Leptin → CB1 → AMPK-SIRT1-PGC-1alpha → FGF21

date		Fri, Aug 15, 2008 at 11:05 PM
subject		Fwd: paper for 8/19 lab meeting

老師：

這篇的作者 Christoph Buettner，想說的故事好像跟我們有像喔！

The Role Of Stat3 Signaling In Leptin´s Pleitropic Action.

Christoph Buettner
Medicinemount Sinai School Of Medicine Of Nyu
of New York University
new York, Ny 100296574

Grant 7K08DK074873-02 from National Institute Of Diabetes And Digestive And Kidney Diseases, IRG: DDK

Abstract: Leptin has potent effects on insulin action, carbohydrate and lipid metabolism, which are largely independent of its effects on feeding behavior. With regard to adipocyte metabolism, leptin leads to a depletion of triglyceride content without a concomitant rise in circulating free fatty acids due to an increase in mitochondrial oxidation and the induction of futile metabolic pathways. Our previous work has revealed that leptin controls adipocyte metabolism by central pathways that descend from the medio-basal hypothalamus (MBH), leading to a strong inhibition of lipogenic gene expression in white adipose tissue (WAT). Remarkably, MBH leptin suppresses the expression and activity of two important transcription factors, sterol-regulatory-element-binding protein-1c (SREBPI-c) and peroxisome proliferator activated receptor (PPAR) gamma, independent of circulating glucose or insulin levels. These effects of central leptin on adipocyte metabolism appear not to require intact signal transducer and activator of transcription (Stat3) signaling, whereas leptin´s acute effects on food intake, hepatic glucose fluxes and gonadotropin secretion are lost when Stat3 signaling is prevented. The aim of this proposal is to delineate the contributions of hypothalamic leptin signaling in controlling adipocyte metabolism. We hypothesize that Stat3 independent effects of leptin play a major role in the regulation of adipocyte metabolism and thereby regulate body adiposity. These studies should lead to a better understanding of the basic biological processes by which central pathways regulate body adiposity independently of food intake

Keywords: adipocyte, biological signal transduction, hypothalamus, leptin, lipid metabolism, transcription factor autonomic nervous system, free fatty acid, gene expression, lipid biosynthesis, obesity, oxidation calorimetry, glucose clamp technique, magnetic resonance imaging, polymerase chain reaction, transfection, western blotting

Project start date: 2006-09-20

Project end date: 2010-08-31

然後他今年八月又發一篇..

Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Bátkai S, Marsicano G, Lutz B, Buettner C, Kunos G.
Hepatic CB(1) receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest. 2008 Aug 1.

老師加油，妳要跑比他更快喔！

　　　※

張惠妹 - 記得

誰還記得是誰先說永遠的愛我　以前的一句話是我們以後的傷口

過了太久沒人記得當初那些溫柔　我和你手牽手說要一起走到最後

我們都忘了　這條路走了多久　心中是清楚的　有一天　有一天都會停的

讓時間說真話　雖然我也害怕　在天黑了以後　我們都不知道會不會有以後

我們都累了　卻沒辦法往回走　兩顆心都迷惑　怎麼說　怎麼說都沒有救

親愛的為什麼　也許你也不懂　兩個相愛的人　等著對方先說想分開的理由

誰還記得愛情開始變化的時候　我和你的眼中看見了不同的天空

走得太遠終於走到分岔路的路口　是不是你和我要有兩個相反的夢

誰還記得是誰先說永遠的愛我　以前的一句話是我們以後的傷口

過了太久沒人記得當初那些溫柔　我和你手牽手說要一起走到最後

我和你手牽手說要一起　走到最後

　　　※

J Clin Invest. 2008 Sep;118(9):3160-9.

Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice.

Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Bátkai S, Marsicano G, Lutz B, Buettner C, Kunos G.

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA.

↓

Nat Med. 2008 Jun;14(6):667-75. Epub 2008 Jun 1.

Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms.

Buettner C, Muse ED, Cheng A, Chen L, Scherer T, Pocai A, Su K, Cheng B, Li X, Harvey-White J, Schwartz GJ, Kunos G, Rossetti L, Buettner C.

Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1005, New York, New York 10029, USA. christoph.buettner@mssm.edu

Comment in:

Nat Med. 2008 Jun;14(6):604-6.

The long reach of leptin.
Maratos-Flier E

http://www.news-medical.net/news/2007/06/08/26184.aspx?page=2
New regulator of fat metabolism identified
8. June 2007 12:27
In this latest paper, Maratos-Flier and colleagues studied mice that had been fed a ketogenic diet high in both saturated fat and unsaturated fat and practically devoid of carbohydrates. “Despite the high fat content of this diet, the study animals maintained normal levels of circulating lipids,” she explains. “We wanted to learn what factors might be responsible for creating this state in which consumed calories were being burned off in the liver rather than being stored as fat.”
Because the physiologic changes in the animals didn't appear to be explained by typical hormonal regulators – neurotransmitters that normally regulate appetite -- the researchers set out to identify which genes were unique to this ketogenic phenotype, exploring the possibility that hepatocytes were playing an active role in the process.
And, using micoarray gene analysis, they discovered that their hunch was correct: FGF21, a liver-derived fibroblast growth factor gene, was significantly increased in the mice that had been fed ketogenic diets.
“FGF21 had previously been identified as a potential metabolic regulator by scientists at Eli Lilly, who showed that transgenic mice that overexpressed FGF21 were protected from diet-induced obesity, had smaller fat cells and had more brown adipose tissue,”says Maratos-Flier. “But little was actually known about FGF21's physiologic roles. Working with Jeffrey Flier's lab, we were able to show that FGF21 is essential for fatty acid oxidation.”
Furthermore, she explains, when FGF21 was inhibited, the mice developed a massive accumulation of fat in the liver and an extreme increase in circulating lipids.
A second study by Maratos-Flier and colleagues published in the June 2007 issue of the American Journal of Physiology further elucidates the unique metabolic changes that occur with the consumption of a ketogenic diet.
“Although the purpose of both of these studies was to glean insights into metabolic physiology, our findings suggest that increased levels of FGF21 may be a potential mechanism behind low-carbohydrate diets' beneficial properties when it comes to lipidmetabolism,” says Maratos-Flier. “Diets that limit carbohydrates and eliminate transfats, and at the same time emphasize fiber and good fats, appear to be healthiest, especially among individuals who are predisposed to developing diabetes.”
This study was supported, in part, by grants from the National Institutes of Health and from Takeda Pharmaceuticals.
Coauthors include BIDMC investigators Michael Badman (lead author), Pavlos Pissios, Adam Kennedy and Jeffrey S. Flier, MD; and George Koukos of Boston University School of Medicine.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the JoslinDiabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit
http://www.bidmc.harvard.edu.

↓

Am J Physiol Endocrinol Metab. 2008 Sep;295(3):E586-94. Epub 2008 Jun 24.

Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice.

Bradley RL, Jeon JY, Liu FF, Maratos-Flier E.

Dept. of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

↓

Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22510-5. Epub 2009 Dec 14.

PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis.

Estall JL, Ruas JL, Choi CS, Laznik D, Badman M, Maratos-Flier E, Shulman GI, Spiegelman BM.

Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11288-93. Epub 2009 Jun 22.
SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats.
Erion DM, Yonemitsu S, Nie Y, Nagai Y, Gillum MP, Hsiao JJ, Iwasaki T, Stark R, Weismann D, Yu XX, Murray SF, Bhanot S,Monia BP, Horvath TL, Gao Q, Samuel VT, Shulman GI.
Howard Hughes Medical Institute, Department of Internal Medicine, Yale University School of Medicine, New Haven CT 06510, USA.

↓

Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12553-8. Epub 2010 Jun 28.

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway.

Chau MD, Gao J, Yang Q, Wu Z, Gromada J.

Cardiovascular and Metabolism Disease Area, Novartis Institute for Biomedical Research, Inc., Cambridge, MA 02139, USA.

Trends Endocrinol Metab. 2010 Dec 29. [Epub ahead of print]

FGF21 reloaded: challenges of a rapidly growing field.

Kharitonenkov A, Larsen P.

Eli Lilly and Company, Diabetes Research, Indianapolis, IN 46285, USA.

↓

J Nutr Metab. 2011;2011:981315. Epub 2011 Feb 6.

FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology.

Murata Y, Konishi M, Itoh N.

Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto 606-8501, Japan.

Am J Clin Nutr. 2011 Feb 23. [Epub ahead of print]

Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis.

Domouzoglou EM, Maratos-Flier E.

Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

http://www.bidmc.org/CentersandDepartments/Departments/DigestiveDiseaseCenter/LiverCenter/NonalcoholicFattyLiverDiseaseProgram/ClinicalResearchTrials.aspx
The Effect of Fasting on Nonalcoholic Fatty Liver Disease
People with nonalcoholic fatty liver disease have excess fat stored in the liver. We recently discovered that people with NAFLD also have elevated levels of a protein called fibroblast growth factor 21 (FGF21). We are investigating whether FGF21 levels in the blood correlate with the amount of fat in the liver.

This study will investigate the effect of a single 72-hour fast on FGF21 levels and the amount of fat stored in the liver. We will use MRI to measure the amount of fat in the liver before and after the 72-hour fasting period. All participants will have a blood test and an MRI of the liver before and after the fasting period. Participants will be given the results of the MRI and will be paid for taking part in the study.

For more information, please email Jody Dushay, MD.
The Effect of a Low-Calorie Diet on Nonalcoholic Fatty Liver Disease
Weight loss is known to be an effective treatment for nonalcoholic fatty liver disease (NAFLD), but it is not known how much less fat is in the liver after a period of weight loss.

This study will investigate the effect of a hypocaloric (low-calorie) diet on the amount of fat stored in the liver and on levels of a protein called fibroblast growth factor 21 (FGF21), which can be measured in the blood. We will use MRI to measure the amount of fat in the liver before and after the dieting period.　All participants will have a blood test and an MRI of the liver before and after the dieting period. Study participants will be required to come to the Clinical Research Center at the Beth Israel Deaconess Medical Center approximately once a week for brief outpatient study visits. The target weight loss is 7-10% of initial body weight. Participants will be paid for taking part in the study. We will also provide all food during the dieting period and parking vouchers for study visits.

For more information, please email Jody Dushay, MD.

Am J Clin Nutr. 2011 Feb 2. [Epub ahead of print]

Energy, evolution, and human diseases: an overview.

Roth J, Szulc AL, Danoff A.

Feinstein Institute for Medical Research, Elmezzi Graduate School of Molecular Medicine, North Shore-Long Island Jewish Health System, Manhasset, NY.

