The role of stress in perinatal depression and anxiety - A systematic review.

Perinatal depression (PND) and anxiety affect around 20% of women, but available pharmacotherapy is not sufficiently effective in 20-60% of them, indicating a need for better understanding of these diseases. Since stress is a significant risk factor for PND, the aim was to examine the role of biological, environmental and psychological stress in PND and anxiety through a systematic literature search. Overall 210 studies were included, among which numerous rodent studies showed that perinatal stress induced depressive-like and anxious behavior, which was associated with HPA-axis alterations and morphological brain changes. Human studies indicated that the relationship between cortisol and perinatal depression/anxiety was not as clear and with many contradictions, although social and psychological stress were clearly positively associated with PND. Finally, oxytocin, synthetic neuroactive steroid and n-3 PUFA diet have been identified as potentially beneficial in the therapy of PND and anxiety, worth to be investigated in the future.

Current state of phoenixin-the implications of the pleiotropic peptide in stress and its potential as a therapeutic target.

Phoenixin is a pleiotropic peptide, whose known functions have broadened significantly over the last decade. Initially first described as a reproductive peptide in 2013, phoenixin is now recognized as being implicated in hypertension, neuroinflammation, pruritus, food intake, anxiety as well as stress. Due to its wide field of involvement, an interaction with physiological as well as psychological control loops has been speculated. It has shown to be both able to actively reduce anxiety as well as being influenced by external stressors. Initial rodent models have shown that central administration of phoenixin alters the behavior of the subjects when confronted with stress-inducing situations, proposing an interaction with the perception and processing of stress and anxiety. Although the research on phoenixin is still in its infancy, there are several promising insights into its functionality, which might prove to be of value in the pharmacological treatment of several psychiatric and psychosomatic illnesses such as anorexia nervosa, post-traumatic stress disorder as well as the increasingly prevalent stress-related illnesses of burnout and depression. In this review, we aim to provide an overview of the current state of knowledge of phoenixin, its interactions with physiological processes as well as focus on the recent developments in stress response and the possible novel treatment options this might entail.

Restraint stress affects circulating NUCB2/nesfatin-1 and phoenixin levels in male rats.

The two peptides phoenixin and nesfatin-1 are colocalized in hypothalamic nuclei involved in the mediation of food intake and behavior. Phoenixin stimulates food intake and is anxiolytic, while nesfatin-1 is an anorexigenic peptide shown to increase anxiety and anhedonia. Interestingly, central activation of both peptides can be stimulated by restraint stress giving rise to a role in the mediation of stress. Thus, the aim of the study was to test whether also peripheral circulating levels of NUCB2/nesfatin-1 and phoenixin are altered by restraint stress. Male ad libitum fed Sprague Dawley rats equipped with a chronic intravenous catheter were subjected to restraint stress and plasma levels of NUCB2/nesfatin-1, phoenixin and cortisol were measured over a period of 240 min and compared to levels of freely moving rats. Peripheral cortisol levels were significantly increased in restrained rats at 30, 60, 120 and 240 min compared to controls (p < 0.05). In contrast, restraint stress decreased plasma phoenixin levels at 15 min compared to unstressed conditions (0.8-fold, p < 0.05). Circulating NUCB2/nesfatin-1 levels were increased only at 240 min in restrained rats compared to those in unstressed controls (1.3-fold, p < 0.05). In addition, circulating NUCB2/nesfatin-1 levels correlated positively with phoenixin levels (r = 0.378, p < 0.001), while neither phoenixin nor nesfatin-1 were associated with cortisol levels (r = 0.0275, and r=-0.143, p> 0.05). These data suggest that both peptides, NUCB2/nesfatin-1 and phoenixin, are affected by restraint stress, although less pronounced than circulating cortisol.

Central blockage of nesfatin-1 has anxiolytic effects but does not prevent corticotropin-releasing factor-induced anxiety in male rats.

