Macrophage-Specific Lactate Dehydrogenase Expression Modulates Inflammatory Function In Vitro.

Background: In acute kidney injury, macrophages play a major role in regulating inflammation. Classically activated macrophages (M1) undergo drastic metabolic reprogramming during their differentiation and upregulate the aerobic glycolysis pathway to fulfill their pro-inflammatory functions. NAD+ regeneration is crucial for the maintenance of glycolysis and the most direct pathway by which this occurs is via the fermentation of pyruvate to lactate, catalyzed by lactate dehydrogenase A (LDHA).

Identification of Cytoprotective Small-Molecule Inducers of Heme-Oxygenase-1.

Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase ½ level.

Functional consequence of myeloid ferritin heavy chain on acute and chronic effects of rhabdomyolysis-induced kidney injury.

Acute kidney injury (AKI) is a serious complication of rhabdomyolysis that significantly impacts survival. Myoglobin released from the damaged muscle accumulates in the kidney, causing heme iron-mediated oxidative stress, tubular cell death, and inflammation. In response to injury, myeloid cells, specifically neutrophils and macrophages, infiltrate the kidneys, and mediate response to injury.

AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.

Metabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression.

Bioenergetic maladaptation and release of HMGB1 in calcineurin inhibitor-mediated nephrotoxicity.

Calcineurin inhibitors (CNIs) are potent immunosuppressive agents, universally used following solid organ transplantation to prevent rejection. Although effective, the long-term use of CNIs is associated with nephrotoxicity. The etiology of this adverse effect is complex, and effective therapeutic interventions remain to be determined.

Author Correction: Metformin reverses established lung fibrosis in a bleomycin model.

In the version of this article originally published, a grant was omitted from the Acknowledgements section. The following sentence should have been included: "R.B.

Metformin reverses established lung fibrosis in a bleomycin model.

Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs. Cellular metabolism regulates tissue repair and remodelling responses to injury. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism.

Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling.

Calcineurin inhibitors (CNIs) are potent immunosuppressants with associated long-term nephrotoxicity mediated by tubular epithelial cell injury and arterial vasoconstriction. We hypothesized that CNI-induced renal injury is regulated by specific microRNAs (miRNAs). In this study, we found that 46 miRNAs were significantly altered in human proximal tubular epithelial cells (HPTECs) following exposure to cyclosporine A (CsA), particularly miR-21 (5.

[Asperger's syndrome in family context--review of studies].

In recent years in the face of still growing number of diagnosis of pervasive developmental disorders there has been an increase in number of research in the functioning of family of children with autism or Asperger's Syndrome. Studies concerning families of children with autism have been predominantly occupied with the stress-coping strategies and also with the therapeutic effect of interaction between disabled children and the rest of the family. New studies with families of children with Asperger's Syndrome, apart from the coping styles of parents and the received support, are also examining the properties of the system of these families, like: cohesion, adaptability, organisation, control, expressiveness or conflict.

Glycogen synthase kinase-3 regulates endoplasmic reticulum (ER) stress-induced CHOP expression in neuronal cells.

Endoplasmic reticulum (ER) stress, often resulting from cellular accumulation of misfolded proteins, occurs in many neurodegenerative disorders, in part because of the relatively long lifetime of neurons. Excessive accumulation of misfolded proteins activates the unfolded protein response (UPR) that dampens protein synthesis and promotes removal of misfolded proteins to support survival of ER-stressed cells. However, the UPR also initiates apoptotic signaling to kill cells if recovery is not achieved.

Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation.

Background: The mammalian forkhead box, class O (FoxO) transcription factors function to regulate diverse physiological processes. Emerging evidence that both brain-derived neurotrophic factor (BDNF) and lithium suppress FoxO activity suggests a potential role of FoxOs in regulating mood-relevant behavior. Here, we investigated whether brain FoxO1 and FoxO3a can be regulated by serotonin and antidepressant treatment and whether their genetic deletion affects behaviors.

HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation.

Stress of the endoplasmic reticulum (ER stress) is caused by the accumulation of misfolded proteins, which occurs in many neurodegenerative diseases. ER stress can lead to adaptive responses or apoptosis, both of which follow activation of the unfolded protein response (UPR). Heat shock proteins (HSP) support the folding and function of many proteins, and are important components of the ER stress response, but little is known about the role of one of the major large HSPs, HSP105.

Mitochondrial-targeted active Akt protects SH-SY5Y neuroblastoma cells from staurosporine-induced apoptotic cell death.

Akt is a serine/threonine protein kinase that plays a vital role in promoting cellular survival. Predominantly cytosolic, upon stimulation with growth-factors or stress, active Akt translocates into mitochondria, but the functions of Akt in mitochondria are not yet fully understood. Mitochondria play a central role in apoptotic pathways and given Akt's functions in the cytoplasm, Akt in mitochondria may help preserve mitochondrial integrity during cellular stress.

Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency.

Deficient signaling by insulin, as occurs in diabetes, is associated with impaired brain function, and diabetes is associated with an increased prevalence of Alzheimer's disease. One of the hallmark pathological characteristics of Alzheimer's disease is the presence of neurofibrillary tangles containing hyperphosphorylated tau, a microtubule-associated protein. Therefore, we tested the hypothesis that insulin depletion caused by administration of streptozotocin may cause tau hyperphosphorylation in mouse brain by using site-specific phosphorylation-dependent tau antibodies to obtain precise identification of the phosphorylation of tau on individual residues.

In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors.

Glycogen synthase kinase-3 (GSK3), which is inhibited by serine-phosphorylation, is involved in the neuropathology of Alzheimer's disease (AD). We tested if the two therapeutic strategies used for AD, inhibition of acetylcholinesterase and of N-methyl-D-aspartate (NMDA) receptors, modulate the phosphorylation state of the two isoforms of GSK3 in mouse brain. Large, rapid increases in the levels of phospho-Ser21-GSK3alpha and phospho-Ser9-GSK3beta occurred in mouse hippocampus, cerebral cortex, and striatum after treatment of mice with the muscarinic agonist pilocarpine or the acetylcholinesterase inhibitor physostigmine.

Physiological and pathological changes in glucose regulate brain Akt and glycogen synthase kinase-3.

Insulin regulates the phosphorylation and activities of Akt and glycogen synthase kinase-3 (GSK3) in peripheral tissues, but in the brain it is less clear how this signaling pathway is regulated in vivo and whether it is affected by diabetes. We found that Akt and GSK3 are sensitive to glucose, because fasting decreased and glucose administration increased by severalfold the phosphorylation of Akt and GSK3 in the cerebral cortex and hippocampus of non-diabetic mice. Brain Akt and GSK3 phosphorylation also increased after streptozotocin administration (3 days), which increased blood glucose and depleted blood insulin, indicating regulation by glucose availability even with deficient insulin.

Anti-apoptotic effects of muscarinic receptor activation are mediated by Rho kinase.

Activation of muscarinic receptors has been shown to be neuroprotective in several different models of apoptosis, but the mechanism of this action is unknown. Therefore, we investigated the intermediate signals mediating the anti-apoptotic action of muscarinic receptor activation in SH-SY5Y cells. Inhibition of most muscarinic receptor-coupled actions had no effect on protection, but inhibition of Rho kinase with HA-1077 concentration-dependently was able to completely block the protection against H(2)O(2)- and camptothecin-induced apoptosis produced by stimulation of muscarinic receptors.

Hypoxia activates glycogen synthase kinase-3 in mouse brain in vivo: protection by mood stabilizers and imipramine.

Background: Glycogen synthase kinase-3 (GSK3), which is primarily regulated by an inhibitory phosphorylation of an N-terminal serine, has been implicated as contributing to mood disorders by the finding that it is inhibited by the mood stabilizer lithium.

Methods: This study tested if the antidepressant imipramine or the mood stabilizers lithium and sodium valproate regulated pathophysiological serine-dephosphorylation of GSK3 caused by hypoxia in mouse brain in vivo.

Results: Hypoxia caused rapid serine-dephosphorylation of both isoforms of GSK3, GSK3beta and GSK3alpha, in mouse cerebral cortex, hippocampus, and striatum.

Heat shock protein-90 dampens and directs signaling stimulated by insulin-like growth factor-1 and insulin.

Heat shock protein-90 (Hsp90) buffers cells from genetic mutations and environmental stresses. To test if this capability reflects a normal physiological function of Hsp90 to buffer cellular signals, the effects of Hsp90 inhibition were measured on activation of Akt. Inhibition of Hsp90 with geldanamycin amplified Akt phosphorylation induced by insulin-like growth factor-1 (IGF-1) or insulin, indicating that Hsp90 normally buffers these signals.

Muscarinic receptor activation protects cells from apoptotic effects of DNA damage, oxidative stress, and mitochondrial inhibition.

The impact of muscarinic receptor stimulation was examined on apoptotic signaling induced by DNA damage, oxidative stress, and mitochondrial impairment. Exposure of human neuroblastoma SH-SY5Y cells to the DNA-damaging agent camptothecin increased p53 levels, activated caspase-3, and caused cell death. Pretreatment with oxotremorine-M, a selective agonist of muscarinic receptors that are expressed endogenously in these cells, did not affect the accumulation of p53 but greatly attenuated caspase-3 activation and protected from cell death to nearly the same extent as treatment with a general caspase inhibitor.

Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage.

Glycogen synthase kinase-3beta (GSK3beta) is a central figure in Wnt signaling, in which its activity is controlled by regulatory binding proteins. Here we show that binding proteins outside the Wnt pathway also control the activity of GSK3beta. DNA damage induced by camptothecin, which activates the tumor suppressor p53, was found to activate GSK3beta.