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https://www.readbyqxmd.com/read/28105274/design-synthesis-and-evaluation-of-novel-and-selective-g-protein-coupled-receptor-120-gpr120-spirocyclic-agonists
#1
Jason M Cox, Hong D Chu, Mariappan V Chelliah, John S Debenham, Keith Eagen, Ping Lan, Matthew Lombardo, Clare London, Michael A Plotkin, Unmesh Shah, Zhongxiang Sun, Henry M Vaccaro, Srikanth Venkatraman, Takao Suzuki, Nengxue Wang, Eric R Ashley, Alejandro Crespo, Maria Madeira, Dennis H Leung, Candice Alleyne, Aimie M Ogawa, Sarah Souza, Brande Thomas-Fowlkes, Jerry Di Salvo, Adam Weinglass, Melissa Kirkland, Michele Pachanski, Mary Ann Powles, Effie Tozzo, Taro E Akiyama, Feroze Ujjainwalla, James R Tata, Christopher J Sinz
Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28102847/curcumin-represses-mouse-3t3-l1-cell-adipogenic-differentiation-via-inhibiting-mir-17-5p-and-stimulating-the-wnt-signalling-pathway-effector-tcf7l2
#2
Lili Tian, Zhuolun Song, Weijuan Shao, William W Du, Lisa R Zhao, Kejing Zeng, Burton B Yang, Tianru Jin
Understanding mechanisms underlying adipogenic differentiation may lead to the discovery of novel therapeutic targets for obesity. Wnt signalling pathway activation leads to repressed adipogenic differentiation while certain microRNAs may regulate pre-adipocyte proliferation and differentiation. We show here that in mouse white adipose tissue, miR-17-5p level is elevated after high fat diet consumption. miR-17-5p upregulates adipogenic differentiation, as its over-expression increased while its inhibition repressed 3T3-L1 differentiation...
January 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28098594/mediators-of-diabetic-neuropathy-is-hyperglycemia-the-only-culprit
#3
Anna Grisold, Brian C Callaghan, Eva L Feldman
PURPOSE OF REVIEW: Diabetic peripheral neuropathy (DPN) is a disabling, highly prevalent complication of both type 1 and type 2 diabetes mellitus (T1DM and T2DM). Large clinical studies support the concept that, in addition to hyperglycemia, components of the metabolic syndrome (MetS) may underlie the pathogenesis of DPN, especially in T2DM. This review will present the evidence supporting the MetS and its individual components as potential causal factors for the development of neuropathy...
January 16, 2017: Current Opinion in Endocrinology, Diabetes, and Obesity
https://www.readbyqxmd.com/read/28092182/an-estrogen-receptor-%C3%AE-selective-agonist-inhibits-non-alcoholic-steatohepatitis-in-preclinical-models-by-regulating-bile-acid-and-xenobiotic-receptors
#4
Suriyan Ponnusamy, Quynh T Tran, Thirumagal Thiyagarajan, Duane D Miller, Dave Bridges, Ramesh Narayanan
Non-alcoholic steatohepatitis (NASH) affects 8-10 million people in the US and up to 75% of obese individuals. Despite this, there are no approved oral therapeutics to treat NASH and therefore the need for novel approaches exists. The estrogen receptor β (ER-β)-selective agonist, β-LGND2, inhibits body weight and white adipose tissue, and increases metabolism, resulting in higher energy expenditure and thermogenesis. Due to favorable effects of β-LGND2 on obesity, we hypothesized that β-LGND2 will prevent NASH directly by reducing lipid accumulation in the liver or indirectly by favorably changing body composition...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28087575/treating-inflammation-and-infection-in-the-21st-century-new-hints-from-decoding-resolution-mediators-and-mechanisms
#5
REVIEW
Charles N Serhan
Practitioners of ancient societies from the time of Hippocrates and earlier recognized and treated the signs of inflammation, heat, redness, swelling, and pain with agents that block or inhibit proinflammatory chemical mediators. More selective drugs are available today, but this therapeutic concept has not changed. Because the acute inflammatory response is host protective to contain foreign invaders, much of today's pharmacopeia can cause serious unwanted side effects, such as immune suppression. Uncontrolled inflammation is now considered pathophysiologic and is associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity, and asthma, as well as classic inflammatory diseases (e...
