflammation-associated genes and many neurodegenerative disorders such as PD. Interferon gamma (IFN-γ), and interleukine (IL)-6 are two of the most potent activators of the JAK/STAT pathway, and it was shown to be elevated in PD. Stimulation of microglial cell with aggregated α-SYN results in production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and IL-1ß in PD. Dysregulation of the JAK/STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach. So far, a variety of synthetic or natural small-molecule JAK inhibitors (Jakinibs) have been found promising in managing a spectrum of ailments, many of which are in preclinical research or clinical trials. Herein, we provided a perspective on the function of the JAK/STAT signaling pathway in PD progression and gathered data that describe the rationale evidence on the potential application of Jakinibs to improve neuroinflammation in PD.

BPA and Nutraceuticals, Simultaneous Effects on Endocrine Functions.

BACKGROUND: Bisphenol A (BPA) is worldwide diffused as a monomer of epoxy resins and polycarbonate plastics and has recognized activity as Endocrine Disruptor (ED). It is capable to interfere or compete with endogenous hormones in many physiological activities thus having adverse outcomes on health. Diet highly affects health status and in addition to macronutrients, provides a large number of substances with recognized pro-heath activity, and thus called nutraceuticals. OBJECTIVE: This mini-review aims at summarizing the possible opposite and simultaneous effects of BPA and nutraceuticals on endocrine functions. The possibility that diet may represent the first instrument to preserve health status against BPA damages has been discussed. METHODS: The screening of recent literature in the field has been carried out. RESULTS: The therapeutic and anti-oxidant properties of many nutraceuticals may reverse the adverse health effects of BPA. CONCLUSION: In vitro and in vivo studies provided evidence that nutraceuticals can preserve the health. Thus, the use of nutraceuticals can be considered a support for clinical treatment. In conclusion, dietary remediation may represent a successful therapeutic approach to maintain and preserve health against BPA damage.

Synaptic Regulation of Metabolism.

Neurons in the brain, particularly those in the hypothalamus, are essential for the maintenance of whole-body metabolic homeostasis. Dysfunctions or dysregulations of them can result in various metabolic diseases, including eating disorders, obesity, and diabetes. In addition to hormonal and peptidergic regulation, accumulating evidence has shown that these neurons are subject to synaptic regulation, which has been largely overlooked. In this chapter, we focus on synaptic neurotransmission of hypothalamic neurons and summarize current knowledge of synaptic plasticity in the maintenance of energy balance. Synaptic modulation engaged by circulating hormones is also discussed.

Hormonal and nutritional regulation of postnatal hypothalamic development.

The hypothalamus is a key centre for regulation of vital physiological functions, such as appetite, stress responsiveness and reproduction. Development of the different hypothalamic nuclei and its major neuronal populations begins prenatally in both altricial and precocial species, with the fine tuning of neuronal connectivity and attainment of adult function established postnatally and maintained throughout adult life. The perinatal period is highly susceptible to environmental insults that, by disrupting critical developmental processes, can set the tone for the establishment of adult functionality. Here, we review the most recent knowledge regarding the major postnatal milestones in the development of metabolic, stress and reproductive hypothalamic circuitries, in the rodent, with a particular focus on perinatal programming of these circuitries by hormonal and nutritional influences. We also review the evidence for the continuous development of the hypothalamus in the adult brain, through changes in neurogenesis, synaptogenesis and epigenetic modifications. This degree of plasticity has encouraging implications for the ability of the hypothalamus to at least partially reverse the effects of perinatal mal-programming.

The central effects of alpha-melanocyte stimulating hormone (α-MSH) in chicks involve changes in gene expression of neuropeptide Y and other factors in distinct hypothalamic nuclei.

