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  • 1.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia..
    Marklund, Niklas
    Department of Clinical Sciences Lund, Neurosurgery, Skåne University Hospital Lund University, Lund, Sweden .
    Differential DNA methylation of the genes for amyloid precursor protein, tau and neurofilaments in human traumatic brain injury2021In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 38, no 12, p. 1679-1688Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration, e.g. amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM) and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients to iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828 888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain and may have implications for the neurodegenerative disorders associated at long-term with TBI. 

  • 2.
    Affatato, Oreste
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dahlén, Amelia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Mwinyi, Jessica
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study2023In: BMC Neurology, E-ISSN 1471-2377, Vol. 23, no 1, article id 284Article in journal (Refereed)
    Abstract [en]

    Background: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls.

    Methods: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume.

    Results: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm(3), 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm(3), 95% CI [-7, 100]) and gray matter (mean difference: 49 mm(3), 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm(3), 95% CI [-7, 40]).

    Conclusion: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

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  • 3.
    Affatato, Oreste
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Miguet, Maud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Major sex differences in migraine prevalence among occupational categories: a cross-sectional study using UK Biobank2021In: Journal of Headache and Pain, ISSN 1129-2369, E-ISSN 1129-2377, Vol. 22, no 1, article id 145Article in journal (Refereed)
    Abstract [en]

    Background Migraine represents one of the most prevalent neurological conditions worldwide. It is a disabling condition with high impact on the working situation of migraineurs. Interestingly, gender-related differences regarding an association of migraine with important occupational characteristics has been hardly studied. Methods The current study scrutinizes gender-specific differences in the prevalence of migraine across a broad spectrum of occupational categories, shedding also light on associations with important job-related features such as shift work, job satisfaction, and physical activity. The study included data from 415 712 participants from the UK Biobank cohort, using the official ICD10 diagnosis of migraine and other health conditions as selection criteria. Prevalence ratios of migraineurs compared to healthy controls among different occupational categories and job-related variables were estimated using log-binomial regression analyses. Statistical models were adjusted for important sociodemographic features such as age, BMI, ethnicity, education and neuroticism. To better highlight specific differences between men and women we stratified by sex. Results We detected a differential prevalence pattern of migraine in relation to different job categories between men and women. Especially in men, migraine appears to be more prevalent in highly physically demanding occupations (PR 1.38, 95% CI [0.93, 2.04]). Furthermore, migraine is also more prevalent in jobs that frequently involve shift or night shift work compared to healthy controls. Interestingly, this prevalence is especially high in women (shift work PR 1.45, 95% CI [1.14, 1.83], night shift work PR 1.46, 95% CI [0.93, 2.31]). Conclusion Our results show that migraine is genderdependently associated with physically demanding jobs and shift working.

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  • 4.
    Affatato, Oreste
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Moulin, Thiago
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Pisanu, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Dept Biomed Sci, Cagliari, Italy..
    Babasieva, Victoria S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Russo, Marco
    Azienda USL IRCCS Reggio Emilia, Neuromotor & Rehabil Dept, Neurol Unit, Reggio Emilia, Italy..
    Aydinlar, Elif I.
    Acibadem Univ, Dept Neurol, Sch Med, Istanbul, Turkey..
    Torelli, Paola
    Univ Parma, Dept Med & Surg, Headache Ctr, Parma, Italy..
    Chubarev, Vladimir N.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Tarasov, Vadim V.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia.;IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    High efficacy of onabotulinumtoxinA treatment in patients with comorbid migraine and depression: a meta-analysis2021In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 19, no 1, article id 133Article, review/survey (Refereed)
    Abstract [en]

    Background: Migraine and depression are highly prevalent and partly overlapping disorders that cause strong limitations in daily life. Patients tend to respond poorly to the therapies available for these diseases. OnabotulinumtoxinA has been proven to be an effective treatment for both migraine and depression. While many studies have addressed the effect of onabotulinumtoxinA in migraine or depression separately, a growing body of evidence suggests beneficial effects also for patients comorbid with migraine and depression. The current meta-analysis systematically investigates to what extent onabotulinumtoxinA is efficient in migraineurs with depression.

    Methods: A systematic literature search was performed based on PubMed, Scopus and Web of Science from the earliest date till October 30th, 2020. Mean, standard deviation (SD) and sample size have been used to evaluate improvement in depressive symptoms and migraine using random- effects empirical Bayes model.

    Results: Our search retrieved 259 studies, eight of which met the inclusion criteria. OnabotulinumtoxinA injections administered to patients with both chronic migraine and major depressive disorder led to mean reduction of - 8.94 points (CI [ - 10.04,- 7.84], p < 0.01) in the BDI scale, of - 5.90 points (CI [ - 9.92,- 1.88], p < 0.01) in the BDI-II scale and of - 6.19 points (CI [ - 9.52,- 2.86], p < 0.01) in the PHQ-9 scale, when evaluating depressive symptoms. In the case of the migraine-related symptoms, we found mean reductions of - 4.10 (CI [ - 7.31,- 0.89], p = 0.01) points in the HIT6 scale, - 32.05 (CI [ - 55.96,- 8.14], p = 0.01) in the MIDAS scale, - 1.7 (CI [ - 3.27,- 0.13], p = 0.03) points in the VAS scale and of - 6.27 (CI [ - 8.48,- 4.07], p < 0.01) migraine episodes per month. Comorbid patients showed slightly better improvements in BDI, HIT6 scores and migraine frequency compared to monomorbid patients. The latter group manifested better results in MIDAS and VAS scores.

    Conclusion: Treatment with onabotulinumtoxinA leads to a significant reduction of disease severity of both chronic migraine and major depressive disorder in patients comorbid with both diseases. Comparative analyses suggest an equivalent strong effect in monomorbid and comorbid patients, with beneficial effects specifically seen for certain migraine features.

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  • 5.
    Affatato, Oreste
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Mwinyi, Jessica
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study2023In: Biomedicines, E-ISSN 2227-9059, Vol. 11, no 9, article id 2528Article in journal (Refereed)
    Abstract [en]

    Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas.

    Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions.

    Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]).

    Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.

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  • 6.
    Agosti, F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Cordisco Gonzalez, S.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Martinez Damonte, V.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Tolosa, M. J.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Di Siervi, N.
    Univ Buenos Aires, CONICET, ININFA, Inst Invest Farmacol, Buenos Aires, DF, Argentina..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Davio, C.
    Univ Buenos Aires, CONICET, ININFA, Inst Invest Farmacol, Buenos Aires, DF, Argentina..
    Perello, M.
    CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina.;Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol, IMBICE,Neurophysiol Lab, La Plata, Buenos Aires, Argentina..
    Raingo, J.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Melanocortin 4 Receptor Constitutive Activity Inhibits L-Type Voltage-Gated Calcium Channels In Neurons2017In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 346, p. 102-112Article in journal (Refereed)
    Abstract [en]

    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist-induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. We have previously shown that neuronal N-type voltage-gated calcium channels (Ca(V)2.2) are inhibited by MC4R agonist-dependent activation, while the Ca-V subtypes that carry L- and P/Q-type current are not. Here, we tested the hypothesis that MC4R constitutive activity can affect Ca-V, with focus on the channel subtypes that can control transcriptional activity coupled to depolarization (L-type, Ca(V)1.2/1.3) and neurotransmitter release (N- and P/Q-type, Ca(V)2.2 and Ca(V)2.1). We found that MC4R constitutive activity inhibits specifically Ca(V)1.2/1.3 and Ca(V)2.1 subtypes of Ca-V. We also explored the signaling pathways mediating this inhibition, and thus propose that agonist-dependent and basal MC4R activation modes signal differentially through G(s) and G(i/o) pathways to impact on different Ca-V subtypes. In addition, we found that chronic incubation with MC4R endogenous inverse agonist, agouti and agouti-related peptide (AgRP), occludes Ca-V inhibition in a cell line and in amygdaloid complex cultured neurons as well. Thus, we define new mechanisms of control of the main mediators of depolarization-induced calcium entry into neurons by a GPCR that displays constitutive activity.

