July-August 2010 l Vol 16 l No 7-8

Research Articles

Attenuated mTOR Signaling and Enhanced Autophagy in Adipocytes from Obese Patients with Type 2 Diabetes
Anita Öst, Kristoffer Svensson, Iida Ruishalme, Cecilia Brännmark, Niclas Franck, Hans Krook, Per Sandström, Preben Kjolhede, and Peter Strålfors
Type 2 diabetes (T2D) is strongly associated with obesity and is characterized by early and marked insulin resistance in adipose tissue. Consequently, T2D is associated with disrupted cellular metabolism. While insulin resistance in T2D is due to defects in signaling, the details remain largely unknown. Target of rapamycin (TOR) plays a key role in cellular metabolism control, cell growth and tolerance to starvation. In mammals, TOR forms a complex with the protein raptor (mTORC1). Öst et al. further investigated the function of mTORC1 in subjects with type 2 diabetes and a BMI greater than 27. Results in adipocytes from obese patients show insulin-activated mTORC1 is attenuated, autophagic activity is increased, and mitochondrial function is impaired. These findings further our understanding of insulin resistance mechanisms in type 2 diabetes.
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Supplementary Data l PDF (373 KB)

Personalized Smoking Cessation: Interactions between Nicotine Dose, Dependence and Quit-Success Genotype Score
Jed E Rose, Frédérique M Behm, Tomas Drgon, Catherine Johnson, and George R Uhl
Cigarette smoking is a significant cause of disease and premature death. While successful quitting reduces these risks to smokers, success rates following attempts to quit smoking remain modest with long-term abstinence rates below 25%. More effective smoking cessation might result from personalizing existing treatments based on characteristics of individual smokers. Here, Rose et al. hypothesized that highly dependent smokers may require higher doses of nicotine replacement therapy (NRT) before and after quit dates. Two NRT doses were compared in precessation smokers, along with quit success, genotype and expired air CO. Results provide support for a personalized and adaptive approach to smoking cessation treatment which tailors the dose of NRT to phenotypic and genotypic characteristic of the individual smoker.
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Supplementary Data l PDF (361 KB)
*Please click here to access the data within the link on page 249. [Download Word.doc 15.2 MB]

Effect of Estrogen on Mitochondrial Function and Intracellular Stress Markers in Rat Liver and Kidney following Trauma-Hemorrhagic Shock and Prolonged Hypotension
Andrey V Kozlov, J Catharina Duvigneau, Tanya C Hyatt, Raghavan Raju, Tricia Behling, Romana T Hartl, Katrin Staniek, Ingrid Miller, Wolfgang Gregor, Heinz Redl, and Irshad H Chaudry
Traumatic hemorrhage followed by resuscitation is often fatal in civilian and military trauma, affecting organs including the liver, kidney, heart and lung. Deleterious effects of trauma-hemorrhage are influenced by sex hormones, and estrogen (E2) improves immune and cardiovascular response parameters. However, the precise mechanism by which estrogen and other sex hormones produce beneficial effects has yet to be determined. In order to target the possible early E2-mediated effects, Kozlov et al. investigated whether oxidative/nitrosylative/endoplasmic reticulum (ER) stress or altered mitochondrial function are involved in prolonged hypotension and whether E2 affects these biochemical processes. Results indicate that trauma-hemorrhage followed by prolonged hypotension significantly affects mitochondrial function, ER stress markers, and free iron levels, and that E2 ameliorated these changes. E2 appears to be a hormonal adjunct that could be slow the progression of trauma-hemorrhage during patient transport to the hospital.
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Supplementary Data l PDF (598 KB)