Nesfatin-1, a pleotropic peptide, was recently implicated in the regulation of anxiety and depression-like behavior in rats. However, the underlying mechanisms remain unclear so far. Thus, this study aimed to investigate the role of endogenous nesfatin-1 in the mediation of anxiety and depression-like behavior induced by corticotropin-releasing factor (CRF). Therefore, normal weight male intracerebroventricularly (icv) cannulated Sprague Dawley rats received two consecutive icv injections of anti-nesfatin-1 antibody or IgG control antibody followed by CRF or saline, before being exposed to a behavioral test. In the elevated zero maze test, assessing anxiety and explorative behavior, blockade of nesfatin-1 using an anti-nesfatin-1 antibody under basal conditions increased the number of entries into the open arms compared to control antibody/vehicle (1.6-fold, p < 0.05) and the time in open arms compared to the other groups (p < 0.05). Control antibody/CRF-treated animals tended to spend less time in the open arms compared to control antibody/vehicle (0.7-fold, p = 0.17), an effect not altered by the nesfatin-1 antibody (control antibody/CRF-treated animals vs. nesfatin-1 antibody/CRF group, p = 1.00). In the novelty-induced hypophagia test, assessing anhedonia as part of depression-like behavior, no significant differences were observed between the four groups for the latency to the first bout, number of bouts and the amount of palatable snack eaten (p > 0.05). In summary, CRF tended to increase anxiety and explorative behavior an effect not altered by blockade of nesfatin-1, whereas no significant effect of CRF on anhedonia was observed. Blockade of endogenous nesfatin-1 significantly decreased anxiety-like behavior giving rise to a physiological role of brain nesfatin-1 in the mediation of anxiety.

Restraint stress increases the expression of phoenixin immunoreactivity in rat brain nuclei.

Phoenixin is a recently discovered peptide, which has been associated with reproduction, anxiety and food intake. Based on a considerable co-localization it has been linked to nesfatin-1, with a possible antagonistic mode of action. Since nesfatin-1 is known to play a role in anxiety and the response to stress, this study aims to investigate the effects of a well-established psychological stress model, restraint stress, on phoenixin-expressing brain nuclei and phoenixin expression in rats. Male Sprague-Dawley rats were subjected to restraint stress (n = 8) or left undisturbed (control, n = 6) and the brains processed for c-Fos- and phoenixin immunohistochemistry. The number of c-Fos expressing cells was counted and phoenixin expression assessed semiquantitatively. Restraint stress significantly increased c-Fos expression in the dorsal motor nucleus of vagus nerve (DMN, 52-fold, p < 0.001), raphe pallidus (RPa, 15-fold, p < 0.001), medial part of the nucleus of the solitary tract (mNTS, 16-fold, p < 0.001), central amygdaloid nucleus, medial division (CeM, 9-fold, p = 0.01), supraoptic nucleus (SON, 9-fold, p < 0.001) and the arcuate nucleus (Arc, 2.5-fold, p < 0.03) compared to control animals. Also phoenixin expression significantly increased in the DMN (17-fold, p < 0.001), RPa (2-fold, p < 0.001) and mNTS (1.6-fold, p < 0.001) with positive correlations between c-Fos and phoenixin (r = 0.74-0.85; p < 0.01) in these nuclei. This pattern of activation suggests an involvement of phoenixin in response to restraint stress. Whether phoenixin mediates stress effects or is activated in a counterbalancing fashion will have to be further investigated.

Intracerebroventricular injection of phoenixin alters feeding behavior and activates nesfatin-1 immunoreactive neurons in rats.

Phoenixin is a novel neuropeptide initially associated with reproductive functions, but subsequently also with feeding behavior. Nesfatin-1 is also involved in the regulation of food intake and has been shown to largely colocalize with phoenixin in the rat brain; however, a functional link is missing so far. The current study investigated whether phoenixin activates nesfatin-1 immunoreactive nuclei in the rat brain. Male Sprague Dawley rats chronically equipped with an intracerebroventricular cannula were injected with vehicle (5 µl ddH2O) or phoenixin (1.7 nmol in 5 µl ddH2O, n = 5-6 group). Behavior was assessed manually and c-Fos as well as nesfatin-1 immunoreactivity using immunohistochemistry. Phoenixin significantly increased feeding and drinking behavior as well as locomotor activity compared to vehicle (p < 0.01). Moreover, phoenixin injected intracerebroventricularly (icv) activated several nuclei throughout the rat brain as assessed using c-Fos; the number of c-Fos/nesfatin-1 immunoreactive neurons was increased in the lateral septal nucleus (4-fold), supraoptic nucleus (107-fold), paraventricular nucleus (6-fold) and the nucleus of the solitary tract (18-fold) compared to vehicle (p < 0.05). In summary, phoenixin activates several nesfatin-1 immunoreactive nuclei in the rat brain. This activation may play a role in the modulation of food intake.

