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Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on‐ (targeting 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase [HMGCR]) and off‐target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb‐b2 receptor tyrosine kinase 2 (HER2) and MET proto‐oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto‐oncogene, non‐receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator‐activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off‐target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off‐target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer. [ABSTRACT FROM AUTHOR]

Aim: Liver‐expressed antimicrobial peptide 2 (LEAP2) dynamics in human plasma and its association with feeding behaviour remain poorly understood. Therefore, this study aims: (a) to investigate fasting LEAP2 in participants with normal weight or with overweight or mild obesity (OW/OB); (b) to study the association between fasting LEAP2 and anthropometric and metabolic traits, feeding behaviour, LEAP2 genetic variants and blood cell DNA methylation status; and (c) to ascertain postprandial changes in LEAP2 after high protein intake and the association with feeding behaviour and food intake. Methods: Anthropometric and behavioural measures, genotyping, methylation profiling, plasma glucose and LEAP2 concentrations were assessed in 327 females and males. A subgroup of 123 participants received an ad libitum high‐protein meal, and postprandial LEAP2 concentration and behavioural measures were assessed. Results: LEAP2 concentration was higher in participants with OW/OB (p < 0.001) and in females (p < 0.001), and was associated with LEAP2 single nucleotide polymorphisms rs765760 (p = 0.012) and rs803223 (p = 0.019), but not with LEAP2 methylation status. LEAP2 concentration was directly related to glycaemia (p = 0.001) and fullness (p = 0.003) in participants with normal weight, whereas it was associated with body mass index (p = 0.018), waist circumference (p = 0.014) and motor impulsivity in participants with OW/OB (p = 0.005). A negative association with reward responsiveness was observed in participants with OW/OB (p = 0.023). LEAP2 concentration was inversely associated with food intake (p = 0.034) and decreased after a high‐protein meal (p < 0.001), particularly in women (p = 0.002). Conclusion: Increased LEAP2 in participants with OW/OB is associated with behavioural characteristics of obesity. Our results show sexual dimorphism in LEAP2 concentration before and after food intake and highlight the role of LEAP2 in feeding regulation. [ABSTRACT FROM AUTHOR]

Aim: To test the hypothesis that liver‐expressed antimicrobial peptide 2 (LEAP2) genetic variants might influence the susceptibility to human obesity. Methods: Using data from the UK Biobank, we identified independent LEAP2 gene single nucleotide polymorphisms (SNPs) and examined their associations with obesity traits and serum insulin‐like growth factor‐1 (IGF‐1) concentration. These associations were evaluated for both individual SNPs and after combining them into a genetic risk score (GRSLEAP2) using linear and logistic regression models. Sex‐stratified analyses were also conducted. Results: Five SNPs showed positive associations with obesity‐related traits. rs57880964 was associated with body mass index (BMI) and waist‐to‐hip ratio adjusted for BMI (WHRadjBMI), in the total population and among women. Four independent SNPs were positively associated with higher serum IGF‐1 concentrations in both men and women. GRSLEAP2 was associated with BMI and WHRadjBMI only in women and with serum IGF‐1 concentration in both sexes. Conclusions: These findings reveal sex‐specific associations between key LEAP2 gene variants and several obesity traits, while also indicating a strong independent association of LEAP2 variants with serum IGF‐1 concentration. [ABSTRACT FROM AUTHOR]

Background and Purpose: Statins are competitive inhibitors of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen‐induced Hmgcr‐knockout (KO) mouse model, a multi‐omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways. Experimental Approach: We established a new mouse strain using the Cre/loxP system, which enabled whole‐body deletion of Hmgcr expression. These mice were crossed with Rosa26Cre mice and treated with tamoxifen to delete Hmgcr in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time‐dependent changes in metabolic functions to identify the pathways leading to cell death in Hmgcr‐KO mice. Key Results: Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid β‐oxidation and very high accumulation of long‐chain (LC) acylcarnitines in both male and female mice. Gene expression and KO‐related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole‐body hypoglycaemia. Conclusion and Implications: Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial β‐oxidation. Moreover, statin‐induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation. [ABSTRACT FROM AUTHOR]