Abstract

In the symposium entitled "Transcriptional controls of energy sensing," the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α), a transcriptional co-activator that has powerful effects on mitochondria; 3) methylation and demethylation in response to metabolic fluctuations; and 4) FGF21 (fibroblast growth factor 21) as an emerging hormone-like intercellular metabolic coordinator. This introduction places these advances within a broad overview of energy sensing and energy balance, with a focus on human evolution and disease. Four key elements of human biology are analyzed: 1) elevated body temperature; 2) complex prolonged reproductive pathways; 3) emergence of 4 large, well-defined fat depots, each with its own functional role; and 4) an immune system that is often up-regulated by nutrition-related signals, independent of the actual presence of a pathogen. We propose that an overactive immune system, including the "metabolic syndrome," was adopted evolutionarily in the distant past to help hold out against unconquerable infections such as tuberculosis, malaria, and trypanosomiasis. This immune activation is advantageous in the absence of other disease management methods, especially under conditions in which life expectancy is short. The inflammation has become a major agent of pathology in wealthy populations in whom the pathogens are a minor threat and life expectancy is long. The "Conclusions" section sketches cautiously how understanding the molecules involved in energy sensing and energy balance may lead to specific therapies for obesity and diabetes and for their complications.

2011-02-27(19:32) :
未分類 :
留言 0 :
引用 0

回到此頁首

PGC-1alpha ─ ERRalpha ─ Sirtuin 3

Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):51-63.

The role of the endocannabinoid system in lipogenesis and fatty acid metabolism.

Vettor R, Pagano C.

Internal Medicine 3, Endocrine-metabolic Laboratory, Department of Medical and Surgical Sciences, University of Padova, via Ospedale 105, 35128 Padova, Italy.

Diabetes. 2008 Aug;57(8):2028-36. Epub 2008 May 13.

Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes.

Tedesco L, Valerio A, Cervino C, Cardile A, Pagano C, Vettor R, Pasquali R, Carruba MO, Marsicano G, Lutz B, Pagotto U, Nisoli E.

Integrated Laboratories Network, Center for Study and Research on Obesity, Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, Milan University, Milan, Italy.

↓

J Clin Invest. 2006 Oct;116(10):2791-8. Epub 2006 Sep 14.

TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents.

Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L, Cantoni O, Clementi E, Moncada S, Carruba MO,Nisoli E.

Integrated Laboratories Network, Center for Study and Research on Obesity, Department of Pharmacology, School of Medicine, University of Milan, Milan, Italy.

→ eNOS, NRF-1, Tfam, PGC1a mRNA were markedly reduced in WAT, BAT, and soleus muscle of ob/ob mice, fa/fa rats, and DIO mice.

↓
[vv] Seminar 20091215 http://tinyurl.com/27v3c2f

↓

Trends Endocrinol Metab. 2008 Oct;19(8):269-76. Epub 2008 Sep 6.

ERRalpha: a metabolic function for the oldest orphan.

Villena JA, Kralli A.

Institut de Recerca Hospital Universitari Vall d'Hebron, Grup de Metabolisme i Obesitat, Barcelona, Spain.

Figure 3

ERRα function in vivo is important for adaptive metabolic responses under conditions of increased energetic demand. Mice lacking ERRα show compromised responses to stresses imposed by exposure to cold, cardiac overload, and bacterial infection. In all three cases, a decreased capacity for oxidative metabolism leads to reduced fitness [44,46,52]. A role for ERRα in skeletal muscle is supported by findings that ERRα null mice have a reduced capacity for exercise (Villena and Kralli, unpublished data). ERRα may have additional roles in other states, as indicated by the increased expression of the gluconeogenic/glyceroneogenic enzyme PEPCK in livers of fed mice [56].

↓

Announcement:
Recent Papers on Aging across Cell Press

FREE Article Access sponsored by Cell Symposia on Metabolism & Aging

Metabolic Regulation of Stem Cell Behavior and Implications for Aging
Heinrich Jasper, D. Leanne Jones

Targeted Expression of Catalase to Mitochondria Prevents Age-Associated Reductions in Mitochondrial Function and Insulin Resistance
Hui-Young Lee et al.

Nuclear Receptor Corepressor SMRT Regulates Mitochondrial Oxidative Metabolism and Mediates Aging-Related Metabolic Deterioration
Shannon M. Reilly et al.

The Cell-Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity
Jenni Durieux et al.

Sirt3 Promotes the Urea Cycle and Fatty Acid Oxidation during Dietary Restriction
William C. Hallows et al.

SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production
Tadahiro Shimazu et al.

Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress
Randa Tao et al.

Calorie Restriction Reduces Oxidative Stress by SIRT3-Mediated SOD2 Activation
Xiaolei Qiu et al.

Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction
Shinichi Someya et al.

↓
Mol Cell. 2011 Jan 21;41(2):139-49.

Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction.

Hallows WC, Yu W, Smith BC, Devires MK, Ellinger JJ, Someya S, Shortreed MR, Prolla T, Markley JL, Smith LM, Zhao S, Guan KL, Denu JM.

¹ Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706, USA

² Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA

³ Department of Genetics, University of Wisconsin, Madison, WI 53706, USA

⁴ Department of Chemistry, University of Wisconsin, Madison, WI 53706, USA

⁵ Molecular and Cell Biology Lab, School of Life Sciences, Fudan University, Shanghai 200032, China
⁶ Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA

Graphical Abstract

Highlights

► High-throughput analyses identify potential targets of Sirt3 ► Sirt3 deacetylates and stimulates ornithine transcarbamoylase ► Caloric restriction induces Sirt3 expression and stimulation of the urea cycle ► Sirt3 regulates amino acid catabolism and β-oxidation during caloric restriction

↓
PLoS One. 2010 Jul 22;5(7):e11707.

Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis.

Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, Fang F, Chang Y.

The National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

An external file that holds a picture, illustration, etc.<br />Object name is pone.0011707.g008.jpg Object name is pone.0011707.g008.jpg

An external file that holds a picture, illustration, etc.<br />Object name is pone.0011707.g008.jpg Object name is pone.0011707.g008.jpg

Figure 8

Scheme illustrating a regulatory pathway including PGC-1α and SIRT3 governing ROS level and mitochondrial biogenesis.

PGC-1α coactivates ERRα to stimulate the expression of mSIRT3, which, in turn, increases the expression of the ROS-detoxifying enzymes GPx1 and SOD2 to suppress the ROS levels. Meanwhile, ectopic expression of SIRT3 leads to an increase of CREB phosphorylation, which subsequently stimulates the expression of PGC-1α and its target gene UCP1, finally decreasing intracellular ROS level. SIRT3 is also involved in mitochondrial biogenesis.

2011-02-19(13:51) :
未分類 :
留言 0 :
引用 0

回到此頁首

From "Slim Body" to "Wii Are Family"

[Part 4] 2009 Taiwan Presentation @ Pardubice (Something More About Taiwan!)

popocat9: This video is made by 2009 Taiwanese Exchange Students in University of Pardubice, Czech Republic, and presented on 10. Dec. 2009 @ University of Pardubice National Evening Activity. Hope that erasmus students from different countries could know more and discover different about Taiwan! (Ps: The History part was made by 2008 CTU Taiwan Presentation Team @ Prague.)

　　　※

Paul:

I see Dr. Noah Fierer's study this weekend. CSI come into university!!!!! COOL!!

http://www.youtube.com/watch?v=K4b7eqZAWuA

↑ National Science Council also posted this video in their general science blog, also in FaceBook..

Physiology at the Crossroads of Biomedical Engineering and Medicine
Physiology In Focus-Physiology and Biomedical Engineering: Partners in Translational Research

Wednesday, April 28� 10:30 AM-12:30 PM

Anaheim Convention Center, Ballroom C

Thanks of APS again. Tell you some other interesting thing about biomedical engineering..

In Taiwan and Japan, "slim body" is very very important to girls and ladies. Thus these are hot and popular in Taiwan and Japan..

http://www.funaicare.com/company2_4e.asp

These products.. really has FDA and EMPT certification!!!

Based on our CB1 and CXCR-4 projects, I presented an interesting J Bone Miner Res paper in 2008 and got very good feedback. My colleagues say vivi these paper really let them want to buy one..

Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17879-84. Epub 2007 Oct 24.

Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals.

Rubin CT, Capilla E, Luu YK, Busa B, Crawford H, Nolan DJ, Mittal V, Rosen CJ, Pessin JE, Judex S.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794, USA.clinton.rubin@sunysb.edu

↓

J Bone Miner Res. 2009 Jan;24(1):50-61.

Mechanical stimulation of mesenchymal stem cell proliferation and differentiation promotes osteogenesis while preventing dietary-induced obesity.

Luu YK, Capilla E, Rosen CJ, Gilsanz V, Pessin JE, Judex S, Rubin CT.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794-2580, USA.

I presented these two papers in my seminar time.

It really has in vivo study in aging mouse!!!!!

Int J Obes (Lond). 2010 Feb;34(2):401-5. Epub 2009 Nov 24.

Development of diet-induced fatty liver disease in the aging mouse is suppressed by brief daily exposure to low-magnitude mechanical signals.

Luu YK, Ozcivici E, Capilla E, Adler B, Chan E, Shroyer K, Rubin J, Judex S, Pessin JE, Rubin CT.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-2580, USA.

　　　※

http://news.cnet.com/8301-17938_105-20005123-1.html

Nintendo, AHA: The Wii, good for your heart

http://missmiumiu.tumblr.com/post/611754500/50-kids-freaking-the-hell-out-over-getting-a-wii

2010-11-09(19:16) :
未分類 :
留言 0 :
引用 0

回到此頁首

PUFA → ChREBP → anti-cancer. So happy there has INSERM & CNRS in the world!!

https://aom3.americaonthemove.org/default.aspx
America On the Move

↓
http://rawfoodlivingdiet.com/cancer-cells-slurp-up-fructose-us-study-finds

Cancer cells slurp up fructose, US study finds

By now everyone knows that hi fructose syrup is bad for you on many levels. This article about a U.S. study dives even deeper:

Aug 2 (Reuters) - Pancreatic tumor cells use fructose to divide and proliferate, U.S. researchers said on Monday in a study that challenges the common wisdom that all sugars are the same.

Tumor cells fed both glucose and fructose used the two sugars in two different ways, the team at the University of California Los Angeles found.

They said their finding, published in the journal Cancer Research, may help explain other studies that have linked fructose intake with pancreatic cancer, one of the deadliest cancer types.

"These findings show that cancer cells can readily metabolize fructose to increase proliferation," Dr. Anthony Heaney of UCLA's Jonsson Cancer Center and colleagues wrote.

"They have major significance for cancer patients given dietary refined fructoseconsumption, and indicate that efforts to reduce refined fructose intake or inhibitfructose-mediated actions may disrupt cancer growth."

Americans take in large amounts of fructose, mainly in high fructose corn syrup, a mix of fructose and glucose that is used in soft drinks, bread and a range of other foods.

Politicians, regulators, health experts and the industry have debated whether high fructose corn syrup and other ingredients have been helping make Americans fatter and less healthy.

