Short communication: TNF-α and IGF-1 regulates epigenetic mechanisms of HDAC2 and HDAC10.

Vascular restenosis often presents as a consequence of injury to the vessel wall, resulting from stenting and other interventional procedures. Such injury to the arteries induces proliferation of Vascular Smooth Muscle Cells (VSMCs), resulting in cellular hyperplasia and restenosis. We and others have previously reported de-novo production of different cytokines and growth factors such as Tumor Necrosis Factor Alpha (TNF-α) and Insulin like Growth Factor 1 (IGF-1), after vascular injury. As complex as it is, the profuse proliferation of VSMCs appears to be occurring due to several induced factors which initiate molecular mechanisms and exacerbate disease conditions. In many pathological events, the deleterious effects of TNF-α and IGF-1 in initiating disease mechanisms was reported. In the present work, we explored whether TNF-α and IGF-1 can regulate epigenetic mechanisms that promote proliferation of VSMCs. We investigated the mechanistic roles of proteins which can structurally interact with DNMT1 and initiate cellular pathways that promote proliferation of VSMCs. Our findings here, identify a novel molecular mechanism that is initiated by TNF-α and IGF-1. It was previously reported that DNMT1 expression is directly induced by TNF-α and IGF-1 treatment and increased/induced expression of DNMT1 causes silencing of genes that are essential to maintaining cellular homeostasis such as the tumor suppressor genes. We have earlier reported that TNF-α and IGF-1 treatment elevates DNMT1 expression in VSMCs and causes increased VSMC proliferation. However, the molecular mechanisms involved were not fully deciphered. Interestingly, in the present study we found that TNF-α and IGF-1 treatment failed to elevate DNMT1 expression levels in absence of HDAC2 and HDAC10. Also, while HDAC2 expression was not affected by HDAC10 knockdown, HDAC2 is essentially required for HDAC10 expression. Further, in TNF-α and IGF-1 induced epigenetic signaling mechanism, the expression of two important proteins EZH2 and PCNA seem to be regulated in an HDAC2-HDAC10 dependent manner. Our results show an inter-dependence of epigenetic mediators in inducing proliferation in VSMCs. To our knowledge, this is the first report that shows HDAC2 dependent expression of HDAC10, and suggests a novel mechanistic link between DNMT1, HDAC10 and HDAC2 that regulates EZH2 and PCNA to enhance cell proliferation of VSMCs which is the underlying cause for neointimal hyperplasia and restenosis.

Acute Blockade of PACAP-Dependent Activity in the Ventromedial Nucleus of the Hypothalamus Disrupts Leptin-Induced Behavioral and Molecular Changes in Rats.

Leptin signaling pathways, stemming primarily from the hypothalamus, are necessary for maintaining normal energy homeostasis and body weight. In both rodents and humans, dysregulation of leptin signaling leads to morbid obesity and diabetes. Since leptin resistance is considered a primary factor underlying obesity, understanding the regulation of leptin signaling could lead to therapeutic tools and provide insights into the causality of obesity. While leptin actions in some hypothalamic regions such as the arcuate nuclei have been characterized, less is known about leptin activity in the hypothalamic ventromedial nuclei (VMN). Recently, pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to reduce feeding behavior and alter metabolism when administered into the VMN in a pattern similar to that of leptin. In the current study, we examined whether leptin and PACAP actions in the VMN share overlapping pathways in the regulation of energy balance. Interestingly, PACAP administration into the VMN increased STAT3 phosphorylation and SOCS3 mRNA expression, both of which are hallmarks of leptin receptor activation. In addition, BDNF mRNA expression in the VMN was increased by both leptin and PACAP administration. Moreover, antagonizing PACAP receptors fully reversed the behavioral and cellular effects of leptin injections into the VMN. Electrophysiological studies further illustrated that leptin-induced effects on VMN neurons were blocked by antagonizing PACAP receptors. We conclude that leptin dependency on PACAP signaling in the VMN suggests a potential common signaling cascade, allowing a tonically and systemically secreted neuropeptide to be more precisely regulated by central neuropeptides.

Gardner-Diamond syndrome: a systematic review of treatment options for a rare psychodermatological disorder.

Gardner-Diamond syndrome (GDS) is a rare psychodermatological condition characterized by the formation of spontaneous, painful skin lesions that develop into ecchymosis following episodes of severe physiological or psychological stress. The majority of GDS cases occur in young adult females, and although the etiology of this rare disorder is unknown, there appears to be a psychological component correlated with the coexistence of previous psychiatric diagnoses. Due to the rare nature of this disorder, there exist few guidelines for prompt clinical diagnosis and optimal treatment. Here, a systematic review was conducted to include 45 cases of patients with GDS to better understand clinical presentation as well as current treatment options. Ultimately, GDS is a diagnosis of exclusion after other coagulopathies and causes of purpura are ruled out. High clinical suspicion following laboratory and clinical exclusion of known physiological causes is necessary for diagnosis. Selective serotonin reuptake inhibitors (SSRIs) and corticosteroids are cost effective first line treatments for GDS with proven efficacy in symptomatic relief. GDS refractory to initial treatment may require regular psychotherapy and titrated SSRI dosages to achieve long-term success. This review of available case studies serves to comprehensively describe the clinical presentation and available treatment approaches to this rare psychodermatological disorder.

Pituitary Adenylate-Cyclase Activating Polypeptide Regulates Hunger- and Palatability-Induced Binge Eating.

While pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the hypothalamic ventromedial nuclei (VMN) has been shown to regulate feeding, a challenge in unmasking a role for this peptide in obesity is that excess feeding can involve numerous mechanisms including homeostatic (hunger) and hedonic-related (palatability) drives. In these studies, we first isolated distinct feeding drives by developing a novel model of binge behavior in which homeostatic-driven feeding was temporally separated from feeding driven by food palatability. We found that stimulation of the VMN, achieved by local microinjections of AMPA, decreased standard chow consumption in food-restricted rats (e.g., homeostatic feeding); surprisingly, this manipulation failed to alter palatable food consumption in satiated rats (e.g., hedonic feeding). In contrast, inhibition of the nucleus accumbens (NAc), through local microinjections of GABA receptor agonists baclofen and muscimol, decreased hedonic feeding without altering homeostatic feeding. PACAP microinjections produced the site-specific changes in synaptic transmission needed to decrease feeding via VMN or NAc circuitry. PACAP into the NAc mimicked the actions of GABA agonists by reducing hedonic feeding without altering homeostatic feeding. In contrast, PACAP into the VMN mimicked the actions of AMPA by decreasing homeostatic feeding without affecting hedonic feeding. Slice electrophysiology recordings verified PACAP excitation of VMN neurons and inhibition of NAc neurons. These data suggest that the VMN and NAc regulate distinct circuits giving rise to unique feeding drives, but that both can be regulated by the neuropeptide PACAP to potentially curb excessive eating stemming from either drive.