Background: Trigeminal neuralgia (TN) is a severe facial pain condition often associated with a neurovascular conflict. However, neuroinflammation has also been implicated in TN, as it frequently co‐occurs with multiple sclerosis (MS). Methods: We analysed protein expression levels of TN patients compared to MS patients and controls. Proximity Extension Assay technology was used to analyse the levels of 92 proteins with the Multiplex Neuro‐Exploratory panel provided by SciLifeLab, Uppsala, Sweden. Serum and CSF samples were collected from TN patients before (n = 33 and n = 27, respectively) and after (n = 28 and n = 8, respectively) microvascular decompression surgery. Additionally, we included samples from MS patients (n = 20) and controls (n = 20) for comparison. Results: In both serum and CSF, several proteins were found increased in TN patients compared to either MS patients, controls, or both, including EIF4B, PTPN1, EREG, TBCB, PMVK, FKBP5, CD63, CRADD, BST2, CD302, CRIP2, CCL27, PPP3R1, WWP2, KLB, PLA2G10, TDGF1, SMOC1, RBKS, LTBP3, CLSTN1, NXPH1, SFRP1, HMOX2, and GGT5. The overall expression of the 92 proteins in postoperative TN samples seems to shift towards the levels of MS patients and controls in both serum and CSF, as compared to preoperative samples. Interestingly, there was no difference in protein levels between MS patients and controls. Conclusions: We conclude that TN patients showed increased serum and CSF levels of specific proteins and that successful surgery normalizes these protein levels, highlighting its potential as an effective treatment. However, the similarity between MS and controls challenges the idea of shared pathophysiology with TN, suggesting distinct underlying mechanisms in these conditions. Significance: This study advances our understanding of trigeminal neuralgia (TN) and its association with multiple sclerosis (MS). By analysing 92 protein biomarkers, we identified distinctive molecular profiles in TN patients, shedding light on potential pathophysiological mechanisms. The observation that successful surgery normalizes many protein levels suggests a promising avenue for TN treatment. Furthermore, the contrasting protein patterns between TN and MS challenge prevailing assumptions of similarity between the two conditions and point to distinct pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Individuals with autism spectrum disorder (ASD) tend to experience lower well‐being as demonstrated mostly for children and adolescents in epidemiological studies. A further investigation of inclusive well‐being, in terms of five well‐being spectrum (5‐WBS) traits including neuroticism, depression, loneliness, life satisfaction, and positive affect, among adults with ASD may deepen our understanding of their well‐being, and lead to the possibility to further modify societal supportive mechanisms for individuals with ASD. This study aims to investigate if a genetic predisposition for ASD is associated with 5‐WBS traits using polygenic risk score (PRS) analysis. PRS for ASD were calculated based on the latest genome‐wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and were created in the independent cohort UK Biobank. Regression analyses were performed to investigate the association between ASD PRS and 5‐WBS traits in the UK Biobank population including 337,423 individuals. ASD PRS were significantly associated with all 5‐WBS traits, showing a positive association with the negative WBS traits, neuroticism (max R2 = 0.04%, p < 1 × 10−4), depression (max R2 = 0.06%, p < 1 × 10−4), loneliness (max R2 = 0.04%, p < 1 × 10−4), and a negative association with the positive WBS traits, life satisfaction (max R2 = 0.08%, p < 1 × 10−4), positive affect (max R2 = 0.10%, p < 1 × 10−4). The findings suggest that adults carrying a high load of risk single nucleotide peptides (SNPs) for ASD are more likely to report decreased well‐being. The study demonstrates a considerable connection between susceptibility to ASD, its underlying genetic etiology and well‐being. Lay Summary: Social studies have shown that individuals with autism spectrum disorder (ASD) often exhibit a neurotic or negative type of personality, and are more depressed, lonelier, less happy, and less satisfied in life compared with individuals without ASD. The inclusive well‐being of an individual is reflected by the five trait well‐being spectrum, which includes negative well‐being traits like neuroticism, depression, and loneliness, and positive well‐being traits like life satisfaction and positive affect. Of note, an investigation of the inclusive well‐being of individuals with ASD, taking the traits of the well‐being spectrum into account has not yet been performed. Furthermore, research regarding aspects of well‐being in ASD hitherto focused on children and adolescents with ASD, while studies on the well‐being of adults with ASD are limited in number and underpowered in sample size. Recent study results suggest that genetics influences the well‐being of individuals. While ASD is highly heritable, the genetic context of the well‐being of individuals with ASD is still unknown. Based on available knowledge of genome‐wide detected genetic variants associated with ASD, we constructed polygenic risk scores for ASD and explored to what extent the additive genetic risk for ASD is associated with well‐being based on a large population‐based dataset from the United Kingdom. We demonstrate that individuals, who are genetically predisposed to ASD are prone to experience poor well‐being, as reflected by higher negative and lower positive well‐being trait scores compared with individuals with a low genetic risk load for ASD. The findings of this study highlight well‐being as an important health‐related factor, which appears to be considerably linked to genetic susceptibility for ASD. [ABSTRACT FROM AUTHOR]

4‐Methylbenzylidene camphor (4‐MBC) is a photo‐absorbing UV filter prevalently used in cosmetics, which can be absorbed into circulation and cause systemic effects. 4‐MBC is continued to be released in the environment despite the growing knowledge about its bioaccumulation and endocrine disrupting effects. Previous reviews have mentioned UV‐filter together but this review considers 4‐MBC alone, due to its prevalence and concerning health effects. This review considers 4‐MBC's potential effects on human health regarding systemic and molecular effects, with the main focus on reproduction. Also, the potential bioaccumulation and interactions with receptor systems such as the oestrogen receptors β and α, and progesterone receptor are covered. Additionally, previous studies about 4‐MBC's effects on mRNA and protein expression, especially in the prostate and the brain are analysed. Furthermore, 4‐MBC is reported to act with inflammatory pathways by activating p38 MAPK and NF‐κB, leading to the production of inflammatory TNF‐α and IL‐6. 4‐MBC was also found to induce apoptosis and inhibit cell proliferation and DNA repair. In conclusion, 4‐MBC has wide‐ranging effects in many different models interacting with multiple pathways causing long‐term effects even at low doses and this knowledge can guide governmental risk assessment, regulation divisions and chemical industries. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the putative causal link between neuroticism (using three genetically distinct subclusters namely depressed affect, worry, and sensitivity to environmental stress and adversity [SESA]) and cardiovascular disease (CVD). Method: A two‐sample bi‐directional Mendelian randomization (MR) approach was used. Genetic instruments were extracted from publically available GWAS summary statistics. Results: In forward MR analyses with neuroticism subclusters as exposures, no causal associations between worry or SESA cluster and any of the CVD traits were observed (p >.05 for all). However, a higher risk of having heart failure (odds ratio (95% confidence interval):1.32(1.12 to 1.56); p =.0011) and myocardial infarction (1.47[1.18 to 1.83]; p = 6.3 × 10‐4) associated with depressed affect cluster was observed. In reverse MR analyses with CVD traits as exposures, no significant associations were observed (p >.05 for all). Conclusions: Individuals with high neuroticism who are more susceptible to depressive symptoms are at higher risk for developing heart failure and myocardial infarction and should be more carefully evaluated for CVD risk in clinical settings. These individuals can potentially benefit from interventions aimed at reducing depressive symptoms to decrease CVD risk. There is no evidence to suggest that being sensitive to environmental stressors or being more worried can increase the risk for CVD. [ABSTRACT FROM AUTHOR]

Recent studies have reported that Fusobacterium nucleatum (Fn) is associated with gastric cancer (GC). Cancer‐derived exosomes contain key regulatory noncoding RNAs and are a crucial medium of intercellular communication. However, the function and regulatory mechanism of exosomes (Fn‐GCEx) secreted from Fn‐infected GC cells remains unclear. In this study, Fn‐GCEx enhanced the proliferation, migration, and invasion capacity of GC cells in vitro, as well as tumor growth and metastasis in vivo. HOTTIP was also upregulated in GC cells treated with Fn‐GCEx. Moreover, knockdown of HOTTIP weakened the effects of Fn‐GCEx in recipient GC cells. Mechanistically, HOTTIP promoted EphB2 expression by sponging microRNA (miR)‐885‐3p, thus activating the PI3K/AKT pathway in Fn‐GCEx treated GC cells. Overall, Fn infection induced the upregulation of exosomal HOTTIP from GC cells that subsequently promoted GC progression through the miR‐885‐3p/EphB2/PI3K/AKT axis. Herein, we identify a potential molecular pathway and therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Every day, we are exposed to many environmental pollutants that can enter our body through different routes and cause adverse effects on our health. Epidemiological studies suggest that these pollutants are responsible for approximately nine million deaths per year. Acute lymphoblastic leukemia (ALL) represents one of the major cancers affecting children, and although substantial progress has been made in its treatment, relapses are frequent after initial treatment and are now one of the leading causes of cancer‐related death in pediatric patients. Currently, relatively little attention is paid to pollutant exposure during drug treatment and this is not taken into account for dose setting or regulatory purposes. In this work, we investigated how bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE), and perfluorooctanoic acid (PFOA) alter vincristine treatment in ALL when administered before or together with the drug. We found that these three pollutants at nanomolar concentrations, lower than those established by current regulations, can reduce the cytotoxic effects of vincristine on ALL cells. Interestingly, we found that this is only achieved when exposure to pollutants occurs prior to administration of the chemotherapeutic drug. Moreover, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. This work strengthens the idea of starting to take into account exposure to pollutants to improve the efficacy of chemotherapy treatments. Every day we are exposed to many environmental pollutants that can enter our body and cause adverse effects on our health. In this study, we found that 24‐h pre‐exposure to bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE) or perfluorooctanoic acid (PFOA), at nanomolar concentrations, can reduce the cytotoxic effects of vincristine in acute lymphoblastic leukemia (ALL) cells. Furthermore, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. [ABSTRACT FROM AUTHOR]