  • 7. Agosti, Francina
    et al.
    Lopez Soto, Eduardo J.
    Cabral, Agustina
    Castrogiovanni, Daniel
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perello, Mario
    Raingo, Jesica
    Melanocortin 4 receptor activation inhibits presynaptic N-type calcium channels in amygdaloid complex neurons2014In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 40, no 5, p. 2755-2765Article in journal (Refereed)
    Abstract [en]

    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor involved in food intake and energy expenditure regulation. MC4R activation modifies neuronal activity but the molecular mechanisms by which this regulation occurs remain unclear. Here, we tested the hypothesis that MC4R activation regulates the activity of voltage-gated calcium channels and, as a consequence, synaptic activity. We also tested whether the proposed effect occurs in the amygdala, a brain area known to mediate the anorexigenic actions of MC4R signaling. Using the patch-clamp technique, we found that the activation of MC4R with its agonist melanotan II specifically inhibited 34.5 +/- 1.5% of N-type calcium currents in transiently transfected HEK293 cells. This inhibition was concentration-dependent, voltage-independent and occluded by the G(s) pathway inhibitor cholera toxin. Moreover, we found that melanotan II specifically inhibited 25.9 +/- 2.0% of native N-type calcium currents and 55.4 +/- 14.4% of evoked inhibitory postsynaptic currents in mouse cultured amygdala neurons. Invivo, we found that the MC4R agonist RO27-3225 increased the marker of cellular activity c-Fos in several components of the amygdala, whereas the N-type channel blocker conotoxin GVIA increased c-Fos expression exclusively in the central subdivision of the amygdala. Thus, MC4R specifically inhibited the presynaptic N-type channel subtype, and this inhibition may be important for the effects of melanocortin in the central subdivision of the amygdala.

  • 8.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chrousos, George P.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Genome wide analysis reveals association of a FTO gene variant with epigenetic changes2012In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 99, no 3, p. 132-137Article in journal (Refereed)
    Abstract [en]

    Variants of the FTO gene show strong association with obesity, but the mechanisms behind this association remain unclear. We determined the genome wide DNA methylation profile in blood from 47 female preadolescents. We identified sites associated with the genes KARS, TERF2IP, DEXI, MSI1,STON1 and BCAS3 that had a significant differential methylation level in the carriers of the FTO risk allele (rs9939609). In addition, we identified 20 differentially methylated sites associated with obesity. Our findings suggest that the effect of the FTO obesity risk allele may be mediated through epigenetic changes. Further, these sites might prove to be valuable biomarkers for the understanding of obesity and its comorbidites.

  • 9.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Shaik, Jafar H. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sreedharan, Smitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Marcus, Claude
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children2010In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 11, p. 58-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    TMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure.

    METHODS:

    The evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131).

    RESULTS:

    TMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002).

    CONCLUSION:

    We conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.

  • 10.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kalnina, Ineta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity2014In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 548, no 1, p. 61-67Article in journal (Refereed)
    Abstract [en]

    The combination of the obesity epidemic and an aging population presents growing challenges for the healthcare system. Obesity and aging are major risk factors for a diverse number of diseases and it is of importance to understand their interaction and the underlying molecular mechanisms. Herein the authors examined the methylation levels of 27578 CpG sites in 46 samples from adult peripheral blood. The effect of obesity and aging was ascertained with general linear models. More than one hundred probes were correlated to aging, nine of which belonged to the KEGG group map04080. Additionally, 10 CpG sites had diverse methylation profiles in obese and lean individuals, one of which was the telomerase catalytic subunit (TERT). In eight of ten cases the methylation change was reverted between obese and lean individuals. One region proved to be differentially methylated with obesity (LINC00304) independent of age. This study provides evidence that obesity influences age driven epigenetic changes, which provides a molecular link between aging and obesity. This link and the identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases.

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  • 11.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nordström, Karl J V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin2009In: BMC Biology, E-ISSN 1741-7007, Vol. 7, p. 50-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Membrane proteins form key nodes in mediating the cell's interaction with the surroundings, which is one of the main reasons why the majority of drug targets are membrane proteins. RESULTS: Here we mined the human proteome and identified the membrane proteome subset using three prediction tools for alpha-helices: Phobius, TMHMM, and SOSUI. This dataset was reduced to a non-redundant set by aligning it to the human genome and then clustered with our own interactive implementation of the ISODATA algorithm. The genes were classified and each protein group was manually curated, virtually evaluating each sequence of the clusters, applying systematic comparisons with a range of databases and other resources. We identified 6,718 human membrane proteins and classified the majority of them into 234 families of which 151 belong to the three major functional groups: receptors (63 groups, 1,352 members), transporters (89 groups, 817 members) or enzymes (7 groups, 533 members). Also, 74 miscellaneous groups with 697 members were determined. Interestingly, we find that 41% of the membrane proteins are singlets with no apparent affiliation or identity to any human protein family. Our results identify major differences between the human membrane proteome and the ones in unicellular organisms and we also show a strong bias towards certain membrane topologies for different functional classes: 77% of all transporters have more than six helices while 60% of proteins with an enzymatic function and 88% receptors, that are not GPCRs, have only one single membrane spanning alpha-helix. Further, we have identified and characterized new gene families and novel members of existing families. CONCLUSION: Here we present the most detailed roadmap of gene numbers and families to our knowledge, which is an important step towards an overall classification of the entire human proteome. We estimate that 27% of the total human proteome are alpha-helical transmembrane proteins and provide an extended classification together with in-depth investigations of the membrane proteome's functional, structural, and evolutionary features.

  • 12.
    Al-Sabri, Mohamed H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Behare, Neha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Alsehli, Ahmed M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. King Abdulaziz Univ & Hosp, Fac Med, Al Ehtifalat St, Jeddah 21589, Saudi Arabia.
    Berkins, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Arora, Aadeya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Antoniou, Eirini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Moysiadou, Eleni I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Anantha-Krishnan, Sowmya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Cosmen, Patricia D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Vikner, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Moulin, Thiago C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Lund Univ, Fac Med, Dept Expt Med Sci, Solvegatan 19,BMC F10, S-22184 Lund, Sweden.
    Ammar, Nourhene
    Univ Rennes, Inst Genet & Dev Rennes IGDR, UMR6290, CNRS, F-35065 Rennes, France..
    Boukhatmi, Hadi
    Univ Rennes, Inst Genet & Dev Rennes IGDR, UMR6290, CNRS, F-35065 Rennes, France..
    Clemensson, Laura E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 22, article id 3528Article in journal (Refereed)
    Abstract [en]

    The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ Drosophila melanogaster to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability. In addition, transmission microscopy of dissected skeletal muscles of fluvastatin-treated flies reveals strong myofibrillar damage, including increased sarcomere lengths and Z-line streaming, which are reminiscent of myopathy, along with fragmented mitochondria of larger sizes, most of which are round-like shapes. Furthermore, chronic fluvastatin treatment is associated with impaired lipid metabolism and insulin signalling. Mechanistically, knockdown of the statin-target Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and lowered general locomotion activity; however, it was not sufficient to alter sarcomere length or elicit myofibrillar damage compared to controls or fluvastatin treatment. Moreover, we found that fluvastatin treatment was associated with reduced expression of the skeletal muscle chloride channel, C1C-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle C1C-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored C1C-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered C1C-a expression. Taken together, these results may indicate the potential role of C1C-a inhibition in statinassociated muscular phenotypes. This study underlines the importance of Drosophila melanogaster as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.

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  • 13.
    Al-Sabri, Mohamed H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Nikpour, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Department of Medical Sciences, Uppsala University, BMC, Husargatan 3, 750 03, Uppsala, Sweden.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    The regulatory role of AP-2 beta in monoaminergic neurotransmitter systems: insights on its signalling pathway, linked disorders and theragnostic potential2022In: Cell & Bioscience, ISSN 2045-3701, Vol. 12, no 1, article id 151Article, review/survey (Refereed)
    Abstract [en]

    Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2 beta, gene: TFAP2B). AP-2 beta regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2B has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2 beta, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2 beta as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2 beta as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.

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  • 14.
    Alsehli, Ahmed M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Al-Sabri, Mohamed H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia2021In: Frontiers in Bioscience-Landmark, Vol. 26, no 12, p. 1453-1463Article in journal (Refereed)
    Abstract [en]

    Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10−4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01–1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). Conclusion: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.

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  • 15.
    Alsehli, Ahmed M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology. King Abdulaziz Univ & Hosp, Fac Med, Al Ehtifalat St, Jeddah 21589, Saudi Arabia..
    Liao, Sifang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Al-Sabri, Mohamed H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Vasionis, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Purohit, Archana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Behare, Neha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Sechenov Biomed Sci & Technol Pk, Inst Translat Med & Biotechnol, Trubetskay Str 8, Moscow 119991, Russia..
    The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in Drosophila2022In: Pharmaceuticals, E-ISSN 1424-8247, Vol. 15, no 1, article id 79Article in journal (Refereed)
    Abstract [en]

    Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal Hmgcr expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the pars intercerebralis (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of Hmgcr expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal Hmgcr knockdown. Conversely, loss of Hmgcr in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of Hmgcr in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies.

