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Darshan Khangura, L Romayne Kurukulasuriya, Adam Whaley-Connell, James R Sowers
The presence of hypertension in individuals with type 2 diabetes augments the risk for cardiovascular morbidity and mortality. In this regard, data support that management of hypertension in this high-risk population is a critical risk reduction strategy. In recent years, a number of work groups have redefined hypertension, management strategies, and targets. In this context, there is still considerable discussion on an appropriate target for blood pressure in the diabetic population. However, despite this discussion on target blood pressure, it is widely recognized that there is considerable residual risk for heightened cardiovascular events in the hypertensive, diabetic population despite widespread awareness and treatment...
March 14, 2018: American Journal of Hypertension
Jana Tchekalarova, Keylla da Conceição Machado, Antonio Luiz Gomes Júnior, Ana Amélia de Carvalho Melo Cavalcante, Albena Momchilova, Rumyana Tzoneva
PURPOSE: Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance both in animal seizure tests and in patients with epilepsy. Few reports considered the role of CB2 receptor on seizure susceptibility and cognitive functions. The aim of the present study was to explore the effect of a selective CB2 receptor agonist β-caryophyllene (BCP) in models of seizures and cognition in mice. METHODS: Dose-dependent effects of BCP was studied in maximal electroshock seizure (MES) test, subcutaneous pentylenetetrazole (scPTZ) test and Morris water maze test...
March 12, 2018: Seizure: the Journal of the British Epilepsy Association
Stephany M Biello, David R Bonsall, Lynsey A Atkinson, Penny C Molyneux, Mary E Harrington, Gurprit S Lall
Robust physiological circadian rhythms form an integral part of well-being. The aging process has been found to negatively impact systems that drive circadian physiology, typically manifesting as symptoms associated with abnormal/disrupted sleeping patterns. Here, we investigated the age-related decline in light-driven circadian entrainment in male C57BL/6J mice. We compared light-driven resetting of circadian behavioral activity in young (1-2 months) and old (14-18 months) mice and explored alterations in the glutamatergic pathway at the level of the circadian pacemaker, the suprachiasmatic nucleus (SCN)...
February 20, 2018: Neurobiology of Aging
Soo Lim, Robert H Eckel, Kwang Kon Koh
The final goal in the management of patients with type 2 diabetes (T2D) is reduction in cardiovascular (CV) complications and total mortality. Various factors including hyperglycemia contribute to these complications and mortality directly and indirectly. In recent years, large-scale CV outcome trials with new antidiabetic medications, such as dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP1) receptor agonists, and sodium glucose cotransporter-2 (SGLT2) inhibitors, have been completed...
March 8, 2018: Atherosclerosis
Rita Turnaturi, Carmela Parenti, Orazio Prezzavento, Agostino Marrazzo, Paschalina Pallaki, Zafiroula Georgoussi, Emanuele Amata, Lorella Pasquinucci
The opioid pharmacological profile of cis -(-)- N -normetazocine derivatives is deeply affected by the nature of their N -substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N -phenylpropanamido substituent. LP1 derivatives 5a - d and 6a - d were characterized by flexible groups at the N -substituent that allow them to reposition themselves relative to cis -(-)- N -normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kelsey Connelly, David Collister, Navdeep Tangri
PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. The purpose of this review is to provide an update on recent findings in the diagnosis and treatment of osteoporosis in patients with CKD. RECENT FINDINGS: Multiple observational studies have shown that bone mineral density measurement using DEXA is equally predictive in CKD stages 1-3, as in the general population...
March 15, 2018: Current Opinion in Nephrology and Hypertension
Joe Dooley, Gareth Ryan, Lianne Gerber Finn, Megan Bollinger, Cai-Lei Matsumoto, Wilma M Hopman, Len Kelly
INTRODUCTION: Opioid use in pregnancy is increasing globally. In northwest Ontario, rates of neonatal abstinence syndrome (NAS) are alarmingly high. We sought to document the increasing rates of opioid exposure during pregnancy and associated cases of NAS over a 7-year period in northwest Ontario. METHODS: We conducted a retrospective chart review at the Sioux Lookout Meno Ya Win Health Centre catchment area (population 29 000) maternity program in northwest Ontario of mother-infant dyads of live births from Jan...