Gene Expression Profiling of the Hedgehog Signaling Pathway in Human Meningiomas
Ingrid Laurendeau, Marcela Ferrer, Delia Garrido, Nicky D’Haene, Patricia Ciavarelli, Armando Basso, Michel Vidaud, Ivan Bieche, Isabelle Salmon, and Irene Szijan
Meningiomas represent 30% of primary cranial tumors and occur in later stages of life. Meningiomas can be divided into three categories: I (benign); II (atypical and highly recurrent); and III (anaplastic and aggressive). The Hedgehog (Hh) signaling pathway plays a fundamental role in development processes such as cell proliferation, differentiation, angiogenesis, cellular matrix remodeling and stem cell homeostasis. While aberrations of this pathway are involved in tumor development, the role of Hh in meningiomas has not yet been studied. Laurendeau et al. measured Hh pathway and target gene expression in varying grades of meningioma clinical samples to determine if a link between gene expression and pathological parameters could be established. Results show Hh target genes for cell proliferation and invasiveness are active in meningioma grades two and three, but not in benign grade one. These results further characterize the biological and clinical aspects of meningiomas and suggest the Hh pathway may be a useful target for gene therapy.
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Upregulation of SPRR3 Promotes Colorectal Tumorigenesis
Dong-Hyung Cho, Yoon Kyung Jo, Seon Ae Roh, Young-Soon Na, Tae Won Kim, Se Jin Jang, Yong Sung Kim, and Jin Cheon Kim
The occurrence of colorectal cancer has gradually increased over the last decade and while several oncogenes and tumor-suppressor genes are known to be involved in the progression of hereditary colorectal cancer, the molecular changes associated with sporadic colorectal cancer are not well understood. Small proline rich repeat protein (SPRR3) is associated with molecular changes and clinicopathological features of sporadic colorectal cancer. In this work, Cho et al. show SPRR3 is upregulated in colorectal cancer and an overexpression of SPRR3 is associated with lymphovascular invasion. A mechanism involving AKT activation of p53 degradation is proposed. These results indicate that SPRR3 promotes cell proliferation and may be a candidate biomarker for colorectal cancer.
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Supplementary Data l PDF (373 KB)

Serum Cholinesterase Activities Distinguish between Stroke Patients and Controls and Predict 12-Month Mortality
Einor Ben Assayag, Shani Shenhar-Tsarfaty, Keren Ofek, Lilach Soreq, Irena Bova, Ludmila Shopin, Ronan MG Berg, Shlomo Berliner, Itzhak Shapira, Natan M Bornstein, and Hermona Soreq
Stroke accounts for approximately 1 of every 17 deaths in the United States, with many of the surviving patients having to contend with severe disabilities. There is currently no reliable diagnostic biomarker for mild stroke so Ben Assayag et al. examined the degrees of acetylcholinesterase (AChE) activity and cholinergic status (CS, or the total capacity for acetylcholine hydrolysis) in suspected stroke patients in hopes of identifying a pattern. Both AchE activity and the systemic inflammatory response are implicated in stroke and carriers of polymorphisms that alter cholinergic activity could be susceptible to inflammatory damage. The authors found that AChE activities were lower and butyrylcholinesterase activities higher in stroke patients than controls. These values correlated with multiple inflammatory biomarkers, including fibrinogen, interleukin-6, and C-reactive protein. These findings suggest that circulation cholinesterase measurements could be useful as early diagnostic tools for the occurrence of stroke, which may in turn open new venues for earlier stroke diagnosis and treatment.
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Supplementary Data l PDF (315 KB)

Molecular Mechanisms Involved in the Interaction Effects of Alcohol and Hepatitis C Virus in Liver Cirrhosis
Valeria R Mas, Ryan Fassnacht, Kellie J Archer, and Daniel Maluf
Alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) infection are jointly the most frequent chronic liver diseases in the western world and frequently coexist in the same individual. The mechanism by which alcohol consumption accelerates liver disease in chronic hepatitis C virus is not well understood. To identify characteristic molecular pathways affected by alcohol in HCV, Mas et al. modeled gene expression in alcoholic cirrhosis and HCV cirrhosis. Profiles from tissues exhibiting an additive effect of HCV and alcohol show an increase in fibrosis development, apoptosis inhibition, and decreased immune response. A better understanding of the underlying molecular mechanism could help to develop new targeted treatment options.
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Supplementary Data l PDF (4.8 MB)

