Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 18, Issue 4, 2018

Background and Objective: Homocysteine (Hcy) is a non-protein α-amino acid, which plays several important roles in human physiology and in the central nervous system. Although Hcy has several known biological properties in one-carbon metabolism, its overproduction might be harmful, and could add to the pathophysiology associated with ASD. We reviewed the current evidence about changes in Hcy concentration in ASD and tried to correlate its changes with the clinical profile Discussion: The concentration of the amino acid in biological fluids (blood and urine) in children/ youngs with ASD is increased in the majority of studies when comparing to typically developing control subjects. Some report demonstrated a significant association between the severity of the disorder and the abnormalities in Hcy levels. Conclusion: Further research is needed to correlate the increase in Hcy with specific symptoms/ deficits in ASD and to evaluate the clinical impact of strategies that can reduce Hcy concentration in ASD.

Background and Objective: Bulimia nervosa, is an eating disorder characterized by excessive influence of weight and body shape on the levels of self-esteem, with pervasive feelings of failure and inadequacy. The eating is characterized by the presence of episodes of uncontrolled eating (Binge), during which the person ingests mass wide variety of foods and the feeling of not being able to stop eating. This review focuses on the metabolic and hormonal alterations in the in bulimia nervosa. Methods: A literature search was conducted using the electronic database Medline and PubMed and with additional hand searches through the reference list obtained from the articles found. Journal were searched up to 2015. Inclusion criteria were: 1) full text available in English; 2) published in a peerreviewed journal and using the following keywords: neurotransmitters (AgRP, BDNF, αMSH, NP Y, endocannabinoids, adiponectin, CCK, ghrelin, GLP-1, insulin, leptin, PP, PYY), hormones (FSH, LH, estrogen, progesterone, testosterone) and bulimia nervosa, eating disorders. Results: All data reported in the present review indicated that changes in the central and peripheral neuroendocrine equilibria may favor the onset and influence the course and prognosis of a DA. However, it is still questionable whether the alterations of the peptides and hormones regulating the mechanisms of eating behavior are the cause or consequence of a compromised diet. Conclusion: The results of the present review indicate that the altered balance of the various peptides or hormones can be relevant not only for the genesis and / or maintenance of altered dietary behaviors, but also for the development of specific psychopathological aspects in eating disorders.

Background: Excessive accumulation of ammonia in the brain is a causative factor of an array of neurological manifestations of hyperammonemic encephalopathies (“hyperammonemias”, HA) among which hepatic encephalopathy (HE) is a major epidemiologic and therapeutic challenge. While ammonia neurotoxicity is symptomatically and mechanistically very complex, there is a consensus with regard to the leading role in its pathogenesis of: i) astrocytes being the primary cellular target of ammonia toxicity; ii) alterations of glutamate (Glu)-dependent neurotransmission (over-excitation followed by inhibition of glutamatergic tone) being the cornerstone of its neurophysiological manifestations; and iii) brain edema, an often lethal consequence of astrocytic swelling, being among other factors caused by the retention of glutamine (Gln) in these cells. Objective: This article critically evaluates the present literature attempting to relate manifestations of HA to changes in astrocytic Glu and Gln transport as observed in different in vivo and in vitro HA and/or HE models. Emphasis is put on two disproportions in the state of the art: i) the paucity of available data regarding ammonia-dependent changes in Glu transport activity vs the relative abundance of information on the expression of astrocytic Glu transporters (GLT-1/EAAT2 and GLAST/EAAT1); ii) the just emerging still not very conclusive knowledge on the response of astrocytic Gln transporters SN1 and SN2. Conclusion: The review on the above issues is complemented by own recent data which fill some of the many gaps in the knowledge. A brief account is included on the roles of heteromeric cell membrane Glu/arginine (Arg) exchanger y+LAT2 and on the mitochondrial Gln transport.

Background and Objective: There is great interest, supported by clinical experience, in the relationship between Eating Disorders (EDs) and psychiatric symptoms and diseases. The psychopathology of EDs is also referred to many risk and protective factors, and there is some evidence in the literature, also about genetic and neurobiological factors involved. The aim of this review is to examine and synthesize the recent scientific literature on this topic, in particular the complex relationship between Anorexia Nervosa and Neuropsychiatric Disorders. Methods: We analyzed the best of published literature on the topic, identifying keywords and MeSH terms in Pubmed and then searching them. The last search was performed on November 2017. Results: Psychiatric comorbidities are very common in anorexia nervosa. Mood disorders, major depressive disorders, anxiety disorders, obsessive-compulsive disorders, developmental disorders among autistic spectrum and attention-deficit hyperactivity disorder and even some personality disorders, substance abuse and borderline traits have been reported, and some observations suggest a positive genetic correlation between anorexia nervosa and schizophrenia. Conclusion: The great amount of scientific articles dealing with the relationship between EDs and psychopathology confirms the complexity of these problems and the difficulties in diagnosis and treatment. An accurate diagnosis and assessment of clinical risk about psychological, psychiatric, nutritional and somatic aspects are therefore essential for an appropriate therapeutic management of patients affected by anorexia nervosa.