Too much sugar of any kind not only adds pounds, but is also a key culprit in diabetes, heart disease and stroke, according to the American Heart Association.

Several states, including New York and California, have weighed a tax on sweetened soft drinks to defray the cost of treating obesity-related diseases such as heart disease, diabetes and cancer.

The American Beverage Association, whose members include Coca-Cola (KO.N) and Kraft Foods (KFT.N) have strongly, and successfully, opposed efforts to tax soda. [ID:nN12233126]

The industry has also argued that sugar is sugar.

Heaney said his team found otherwise. They grew pancreatic cancer cells in lab dishes and fed them both glucose and fructose.

Tumor cells thrive on sugar but they used the fructose to proliferate. "Importantly,fructose and glucose metabolism are quite different," Heaney's team wrote.

"I think this paper has a lot of public health implications. Hopefully, at the federal level there will be some effort to step back on the amount of high fructose corn syrup in our diets," Heaney said in a statement.

Now the team hopes to develop a drug that might stop tumor cells from making use offructose.

U.S. consumption of high fructose corn syrup went up 1,000 percent between 1970 and 1990, researchers reported in 2004 in the American Journal of Clinical Nutrition.

(Reporting by Maggie Fox; Editing by Cynthia Osterman)

↓

Cancer Res. 2010 Aug 1;70(15):6368-76. Epub 2010 Jul 20.

Fructose induces transketolase flux to promote pancreatic cancer growth.

Liu H, Huang D, McArthur DL, Boros LG, Nissen N, Heaney AP.

Authors' Affiliations: Departments of Medicine and Neurosurgery, David Geffen School of Medicine, University of California; SiDMAP LLC; Cedars-Sinai Medical Center, Los Angeles, California.

Abstract

Carbohydrate metabolism via glycolysis and the tricarboxylic acid cycle is pivotal for cancer growth, and increased refined carbohydrate consumption adversely affects cancer survival. Traditionally,glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolized, and little attention has been given to sugars other than glucose. However,fructose intake has increased dramatically in recent decades and cellular uptake of glucose andfructose uses distinct transporters. Here, we report that fructose provides an alternative substrate to induce pancreatic cancer cell proliferation. Importantly, fructose and glucose metabolism are quite different; in comparison with glucose, fructose induces thiamine-dependent transketolase flux and is preferentially metabolized via the nonoxidative pentose phosphate pathway to synthesize nucleic acids and increase uric acid production. These findings show that cancer cells can readily metabolize fructose to increase proliferation. They have major significance for cancer patients given dietary refined fructose consumption, and indicate that efforts to reduce refined fructose intake or inhibit fructose-mediated actions may disrupt cancer growth.

Figure 5.

Schematic model summarizing the differences in glucose (A) and fructose (B) metabolism in pancreatic cancer cells showing the preferential use of fructose in the TK-dependent nonoxidative pentose phosphate shunt.

↓

Cell Metab. 2006 Aug;4(2):107-10.

Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis.

Uyeda K, Repa JJ.

Dallas Veterans Affairs Medical Center, Dallas, Texas 75390, USA. kosaku.uyeda@utsouthwestern.edu

Abstract

The ability of an organism to sense and store nutrients is vital to survival. The liver is the major organ responsible for converting excess dietary carbohydrate to lipid for storage. An elegant molecular pathway has evolved that allows increased glucose flux into hepatocytes to generate a signaling molecule, xylulose 5-phosphate, that triggers rapid changes in glycolytic enzyme activities and nuclear import of a transcription factor, ChREBP, which coordinates the transcriptional regulation of enzymes that channel the glycolytic end-products into lipogenesis. Further understanding of this metabolic cascade should provide insights on conditions such as fatty liver, obesity, and the metabolic syndrome.

Figure 3. The central role of ChREBP in linking glycolysis and lipogenesis in hepatocytes Catabolism of glucose yields pyruvate, which can be channeled into fatty acid synthesis. Proteins are indicated in italicized uppercase letters, metabolic intermediates in lowercase letters. The allosteric regulation of early steps in glycolysis are indicated in blue: xylulose-5-phosphate (Xu-5-P) and fructose-2,6-bisphosphate (Fru-2,6-P₂) positively affect key enzymes PP2A, the kinase moiety of the bifunctional enzyme PF2K-Pase, and phosphofructokinase (PFK). Transcriptional regulation of the terminal step of glycolysis (via L-PK) and key enzymes of lipogenesis is controlled by ChREBP (shown in red). Concomitant production of NADPH by the hexose monophosphate shunt pathway (HMP Shunt) in the production of Xu-5-P and the recycling of pyruvate from citrate-liberated oxaloacetate (OAA) by malic enzyme (ME) provides reducing equivalents necessary for fatty acid synthesis.

↓

J Clin Invest. 2008 Mar;118(3):956-64.

ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver.

Denechaud PD, Bossard P, Lobaccaro JM, Millatt L, Staels B, Girard J, Postic C.

Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS, UMR 8104, Paris, France.

Comment in:

J Clin Invest. 2008 Mar;118(3):841-4.

Abstract

The transcription factor carbohydrate-responsive element-binding protein (ChREBP) has emerged as a central regulator of lipid synthesis in liver because it is required for glucose-induced expression of the glycolytic enzyme liver-pyruvate kinase (L-PK) and acts in synergy with SREBP to induce lipogenic genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Liver X receptors (LXRs) are also important regulators of the lipogenic pathway, and the recent finding that ChREBP is a direct target of LXRs and that glucose itself can bind and activate LXRs prompted us tostudy the role of LXRs in the induction of glucose-regulated genes in liver. Using an LXR agonist in wild-type mice, we found that LXR stimulation did not promote ChREBP phosphorylation or nuclear localization in the absence of an increased intrahepatic glucose flux. Furthermore, the induction of ChREBP, L-PK, and ACC by glucose or high-carbohydrate diet was similar in LXRalpha/beta knockout compared with wild-type mice, suggesting that the activation of these genes by glucoseoccurs by an LXR-independent mechanism. We used fluorescence resonance energy transfer analysis to demonstrate that glucose failed to promote the interaction of LXRalpha/beta with specific cofactors. Finally, siRNA silencing of ChREBP in LXRalpha/beta knockout hepatocytes abrogatedglucose-induced expression of L-PK and ACC, further demonstrating the central role of ChREBP inglucose signaling. Taken together, our results demonstrate that glucose is required for ChREBP functional activity and that LXRs are not necessary for the induction of glucose-regulated genes in liver.

J Lipid Res. 2006 Sep;47(9):2028-41. Epub 2006 Jun 21.

Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity.

Wang Y, Botolin D, Xu J, Christian B, Mitchell E, Jayaprakasam B, Nair MG, Peters JM, Busik JV, Olson LK, Jump DB.

Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.

Erratum in:

J Lipid Res. 2006 Oct;47(10):2353. Nair, Muraleedharan [corrected to Nair, Muraleedharan G]; Peters, Jeffery M [corrected to Peters, Jeffrey M]; Busik, Julia [corrected to Busik, Julia V].

Abstract

Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice establish that PPARalpha was required for WY14643-mediated induction of fatty acid elongase-5 (Elovl-5), Elovl-6, and all three desaturases [Delta(5) desaturase (Delta(5)D), Delta(6)D, and Delta(9)D]. Increased nuclear sterol-regulatory element binding protein-1 (SREBP-1) correlated with enhanced expression of Elovl-6, Delta(5)D, Delta(6)D, and Delta(9)D. Only Delta(9)D was also regulated independently by liver X receptor (LXR) agonist. Glucose induction of l-type pyruvate kinase, Delta(9)D, and Elovl-6 expression required the carbohydrate-regulatory element binding protein/MAX-like factor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and Delta(9)D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose-intolerant mice correlated with low levels of nuclear SREBP-1. In leptin-deficient obese mice (Lep(ob/ob)), increased SREBP-1 and MLX nuclear content correlated with the induction of Elovl-5, Elovl-6, and Delta(9)D expression and the massive accumulation of monounsaturated fatty acids (18:1,n-7 and 18:1,n-9) in neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression. In conclusion, these studies establish a role for PPARalpha, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition.

→ my educational background, thus..

↓

J Clin Invest. 2005 Oct;115(10):2843-54. Epub 2005 Sep 22.

Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation.

Dentin R, Benhamed F, Pégorier JP, Foufelle F, Viollet B, Vaulont S, Girard J, Postic C.

Département d'Endocrinologie, Institut Cochin, INSERM U567 CNRS UMR8104, Université René Descartes, Paris, France.

Abstract

Dietary polyunsaturated fatty acids (PUFAs) are potent inhibitors of hepatic glycolysis and lipogenesis. Recently, carbohydrate-responsive element-binding protein (ChREBP) was implicated in the regulation by glucose of glycolytic and lipogenic genes, including those encoding L-pyruvate kinase (L-PK) and fatty acid synthase (FAS). The aim of our study was to assess the role of ChREBP in the control of L-PK and FAS gene expression by PUFAs. We demonstrated in mice, both in vivo and in vitro, that PUFAs [linoleate (C18:2), eicosapentanoic acid (C20:5), and docosahexaenoic acid (C22:6)] suppressed ChREBP activity by increasing ChREBP mRNA decay and by altering ChREBP translocation from the cytosol to the nucleus, independently of an activation of the AMP-activated protein kinase, previously shown to regulate ChREBP activity. In contrast, saturated [stearate (C18)] and monounsaturated fatty acids [oleate (C18:1)] had no effect. Since glucose metabolism via the pentose phosphate pathway is determinant for ChREBP nuclear translocation, the decrease in xylulose 5-phosphate concentrations caused by a PUFA diet favors a PUFA-mediated inhibition of ChREBP translocation. In addition, overexpression of a constitutive nuclear ChREBP isoform in cultured hepatocytes significantly reduced the PUFA inhibition of both L-PK and FAS gene expression. Our results demonstrate that the suppressive effect of PUFAs on these genes is primarily caused by an alteration of ChREBP nuclear translocation. In conclusion, we describe a novel mechanism to explain the inhibitory effect of PUFAs on the genes encoding L-PK and FAS and demonstrate that ChREBP is a pivotal transcription factor responsible for coordinating the PUFA suppression of glycolytic and lipogenic genes.

Thus...

[1]

Biochimie. 2005 Jan;87(1):81-6.

Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver.

Dentin R, Girard J, Postic C.

Département d'Endocrinologie, Institut Cochin, Inserm U567, CNRS UMR8104, Université Paris V René Descartes, 24, rue du Faubourg Saint Jacques, 75014 Paris, France.