The Synergistic Effect of Tautomycetin on Cyclosporine A–Mediated Immunosuppression in a Rodent Islet Allograft Model
Yu-Mee Wee, Monica Young Choi, Choong-Hoon Kang, Yang-Hee Kim, Jin-Hee Kim, Sang-Kyou Lee, Seung-Young Yu, Song-Cheol Kim, and Duck-Jong Han
Patients with type 1 diabetes face the prospect of complications such as nephropathy, neuropathy, retinopathy and cardiovascular disease. A successful pancreas transplant provides almost normal glucose homeostasis, but patients require lifelong immunosuppressive medication. Wee et al. investigated the effect of the T-cell apoptosis compound tautomycetin (TMC) on rat islet transplantation both alone and in combination with cyclosporine A (CsA). They demonstrate that TMC inhibits T-cell proliferation without affecting islet or splenocyte viability. The authors also found that islet allograft survival could be prolonged through a combination of TMC and subtherapeutic doses of CsA. Furthermore, the same experimental doses of either immunosuppressive agent alone did not result in any beneficial effect on islet allografts. This novel combination of known agents may lead to greater long-term success of pancreas transplants in those suffering with diabetes.
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ERK-MAPK Signaling Opposes Rho-Kinase to Reduce Cardiomyocyte Apoptosis in Heart Ischemic Preconditioning
Juan-Zhang, Hong-Jun Bian, Xiao-Xing Li, Xiao-Bo Liu, Jun-Ping Sun, Na-Li, Yun-Zhang, and Xiao-Ping Ji
Rho-kinase plays a key role in the pathogenesis resulting from heart ischemia reperfusion (I/R) injury. Ischemic preconditioning (IPC), brief periods of repetitive cardiac ischemia reperfusion, protects against subsequent lethal periods of ischemia, decreases Rho-kinase activation, and reduces infarct size. While these results are beneficial, little is known about the mechanism of action. Here, Zhang et al. show that ERK-MAPK signaling is required in ischemic preconditioning in order to oppose the Rho-kinase signaling which leads to apoptosis in vivo. These data may lead to new treatment possibilities for patients suffering from coronary heart disease.
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Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease
Jonathan P Desnick, Jungmin Kim, Xingxuan He, Melissa P Wasserstein, Calogera M Simonaro, and Edward H Schuchman
Types A and B Niemann-Pick disease (NPD) are autosomal recessive sphingolipidoses caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Type A disease results in infantile neurodegeneration and hepatosplenomegaly with demise in the first few years of life, while Type B includes hepatosplenomegaly, pulmonary disease and survival into adolescence or adulthood. While mutations have been reported in types A and B phenotypes, expression studies are the most accurate way to predict which mutations have residual enzyme activity and may be neuroprotective. Here, Desnick et al. present clinical and molecular findings for six unrelated type A and B patients. The results provide additional information for predicting clinical phenotypes in newly diagnosed infants and children with Niemann-Pick disease.
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Thrombin and Its Receptor Enhance ST-Segment Elevation in Acute Myocardial Infarction by Activating the KATP Channel
Ming Long, Lei Yang, Genya Huang, Liping Liu, Yugang Dong, Zhimin Du, Anli Tang, Chenghen Hu, Ruimin Gu, Xiuren Gao, and Lilong Tang
ST segment elevation is used to diagnose acute myocardial infarction (AMI) and is the major clinical criterion for committing patients with chest pain to emergent coronary revascularizations. Despite its frequent usage, the mechanism responsible for ST segment elevation remains unclear. Since ST segment elevation is the major criteria for thrombolytic therapy, Long et al. examined the role of thrombin and its receptor activation in ST segment elevation during acute myocardial infarction. The results demonstrate that thrombin and activation of its receptor significantly enhance ST segment elevation during AMI. This observation suggests that more robust and accurate methods than reduced ST segment times may be required to assess efficacy of anti-thrombin therapies.
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