Serp-2, a virus-derived apoptosis and inflammasome inhibitor, attenuates liver ischemia-reperfusion injury in mice.

Background: Ischemia-reperfusion injury (IRI) is an antigen-independent, innate immune response to arterial occlusion and ischemia with subsequent paradoxical exacerbation after reperfusion. IRI remains a critical problem after vessel occlusion and infarction or during harvest and surgery in transplants. After transplant, liver IRI (LIRI) contributes to increased acute and chronic rejection and graft loss.

Mouse Gamma Herpesvirus MHV-68 Induces Severe Gastrointestinal (GI) Dilatation in Interferon Gamma Receptor-Deficient Mice (IFNγR) That Is Blocked by Interleukin-10.

Inflammatory bowel disease (IBD) and infection cause gastrointestinal (GI) distension and, in severe cases, toxic megacolon with risk of perforation and death. Herpesviruses have been linked to severe GI dilatation. MHV-68 is a model for human gamma herpesvirus infection inducing GI dilatation in interleukin-10 (IL-10)-deficient mice but is benign in wildtype mice.

Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection.

Early damage to transplanted organs initiates excess inflammation that can cause ongoing injury, a leading cause for late graft loss. The endothelial glycocalyx modulates immune reactions and chemokine-mediated haptotaxis, potentially driving graft loss. In prior work, conditional deficiency of the glycocalyx-modifying enzyme N-deacetylase-N-sulfotransferase-1 (Ndst1 TekCre) reduced aortic allograft inflammation.

Atrial Fibrillation Ablation Increases Inflammation-Chemokine Modulation Suppresses Activation of Leukocytes Isolated after Ablation.

Aims: Atrial fibrillation (AF) ablation is associated with increased circulating markers of inflammation. Innate immune or inflammation pathways up-regulate mononuclear cell responses and may increase the risk for recurrent arrhythmia. Chemokines and serine protease coagulation pathways both activate innate immune responses.

Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE null Mice.

Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE null mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression.

Periodontal pathogens invade gingiva and aortic adventitia and elicit inflammasome activation in αvβ6 integrin-deficient mice.

The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin β6(-/-) mouse model to study the causality. We investigated the ability of a polymicrobial consortium of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum to colonize the periodontium and induce local and systemic inflammatory responses.

Fusobacterium nucleatum Alters Atherosclerosis Risk Factors and Enhances Inflammatory Markers with an Atheroprotective Immune Response in ApoE(null) Mice.

The American Heart Association supports an association between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) but does not as of yet support a causal relationship. Recently, we have shown that major periodontal pathogens Porphyromonas gingivalis and Treponema denticola are causally associated with acceleration of aortic atherosclerosis in ApoEnull hyperlipidemic mice. The aim of this study was to determine if oral infection with another significant periodontal pathogen Fusobacterium nucleatum can accelerate aortic inflammation and atherosclerosis in the aortic artery of ApoEnull mice.

Chronic oral infection with major periodontal bacteria Tannerella forsythia modulates systemic atherosclerosis risk factors and inflammatory markers.

Tannerella forsythia is a Gram-negative anaerobic organism that inhabits the subgingival cavity and initiates connective tissue destruction and alveolar bone resorption in periodontal disease (PD). PD is a chronic immunoinflammatory disease and has been linked to several systemic diseases including atherosclerosis. This study evaluated the effects of a chronic oral infection with T.

Serpin treatment suppresses inflammatory vascular lesions in temporal artery implants (TAI) from patients with giant cell arteritis.

Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide range of animal models.

Active invasion of oral and aortic tissues by Porphyromonas gingivalis in mice causally links periodontitis and atherosclerosis.

Atherosclerotic vascular disease is a leading cause of myocardial infarction and cerebrovascular accident, and independent associations with periodontal disease (PD) are reported. PD is caused by polymicrobial infections and aggressive immune responses. Genomic DNA of Porphyromonas gingivalis, the best-studied bacterial pathogen associated with severe PD, is detected within atherosclerotic plaque.

Invasion of oral and aortic tissues by oral spirochete Treponema denticola in ApoE(-/-) mice causally links periodontal disease and atherosclerosis.

Treponema denticola is a predominantly subgingival oral spirochete closely associated with periodontal disease and has been detected in atherosclerosis. This study was designed to evaluate causative links between periodontal disease induced by chronic oral T. denticola infection and atherosclerosis in hyperlipidemic ApoE(-/-) mice.

Orthotopic kidney transplantation in mice: technique using cuff for renal vein anastomosis.

Mouse renal transplantation is a technically challenging procedure. Although the first kidney transplants in mice were performed over 34 years ago and refined some years later, the classical techniques of mouse renal transplantation required clamping both vena cava and aorta simultaneously and carry out suture anastomoses of the renal artery and vein in a heterotopic position. In our laboratory, we have successfully developed mouse orthotopic kidney transplantation for the first time, using a rapid "cuffed" renal vein technique for vessel anastomosis, wherein the donor's renal vein was inserted through an intravenous catheter, folded back and tied.