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  • 16.
    Alsehli, Ahmed M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. King Abdulaziz Univ, Dept Physiol, Fac Med, Al Ehtifalat St, Jeddah 21589, Saudi Arabia..
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Sechenov Biomed Sci & Technol Pk,Trubetskay Str 8, Moscow 119991, Russia..
    The Cognitive Effects of Statins are Modified by Age2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 6187Article in journal (Refereed)
    Abstract [en]

    To reveal new insights into statin cognitive effects, we performed an observational study on a population-based sample of 245,731 control and 55,114 statin-taking individuals from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups (within 5-10 years). Subjects were classified depending on age (up to 65 and over 65 years) and treatment duration (1-4 years, 5-10 years and over 10 years). Data were adjusted for health- and cognition-related covariates. Subjects generally improved in test performance with repeated assessment and middle-aged persons performed better than older persons. The effect of statin use differed considerably between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. Our analysis suggests a modulatory impact of age on the cognitive side effects of statins, revealing a possible reason for profoundly inconsistent findings on statin-related cognitive effects in the literature. The study highlights the importance of characterising modifiers of statin effects to improve knowledge and shape guidelines for clinicians when prescribing statins and evaluating their side effects in patients.

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  • 17.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Birgner, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Björkblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Isaksson, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bergström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Impact of nandrolone decanoate on gene expression in endocrine systems related to the adverse effects of anabolic androgenic steroids2009In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 105, no 5, p. 307-314Article in journal (Refereed)
    Abstract [en]

    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 beta(3)-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.

  • 18.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Feed-forward mechanisms: Addiction-like behavioral and molecular adaptations in overeating2012In: Frontiers in neuroendocrinology (Print), ISSN 0091-3022, E-ISSN 1095-6808, Vol. 33, no 2, p. 127-139Article, review/survey (Refereed)
    Abstract [en]

    Food reward, not hunger, is the main driving force behind eating in the modern obesogenic environment. Palatable foods, generally calorie-dense and rich in sugar/fat, are thus readily overconsumed despite the resulting health consequences. Important advances have been made to explain mechanisms underlying excessive consumption as an immediate response to presentation of rewarding tastants. However, our understanding of long-term neural adaptations to food reward that oftentimes persist during even a prolonged absence of palatable food and contribute to the reinstatement of compulsive overeating of high-fat high-sugar diets, is much more limited. Here we discuss the evidence from animal and human studies for neural and molecular adaptations in both homeostatic and non-homeostatic appetite regulation that may underlie the formation of a "feed-forward" system, sensitive to palatable food and propelling the individual from a basic preference for palatable diets to food craving and compulsive, addiction-like eating behavior.

  • 19.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Norbäck, A. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gunnarsson, Z. E. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, A. S.
    Pickering, Chris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dopamine D1 receptor gene expression decreases in the nucleus accumbens upon long-term exposure to palatable food and differs depending on diet-induced obesity phenotype in rats2010In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 171, no 3, p. 779-787Article in journal (Refereed)
    Abstract [en]

    The nucleus accumbens (NAcc) mediates feeding reward; its activity reflects tastants' hedonic value. NAcc dopamine guides immediate responses to reward, however, its involvement in establishing long-term responses after a period of exposure to palatable foods has not been defined. Furthermore, reward-driven overeating propels weight increase, but the scale of weight gain depends on animals' obesity-prone (OP) or -resistant (OR) phenotype. It is unclear whether the NAcc dopamine response to palatable food depends on obesity susceptibility. We investigated the effect of unrestricted extended access to high-fat high-sugar (HFHS) diet on expression of genes encoding dopamine receptors in the NAcc of OP and OR rats. We examined persistence of HFHS diet-induced changes in D(1) and D(2) gene expression in OP and OR rats subjected to HFHS withdrawal (bland chow for 18 days). Effects of restricted access to HFHS by pair-feeding were also studied. Using reverse transcriptase PCR (RT-PCR), we found that NAcc D(1) mRNA was downregulated after long-term HFHS access in OP vs. OR animals. The effect was also observed after 18 days of HFHS withdrawal. Furthermore, restricted HFHS led to downregulation of D(1) as well as of D(2) mRNA levels compared to chow-fed controls. A difference in the expression of mu opioid receptor in the NAcc was also detected between the OP and OR rats during access to palatable food but not after withdrawal. We conclude that exposure to HFHS diets has lasting consequences for the NAcc dopamine system, perhaps modifying the motivation to search for food reward. The fact that the NAcc D(1) expression changes in OP animals after long-term exposure to palatable food and that this effect extends well into the reward discontinuation phase, implicates the D(1) receptor in the propensity to overeat and, in effect, gain weight in obesity prone individuals.

  • 20.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pickering, Chris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Motivation for sucrose in sated rats is predicted by low anxiety-like behavior2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 454, no 3, p. 193-197Article in journal (Refereed)
    Abstract [en]

    Anxiety has been implicated in obesity and in the overconsumption of highly palatable foods such as those high in fat, sugar, or both. Also, the novelty-seeking trait has been associated with failure in weight-loss programs. The aim of this study was to investigate the associations of experimental anxiety and the self-administration of sucrose and high fat pellets in non-food deprived rats across different operant schedules. Male Wistar rats were subjected to the elevated plus-maze test (EPM) of anxiety-like behavior. The rats were tested for fixed ratio 5 (FR5) and progressive ratio (PR) operant responding for 50% sucrose, 95% sucrose, and high-fat pellets. PR active lever press response for 95% sucrose, but not the other pellet types, was correlated to % time spent on open arms (P=0.019) in the EPM. On the FR5 schedule, activity (closed arm entries) was correlated to the self-administration of 50% sucrose (P=0.027) and high-fat (P=0.002). This indicates an association of novelty-induced activity and self-administration of palatable food in sated rats, as well as a specific association of PR lever press response for 95% sucrose and low anxiety-like behavior. It has been argued that such active lever press response on PR may be interpreted as craving for the reinforcer; thus, our findings indicate an inverse relationship of experimental anxiety and craving for sucrose. This connection may have implications for human situations, since anxiety and novelty-seeking have been associated with obesity and failure in weight-loss programs.

  • 21.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Pickering, Christopher
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Anxiolytic response after palatable diet consumption but not food restriction in rats2009In: Appetite, ISSN 0195-6663, E-ISSN 1095-8304, Vol. 52, no 3, p. 816-816Article in journal (Other academic)
  • 22.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chavan, Rohit A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Exposure to a high-fat high-sugar diet causes strong up-regulation of proopiomelanocortin and differentially affects dopamine D1 and D2 receptor gene expression in the brainstem of rats2014In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 559, p. 18-23Article in journal (Refereed)
    Abstract [en]

    A strong link between obesity and dopamine (DA) has been established by studies associating body weight status to variants of genes related to DA signalling. Human and animal studies investigating this relationship have so far focused mainly on the role of DA within the mesolimbic pathway. The aim of this study was to investigate potential DA receptor dysregulation in the brainstem, where these receptors play a potential role in meal termination, during high-fat high-sugar diet (HFHS) exposure. Expression of other key genes, including proopiomelanocortin (POMC), was also analyzed. We randomized rats into three groups; ad libitum access to HFHS (n=24), restricted HFHS access (n=10), or controls (chow-fed, n=10). After 5 weeks, brainstem gene expression was investigated by qRT-PCR. We observed an increase in POMC expression in ad libitum HFHS-fed rats compared to chow-fed controls (p<0.05). Further, expression of DA D2 receptor mRNA was down-regulated in the brainstem of the HFHS ad libitum-fed rats (p<0.05), whereas expression of the DA D1 receptor was upregulated (p<0.05) in these animals compared to chow-fed rats. In control experiments, we observed no effect relative to chow-fed controls on DA-receptor or POMC gene expression in the hypothalamus of HFHS diet-exposed rats, or in the brainstem of acutely food deprived rats. The present findings suggest brainstem POMC to be responsive to palatable foods, and that DA dysregulation after access to energy-dense diets occurs not only in striatal regions, but also in the brainstem, which could be relevant for overeating and for the development and maintenance of obesity.