Background and Objective: Eating Disorder (ED) is characterized by persistently and severely disturbed eating behaviours. They arise from a combination of long-standing behavioural, emotional, psychological, interpersonal, and social factors and result in insufficient nutrient ingestion and/or adsorption. The three main EDs are: anorexia nervosa, bulimia nervosa, and binge eating disorder. We review the role of peripheral endocannabinoids in eating behaviour. Discussion: The neuronal pathways involved in feeding behaviours are closely related to catecholaminergic, serotoninergic and peptidergic systems. Accordingly, feeding is promoted by serotonin, dopamine, and prostaglandin and inhibited by neuropeptide Y, norepinephrine, GABA, and opioid peptides. The endocannabinoid system plays a role in EDs, and multiple lines of evidence indicate that the cannabinoid signalling system is a key modulatory factor of the activity in the brain areas involved in EDs as well as in reward processes. Conclusion: Besides their central role in controlling food behaviours, peripheral cannabinoids are also involved in regulating adipose tissue and insulin signalling as well as cell metabolism in peripheral tissues such as liver, pancreas, fatty tissue, and skeletal muscle. Altogether, these data indicate that peripheral cannabinoids can provide new therapeutic targets not only for EDs but also for metabolic disease.

Background and Objective: The preventive effects of olive oil against different diseases have been attributed to its high phenolic compound content. The objective of this study was to examine available scientific evidence on the beneficial effects against chronic diseases of olive oil phenolic compounds. Method: This article examines recently published data on olive oil phenolic compounds and their potential benefits in the prevention of cardiovascular disease, cancer, neurodegenerative disease, and osteoporosis. Results: The antioxidant, anti-proliferative, pro-apoptotic, and anti-inflammatory activities of olive oil phenolic compounds have preventive effects against heart disease and cancer. These compounds also exert neuroprotective and neuromodulator effects against neurodegenerative disease, inhibiting the development of amyloid plaques. Finally, they are known to protect against osteoporosis, favoring bone regeneration. Conclusion: Dietary intake of olive oil can be recommended by healthcare professionals as an important source of phenolic compounds that play a role in the prevention of chronic disease and the consequent improvement in quality of life.

Background and Objective: Although the neurohypophyseal hormones vasopressin (VP) and oxytocin (OT) are mostly known for their role respectively in antidiuresis, and in labour, lactation and maternal behavior, both might exert widespread influences either on emotion and cognition in healthy subjects, showing some gender-related differences. They interact with each other facilitating shifts between positive socially- oriented and defensive states. In fact, VP amplifies the reactivity to stressors showing also beneficial effects on attention, verbal learning as well as memory, whereas OT reduces the amplitude of the stress response, improves emotion processing, and can play a negative effect on memory and verbal learning in healthy individuals. Several data indicate the possible involvement of these neuropeptides in the pathophysiology of psychiatric conditions involving social interactions, such as autism, as well as in schizophrenia and depression. The aim of this paper is to review the literature relating to the role played by neurohypophyseal hormones in neuropsychiatric disorders. Methods: We analyzed the best of published literature dealing with the relationships between neurohypophyseal hormones and neuropsychiatric conditions like autism (AD), major depressive disorder (MDD), bipolar disorder (BD) and schozophrenia, identifying keywords and MeSH terms in Pubmed and then searching them. The last search was performed on December 2017. Results: Several studies indicate a role played by OT and VP in AD, schizophrenia, MDD and BD. Even if conflicting data have been reported, several mechanisms may be involved in these behavioral diseases, such as differences in aminoacid sequence and peptide biological activity, neurotransmission and genetic disorders involving OT and VP receptors. Conclusion: The involvment of VP and OT in neurpopsychiatric disorders can support a possible beneficial therapy with OT or with VP antagonists. The target may be obtained using effective drug delivery methods as well as the association with other drugs.