2018: Canadian Journal of Rural Medicine
Nick Zwart, Shan Li Nio, Corine J Houtman, Jacob De Boer, Jeroen Kool, Timo Hamers, Marja H Lamoree
Effect-Directed Analysis (EDA) is a commonly used approach for effect-based identification of endocrine disruptive chemicals in complex (environmental) mixtures. For routine toxicity assessment of e.g. water samples however, current EDA approaches are considered time consuming and laborious. We achieved faster EDA and identification, by downscaling of sensitive cell-based hormone reporter gene assays and increasing fractionation resolution to allow testing of smaller fractions with reduced complexity. The high-resolution EDA approach is demonstrated by analysis of four environmental passive sampler extracts...
March 16, 2018: Environmental Science & Technology
Carol H Wysham, Dominic Pilon, Mike Ingham, Marie-Hélène Lafeuille, Bruno Emond, Rhiannon Kamstra, Michael Pfeifer, Patrick Lefebvre
OBJECTIVE: To compare glycated hemoglobin (HbA1c) control and medication costs between patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin 300 mg (CANA) or a glucagon-like peptide 1 receptor agonist (GLP-1 RA) in a real-world setting. METHODS: Adults with T2DM newly initiated on CANA or a GLP-1 RA (index date) were identified from IQVIA™ Real-World Data Electronic Medical Records U.S. database (March 29, 2012-April 30, 2016). Inverse probability of treatment weighting accounted for differences in baseline characteristics...
March 2018: Endocrine Practice
Martin A Bewley, Richard C Budd, Eilise Ryan, Joby Cole, Paul Collini, Jennifer Marshall, Umme Kolsum, Gussie Beech, Richard D Emes, Irina Tcherniaeva, Guy A M Berbers, Sarah R Walmsley, Gavin Donaldson, Jadwiga A Wedzicha, Iain Kilty, William Rumsey, Yolanda Sanchez, Christopher E Brightling, Louise E Donnelly, Peter J Barnes, Dave Singh, Moira K B Whyte, David H Dockrell
RATIONALE: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AM) in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms and clinical consequences remain incompletely defined. OBJECTIVES: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences and potential for therapeutic manipulation of these defects. METHODS: We isolated alveolar macrophages (AM) and monocyte-derived macrophages (MDM) from a cohort of COPD patients and controls within the MRC COPD-MAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features...
March 16, 2018: American Journal of Respiratory and Critical Care Medicine
Mikael Tiger, Katarina Varnäs, Yoshiro Okubo, Johan Lundberg
Major depressive disorder (MDD) is the leading cause of disability worldwide. The serotonin hypothesis may be the model of MDD pathophysiology with the most support. The majority of antidepressants enhance synaptic serotonin levels quickly, while it usually takes weeks to discern MDD treatment effect. It has been hypothesized that the time lag between serotonin increase and reduction of MDD symptoms is due to downregulation of inhibitory receptors such as the serotonin 1B receptor (5-HT1BR). The research on 5-HT1BR has previously been hampered by a lack of selective ligands for the receptor...
March 15, 2018: Psychopharmacology
Irene E G van Hellemond, Ingeborg J H Vriens, Petronella G M Peer, Astrid C P Swinkels, Carolien H Smorenburg, Caroline M Seynaeve, Maurice J C van der Sangen, Judith R Kroep, Hiltje de Graaf, Aafke H Honkoop, Frans L G Erdkamp, Franchette W P J van den Berkmortel, Jos J E M Kitzen, Maaike de Boer, Wïlfred K de Roos, Sabine C Linn, Alexander L T Imholz, Vivianne C G Tjan-Heijnen
Background: Aromatase inhibitors (AIs) are given as adjuvant therapy for hormone receptor-positive breast cancer in postmenopausal women, also to those with chemotherapy-induced ovarian function failure. The current analysis reports on endocrine data of patients with chemotherapy-induced ovarian function failure who were included in the phase III DATA study assessing different durations of adjuvant anastrozole after tamoxifen. Methods: We identified all patients with chemotherapy-induced ovarian function failure...
December 1, 2017: Journal of the National Cancer Institute
Zhenhua Ji, Yuting Xie, Yu Guan, Yujian Zhang, Kin-Sang Cho, Min Ji, Yongping You
Previous studies have demonstrated that activation of P2X7 receptors (P2X7 R) results in the proliferation and migration of some types of tumor. Here, we asked whether and how the activated P2X7 R contribute to proliferation and migration of human glioma cells. Results showed that the number of P2X7 R positive cells was increasing with grade of tumor. In U87 and U251 human glioma cell lines, both expressed P2X7 R and the expression was enhanced by 3'-O-(4-benzoylbenzoyl) ATP (BzATP), the agonist of P2X7 R, and siRNA...