  • 23.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hulting, Anna-Lena
    Meyerson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Anxiety-like behaviour predicts the preference for a high-carbohydrate diet in outbred rats2007In: Behavioural Pharmacology, ISSN 0955-8810, E-ISSN 1473-5849, Vol. 18, p. S41-S41Article in journal (Other academic)
  • 24.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jonsson, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Minnesota Obesity Center, VA Medical Center, Minneapolis, MN, USA.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 22009In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, no 2, p. 193-202Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.

  • 25.
    Andreoli, María F
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Instituto de Desarrollo e Investigaciones Pediátricas (IDIP), HIAEP Sor María Ludovica de la Plata, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC-PBA), Calle 63 # 1069, La Plata, Buenos Aires, Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), La Plata, Argentina. mfandreoli@fbcb.unl.edu.ar..
    Fittipaldi, Antonela S
    Castrogiovanni, Daniel
    De Francesco, Pablo N
    Valdivia, Spring
    Heredia, Florencia
    Ribet-Travers, Carole
    Mendez, Ignacio
    Fasano, María V
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Doi, Suhail A
    Habib, Abdella M
    Perello, Mario
    Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner.2023In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The liver-expressed antimicrobial peptide 2 (LEAP2) is a newly recognized peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) blunting the effects of ghrelin and displaying ghrelin-independent actions. Since the implications of LEAP2 are beginning to be elucidated, we investigated if plasma LEAP2 concentration varies with feeding status or sex and whether it is associated with glucose metabolism and appetite sensations.

    METHODS: We performed a single test meal study, in which plasma concentrations of LEAP2, ghrelin, insulin and glucose as well as visual analogue scales for hunger, desire to eat, prospective food consumption, fullness were assessed before and 60 min after breakfast in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB).

    RESULTS: Pre-prandial plasma LEAP2 concentration was ~ 1.6-fold higher whereas ghrelin was ~ 2.0-fold lower in individuals with OW/OB (p < 0.001) independently of sex. After adjusting for body mass index (BMI) and sex, pre-prandial plasma LEAP2 concentration displayed a direct relationship with BMI (β: 0.09; 95%CI: 0.05, 0.13; p < 0.001), fat mass (β: 0.05; 95%CI: 0.01, 0.09; p = 0.010) and glycemia (β: 0.24; 95%CI: 0.05, 0.43; p = 0.021), whereas plasma ghrelin concentration displayed an inverse relationship with BMI and fat mass but not with glycemia. Postprandial plasma LEAP2 concentration increased ~ 58% in females with OW/OB (p = 0.045) but not in females with NW or in males. Pre-prandial plasma LEAP2 concentration displayed an inverse relationship with hunger score (β: - 11.16; 95% CI: - 18.52, - 3.79; p = 0.004), in a BMI-, sex- and ghrelin-independent manner.

    CONCLUSIONS: LEAP2 emerges as a key hormone implicated in the regulation of metabolism and appetite in humans.

    TRIAL REGISTRATION: The study was retrospectively registered in clinicaltrials.gov (April 2023).

    CLINICALTRIALS: gov Identifier: NCT05815641.

  • 26. Araç, Demet
    et al.
    Aust, Gabriela
    Calebiro, Davide
    Engel, Felix B
    Formstone, Caroline
    Goffinet, André
    Hamann, Jörg
    Kittel, Robert J
    Liebscher, Ines
    Lin, Hsi-Hsien
    Monk, Kelly R
    Petrenko, Alexander
    Piao, Xianhua
    Prömel, Simone
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schwartz, Thue W
    Stacey, Martin
    Ushkaryov, Yuri A
    Wobus, Manja
    Wolfrum, Uwe
    Xu, Lei
    Langenhan, Tobias
    Dissecting signaling and functions of adhesion G protein-coupled receptors2012In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1276, no 1, p. 1-25Article in journal (Refereed)
    Abstract [en]

    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.

  • 27.
    Ashworth, Emma
    et al.
    Liverpool John Moores Univ, Fac Hlth, Sch Psychol, Liverpool, Merseyside, England..
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Liverpool John Moores Univ, Fac Hlth, Sch Psychol, Liverpool, Merseyside, England.;Univ Witwatersrand, Sch Human & Community Dev, Dept Psychol, Johannesburg, South Africa..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Neural activation of anxiety and depression in children and young people: A systematic meta-analysis of fMRI studies2021In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 311, article id 111272Article in journal (Refereed)
    Abstract [en]

    Functional magnetic resonance imaging (fMRI) studies consistently demonstrate altered neural activation in youth experiencing anxiety and depression in a way that is distinct from adult-onset disorders. However, there is a paucity of research systematically reviewing this, and no meta-analyses have been conducted using Activation Likelihood Estimation (ALE). The present study conducted a systematic literature search to identify fMRI studies in youth (age 4?18) with depression or anxiety disorders. 48 studies with over 2000 participants were identified that met the inclusion criteria. Significant foci were extracted. Five ALE meta-analyses were conducted: a) activation for both anxiety disorders and depression; b) activation for anxiety disorders only; c) activation for depression only; d) deactivation for both anxiety disorders and depression; e) deactivation for depression. Results indicated significant clusters of increased activation in the bilateral amygdala for youth with internalising disorders, and specifically for those with anxiety disorders. Significant increased activation extended into the dorsal anterior cingulate, entorhinal cortex, the putamen, and the medial and lateral globus pallidus in youth with anxiety disorders. These findings help to detail the nature of anxiety being an amygdala hyperactivity disorder, whilst also defining the distinction between neural activation patterns in anxiety and depression.

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  • 28.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Fabbro, Doriano
    Sokolov, Aleksandr V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Knapp, Stefan
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Trends in kinase drug discovery: targets, indications and inhibitor design2021In: Nature reviews. Drug discovery, ISSN 1474-1776, E-ISSN 1474-1784, Vol. 20, no 11, p. 839-861Article in journal (Refereed)
    Abstract [en]

    The FDA approval of imatinib in 2001 was a breakthrough in molecularly targeted cancer therapy and heralded the emergence of kinase inhibitors as a key drug class in the oncology area and beyond. Twenty years on, this article analyses the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications. There are currently 71 small-molecule kinase inhibitors (SMKIs) approved by the FDA and an additional 16 SMKIs approved by other regulatory agencies. Although oncology is still the predominant area for their application, there have been important approvals for indications such as rheumatoid arthritis, and one-third of the SMKIs in clinical development address disorders beyond oncology. Information on clinical trials of SMKIs reveals that approximately 110 novel kinases are currently being explored as targets, which together with the approximately 45 targets of approved kinase inhibitors represent only about 30% of the human kinome, indicating that there are still substantial unexplored opportunities for this drug class. We also discuss trends in kinase inhibitor design, including the development of allosteric and covalent inhibitors, bifunctional inhibitors and chemical degraders.

  • 29.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Soluble ligands as drug targets2020In: Nature reviews. Drug discovery, ISSN 1474-1776, E-ISSN 1474-1784, Vol. 19, no 10, p. 695-710Article, review/survey (Refereed)
    Abstract [en]

    Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases. With the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. This Review analyses drugs targeting ligands that have reached clinical development in the past three decades and discusses strategic issues such as the pros and cons of different ligand-targeting therapeutic modalities.

  • 30.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Krishnan, Arunkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pivotti, Valentina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Yazdi, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome2016In: BMC Genomics, E-ISSN 1471-2164, Vol. 17, article id 268Article in journal (Refereed)
    Abstract [en]

    Background: Membrane proteins are key components in a large spectrum of diverse functions and thus account for the major proportion of the drug-targeted portion of the genome. From a structural perspective, the a-helical transmembrane proteins can be categorized into major groups based on the number of transmembrane helices and these groups are often associated with specific functions. When compared to the well-characterized seven-transmembrane containing proteins (7TM), other TM groups are less explored and in particular the 4TM group. In this study, we identify the complete 4TM complement from the latest release of the human genome and assess the 4TM structure group as a whole. We functionally characterize this dataset and evaluate the resulting groups and ubiquitous functions, and furthermore describe disease and drug target involvement.

