Oxytocin and Addiction: Potential Glutamatergic Mechanisms

Recently, oxytocin (OXT) has been investigated for its potential therapeutic role in addiction. OXT has been found to diminish various drug-seeking and drug-induced behaviors. Although its behavioral effects are well-established, there is not much consensus on how this neuropeptide exerts its effects. Previous research has given thought to how dopamine (DA) may be involved in oxytocinergic mechanisms, but there has not been as strong of a focus on the role that glutamate (Glu) has. The glutamatergic system is critical for the processing of rewards and the disruption of glutamatergic projections produces the behaviors seen in drug addicts. We introduce the idea that OXT has direct effects on Glu transmission within the reward processing pathway. Thus, OXT may reduce addictive behaviors by restoring abnormal drug-induced changes in the glutamatergic system and in its interactions with other neurotransmitters. This review offers insight into the mechanisms through which a potentially viable therapeutic target, OXT, could be used to reduce addiction-related behaviors.     

Co-Stimulation of Oxytocin and Arginine-Vasopressin Receptors Affect Hypothalamic Neurospheroid Size

Oxytocin (OXT) is a neuropeptide involved in a plethora of behavioral and physiological processes. However, there is a prominent lack of 3D cell culture models that investigate the effects of OXT on a cellular/molecular level. In this study, we established a hypothalamic neuronal spheroid model to investigate the cellular response in a more realistic 3D setting. Our data indicate that the formation of spheroids itself does not alter the basic characteristics of the cell line and that markers of cellular morphology and connectivity are stably expressed. We found that both OXT and arginine vasopressin (AVP) treatment increase spheroid size (surface area and volume), as well as individual nucleus size, which serves as an indicator for cellular proliferation. The cellular response to both OXT and AVP seems mainly to be mediated by the AVP receptor 1a (V1aR); however, the OXT receptor (OXTR) contributes significantly to the observed proliferative effect. When we blocked the OXTR pharmacologically or knocked down the OXTR by siRNA, the OXT- or AVP-induced cellular proliferation decreased. In summary, we established a 3D cell culture model of the neuronal response to OXT and AVP and found that spheroids react to the treatment via their respective receptors but also via cross-talk between the two receptor types.     

Glucocorticoids,Stress and Delta-9 Tetrahydrocannabinol (THC) during Early Embryonic Development

Elevated molecular stress in women is known to have negative impacts on the reproductive development of oocytes and the embryos prior to implantation. In recent years, the prevalence of cannabis use among women of reproductive age has risen due to its ability to relieve psychological stress and nausea, which are mediated by its psychoactive component, ∆-9-tetrahydrocannabinol (THC). Although cannabis is the most popular recreational drug of the 21st century, much is unknown about its influence on molecular stress in reproductive tissues. The current literature has demonstrated that THC causes dose- and time-dependent alterations in glucocorticoid signaling, which have the potential to compromise morphology, development, and quality of oocytes and embryos. However, there are inconsistencies across studies regarding the mechanisms for THC-dependent changes in stress hormones and how either compounds may drive or arrest development. Factors such as variability between animal models, physiologically relevant doses, and undiscovered downstream gene targets of both glucocorticoids and THC could account for such inconsistencies. This review evaluates the results of studies which have investigated the effects of glucocorticoids on reproductive development and how THC may alter stress signaling in relevant tissues.     

Analgesic,Anxiolytic and Anaesthetic Effects of Melatonin: New Potential Uses in Pediatrics

Exogenous melatonin is used in a number of situations, first and foremost in the treatment of sleep disorders and jet leg. However, the hypnotic, antinociceptive, and anticonvulsant properties of melatonin endow this neurohormone with the profile of a drug that modulates effects of anesthetic agents, supporting its potential use at different stages during anesthetic procedures, in both adults and children. In light of these properties, melatonin has been administered to children undergoing diagnostic procedures requiring sedation or general anesthesia, such as magnetic resonance imaging, auditory brainstem response tests and electroencephalogram. Controversial data support the use of melatonin as anxiolytic and antinociceptive agents in pediatric patients undergoing surgery. The aim of this review was to evaluate available evidence relating to efficacy and safety of melatonin as an analgesic and as a sedative agent in children. Melatonin and its analogs may have a role in antinociceptive therapies and as an alternative to midazolam in premedication of adults and children, although its effectiveness is still controversial and available data are clearly incomplete.     