January 13, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28087443/an-update-on-the-physiological-and-therapeutic-relevance-of-gpcr-oligomers
#6
REVIEW
Batoul Farran
The traditional view on GPCRs held that they function as single monomeric units composed of identical subunits. This notion was overturned by the discovery that GPCRs can form homo- and hetero-oligomers, some of which are obligatory, and can further assemble into receptor mosaics consisting of three or more protomers. Oligomerisation exerts significant impacts on receptor function and physiology, offering a platform for the diversification of receptor signalling, pharmacology, regulation, crosstalk, internalization and trafficking...
January 11, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28074253/c-abl-inhibition-mitigates-diet-induced-obesity-through-improving-insulin-sensitivity-of-subcutaneous-fat-in-mice
#7
Rong Wu, Jian-Guang Sun, Ji-Qiu Wang, Binhua Li, Qingsong Liu, Guang Ning, Wanzhu Jin, Zengqiang Yuan
AIMS/HYPOTHESIS: High-energy diets are among the main causes of the global epidemic of metabolic disorders, including obesity and type 2 diabetes. The mechanisms of high-energy-diet-induced metabolic disorders are complex and largely unknown. The non-receptor tyrosine kinase c-Abl plays an important role in adipogenesis in vitro but its role in vivo in the regulation of metabolism is still elusive. Hence, we sought to address the role of c-Abl in diet-induced obesity and obesity-associated insulin resistance...
January 10, 2017: Diabetologia
https://www.readbyqxmd.com/read/28063114/histopathological-changes-in-laparoscopic-sleeve-gastrectomy-specimens-prevalence-risk-factors-and-value-of-routine-histopathologic-examination
#8
Tamer Safaan, Moataz Bashah, Walid El Ansari, Mohsen Karam
BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a common surgical therapeutic option for obese patients, with debate about the value of routine histopathologic examination of LSG specimens. We assessed the following: prevalence of different histopathologic changes in LSG specimens, risk factors associated with premalignant and with frequent histopathologic changes, and whether routine histopathologic examination is warranted for LSG patients with nonsignificant clinical history. METHODS: Retrospective review of records of all LSG patients operated upon at Hamad General Hospital, Qatar (February 2011-July 2014, n = 1555), was conducted...
January 6, 2017: Obesity Surgery
https://www.readbyqxmd.com/read/28049280/new-therapeutic-agents-in-diabetic-nephropathy
#9
REVIEW
Yaeni Kim, Cheol Whee Park
Studies investigating diabetic nephropathy (DN) have mostly focused on interpreting the pathologic molecular mechanisms of DN, which may provide valuable tools for early diagnosis and prevention of disease onset and progression. Currently, there are few therapeutic drugs for DN, which mainly consist of antihypertensive and antiproteinuric measures that arise from strict renin-angiotensin-aldosterone system inactivation. However, these traditional therapies are suboptimal and there is a clear, unmet need for treatments that offer effective schemes beyond glucose control...
January 2017: Korean Journal of Internal Medicine
https://www.readbyqxmd.com/read/28049156/rutin-ameliorates-obesity-through-brown-fat-activation
#10
Xiaoxue Yuan, Gang Wei, Yilin You, Yuanyuan Huang, Hyuek Jong Lee, Meng Dong, Jun Lin, Tao Hu, Hanlin Zhang, Chuanhai Zhang, Huiqiao Zhou, Rongcai Ye, Xiaolong Qi, Baiqiang Zhai, Weidong Huang, Shunai Liu, Wen Xie, Qingsong Liu, Xiaomeng Liu, Chengbi Cui, Donghao Li, Jicheng Zhan, Jun Cheng, Zengqiang Yuan, Wanzhu Jin
Increasing energy expenditure through activation of brown adipose tissue (BAT) is a critical approach to treating obesity and diabetes. In this study, rutin, a natural compound extracted from mulberry and a drug used as a capillary stabilizer clinically for many years without any side effects, regulated whole-body energy metabolism by enhancing BAT activity. Rutin treatment significantly reduced adiposity, increased energy expenditure, and improved glucose homeostasis in both genetically obese (Db/Db) and diet-induced obesity (DIO) mice...
