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Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers. The expression of OX1R in various cancers including colon, pancreas and prostate cancers associated with its ability to induce a proapoptotic activity in tumor cells, suggested that the orexins/OX1R system could have a promising therapeutic role. The present review summarizes the relationship between cancers and orexins/OX1R system as an emerging target.

Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX 1 ) and type 2 (OX 2 ), well-known drug targets in the treatment of sleep disorders, that have recently been shown to play a significant role in different cancers. Lemborexant is one of a few orexin receptor antagonists that have been approved for the treatment of insomnia. Despite being classified as an antagonist, lemborexant may display agonist-like behavior in the non-canonical signaling pathway of the orexin receptors, as confirmed recently in cancer cell models. Here, we generated a model of OX 2 in complex with the full-length G q protein and used it in the molecular dynamics (MD) study. We compared the impact of lemborexant and the OX 2 -selective, potent agonist compound 1 on OX 2 activation and subsequent guanosine diphosphate (GDP) to guanosine triphosphate (GTP) exchange in the Gα q subunit. These 2 µs MD simulations showed that both ligands evoke similar, activation-like conformational changes in OX 2 and explained the observed lemborexant-mediated apoptosis of cancer cells. In addition, MD simulations of the active-state OX 2 -G q complexes allowed us to uncover a sequence of micro- and macroscale events during the activation of G q  and to detect important micro- and macroswitches in the Gα subunit.

Orexin-A and -B are hypothalamic neuropeptides of 33 and 28-amino acids, which regulate many homeostatic systems including sleep/wakefulness states, energy balance, energy homeostasis, reward seeking and drug addiction. Orexin-A treatment was also shown to reduce tumor development in xenografted nude mice and is thus a potential treatment for carcinogenesis. The aim of this work was to explore in healthy mice the consequences on energy expenditure components of an orexin-A treatment at a dose previously shown to be efficient to reduce tumor development. Physiological approaches were used to evaluate the effect of orexin-A on food intake pattern, energy metabolism body weight and body adiposity. Modulation of the expression of brain neuropeptides and receptors including NPY, POMC, AgRP, cocaine- and amphetamine related transcript (CART), corticotropin-releasing hormone (CRH) and prepro-orexin (HCRT), and Y2 and Y5 neuropeptide Y, MC4 (melanocortin), OX1 and OX2 orexin receptors (Y2R, Y5R, MC4R, OX1R and OX2R, respectively) was also explored. Our results show that orexin-A treatment does not significantly affect the components of energy expenditure, and glucose metabolism but reduces intraperitoneal fat deposit, adiposity and the expression of several brain neuropeptide receptors suggesting that peripheral orexin-A was able to reach the central nervous system. These findings establish that orexin-A treatment which is known for its activity as an inducer of tumor cell death, do have minor parallel consequence on energy homeostasis control.

Background The Multidomain Alzheimer Preventive Trial (MAPT) was designed to assess the efficacy of omega-3 fatty acid supplementation, multidomain intervention (MI), or a combination of both on cognition. Although the MAPT study was negative, an effect of MI in maintaining cognitive functions compared to placebo group was showed in positive amyloid subjects. A FDG PET study (MAPT-NI) was implemented to test the impact of MI on brain glucose metabolism. Methods MAPT-NI was a randomized, controlled parallel-group single-center study, exploring the effect of MI on brain glucose metabolism. Participants were non-demented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. Participants were randomly assigned (1:1) to “MI group” or “No MI group.” The MI consisted of group sessions focusing on 3 domains: cognitive stimulation, physical activity, nutrition, and a preventive consultation. [ 18 F]FDG PET scans were performed at baseline, 6 months, and 12 months, and cerebral magnetic resonance imaging scans at baseline. The primary objective was to evaluate the MI effect on brain glucose metabolism assessed by [ 18 F]FDG PET imaging at 6 months. The primary outcome was the quantification of regional metabolism rate for glucose in cerebral regions involved early in Alzheimer disease by relative semi-quantitative SUVr (FDG-based AD biomarker). An exploratory voxel-wise analysis was performed to assess the effect of MI on brain glucose metabolism without anatomical hypothesis. Results The intention-to-treat population included 67 subjects (34 in the MI group and 33 in the No MI group. No significant MI effect was observed on primary outcome at 6 months. In the exploratory voxel-wise analysis, we observed a difference in favor of MI group on the change of cerebral glucose metabolism in limbic lobe (right hippocampus, right posterior cingulate, left posterior parahippocampal gyrus) at 6 months. Conclusions MI failed to show an effect on metabolism in FDG-based AD biomarker, but exploratory analysis suggested positive effect on limbic system metabolism. This finding could suggest a delay effect of MI on AD progression. Trial registration ClinicalTrials.gov Identifier, NCT01513252 .