Sex Differences in the Hypothalamic Oxytocin Pathway to Locus Coeruleus and Augmented Attention with Chemogenetic Activation of Hypothalamic Oxytocin Neurons

The tightly localized noradrenergic neurons (NA) in the locus coeruleus (LC) are well recognized as essential for focused arousal and novelty-oriented responses, while many children with autism spectrum disorder (ASD) exhibit diminished attention, engagement and orienting to exogenous stimuli. This has led to the hypothesis that atypical LC activity may be involved in ASD. Oxytocin (OXT) neurons and receptors are known to play an important role in social behavior, pair bonding and cognitive processes and are under investigation as a potential treatment for ASD. However, little is known about the neurotransmission from hypothalamic paraventricular (PVN) OXT neurons to LC NA neurons. In this study, we test, in male and female rats, whether PVN OXT neurons excite LC neurons, whether oxytocin is released and involved in this neurotransmission, and whether activation of PVN OXT neurons alters novel object recognition. Using “oxytocin sniffer cells” (CHO cells that express the human oxytocin receptor and a Ca indicator) we show that there is release of OXT from hypothalamic PVN OXT fibers in the LC. Optogenetic excitation of PVN OXT fibers excites LC NA neurons by co-release of OXT and glutamate, and this neurotransmission is greater in males than females. In male, but not in female animals, chemogenetic activation of PVN OXT neurons increases attention to novel objects.     

Involvement of cAMP-Dependent Protein Kinase in the Nucleus Accumbens in Cocaine Versus Social Interaction Reward

Evidence suggests that PKA activity in the nucleus accumbens (NAc) plays an essential role in reward-related learning. In this study, we investigated whether PKA is differentially involved in the expression of learning produced by either natural reinforcers or psychostimulants. For that purpose, we inhibited PKA through a bilateral infusion of Rp-cAMPS, a specific PKA inhibitor, directly into the NAc. The effects of PKA inhibition in the NAc on the expression of concurrent conditioned place preference (CPP) for cocaine (drug) and social interaction (natural reward) in rats were evaluated. We found that PKA inhibition increased the expression of cocaine preference. This effect was not due to altered stress levels or decreased social reward. PKA inhibition did not affect the expression of natural reward as intra-NAc Rp-cAMPS infusion did not affect expression of social preference. When rats were trained to express cocaine or social interaction CPP and tested for eventual persisting preference 7 and 14 days after CPP expression, cocaine preference was persistent, but social preference was abolished after the first test. These results suggest that PKA in the NAc is involved in drug reward learning that might lead to addiction and that only drug, but not natural, reward is persistent.     

Beneficial Effects of Metformin on the Central Nervous System,with a Focus on Epilepsy and Lafora Disease

Metformin is a drug in the family of biguanide compounds that is widely used in the treatment of type 2 diabetes (T2D). Interestingly, the therapeutic potential of metformin expands its prescribed use as an anti-diabetic drug. In this sense, it has been described that metformin administration has beneficial effects on different neurological conditions. In this work, we review the beneficial effects of this drug as a neuroprotective agent in different neurological diseases, with a special focus on epileptic disorders and Lafora disease, a particular type of progressive myoclonus epilepsy. In addition, we review the different proposed mechanisms of action of metformin to understand its function at the neurological level.     

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders

Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of stress response and aberrant glucocorticoid signaling has been associated with an increased risk for psychiatric and mood disorders, including schizophrenia, post-traumatic stress disorder and depression. Emerging evidence suggests that life-stress experiences can alter the epigenetic landscape and impact the function of genes involved in the regulation of stress response. More importantly, epigenetic changes induced by stressors persist over time, leading to increased susceptibility for a number of stress-related disorders. In this review, we discuss the role of glucocorticoids in the regulation of stress response, the mechanism through which stressful experiences can become biologically embedded through epigenetic alterations, and we underline potential associations between epigenetic changes and the development of stress-related disorders.     

