March-April 2008 l Vol 14 l No 3-4

Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis
Hani A Jouihan, Paul A Cobine, Robert C Cooksey, Emily A Hoagland, Sihem Boudina, E Dale Abel, Dennis R Winge, and Donald A McClain
Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Patients with hereditary hemochromatosis accumulate large quantities of iron and often have diabetes, although this pathogenesis is not well understood.  Mitochondria play a crucial role in apoptosis and glucose-stimulated insulin secretion. Jouihan et al. (98-108) used a combination of knockout mice and molecular techniques to test their hypothesis that increased levels of iron may result in mitochondrial dysfunction. Their data suggest that a novel mechanism of iron-induced cellular dysfunction in mitochondria, namely altered uptake of transition metals such as manganese, may play a role in the onset of hereditary hemocromatosis and may represent a therapeutic target for this disease.
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High Mobility Group Box Protein-1 Correlates with Renal Function in Chronic Kidney Disease (CKD)
Annette Bruchfeld, Abdul Rashid Qureshi, Bengt Lindholm, Peter Barany, LiHong Yang, Peter Stenvinkel, and Kevin J Tracey
Chronic kidney disease (CKD) is associated with inflammation, malnutrition and an increased risk of cardiovascular disease. High mobility group box 1 (HMGB1), a proinflammatory mediator of tissue injury, is implicated in several inflammatory diseases. Bruchfeld et al. (109-115) completed a post-hoc, cross-sectional study analyzing CKD patients to determine if HMGB1 is elevated. Results reveal that HMGB1 is significantly elevated in CKD patients and correlates with glomerular filtration rate and markers of inflammation and malnutrition. Future studies are needed to determine if HMGB1 may be used as a marker of disease activity, severity and outcome in CKD.
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Critical Role of Hypoxia and A2A Adenosine Receptors in Liver Tissue-Protecting Physiological Anti-Inflammatory Pathway
Alexander Choukèr, Manfred Thiel, Dmitriy Lukashev, Jerrold M Ward, Ines Kaufmann, Sergey Apasov, Michail V Sitkovsky, and Akio Ohta
Acute or chronic hepatitis due to viral infections or autoimmunity affects millions of patients and results in high morbidity. It is important to uncover the mechanisms that regulate immune responses in the liver and those that protect liver tissues from excessive collateral damage. Choukèr et al. (116-123) focused on the relationship between tissue hypoxia and extracellular adenosine-mediated immunosuppression. They tested whether inflammatory tissue damage-associated hypoxia and extracellular adenosine receptor (A2AR) signaling play a role in the physiological anti-inflammatory mechanism that limits liver damage during fulminant hepatitis.  Their data demonstrate that the total body hypoxia-triggered pathway provides protection in acute hepatitis and that hypoxia and A2AR function in the same immunosuppressive and liver tissue-protecting pathway. 
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Macrophage Migration Inhibitory Factor in Pediatric Patients Undergoing Surgery for Congenital Heart Repair
Sanah Merchant, Sumekala Nadaraj, Devyani Chowdhury, Vincent A Parnell, Cristina Sison, Edmund J Miller, and Kaie Ojamaa
Cardiopulmonary bypass (CPB) surgery induces a complex inflammatory reaction that may result in multiorgan dysfunction including cardiac contractile depression. Macrophage migration inhibitory factor (MIF) is a central mediator of the innate immune response in patients with autoimmune disorders, severe sepsis, and respiratory distress syndrome. Pediatric cardiac surgery involving CPB induced proinflammatory cytokine production that correlated with postoperative morbidity and cardiopulmonary dysfunction. Merchant et al. (124-130) measured circulating levels of MIF before and after CPB in children and correlated these findings with intra-operative variables and postoperative outcomes. Their data suggest a potential negative effect of high circulating levels of MIF on respiratory and cardiovascular functions in the immediate postoperative period. This supports the development of therapeutic strategies targeting MIF function in this clinical setting.