Abstract

In mammals, the regulation of hepatic metabolism plays a key role in whole body energy balance, since the liver is the major site of carbohydrate metabolism (glycolysis and glycogen synthesis) and triglyceride synthesis (lipogenesis). Lipogenesis is regulated through the acute control of key enzyme activities by means of allosteric and covalent modifications. Moreover, the synthesis of most glycolytic and lipogenic enzymes is regulated in response to dietary status, in which glucose, in particular, is a crucial energy nutrient. This latter response occurs in large part through transcriptional regulation of genes encoding glycolytic and lipogenic enzymes. In the past few years, recent advances have been made in understanding the transcriptional regulation of hepatic glycolytic and lipogenic genes by insulin and glucose. Although insulin is a major regulator of hepatic lipogenesis, there is increasing evidence that glucose also contributes to the coordinated regulation of carbohydrate and lipid metabolism in liver. Here, we review the respective roles of the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) in mediating the effect of insulin on hepatic gene expression, and the role of carbohydrate responsive element binding protein (ChREBP) in regulating gene transcription by glucose.

[2]

PLoS One. 2009 Aug 27;4(8):e6812.

Inhibition of stearoylCoA desaturase-1 inactivates acetyl-CoA carboxylase and impairs proliferation in cancer cells: role of AMPK.

Scaglia N, Chisholm JW, Igal RA.

Department of Nutritional Sciences and Rutgers Center for Lipid Research, Rutgers, the State University of New Jersey, New Brunswick, NJ, USA.

Abstract

Cancer cells activate the biosynthesis of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) in order to sustain an increasing demand for phospholipids with appropriate acyl composition during cell replication. We have previously shown that a stable knockdown of stearoyl-CoA desaturase 1 (SCD1), the main Delta9-desaturase that converts SFA into MUFA, in cancer cells decreases the rate of lipogenesis, reduces proliferation and in vitro invasiveness, and dramatically impairs tumor formation and growth. Here we report that pharmacological inhibition of SCD1 with a novel small molecule in cancer cells promoted the activation of AMP-activated kinase (AMPK) and the subsequent reduction of acetylCoA carboxylase activity, with a concomitant inhibition of glucose-mediated lipogenesis. The pharmacological inhibition of AMPK further decreased proliferation of SCD1-depleted cells, whereas AMPK activation restored proliferation to control levels. Addition of supraphysiological concentrations of glucose or pyruvate, the end product of glycolysis, did not reverse the low proliferation rate of SCD1-ablated cancer cells. Our data suggest that cancer cells require active SCD1 to control the rate of glucose-mediated lipogenesis, and that when SCD1 activity is impaired cells downregulate SFA synthesis via AMPK-mediated inactivation of acetyl-CoA carboxylase, thus preventing the harmful effects of SFA accumulation.

↓

PLoS One. 2010 Jun 30;5(6):e11394.

Inhibition of stearoylCoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells.

Hess D, Chisholm JW, Igal RA.

Department of Nutritional Sciences and Rutgers Center for Lipid Research, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America.

Abstract

Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic lung cancer is approximately 5%, hence alternative therapeutic strategies to treat this disease are critically needed. Recent studies suggest that lipid biosynthetic pathways, particularly fatty acid synthesis and desaturation, are promising molecular targets for cancer therapy. We have previously reported that inhibition of stearoylCoA desaturase-1 (SCD1), the enzyme that produces monounsaturated fatty acids (MUFA), impairs lung cancer cell proliferation, survival and invasiveness, and dramatically reduces tumor formation in mice. In this report, we show that inhibition of SCD activity in human lung cancer cells with the small molecule SCD inhibitor CVT-11127 reduced lipid synthesis and impaired proliferation by blocking the progression of cell cycle through the G(1)/S boundary and by triggering programmed cell death. These alterations resulting from SCD blockade were fully reversed by either oleic (18:1n-9), palmitoleic acid (16:1n-7) or cis-vaccenic acid (18:1n-7) demonstrating that cis-MUFA are key molecules for cancer cell proliferation. Additionally, co-treatment of cells with CVT-11127 and CP-640186, a specific acetylCoA carboxylase (ACC) inhibitor, did not potentiate the growth inhibitory effect of these compounds, suggesting that inhibition of ACC or SCD1 affects a similar target critical for cell proliferation, likely MUFA, the common fatty acid product in the pathway. This hypothesis was further reinforced by the observation that exogenous oleic acid reverses the anti-growth effect of SCD and ACC inhibitors. Finally, exogenous oleic acid restored the globally decreased levels of cell lipids in cells undergoing a blockade of SCD activity, indicating that active lipid synthesis is required for the fatty acid-mediated restoration of proliferation in SCD1-inhibited cells. Altogether, these observations suggest that SCD1 controls cell cycle progression and apoptosis and, consequently, the overall rate of proliferation in cancer cells through MUFA-mediated activation of lipid synthesis.

Finally..

Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21660-5. Epub 2009 Dec 7.

The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation.

Tong X, Zhao F, Mancuso A, Gruber JJ, Thompson CB.

Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Room 451, BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.

Abstract

Tumor cells are metabolically reprogrammed to fuel cell proliferation. Most transformed cells take up high levels of glucose and produce ATP through aerobic glycolysis. In cells exhibiting aerobic glycolysis, a significant fraction of glucose carbon is also directed into de novo lipogenesis and nucleotide biosynthesis. The glucose-responsive transcription factor carbohydrate responsive element binding protein (ChREBP) was previously shown to be important for redirecting glucosemetabolism in support of lipogenesis in nonproliferating hepatocytes. However, whether it plays a more generalized role in reprogramming metabolism during cell proliferation has not been examined. Here, we demonstrated that the expression of ChREBP can be induced in response to mitogenic stimulation and that the induction of ChREBP is required for efficient cell proliferation. Suppression of ChREBP resulted in diminished aerobic glycolysis, de novo lipogenesis, and nucleotide biosynthesis, but stimulated mitochondrial respiration, suggesting a metabolic switchfrom aerobic glycolysis to oxidative phosphorylation. Cells in which ChREBP was suppressed by RNAi exhibited p53 activation and cell cycle arrest. In vivo, suppression of ChREBP led to a p53-dependent reduction in tumor growth. These results demonstrate that ChREBP plays a key role both in redirecting glucose metabolism to anabolic pathways and suppressing p53 activity.

　　　※

http://www.keystonesymposia.org/meetings/viewMeetings.cfm?MeetingID=1113

Lipid Biology and Lipotoxicity (E2)

Organized in Collaboration with Science Foundation Ireland
Organizers: Scott A. Summers and Rudolf Zechner
May 15 - 20, 2011 • INEC-Ireland's National Events & Conference Centre • Killarney, Co. Kerry, Ireland

Monday, May 16

5:00 - 7:00 PM

Fatty Liver/NASH

Catherine Postic, Institut Cochin INSERM U 567/ CNRS UMR 8104, France
ChREBP and Hepatic Steatosis

2010-10-01(13:59) :
未分類 :
留言 0 :
引用 0

回到此頁首

Wow~ Pdx1 is really really a MIRACLE!!!!!!

Am J Physiol Endocrinol Metab. 2008 Mar;294(3):E607-14. Epub 2008 Jan 8.

Insulin-resistant muscle is exercise resistant: evidence for reduced response of nuclear-encoded mitochondrial genes to exercise.

De Filippis E, Alvarez G, Berria R, Cusi K, Everman S, Meyer C, Mandarino LJ.

Center for Metabolic Biology, Arizona State University, P. O. Box 873704 Tempe, AZ 85287-3704, USA.

Abstract

Mitochondrial dysfunction, associated with insulin resistance, is characterized by low expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and nuclear-encoded mitochondrial genes. This deficit could be due to decreased physical activity or a decreased response of gene expression to exercise. The objective of this study was to investigate whether a bout of exercise induces the same increase in nuclear-encoded mitochondrial gene expression in insulin-sensitive and insulin-resistant subjects matched for exercise capacity. Seven lean and nine obese subjects took part. Insulin sensitivity was assessed by an 80 mU.m(-2).min(-1) euglycemic clamp. Subjects were matched for aerobic capacity and underwent a single bout of exercise at 70 and 90% of maximum heart rate with muscle biopsies at 30 and 300 min postexercise. Quantitative RT-PCR and immunoblot analyses were used to determine the effect of exercise on gene expression and protein abundance and phosphorylation. In the postexercise period, lean subjects immediately increased PGC-1alpha mRNA level (reaching an eightfold increase by 300 min postexercise) and protein abundance and AMP-dependent protein kinase phosphorylation. Activation of PGC-1alpha was followed by increase of nuclear respiratory factor-1 and cytochrome c oxidase (subunit VIc). However, in insulin-resistant subjects, there was a delayed and reduced response in PGC-1alpha mRNA and protein, and phosphorylation of AMP-dependent protein kinase was transient. None of the genes downstream of PGC-1alpha was increased after exercise in insulin resistance. Insulin-resistant subjects have a reduced response of nuclear-encoded mitochondrial genes to exercise, and this could contribute to the origin and maintenance of mitochondrial dysfunction.

then.. a new research in 2010:

Int J Dev Biol. 2010;54(4):699-705.

Pdx1-transfected adipose tissue-derived stem cells differentiate into insulin-producing cells in vivo and reduce hyperglycemia in diabetic mice.

Kajiyama H, Hamazaki TS, Tokuhara M, Masui S, Okabayashi K, Ohnuma K, Yabe S, Yasuda K, Ishiura S, Okochi H, Asashima M.

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.

Abstract

Insulin-dependent diabetes mellitus (IDDM) is characterized by the rapid development of potentially severe metabolic abnormalities resulting from insulin deficiency. The transplantation of insulin-producing cells is a promising approach for the treatment of IDDM. The transcription factor pancreatic duodenal homeobox 1 (Pdx1) plays an important role in the differentiation of pancreatic beta cells. In this study, the human Pdx1 gene was transduced and expressed in murine adipose tissue-derived stem cells (ASCs). To evaluate pancreatic repair, we used a mouse model of pancreatic damage resulting in hyperglycemia, which involves injection of mice with streptozotocin (STZ). STZ-treated mice transplanted withPdx1-transduced ASCs (Pdx1-ASCs) showed significantly decreased blood glucose levels and increased survival, when compared with control mice. While stable expression of Pdx1 in ASCs did not induce the pancreatic phenotype in vitro in our experiment, the transplanted stem cells became engrafted in the pancreas, wherein they expressed insulin and C-peptide, which is a marker of insulin-producing cells. These results suggest that Pdx1-ASCs are stably engrafted in the pancreas, acquire a functional beta-cell phenotype, and partially restore pancreatic function in vivo. The ease and safety associated with extirpating high numbers of cells from adipose tissues support the applicability of this system to developing a new cell therapy for IDDM.

Thus.. this Chinese research (in 2005).. seems interesting??

(↓ Turning Muscle into beta-cells: A Dream and the Reality ← guess people will prefer this title!!)