January 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28045403/immunologic-impact-of-the-intestine-in-metabolic-disease
#11
Daniel A Winer, Shawn Winer, Helen J Dranse, Tony K T Lam
Obesity and diabetes are associated with increased chronic low-grade inflammation and elevated plasma glucose levels. Although inflammation in the fat and liver are established features of obesity-associated insulin resistance, the intestine is emerging as a new site for immunologic changes that affect whole-body metabolism. Specifically, microbial and dietary factors incurred by diet-induced obesity influence underlying innate and adaptive responses of the intestinal immune system. These responses affect the maintenance of the intestinal barrier, systemic inflammation, and glucose metabolism...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28045396/hypothalamic-inflammation-in-obesity-and-metabolic-disease
#12
Alexander Jais, Jens C Brüning
Over the last years, hypothalamic inflammation has been linked to the development and progression of obesity and its sequelae. There is accumulating evidence that this inflammation not only impairs energy balance but also contributes to obesity-associated insulin resistance. Elevated activation of key inflammatory mediators such as JNK and IκB kinase (IKK) occurs rapidly upon consumption of a high-fat diet, even prior to significant weight gain. This activation of hypothalamic inflammatory pathways results in the uncoupling of caloric intake and energy expenditure, fostering overeating and further weight gain...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28040759/novel-application-of-a-percutaneous-left-ventricular-assist-device-as-a-bridge-to-transplant-in-a-paediatric-patient-with-severe-heart-failure-due-to-viral-myocarditis
#13
Paul Perry, Elizabeth David, Broadus Atkins, Gary Raff
A 13-year obese female with suspected viral myocarditis presented with acute decompensated heart failure. Due to her body habitus, she was a poor candidate for immediate heart transplantation. A peripherally inserted left ventricular assist device (LVAD) was implanted via the right axillary artery. Following device insertion the patient experienced rapid improvement in symptoms. The LVAD provided effective left ventricular unloading for 50 days, promoting myocardial recovery and maintaining excellent patient performance status...
December 31, 2016: Interactive Cardiovascular and Thoracic Surgery
https://www.readbyqxmd.com/read/28034759/targeting-p-selectin-glycoprotein-ligand-1-p-selectin-interactions-as-a-novel-therapy-for-metabolic-syndrome
#14
REVIEW
Madhukar S Patel, David Miranda-Nieves, Jiaxuan Chen, Carolyn A Haller, Elliot L Chaikof
Obesity-induced insulin resistance and metabolic syndrome continue to pose an important public health challenge worldwide as they significantly increase the risk of type 2 diabetes and atherosclerotic cardiovascular disease. Advances in the pathophysiologic understanding of this process has identified that chronic inflammation plays a pivotal role. In this regard, given that both animal models and human studies have demonstrated that the interaction of P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin is not only critical for normal immune response but also is upregulated in the setting of metabolic syndrome, PSGL-1/P-selectin interactions provide a novel target for preventing and treating resultant disease...
December 9, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/28027231/the-lipo-body-lift-a-new-circumferential-body-contouring-technique-useful-after-bariatric-surgery
#15
Nicolas Bertheuil, Benoit Chaput, Antoine De Runz, Paul Girard, Raphael Carloni, Eric Watier
BACKGROUND: After bariatric surgery, lifting of the lower body involves a contouring technique used to achieve optimal lower trunk reconstruction. The authors describe an innovative procedure applicable after massive weight loss: the lipo-body lift method. The authors describe their experience with this novel, safe procedure. METHODS: Twenty-five abdominal body-contouring reconstructions following massive weight loss were treated by means of circumferential lipo-body lift...