Alpha-melanocyte stimulating hormone (α-MSH) is a satiety-inducing factor in birds and mammals although central mechanisms mediating its effects on appetite in birds are poorly understood. Thus, the objective of the present study was to determine effects of centrally-injected α-MSH on c-Fos and gene expression in chick appetite-associated hypothalamic nuclei. At 4days post-hatch, 3h-fasted chicks were intracerebroventricularly (ICV) injected with 0 (vehicle) or 0.12nmol α-MSH and 1h later, hypothalamus samples were collected for measuring c-Fos immunoreactivity and mRNA abundance of appetite-associated factors in hypothalamic nuclei. There were more c-Fos immunoreactive cells in the arcuate nucleus (ARC), dorsomedial nucleus (DMN), lateral hypothalamus (LH), and paraventricular nucleus (PVN) of α-MSH- than vehicle-injected chicks. Neuropeptide Y (NPY), oxytocin receptor (OXTR), and agouti-related peptide (AgRP) mRNAs were greater in α-MSH- than vehicle-injected chicks in the ARC. In the PVN, NPY receptor sub-type 1 (NPYR1) mRNA was reduced while c-Fos mRNA was increased in response to treatment with α-MSH. NPY, c-Fos, and DOPA decarboxylase (DDC) mRNAs were greater in treated than vehicle-injected chicks in the DMN. Results suggest that during the first hour post-injection, the appetite-inhibiting effects of α-MSH involve activation of the ARC, DMN, PVN, and LH, and corresponding changes in transcriptional regulation of factors involved with NPY, AgRP and mesotocin signaling, and monoamine synthesis. The effects of these changes may include an inhibition of NPY signaling in the PVN to induce satiety and stimulation of NPY/AgRP neurons in the ARC in an attempt to restore homeostatic levels of food intake.

Neuroendocrine-immune circuits, phenotypes, and interactions.

Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions.

Impact of obesity on bone metabolism. / Influencia de la obesidad sobre el metabolismo óseo.

High weight is a protective factor against osteoporosis and risk of fracture. In obesity, however, where overweight is associated to excess fat, this relationship does not appear to be so clear, excess weight has sometimes been associated to decreased bone mass. Obesity interferes with bone metabolism through mechanical, hormonal, and inflammatory factors. These factors are closely related to weight, body composition, and dietary patterns of these patients. The net beneficial or harmful effect on bone mass or risk of fracture of the different components of this condition is not well known. We need to recognize patients at a greater risk of bone disease related to obesity to start an adequate intervention.

New Insights into the Regulation of Chylomicron Production.

Dietary lipids are efficiently absorbed by the small intestine, incorporated into triglyceride-rich lipoproteins (chylomicrons), and transported in the circulation to various tissues. Intestinal lipid absorption and mobilization and chylomicron synthesis and secretion are highly regulated processes. Elevated chylomicron production rate contributes to the dyslipidemia seen in common metabolic disorders such as insulin-resistant states and type 2 diabetes and likely increases the risk for atherosclerosis seen in these conditions. An in-depth understanding of the regulation of chylomicron production may provide leads for the development of drugs that could be of therapeutic utility in the prevention of dyslipidemia and atherosclerosis. Chylomicron secretion is subject to regulation by various factors, including diet, body weight, genetic variants, hormones, nutraceuticals, medications, and emerging interventions such as bariatric surgical procedures. In this review we discuss the regulation of chylomicron production, mechanisms that underlie chylomicron dysregulation, and potential avenues for future research.

Human sickness behavior: Ultimate and proximate explanations.

Sickness behavior, a coordinated set of behavioral changes in response to infection, lies at the intersection of immunology, endocrinology, and evolutionary biology. Sickness behavior is elicited by pro-inflammatory cytokines, is thought to be an adaptive means of redirecting energy away from disadvantageous behaviors and toward mounting an effective immune response, and may be modulated by hormones, including testosterone and oxytocin. Research on sickness behavior in humans has lagged behind non-human animal research due to methodological complexities. Here we review what is known about sickness behavior in humans, the effects of various hormones on sickness behavior, the possible role of cytokine gene variation in influencing sickness behavior responses, and the ways in which culture and gender norms could similarly influence these behavioral changes. We also propose methodologies for advancing further studies of sickness behavior in humans.