Cytotoxic Autophagy in Cancer Therapy

Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles, and misfolded or damaged proteins to eliminate these components that might otherwise be deleterious to cellular survival. Consequently, autophagy has generally been considered a prosurvival response. Many, if not most chemotherapeutic drugs and radiation also promote autophagy, which is generally considered a cytoprotective response, in that its inhibition frequently promotes apoptotic cells death. Furthermore, it has been shown that conventional chemotherapeutic drugs and radiation alone rarely induce a form of autophagy that leads to cell death. However, there are multiple examples in the literature where newer chemotherapeutic agents, drug combinations or drugs in combination with radiation promote autophagic cell death. This review will describe autophagic cell death induced in breast tumor cells, lung cancer cells as well as glioblastoma, demonstrating that it cannot be concluded that stress induced autophagy is, of necessity, cytoprotective in function.     

Role of the Novel Peptide Phoenixin in Stress Response and Possible Interactions with Nesfatin-1

The novel peptide phoenixin was shown to be involved in several physiological processes ranging from reproduction to food intake. Interest in this protein has steadily increased over the last few years and its known implications have become much broader, playing a role in glucose homeostasis, anxiety, nociception, and pruritus. Phoenixin is expressed in a multitude of organs such as the small intestine, pancreas, and in the hypothalamus, as well as several other brain nuclei influencing numerous physiological functions. Its highly conserved amino-acid sequence amongst species leads to the assumption, that phoenixin might be involved in essential physiological functions. Its co-expression and opposing functionality to the extensively studied peptide nesfatin-1 has given rise to the idea of a possible counterbalancing role. Several recent publications focused on phoenixin’s role in stress reactions, namely restraint stress and lipopolysaccharide-induced inflammation response, in which also nesfatin-1 is known to be altered. This review provides an overview on the phoenixins and nesfatin-1 properties and putative effects, and especially highlights the recent developments on their role and interaction in the response to response.     

Chemical neuroimmunology: health in a nutshell bidirectional communication between immune and stress (limbic-hypothalamic-pituitary-adrenal) systems

Stress is a ubiquitous and pervasive part of modern life that is frequently blamed for causing a plethora of diseases and other discomforting medical conditions. All higher organisms, including humans, experience stress in the form of a wide variety of stressors that range from environmental pollutants and drugs to traumatic events or self-induced trauma. Stressors registered by the central nervous system (CNS) generate physiological stress responses in the body (periphery) by means of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis. This LHPA axis operates through the use of chemical messengers such as the stress hormones corticotropin-releasing hormone (CRH) and glucocorticoids (GCs). Under conditions of frequent exposure to acute stress and/or chronic, long-term exposure to stress, the LHPA axis becomes dysfunctional and in the process frequently overproduces both CRH and GCs, which results in many mild to severely toxic side effects. Bidirectional communication between the LHPA axis and immune/inflammatory systems can dramatically potentiate these side effects and create environments in the CNS and periphery ripe for the triggering and/or promotion of tissue degeneration and disease. This review aims to present as far as possible a molecular view of the processes involved so as to provide a bridge from the diffuse range of studies on molecular structure and receptor interactions to the burgeoning biological and medical literature that describes the empirical interplay between stress and disease. We hope that our review of this fast-growing field, which we christen chemical neuroimmunology, will give a clear indication of the striking range and depth of current molecular, cellular and medical evidence linking stress hormones to degeneration and disease. In so doing, we hope to provide encouragement for others to become interested in this critical and far-reaching field of research, which is very much at the heart of many important disease processes and very much a critical part of the crucial interface between chemistry and biology.     

The Role of PERK in Understanding Development of Neurodegenerative Diseases

Neurodegenerative diseases are an ever-increasing problem for the rapidly aging population. Despite this, our understanding of how these neurodegenerative diseases develop and progress, is in most cases, rudimentary. Protein kinase RNA (PKR)-like ER kinase (PERK) comprises one of three unfolded protein response pathways in which cells attempt to manage cellular stress. However, because of its role in the cellular stress response and the far-reaching implications of this pathway, error within the PERK pathway has been shown to lead to a variety of pathologies. Genetic and clinical studies show a correlation between failure of the PERK pathway in neural cells and the development of neurodegeneration, but the wide array of methodology of these studies is presenting conflicting narratives about the role of PERK in these affected systems. Because of the connection between PERK and pathology, PERK has become a high value target of study for understanding neurodegenerative diseases and potentially how to treat them. Here, we present a review of the literature indexed in PubMed of the PERK pathway and some of the complexities involved in investigating the protein’s role in the development of neurodegenerative diseases as well as how it may act as a target for therapeutics.     