January 2017: Plastic and Reconstructive Surgery
https://www.readbyqxmd.com/read/28025059/microrna-206-prevents-hepatosteatosis-and-hyperglycemia-by-facilitating-insulin-signaling-and-impairing-lipogenesis
#16
Heng Wu, Tianpeng Zhang, Fei Pan, Clifford J Steer, Zhuoyu Li, Xin Chen, Guisheng Song
BACKGROUND & AIMS: The paradox of selective hepatic insulin resistance, wherein the insulin-resistant liver fails to suppress glucose production but continues to produce lipids, has been central to the pathophysiology of hepatosteatosis and hyperglycemia. Our study was designed to investigate the mechanism(s) by which microRNA-206 alleviates the pathogenesis of hepatosteatosis and hyperglycemia. METHODS: Dietary obese mice induced by a high fat diet were used to study the role of microRNA-206 in the pathogenesis of hepatosteatosis and hyperglycemia...
December 23, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/28025030/apelin-apj-system-a-novel-promising-therapy-target-for-pathological-angiogenesis
#17
REVIEW
Lele Wu, Linxi Chen, Lanfang Li
Apelin is the endogenous ligand of the G protein-coupled receptor APJ. Both Apelin and APJ receptor are widely distributed in various tissues such as heart, brain, limbs, retina and liver. Recent research indicates that the Apelin/APJ system plays an important role in pathological angiogenesis which is a progress of new blood branches developing from preexisting vessels via sprouting. In this paper, we review the important role of the Apelin/APJ system in pathological angiogenesis. The Apelin/APJ system promotes angiogenesis in myocardial infarction, ischemic stroke, critical limb ischemia, tumor, retinal angiogenesis diseases, cirrhosis, obesity, diabetes and other related diseases...
December 23, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28013341/emerging-role-of-intestinal-microbiota-and-microbial-metabolites-in-metabolic-control
#18
EDITORIAL
Hilde Herrema, Richard G IJzerman, Max Nieuwdorp
The role of the intestinal microbiota and microbial metabolites in the maintenance of host health and development of metabolic disease has gained significant attention over the past decade. Mechanistic insight revealing causality, however, is scarce. Work by Ussar and co-workers demonstrates that a complex interaction between microbiota, host genetics and environmental factors is involved in metabolic disease development in mice. In addition, Perry and co-workers show that the microbial metabolite acetate augments insulin resistance in rats...
December 24, 2016: Diabetologia
https://www.readbyqxmd.com/read/28008835/-microbiotes-and-metabolic-diseases-the-bases-for-therapeutic-strategies
#19
Rémy Burcelin, Simon Nicolas, Vincent Blasco-Baque
After more than one and a half century, i.e. since Louis Pasteur work on microbes, fermentation, and diseases, biological science has made a giant step in bacteria knowledge. Thanks to an ultra-powerful "microscope", i.e. ultra-fast DNA sequencing, scientists have been able to read and group within a catalog over the last decade, the gene code of bacteria, i.e. the metagenome at the surface of our epithelia. More recently, live bacteria within adipose tissue, defining a tissue microbiota, as well as bacterial fragments such as DNA within the liver, the brain and the blood have been identified...
November 2016: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/28005376/neoglycolipids-for-prolonging-the-effects-of-peptides-self-assembling-glucagon-like-peptide-1-analogues-with-albumin-binding-properties-and-potent-in-vivo-efficacy
#20
Søren B van Witteloostuijn, Karin Mannerstedt, Pernille Wismann, Esben M Bech, Mikkel B Thygesen, Niels Vrang, Jacob Jelsing, Knud J Jensen, Søren L Pedersen
Novel principles for optimizing the properties of peptide-based drugs are needed in order to leverage their full pharmacological potential. We present the design, synthesis, and evaluation of a library of neoglycolipidated glucagon-like peptide 1 (GLP-1) analogues, which are valuable drug candidates for treatment of type 2 diabetes and obesity. Neoglycolipidation of GLP-1 balanced the lipophilicity, directed formation of soluble oligomers, and mediated albumin binding. Moreover, neoglycolipidation did not compromise bioactivity, as in vitro potency of neoglycolipidated GLP-1 analogues was maintained or even improved compared to native GLP-1...
January 3, 2017: Molecular Pharmaceutics
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