Generation and Export of Red Blood Cell ATP in Health and Disease.

Metabolic homeostasis in animals depends critically on evolved mechanisms by which red blood cell (RBC) hemoglobin (Hb) senses oxygen (O) need and responds accordingly. The entwined regulation of ATP production and antioxidant systems within the RBC also exploits Hb-based O-sensitivity to respond to various physiologic and pathophysiologic stresses. O offloading, for example, promotes glycolysis in order to generate both 2,3-DPG (a negative allosteric effector of Hb O binding) and ATP.

Twist1 in podocytes ameliorates podocyte injury and proteinuria by limiting CCL2-dependent macrophage infiltration.

The transcription factor Twist1 regulates several processes that could impact kidney disease progression, including epithelial cell differentiation and inflammatory cytokine induction. Podocytes are specialized epithelia that exhibit features of immune cells and could therefore mediate unique effects of Twist1 on glomerular disease. To study Twist1 functions in podocytes during proteinuric kidney disease, we employed a conditional mutant mouse in which Twist1 was selectively ablated in podocytes (Twist1-PKO).

Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis Matrix Metallopeptidase 13-Mediated Matrix Degradation.

Background: Following an acute insult, macrophages regulate renal fibrogenesis through the release of various factors that either encourage the synthesis of extracellular matrix synthesis or the degradation of matrix endocytosis, proteolysis, or both. However, the roles of infiltrating versus resident myeloid cells in these opposing processes require elucidation. The transcription factor Twist1 controls diverse essential cellular functions through induction of several downstream targets, including matrix metalloproteinases (MMPs).

Characterization and Functional Phenotyping of Renal Immune Cells via Flow Cytometry.

A variety of immune cell subsets contribute to the pathogenesis of hypertension and associated kidney damage following inappropriate activation of the renin-angiotensin system (RAS). These immune cell subsets often express common surface markers, which complicates their separation and characterization in vivo. Accordingly, flow cytometry has become an invaluable tool for parsing immune cell populations because this technique permits the simultaneous detection of up to 18 markers on a single cell.

The role of chemokines in hypertension and consequent target organ damage.

Immune cells infiltrate the kidney, vasculature, and central nervous system during hypertension, consequently amplifying tissue damage and/or blood pressure elevation. Mononuclear cell motility depends partly on chemokines, which are small cytokines that guide cells through an increasing concentration gradient via ligation of their receptors. Tissue expression of several chemokines is elevated in clinical and experimental hypertension.

Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Rats.

Postoperative neurocognitive disorders are common complications in elderly patients following surgery or critical illness. High mobility group box 1 protein (HMGB1) is rapidly released after tissue trauma and critically involved in response to sterile injury. Herein, we assessed the role of HMGB1 after liver surgery in aged rats and explored the therapeutic potential of a neutralizing anti-HMGB1 monoclonal antibody in a clinically relevant model of postoperative neurocognitive disorders.

Pyrrolidine Dithiocarbamate Prevents Neuroinflammation and Cognitive Dysfunction after Endotoxemia in Rats.

Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood.

Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion.

Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice.

Engineered zinc finger-activating vascular endothelial growth factor transcription factor plasmid DNA induces therapeutic angiogenesis in rabbits with hindlimb ischemia.

Background: Therapeutic angiogenesis seeks to promote blood vessel growth to improve tissue perfusion. Vascular endothelial growth factor (VEGF) exists in multiple isoforms. We investigated an engineered zinc finger-containing transcription factor plasmid designed to activate the endogenous VEGF gene (ZFP-VEGF).

The role of cpg sequences in the induction of anti-DNA antibodies.

To investigate the role of CpG sequences in anti-DNA induction, immunization experiments were performed in mice to assess the immunogenicity of native Escherichia coli (EC) and calf thymus (CT) in incomplete Freund's adjuvant. The effects of CpG sequences were further tested by comparing the adjuvant properties of a synthetic phosphorothioate oligonucleotide with a CpG motif to one with a GpC sequence. Both EC and CT DNA alone induced a limited anti-DNA response.

Anti-DNA and autoantibodies.

Systemic lupus erythematosus is a prototypic autoimmune disease characterized by antinuclear antibodies (ANAs), including pathogenic specificities to DNA. As shown by recent research, ANA production is a genetically determined process in which self antigens drive B and T cells that have escaped the normal mechanisms of tolerance. Although antibodies can bind isolated protein or nucleic acid species, the in vivo driving antigens likely exist as complexes that have been released from apoptotic cells.

Malignant mesothelioma in women.

About 8% of our cases of mesothelioma occur in women, with a median age of 59 years. Our percentage is lower than other series reported in the literature because of the large number of occupationally exposed men referred to our laboratory. Tumor arose in the pleura in 86% of the women in our study, and the majority were epithelial.