2018: BioMed Research International
Xiang Song, Yan Zhang, Li Zhang, Wengang Song, Lixin Shi
Hypoxia-associated metabolic reprogramming modulates the biological functions of many immune and non-immune cells, and affects immune response types and intensities. Adenosine and indoleamine 2,3-dioxygenase (IDO) are known immunosuppressors, and adenosine is a hypoxia-associated product. We investigated the impact of hypoxia on IDO production in dendritic cells (DCs). We found that hypoxia (1% O2 ) enhances IDO production in DCs, and this increase was dependent on the adenosine A3 receptor (A3R), but not A2aR or A2bR...
February 20, 2018: Oncotarget
Zhaodong Li, Ludovica F Buttó, Kristine-Anne Buela, Li-Guo Jia, Minh Lam, John D Ward, Theresa T Pizarro, Fabio Cominelli
Death receptor 3 (DR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, has been implicated in regulating T-helper type-1 (TH 1), type-2 (TH 2), and type-17 (TH 17) responses as well as regulatory T cell (Treg ) and innate lymphoid cell (ILC) functions during immune-mediated diseases. However, the role of DR3 in controlling lymphocyte functions in inflammatory bowel disease (IBD) is not fully understood. Recent studies have shown that activation of DR3 signaling modulates Treg expansion suggesting that stimulation of DR3 represents a potential therapeutic target in human inflammatory diseases, including Crohn's disease (CD)...
2018: Frontiers in Immunology
Lorenza Tulli, Francesca Cattaneo, Juliette Vinot, Cosima T Baldari, Ugo D'Oro
Toll-like receptors (TLRs) play a key role in the activation of innate immune cells, in which their engagement leads to production of cytokines and co-stimulatory molecules. TLRs signaling requires recruitment of toll/IL-1R (TIR) domain-containing adaptors, such as MyD88 and/or TRIF, and leads to activation of several transcription factors, such as NF-κB, the AP1 complex, and various members of the interferon regulatory factor (IRF) family, which in turn results in triggering of several cellular functions associated with these receptors...
2018: Frontiers in Immunology
Ken Matsui, Makoto Ozawa, Maki Kiso, Makoto Yamashita, Toshihiko Maekawa, Minoru Kubota, Sumio Sugano, Yoshihiro Kawaoka
Influenza A viruses cause seasonal epidemics and occasional pandemics. The emergence of viruses resistant to neuraminidase (NA) inhibitors and M2 ion channel inhibitors underlines the need for alternate anti-influenza drugs with novel mechanisms of action. Here, we report the discovery of a host factor as a potential target of anti-influenza drugs. By using cell-based virus replication screening of a chemical library and several additional assays, we identified clonidine as a new anti-influenza agent in vitro...
March 15, 2018: Scientific Reports
Michael D Oberst, Catherine Auge, Chad Morris, Stacy Kentner, Kathy Mulgrew, Kelly McGlinchey, James Hair, Shino Hanabuchi, Qun Du, Melissa Damschroder, Hui Feng, Steven Eck, Nicholas Buss, Lolke de Haan, Andrew J Pierce, Haesun Park, Andrew Sylwester, Michael K Axthelm, Louis Picker, Nicholas P Morris, Andrew Weinberg, Scott A Hammond
Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells...
March 15, 2018: Molecular Cancer Therapeutics
Danuta Jarocha, Karen K Vo, Randolph B Lyde, Vincent Hayes, Rodney M Camire, Mortimer Poncz
In vitro-grown megakaryocytes for generating platelets may have value in meeting the increasing demand for platelet transfusions. Remaining challenges have included the poor yield and quality of in vitro-generated platelets. We have shown that infusing megakaryocytes leads to intrapulmonary release of functional platelets. A Src kinase inhibitor (SU6656), a Rho-associated kinase inhibitor (Y27632), and an aurora B kinase inhibitor (AZD1152) have been shown to increase megakaryocyte ploidy and in vitro proplatelet release...
March 27, 2018: Blood Advances
Anaïs Briot, Pauline Decaunes, Fanny Volat, Chloé Belles, Muriel Coupaye, Séverine Ledoux, Anne Bouloumié
OBJECTIVE: Adipose tissue (AT) dysfunction associated with obesity or aging is a major cause for lipid redistribution and the progression of cardiometabolic disorders. Our goal is to decipher the contribution of human AT microvascular endothelial cells (ECs) in the maintenance of fatty acid (FA) fluxes and the impact of senescence on their function. APPROACH AND RESULTS: We used freshly isolated primary microvascular ECs from human AT. Our data identified the endothelial FA handling machinery including FATPs (FA transport proteins) FATP1, FATP3, FATP4, and CD36 as well as FABP4 (FA binding protein 4)...
March 15, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
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