IntroductionResearch has shown that potentially inappropriate drug prescription (PIDP) is highly prevalent in older people. The presence of PIDPs is associated with adverse health outcomes. This study aims to evaluate the impact of a PHARmacist-included MObile Geriatrics (PharMoG) team intervention on PIDPs in older patients hospitalised in the medical, surgical and emergency departments of a university hospital.Methods and analysisThe PharMoG study is a prospective, interventional, single-centre feasibility study describing the impact of a PharMoG team on PIDPs in older hospitalised patients. Pharmacist intervention will be a treatment optimisation (clinical medication review) based on a combination of explicit and implicit criteria to detect PIDPs. The primary outcome is the acceptance rate of the mobile team’s proposed treatment optimisations related to PIDPs, measured at the patient’s discharge from the department. This pharmacist will work in cooperation with the physician of the mobile geriatric team. After the intervention of the mobile geriatric team, the proposals for improving therapy will be sent to the hospital medical team caring for the patient and to the patient’s attending physician. The patient will be followed for 3 months after discharge from the hospital.Ethics and disseminationThis study was approved by the South-West and Overseas Territories II Ethics Committee. Oral consent must be obtained prior to participation, either from the patient or from the patient’s representative (trusted person and/or a family member). The results will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberNCT04151797.

Orexins Control Intestinal Glucose Transport by Distinct Neuronal, Endocrine, and Direct Epithelial Pathways Robert Ducroc , Thierry Voisin , Aadil El Firar and Marc Laburthe From the Institut National de la Santé et de la Recherche Médicale U773, Centre de Recherche Biomédicale Bichat-Beaujon, Université Denis Diderot, Unité Mixte de Recherche S773, Paris, France Address correspondence and reprint requests to Robert Ducroc, Institut National de la Santé et de la Recherche Médicale U773, Centre de Recherche Biomédicale Bichat-Beaujon, 16 rue Henri Huchard, BP16, 75870 Paris cedex 18, France. E-mail: ducroc{at}bichat.inserm.fr Abstract OBJECTIVE— Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and orexin B (OxB) on intestinal glucose transport in the rat. RESEARCH DESIGN AND METHODS AND RESULTS— Injection of orexins led to a decrease in the blood glucose level in oral glucose tolerance tests (OGTTs). Effects of orexins on glucose entry were analyzed in Ussing chambers using the Na + -dependent increase in short-circuit current (Isc) to quantify jejunal glucose transport. The rapid and marked increase in Isc induced by luminal glucose was inhibited by 10 nmol/l OxA or OxB (53 and 59%, respectively). Response curves to OxA and OxB were not significantly different with half-maximal inhibitory concentrations at 0.9 and 0.4 nmol/l, respectively. On the one hand, OxA-induced inhibition of Isc was reduced by the neuronal blocker tetrodotoxin (TTX) and by a cholecystokinin (CCK) 2R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX 1 R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX 2 R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX 1 R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX 1 R. These distinct effects of OxA and OxB are consistent with the expression of OX 1 R and OX 2 R mRNA in the epithelial and nonepithelial tissues, respectively. CONCLUSIONS— Our data delineate a new function for orexins as inhibitors of intestinal glucose absorption and provide a new basis for orexin-induced short-term control of energy homeostasis. CCK, cholecystokinin CNS, central nervous system GAPDH, glyceraldehyde-3-phosphate dehydrogenase IC50, half-maximal inhibitory concentration Isc, short-circuit current OGTT, oral glucose tolerance test OxA, orexin A OxB, orexin B SGLT1, sodium-dependent glucose transporter 1 TTX, tetrodotoxin Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 12 July 2007. DOI: 10.2337/db07-0614. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 6, 2007. Received May 7, 2007. DIABETES