Transduced adult stem cells into insulin-secreting cells

Chuan Yang, Hua Cheng1, Yan Li, Dan Liu, Chuan Wang, Li Yan, Zuzhi Fu

Department of Endocrinology, The Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, P. R. China.

Abstract

The promising results in replacement of the beta-cell mass have been accomplished by beta-cells implanting. However, the demand for beta-cells is far greater than the supply. The transdifferentiation of stem cells into insulin-secreting cells could potentially provide a new help for beta-cell supplying. To determine whether the myoblast cell line C2C12 could be induced to transdifferentiate into insulin-secreting cells by pancreatic-duodenum homeobox-1 (PDX-1). A myoblast cell line (C2C12) was transfected by the PDX-1 constructing to overexpress PDX-1 protein and then treated with various concentrations of glucagon-like peptide-1 (GLP-1). The Expression of PDX-1 and insulin mRNA was determined by in situ hybridization and the intracellular insulin was determined by immunocytochemistry. The result shows that the PDX-1 transfected cells expressed more insulin and secreted more insulin than the vector transfected cells. We conclude that PDX-1 and GLP-1 might induce myoblasts to transdifferentiate into insulin-secreting cells.

↓

http://www.cell.com/abstract/S0092-8674(10)00952-9#Summary

Viable Rat-Mouse Chimeras: Where Do We Go from Here?

Cell, Volume 142, Issue 5, 676-678, 3 September 2010

Summary

In a tour-de-force study, Kobayashi et al., 2010 describe the first viable rat-mouse chimeras and demonstrate that rat induced pluripotent stem (iPS) cells can rescue organ deficiency in mice. Rat iPS cells formed a fully functional pancreas when injected into mouse blastocysts lacking the Pdx1 gene required for pancreas formation.

&
http://www.cell.com/abstract/S0092-8674(10)00843-3

Generation of Rat Pancreas in Mouse by Interspecific Blastocyst Injection of Pluripotent Stem Cells

Cell, Volume 142, Issue 5, 787-799, 3 September 2010

Highlights

Pdx1^−/− mice provide developmental niche for blastocyst complementation approach
Mouse pluripotent stem cell (PSC)-derived pancreas is generated in Pdx1^−/− mice
Generation of interspecific chimeras between mouse and rat using PSCs of each
Generation of rat pancreas in mouse via interspecific blastocyst complementation

Summary

The complexity of organogenesis hinders in vitro generation of organs derived from a patient's pluripotent stem cells (PSCs), an ultimate goal of regenerative medicine. Mouse wild-type PSCs injected into Pdx1^−/− (pancreatogenesis-disabled) mouse blastocysts developmentally compensated vacancy of the pancreatic “developmental niche,” generating almost entirely PSC-derived pancreas. To examine the potential for xenogenic approaches in blastocyst complementation, we injected mouse or rat PSCs into rat or mouse blastocysts, respectively, generating interspecific chimeras and thus confirming that PSCs can contribute to xenogenic development between mouse and rat. The development of these mouse/rat chimeras was primarily influenced by host blastocyst and/or foster mother, evident by body size and species-specific organogenesis. We further injected rat wild-type PSCs into Pdx1^−/−mouse blastocysts, generating normally functioning rat pancreas in Pdx1^−/− mice. These data constitute proof of principle for interspecific blastocyst complementation and for generation in vivo of organs derived from donor PSCs using a xenogenic environment.

2010-09-11(00:21) :
未分類 :
留言 0 :
引用 0

回到此頁首

This paper is fully favored.. Part II

http://inphysiologywetrust.blog131.fc2.com/blog-entry-36.html

Environmental and Genetic Activation of a Brain-Adipocyte BDNF/Leptin Axis Causes Cancer Remission and Inhibition

Cell, Volume 142, Issue 1, 52-64, 9 July 2010

Authors

Lei Cao, Xianglan Liu, En-Ju D. Lin, Chuansong Wang, Eugene Y. Choi, Veronique Riban, Benjamin Lin, Matthew J. During

Highlights
Mice housed in an enriched environment (EE) show decreased cancer growth and remission
EE stimulates the expression of BDNF within the hypothalamus
BDNF, via a sympatho-adipocyte axis, shuts down the fat hormone leptin
The suppression of leptin mediates the anticancer effects

Summary

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural β-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

↓
http://jaxmice.jax.org/news/2010/CancerEE.html

Enriched Environments Slow Tumor Growth in Mice

Cancer progression depends on a complex network of cancer susceptibility genes, exposure to inducing agents, and/or exogenous environmental conditions. In a ground-breaking study, a team of researchers from Ohio State and Cornell Universities demonstrated that an enriched environment (EE) – more space, more opportunity for physical activity and social interaction, toys, etc. – significantly slows cancer progression in mice (Cao et al. 2010). Led by Dr. Matthew J. During, the team demonstrated that mice living in an EE express increased levels of hypothalamic brain-derived neurotrophic factor (BDNF), lowering leptin levels and suppressing tumor progression. The findings suggest that either genetic or environmental activation of the BDNF/leptin axis might inhibit or slow cancer progression in humans.

EE slows tumor growth

C57BL/6J mice housed in enriched environments (18-20 mice per large 1.5m x 1.5m x 1.0m cage supplemented with running wheels, tunnels, igloos, huts, retreats, wood toys, a maze, and nesting material) develop smaller tumors than do conventionally caged controls (five mice/cage).

During's team investigated the effects of an EE on tumor progression in several transplantation and genetic mouse models. They found that EE-housed mice from JAX^® Mice strain C57BL/6J (B6J, 000664) transplanted with either B16 melanoma or MC38 colon cancer cells develop smaller and later tumors and exhibit significantly less active tumor-proliferating pathways than conventionally caged controls. Likewise, EE-housed mice from JAX^® Mice strain C57BL/6J-Apc^Min/J (002020), an intestinal/colon cancer model, develop fewer and smaller polyps, exhibit attenuated splenomegaly, and live longer than conventionally caged controls.

EE suppresses tumorigenesis by activating the BDNF/leptin pathway

During's team found that numerous metabolic and genetic changes are associated with EE-housed mouse cancer models. Cancer cell-engrafted mice weigh less, have lower levels of insulin-like growth factor 1 (IGF1), higher levels of adiponectin, adrenal glucocorticoid and the stress hormone corticosterone, and significantly lower levels of serum leptin, a mitogen in many peripheral organs and recently linked to increased risk of prostate cancer, breast cancer, and melanoma. Similarly, EE-housed Apc^Min mice exhibit significantly lower leptin, higher adiponectin and corticosterone, and lower triglyceride levels than conventionally caged controls.

BDNF mutant mice mimic EE effects

JAX^® Mice strain C57BL/6J-Apc^Min/J is highly susceptible to spontaneous intestinal adenomas.

To determine what neurological pathways are affected by an EE, During's team assessed the gene expression pattern in the hypothalamus, a brain region critical in regulating energy balance and neuroendocrine-immune interactions. They found that only one gene, brain-derived neurotrophic factor (Bdnf), is significantly up-regulated in EE-housed mice. BDNF plays an important role in brain development and plasticity, and its expression is greatly influenced by activity and the environment.

During's team found that mice in which gene therapy was used to over-express human BDNF in the hypothalamus weigh significantly less, develop slower and smaller tumors, and exhibit stronger immune responses than controls. Their serum has the same characteristics as that of EE-housed mice – low levels of IGF1 and leptin and high levels of the soluble leptin receptor, adiponectin, and corticosterone. Additionally, their serum slows the growth of cultured B16 melanoma cells. In contrast, whether EE-housed or conventionally caged, mice with hypothalamic knockdown of Bdnf have higher leptin and lower adiponectin levels, gain more weight, and develop larger tumors than controls.

A BDNF-leptin signaling pathway is proposed

JAX^® Mice strain B6.V-Lep^ob/J is widely used in obesity and diabetes research.

During and his colleagues wanted to know what part leptin plays in suppressing tumor growth in EE-housed mice. After conducting a series of experiments involving diet-induced B6J mice, leptin-deficientob/ob mice – B6.V-Lep^ob/J (000632), the hypothalamic BDNF overexpressing model mentioned above, and syngeneic transplantations of tumor cells, they proposed the following signaling pathway: EE stimulates the hypothalamus, which releases BDNF and induces signal transduction genes, such as Fos and Junb. This signaling stimulates white adipose tissue (and the sympathetic nervous system) to release norepinephrine, which activates beta-adrenergic receptors. These activated receptors mediate the increased expression of adiponectin and the inhibition of leptin, increasing energy consumption, reducing body weight, and ultimately suppressing tumor growth.

The findings by the During team substantiate and mechanistically explain many physicians' observations that healthy and stimulating social and physical environments may help people fight cancer. They also suggest new and potentially very powerful cancer-fighting tools – therapies that activate the BDNF/leptin axis.

Check out the resources for cancer research at The Jackson Laboratory

Reference

Lei Cao, Xianglan Liu, En-Ju D. Lin, Chuansong Wang, Eugene Y. Choi, Veronique Riban, Benjamin Lin, Matthew J. During. 2010. Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell 142:52-64.

2010-09-10(23:53) :
未分類 :
留言 0 :
引用 0

回到此頁首

Let's see the power of the Senior Medicinal Chemist!

http://www.keystonesymposia.org/Meetings/ViewMeetings.cfm?MeetingID=1114&AllowFutureView=1

Type 2 Diabetes, Insulin Resistance and Metabolic Dysfunction (J1)

Sponsored by Eli Lilly and Company, Hoffmann-La Roche, Inc. and Takeda Pharmaceutical Company Limited
Organizers: Deborah M. Muoio and Rosalind A. Coleman
January 12 - 17, 2011 • Keystone Resort • Keystone, Colorado

Keynote Session (Joint)

Stephen O'Rahilly, University of Cambridge, UK

Genetics of Obesity and Insulin Resistance

David A. Sinclair, Harvard Medical School, USA

Sirtuins as Modulators of Metabolism and Age-Related Diseases

　　　※

↓
http://tinyurl.com/ppp4bm
In the Pipeline │ May 13, 2009
Exercise and Vitamins: Now, Wait A Minute. . .

+
http://tinyurl.com/25o7pl2
In the Pipeline │ Oct 5, 2009
A Nobel for Telomerase

Nat Med. 2009 Sep;15(9):1082-7. Epub 2009 Aug 30.

A crucial role for adipose tissue p53 in the regulation of insulin resistance.

Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I.

Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.

Comment in:

Nat Med. 2009 Sep;15(9):996-7.

Connecting obesity, aging and diabetes.

Ahima RS.