    Results: We classified 373 proteins, which represents similar to 7 % of the human membrane proteome, and includes 69 more proteins than our previous estimate. We have characterized the 4TM dataset based on functional, structural, and/or evolutionary similarities. Proteins that are involved in transport activity constitute 37 % of the dataset, 23 % are receptor-related, and 13 % have enzymatic functions. Intriguingly, proteins involved in transport are more than double the 15 % of transporters in the entire human membrane proteome, which might suggest that the 4TM topological architecture is more favored for transporting molecules over other functions. Moreover, we found an interesting exception to the ubiquitous intracellular N- and C-termini localization that is found throughout the entire membrane proteome and 4TM dataset in the neurotransmitter gated ion channel families. Overall, we estimate that 58 % of the dataset has a known association to disease conditions with 19 % of the genes possibly involved in different types of cancer.

    Conclusions: We provide here the most robust and updated classification of the 4TM complement of the human genome as a platform to further understand the characteristics of 4TM functions and to explore pharmacological opportunities.

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  • 31.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Krishnan, Arunkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Highly diversified expansions shaped the evolution of membrane bound proteins in metazoans2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 12387Article in journal (Refereed)
    Abstract [en]

    The dramatic increase in membrane proteome complexity is arguably one of the most pivotal evolutionary events that underpins the origin of multicellular animals. However, the origin of a significant number of membrane families involved in metazoan development has not been clarified. In this study, we have manually curated the membrane proteomes of 22 metazoan and 2 unicellular holozoan species. We identify 123,014 membrane proteins in these 24 eukaryotic species and classify 86% of the dataset. We determine 604 functional clusters that are present from the last holozoan common ancestor (LHCA) through many metazoan species. Intriguingly, we show that more than 70% of the metazoan membrane protein families have a premetazoan origin. The data show that enzymes are more highly represented in the LHCA and expand less than threefold throughout metazoan species; in contrast to receptors that are relatively few in the LHCA but expand nearly eight fold within metazoans. Expansions related to cell adhesion, communication, immune defence, and developmental processes are shown in conjunction with emerging biological systems, such as neuronal development, cytoskeleton organization, and the adaptive immune response. This study defines the possible LHCA membrane proteome and describes the fundamental functional clusters that underlie metazoan diversity and innovation.

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  • 32.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Orphan Drugs and Their Impact on Pharmaceutical Development2018In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, no 6, p. 525-535Article, review/survey (Refereed)
    Abstract [en]

    High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.

  • 33.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Orphan Drugs and Their Impact on Pharmaceutical Development2018In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, no 12, article id 1077Article in journal (Refereed)
  • 34.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Characterization of five transmembrane proteins: With focus on the Tweety, Sidoreflexin, and YIP1 domain families2021In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 9, article id 708754Article in journal (Refereed)
    Abstract [en]

    Transmembrane proteins are involved in many essential cell processes such as signal transduction, transport, and protein trafficking, and hence many are implicated in different disease pathways. Further, as the structure and function of proteins are correlated, investigating a group of proteins with the same tertiary structure, i.e. the same number of transmembrane regions, may give understanding about their functional roles and potential as therapeutic targets. This analysis investigates the previously unstudied group of proteins with five transmembrane-spanning regions (5TM). More than half of the 58 proteins identified with the 5TM architecture belong to twelve families with two or more members, with ten complete families that do not have any other homologous human proteins identified. Interestingly, more than half the proteins in the dataset function in localization activities through movement or tethering of cell components and more than one-third are involved in transport activities, particularly in the mitochondria. Surprisingly, no receptor activity was identified within this family in large contrast with other TM families. The three major 5TM families include the Tweety family, which are pore-forming subunits of the swelling-dependent volume regulated anion channel in astrocytes; the sidoreflexin family that act as mitochondrial amino acid transporters; and the Yip1 domain family engaged in vesicle budding and intra-Golgi transport.  About 30% of the 5TM proteins have enhanced expression in the brain, liver, or testis. Importantly, 60% of these proteins are identified as cancer prognostic markers, where they are associated with clinical outcomes of various tumour types, indicating further investigation into the function and expression of these proteins is important. This study provides the first comprehensive analysis of proteins with 5TM providing details of the unique characteristics

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  • 35.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Classification of Trispanins: A Diverse Group of Proteins That Function in Membrane Synthesis and Transport Mechanisms2020In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 7, article id 386Article in journal (Refereed)
    Abstract [en]

    As the structure and functions of proteins are correlated, investigating groups of proteins with the same gross structure may provide important insights about their functional roles. Trispanins, proteins that contain three alpha-helical transmembrane (3TM) regions, have not been previously studied considering their transmembrane features. Our comprehensive identification and classification using bioinformatic methods describe 152 3TM proteins. These proteins are frequently involved in membrane biosynthesis and lipid biogenesis, protein trafficking, catabolic processes, and in particular signal transduction due to the large ionotropic glutamate receptor family. Proteins that localize to intracellular compartments are overrepresented in the dataset in comparison to the entire human transmembrane proteome, and nearly 45% localize specifically to the endoplasmic reticulum (ER). Furthermore, nearly 20% of the trispanins function in lipid metabolic processes and transport, which are also overrepresented. Nearly one-third of trispanins are identified as being targeted by drugs and/or being associated with diseases. A high number of 3TMs have unknown functions and based on this analysis we speculate on the functional involvement of uncharacterized trispanins in relationship to disease or important cellular activities. This first overall study of trispanins provides a unique analysis of a diverse group of membrane proteins.

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  • 36.
    Babenko, Vladislav V.
    et al.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Podgorny, Oleg, V
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Russian Acad Sci, Koltzov Inst Dev Biol, 26 Vavilov Str, Moscow 119334, Russia..
    Manuvera, Valentin A.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Kasianov, Artem S.
    Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia.;Russian Acad Sci, Vavilov Inst Gen Genet, 3 Gubkina Str, Moscow 119991, Russia..
    Manolov, Alexander, I
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Grafskaia, Ekaterina N.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Shirokov, Dmitriy A.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Kurdyumov, Alexey S.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Vinogradov, Dmitriy V.
    Russian Acad Sci, AA Kharkevich Inst Informat Transmiss Problems, 19 Bolshoi Karetnyi Per, Moscow 127051, Russia.;Skolkovo Inst Sci & Technol, 3 Nobelya Ulitsa Str, Moscow 121205, Russia..
    Nikitina, Anastasia S.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Kovalchuk, Sergey, I
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, 16-10 Miklukho Maklaya Str, Moscow 117997, Russia..
    Anikanov, Nickolay A.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, 16-10 Miklukho Maklaya Str, Moscow 117997, Russia..
    Butenko, Ivan O.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Pobeguts, Olga, V
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Matyushkina, Daria S.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Rakitina, Daria, V
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Kostryukova, Elena S.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Zgoda, Victor G.
    Russian Acad Med Sci, VN Orekhovich Res Inst Biomed Chem, 10 Pogodinskaja Str, Moscow 119832, Russia..
    Baskova, Isolda P.
    Lomonosov Moscow State Univ, Fac Biol, 1-12 Leninskie Gory, Moscow 119991, Russia..
    Trukhan, Vladimir M.
    IM Sechenov First Moscow State Med Univ, Minist Healthcare Russian Federat, Sechenovskiy Univ, Trubetskaya Str 8-2, Moscow 119991, Russia..
    Gelfand, Mikhail S.
    Russian Acad Sci, AA Kharkevich Inst Informat Transmiss Problems, 19 Bolshoi Karetnyi Per, Moscow 127051, Russia.;Skolkovo Inst Sci & Technol, 3 Nobelya Ulitsa Str, Moscow 121205, Russia.;Natl Res Univ Higher Sch Econ, Fac Comp Sci, 20 Myasnitskaya Str, Moscow 101000, Russia.;Lomonosov Moscow State Univ, Fac Bioengn & Bioinformat, 1-73 Leninskie Gory, Moscow 119991, Russia..
    Govorun, Vadim M.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Minist Healthcare Russian Federat, Sechenovskiy Univ, Trubetskaya Str 8-2, Moscow 119991, Russia.
    Lazarev, Vassili N.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Draft genome sequences of Hirudo medicinalis and salivary transcriptome of three closely related medicinal leeches2020In: BMC Genomics, E-ISSN 1471-2164, Vol. 21, no 1Article in journal (Refereed)
    Abstract [en]

    Background

    Salivary cell secretion (SCS) plays a critical role in blood feeding by medicinal leeches, making them of use for certain medical purposes even today.

    Results

    We annotated the Hirudo medicinalis genome and performed RNA-seq on salivary cells isolated from three closely related leech species, H. medicinalis, Hirudo orientalis, and Hirudo verbana. Differential expression analysis verified by proteomics identified salivary cell-specific gene expression, many of which encode previously unknown salivary components. However, the genes encoding known anticoagulants have been found to be expressed not only in salivary cells. The function-related analysis of the unique salivary cell genes enabled an update of the concept of interactions between salivary proteins and components of haemostasis.