There is a growing interest in the psychiatric properties of the dissociative anaesthetic ketamine, as single doses have been shown to have fast‐acting mood‐enhancing and anxiolytic effects, which persist for up to a week after the main psychoactive symptoms have diminished. Therefore, ketamine poses potential beneficial effects in patients with refractory anxiety disorders, where other conventional anxiolytics have been ineffective. Ketamine is a noncompetitive antagonist of the N‐methyl‐d‐aspartate (NMDA) glutamate receptor, which underlies its induction of pain relief and anaesthesia. However, the role of NMDA receptors in anxiety reduction is still relatively unknown. To fill this paucity in the literature, this systematic review assesses the evidence that ketamine significantly reduces refractory anxiety and discusses to what extent this may be mediated by NMDA receptor antagonism and other receptors. We highlight the temporary nature of the anxiolytic effects and discuss the high discrepancy among the study designs regarding many fundamental factors such as administration routes, complementary treatments and other treatments. [ABSTRACT FROM AUTHOR]

A growing number of studies report dermal malignancies mimicking diabetic foot ulcers (DFUs). We reviewed clinical cases reporting malignant tumours misdiagnosed to be DFU aiming to identify factors contributing to misdiagnosis. We systematically searched in PubMed for clinical cases reporting on misdiagnosis of DFU in patients with cancer. A chi‐square analysis was conducted to show the link between the incidence of initial DFU misdiagnosis and patient age, gender and wound duration. Lesions misdiagnosed to be DFU were subsequently diagnosed as melanoma (68% of the cases), Kaposi's sarcoma (14%), squamous cell carcinoma (11%), mantle cell lymphoma, and diffuse B‐cell lymphoma (both by 4%). Older age (≥65 years) was associated with a significantly increased risk of malignancy masked as DFU (OR: 2.452; 95% CI: 1.132 to 5.312; P value =.019). The risk of such suspicion in older patients (age ≥ 65 years) was 145% higher than in younger patients (age < 65 years). Clinicians should maintain a high level of awareness towards potentially malignant foot lesions in elderly patients with diabetes (age ≥ 65). [ABSTRACT FROM AUTHOR]

There is a growing awareness that the large number of environmental pollutants we are exposed to on a daily basis are causing major health problems. Compared to traditional studies that focus on individual pollutants, there are relatively few studies on how pollutants mixtures interact. Several studies have reported a relationship between environmental pollutants and the development of cancer, even when pollutant levels are below toxicity reference values. The possibility of synergistic interactions between different pollutants could explain how even low concentrations can cause major health problems. These intricate that molecular interactions can occur through a wide variety of mechanisms, and our understanding of the physiological effects of mixtures is still limited. The purpose of this paper is to discuss recent reports that address possible synergistic interactions between different types of environmental pollutants that could promote cancer development. Our literature studies suggest that key biological pathways are frequently implicated in such processes. These include increased production of reactive oxygen species, activation by cytochrome P450, and aryl hydrocarbon receptor signaling, among others. We discuss the need to understand individual pathological vulnerability not only in relation to basic genetics and gene expression, but also in terms of measurable exposure to contaminants. We also mention the need for significant improvements in future studies using a multitude of disciplines, such as the development of high‐throughput study models, better tools for quantifying pollutants in cancer patients, innovative pharmacological and toxicological studies, and high‐efficiency computer analysis, which allow us to analyze the molecular mechanisms of mixtures. Plain Language Summary: In general, every day we are exposed to many pollutants at the same time, and each pollutant can interact with others in different ways. Notably, two or more pollutants can interact and enhance their effects through a phenomenon called synergy and this would explain why, even at low concentrations, pollutants can have important health effects. Several studies have reported a link between environmental pollutants and cancer. Thus, our review of the literature suggests that synergy phenomena between pollutants can alter key points in cells and facilitate cancer development. Similarly, we mention the complications and needs to assess these complex interactions in subsequent studies. Key Points: There are an increasing number of reports on the synergetic actions of pollutants in cancerMixtures of pollutants can interact (synergy/antagonism) affecting different biological pathwaysKey pathways frequently implicated in synergetic action are reactive oxygen species, cytochrome P450, and aryl hydrocarbon receptor [ABSTRACT FROM AUTHOR]

The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC‐inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non‐oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA‐approved agents; however, it often results in increased treatment‐related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising. [ABSTRACT FROM AUTHOR]

Migraine is the sixth most prevalent disease globally, a major cause of disability, and it imposes an enormous personal and socio‐economic burden. Migraine treatment is often limited by insufficient therapy response, leading to the need for individually adjusted treatment. In this review, we analyse historical and current pharmaceutical development approaches in acute and chronic migraine based on a comprehensive and systematic analysis of Food and Drug Administration (FDA)‐approved drugs and those under investigation. The development of migraine therapeutics has significantly intensified during the last 3 years, as shown by our analysis of the trends of drug development between 1970 and 2020. The spectrum of drug targets has expanded considerably, which has been accompanied by an increase in the number of specialised clinical trials. This review highlights the mechanistic implications of FDA‐approved and currently investigated drugs and discusses current and future therapeutic options based on identified drug classes of interest. [ABSTRACT FROM AUTHOR]

The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population‐based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES‐D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES‐D score, occurrence of a major depressive episode (MDE) during follow‐up and regular antidepressant treatment during the 6 months preceding follow‐up assessment as outcomes. The GRS was associated with MDE occurrence (p =.02) and ln CES‐D score (p =.001). The HTR1A rs878567 variant was associated with ln CES‐D after adjustment for demographic and clinical variables [p =.02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six‐fold higher likelihood of regular AD therapy at follow‐up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p =.03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs. [ABSTRACT FROM AUTHOR]