Rexford S. Ahima is in the Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, the Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

↓

http://pipeline.corante.com/archives/aging_and_lifespan/
In the Pipeline > Aging and Lifespan

[Nov 20, 2005] Sir2 Surprise
[Nov 01, 2006] And Thee, O Time
[Sep 24, 2007] More Sirtuins With More Effects
[Apr 24, 2008] $720 Million Worth of Sirtuin Research
[Apr 25, 2008] Why Buy, Anyway?
[Jun 06, 2008] Resveratrol in Mice
[Nov 05, 2009] What Exactly Does Resveratrol Do?
[Jan 12, 2010] The Sirtris Compounds: Worthless? Really?
[Jan 15, 2010] Sirtuin Scenarios
[Jan 25, 2010] GSK and Sirtris: A Bit More
[Mar 09, 2010] A GSK/Sirtris Wrap-Up
[Apr 28, 2010] Sirtris's Compounds: Everyone Agrees?
[May 03, 2010] SRT501 - A Trial Suspended
[May 17, 2010] The Memory Goes Because. . .the Acetyl Groups Go?
[Aug 12, 2010] Resveratrol (SRT501): Buy Now - Why Wait?
[Aug 25, 2010] GSK's Response to the Sirtuin Critics

↓

Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11288-93. Epub 2009 Jun 22.

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats.

Erion DM, Yonemitsu S, Nie Y, Nagai Y, Gillum MP, Hsiao JJ, Iwasaki T, Stark R, Weismann D, Yu XX, Murray SF, Bhanot S,Monia BP, Horvath TL, Gao Q, Samuel VT, Shulman GI.

Howard Hughes Medical Institute, Department of Internal Medicine, Yale University School of Medicine, New Haven CT 06510, USA.

→ SirT1 ─ STAT3 ─ hepatic gluconeogenesis ─ T2DM

↓

Diabetologia. 2009 Oct;52(10):2015-26. Epub 2009 Jun 23.

Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with 'exercise mimetics'.

Carey AL, Kingwell BA.

Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. andrew.carey@bakeridi.edu.au

→ PGC1alpha is a topic in Experimental Biology 2010 Meeting. PGC1alpha / AMPK / SirT1 are important pharmacological candidate targets to combat obesity and insulin resistance.

↓

[vv] Seminar 20091215 http://tinyurl.com/27v3c2f

↓

http://tinyurl.com/22l6lr7

Drug Discovery Opinion │ 2009 Dec 21

Inhibition of Sirt1 May be the Way to Control Obesity

PLoS One. 2009 Dec 15;4(12):e8322.

Hypothalamic Sirt1 regulates food intake in a rodent model system.

Cakir I, Perello M, Lansari O, Messier NJ, Vaslet CA, Nillni EA.

Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, United States of America.

↓

Trends Cell Biol. 2007 Jun;17(6):292-301. Epub 2007 May 1.

Transcriptional coregulators in the control of energy homeostasis.

Feige JN, Auwerx J.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, Illkirch, France.
+

Curr Opin Lipidol. 2009 Apr;20(2):98-105.

PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure.

Cantó C, Auwerx J.

Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Int J Biol Sci. 2009;5(2):147-52. Epub 2009 Jan 21.

SIRT1, is it a tumor promoter or tumor suppressor?

Deng CX.

Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA. chuxiad@bdg10.niddk.nih.gov

↓

Nat Rev Drug Discov. 2010 Apr;9(4):255-6. Epub 2010 Mar 12.

NIH encourages translational collaboration with industry.

Wadman M.

How exactly would this untapped synergism work? Garret FitzGerald, Director of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania in Philadelphia, USA, notes that the CTSA and industry can each bring assets to the table that the other can't provide. “We have access to patients they don't have. They have medicinal chemists we don't have. Let's try to bring different pieces of the puzzle together,” he says.

　　　※

http://www.keystonesymposia.org/Meetings/ViewMeetings.cfm?MeetingID=1093

Evolving Approaches to Early-Stage Drug Discovery (Z2)

Sponsored by Gilead Sciences, Inc.
Organizers: Craig W. Lindsley and Linda Brady
April 3 - 7, 2011 • Snowbird Resort • Snowbird, Utah

http://www.keystonesymposia.org/Meetings/ViewMeetings.cfm?MeetingID=1095

Drugs from Bugs: The Anti-Inflammatory Drugs of Tomorrow (Z1)

Supported by the Directors’ Fund
Organizers: Padraic G. Fallon, Grant McFadden and Amanda E.I. Proudfoot Fichard
April 3 - 7, 2011 • Snowbird Resort • Snowbird, Utah

　　　※

They Senior Medicinal Chemists.. are "treasure".

2010-09-04(16:09) :
未分類 :
留言 0 :
引用 0

回到此頁首

FASEB DREAM Grant: Diversity Resources for Enrichment, Access and Mentoring

Can't you believe that you light up my way

No matter how that ease my path

I'll never lose my faith

See me fly

I'm proud to fly up high

Show you the best of mine

Till the end of the time

Believe me I can fly

I'm singing in the sky

Show you the best of mine

The heaven in the sky

　　　※

FASEB MARC Program FASEB AWARDED A $7.82 MILLION GRANT IN SUPPORT OF UNDERREPRESENTED STUDENTS, SCIENTISTS

The Federation of American Societies for Experimental Biology (FASEB) has been awarded a five-year, $7.82 million “Diversity Resources for Enrichment, Access and Mentoring” (DREAM) grant from the National Institute of General Medical Sciences/National Institutes of Health(NIGMS/NIH).

The goal of the DREAM grant is to increase the number and competitiveness of underrepresented minority scientists in the biomedical and behavioral disciplines by providing minority institutions,faculty, post-doctorates, and students with resources, programs, and opportunities to gain access toand participate in cutting-edge biomedical and behavioral research. This grant will support the continuation of the FASEB Minority Access to Research Careers (MARC) Program activities, which have been ongoing since 1982.

The FASEB MARC program supports a variety of student, post-doctorate, and faculty development programs, resources, and training opportunities for underrepresented minorities and minority-servinginstitutions. Over the next five years, the FASEB MARC Program activities will include:

• Training seminars on grantsmanship and writing for biomedical publications for researchinvestigators and faculty at minority institutions
• Travel awards to FASEB Societies’ scientific meetings, SACNAS, ABRCMS, LANS,Compact for Faculty Diversity Conference, FASEB Summer Research Conferences andmeetings managed by FASEB Managed Society Services
• Funding support for FASEB Societies’ Diversity Programs Initiatives

“We are extremely pleased that the NIGMS/NIH recognizes the value of the work FASEB has been doing to support diversity in the life sciences,” said Jacquelyn Roberts, Director for the FASEB MARC Program. “Helping to increase the number and competitiveness of underrepresented students, postdoctorates and minority scientists participating in biomedical and behavioral research is a perpetual goal, and we will continue to work towards it.”

To learn more about the FASEB MARC Program, please visithttp://www.FASEB.org/MARC.

FASEB MARC Program News Room

www.faseb.org

Minority Access To Research Careers

　　　※

http://www.faseb.org/Meetings-and-Conferences/FASEB-Summer-Research-Conferences.aspx

FASEB SRCs
35 conferences held June-September.
Small groups. Intimate. Cutting edge.

2010-07-29(13:17) :
未分類 :
留言 0 :
引用 0

回到此頁首

[Int J Biol Sci] Krüppel-like family of transcription factors: an emerging new frontier in fat biology

Paul, Eric!!!!!

Cancer Res. 2009 Nov 1;69(21):8284-92. Epub 2009 Oct 13.

Role for Kruppel-like factor 4 in determining the outcome of p53 response to DNA damage.

Zhou Q, Hong Y, Zhan Q, Shen Y, Liu Z.

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Cell Cycle. 2008 Jan 15;7(2):154-7. Epub 2007 Oct 22.

P53 promoter selection: choosing between life and death.

Das S, Boswell SA, Aaronson SA, Lee SW.

Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.

J Biol Chem. 2003 Jan 24;278(4):2101-5. Epub 2002 Nov 8.

Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage.

Yoon HS, Chen X, Yang VW.

Division of Digestive Diseases, Department of Medicine and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Oncogene. 2009 Aug 13;28(32):2894-902. Epub 2009 Jun 8.

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERalpha.

Akaogi K, Nakajima Y, Ito I, Kawasaki S, Oie SH, Murayama A, Kimura K, Yanagisawa J.

Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.

Abstract

Kruppel-like factor 4 (KLF4) is a transcription factor that participates in both tumor suppression and oncogenesis. To determine the association of KLF4 with tumorigenesis, we integrated data assembled in the Oncomine database and discovered a decrease in KLF4 gene transcripts in breast cancers. Further analysis of the database also showed a correlation between KLF4 expression and estrogen receptor-alpha (ERalpha) positivity. Knockdown of KLF4 in MCF-7 cells elevated the growth rate of these cells in the presence of estrogen. Therefore, we examined the interaction between KLF4 and ERalpha, and found that KLF4 bound to the DNA-binding region of ERalpha. KLF4 thus inhibits the binding of ERalpha to estrogen response elements in promoter regions, resulting in a reduction in ERalpha target gene transcription. Earlier studies have reported that KLF4 is transcriptionally activated by p53 following DNA damage. We also showed that activation of p53 decreased the transcriptional activity of ERalpha by elevating KLF4 expression. Our studies discovered a novel molecular network between p53, KLF4 and ERalpha. As both p53 and ERalpha are involved in cell growth and apoptosis, these results may explain why KLF4 possesses both tumor suppressive and oncogenic functions in breast cancers.

Curr Cancer Drug Targets. 2008 Nov;8(7):597-610.

Interaction between estrogen receptor alpha and insulin/IGF signaling in breast cancer.

Lanzino M, Morelli C, Garofalo C, Panno ML, Mauro L, Andò S, Sisci D.

Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, CS, 87036, Italy.

J Steroid Biochem Mol Biol. 2008 Mar;109(1-2):185-96. Epub 2008 Feb 8.

Role of the insulin-like growth factor system on an estrogen-dependent cancer phenotype in the MCF-7 human breast cancer cell line.

Bradley LM, Gierthy JF, Pentecost BT.

Department of Environmental Health and Toxicology, School of Public Health, State University at Albany, Albany, NY, USA.

Oncogene. 2009 May 7;28(18):1993-2002. Epub 2009 Apr 6.

Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells.

Zhou J, Huang W, Tao R, Ibaragi S, Lan F, Ido Y, Wu X, Alekseyev YO, Lenburg ME, Hu GF, Luo Z.

Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.