    Conclusions

    Here we report a genome draft of Hirudo medicinalis and describe identification of novel salivary proteins and new homologs of genes encoding known anticoagulants in transcriptomes of three medicinal leech species. Our data provide new insights in genetics of blood-feeding lifestyle in leeches.

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  • 37.
    Badiali, Luca
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Vergoni, Anna V
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Adhesion GPCRs are widely expressed throughout the subsections of the gastrointestinal tract2012In: BMC Gastroenterology, E-ISSN 1471-230X, Vol. 12, p. 134-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: G protein-coupled receptors (GPCRs) represent one of the largest families of transmembrane receptors and the most common drug target. The Adhesion subfamily is the second largest one of GPCRs and its several members are known to mediate neural development and immune system functioning through cell-cell and cell-matrix interactions. The distribution of these receptors has not been characterized in detail in the gastrointestinal (GI) tract. Here we present the first comprehensive anatomical profiling of mRNA expression of all 30 Adhesion GPCRs in the rat GI tract divided into twelve subsegments.

    METHODS: Using RT-qPCR, we studied the expression of Adhesion GPCRs in the esophagus, the corpus and antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum.

    RESULTS: We found that twenty-one Adhesion GPCRs (70%) had a widespread (expressed in five or more segments) or ubiquitous (expressed in eleven or more segments) distribution, seven (23%) were restricted to a few segments of the GI tract and two were not expressed in any segment. Most notably, almost all Group III members were ubiquitously expressed, while the restricted expression was characteristic for the majority of group VII members, hinting at more specific/localized roles for some of these receptors.

    CONCLUSIONS: Overall, the distribution of Adhesion GPCRs points to their important role in GI tract functioning and defines them as a potentially crucial target for pharmacological interventions.

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  • 38.
    Bandstein, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ernst, Barbara
    eSwiss Medical & Surgical Center, Interdisciplinary Obesity Center, St. Gallen, Switzerland..
    Thurnheer, Martin
    eSwiss Medical & Surgical Center, Interdisciplinary Obesity Center, St. Gallen, Switzerland..
    Schultes, Bernd
    eSwiss Medical & Surgical Center, Interdisciplinary Obesity Center, St. Gallen, Switzerland.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A genetic variant in proximity to the gene LYPLAL1 is associated with lower hunger feelings and increased weight loss following Roux-en Y gastric bypass surgery2016In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 51, no 9, p. 1050-1055Article in journal (Refereed)
    Abstract [en]

    Objective: Bariatric surgery is the most efficient treatment of severe obesity. We investigated to what extent BMI- or waist-hip ratio (WHR)-related genetic variants are associated with excess BMI loss (EBMIL) two years after Roux-en-Y gastric bypass (RYGB) surgery, and elucidated the affected biological pathways.

    Methods: Two-hundred fifty-one obese patients (age: 4310.7, preoperative BMI: 45.16.1kg/m(2), 186 women) underwent RYGB surgery and were followed up after two years with regard to BMI. Patients were genotyped for 32 single-nucleotide polymorphisms (SNPs) that were investigated with regard to their impact on response to RYGB and preoperatively measured Three Factor Eating Questionnaire (TFEQ) scores.

    Results: Homozygous T carriers of the SNP rs4846567 in proximity to the Lysophospholipase-like 1 (LYPLAL1) gene showed a 7% higher EBMIL compared to wild-type and heterozygous carriers (p=0.031). TT-allele carriers showed furthermore lower scores for Hunger (74%, p<0.001), lower Disinhibition (53%, p<0.001), and higher Cognitive restraint (21%, p=0.017) than GG/GT carriers in the TFEQ. Patients within the lowest quartile of Hunger scores had a 32% greater EBMIL compared to patients in the highest quartile (p<0.001).

    Conclusion: The LYPLAL1 genotype is associated with differences in eating behavior and loss of extensive body weight following RYGB surgery. Genotyping and the use of eating behavior-related questionnaires may help to estimate the RYGB-associated therapy success.

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  • 39.
    Bandstein, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    eSwiss Med & Surg Ctr, Interdisciplinary Obes Ctr, St Gallen, Switzerland..
    Ernst, Barbara
    eSwiss Med & Surg Ctr, Interdisciplinary Obes Ctr, St Gallen, Switzerland..
    Thurnheer, Martin
    eSwiss Med & Surg Ctr, Interdisciplinary Obes Ctr, St Gallen, Switzerland..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The Role of FTO and Vitamin D for the Weight Loss Effect of Roux-en-Y Gastric Bypass Surgery in Obese Patients2015In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 25, no 11, p. 2071-2077Article in journal (Refereed)
    Abstract [en]

    A recent study in children demonstrated that the rs9939609 single-nucleotide polymorphism in the fat mass and obesity (FTO) gene influences prospective weight gain, however, only in those who were vitamin D-deficient. If this might also be the case for Roux-en-Y gastric bypass (RYGB), surgery-induced weight loss is however unknown. The objective of this study is to examine if the magnitude of RYGB surgery-induced weight loss after 2 years depends on patients' FTO rs9939609 genotype (i.e., TT, AT, and AA) and presurgery vitamin D status (< 50 nmol/L equals deficiency). Before and at 24 months after RYGB surgery, BMI was measured in 210 obese patients (mean BMI 45 kg/m(2), 72 % females). Serum 25-hydroxyvitamin D3 levels were also repeatedly measured. Following surgery, vitamin D was supplemented. Possible weight loss differences between genotypes were tested with multiple linear regressions. The per-allele effect of each FTO A-allele on excessive BMI loss (EBMIL) was 3 % (P = 0.02). When split by baseline status, the EBMIL of vitamin D-deficient patients carrying AA exceeded that of vitamin D-deficient patients carrying TT by similar to 14 % (P = 0.03). No such genotypic differences were found in patients without presurgery vitamin D deficiency. Post-surgery serum levels of vitamin D did not differ between groups. Our data suggest that presurgery vitamin D levels influence the size of genotype effects of FTO rs9939609 on RYGB surgery-induced weight loss in obese patients.

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  • 40.
    Bandstein, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    eSwiss Medical & Surgical Center, Interdisciplinary Obesity Center, St. Gallen, Switzerland.
    Ernst, Barbara
    eSwiss Medical & Surgical Center, Interdisciplinary Obesity Center, St. Gallen, Switzerland.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A genetic risk score is associated with weight loss following Roux-Y gastric bypass surgery2016In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 26, no 9, p. 2183-2189Article in journal (Refereed)
    Abstract [en]

    Currently, Roux-en Y gastric bypass (RYGB) is the most efficient therapy for severe obesity. Weight loss after surgery is, however, highly variable and genetically influenced. Genome-wide association studies have identified several single nucleotide polymorphisms (SNP) associated with body mass index (BMI) and waist-hip ratio (WHR). We aimed to identify two genetic risk scores (GRS) composed of weighted BMI and WHR-associated SNPs to estimate their impact on excess BMI loss (EBMIL) after RYGB surgery. Two hundred and thirty-eight obese patients (BMI 45.1 +/- 6.2 kg/m(2), 74 % women), who underwent RYGB, were genotyped for 35 BMI and WHR-associated SNPs and were followed up after 2 years. SNPs with high impact on post-surgical weight loss were filtered out using a random forest model. The filtered SNPs were combined into a GRS and analyzed in a linear regression model. An up to 11 % lower EBMIL with higher risk score was estimated for two GRS models (P = 0.026 resp. P = 0.021) composed of seven BMI-associated SNPs (closest genes: MC4R, TMEM160, PTBP2, NUDT3, TFAP2B, ZNF608, MAP2K5, GNPDA2, and MTCH2) and of three WHR-associated SNPs (closest genes: HOXC13, LYPLAL1, and DNM3-PIGC). Patients within the lowest GRS quartile had higher EBMIL compared to patients within the other three quartiles in both models. We identified two GRSs composed of BMI and WHR-associated SNPs with significant impact on weight loss after RYGB surgery using random forest analysis as a SNP selection tool. The GRS may be useful to pre-surgically evaluate the risks for patients undergoing RYGB surgery.