Objective: Patients with atypical anorexia nervosa (AN) are often in the normal‐weight range at presentation; however, signs of starvation and medical instability are not rare. White matter (WM) microstructural correlates of atypical AN have not yet been investigated, leaving an important gap in our knowledge regarding the neural pathogenesis of this disorder. Method: We investigated WM microstructural integrity in 25 drug‐naïve adolescent patients with atypical AN and 25 healthy controls, using diffusion tensor imaging (DTI) with a tract‐based spatial statistics (TBSS) approach. Psychological variables related to the eating disorder and depressive symptoms were also evaluated by administering the eating disorder examination questionnaire (EDE‐Q) and the Montgomery–Åsberg depression rating scale (MADRS‐S) respectively, to all participants. Results: Patients and controls were in the normal‐weight range and did not differ from the body mass index standard deviations for their age. No between groups difference in WM microstructure could be detected. Discussion: Our findings support the hypothesis that brain structural alterations may not be associated to early‐stage atypical AN. These findings also suggest that previous observations of alterations in WM microstructure in full syndrome AN may constitute state‐related consequences of severe weight loss. Whether the preservation of WM structure is a pathogenetically discriminant feature of atypical AN or only an effect of a less severe nutritional disturbance, will have to be verified by future studies on larger samples, possibly directly comparing AN and atypical AN. [ABSTRACT FROM AUTHOR]

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Abstract: The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq‐related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC‐1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time. [ABSTRACT FROM AUTHOR]

Objective Patients with atypical anorexia nervosa (AN) have many features overlapping with AN in terms of genetic risk, age of onset, psychopathology and prognosis of outcome, although the weight loss may not be a core factor. While brain structural alterations have been reported in AN, there are currently no data regarding atypical AN patients. Method We investigated brain structure through a voxel-based morphometry analysis in 22 adolescent females newly-diagnosed with atypical AN, and 38 age- and sex-matched healthy controls (HC). ED-related psychopathology, impulsiveness and obsessive-compulsive traits were assessed with the Eating Disorder Examination Questionnaire (EDE-Q), Barratt Impulsiveness Scale (BIS-11) and Obsessive-compulsive Inventory Revised (OCI-R), respectively. Body mass index (BMI) was also calculated. Results Patients and HC differed significantly on BMI ( p < .002), EDE-Q total score ( p < .000) and OCI-R total score ( p < .000). No differences could be detected in grey matter (GM) regional volume between groups. Discussion The ED-related cognitions in atypical AN patients would suggest that atypical AN and AN could be part of the same spectrum of restrictive-ED. However, contrary to previous reports in AN, our atypical AN patients did not show any GM volume reduction. The different degree of weight loss might play a role in determining such discrepancy. Alternatively, the preservation of GM volume might indeed differentiate atypical AN from AN. [ABSTRACT FROM AUTHOR]

Background: The interplay of genetic and environmental factors can trigger a cascade of neuropathological changes leading to individual differences in brain aging. The apparent age of the brain (brain age) can differ from chronological age, potentially reflecting different resilience mechanisms. Brain age has also the potential as biomarker to predict future cognitive impairments and dementia. In this study, we developed a biological measure of brain age, based on the differences between predicted brain age (PBA) and chronological age (CA) using deep learning model (DLM). Method: The sample included 16734 T1‐w MRI from multiple time‐points of 15115 healthy individuals, aged 32‐96 yrs., from: 1) ADNI (n = 1489); 2) AIBL (n = 957); GENIC (n = 406); 4) UK Biobank (n = 13882). Healthy status was defined as absence of dementia/cognitive impairment, neuro‐psychiatric disorders, and/or self‐report of good health. Medical diagnoses were collected through physician‐/self‐reports or medical records following the International Classification of Diseases. A DLM based on convolutional neural networks was trained to develop an algorithm to predict brain age from raw MRI images registered to the MNI space using training (90%) and hold‐out test (10%) sets. To assess the model generalizability, we applied the algorithm in the Gothenburg H70‐Birth Cohort 1944 (n = 792 septuagenarians). Result: The hold‐out method achieved a mean absolute error (MAE) error, between PBA and CA, of 3.04 yrs. In the H70 cohort the mean PBA was 73.9±1.49 [64.7‐86.1] years. Conclusion: The model shows accurate predictions, comparable with those from previous studies using other computation methods. As next steps, we will evaluate hyperparameter optimization and implementation of a cross‐validation methodology. We also seek to include further cohorts of healthy individuals with heterogeneous age‐span to increase the model reliability and generalizability. This will enable to address e.g., differences between normal and pathological aging as well as exploring resilience mechanisms. [ABSTRACT FROM AUTHOR]

Past studies utilizing resting-state functional MRI (rsf MRI), have shown that obese humans exhibit altered activity in brain areas related to reward compared to normal-weight controls. However, to what extent bariatric surgery-induced weight loss alters resting-state brain activity in obese humans is less well-studied. Thus, we measured the fractional amplitude of low-frequency fluctuations from eyes-closed, rsf MRI in obese females ( n = 11, mean age = 42 years, mean BMI = 41 kg/m2) in both a pre- and postprandial state at two time points: four weeks before, and four weeks after bariatric surgery. Several brain areas showed altered resting-state activity following bariatric surgery, including the putamen, insula, cingulate, thalamus and frontal regions. Activity augmented by surgery was also dependent on prandial state. For example, in the fasted state, activity in the middle frontal and pre- and postcentral gyri was found to be decreased after surgery. In the sated state, activity within the insula was increased before, but not after surgery. Collectively, our results suggest that resting-state neural functions are rapidly affected following bariatric surgery and the associated weight loss and change in diet. [ABSTRACT FROM AUTHOR]

Bis-(2-ethylhexyl) phthalate ( DEHP) is one of the most widely used plasticizers, and human beings are exposed to DEHP via polyvinyl chloride ( PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long-term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions. [ABSTRACT FROM AUTHOR]

