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Articles from this Volume

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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Posted by MolMed Editor on Aug 1, 2010 12:00 AM CDT
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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Posted by MolMed Editor on Jul 6, 2010 12:00 AM CDT
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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Posted by MolMed Editor on Jul 5, 2010 12:00 AM CDT
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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Posted by MolMed Editor on Jul 4, 2010 12:00 AM CDT
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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Posted by MolMed Editor on Jul 3, 2010 12:00 AM CDT
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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Posted by MolMed Editor on Jul 2, 2010 12:00 AM CDT
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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Posted by MolMed Editor on Jul 1, 2010 12:00 AM CDT
Review Article

Jennifer E Ziello, Yan Huang, and Ion S Jovin

Gene therapy is presently being investigated for its therapeutic potential in treating a number of maladies. Gene therapy relies upon a variety of viral and nonviral vectors which are delivered to target body cells and subsequently endocytosed and dissembled. The mechanisms by which vectors such as adenoviruses, adeno-associated viruses, retroviruses and liposomes enter the cell are being increasingly focused upon, as the effort to increase the efficiency of gene therapy continues. Ziello et al. focus on the mechanisms of endocytosis and how they relate to the trafficking of viral and nonviral vectors in gene therapy.

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Posted by MolMed Editor on Jun 5, 2010 12:00 AM CDT
Koji Higuchi, Makoto Yoshimitsu, Xin Fan, Xiaoxin Guo, Vanessa I Rasaiah, Jennifer Yen, Chuwa Tei, Toshihiro Takenaka, and Jeffrey A Medin

Fabry disease is a lysosomal storage disorder (LSD) caused by a deficiency of α-galactosidase A activity (α-gal A). This leads to buildup of globotriaosylceramide (Gb3) resulting in cardiac, renal and cerebrovascular disease. Fabry disease is the second most prevalent LSD and a model for the development of therapy for single gene defects. While enzyme replacement therapy is available, it requires frequent lifelong infusions and only seems to slow progression of the disorder. Because gene therapy is a promising approach for Fabry disease, Higuchi et al. sought to optimize a construct for α-gal A delivery. The authors demonstrate that administration of a lentivector containing α-gal A fused to a region of Tat (a protein transduction domain from HIV that allows proteins to penetrate the cell membrane) more efficiently reduces Gb3 accumulation in Fabry hearts and kidneys than the vector with α-gal A alone. These data may advance gene therapy for Fabry disease, and suggest that α-gal A linked to Tat may render enzyme replacement therapy more effective.

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Posted by MolMed Editor on Jun 4, 2010 12:00 AM CDT
Rodrigo A Fraga-Silva, Brian S Sorg, Mamta Wankhede, Casey deDeugd, Joo Y Jun, Matthew B Baker, Yan Li, Ronald K Castellano, Michael J Katovich, Mohan K Raizada, and Anderson J Ferreira

Thrombogenic events, such as ischemic stroke, pulmonary embolism, deep venous thrombosis, mesenteric ischemia and acute coronary syndrome, are major complications of certain pathological conditions, such as hypertension, atherosclerosis and diabetes mellitus. Despite many therapeutic advances and increasingly effective drug treatments, thrombogenic events remain the major cause of morbidity and mortality worldwide. Recent data suggest activation of the ACE2/Ang-(1-7)/Mas axis produces antithrombotic activity. In this work, Fraga-Silva et al. evaluated the role of ACE2 in thrombus formation in normotension and hypertension in vivo and tested a novel ACE2 activator (XNT) on thrombus formation. Results demonstrate the pharmacological activation of ACE2 by XNT attenuated platelet attachment to vessels and thrombus formation. These results suggest that XNT could be a potential lead compound for the treatment of thrombogenic diseases.

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Posted by MolMed Editor on Jun 3, 2010 12:00 AM CDT
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