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Thrombin Receptor and the Ventricular Arrhythmias after Acute Myocardial Infarction
Lilong Tang, Chunyu Deng, Ming Long, Anli Tang, Shulin Wu, Yugang Dong, Louis D Saravolatz, and Julius M Gardin
Acute myocardial infarction (AMI) has been a major public health problem for decades. Nearly 1 million patients in the U.S. suffer from AMI annually. While AMI mortality has decreased with the advent of new procedures, it still reaches twenty percent.  The mechanism mediating ventricular arrhythmia after AMI remains ambiguous. Tang et al. (131-140) tested the role of thrombin receptor activation in the generation of post-AMI ventricular arrhythmia. Results indicate that increased thrombin receptor activation and expression in the infarcted left ventricle after AMI may contribute to ventricular arrhythmia through a mechanism involving glibenclamide-sensitive potassium channels. These findings open the door for new therapeutic targets in acute myocardial infarction.
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Neuronal Nitric Oxide Synthase Contributes to the Regulation of Hematopoiesis
Peter Krasnov, Tatyana Michurina, Michael A Packer, Yuri Stasiv, Naoki Nakaya, Kateri A Moore, Kenneth E Drazan, and Grigori Enikolopov
Nitric oxide (NO), a crucial regulator of vasodilation, immunity and neurotransmission, is also involved in regulating the balance between proliferation and differentiation in several developmental and differentiation settings. In the hematopoietic system, NO contributes to the regulation of hematopoietic stem and progenitor cells in the bone marrow.  While action of NO in the hematopoietic system can be readily demonstrated, neither the contribution of individual NO synthase (NOS) isoforms nor their mode of action are understood. In this work, Krasnov et al. (141-149) investigated these mechanisms and their results suggest that nNOS-produced NO acts as a paracrine regulator of hematopoietic stem cells and that nNOS-selective inhibitors may have therapeutic potential for hematopoiesis-related disorders.
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IL-1β Regulates FHL2 and Other Cytoskeleton Related Genes in Human Chondrocytes
Helga Joos, Wolfgang Albrecht, Stefan Laufer, Heiko Reichel, and Rolf E Brenner
Osteoarthritis is one of the most common joint diseases and severely restricts patient mobility. The cartilage destruction that takes place is not only associated with an imbalance of anabolic and catabolic processes, but also with poorly understood alterations in the cytoskeletal organization of chondrocytes. In this work, Joos et al. (150-158) investigated the effects of IL-1β on components of the chondrocyte cytoskeleton on different expression levels. Results show that IL-1β is involved in the regulation of various cytoskletal components in human chondrocytes and may be relevant in osteoarthritis pathogenesis. A deeper knowledge of these molecular processes may set the pathogenetic mechanisms of degenerative joint diseases in a novel context.
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Involvement of the p38 MAPK–NF-κB Signal Transduction Pathway and COX-2 in the Pathobiology of Meniscus Degeneration in Humans
Dionysios J Papachristou, Eugenia Papadakou, Efthimia K Basdra, Panagiotis Baltopoulos, Elias Panagiotopoulos, and Athanasios G Papavassiliou
Menisci, located in the knee, are wedge-shaped half moon structures made of cartilage. Menisci can fail due to biomechanical or biochemical cues, the latter often attributed to osteoarthritis of the knee. The molecular events underpinning the pathogenesis of meniscal degeneration remain elusive.  Papachristou et al. (160-166) immunohistochemically examined the expression of p38 MAPK, its phosphorylated/activated form (p-p38), its target NF-kB, and COX-2 in ruptured menisci. Further, they also investigated their involvement in meniscal degeneration development. Their findings demonstrate increased expression of elements of the p38-NF-kB pathway and COX-2 in disintegrated fibrocartilage, suggesting a role for these molecules in the pathobiochemistry of meniscal degeneration and consequential rupture.