The serpin solution; targeting thrombotic and thrombolytic serine proteases in inflammation.

Serpins in the mammalian body are highly potent serine protease inhibitors which modulate both thrombotic and thrombolytic pathway activation, with direct and indirect crosstalk with immune and inflammatory pathways. In this review, we discuss mammalian and viral serpins as regulators of coagulation and inflammation. We focus first on the thrombotic and thrombolytic serine proteases and known interactions between these protease cascades and elements of the innate immune response.

Myxomaviral Anti-Inflammatory Serpin Reduces Myeloid-Derived Suppressor Cells and Human Pancreatic Cancer Cell Growth in Mice.

Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with critical roles in tumor invasion, growth, angiogenesis, and metastasis. Increased thrombolytic cascade serine proteases, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell migration, pancreatic cancer growth, invasion and unfavorable outcomes. Inflammation in pancreatic cancer is linked with myeloid-derived suppressor cell (MDSC) activity and cancer progression.

Myxomavirus-derived serpin prolongs survival and reduces inflammation and hemorrhage in an unrelated lethal mouse viral infection.

Lethal viral infections produce widespread inflammation with vascular leak, clotting, and bleeding (disseminated intravascular coagulation [DIC]), organ failure, and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by an inflammatory cytokine storm and also can induce systemic inflammation with loss of normal serine protease inhibitor (serpin) regulation. Myxomavirus secretes a potent anti-inflammatory serpin, Serp-1, that inhibits clotting factor X (fX) and thrombolytic tissue- and urokinase-type plasminogen activators (tPA and uPA) with anti-inflammatory activity in multiple animal models.

Virus-derived anti-inflammatory proteins: potential therapeutics for cancer.

Inflammatory responses now have a defined central role in cancer cell growth, invasion, and metastases. Anti-inflammatory proteins from viruses target key stages in immune response pathways and have potential as novel therapeutics for cancer, including highly potent virus-derived inhibitors of protease, chemokine, cytokine, and apoptotic cascades that have been identified. Serine proteases, in addition to their conventional roles in thrombosis, thrombolysis, and apoptotic pathways, are essential regulators of inflammation and are associated with developing cancers.

Viral serpin therapeutics from concept to clinic.

Over the past 19 years, we have developed a novel myxoma virus-derived anti-inflammatory serine protease inhibitor, termed a serpin, as a new class of immunomodulatory therapeutic. This review will describe the initial identification of viral serpins with anti-inflammatory potential, beginning with preclinical analysis of viral pathogenesis and proceeding to cell and molecular target analyses, and successful clinical trial. The central aim of this review is to describe the development of two serpins, Serp-1 and Serp-2, as a new class of immune modulating drug, from inception to implementation.

A novel strategy to inhibit FAK and IGF-1R decreases growth of pancreatic cancer xenografts.

Deregulation of insulin-like growth factor-1 receptor (IGF-1R) and focal adhesion kinase (FAK) signaling pathways plays an important role in cancer cell proliferation and metastasis. In pancreatic cancer cells, the crosstalk and compensatory mechanisms between these two pathways reduce the efficacy of the treatments that target only one of the pathways. Ablation of IGF-1R signaling by siRNA showed minimal effects on the survival and growth of pancreatic cancer cells.

Targeting of the protein interaction site between FAK and IGF-1R.

The interaction of focal adhesion kinase (FAK) and insulin-like growth factor-1 receptor (IGF-1R) plays an important role in cancer cell survival. Targeting this interaction with small molecule drugs could be a novel strategy in cancer therapy. By a series of pull-down assays using GST-tagged FAK fragments and His-tagged IGF-1R intracellular fragments, we showed that the FAK-NT2 (a.

A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer.

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that is overexpressed in many types of tumors, including pancreatic cancer, and plays an important role in cell adhesion and survival signaling. Pancreatic cancer is a lethal disease and is very resistant to chemotherapy, and FAK has been shown recently to assist in tumor cell survival. Therefore, FAK is an excellent potential target for anti-cancer therapy.

Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss.

To examine the role of the brain stem melanocortin system in long-term energy regulation, we assessed the effects of overproduction of proopiomelanocortin (POMC) in the caudal brain stem of F344xBN rats with adult-onset obesity. Recombinant adeno-associated viral vector encoding POMC gene was delivered to the nucleus of solitary tract (NTS) in the hindbrain, and food intake, body weight, glucose and fat metabolism, brown adipose tissue thermogenesis, and mRNA levels of neuropeptides and melanocortin receptors were assessed. POMC delivery resulted in sustained reduction in food intake and body weight over 42 days and improved insulin sensitivity.

Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration.

Background And Aims: The ability of the bone marrow cells to differentiate into liver, pancreas, and other tissues led to the speculation that these cells might be the source of adult stem cells found in these organs. The present study analyzed whether the bone marrow cells are a source of hepatic oval cells involved in rat liver regeneration induced by 2-acetylaminofluorene (2-AAF) and 70% partial hepatectomy (PHx).

Methods: Three groups of mutant F344 dipeptidyl peptidase IV-deficient (DPPIV(-)) rats were required for the study.