Alteration of peptidergic gut-brain signaling under conditions of obesity.

The prevalence of obesity is rising worldwide; therefore, the World Health Organization introduced the term 'globesity'. This rise also causes an increase of associated diseases such as cardiovascular diseases, type 2 diabetes, several malignomas as well as psychiatric disorders. In order to face this medical challenge, a better understanding of the pathophysiological alterations under conditions of obesity is necessary. Hunger and satiety are largely regulated by peptidergic hormones predominantly produced in the gastrointestinal tract and signaling to the brain via the gut-brain axis. While several hormones are known to decrease food intake such as nesfatin-1, cholecystokinin (CKK), glucagon-like peptide 1 (GLP-1), pancreatic polypeptide (PP) and peptide YY (PYY), only one peripherally produced and centrally acting hormone - ghrelin - is known so far that stimulates food intake. Several alterations of the signaling of these hormones have been described in the past years e.g. an attenuated postprandial response of CCK, GLP-1 and PYY as well as a reduced postprandial suppression of ghrelin that might contribute to the development and/or maintenance of obesity and will be discussed in the present review. Lastly, gaps in knowledge will be highlighted.

Number of RUNX1 mutations, wild-type allele loss and additional mutations impact on prognosis in adult RUNX1-mutated AML.

RUNX1-mutated acute myeloid leukemia (AML) show a distinct pattern of genetic abnormalities and an adverse prognosis. We analyzed the impact of multiple RUNX1 mutations and RUNX1 wild-type (WT) loss in 467 AML with RUNX1 mutations (mut): (1) RUNX1 WT loss (n=53), (2) >1 RUNX1mut (n=94) and (3) 1 RUNX1mut (n=323). In 1 RUNX1mut, +8 was most frequent, whereas in WT loss +13 was the most abundant trisomy (+8: 66% vs 31%, P=0.022; +13: 15% vs 62%, P<0.001). Analyses of 28 genes in 163 selected cases revealed SRSF2 (39%), ASXL1 (36%), DNMT3A (19%), IDH2 (17%) and SF3B1 (17%) as most frequently mutated genes. RUNX1 WT loss showed a higher frequency of ASXL1mut compared with the other cases (50% vs 29%, P=0.009). Median overall survival (OS) in the total cohort was 14 months. WT loss (OS: 5 months) and >1 RUNX1mut (14 months) showed an adverse impact on prognosis compared with 1 RUNX1mut (22 months; P=0.002 and 0.048, respectively). Mutations in ASXL1 and ⩾2 additional mutations correlated with shorter OS (10 vs 18 months, P=0.028; 12 vs 20 months, P=0.017). Thus, the number of RUNX1mut, RUNX1 WT loss and the number and type of additional mutations is biologically and clinically relevant.

The X/A-like cell revisited - spotlight on the peripheral effects of NUCB2/nesfatin-1 and ghrelin.

The gastric X/A-like cell was long thought to be restricted to the production of acyl ghrelin. However, the subsequent years witnessed the discovery of other peptide products derived from this cell, namely desacyl ghrelin, obestatin and nesfatin-1. While the role of obestatin remains highly questionable and is very critically discussed in the literature, besides acyl ghrelin also desacyl ghrelin and nesfatin-1 have been implicated in the regulation of food intake. As observed for several other peptide hormones before, ghrelin and nesfatin-1 are not restricted to one function but rather exert pleiotropic actions including effects on gastrointestinal motility, thermogenesis, lipid and glucose homeostasis, stress mediation, cardiovascular as well as reproductive functions. These often counter-regulatory effects of nesfatin-1 and ghrelin will be discussed in the present review.

Deep brain stimulation alters light phase food intake microstructure in rats.