Understanding how genetics influences obesity, brain activity and eating behaviour will add important insight for developing strategies for weight-loss treatment, as obesity may stem from different causes and as individual feeding behaviour may depend on genetic differences. To this end, we examined how an obesity risk allele for the FTO gene affects brain activity in response to food images of different caloric content via functional magnetic resonance imaging (f MRI). Thirty participants homozygous for the rs9939609 single nucleotide polymorphism were shown images of low- or high-calorie food while brain activity was measured via f MRI. In a whole-brain analysis, we found that people with the FTO risk allele genotype ( AA) had increased activity compared with the non-risk ( TT) genotype in the posterior cingulate, cuneus, precuneus and putamen. Moreover, higher body mass index in the AA genotype was associated with reduced activity to food images in areas important for emotion (cingulate cortex), but also in areas important for impulse control (frontal gyri and lentiform nucleus). Lastly, we corroborate our findings with behavioural scales for the behavioural inhibition and activation systems. Our results suggest that the two genotypes are associated with differential neural processing of food images, which may influence weight status through diminished impulse control and reward processing. [ABSTRACT FROM AUTHOR]

The present study sought to investigate whether a single night of partial sleep deprivation ( PSD) would alter fasting insulin sensitivity and cephalic phase insulin release ( CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin's anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25 h sleep) versus one night of full sleep (8.5 h sleep). In the morning following each sleep condition, subjects' oral cavities were rinsed with a 1-molar sucrose solution for 45 s, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (−3, +3, +5, +7, +10 and +20 min). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P = 0.025). In contrast, no CPIR was observed in any of the two sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. In contrast, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans. [ABSTRACT FROM AUTHOR]

Objective To study the association between self-reported sleep disturbances and dementia risk. Methods Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1–40 and 1–42 were measured at ages 70, 77, and 82 years. Results Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels. Conclusion Improving sleep quality may help reduce the neurodegenerative risk in older men. [ABSTRACT FROM AUTHOR]

In Drosophila, serotonin (5- HT) regulates aggression, mating behaviour and sleep/wake behaviour through different receptors. Currently, how these various receptors are themselves regulated is still not completely understood. The KCTD12-family of proteins, which have been shown to modify G-protein-coupled receptor ( GPCR) signalling in mammals, are one possibility of auxiliary proteins modulating 5- HT receptor signalling. The KCTD12-family was found to be remarkably conserved and present in species from C. elegans to humans. The Drosophila KCTD12 homologue Kctd12-like ( Ktl) was highly expressed in both the larval and adult CNS. By performing behavioural assays in male Drosophila, we now reveal that Ktl is required for proper male aggression and mating behaviour. Previously, it was shown that Ktl is in a complex with the Drosophila 5- HT receptor 5- HT7, and we observed that both Ktl and the 5- HT1A receptor are required in insulin-producing cells ( IPCs) for proper adult male behaviour, as well as for hyperaggressive activity induced by the mammalian 5- HT1A receptor agonist 8-hydroxy-2-dipropylaminotetralin-hydrobromide. Finally, we show that Ktl expression in the IPCs is necessary to regulate locomotion and normal sleep/wake patterns in Drosophila, but not the 5- HT1A receptor. Similar to what was observed with mammalian KCTD12-family members that interact physically with a GPCR receptor to regulate desensitization, in Drosophila Ktl may function in GPCR 5- HT receptor pathways to regulate their signalling, which is required for proper adult male behaviour. [ABSTRACT FROM AUTHOR]

Objective To investigate whether acute total sleep deprivation (TSD) leads to decreased cognitive control when food cues are presented during a task requiring active attention, by assessing the ability to cognitively inhibit prepotent responses. Methods Fourteen males participated in the study on two separate occasions in a randomized, crossover within-subject design: one night of TSD versus normal sleep (8.5 hours). Following each nighttime intervention, hunger ratings and morning fasting plasma glucose concentrations were assessed before performing a go/no-go task. Results Following TSD, participants made significantly more commission errors when they were presented 'no-go' food words in the go/no-go task, as compared with their performance following sleep (+56%; P<0.05). In contrast, response time and omission errors to 'go' non-food words did not differ between the conditions. Self-reported hunger after TSD was increased without changes in fasting plasma glucose. The increase in hunger did not correlate with the TSD-induced commission errors. Conclusions Our results suggest that TSD impairs cognitive control also in response to food stimuli in healthy young men. Whether such loss of inhibition or impulsiveness is food cue-specific as seen in obesity-thus providing a mechanism through which sleep disturbances may promote obesity development-warrants further investigation. [ABSTRACT FROM AUTHOR]

Exposure to bisphenol A ( BPA) in rodents was shown to induce obesity, yet the mechanism by which BPA might induce obesity is still unclear. We employed the genetically tractable model organism, Drosophila melanogaster, to test the effects of raising them on food containing various concentrations of BPA. Of note, raising males on food containing BPA were susceptible to starvation, possibly by inhibiting their ability to perform lipolysis during starvation, leading to significantly increased lipid content after 24 hr of fasting. Furthermore, feeding males with BPA significantly inhibited the expression of insulin-like peptides. From these results, we conclude that BPA may inhibit lipid recruitment during starvation in Drosophila. [ABSTRACT FROM AUTHOR]

Objective To investigate if acute sleep deprivation affects food purchasing choices in a mock supermarket. Design and Methods On the morning after one night of total sleep deprivation (TSD) or after one night of sleep, 14 normal-weight men were given a fixed budget (300 SEK-approximately 50 USD). They were instructed to purchase as much as they could out of a possible 40 items, including 20 high-caloric foods (>2 kcal/g) and 20 low-caloric foods (<2 kcal/g). The prices of the high-caloric foods were then varied (75%, 100% (reference price), and 125%) to determine if TSD affects the flexibility of food purchasing. Before the task, participants received a standardized breakfast, thereby minimizing the potential confound produced by hunger. In addition, morning plasma concentrations of the orexigenic hormone ghrelin were measured under fasting conditions. Results Independent of both type of food offered and price condition, sleep-deprived men purchased significantly more calories (+9%) and grams (+18%) of food than they did after one night of sleep (both P < 0.05). Morning plasma ghrelin concentrations were also higher after TSD ( P < 0.05). However, this increase did not correlate with the effects of TSD on food purchasing. Conclusions This experiment demonstrates that acute sleep loss alters food purchasing behavior in men. [ABSTRACT FROM AUTHOR]