Non-Thermal Plasma—A New Green Priming Agent for Plants?

Since the earliest agricultural attempts, humankind has been trying to improve crop quality and yields, as well as protect them from adverse conditions. Strategies to meet these goals include breeding, the use of fertilisers, and the genetic manipulation of crops, but also an interesting phenomenon called priming or adaptive response. Priming is based on an application of mild stress to prime a plant for another, mostly stronger stress. There are many priming techniques, such as osmopriming, halopriming, or using physical agents. Non-thermal plasma (NTP) represents a physical agent that contains a mixture of charged, neutral, and radical (mostly reactive oxygen and nitrogen species) particles, and can cause oxidative stress or even the death of cells or organisms upon interaction. However, under certain conditions, NTP can have the opposite effect, which has been previously documented for many plant species. Seed surface sterilization and growth enhancement are the most-reported positive effects of NTP on plants. Moreover, some studies suggest the role of NTP as a promising priming agent. This review deals with the effects of NTP treatment on plants from interaction with seed and cell surface, influence on cellular molecular processes, up to the adaptive response caused by NTP.     

Gliadin Peptides as Triggers of the Proliferative and Stress/Innate Immune Response of the Celiac Small Intestinal Mucosa

Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. Undigested gliadin peptides induce innate and adaptive T cell-mediated immune responses. The major mediator of the stress and innate immune response to gliadin peptides (i.e., peptide 31–43, P31–43) is the cytokine interleukin-15 (IL-15). The role of epithelial growth factor (EGF) as a mediator of enterocyte proliferation and the innate immune response has been described. In this paper, we review the most recent literature on the mechanisms responsible for triggering the up-regulation of these mediators in CD by gliadin peptides. We will discuss the role of P31–43 in enterocyte proliferation, structural changes and the innate immune response in CD mucosa in cooperation with EGF and IL-15, and the mechanism of up-regulation of these mediators related to vesicular trafficking. We will also review the literature that focuses on constitutive alterations of the structure, signalling/proliferation and stress/innate immunity pathways of CD cells. Finally, we will discuss how these pathways can be triggered by gliadin peptide P31–43 in controls, mimicking the celiac cellular phenotype.     

Distinct Regulation of Dopamine D3 Receptor in the Basolateral Amygdala and Dentate Gyrus during the Reinstatement of Cocaine CPP Induced by Drug Priming and Social Stress

Relapse in the seeking and intake of cocaine is one of the main challenges when treating its addiction. Among the triggering factors for the recurrence of cocaine use are the re-exposure to the drug and stressful events. Cocaine relapse engages the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which are responsible for emotional and episodic memories. Moreover, D3 receptor (D3R) antagonists have recently arisen as a potential treatment for preventing drug relapse. Thus, we have assessed the impact of D3R blockade in the expression of some dopaminergic markers and the activity of the mTOR pathway, which is modulated by D3R, in the BLA and DG during the reinstatement of cocaine-induced conditioned place preference (CPP) evoked by drug priming and social stress. Reinstatement of cocaine CPP paralleled an increasing trend in D3R and dopamine transporter (DAT) levels in the BLA. Social stress, but not drug-induced reactivation of cocaine memories, was prevented by systemic administration of SB-277011-A (a selective D3R antagonist), which was able, however, to impede D3R and DAT up-regulation in the BLA during CPP reinstatement evoked by both stress and cocaine. Concomitant with cocaine CPP reactivation, a diminution in mTOR phosphorylation (activation) in the BLA and DG occurred, which was inhibited by D3R blockade in both nuclei before the social stress episode and only in the BLA when CPP reinstatement was provoked by a cocaine prime. Our data, while supporting a main role for D3R signalling in the BLA in the reactivation of cocaine memories evoked by social stress, indicate that different neural circuits and signalling mechanisms might mediate in the reinstatement of cocaine-seeking behaviours depending upon the triggering stimuli.     