The role of oxidative, inflammatory and neuroendocrinological systems during exercise stress in athletes: implications of antioxidant supplementation on physiological adaptation during intensified physical training.

During periods of intensified physical training, reactive oxygen species (ROS) release may exceed the protective capacity of the antioxidant system and lead to dysregulation within the inflammatory and neuroendocrinological systems. Consequently, the efficacy of exogenous antioxidant supplementation to maintain the oxidative balance in states of exercise stress has been widely investigated. The aim of this review was to (1) collate the findings of prior research on the effect of intensive physical training on oxidant-antioxidant balance; (2) summarise the influence of antioxidant supplementation on the reduction-oxidation signalling pathways involved in physiological adaptation; and (3) provide a synopsis on the interactions between the oxidative, inflammatory and neuroendocrinological response to exercise stimuli. Based on prior research, it is evident that ROS are an underlying aetiology in the adaptive process; however, the impact of antioxidant supplementation on physiological adaptation remains unclear. Equivocal results have been reported on the impact of antioxidant supplementation on exercise-induced gene expression. Further research is required to establish whether the interference of antioxidant supplementation consistently observed in animal-based and in vivo research extends to a practical sports setting. Moreover, the varied results reported within the literature may be due to the hormetic response of oxidative, inflammatory and neuroendocrinological systems to an exercise stimulus. The collective findings suggest that intensified physical training places substantial stress on the body, which can manifest as an adaptive or maladaptive physiological response. Additional research is required to determine the efficacy of antioxidant supplementation to minimise exercise-stress during intensive training and promote an adaptive state.

Development of food intake controls: neuroendocrine and environmental regulation of food intake during early life.

This article is part of a Special Issue "Energy Balance". The development of neuroendocrine regulation of food intake during early life has been shaped by natural selection to allow for optimal growth and development rates needed for survival. In vertebrates, neonates or early larval forms typically exhibit "feeding drive," characterized by a developmental delay in 1) responsiveness of the hypothalamus to satiety signals (e.g., leptin, melanocortins) and 2) sensitivity to environmental cues that suppress food intake. Homeostatic regulation of food intake develops once offspring transition to later life history stages when growth is slower, neuroendocrine systems are more mature, and appetite becomes more sensitive to environmental or social cues. Across vertebrate groups, there is a tremendous amount of developmental plasticity in both food intake regulation and stress responsiveness depending on the environmental conditions experienced during early life history stages or by pregnant/brooding mothers. This plasticity is mediated through the organizing effects of hormones acting on the food intake centers of the hypothalamus during development, which alter epigenetic expression of genes associated with ingestive behaviors. Research is still needed to reveal the mechanisms through which environmental conditions during development generate and maintain these epigenetic modifications within the lifespan or across generations. Furthermore, more research is needed to determine whether observed patterns of plasticity are adaptive or pathological. It is clear, however, that developmental programming of food intake has important effects on fitness, and therefore, has ecological and evolutionary implications.

Adolescent growth: genes, hormones and the peer group. Proceedings of the 20th Aschauer Soiree, held at Glücksburg castle, Germany, 15th to 17th November 2013.

The association between poverty, malnutrition, illness and poor socioeconomic conditions on the one side, and poor growth and short adult stature on the other side, is well recognized. Yet, the simple assumption by implication that poor growth and short stature result from poor living conditions, should be questioned. Recent evidence on the impact of the social network on adolescent growth and adult height further challenges the traditional concept of growth being a mirror of health. Twenty-nine scientists met at Glücksburg castle, Northern Germany, November 15th - 17th 2013, to discuss genetic, endocrine, mathematical and psychological aspects and related issues, of child and adolescent growth and final height.

Life-history evolution: at the origins of metamorphosis.

Metamorphosis is a widespread life history strategy of animals but apart from some model organisms it is poorly characterized. A recent study of moon jellies highlights the similarities and differences between the various types of metamorphosis and illuminates its molecular determinants.

Regulation of polyp-to-jellyfish transition in Aurelia aurita.

