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Crystal Structure of the Human Cannabinoid Receptor CB1

Crystal Structure of the Human Cannabinoid Receptor CB1 | Endocrinologist Nation | Scoop.it
Summary Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.

Via Krishan Maggon
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Krishan Maggon 's curator insight, October 22, 2016 7:22 PM
Cell Volume 167, Issue 3, p750–762.e14, 20 October 2016 

 Crystal Structure of the Human Cannabinoid Receptor CB1 

 Tian Hua, Kiran Vemuri, Mengchen Pu, Lu Qu, Gye Won Han, Yiran Wu, Suwen Zhao, Wenqing Shui, Shanshan Li, Anisha Korde, Robert B. Laprairie, Edward L. Stahl, Jo-Hao Ho, Nikolai Zvonok, Han Zhou, Irina Kufareva, Beili Wu, Qiang Zhao, Michael A. Hanson, Laura M. Bohn, Alexandros Makriyannis, Raymond C. Stevens, Zhi-Jie Liu 

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Yale Medicine doctors combat heartbreaking hair loss > Yale Medicine | Yale School of Medicine

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Effects of milk proteins on blood pressure: a meta-analysis of randomized control trials. - PubMed - NCBI

Effects of milk proteins on blood pressure: a meta-analysis of randomized control trials. - PubMed - NCBI | Endocrinologist Nation | Scoop.it
Hypertens Res. 2016 Oct 13. doi: 10.1038/hr.2016.135. [Epub ahead of print]
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A Game Changer for Detecting Complications From Obesity - Children's National Health System

A Game Changer for Detecting Complications From Obesity - Children's National Health System | Endocrinologist Nation | Scoop.it
There is a direct relationship between the amount of visceral adipose, or belly fat, a person has and development of some of the most common and life-threatening complications of obesity, including cardiovascular disease and the insulin resistance that leads to diabetes. What remained unclear, until recently, were the precise mechanisms for how the increase in belly fat triggers the onset of additional disease.
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A stem cell gene found to command skeletal muscle regeneration | University of Helsinki

A stem cell gene found to command skeletal muscle regeneration | University of Helsinki | Endocrinologist Nation | Scoop.it
Prox1 gene has long been known to play an important role in fetal development. Finnish researchers have now discovered that Prox1 is essential also for skeletal muscle stem cell differentiation.
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Smart drug clears fat from liver and blood

Smart drug clears fat from liver and blood | Endocrinologist Nation | Scoop.it
Scientists of Helmholtz Zentrum München and Technical University of Munich have developed a ‘smart’ drug that safely clears the liver of fat and prevents blood vessels from clogging up. Similar to a trojan horse, the drug enters the liver with a trick: It uses the pancreatic hormone glucagon as vehicle to shuttle thyroid hormone T3 the live while keeping it away from other organs, thereby improving cholesterol and lipid metabolism while avoiding typical side effects of thyroid hormone.
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Gene could help explain insulin resistance

Gene could help explain insulin resistance | Endocrinologist Nation | Scoop.it
Shutting off a gene implicated in insulin resistance leads to damaged mitochondria and decreased exercise capacity in mice.
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Gene Identified that Drives Aggressive Prostate Cancer

Gene Identified that Drives Aggressive Prostate Cancer | Endocrinologist Nation | Scoop.it
An overactive gene appears to cause some prostate cancers to transform from a typical tumor type to a much more aggressive form of the disease.
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‘Game-changing’ immunotherapy doubles head and neck cancer survival - The Institute of Cancer Research, London

‘Game-changing’ immunotherapy doubles head and neck cancer survival - The Institute of Cancer Research, London | Endocrinologist Nation | Scoop.it
An immunotherapy drug has been hailed as a potential ‘game changer’ after being found to greatly improve survival for patients with relapsed head and neck cancer — a disease which is notoriously difficult to treat.
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Heavy hitters: Obesity rate soars among professional baseball players

Heavy hitters: Obesity rate soars among professional baseball players | Endocrinologist Nation | Scoop.it
Major League Baseball players have become overwhelmingly overweight and obese during the last quarter century, say health researchers.
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Fat cells that amplify nerve signals in response to cold also affect blood sugar metabolism: September 2016 News Releases - UT Southwestern, Dallas, TX

Fat cells that amplify nerve signals in response to cold also affect blood sugar metabolism: September 2016 News Releases - UT Southwestern, Dallas, TX | Endocrinologist Nation | Scoop.it
But since white fat cells have very few nerves, how do beige fat cells get the message that it’s cold outside?
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Conversion of Vertical Sleeve Gastrectomy to a Functional Single-Anastomosis Gastric Bypass: Technique and Preliminary Results Using a Non-Adjustab... - PubMed - NCBI