Truncated receptor ectodomains have been described for several classes of cell surface receptors, including those that bind to growth factors, cytokines, immunoglobulins, and adhesion molecules. Soluble receptor isoforms are typically generated by proteolytic cleavage of the cell surface receptor or by alternative splicing of RNA transcripts arising from the same gene encoding the full-length receptor. Both the epidermal growth factor receptor ( EGFR) and the insulin receptor ( INSR) families produce soluble receptor splice variants in vertebrates and truncated forms of insulin receptor-like sequences have previously been described in Drosophila. The EGFR and INSR ectodomains share significant sequence homology with each other suggestive of a common evolutionary origin. We discovered novel truncated insulin receptor-like variants in several arthropod species. We carried out a phylogenetic analysis of the conserved extracellular receptor L1 and L2 subdomains in invertebrate species. Although the segregation of insulin receptor-like L1 and L2 domains indicated that an internal domain duplication had occurred only once, the generation of truncated insulin receptor-like sequences has occurred multiple times. The significance of this work is the previously unknown and widespread occurrence of truncated isoforms in arthropods, signifying that these isoforms play an important functional role, potentially related to such isoforms in mammals. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) comprise an expanded superfamily of receptors in the human genome. Adhesion class G protein-coupled receptors (adhesion-GPCRs) form the second largest class of GPCRs. Despite the abundance, size, molecular structure, and functions in facilitating cell and matrix contacts in a variety of organ systems, adhesion-GPCRs are by far the most poorly understood GPCR class. Adhesion-GPCRs possess a unique molecular structure, with extended N-termini containing various adhesion domains. In addition, many adhesion-GPCRs are autoproteolytically cleaved into an N-terminal fragment (NTF, NT, α-subunit) and C-terminal fragment (CTF, CT, β-subunit) at a conserved GPCR autoproteolysis-inducing (GAIN) domain that contains a GPCR proteolysis site (GPS). These two features distinguish adhesion-GPCRs from other GPCR classes. Though active research on adhesion-GPCRs in diverse areas, such as immunity, neuroscience, and development and tumor biology has been intensified in the recent years, the general biological and pharmacological properties of adhesion-GPCRs are not well known, and they have not yet been used for biomedical purposes. The '6th International Adhesion-GPCR Workshop,' held at the Institute of Physiology of the University of Würzburg on September 6-8, 2012, assembled a majority of the investigators currently actively pursuing research on adhesion-GPCRs, including scientists from laboratories in Europe, the United States, and Asia. The meeting featured the nascent mechanistic understanding of the molecular events driving the signal transduction of adhesion-GPCRs, novel models to evaluate their functions, and evidence for their involvement in human disease. [ABSTRACT FROM AUTHOR]

The purinergic 12 receptor (P2Y12) is a major drug target for anticoagulant therapies, but little is known about the regions involved in ligand binding and activation of this receptor. We generated four randomized P2Y12 libraries and investigated their ligand binding characteristics. P2Y12 was expressed in a Saccharomyces cerevisiae model system. Four libraries were generated with randomized amino acids at positions 181, 256, 265 and 280. Mutant variants were screened for functional activity in yeast using the natural P2Y12 ligand ADP. Activation results were investigated using quantitative structure-activity relationship (QSAR) models and ligand-receptor docking. We screened four positions in P2Y12 for functional activity by substitution with amino acids with diverse physiochemical properties. This analysis revealed that positions E181, R256 and R265 alter the functional activity of P2Y12 in a specific manner. QSAR models for E181 and R256 mutant libraries strongly supported the experimental data. All substitutions of amino acid K280 were completely inactive, highlighting the crucial role of this residue in P2Y12 function. Ligand-receptor docking revealed that K280 is likely to be a key element in the ligand-binding pocket of P2Y12. The results of this study demonstrate that positions 181, 256, 265 and 280 of P2Y12 are important for the functional integrity of the receptor. Moreover, K280 appears to be a crucial feature of the P2Y12 ligand-binding pocket. These results are important for rational design of novel antiplatelet agents. [ABSTRACT FROM AUTHOR]

The Rhodopsin family of G protein coupled receptors (GPCRs) includes the phylogenetic α-group consisting of about 100 human members. The α-group is the only group of GPCRs that has many receptors for biogenic amines which are major drug targets. Several members of this group are orphan receptors and their functions are elusive. In this study we present a detailed phylogenetic and anatomical characterization of the Gpr153 receptor and also attempt to study its functional role. We identified the homologue of Gpr153 in the elephant shark genome and phylogenetic and synteny analyses revealed that Gpr162 and Gpr153 share a common ancestor that split most likely through a duplication event before the divergence of the tetrapods and the teleost lineage. A quantitative real-time PCR study reveals widespread expression of Gpr153 in the central nervous system and all the peripheral tissues investigated. Detailed in situ hybridization on mouse brain showed specifically high expression in the thalamus, cerebellum and the arcuate nucleus. The antisense oligodeoxynucleotide knockdown of Gpr153 caused a slight reduction in food intake and the elevated plus maze test showed significant reduction in the percentage of time spent in the centre square, which points towards a probable role in decision making. This report provides the first detailed characterization of the evolution, expression and primary functional properties of the Gpr153 gene. Database [ABSTRACT FROM AUTHOR]

The beneficial effect of the ‘1-drink-a-day’ lifestyle is suggested by studies of cardiovascular health, and this recommendation is increasingly followed in many countries. The main objective of this study was to determine whether this pattern of ethanol use would be detrimental to a pregnant woman. We exposed a primary culture of rat cerebellum from embryonic day 17 (corresponding to second trimester in humans) to ethanol at a concentration of 17.6 mM which is roughly equivalent to one glass of wine. Acutely, there was no change in cell viability after 5 or 8 days of exposure relative to control. By 11 days, a reduction in the number of viable cells was observed without an accompanying change in caspase-3 activity (marker of apoptotic cell death), suggesting changes in cell proliferation. As the proportion of nestin-positive cells was higher in the ethanol-treated cultures after 5 days, we hypothesized that an increase in differentiation to neurons would compensate for the ongoing neuronal death. However, there were limits to this compensatory ability as the relative proportion of nestin-positive cells was decreased after 11 days. To further illustrate the negative long-term effects of this ethanol dose, cultures were exposed for 30 days. After this period, virtually no neurons or myelinating oligodendrocytes were present in the ethanol-treated cultures. In conclusion, chronic exposure to ethanol, even at small doses, dramatically and persistently affects normal development. [ABSTRACT FROM AUTHOR]