Objective: To compare the relation symptom severity and testosterone levels, and DHEA-S and cortisol in premenopausal women with schizophrenia and an age- and sex-matched control group. Methods: Thirty-two women with schizophrenia and 32 age- and sex-matched healthy controls were included in the study. All participants were aged between 20 and 45 years, and their previous treatments were olanzapine (n=14) and quetiapine (n=18). Symptom severity was assessed using the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS). A chemiluminescence immunoassay was used to investigate hormone profiles of the two groups, which were then compared and analyzed. The relation between the hormone levels and SANS and SAPS scores of the study group and controls was examined. Results: There were statistically significantly higher levels of serum DHEA-S (p=0.002) in the study group than in the control group. No statistically significant difference was determined between the groups regarding serum testosterone and cortisol levels. A positive correlation was determined between the study groups’ SANS scores and DHEA-S levels (p=0.012, r=0.440). Conclusion: DHEA-S might be a potential biologic marker for schizophrenia because there is evidence of an association between DHEA-S and the pathophysiology of schizophrenia. However, further research with greater patient numbers is required to verify these findings.

Introduction: Delirium is common in geriatric patients admitted to nursing homes, with an incidence of 22-79% among long-term residents. Aim: To establish a predictive model of the risk of delirium episodes in a sample of elderly people living in nursing homes. Material and Methods: A retrospective, cross-sectional case-control study covering a period of 12 consecutive months (April 2014 – March 2015) was carried out. The included cases had suffered at least one episode of delirium during the study period. Sociodemographic and clinical variables as well as risk factors predisposing to or triggering episodes of delirium were recorded. Results: A total of 193 cases and 123 controls were recruited. The mean age of the cases was 89.6 years (SD 6.9), and 75.1% were women. The mean age of the controls was 84.7 years (SD 7.42), and 75.6% were women. The prevalence of delirium was 60.7%. The presence of infections (with the exception of urinary tract infections) was the variable offering the best predictive capacity (OR=7.08; 95% CI: 3.30-15.02; p<0.001). Other predictors of delirium were also identified, such as a previous diagnosis of dementia (OR=3.14; 95% CI: 1.81-5.45; p<0.001), the use of anticholinergic drugs (OR=2.98; 95% CI: 1.34-6.60; p=0.007), a diagnosis of depression (OR=1.92; 95% CI: 1.03-3.56; p=0.039), and urinary incontinence (OR=1.73; 95% CI: 0.97-3.08; p=0.065). The area under the curve (AUC) was 0.794 (95% CI: 0.74-0.84; p<0.001). Conclusions: The prevalence of delirium among elderly subjects admitted to nursing homes was 60.7%. Infections (with the exception of urinary tract infections), dementia, anticholinergic drug use, depression and urinary incontinence were predictive of the presence of delirium.

Background: Severe pain reduces quality of life of patients with various diseases, often because chronic morphine therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing adverse effects. Nitric oxide (NO) plays a role in morphine tolerance and dependence. Objective: Venlafaxine, an antidepressant, is known to modulate nitric oxide (NO) pathway in nervous tissues. In the present study, the effect of systemic venlafaxine (VLF) on the development of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the L-arginine/NO/cGMP pathway in these effects were investigated in mice. Methods: Animals developed tolerance to the antinociceptive effect of morphine (50 mg/kg, s.c. daily) for 3 consecutive days. NO modulators like L-NAME (NO synthase inhibitor) and L-Arginine (L-Arg, substrate for NO synthase), sildenafil (cGMP-PDE inhibitor) alone or in combination with venlafaxine were used. Results: The results showed that i.p. administration of VLF (5-40 mg/kg) produced antinociceptive effect in a dose-dependent way. Pretreatment with L-Arg (200 mg/kg, i.p.) reversed the antinociception and L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.) potentiated the antinociceptive effect. Moreover, co-administration of VLF in non-effective dose (5 mg/kg) with morphine, potentiated acute morphine-induced analgesia (5 mg/kg, s.c.). This effect was antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.). On the other hand, VLF was prevented the development of morphine antinociceptive tolerance and dependence. These effects were antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.). Conclusion: Our data suggest that the combination of VLF with morphine may be a relevant therapeutic implication to manage pain even when tolerance to morphine exists. Moreover, our data demonstrates the involvement of L-Arg/NO/cGMP pathway in the prevention of morphine tolerance and dependence by venlafaxine.