Conversion of Vertical Sleeve Gastrectomy to a Functional Single-Anastomosis Gastric Bypass: Technique and Preliminary Results Using a Non-Adjustab... - PubMed - NCBI | Endocrinologist Nation | Scoop.it
Obes Surg. 2016 Oct 5. [Epub ahead of print]
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Capsaicin 8% Patch in Painful Diabetic Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study. - PubMed - NCBI

Capsaicin 8% Patch in Painful Diabetic Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study. - PubMed - NCBI | Endocrinologist Nation | Scoop.it
J Pain. 2016 Oct 13. pii: S1526-5900(16)30244-9. doi: 10.1016/j.jpain.2016.09.008. [Epub ahead of print]
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Levels of metabolic markers in drug-naive prediabetic and type 2 diabetic patients. - PubMed - NCBI

Levels of metabolic markers in drug-naive prediabetic and type 2 diabetic patients. - PubMed - NCBI | Endocrinologist Nation | Scoop.it
Acta Diabetol. 2016 Oct 18. [Epub ahead of print]
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Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes. - PubMed - NCBI

Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes. - PubMed - NCBI | Endocrinologist Nation | Scoop.it
Diabetes Ther. 2016 Oct 12. [Epub ahead of print] REVIEW
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Rescooped by Liz Ciccio from Hepatitis C New Drugs Review
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JCI - Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance

JCI - Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance | Endocrinologist Nation | Scoop.it
RT @jclinicalinvest: PKEe targets phosphorylated #insulin receptor Thr1160 in hepatic insulin resistance https://t.co/48g5bPxvJO @YaleMed #…

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C-ε (PKCε) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCε inhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site Thr1160 as a PKCε substrate in the functionally critical INSR kinase activation loop. We hypothesized that Thr1160 phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCε in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue Thr1150 (InsrT1150A mice) were protected from high fat diet–induced hepatic insulin resistance. InsrT1150A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR Thr1160 phosphorylation and provide further mechanistic links between PKCε and INSR in mediating NAFLD-induced hepatic insulin resistance.

Via Krishan Maggon
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Krishan Maggon 's curator insight, October 17, 2016 7:45 PM
Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance Max C. Petersen ... Jesse Rinehart, Gerald I. Shulman Published October 17, 2016 Citation Information: J Clin Invest. 2016. doi:10.1172/JCI86013.
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Indigenous group add to evidence tying cesarean birth to obesity - Purdue University

Indigenous group add to evidence tying cesarean birth to obesity - Purdue University | Endocrinologist Nation | Scoop.it
A Purdue University study of an indigenous group of Maya people reinforces the link between Cesarean births and obesity.
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Study Finds New Approach to Block Binge Eating | Public Relations

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ESMO 2016: Metformin Significantly Lowers the Risk of Cancer Progression in Patients with Diabetes and Advanced pNETs | ESMO

ESMO 2016: Metformin Significantly Lowers the Risk of Cancer Progression in Patients with Diabetes and Advanced pNETs | ESMO | Endocrinologist Nation | Scoop.it
Large retrospective analysis shows diabetic patients with pNETs on metformin have prolonged PFS
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Regenerative Bandage Heals Diabetic Wounds Faster

Regenerative Bandage Heals Diabetic Wounds Faster | Endocrinologist Nation | Scoop.it
Guillermo Ameer’s antioxidant bandage heals wounds four times faster by delivering a protein that promotes cell repair.
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Patient-reported outcomes in transition from high-dose U-100 insulin to human regular U-500 insulin in severely insulin-resistant patients with typ... - PubMed - NCBI

Patient-reported outcomes in transition from high-dose U-100 insulin to human regular U-500 insulin in severely insulin-resistant patients with typ... - PubMed - NCBI | Endocrinologist Nation | Scoop.it
Health Qual Life Outcomes. 2016 Sep 30;14(1):139.
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Brain’s biological clock stimulates thirst before sleep | Newsroom - McGill University

Brain’s biological clock stimulates thirst before sleep | Newsroom - McGill University | Endocrinologist Nation | Scoop.it
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Combined Exercise Training Improves Glycemic Control in Adult With Cystic Fibrosis. - PubMed - NCBI

Combined Exercise Training Improves Glycemic Control in Adult With Cystic Fibrosis. - PubMed - NCBI | Endocrinologist Nation | Scoop.it
Med Sci Sports Exerc. 2016 Sep 23. [Epub ahead of print]
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