Abstract

AMP-activated protein kinase (AMPK) serves as a fuel-sensing enzyme that is activated by binding of AMP and subsequent phophorylation by upstream kinases such as the tumor suppressor LKB1, when cells sense an increase in the ratio of AMP to ATP. Acute activation of AMPK stimulates fatty acid oxidation to generate more ATP and simultaneously inhibits ATP-consuming processes including fatty acid and protein syntheses, thereby preserving energy for acute cell-surviving program, whereas chronic activation leads to inhibition of cell growth. The goal of the present study is to explore the mechanisms by which AMPK regulates cell growth. Toward this end, we established stable cell lines by introducing a dominant-negative mutant of AMPK alpha1 subunit or its shRNA into the prostate cancer C4-2 cells and other cells, or wild type LKB1 into the lung adenocarcinoma A549 and breast MB-MDA-231 cancer cells, both of which lack functional LKB1. Our results showed that the inhibition of AMPK accelerated cell proliferation and promoted malignant behavior such as increased cell migration and anchorage-independent growth. This was associated with decreased G1 population, downregulation of p53 and p21, and upregulation of S6K, IGF-1 and IGF1R. Conversely, treatment of the C4-2 cells with 5-aminoimidazole-4-carboxamide 1-D-ribonucleoside (AICAR), a prototypical AMPK activator, caused opposite changes. In addition, our study using microarray and RT-PCR revealed that AMPK regulated gene expression involved in tumor cell growth and survival. Thus, our study provides novel insights into the mechanisms of AMPK action in cancer cells and presents AMPK as an ideal drug target for cancer therapy.

BMC Pharmacol. 2009 Feb 12;9:2.

AICAR activates the pluripotency transcriptional network in embryonic stem cells and induces KLF4 and KLF2 expression in fibroblasts.

Adamo L, Zhang Y, García-Cardeña G.

Department of Pathology, Laboratory for Systems Biology, Center for Excellence in Vascular Biology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. ladamo@hms.harvard.edu

Abstract

BACKGROUND: Pluripotency, the property of a cell to differentiate into all cellular types of a given organism, is central to the development of stem cell-based therapies and regenerative medicine. Stem cell pluripotency is the result of the orchestrated activation of a complex transcriptional network characterized by the expression of a set of transcription factors including the master regulators of pluripotency Nanog and Oct4. Recently, it has been shown that pluripotency can be induced in somatic cells by viral-mediated expression of the transcription factors Oct3/4, Sox2, Klf4, and c-Myc. RESULTS: Here we show that 5-Aminoimidazole-4-carboxamide-1-b-riboside (AICAR) is able to activate the molecular circuitry of pluripotency in mouse embryonic stem cells (mESC) and maintain Nanog and Oct4 expression in mESC exposed to the differentiating agent retinoic acid. We also show that AICAR is able to induce Klf4, Klf2 and Myc expression in both mESC and murine fibroblasts. CONCLUSION: AICAR is able to activate the molecular circuitry of pluripotency in mESC and to induce the expression of several key regulators of pluripotency in somatic cells. AICAR is therefore a useful pharmacological entity for studying small molecule mediated induction of pluripotency.

Cell Metab. 2008 Apr;7(4):339-47.

Transcriptional regulation of adipogenesis by KLF4.

Birsoy K, Chen Z, Friedman J.

Laboratory of Molecular Genetics, Rockefeller University, New York, NY 10021, USA.

Abstract

While adipogenesis is known to be controlled by a complex network of transcription factors, less is known about the transcriptional cascade that initiates this process. We report here the characterization of Krüppel-like factor 4 (KLF4) as an essential early regulator of adipogenesis. Klf4 is expressed in 3T3-L1 cells within 30 min after exposure to a standard adipogenic cocktail of insulin, glucocorticoids, and IBMX. Knockdown of KLF4 inhibits adipogenesis and downregulates C/EBPbeta levels. KLF4 binds directly to the C/EBPbeta (Cebpb) promoter as shown by chromatin immunoprecipitation and gel shift assays and, together with Krox20, cooperatively transactivates a C/EBPbeta reporter. C/EBPbeta knockdown increases levels of KLF4 and Krox20, suggesting that C/EBPbeta normally suppresses Krox20 and KLF4 expression via a tightly controlled negative feedback loop. KLF4 is specifically induced in response to cAMP, which by itself can partially activate adipogenesis. These data suggest that KLF4 functions as an immediate early regulator of adipogenesis to induce C/EBPbeta.

Cell Metab. 2005 Feb;1(2):93-106.

Krox20 stimulates adipogenesis via C/EBPbeta-dependent and -independent mechanisms.

Chen Z, Torrens JI, Anand A, Spiegelman BM, Friedman JM.

Laboratory of Molecular Genetics, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.

Comment in:

Cell Metab. 2005 Feb;1(2):85-6.

http://www.asbmb.org/News.aspx?id=8512

NEW JBC PAPER OF THE WEEK PODCAST

July 1, 2010--In this podcast, JBC Associate Editor Joan Conaway of the Stowers Institute interviews Paper of the Week author Peter Johnson from the National Cancer Institute about his research on CEPB-β. In his recent JBC paper "CCAAT/enhancer binding protein β DNA binding is auto-inhibited by multiple elements that also mediate association with p300/CBP," he describes this transcription factor's novel auto-inhibitory mechanism and its dual role in oncogenesis and cell senescence. The pair first talk about CEPB-β's normal physiological roles and its interactions with oncogenic ras, a series of techniques used to identify the important regulatory domains and conformational changes that correspond with the activation of this normally inert protein. The interview wraps up with how Johnson's findings might be translated to other important transcription factors and cancer research in general.

↑ This is already very surprising to me..

Dr. Jeffrey Friedman!!!!!! The discoverer of Leptin..

↓ But this one is a much more surprising story to me..

Peptides. 2009 Feb;30(2):181-90. Epub 2008 Nov 20.

Enterostatin affects cyclic AMP and ERK signaling pathways to regulate Agouti-related protein (AgRP) expression.

Park M, Oh H, York DA.

Center for Advanced Nutrition, Utah State University, 4715 Old Main Hill, Logan, UT 84322-4715, USA.

Fig. 8. Schematic view of enterostatin regulation of AgRP gene expression. Enterostatin binding to its receptor protein F1-ATPaseβ subunit protein may regulate the extracellular ATP/ADP ratios which through a purinergic P2Y receptor activates adenyl cyclase. The increase in cAMP initiates an increase in AgRP gene expression which may be mediated through pCREB or by rapid changes in KLF4 gene expression. Activation of PKA is proposed to stimulate pERK which inhibits KLF4 gene expression and AgRP gene transcription.

God I can't believe these..

How lucky I was to meet you two professors at 2009 summer...

　　　※

BIOLOGY AND PATHOBIOLOGY OF

KRÜPPEL-LIKE FACTORS (KLFS)

AUGUST 8 – 13, 2010

STEAMBOAT SPRINGS, COLORADO

ORGANIZERS:

Vincent W. Yang

Scott L. Friedman

Mukesh K. Jain

Ryozo Nagai

THE FEDERATION GRATEFULLY ACKNOWLEDGES

THE FOLLOWING EDUCATIONAL GRANTS FOR THE

FASEB SUMMER RESEARCH CONFERENCES:

Platinum Level Support

Merck Sharp & Dohme Corp.

Gold Level Support

The University of Tokyo

Silver Level Support

Banyu Pharmaceutical Co., Ltd.

Dainippon Sumitomo Pharma Co., Ltd.

Kowa Pharmaceutical Co., Ltd.

*National Cancer Institute

Novartis Pharma K.K.

Roche Diagnostics Corporation

Bronze Level Support

Astellas Pharma Inc

Consumables

https://secure.faseb.org/faseb/meetings/Summrconf/Programs/11758.pdf

2010-07-28(23:38) :
未分類 :
留言 0 :
引用 0

回到此頁首

Things about Lipids Research

American Society for Biochemistry and Molecular Biology JLR: Discovery points to new approach for diabetes therapy

http://www.asbmb.org/News.aspx?id=8628

ASBMB News

www.asbmb.org

July 19, 2010 -- Researchers writing in the Journal of Lipid Research were able to increase levels of a key enzyme, called fatty acid elongase-5, which restored normal function to diseased livers in mice, restored normal levels of blood glucose and insulin, and effectively corrected the risk factors...

CITATION

Elevated hepatic fatty acid elongase-5 (Elovl5) activity corrects dietary fat induced hyperglycemia in obese C57BL/6 mice. Sasmita Tripathy, Moises Torres-Gonzalez and Donald B. Jump. Papers In Press, published online ahead of print May 19, 2010. J. Lipid Res., doi:10.1194/jlr.M006080

↓

This is my favorite paper at that time I wrote my thesis-

Annu Rev Cell Dev Biol. 2005;21:633-57.

Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you.

Marszalek JR, Lodish HF.

Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. joseph_marszalek@merck.com

Abstract

In contrast to other tissues, the nervous system is enriched in the polyunsaturated fatty acids (PUFAs): arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3). Despite their abundance in the nervous system, AA and DHA cannot be synthesized de novo by mammals; they, or their precursors, must be ingested from dietary sources and transported to the brain. During late gestation and the early postnatal period, neurodevelopment is exceptionally rapid, and substantial amounts of PUFAs, especially DHA, are critical to ensure neurite outgrowth as well as proper brain and retina development. Here, we review the various functions of DHA in the nervous system, the proteins involved in its internalization and metabolism into phospholipids, and its relationship to several neurological disorders, including Alzheimer's disease and depression.

Eric:

It seems interesting and useful. But the problem is that mouse is small....

Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G299-305. Epub 2009 Jun 11.

Stimulation of incretin secretion by dietary lipid: is it dose dependent?

Yoder SM, Yang Q, Kindel TL, Tso P.

University of Cincinnati, Department of Pathology and Laboratory Medicine, ML 0507, Cincinnati, OH 45237, USA.

yodersy@email.uc.edu

After the ingestion of nutrients, secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) by the enteroendocrine cells increases rapidly. Previous studies have shown that oral ingestion of fat stimulates secretion of both incretins; however, it is unclear whether there is a dose-dependent relationship between the amount of lipid ingested and the secretion of the hormones in vivo. Recently, we found a higher concentration of the incretin hormones in intestinal lymph than in peripheral or portal plasma. We therefore used the lymph fistula rat model to test for a dose-dependent relationship between the secretion of GIP and GLP-1 and dietary lipid. Under isoflurane anesthesia, the major mesenteric lymphatic duct of male Sprague-Dawley rats was cannulated. Each animal received a single, intraduodenal bolus of saline or varying amounts of the fat emulsion Liposyn II (0.275, 0.55, 1.1, 2.2, and 4.4 kcal). Lymph was continuously collected for 3 h and analyzed for triglyceride, GIP, and GLP-1 content. In response to increasing lipid calories, secretion of triglyceride, GIP, and GLP-1 into lymph increased dose dependently. Interestingly, the response to changes in intraluminal lipid content was greater in GLP-1- than in GIP-secreting cells. The different sensitivities of the two cell types to changes in intestinal lipid support the concept that separate mechanisms may underlie lipid-induced GIP and GLP-1 secretion. Furthermore, we speculate that the increased sensitivity of GLP-1 to intestinal lipid content reflects the hormone's role in the ileal brake reflex. As lipid reaches the distal portion of the gut, GLP-1 is secreted in a dose-dependent manner to reduce intestinal motility and enhance proximal fat absorption.

Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1130-8. Epub 2008 Mar 27.

Using the lymph fistula rat model to study the potentiation of GIP secretion by the ingestion of fat and glucose.

Lu WJ, Yang Q, Sun W, Woods SC, D'Alessio D, Tso P.

Department of Molecular and Cellular Physiology, Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.

Glucose-dependent insulinotropic polypeptide (GIP) is an important incretin produced in the K cells of the intestine and secreted into the circulating blood following ingestion of carbohydrate- and fat-containing meals. GIP contributes to the regulation of postprandial insulin secretion and is essential for normal glucose tolerance. We have established a method of assaying GIP in response to nutrients using the intestinal lymph fistula model. Administration of Ensure, a mixed-nutrient liquid meal, stimulated a significant increase in intestinal lymphatic GIP levels that were approximately threefold those of portal plasma. Following the meal, lymph GIP peaked at 60 min (P < 0.001) and remained elevated for 4 h. Intraduodenal infusions of isocaloric and isovolumetric lipid emulsions or glucose polymer induced lymph GIP concentrations that were four and seven times the basal levels, respectively. The combination of glucose plus lipid caused an even greater increase of lymph GIP than either nutrient alone. In summary, these findings demonstrated that intestinal lymph contains high concentrations of GIP that respond to both enteral carbohydrate and fat absorption. The change in lymphatic GIP concentration is greater than the change observed in the portal blood. These studies allow the detection of GIP levels at which they exert their local physiological actions. The combination of glucose and lipid has a potentiating effect in the stimulation of GIP secretion. We conclude from these studies that the lymph fistula rat is a novel approach to study in vivo GIP secretion in response to nutrient feeding in conscious rats.

Eric:

I really really like AHA.

Thus I reread some of Dr. Tso's papers..

Atheroscler Suppl. 2010 Jun;11(1):11-6.

The mechanism of the formation and secretion of chylomicrons.

Kindel T, Lee DM, Tso P.
University of Cincinnati College of Medicine, United States.

Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G344-52. Epub 2007 Nov 15.

Why does the gut choose apolipoprotein B48 but not B100 for chylomicron formation?

Lo CM, Nordskog BK, Nauli AM, Zheng S, Vonlehmden SB, Yang Q, Lee D, Swift LL, Davidson NO, TsoP.

Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45237, USA.

J Clin Biochem Nutr. 2009 Jul;45(1):82-5. Epub 2009 Jun 30.

Increased lipid absorption and transport in the small intestine of zucker obese rats.

Anzai K, Fukagawa K, Iwakiri R, Fujimoto K, Akashi K, Tso P.

Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, Fukuoka, Jonan-Nanakuma 814-0180, Japan.

Then I found I forgot to tell you why I told you Dr. Tso's research at that time I show you his publications.

Not only because after Wen-Chi presented your MGAT2 paper thus I read some of his review papers-

Front Biosci. 2001 Mar 1;6:D299-319.

Intestinal lipid absorption and transport.

Phan CT, Tso P.

Department of Pathology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.

Biochem Soc Trans. 2004 Feb;32(Pt 1):75-8.

Enterocyte fatty acid uptake and intestinal fatty acid-binding protein.

Tso P, Nauli A, Lo CM.

Department of Pathology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA. tsopp@email.uc.edu

The most important reason is I read Dr. Alessandro Pocai's study for a long long time..

J Biol Chem. 2006 Apr 14;281(15):10105-17. Epub 2006 Feb 21.

FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.

Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J, Klotsas A, Matika R, Xiao X, Franks R, Heidenreich KA, Sajan MP, Farese RV, Stolz DB, Tso P, Koo SH, Montminy M, Unterman TG.

Departments of Medicine and Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA.

Nat Med. 2007 Feb;13(2):171-80. Epub 2007 Feb 4.

Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins.

Lam TK, Gutierrez-Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L.

Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

From my preparation to attend FASEB conference, I also know Dr. Deborah Clegg and Dr. Stephen Benoit were also collaborated with Dr. Tso..

That's very... unbelievable..

Cause I also know Dr. Tso.. I read his papers not only at my graduate school time, but also in my job.

Lipids. 2001 Dec;36(12):1289-305.

Factors affecting the storage and excretion of toxic lipophilic xenobiotics.

Jandacek RJ, Tso P.

The University of Cincinnati, Department of Pathology, Ohio 45267, USA. ronald.jandacek@uc.edu

Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R268-73. Epub 2006 Sep 21.

Mechanism of the induction of brain c-Fos-positive neurons by lipid absorption.

Lo CM, Ma L, Zhang DM, Lee R, Qin A, Liu M, Woods SC, Sakai RR, Raybould HE, Tso P.

Department of Pathology, University of Cincinnati, Cincinnati, OH 45237, USA.

FASEB J. 2004 Dec;18(15):1870-8.

Obesity-related leptin regulates Alzheimer's Abeta.

Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Neuroreport. 2001 Oct 8;12(14):3111-5.

Dietary fat up-regulates the apolipoprotein E mRNA level in the Zucker lean rat brain.

Knight DS, Mahajan DK, Qiao X.

Department of Cellular Biology and Anatomy, LSUHSC, 1501 Kings Highway, PO Box 33932, Shreveport, LA 71130, USA.

Am J Physiol. 1998 May;274(5 Pt 2):H1836-40.

Apolipoprotein AIV: a potent endogenous inhibitor of lipid oxidation.

Qin X, Swertfeger DK, Zheng S, Hui DY, Tso P.

Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Ohio 45267-0529, USA.

I read Dr. Tso's brain study.. not only because of Alzheimer's disease, but also because of erythrocyte and brain DHA composition..

Psychoneuroendocrinology. 2009 May;34(4):532-9. Epub 2008 Nov 28.

Gender differences in rat erythrocyte and brain docosahexaenoic acid composition: role of ovarian hormones and dietary omega-3 fatty acid composition. ← Actually, this is the goal Jen-Jui try to achieve in her thesis..

McNamara RK, Able J, Jandacek R, Rider T, Tso P.

Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0516, United States. robert.mcnamara@psychiatry.uc.edu

Prostaglandins Leukot Essent Fatty Acids. 2008 Apr-May;78(4-5):293-304. Epub 2008 May 21.

The aging human orbitofrontal cortex: decreasing polyunsaturated fatty acid composition and associated increases in lipogenic gene expression and stearoyl-CoA desaturase activity.

McNamara RK, Liu Y, Jandacek R, Rider T, Tso P.

Department of Psychiatry, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA. robert.mcnamara@psychiatry.uc.edu

J Affect Disord. 2010 Apr 20. [Epub ahead of print]

Selective deficits in erythrocyte docosahexaenoic acid composition in adult patients with bipolar disorder and major depressive disorder.

McNamara RK, Jandacek R, Rider T, Tso P, Dwivedi Y, Pandey GN.

Department of Psychiatry, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, 260 Stetson Street, Cincinnati, OH 45219-0516, United States.

Oh.. this professor's research... is really awesome in Nutrition Sciences!!!!!!

vivi

2010-07-25(19:53) :
未分類 :
留言 0 :
引用 0

回到此頁首

主頁下一頁 »

回到此頁首

Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice.

Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms.

The long reach of leptin.

Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice.

PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis.

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats.

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway.

FGF21 reloaded: challenges of a rapidly growing field.

FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology.

Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis.

The Effect of Fasting on Nonalcoholic Fatty Liver Disease

The Effect of a Low-Calorie Diet on Nonalcoholic Fatty Liver Disease

Energy, evolution, and human diseases: an overview.

Abstract

The role of the endocannabinoid system in lipogenesis and fatty acid metabolism.

Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes.

TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents.

ERRalpha: a metabolic function for the oldest orphan.

Announcement:Recent Papers on Aging across Cell Press

Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction.

Graphical Abstract

Highlights

Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis.

Physiology at the Crossroads of Biomedical Engineering and MedicinePhysiology In Focus-Physiology and Biomedical Engineering: Partners in Translational Research

Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals.

Mechanical stimulation of mesenchymal stem cell proliferation and differentiation promotes osteogenesis while preventing dietary-induced obesity.

Development of diet-induced fatty liver disease in the aging mouse is suppressed by brief daily exposure to low-magnitude mechanical signals.

Fructose induces transketolase flux to promote pancreatic cancer growth.

Abstract

Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis.

Abstract

ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver.

Abstract

Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity.

Abstract

Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation.

Abstract

Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver.

Abstract

Inhibition of stearoylCoA desaturase-1 inactivates acetyl-CoA carboxylase and impairs proliferation in cancer cells: role of AMPK.

Abstract

Inhibition of stearoylCoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells.

Abstract

The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation.

Abstract

Insulin-resistant muscle is exercise resistant: evidence for reduced response of nuclear-encoded mitochondrial genes to exercise.

Abstract

Pdx1-transfected adipose tissue-derived stem cells differentiate into insulin-producing cells in vivo and reduce hyperglycemia in diabetic mice.

Abstract

Viable Rat-Mouse Chimeras: Where Do We Go from Here?

Summary

Generation of Rat Pancreas in Mouse by Interspecific Blastocyst Injection of Pluripotent Stem Cells

Summary

Environmental and Genetic Activation of a Brain-Adipocyte BDNF/Leptin Axis Causes Cancer Remission and Inhibition

Authors

Summary

Enriched Environments Slow Tumor Growth in Mice

EE slows tumor growth

EE suppresses tumorigenesis by activating the BDNF/leptin pathway

BDNF mutant mice mimic EE effects

A BDNF-leptin signaling pathway is proposed

Check out the resources for cancer research at The Jackson Laboratory

Reference

Type 2 Diabetes, Insulin Resistance and Metabolic Dysfunction (J1)

A crucial role for adipose tissue p53 in the regulation of insulin resistance.

Connecting obesity, aging and diabetes.

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats.

Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with 'exercise mimetics'.

Hypothalamic Sirt1 regulates food intake in a rodent model system.

Transcriptional coregulators in the control of energy homeostasis.

PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure.

SIRT1, is it a tumor promoter or tumor suppressor?

NIH encourages translational collaboration with industry.

Evolving Approaches to Early-Stage Drug Discovery (Z2)

Drugs from Bugs: The Anti-Inflammatory Drugs of Tomorrow (Z1)

FASEB SRCs35 conferences held June-September.Small groups. Intimate. Cutting edge.

Role for Kruppel-like factor 4 in determining the outcome of p53 response to DNA damage.

P53 promoter selection: choosing between life and death.

Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage.

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERalpha.

Announcement:
Recent Papers on Aging across Cell Press

Physiology at the Crossroads of Biomedical Engineering and Medicine
Physiology In Focus-Physiology and Biomedical Engineering: Partners in Translational Research

FASEB SRCs
35 conferences held June-September.
Small groups. Intimate. Cutting edge.