In contrast with the earlier stages and, in particular, the predementia stage, of Alzheimer’s disease (AD), severe dementia is often neglected. However, the advanced stages of dementia are just as important as the earlier stages because of their frequency, their impact on the lives of patients and their caregivers, and their economic consequences. All patients with moderately severe to severe dementia must be evaluated for cognitive, functional, psychological and behavioural symptoms. Thorough and regular evaluation of patients in the advanced stages of the disease has the following objectives: improving patients’ quality of life by encouraging use of their remaining capacities; setting up or modifying a care plan; playing a role in the follow-up of measures instituted; and documenting the natural history of the disease. Therapeutic trials with cholinesterase inhibitors and memantine have been conducted in patients with severe stages of AD. As a consequence, memantine has been approved by numerous drug agencies and donepezil has been approved by the US FDA for use in severe stages of the disease. However, it is important to note that at this stage of AD, and perhaps more than in any other, management must be global and multidisciplinary because of the expression of the disease, its complications and intercurrent disorders. Indeed, thorough knowledge by health professionals of the expression of all disease disorders and intercurrent disorders, and of their significance during the severe stage of AD, is important in the management of these patients to limit complications and facilitate prompt establishment of appropriate care. More effort is needed in both clinical and research settings to ensure that patients with severe AD and their relatives can be offered optimal management.

Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX ) and type 2 (OX ), well-known drug targets in the treatment of sleep disorders, that have recently been shown to play a significant role in different cancers. Lemborexant is one of a few orexin receptor antagonists that have been approved for the treatment of insomnia. Despite being classified as an antagonist, lemborexant may display agonist-like behavior in the non-canonical signaling pathway of the orexin receptors, as confirmed recently in cancer cell models. Here, we generated a model of OX in complex with the full-length G protein and used it in the molecular dynamics (MD) study. We compared the impact of lemborexant and the OX -selective, potent agonist compound 1 on OX activation and subsequent guanosine diphosphate (GDP) to guanosine triphosphate (GTP) exchange in the Gα subunit. These 2 µs MD simulations showed that both ligands evoke similar, activation-like conformational changes in OX and explained the observed lemborexant-mediated apoptosis of cancer cells. In addition, MD simulations of the active-state OX -G complexes allowed us to uncover a sequence of micro- and macroscale events during the activation of G  and to detect important micro- and macroswitches in the Gα subunit.

Background: Comprehensive geriatric assessments of patients entering the severe stage of Alzheimer’s disease (AD) are scarce. Methods: Cross-sectional study of 126 patients entering the severe stage of AD in the longitudinal study of REAL.FR cohort. Patients who had a first MMSE score <10 during follow-up underwent cognitive, behavioral, nutritional and functional assessment. Support requirements were also evaluated. Results: The best-preserved cognitive abilities were social interaction and response to own name, while praxis, orientation, memory and language showed the largest declines. Regarding independence in daily living, locomotion was best preserved (71% of patients independent) while personal hygiene deteriorated most (15.5%). Behavioral disorders were frequent, and consisted principally of apathy, aberrant motor behavior, and agitation. The Mini Nutritional Assessment showed that 68.5% of patients were malnourished or at risk of malnutrition. Caregiver burden remained mild to moderate in 69.8% of cases. In addition, 80% of patients still lived at home and 71.6% used at least 2 support services, consisting mainly of physician visits and home help. Conclusion: Assessment of remaining cognitive, functional abilities and behavioral disorders at entry to severe AD should help to improve targeted management aimed at preserving these abilities and treating complications, thereby optimizing these patients’ quality of life.

Purpose Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer’s disease (AD). The aim of this study was to test the feasibility of using PET imaging with 18 F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC). Methods In this study, 46 subjects (20 men and 26 women, mean age of 69.0 ± 7.6 years), including 13 with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50 min after injection of florbetapir (mean ± SD of radioactivity injected, 259 ± 57 MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region. Results The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p  = 0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.97-1.28) compared with HC subjects (median 0.95, Q1-Q3 0.82-1.02; p  = 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55–0.98) and a specificity of 38.1% (95% CI 0.18–0.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894). Conclusion These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools.