|
September-October 2010 l Vol 16 l No 9-10
Research Articles
Peroxynitrite-Induced Nitration of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Promotes Their Binding in Diabetic Angiopathy
Yanning Li, Jinsheng Qi, Kun Liu, Bin Li, Hui Wang, and Jinhai Jia
Chronic vascular complications of diabetes, including microvascular (nephropathy) and macrovascular (atherosclerosis) diseases, are major causes of morbidity and premature mortality. Evidence shows that inflammation and oxidative stress play important roles in this pathophysiology. While peroxynitrite is a key mediator of diabetic complications, the effect of peroxynitrite on nitration of two key enzymes with roles in inflammation and oxidative stress, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), remains unknown. Li et al. examined this issue and concluded that in vivo binding of COX-2 and iNOS exists in diabetic angiopathy, and peroxynitrite-induced nitration of COX-2 and iNOS can promote binding, which contributes to diabetic angiopathy. Therefore, scavenging peroxynitrite in order to attenuate binding of COX-2 and iNOS may represent a more effective intervention for this disease.
Page 335 l View article: PDF (8 MB) HTML
Immunomodulatory Drugs Regulate HMGB1 Release from Activated Human Monocytes
Hanna Schierbeck, Heidi Wähämaa, Ulf Andersson, And Helena Erlandsson Harris
High mobility group box-1 (HMGB1) is a ubiquitous nonhistone nuclear protein as well as an extracellular molecule regulating innate and adaptive immunity. Extracellular HMGB1 plays an important pathogenic role in infectious and sterile inflammation. Several HMGB1 specific antagonists have provided beneficial results in multiple preclinical models of inflammatory disease. However, since no HMGB1 blocking therapies have been approved for clinical use, Scheirbeck et al. studied effects on HMGB1 release by well-established antirheumatic compounds. Results demonstrate that treatment with dexamethasone, chloroquine or gold sodium thiomalate have the ability to inhibit HMGB1 release and that further study in this area is warranted.
Page 343 l View article: PDF (1.5 MB) HTML
mTOR Regulates the Invasive Properties of Synovial Fibroblasts in Rheumatoid Arthritis
Teresina Laragione And Pércio S Gulko
Rheumatoid arthritis (RA) is a common chronic autoimmune disease affecting about one percent of the population and is commonly associated with disability and deformities. RA joint pathology is characterized by inflammation of the synovium, which produces several proinflammatory cytokines and proteases. Like a malignant tumor, synovial inflammation invades and destroys cartilage and bone. Fibroblast-like synoviocytes (FLS) have a central role in cartilage and bone invasion and destruction. Laragione and Gulko used rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), to assess the role of the mTOR pathway in invasive FLS. Rapamycin significantly reduced RA and FLS invasion suppressing the mTOR signaling pathway. This suggests rapamycin may play a role in RA therapy by reducing damage and erosive changes mediated by FLS.
Page 352 l View article: PDF (3.5 MB) HTML
Supplementary Data l PDF (324 KB)
PRAS40 Regulates Protein Synthesis and Cell Cycle in C2C12 Myoblasts
Abid A Kazi and Charles H Lang
Muscle serves as the largest protein reservoir in the body and may be used as an energy source when necessary. Muscle wasting is associated with catabolic insults such as sepsis, alcohol abuse and aging. Proline Rich Akt Substrate 40kDa (PRAS40) is a binding protein which has complex effects on cell metabolism. Despite reports implicating PRAS40 as a regulator of protein translation initiation in a variety of cells, there is a paucity of information related to its role in skeletal muscle. To address this, Kazi and Lang examined changes in myocyte protein synthesis, cell proliferation and cell cycle in response to PRAS40 knockdown. Results indicate PRAS40 plays an important role in cell size regulation and affects cell proliferation and differentiation. Understanding the role of PRAS40 may prove important in designing new strategies to manage muscle wasting associated with catabolic insults.
Page 359 l View article: PDF (3.6 MB) HTML
N-Methyl-D-Aspartate Receptor and Neuronal Nitric Oxide Synthase Activation Mediate Bilirubin-Induced Neurotoxicity
Maria A Brito, Ana R Vaz, Sandra L Silva, Ana S Falcão, Adelaide Fernandes, Rui FM Silva, and Dora Brites
Hyperbilirubinemia, or increased levels of bilirubin in the blood, may lead to neurotoxicity and neuronal death. Although the mechanisms of nerve cell damage by unconjugated bilirubin (UCB) appear to involve a disruption of redox status and excitotoxicity, the contribution of nitric oxide (NO) and N-methyl-D-aspartate (NMDA) glutamate receptors is unclear. Brito et al. therefore investigated the role of NO and NMDA glutamate receptors in UCB neurotoxicity. Results reinforce the involvement of oxidative stress and data highlight important steps in neuronal oxidative damage by UCB. Inhibitors and receptor antagonists may represent therapeutic tools to reduce risk associated with oxidative stress and neurotoxicity in unconjugated hyperbilirubinemia.
Page 372 l View article: PDF (299 KB) HTML
Feline Congenital Erythropoietic Porphyria: Two Homozygous UROS Missense Mutations Cause the Enzyme Deficiency and Porphyrin Accumulation
Sonia Clavero, David F Bishop, Urs Giger, Mark E Haskins, and Robert J Desnick
Congenital Erythropoietic Porphyria (CEP) is an enzyme deficiency which occurs in red blood cells at birth. As a result, exposure to sunlight may lead to skin blistering, vesicle formation and scarring, while secondary infections in these lesions may lead to disfigurement of the face and hands. Medical management is focused on protecting affected individuals from sunlight or ultraviolet light exposure. In this work, Clavero et al. identified the first feline model of CEP based on clinical phenotype and confirmed by biochemical and molecular genetic studies. Results indicate a synergistic interaction of two mutations in the URO-synthase polypeptide caused this feline model of human CEP. Future identification of cats with a CEP-like phenotype may permit the establishment of a colony and the opportunity to evaluate stem cell and gene transfer therapies prior to human trials.
Page 381 l View article: PDF (1.1 MB) HTML
APOE/C1/C4/C2 Gene Cluster Genotypes, Haplotypes and Lipid Levels in Prospective Coronary Heart Disease Risk Among UK Healthy Men
Gie Ken-Dror, Philippa J Talmud, Steve E Humphries, and Fotios Drenos
While the role of common Apolipoprotein E (APOE) variants on Coronary Heart Disease (CHD) is well known, the influence of other nearby apolipoprotein genes is unclear. Ken-Dror et al. examined the association between gene cluster variations of apolipoproteins in the genotypes of over 2700 middle-aged men, including 275 CHD events, over a 15-year follow-up period. Results indicate carriers of the APOE ε2 and APOC2 single nucleotide polymorphisms (SNPs) had a significantly lower risk of CHD when compared with non-carriers, while carriers of the APOC1 SNP had higher risk of CHD. The common APOE polymorphism may explain the majority of the locus genetic determinants of plasma lipid levels; however, additional SNPs in the APOC1/C2 region may contribute to CHD risk. This work exposes the potential of non-APOE SNPs as potential risk factors for CHD.
Page 389 l View article: PDF (406 KB) HTML
Supplementary Data l PDF (612 KB)
ISO-1, a Macrophage Migration Inhibitory Factor Antagonist, Inhibits Airway Remodeling in a Murine Model of Chronic Asthma
Pei-Fen Chen, Ya-ling Luo, Wei Wang, Jiang-xin Wang, Wen-yan Lai, Si-ming Hu, KaiFan Cheng, and Yousef Al-Abed
Asthmatic airway remodeling, characterized by structural and morphometric changes of the airway epithelium, is believed to be the result of chronic inflammation in the bronchial wall. Since macrophage migration inhibitory factor (MIF) is required for allergic asthma, Chen et al. investigated its effects on the development of airway remodeling using a small molecule MIF antagonist called ISO-1. Results demonstrate MIF small-molecule antagonism has significant antiinflammatory effects on allergen-induced lung inflammation and can prevent changes in airway remodeling in experimental models. This suggests that MIF antagonism may be an attractive alternative therapy for asthmatic patients.
Page 400 l View article: PDF (6.7 MB) HTML
MicroRNA-34a Is Induced via p53 during Cisplatin Nephrotoxicity and Contributes to Cell Survival
Kirti Bhatt, Li Zhou, Qing-Sheng Mi, Shuang Huang, Jin-Xiong She, and Zheng Dong
Acute Kidney Injury (AKI) may occur in cancer patients due to the potent chemotherapy drug Cisplatin, which accumulates in renal tubular cells resulting in cell injury and death. MicroRNAs, small non-coding RNAs produced endogenously, have emerged as important regulators in pathophysiological conditions such as development and tumorigenesis. Little is known regarding the role of microRNAs in renal diseases such as AKI. Here, Bhatt et al. examine the regulation of microRNA-34a (miR-34a), a target gene of p53, in experimental models of Cisplatin-induced AKI or nephrotoxicity. Results demonstrate microRNA regulation in a model of acute kidney injury and indicate that Cisplatin-induced miR-34a may play a cytoprotective role in cell survival.
Page 409 l View article: PDF (1.5 MB) HTML
Role of Hydrogen Sulfide in Severe Burn Injury–Induced Inflammation in Mice
Jing Zhang, Selena Wei Shan Sio, Shabbir Moochhala, and Madhav Bhatia
Patients with severe burns are susceptible to sepsis, a systemic inflammatory condition that may lead to multiple organ failure and shock, which are common causes of morbidity and mortality. Full-thickness burns exceedin 25% of the total body surface area produce a profound systemic inflammatory reaction characterized by leukocyte activation and plasma leakage in the microvasculature of tissues and organs remote from the wound. Endogenous hydrogen sulfide (H2S) is naturally synthesized in many types of mammalian cells and plays a proinflammatory role in various experimental models. Here, Zhang et al. investigate the effect of local burn injury on H2S release in distant organs. Burn injury significantly increased plasma and liver H2S levels. Prophylactic as well as therapeutic administration of an inhibitor of H2S synthesis significantly reduced systemic inflammation. These findings highlight the role of H2S in contributing to inflammatory damage after burn injury and contribute to our understanding of this process.
Page 417 l View article: PDF (2.5 MB) HTML
MTHFR, MTR, and MTRR Polymorphisms in Relation to p16INK4A Hypermethylation in Mucosa of Patients with Colorectal Cancer
Yvonne Wettergren, Elisabeth Odin, Göran Carlsson, and Bengt Gustavsson
Hypermethylation of p16 is associated with reduced survival in patients with colorectal cancer. In this work, Wettergren et al. investigated whether polymorphisms in folate- and methyl-associated genes were linked with p16 hypermethylation in colorectal cancer patients. Results indicate patients with MTRR gene variants exhibit significantly worse cancer-specific survival when the mucosa is positive for p16 hypermethylation. The authors hypothesize this may be due to oxidative stress associated with this genotype as well as with p16. These data begin to unravel a mechanism which may be responsible for increased risk of recurrent disease as well as poor cancer-specific survival.
Page 425 l View article: PDF (475 KB) HTML
Review Articles
Stem Cell Transplantation in Brain Tumors: A New Field for Molecular Imaging?
Nora Sandu and Bernhard Schaller
Neutral stem cells have the potential to become a new and promising treatment modality in different pathologies of the central nervous system, including malignant brain tumors. Novel therapies to eliminate these tumors are already aided by current stem cell research and stem cell regulation monitored by molecular imaging. This review describes the current molecular imaging techniques used on neutral stem cells affected by therapeutic experimental brain tumor models.
Page 433 l View article: PDF (74 KB) HTML
ATP-Binding Membrane Cassette Transporter A1 (ABCA1): A Possible Link between Inflammation and Reverse Cholesterol Transport
Kai Yin, Duan-fang Liao, and Chao-ke Tang
Atherosclerosis, a chronic inflammatory disease of the artery wall, involves numerous cellular and molecular inflammatory components. ATP-binding membrane cassette transporter A1 (ABCA1) is a crucial protein involved in cellular cholesterol efflux and reverse cholesterol transport. Recent studies suggest ABCA1 may be the molecular basis for the interaction between inflammation and RCT. Here, Yin et al. review recent findings on the role of inflammatory cytokines, inflammatory proteins, inflammatory lipids and endotoxin-mediated inflammatory process in expression of ABCA1. Additionally, the authors cover ABCA1's function in modulating immunity and inflammation through direct and indirect anti-inflammatory mechanisms.
Page 438 l View article: PDF (303 KB) HTML
Supplementary Data l PDF (303 KB)
|