Treatment of eating disorders like obesity or anorexia is challenging. Options are limited and new approaches desired. An interesting approach is the application of deep brain stimulation (DBS). The nucleus accumbens (NAcc) is part of the food reward system. A pilot study reported that DBS of the NAcc shell modulates food intake and body weight in rats. Underlying mechanisms such as the food intake microstructure are unknown so far. Normal weight female Sprague-Dawley rats were equipped with a custom-made DBS electrode placed unilaterally in the NAcc shell. Biphasic stimulation was performed for seven days. Body weight and food intake including the microstructure were assessed over the experimental period. Behavior was monitored manually. DBS tended to increase body weight gain (28.1 ± 5.4 g) compared to sham-stimulated controls (16.7 ± 3.4, P = 0.05) without affecting daily food intake (P > 0.05). Further analyses showed that light phase food intake was stimulated, whereas dark phase food intake was decreased in the DBS group (P < 0.05). During the light phase bout frequency (+50%), bout duration (+64%), meal duration (+71%) and overall time spent in meals (+92%) were increased in DBS rats (P < 0.05), while during the dark phase no alterations were observed (P > 0.05). Behavior did not show differences regarding overall eating and drinking behavior (including food/water approach), grooming or locomotion (P > 0.05). Summarized, although overall food intake was not changed by DBS, light phase food intake was stimulated likely via a reduction of satiation.

The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases.

Alterations in TP53 have been described in many cancer types including hematological neoplasms. We aimed at comparing TP53 mutations (mut) and deletions (del) in a large cohort of patients with hematological malignancies (n=3307), including AML (n=858), MDS (n=943), ALL (n=358), CLL (n=1148). Overall, alterations in TP53 were detected in 332/3307 cases (10%). The highest frequency was observed in ALL (total: 19%; mut+del: 6%; mut only: 8%; del only: 5%) and AML (total: 13%; mut+del: 5%; mut only: 7%; del only: 1%), whereas TP53 alterations occurred less frequently in CLL (total: 8%) and MDS (total: 7%). TP53 mutations were significantly more frequent in patients ⩾60 vs <60 years in AML (9% vs 2%, P<0.001) and ALL (12% vs 6%, P<0.001). TP53mut+del had a significant negative impact on overall survival in all entities, whereas differences were observed regarding TP53mut only or TP53del only: TP53mut only impacted survival in AML (36 vs 9 months, P<0.001) and MDS (65 vs 19 months, P<0.001), TP53del only in CLL (not reached vs 64 months, P=0.008) and MDS (65 vs 24 months, P=0.011). As substantial differences between the entities are observed regarding correlation to age and survival, we suggest evaluation of both TP53 deletion and mutation status.

The exercise-induced myokine irisin does not show an association with depressiveness, anxiety and perceived stress in obese women.

Irisin has recently been proposed to act as a myokine secreted from skeletal muscle following exercise and to exert several health-beneficial effects, although its role is far from being established. In contrast to the growing body of literature on the biological regulation and function of irisin, there is no evidence on potential associations with mental functions. Since physical activity has been reported to have favorable impact on mental functions, we investigated the association of irisin with depressiveness, perceived stress, and anxiety as well as eating disorder symptoms in obese women. We included 98 female obese inpatients (age: mean ± S.D. 43.9 ± 12.5 years; body mass index 49.2 ± 8.3 kg/m(2)) covering a broad spectrum of psychopathology. Depressiveness (PHQ-9), perceived stress (PSQ-20), anxiety (GAD-7), and eating disorder symptoms (EDI-2) were assessed psychometrically. Plasma irisin obtained at the same time was determined by ELISA. Irisin did not correlate with depressiveness (r = -0.03, P = 0.80), anxiety (r = 0.14, P = 0.17) and perceived stress (r = -0.14, P = 0.18) as well as eating disorder symptoms in general (r = -0.09, P = 0.39). No correlation of irisin was observed with any subscales of the PSQ-20 and EDI-2 (after Bonferroni correction). In conclusion, irisin is not associated with depressiveness, anxiety and perceived stress in female obese patients. These results do not support the assumption of irisin being involved in psychoendocrine pathways of the regulation of depression or other mental functions such as anxiety and perceived stress.