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  • 41.
    Barrile, Franco
    et al.
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Cassano, Daniela
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Fernandez, Gimena
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    De Francesco, Pablo N.
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Reynaldo, Mirta
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Cantel, Sonia
    Univ Montpellier, Inst Biomol Max Mousseron, CNRS, ENSCM, Montpellier, France..
    Fehrentz, Jean-Alain
    Univ Montpellier, Inst Biomol Max Mousseron, CNRS, ENSCM, Montpellier, France..
    Donato Jr, Jose
    Univ Sao Paulo, Inst Ciencias Biomed, Dept Physiol & Biophys, Sao Paulo, Brazil..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Zigman, Jeffrey M.
    UT Southwestern Med Ctr, Ctr Hypothalam Res, Dept Internal Med, Dallas, TX USA..
    Perello, Mario
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.;Multidisciplinary Inst Cell Biol, Lab Neurophysiol, Calle 526 S-N Entre 10 & 11, RA-1900 La Plata, Buenos Aires, Argentina..
    Ghrelin's orexigenic action in the lateral hypothalamic area involves indirect recruitment of orexin neurons and arcuate nucleus activation2023In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 156, article id 106333Article in journal (Refereed)
    Abstract [en]

    Objective: Ghrelin is a potent orexigenic hormone, and the lateral hypothalamic area (LHA) has been suggested as a putative target mediating ghrelin's effects on food intake. Here, we aimed to investigate the presence of neurons expressing ghrelin receptor (a.k.a. growth hormone secretagogue receptor, GHSR) in the mouse LHA (LHAGHSR neurons), its physiological implications and the neuronal circuit recruited by local ghrelin action.Methods: We investigated the distribution of LHAGHSR neurons using different histologic strategies, including the use of a reporter mice expressing enhanced green fluorescent protein under the control of the GHSR promoter. Also, we investigated the physiological implications of local injections of ghrelin within the LHA, and the extent to which the orexigenic effect of intra-LHA-injected ghrelin involves the arcuate nucleus (ARH) and orexin neurons of the LHA (LHAorexin neurons)Results: We found that: 1) LHAGHSR neurons are homogeneously distributed throughout the entire LHA; 2) intraLHA injections of ghrelin transiently increase food intake and locomotor activity; 3) ghrelin's orexigenic effect in the LHA involves the indirect recruitment of LHAorexin neurons and the activation of ARH neurons; and 4) LHAGHSR neurons are not targeted by plasma ghrelin.Conclusions: We provide a compelling neuroanatomical and functional characterization of LHAGHSR neurons in male mice that indicates that LHAGHSR cells are part of a hypothalamic neuronal circuit that potently induces food intake.

  • 42.
    Belen Poretti, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Consejo Nacl Invest Cient & Tecn, FCM, Inst Fisiol, INICSA, Cordoba, Argentina.
    Frautschi, Camila
    Univ Nacl Cordoba, Fac Ciencias Med, Catedra Fisiol Humana, Cordoba, Argentina..
    Luque, Eugenia
    Consejo Nacl Invest Cient & Tecn, FCM, Inst Fisiol, INICSA, Cordoba, Argentina..
    Bianconi, Santiago
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Nacl Cordoba, Fac Ciencias Med, Catedra Fisiol Humana, Cordoba, Argentina..
    Carolina Martini, Ana
    Consejo Nacl Invest Cient & Tecn, FCM, Inst Fisiol, INICSA, Cordoba, Argentina..
    Stutz, Graciela
    Univ Nacl Cordoba, Fac Ciencias Med, Catedra Fisiol Humana, Cordoba, Argentina..
    Vincenti, Laura
    Univ Nacl Cordoba, Fac Ciencias Med, Catedra Fisiol Humana, Cordoba, Argentina..
    Emilia Santillan, Maria
    Univ Nacl Cordoba, Fac Ciencias Med, Catedra Fisiol Humana, Cordoba, Argentina..
    Ponzio, Marina
    Consejo Nacl Invest Cient & Tecn, FCM, Inst Fisiol, INICSA, Cordoba, Argentina..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fiol de Cuneo, Marta
    Univ Nacl Cordoba, Fac Ciencias Med, Catedra Fisiol Humana, Cordoba, Argentina..
    Paola Carlini, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Consejo Nacl Invest Cient & Tecn, FCM, Inst Fisiol, INICSA, Cordoba, Argentina.
    Reproductive performance of male mice after hypothalamic ghrelin administration2018In: Reproduction, ISSN 1470-1626, E-ISSN 1476-3990, Vol. 156, no 2, p. 121-132Article in journal (Refereed)
    Abstract [en]

    It has been demonstrated that food intake and reproductive physiology are both simultaneously modulated to optimize reproductive success under fluctuating metabolic conditions. Ghrelin (GHRL) is an orexigenic peptide identified as the endogenous ligand of the growth hormone secretagogue receptor that is being investigated for its potential role on reproduction. Considering that data available so far are still limited and characterization of GHRL action mechanism on the reproductive system has not been fully elucidated, we studied the participation of hypothalamus in GHRL effects on sperm functional activity, plasma levels of gonadotropins and histological morphology in mice testes after hypothalamic infusion of 0.3 or 3.0 nmol/day GHRL or artificial cerebrospinal fluid (ACSF) at different treatment periods. We found that GHRL 3.0 nmol/day administration for 42 days significantly reduced sperm concentration (GHRL 3.0 nmol/day =14.05 +/- 2.44 x 10(6)/mL vs ACSF =20.33 +/- 1.35 x10(6)/mL, P< 0.05) and motility (GHRL 3.0 nmol/day =59.40 +/- 4.20% vs ACSF =75.80 +/- 1.40%, P< 0.05). In addition, histological studies showed a significant decrease percentage of spermatogonia (GHRL 3.0 nmol/day =6.76 +/- 0.68% vs ACSF =9.56 +/- 0.41%, P< 0.05) and sperm (GHRL 3.0 nmol/day =24.24 +/- 1.92% vs ACSF =31.20 +/- 3.06%, P< 0.05). These results were associated with a significant reduction in luteinizing hormone and testosterone plasma levels (P < 0.05). As GHRL is an orexigenic peptide, body weight and food intake were measured. Results showed that GHRL increases both parameters; however, the effect did not last beyond the first week of treatment. Results presented in this work confirm that central GHRL administration impairs spermatogenesis and suggest that this effect is mediated by inhibition of hypothalamic-pituitary-gonadal axis.

  • 43.
    Belyaeva, Irina I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Subbotina, Anna G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Eremenko, Ivan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Tarasov, Vadim V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia.;IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Chubarev, Vladimir N.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Pharmacogenetics in Primary Headache Disorders2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, article id 820214Article, review/survey (Refereed)
    Abstract [en]

    Primary headache disorders, such as migraine, tension-type headache (TTH), and cluster headache, belong to the most common neurological disorders affecting a high percentage of people worldwide. Headache induces a high burden for the affected individuals on the personal level, with a strong impact on life quality, daily life management, and causes immense costs for the healthcare systems. Although a relatively broad spectrum of different pharmacological classes for the treatment of headache disorders are available, treatment effectiveness is often limited by high variances in therapy responses. Genetic variants can influence the individual treatment success by influencing pharmacokinetics or pharmacodynamics of the therapeutic as investigated in the research field of pharmacogenetics. This review summarizes the current knowledge on important primary headache disorders, including migraine, TTH, and cluster headache. We also summarize current acute and preventive treatment options for the three headache disorders based on drug classes and compounds taking important therapy guidelines into consideration. Importantly, the work summarizes and discusses the role of genetic polymorphisms regarding their impact on metabolism safety and the effect of therapeutics that are used to treat migraine, cluster headache, and TTH exploring drug classes such as nonsteroidal anti-inflammatory drugs, triptans, antidepressants, anticonvulsants, calcium channel blockers, drugs with effect on the renin-angiotensin system, and novel headache therapeutics such as ditans, anti-calcitonin-gene-related peptide antibodies, and gepants. Genetic variants in important phase I-, II-, and III-associated genes such as cytochrome P450 genes, UGT genes, and different transporter genes are scrutinized as well as variants in genes important for pharmacodynamics and several functions outside the pharmacokinetic and pharmacodynamic spectrum. Finally, the article evaluates the potential and limitations of pharmacogenetic approaches for individual therapy adjustments in headache disorders.