Background: Depression represents one of the most common disorders in diabetic patients and frequently complicates the health care of this population. Poor self-efficacy has been associated with increased depressive symptoms as well as poor glycemic control. Objective: To assess depression and self-efficacy in adults with type 2 diabetes in Northern Greece and to explore the factors which may affect them in this group of population. Method: A descriptive study was conducted in a tertiary hospital in the largest city of Northern Greece. The study group included a convenience sample of 170 adults with type 2 diabetes mellitus who completed the General Health Questionnaire-28 (GHQ-28) and the Diabetes Empowerment Scale- short form (DES) questionnaire. Results: The overall rate of diabetic patients showing psychological distress in the present study was 50.6%. Adults with low and moderate income experienced higher levels of depression and anxiety, compared to those with high economical status (p<0,001). Also, adults who graduated elementary education experienced higher levels of depressive and anxiety symptoms than those with a higher educational level (p =0,038). There was a statistically significant difference between age (p<0.001), type of residence (p=0.019), family status (p=0,002), financial status (p<0.001) and self-efficacy. Also, there was a negative correlation between BMI and self-efficacy (r=-0.206, p<0.001) and a negative correlation between depression and self-efficacy scale (r=-0.439, p<0.001). Conclusion: The results of the present study highlight the importance of well-planned interventions in order to reduce depression and increase self-efficacy in diabetic adults and to help them further improve their quality of life.

Background: People with schizophrenia and other severe mental disorders have an increased mortality mainly attributed to natural causes, specifically cardiovascular disease and cancer. The metabolic syndrome and the Framingham Risk Score are epidemiologic tools related to long-term cardiovascular disease risk and they are increased in people with severe mental disorders. This increase has been attributed both to the disorder itself and to the use of antipsychotic drugs. Objective: To quantify the cardiovascular risk in a group of people treated with long-acting injectable antipsychotics. Methods: This is a cross-sectional study developed in an outpatient mental health clinic in which the prevalence of metabolic syndrome was estimated and the cardiovascular risk was measured using the Framingham Risk Score. All the analyses were separated by gender. Results: 130 people (81 men) were recruited. According to the International Diabetes Federation criteria, 60 participants (46,2%) had metabolic syndrome. The individual criterion most often met in both genders was obesity. The mean Framingham Risk Score for the sample was moderate, 7,7 (SD: 6,3). For women, the risk was lower (mean 5,7, SD: 4,9) than for men (mean=9, SD: 6,7). There were no significant differences in the prevalence of metabolic syndrome and Framingham Risk Scores by longacting injectable antipsychotic or years of treatment. Conclusion: The prevalence of metabolic syndrome and the cardiovascular risk are high in people with psychosis treated with long acting injectable antipsychotics. To better address this vulnerability, the recommendations involve both behavioral and pharmacological interventions.

Background and Objective: Goldenhar syndrome (ocular-auricular-vertebral syndrome), a rare congenital condition arising from defects in the first and second brachial arches, consists in clinical variety of features ranging from facial abnormalities, ear-eye abnormalities, vertebral defects and congenital heart problems and severe obstructive sleep apnea. Due to craniofacial abnormalities, patients presents mechanical obstructive phenomena and sialorrhea that cause prone position, language’s fastening, use of nasopharyngeal cannulas and tracheal intubation. Methods: In this article, we report a case of a 16 years old child affected by Goldenhar syndrome and sialorrhea to demonstrate improvement of the daily patient management, through inoculations of botulinum toxin type A. Due to severe sialorrhea which caused tracheobronchial daily aspirations, the caregivers used an external aspirators. Results: In the first infiltration (August 2016) the parotid and submandibular glands bilaterally were inoculated with incobotulinum toxin type A (Xeomin®, Merz Pharma) with dosages of 5 UI for each of them, for a total of 20 UI without clinical efficacy (no quantitative and qualitative saliva reducing during 3 months). In the second (November 2016) and third (February 2017) infiltrations each parotid and each submandibular glands were injected with a (dosage of 7 UI and 5 UI respectively (total of 24 UI of incobotulinumtoxin A) with important clinical results (saliva production and tracheo-bronchial aspirations reduced). Conclusion: Therefore, botulinum toxin type A could be a good and non invasive treatment of sialorrhea in Goldenhar syndrome to improve oral hygiene and daily patient management.