Elite athletes, body builders and adolescents misuse anabolic-androgenic steroids (AAS) in order to increase muscle mass or to enhance physical endurance and braveness. The high doses misused are associated with numerous adverse effects. The purpose of this study was to evaluate the impact of chronic supratherapeutic AAS treatment on circulating hormones and gene expression in peripheral tissues related to such adverse effects. Quantitative real-time PCR was used to measure expression levels of in total 37 genes (including peptide hormones, cell membrane receptors, nuclear receptors, steroid synthesising enzymes and other enzymes) in the pituitary, testes, adrenals, adipose tissue, kidneys and liver of male Sprague–Dawley rats after 14-day administration of the AAS nandrolone decanoate, 3 or 15 mg/kg. Plasma glucose and levels of adrenocorticotropic hormone (ACTH), adiponectin, corticosterone, ghrelin, insulin and leptin were also measured. We found several expected effects on the hypothalamic-pituitary-gonadal axis, while the treatment also caused a number of other not previously identified changes in circulating factors and gene transcription levels such as the dose-dependent reduction of the β3-adrenergic receptor in adipose tissue, reduction of both circulating and mRNA levels of adiponectin, up-regulation of both hydroxymethylglutaryl-CoA-reductase, the rate-limiting enzyme in de novo synthesis of cholesterol, and the receptor for ACTH in the adrenals. The results provide evidence for wide ranging effects of AAS on the hypothalamic-pituitary-adrenal axis, adipose tissue and substrates of the renal control of blood pressure. [ABSTRACT FROM AUTHOR]

Abstract: Solute carriers (SLCs) is the largest group of transporters, embracing transporters for inorganic ions, amino acids, neurotransmitters, sugars, purines and fatty acids among other substrates. We mined the finished assembly of the human genome using Hidden Markov Models (HMMs) obtaining a total of 384 unique SLC sequences. Detailed clustering and phylogenetic analysis of the entire SLC family showed that 15 of the families place into four large phylogenetic clusters with the largest containing eight SLC families, suggesting that many of the distinct families of SLCs have a common evolutionary origin. This study represents the first overall genomic roadmap of the SLCs providing large sequence sets and clarifies the phylogenetic relationships among the families of the second largest group of membrane proteins. [Copyright &y& Elsevier]

Here we present an approach for allelotyping combining the multiplexing features of the trinucleotide threading (TnT) method with pooling of genomic DNA and massively parallel pyrosequencing, enabling reliable allele frequency estimation in large cohorts. The approach offers several benefits as compared to array-based methods and allows undertaking highly complex studies without compromising accuracy, while keeping the workload to a minimum. This proof-of-concept study involves formation of trinucleotide threads, targeting a total of 147 single-nucleotide polymorphisms (SNPs) related to obesity and cancer, for multiplex amplification and allele extraction from a pool of 462 genomes, followed by massively parallel pyrosequencing. Approximately 177k reads were approved, identified, and assigned to SNP-carrying threads rendering representative allele frequencies in the cohort. Hum Mutat 29(2), 323-329, 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The Adhesion family of G protein-coupled receptors (GPCRs) includes 33 receptors and is the second largest GPCR family. Most of these proteins are still orphans and fairly little is known of their tissue distribution and evolutionary context. We report the evolutionary history of the Adhesion family protein GPR123 as well as mapping of GPR123 mRNA expression in mouse and rat using in situ hybridization and real-time PCR, respectively. GPR123 was found to be well conserved within the vertebrate lineage, especially within the transmembrane regions and in the distal part of the cytoplasmic tail, containing a potential PDZ binding domain. The real-time PCR data indicates that GPR123 is predominantly expressed in CNS. The in situ data show high expression in thalamic nuclei and regions containing large pyramidal cells like cortex layers 5 and 6 and subiculum. Moreover, we found distinct expression in amygdala, hypothalamus, inferior olive and spinal cord. The CNS specific expression, together with the high sequence conservation between the vertebrate sequences investigated, indicate that GPR123 may have an important role in the regulation of neuronal signal transduction. [ABSTRACT FROM AUTHOR]

The C-terminal tripeptide of the α-melanocyte stimulating hormone (α-MSH11-13) possesses strong antiinflammatory activity without known cellular target. In order to better understand the structural requirements for function of such motif, we designed, synthesized and tested out Trp- and Tyr-containing analogues of the α-MSH11-13. Seven α-MSH11-13 analogues were synthesized and characterized for their binding to the melanocortin receptors recombinantly expressed in insect (Sf9) cells, infected with baculovirus carrying corresponding MC receptor DNA. We also tested these analogues on B16-F1 mouse melanoma cells endogenously expressing the MC1 receptor for binding and for ability to increase cAMP levels as well as on COS-7 cells transfected with the human MC receptors. The data indicate that HS401 (Ac-Tyr-Lys-Pro-Val-NH2) and HS402 (Ac-Lys-Pro-Val-Tyr-NH2) selectively bound to the MC1 receptor and stimulated cAMP generation in a concentration dependent way while the other Tyr- and Trp-containing α-MSH11-13 analogues neither bound to MC receptors nor stimulated cAMP. We have thus identified new MC receptor binding motif derived from the C-terminal sequence of α-MSH. The tetrapeptides have novel properties as the both act via MC-ergic pathways and also carry the anti-inflammatory α-MSH11-13 message sequence. [ABSTRACT FROM AUTHOR]

Dieting as a strategy to reduce body weight often fails as it causes food cravings leading to bingeing and weight regain. Evidence from several lines of research suggests the presence of shared elements for neural regulation of food and drug craving. We quantified the expression of eight genes involved in dopamine signalling in brain regions related to the mesolimbic and nigrostriatal dopamine system in male rats subjected to chronic food restriction using quantitative real-time polymerase chain reaction. Food restriction strongly increased mRNA levels of tyrosine hydroxylase and the dopamine transporter in the ventral tegmental area. Quantitative autoradiography indicated that the dopamine transporter was also upregulated at the protein level in the shell of the nucleus accumbens. However, these effects were not observed after acute food deprivation. We suggest that the results reflect a sensitization of the mesolimbic dopamine pathway characterized by increased clearance of extracellular dopamine in the nucleus accumbens shell. Such sensitization of the mesolimbic dopamine system may be one of the underlying causes for the food cravings that interfere with dietary compliance. [ABSTRACT FROM AUTHOR]

The melanocortin (MC) receptors are found in five subtypes in mammals and chicken, while recent studies have shown that the Fugu (Takifugu rubripes) genome has only four MC receptors and the zebrafish genome has six subtypes. The MC3 receptor seems to be missing from the two closely related pufferfishes, Fugu and Tetraodon (Tetraodon nigroviridis). The MC2 and MC5 receptors in the pufferfish have introns. Moreover, these two receptors are found in a tandem that is remarkably conserved in several vertebrate species. Here, we speculate about the genomic origin of the MC receptors. [ABSTRACT FROM AUTHOR]

We performed an intensive search on sequence databases to identify orthologues of ASIP and AGRP peptides in a number of different species, revealing a number of genomic fragments coding for the C-terminal part of agouti-related motifs, different from annotated peptide sequences, including one fragment from chicken, two from zebrafish, two from Fugu (Takifugu rubripes), and three from Tetraodon (Tetraodon nigroviridis). We have thus shown for the first time that both AGRP and ASIP genes exist in many species in "lower vertebrates" and were most probably present in early stages of vertebrate evolution. [ABSTRACT FROM AUTHOR]