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  • 44.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Söderberg, Stefan
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The fat mass and obesity-associated gene (FTO) is linked to higher plasma levels of the hunger hormone ghrelin and lower serum levels of the satiety hormone leptin in older adults2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 11, p. 3955-3959Article in journal (Refereed)
    Abstract [en]

    The mechanisms through which common polymorphisms in the fat mass and obesity-associated gene (FTO) drive the development of obesity in humans are poorly understood. By using C: ross-sectional data from 985 elderly (50% females) who participated at age 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors, circulating levels of ghrelin and leptin were measured after an overnight fast. In addition, subjects were genotyped for FTO rs17817449 (AA, n=345 (35%); AC/CA, n=481 (48.8%); CC, n=159 (16.1%). Linear regression analyses controlling for sex, self-reported physical activity level, fasting plasma glucose, and body mass index were utilized. A positive relationship between the number of FTO C risk alleles and plasma ghrelin levels was found (P=0.005; relative plasma ghrelin difference between CC and AA carriers = ∼9%). In contrast, serum levels of the satiety enhancing hormone leptin were inversely linked to the number of FTO C risk alleles (P=0.001; relative serum leptin difference between CC and AA carriers = ∼11%). These associations were also found when controlling for waist circumference. The present findings suggest that FTO may facilitate weight gain in humans by shifting the endocrine balance from the satiety hormone leptin toward the hunger promoting hormone ghrelin.

  • 45.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brede, Swantje
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lehnert, Hendrik
    Schultes, Bernd
    Born, Jan
    Hallschmid, Manfred
    Intranasal Insulin Enhances Postprandial Thermogenesis and Lowers Postprandial Serum Insulin Levels in Healthy Men2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 1, p. 114-118Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

     Animal studies indicate a prominent role of brain insulin signaling in the regulation of peripheral energy metabolism. We determined the effect of intranasal insulin, which directly targets the brain, on glucose metabolism and energy expenditure in humans.

    RESEARCH DESIGN AND METHODS

    In a double-blind, placebo-controlled, balanced within-subject comparison, 19 healthy normal-weight men (18-26 years old) were intranasally administered 160 IU human insulin after an overnight fast. Energy expenditure assessed via indirect calorimetry and blood concentrations of glucose, insulin, C-peptide, and free fatty acids (FFAs) were measured before and after insulin administration and the subsequent consumption of a high-calorie liquid meal of 900 kcal.

    RESULTS

    Intranasal insulin, compared with placebo, increased postprandial energy expenditure, i.e., diet-induced thermogenesis, and decreased postprandial concentrations of circulating insulin and C-peptide, whereas postprandial plasma glucose concentrations did not differ from placebo values. Intranasal insulin also induced a transient decrease in prandial serum FFA levels.

    CONCLUSIONS

    Enhancing brain insulin signaling by means of intranasal insulin administration enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the control of whole-body energy homeostasis in humans.

  • 46.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Burgos, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kempton, Matthew J
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Craft, Suzanne
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Impaired Insulin Sensitivity as Indexed by the HOMA Score Is Associated With Deficits in Verbal Fluency and Temporal Lobe Gray Matter Volume in the Elderly2012In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 35, no 3, p. 488-494Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    Impaired insulin sensitivity is linked to cognitive deficits and reduced brain size. However, it is not yet known whether insulin sensitivity involves regional changes in gray matter volume. Against this background, we examined the association between insulin sensitivity, cognitive performance, and regional gray matter volume in 285 cognitively healthy elderly men and women aged 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

    RESEARCH DESIGN AND METHODS

    Insulin sensitivity was calculated from fasting serum insulin and plasma glucose determinations using the homeostasis model assessment of insulin resistance (HOMA-IR) method. Cognitive performance was examined by a categorical verbal fluency. Participants also underwent a magnetic resonance imaging (MRI) brain scan. Multivariate analysis using linear regression was conducted, controlling for potential confounders (sex, education, serum LDL cholesterol, mean arterial blood pressure, and abdominal visceral fat volume).

    RESULTS

    The HOMA-IR was negatively correlated with verbal fluency performance, brain size (S1), and temporal lobe gray matter volume in regions known to be involved in speech production (Brodmann areas 21 and 22, respectively). No such effects were observed when examining diabetic (n = 55) and cognitively impaired (n = 27) elderly subjects as separate analyses.

    CONCLUSIONS

    These cross-sectional findings suggest that both pharmacologic and lifestyle interventions improving insulin signaling may promote brain health in late life but must be confirmed in patient studies.

  • 47.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Burgos, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Le Grevès, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association between physical activity and brain health in older adults2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 1, p. 83-90Article in journal (Refereed)
    Abstract [en]

    In the present cross-sectional study, we examined physical activity (PA) and its possible association with cognitive skills and brain structure in 331 cognitively healthy elderly. Based on the number of self-reported light and hard activities for at least 30 minutes per week, participants were assigned to 4 groups representing different levels of PA. The cognitive skills were assessed by the Mini Mental State Examination score, a verbal fluency task, and the Trail-making test as a measure of visuospatial orientation ability. Participants also underwent a magnetic resonance imaging of the brain. Multiple regression analysis revealed that greater PA was associated with a shorter time to complete the Trail-making test, and higher levels of verbal fluency. Further, the level of self-reported PA was positively correlated with brain volume, white matter, as well as a parietal lobe gray matter volume, situated bilaterally at the precuneus. These present cross-sectional results indicate that PA is a lifestyle factor that is linked to brain structure and function in late life.

  • 48.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    O'Daly, Owen G
    Almèn, Markus S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Morell, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Åberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Schultes, Bernd
    Hallschmid, Manfred
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute Sleep Deprivation Enhances the Brain's Response to Hedonic Food Stimuli: An fMRI Study2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 3, p. E443-447Article in journal (Refereed)
    Abstract [en]

    Context:

    There is growing recognition that a large number of individuals living in Western society are chronically sleep deprived. Sleep deprivation is associated with an increase in food consumption and appetite. However, the brain regions that are most susceptible to sleep deprivation-induced changes when processing food stimuli are unknown.

    Objective:

    Our objective was to examine brain activation after sleep and sleep deprivation in response to images of food.

    Intervention:

    Twelve normal-weight male subjects were examined on two sessions in a counterbalanced fashion: after one night of total sleep deprivation and one night of sleep. On the morning after either total sleep deprivation or sleep, neural activation was measured by functional magnetic resonance imaging in a block design alternating between high- and low-calorie food items. Hunger ratings and morning fasting plasma glucose concentrations were assessed before the scan, as were appetite ratings in response to food images after the scan.

    Main Outcome Measures:

    Compared with sleep, total sleep deprivation was associated with an increased activation in the right anterior cingulate cortex in response to food images, independent of calorie content and prescan hunger ratings. Relative to the postsleep condition, in the total sleep deprivation condition, the activation in the anterior cingulate cortex evoked by foods correlated positively with postscan subjective appetite ratings. Self-reported hunger after the nocturnal vigil was enhanced, but importantly, no change in fasting plasma glucose concentration was found.

    Conclusions:

    These results provide evidence that acute sleep loss enhances hedonic stimulus processing in the brain underlying the drive to consume food, independent of plasma glucose levels. These findings highlight a potentially important mechanism contributing to the growing levels of obesity in Western society.

  • 49.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brytting, Maria
    Markström, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute sleep deprivation has no lasting effects on the human antibody titer response following a novel influenza A H1N1 virus vaccination2012In: BMC Immunology, E-ISSN 1471-2172, Vol. 13, p. 1-Article in journal (Refereed)
    Abstract [en]

    Background: Experimental studies in humans have yielded evidence that adaptive immune function, including the production of antigen-specific antibodies, is distinctly impaired when sleep is deprived at the time of first antigen exposure. Here we examined the effects of a regular 24- hour sleep-wake cycle (including 8 hours of nocturnal sleep) and a 24-hour period of continuous wakefulness on the 7 week antibody production in 11 males and 13 females in response to the H1N1 (swine flu) virus vaccination. The specific antibody titer in serum was assayed by the hemagglutination inhibition test on the days 5, 10, 17, and 52 following vaccination.

    Results: In comparison to the sleep group, sleep-deprived males but not females had reduced serum concentration of H1N1-specific antibodies five days after vaccination, whereas antibody titers at later time points did not differ between the conditions.

    Conclusions: These findings concur with the notion that sleep is a supportive influence in the very early stage of an adaptive immune response to a viral antigen. However, our results do not support the view that acute sleep deprivation has lasting effects on the human antibody titer response to influenza vaccination.

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  • 50.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hogenkamp, Pleunie S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Giedratis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Self-reported sleep disturbance is associated with Alzheimer's disease risk in men2015In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 9, p. 1090-1097Article in journal (Refereed)
    Abstract [en]

    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.

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    fulltext
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