Background and Objective: Patients with Klinefelter Syndrome (KS) have increased cardiometabolic risk however the pathogenesis is not clear. We investigated the presence of endothelial dysfunction, insulin resistance and inflammation in an unconfounded population of KS. Methods: A total of 32 patients with KS (mean age 21.59 ± 1.66 years) and 33 healthy control subjects (mean age: 22.15 ± 1.03 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), homeostatic model assessment of insulin resistance (HOMA-IR) index and highsensitivity C-reactive protein (hs-CRP) levels were measured. Results: The patients had higher Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), insulin, HOMA-IR and ADMA levels (p < 0.001 for all) and lower High Density Lipoprotein Cholesterol (HDL-C) and total testosterone levels (p=0.002 and p<0.001, respectively), compared to the healthy controls. Total testosterone levels were significantly negatively correlated to ADMA (r = - 0.479, p < 0,001), hs-CRP (r = -0.291, p = 0.034) and positively correlated to HDL-C (r = 0.429, p = 0.001) levels. The multivariate analysis has shown that total testosterone (β = -0.412, p = 0.001) and TG (β = 0.332, p = 0.009) levels were the significant independent determinants of the plasma ADMA levels. Conclusion: The results of the present study show that endothelial dysfunction and insulin resistance are prevalent even in the very young subjects with KS, who have no metabolic or cardiac problems at present. Also, hypogonadism seems to play an important role for increased cardiometabolic risk in patients with KS.

Introduction: In obese patients, the incidences of several thyroid disorders have increased in comparison to the general population. This study is aimed to investigate the effect of laparoscopic sleeve gastrectomy (LSG) on thyroid function tests in obese patients. Methods: The patient files of 186 individuals who underwent laparoscopic sleeve gastrectomy surgery were examined retrospectively. Forty-nine females and 29 males comprising a total of 78 patients were included in the study. The routine physical examination findings and laboratory parameters recorded preoperatively were compared with their counterparts obtained in the postoperative sixth month. Results: The mean preoperative body mass index (BMI) levels of the patients in the study was calculated as 46.91 kg/m2, whereas the mean BMI in the postoperative sixth month was 30.35 kg/m2 (p<0.001). Prior to the sleeve gastrectomy, the mean thyroid stimulating hormone (TSH) level of the patients was 2.53 ±2.06 μIU/mL; however, a significant reduction was observed in the mean TSH level during the postoperative sixth month, which was calculated as 1.77 ±1.12 μIU/mL (p=0.015). The mean free T4 level was 1.18±0.1 ng/dL in the preoperative period, but this increased to 1.22 ±0.24 ng/dL postoperatively, an insignificant change. The decrease in the TSH levels after the LSG was determined not to be correlated with the decrease in body weight. Conclusion: The results of our study demonstrate that the levels of TSH decreased significantly in patients who underwent LSG and that the decrease was independent of the changes in BMI.

Background: Previous studies have demonstrated that flagellin, a component of bacterial flagella, engages Toll-Like receptor 5 (TLR-5) causing the activation of the Myeloid Differentiation Factor-88 (MYD-88) pathway that leads to the production of pro-inflammatory cytokines including Tumor Necrosis Factor–alpha (TNF-α) and Interleukin-12 (IL-12). In physiological levels, cytokines can aid in protection against infectious agents. However, excessive production of cytokines can lead to septic shock during sepsis. Objective: In this study, we aimed at investigating the effect of denatured flagellin on hindering the effects induced by intact flagellin or flagellated Pseudomonas aeruginosa on the Toll-Like Receptor-5 (TLR-5) in mice. Methods: Mouse mononuclear cells (MNCs) were cultured with intact flagellin, heat-denatured flagellin, TLR-5 antagonist, Pseudomonas aeruginosa, and TLR-4 antagonist each alone or in combinations. Supernatants were collected at 4 hours post incubation to assess the levels of IL-12 and TNF-α by Enzyme-Linked ImmunoAssay (ELISA). Furthermore, groups of BALB/c mice were injected intraperitoneally (IP) with Pseudomonas aeruginosa, LPS-RS, intact flagellin, and denatured flagellin, each alone or in different combinations. Serum levels of IL-12 and TNF-α were measured at 2, 4, and 6 hours post injections of Pseudomonas aeruginosa or intact flagellin. Results: Pretreatment with denatured flagellin significantly reduced the amount of TNF-α and IL-12 produced both in vitro and in vivo by intact flagellin or Pseudomonas aeruginosa. Conclusion: Denatured flagellin suppressed the production of the pro-inflammatory cytokines induced by intact flagellin or Pseudomonas aeruginosa both in vitro and in vivo, probably by blocking TLR5. Denatured flagellin might be considered as an anti-septic shock agent.