Searches in genomic databases for human, mouse, zebrafish, and pufferfish genes resulted in the identification of more than 180 protein predictions belonging to the glutamate family of G-protein-coupled receptors (GPCRs). Comparison of data sets from the different species showed that most of the receptor subgroups that form the glutamate family are present in both mammalian and bony fish lineage. This finding indicates that these groups share a phylogenetically ancient origin. The present study also shows that the pheromone-receptor subgroup has undergone independent expansions in three of the four species, leaving the human genome completely deprived of all pheromone receptors. [ABSTRACT FROM AUTHOR]

We have used sequence hidden Markov models to identify and classify all G-protein-coupled receptors (GPCRs) from 13 eukaryotic genomes. We found that the 5 main families found in mammals are present before the divergence of nematodes. We also found that several classes of GPCRs are not present within the vertebrate lineage, whereas they are present in several other taxa. The superfamily of GPCRs has a very dynamic gene repertoire, as evidenced by the several lineage-specific expansions of various families of GPCRs that we found. Further, the number of GPCRs has gradually increased with increased complexity of the organism. [ABSTRACT FROM AUTHOR]

Both in mammalian tissues and in transfected cells, only low levels ofa1D-adrenoceptors are detected in radioligand binding studies. It has been implicated that the comparatively long N-terminal tail of thea1D-adrenoceptor is responsible for the inefficient surface expression of the receptor.In the present study, we created gene constructs for six N-terminally truncated variants of the humana1D-adrenoceptor. These constructs were used to transfect Neuro2A cells. We show that the density ofa1D-adrenoceptors, observed by[3H]-prazosin binding, gradually increased with longer truncations of the N-terminus. This seems to indicate that the long N-terminal tail nonspecifically interferes with receptor translocation to the plasma membrane.The addition of a 16 amino acids long signal peptide to the N-terminus of the wild-typea1D-adrenoceptor increased the density of receptor binding sites 10-fold in Neuro2A and COS-7 cells. This indicates that, after the addition of a signal peptide, the long N-terminal tail of thea1D-adrenoceptor does not interfere with proper translocation of the receptor to the plasma membrane. This, in turn, indicates that the N-terminal tail of the wild-typea1D-adrenoceptor, merely by its long length, hinders the first transmembrane helix of the receptor from being a signal anchor.Neither the wild-typea1D-adrenoceptor (for which the expression level of[3H]-prazosin binding sites is low) nor the truncateda1D-adrenoceptor variant (for which the expression level of[3H]-prazosin binding sites is high) showed any constitutive activity in stimulating inositol phosphate accumulation. This indicates that the low expression level of[3H]-prazosin binding sites, after transfection with the wild-typea1D-adrenoceptor, is not caused by constitutive activity of the receptor and subsequent receptor downregulation.British Journal of Pharmacology (2005) 144, 651-659. doi:10.1038/sj.bjp.0706087 [ABSTRACT FROM AUTHOR]

Abstract: Large amounts of refined sequence material in the form of predicted, curated and annotated genes and expressed sequences tags (ESTs) have recently been added to the NCBI databases. We matched the transcript-sequences of RefSeq, Ensembl and dbEST in an attempt to provide an updated overview of how many unique human genes can be found. The results indicate that there are about 25000 unique genes in the union of RefSeq and Ensembl with 12–18% and 8–13% of the genes in each set unique to the other set, respectively. About 20% of all genes had splice variants. There are a considerable number of ESTs (2200000) that do not match the identified genes and we used an in-house pipeline to identify 22 novel genes from Genscan predictions that have considerable EST coverage. The study provides an insight into the current status of human gene catalogues and shows that considerable refinement of methods and datasets is needed to come to a conclusive gene count. [Copyright &y& Elsevier]

1 Melanocortin (MC) receptors are widely distributed throughout the body of chicken, like in mammals, and participate in a wide range of physiological functions. 2 To clarify the pharmacological impact of ligands acting in the MC system, we expressed the chicken MC1, MC2, MC3, MC4 and MC5 (cMC1–5) receptors in eukaryotic cells and performed comprehensive pharmacological characterization of the potency of endogenous and synthetic melanocortin peptides. 3 Remarkably, the cMC mentors displayed high affinity for ACTH-derived peptides and in general low affinity for α-MSH. It is evident that not only the cMC2 receptor but also the other cMC receptors interact with ACTH-derived peptide through an epitope beyond the sequence of α-MSH. 4 The synthetic ligand MTII was found to be a potent agonist whereas HS024 was a potent antagonist at the cMC4 receptor, indicating that these ligands are suitable for physiological studies in chicken. 5 We also show the presence of prohormone convertase 1 (PC1) and PC2 genes in chicken, and that these peptides are coexpressed with proopiomelanocortin (POMC) in various tissues. [ABSTRACT FROM AUTHOR]

We report the cloning and characterization of two melanocortin receptors (MCRs) from the spiny dogfish (Squalus acanthias) (Sac). Phylogenetic analysis shows that these shark receptors are orthologues of the MC3R and MC5R subtypes, sharing 65% and 70% overall amino acid identity with the human counterparts, respectively. The SacMC3R was expressed and pharmacologically characterized in HEK293 cells. The radioligand binding results show that this receptor has high affinity for adrenocorticotropic hormone (ACTH)-derived peptides while it has comparable affinity forα- andβ-melanocyte stimulating hormone (MSH), and slightly lower affinity forγ-MSH when compared with the human orthologue. ACTH(1–24)has high potency in a second-messenger cAMP assay whileα- andγ-MSH had slightly lower potency in cells expressing the SacMC3R. We used receptor–enhanced green fluorescence protein (EGFP) fusion to show the presence of SacMC3R in plasma membrane of Chinese hamster ovary and HEK293 cells but the SacMC5R was retained in intracellular compartments of these cells hindering pharmacological characterization. The anatomical distribution of the receptors were determined using reverse transcription PCR. The results showed that the SacMC3R is expressed in the hypothalamus, brain stem and telencephalon, optic tectum and olfactory bulbs, but not in the cerebellum of the spiny dogfish while the SacMC5R was found only in the same central regions. This report describes the first molecular characterization of a MC3R in fish. The study indicates that many of the important elements of the MC system existed before radiation of gnathostomes, early in vertebrate evolution, at least 450 million years ago. [ABSTRACT FROM AUTHOR]