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Upregulated ATM Gene Expression and Activated DNA Crosslink-Induced Damage Response CheckpointIin Fanconi Anemia: Implications for Carcinogenesis
Kazuhiko Yamamoto, Abdallah Nihrane, Jason Aglipay, Juan Sironi, Steven Arkin, Jeffrey M Lipton, Toru Ouchi, and Johnson M Liu
Fanconi anemia is a genetic disorder that predisposes affected individuals to hematopoietic failure, birth defects, leukemia and squamous cell carcinoma of the head, neck and cervix. Pre-cancerous legions are believed to trigger the DNA damage response (DDR). Yamamoto et al. (167-174) focused on the DDR in Fanconi anemia and its putative role as a checkpoint barrier to cancer. They describe a processing defect that leads to general DDR upregulation and suggest that cancer in Fanconi anemia may arise from selection for cells that escape from a chronically activated DDR checkpoint.
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α-Lipoic Acid Modulates Extracellular Matrix and Angiogenesis Gene Expression in Non-Healing Wounds Treated with Hyperbaric Oxygen Therapy
Renata Alleva, Marco Tomasetti, Davide Sartini, Monica Emanuelli, Emanuele Nasole, Ferruccio Di Donato, Battista Borghi, Lory Santarelli, and Jiri Neuzil
Non-healing ulceration is a serious complication of diabetes mellitus, conditions such as paralysis that inhibit movement, and aging. Wound healing is a complex process and chronic wounds arise from recurrent or chronic injuries and/or low levels of bacterial contamination. These injuries often fail to heal because persistently elevated levels of proinflammatory cytokines lead to high concentrations of proteases, which degrade growth factors and matrix metalloproteinase proteins (MMPs) essential to normal wound healing. Hyperbaric oxygen (HBO) therapy in conjunction with α-lipoic acid (LA) administration has been used for the successful treatment of non-healing wounds by inhibiting reactive oxygen species and inflammatory mediators, and accelerating ulcer regression. Alleva et al. (175-183) evaluated the effect of LA on gene expression in chronic wound patients treated with HBO. Results show that LA supplementation in combination with HBO therapy downregulated inflammatory cytokines and growth factors, in turn affecting expression of MMPs and promoting the healing process.
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Catecholamines – Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?
Michael A Flierl, Daniel Rittirsch, Markus Huber-Lang, J Vidya Sarma, and Peter A Ward
Catecholamines, which regulate immune and inflammatory responses, derive from the adrenal medulla and presynaptic neurons. Recent studies reveal that T cells also can synthesize and release catecholamines which then can regulate T cell function. Macrophages and neutrophils, when stimulated, can generate and release catecholamines de novo which, in an autocrine/paracrine manner, regulate mediator release via engagement of adrenergic receptors. Here, Flierl et al. (195-204) review the roles of catecholamines and their receptors in immunity and inflammation. 
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The Pathogenesis of Lyme Neuroborreliosis – From Infection to Inflammation
Tobias A Rupprecht, Uwe Koedel, Volker Fingerle, and Hans-Walter Pfister
Lyme borreliosis is the most common human tick-borne disease in the Northern hemisphere. It is caused by the spirochete Borrelia burgdorferi which enters the host through a tick bite on the skin. In this review, Rupprecht et al. (205-212) describe current knowledge regarding the pathogenesis of acute Lyme neuroborreliosis (LNB), from invasion to inflammation of the central system.
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Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage-Induced Immunological Alterations
Raghavan Raju, Kirby I Bland, and Irshad H Chaudry
Trauma-hemorrhage leads to prolonged immune suppression, sepsis and multiple organ failure. The immunological events following trauma-hemorrhage have been elucidated and may be gender dependent. The hormone estrogen protects women from complications associated with injury, trauma and sepsis. In this review, Raju et al. (213-221) summarize current knowledge regarding estrogen modulation of immunity and its promise as a therapeutic for the treatment of adverse conditions following trauma-hemorrhage.
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Inflammatory Mechanisms in the Regulation of Insulin Resistance
Herbert Tilg and Alexander R Moschen
The number of obese and overweight individuals has risen dramatically over the last two decades.  Insulin resistance is the key primary defect underlying the development of type 2 diabetes, and plays an essential role in this and other obesity-related diseases.  Insulin resistance has also frequently been associated with a state of low-grade inflammation and is assumed to contribute to its development. In this review, Tilg et al. (222-231) summarize the link between inflammation, anti-inflammatory strategies and insulin resistance. 
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