Treatment with the ghrelin-O-acyltransferase (GOAT) inhibitor GO-CoA-Tat reduces food intake by reducing meal frequency in rats.

The ghrelin acylating enzyme ghrelin-O-acyltransferase (GOAT) was recently identified and implicated in several biological functions. However, the effects on food intake warrant further investigation. While several genetic GOAT mouse models showed normal food intake, acute blockade using a GOAT inhibitor resulted in reduced food intake. The underlying food intake microstructure remains to be established. In the present study we used an automated feeding monitoring system to assess food intake and the food intake microstructure. First, we validated the basal food intake and feeding behavior in rats using the automated monitoring system. Afterwards, we assessed the food intake microstructure following intraperitoneal injection of the GOAT inhibitor, GO-CoA-Tat (32, 96 and 288 µg/kg) in freely fed male Sprague-Dawley rats. Rats showed a rapid habituation to the automated food intake monitoring system and food intake levels were similar compared to manual monitoring (P = 0.43). Rats housed under these conditions showed a physiological behavioral satiety sequence. Injection of the GOAT inhibitor resulted in a dose-dependent reduction of food intake with a maximum effect observed after 96 mg/kg (-27%, P = 0.03) compared to vehicle. This effect was delayed in onset as the first meal was not altered and lasted for a period of 2 h. Analysis of the food intake microstructure showed that the anorexigenic effect was due to a reduction of meal frequency (-15%, P = 0.04), whereas meal size (P = 0.29) was not altered compared to vehicle. In summary, pharmacological blockade of GOAT reduces dark phase food intake by an increase of satiety while satiation is not affected.

Role of NUCB2/Nesfatin-1 in the hypothalamic control of energy homeostasis.

Hunger and satiety are regulated in a complex fashion by a few food intake stimulatory (orexigenic) and a multitude of inhibitory (anorexigenic) factors produced in the periphery (mainly in the gastrointestinal tract) or directly in the brain. Within the brain, the hypothalamus plays a pivotal role as a production site of food intake regulatory factors. Importantly, this site integrates peripheral and central signaling factors to orchestrate food intake and in the long term body weight. Our knowledge on these regulatory pathways is not static but rather rapidly changing as new factors as well as up- and downstream signaling pathways of already known transmitters are uncovered. Hypothalamic nucleobindin2 (NUCB2), the precursor of nesfatin-1, was first described in 2006 and nesfatin-1 found to be a novel anorexigenic modulator of food intake and body weight. The initial report stimulated several groups to investigate the biological actions of nesfatin-1 and subsequent studies delineated the underlying brain mechanisms involved in its food reducing effect. Of interest was the demonstration that NUCB2 also exerts its anorexigenic action in the paraventricular nucleus of the hypothalamus and is regulated at this site by changes in metabolic status with a diurnal rhythm inversely related to that of feeding in rats. The present review describes the current state-of-knowledge on central nesfatin-1's effects on food intake and body weight and highlights important missing links regarding cellular signaling mechanisms involved in nesfatin-1's action.

The role of nesfatin-1 in the regulation of food intake and body weight: recent developments and future endeavors.

Nesfatin-1 was discovered in 2006 and introduced as a potential novel anorexigenic modulator of food intake and body weight. The past years have witnessed increasing evidence establishing nesfatin-1 as a potent physiological inhibitor of food intake and body weight and unravelled nesfatin-1's interaction with other brain transmitters to exert its food consumption inhibitory effect. As observed for other anorexigenic brain neuropeptides, nesfatin-1 is also likely to exert additional, if not pleiotropic, actions in the brain and periphery. Recent studies established the prominent expression of the nesfatin-1 precursor, nucleobindin2 (NUCB2), in the stomach and pancreas, where nesfatin-1 influences endocrine secretion. This review will highlight the current experimental state-of-knowledge on the effects of NUCB2/nesfatin-1 on food intake, body weight and glucose homeostasis. Potential implications in human obesity will be discussed in relation to the evidence of changes in circulating levels of NUCB2/nesfatin-1 in disease states, the occurrence of genetic NUCB2 polymorphisms and--in contrast to several other hormones--the independence of leptin signalling known to be blunted under conditions of chronically increased body weight.