Plant Parasites under Pressure: Effects of Abiotic Stress on the Interactions between Parasitic Plants and Their Hosts

Parasitic angiosperms, comprising a diverse group of flowering plants, are partially or fully dependent on their hosts to acquire water, mineral nutrients and organic compounds. Some have detrimental effects on agriculturally important crop plants. They are also intriguing model systems to study adaptive mechanisms required for the transition from an autotrophic to a heterotrophic metabolism. No less than any other plant, parasitic plants are affected by abiotic stress factors such as drought and changes in temperature, saline soils or contamination with metals or herbicides. These effects may be attributed to the direct influence of the stress, but also to diminished host availability and suitability. Although several studies on abiotic stress response of parasitic plants are available, still little is known about how abiotic factors affect host preferences, defense mechanisms of both hosts and parasites and the effects of combinations of abiotic and biotic stress experienced by the host plants. The latter effects are of specific interest as parasitic plants pose additional pressure on contemporary agriculture in times of climate change. This review summarizes the existing literature on abiotic stress response of parasitic plants, highlighting knowledge gaps and discussing perspectives for future research and potential agricultural applications.     

NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction

The nuclear factor of activated T cells 5 (NFAT5) is well known for its sensitivity to cellular osmolarity changes, such as in the kidney medulla. Accumulated evidence indicates that NFAT5 is also a sensitive factor to stress signals caused by non-hypertonic stimuli such as heat shock, biomechanical stretch stress, ischaemia, infection, etc. These osmolality-related and -unrelated stimuli can induce NFAT5 upregulation, activation and nuclear accumulation, leading to its protective role against various detrimental effects. However, dysregulation of NFAT5 expression may cause pathological conditions in different tissues, leading to a variety of diseases. These protective or pathogenic effects of NFAT5 are dictated by the regulation of its target gene expression and activation of its signalling pathways. Recent studies have found a number of kinases that participate in the phosphorylation/activation of NFAT5 and related signal proteins. Thus, this review will focus on the NFAT5-mediated signal transduction pathways. As for the stimuli that upregulate NFAT5, in addition to the stresses caused by hyperosmotic and non-hyperosmotic environments, other factors such as miRNA, long non-coding RNA, epigenetic modification and viral infection also play an important role in regulating NFAT5 expression; thus, the discussion in this regard is another focus of this review. As the heart, unlike the kidneys, is not normally exposed to hypertonic environments, studies on NFAT5-mediated cardiovascular diseases are just emerging and rapidly progressing. Therefore, we have also added a review on the progress made in this field of research.     

Natural Antioxidants in Anemia Treatment

Anemia, characterized by a decrease of the hemoglobin level in the blood and a reduction in carrying capacity of oxygen, is a major public health problem which affects people of all ages. The methods used to treat anemia are blood transfusion and oral administration of iron-based supplements, but these treatments are associated with a number of side effects, such as nausea, vomiting, constipation, and stomach pain, which limit its long-term use. In addition, oral iron supplements are poorly absorbed in the intestinal tract, due to overexpression of hepcidin, a peptide hormone that plays a central role in iron homeostasis. In this review, we conducted an analysis of the literature on biologically active compounds and plant extracts used in the treatment of various types of anemia. The purpose of this review is to provide up-to-date information on the use of these compounds and plant extracts, in order to explore their therapeutic potential. The advantage of using them is that they are available from natural resources and can be used as main, alternative, or adjuvant therapies in many diseases, such as various types of anemia.     

A rheometer for measuring the viscoelastic response of polymer melts in arbitrary planar and biaxial extensional flow fields

In this paper we describe the operation of a rheometer that is capable of measuring the viscoelastic response of a polymer melt in a biaxial or planar extensional flow field under circumstances wherein the deformation history can be varied in an arbitrary manner. The principal feature of this rheometer is the use of a closed loop feedback system to control the inflation of a flat, molten polymer sheet clamped around its periphery. The feedback system is especially designed so that either stress or strain can be used as the reference point, thus permitting the deformation history to be varied arbitrarily. Illustrative data are presented on the viscoelastic response of a molten acrylonitrile-butadiene-styrene copolymer subjected to a planar extensional flow for the following deformation histories: constant stress, constant strain, constant strain rate, oscillatory stress and oscillatory strain.