BACKGROUND: The life cycle of scyphozoan cnidarians alternates between sessile asexual polyps and pelagic medusa. Transition from one life form to another is triggered by environmental signals, but the molecular cascades involved in the drastic morphological and physiological changes remain unknown. RESULTS: We show in the moon jelly Aurelia aurita that the molecular machinery controlling transition of the sessile polyp into a free-swimming jellyfish consists of two parts. One is conserved and relies on retinoic acid signaling. The second, novel part is based on secreted proteins that are strongly upregulated prior to metamorphosis in response to the seasonal temperature changes. One of these proteins functions as a temperature-sensitive "timer" and encodes the precursor of the strobilation hormone of Aurelia. CONCLUSIONS: Our findings uncover the molecule framework controlling the polyp-to-jellyfish transition in a basal metazoan and provide insights into the evolution of complex life cycles in the animal kingdom.

Obesity and psoriasis: inflammatory nature of obesity, relationship between psoriasis and obesity, and therapeutic implications.

Obesity, particularly abdominal obesity, is currently considered a chronic low-grade inflammatory condition that plays an active role in the development of the pathophysiologic phenomena responsible for metabolic syndrome and cardiovascular disease through the secretion of proinflammatory adipokines and cytokines. In recent years clear genetic, pathogenic, and epidemiologic links have been established between psoriasis and obesity, with important implications for health. The relationship between the 2 conditions is probably bidirectional, with obesity predisposing to psoriasis and psoriasis favoring obesity. Obesity also has important implications in the treatment of psoriasis, such as a greater risk of adverse effects with conventional systemic drugs and reduced efficacy and/or increased cost with biologic agents, for which dosage should be adjusted to the patient's weight.

Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance.

Alterations in adequate energy balance maintenance result in serious metabolic disturbances such as obesity. In mammals, this complex process is orchestrated by multiple and distributed neuronal circuits. Hypothalamic and brainstem neuronal circuits are critically involved in the sensing of circulating and local factors conveying information about the energy status of the organism. The integration of these signals culminates in the generation of specific and coordinated physiological responses aimed at regulating energy balance through the modulation of appetite and energy expenditure. In this article, we review current knowledge on the homeostatic regulation of energy balance, emphasizing recent advances in mouse genetics, electrophysiology, and optogenetic techniques that have greatly contributed to improving our understanding of this central process.

Effects of coffee consumption, smoking, and hormones on risk for primary sclerosing cholangitis.

BACKGROUND & AIMS: Little is known about nongenetic risk factors for primary sclerosing cholangitis (PSC), except a possible protective effect of smoking. We investigated the relationship between environmental risk factors and susceptibility to PSC. METHODS: A questionnaire was distributed to patients with PSC, recruited from Oslo University Hospital Rikshospitalet in Norway through 2011, and randomly chosen individuals from the Norwegian Bone Marrow Donor Registry (control subjects). Data were analyzed from 240 patients with PSC and 245 control subjects, matched for gender and age. RESULTS: A lower proportion of patients with PSC were daily coffee drinkers than control subjects, both currently (76% vs 86%; odds ratio [OR], 0.52; 95% confidence interval [CI], 0.32-0.82; P = .006) and at the age of 18 years (35% vs 49%; OR, 0.58; 95% CI, 0.40-0.83; P = .003). The associations were mainly attributed to differences observed in men. Twenty percent of the patients were ever (current or former) daily smokers compared with 43% of control subjects (OR, 0.33; 95% CI, 0.22-0.50; P < .001). Ever daily smoking before PSC diagnosis was associated with older age at diagnosis (42 years vs 32 years; P < .001). Ever daily smoking (P < .001) and being a coffee drinker at the age of 18 years (P = .048) were independently and negatively associated with PSC. Fewer female patients with PSC than control subjects reported ever use of hormonal contraception (51% vs 85%; P < .001). Among female patients, there was a strong correlation between increasing number of children before the diagnosis of PSC and increasing age at diagnosis (r = 0.63; P < .001). CONCLUSIONS: Coffee consumption and smoking might protect against development of PSC. In women, the disease might be influenced by hormonal factors.