• Antioxidants in periodontitis: A systematic review

      Blasi Beriain, Gonzalo; Aichelmann-Reidy, Mary Beth (2016)
      The involvement of reactive oxygen species in periodontal disease is still not clear but it will possibly be modulated by antioxidants defense. There is some evidence of reduced antioxidant defense in periodontitis. The goal of this review is to determine local antioxidant capacity in gingival crevicular fluid as seen in periodontal disease and in health. A comprehensive literature search through January 2016 was performed using Ovid Medline, Scopus and Cochrane Library for all literature related to antioxidant markers in gingival crevicular fluid in health and disease in humans. Seventeen articles satisfied the inclusion and exclusion criteria. Four antioxidants including, total antioxidant capacity (TAOC), superoxide dismutase (SOD), melatonin, and lactoferrin, were significantly reduced in periodontitis when compared to healthy controls. In conclusion, our findings suggest that TAOC, SOD and melatonin are quantitatively higher in healthy gingiva than diseased and appear to reflect increased oxygen radical activity during periodontal inflammation. In contrast lactoferrin levels increase in periodontal disease GCF.
    • The Effect of Non-Surgical Therapy on the Markers of Oxidative Stress in Patients with Chronic Periodontitis

      Akhtar, Sheema Shireen; Aichelmann-Reidy, Mary Beth (2016)
      Background and Purpose: Several investigators have analyzed the role of oxidative stress in the pathogenesis of periodontitis. Chronic inflammatory disease may be associated with an imbalance of increased markers of oxidative stress and reduced antioxidant defenses, which has been shown to return to normal levels with successful non-surgical therapy. This systematic review focused on all available evidence of the effect of non-surgical periodontal therapy on markers of localized oxidative stress in patients with periodontitis. Methods: An electronic search was conducted to identify all clinical trials that evaluated oxidative stress biomarkers in patients pre- and post-treatment with periodontitis and clinical parameters of the disease. Three reviewers conducted the search and verification of article selection. Eligibility criteria were applied to determine the final selection of publications for full text review. Bibliographies of relevant papers were searched for additional studies and a search of periodontal journals published in the last 3 years was performed to verify inclusion of all available clinical trials. Results: The initial search of three databases yielded 2,523 articles. The final selection consisted of 13 articles after removing those that did not include non-surgical therapy of periodontitis or markers of oxidative stress in systemically healthy patients. Change of oxidative stress markers (OSM) ranged from 0 to 81 percent. A statistically significant reduction of OSM was reported in 8 studies. 5 studies were used to calculate the unweighted percent change, which was 48.74%, and the weighted percent change, which was 57.83%. Conclusions: There is high variability in the OSM concentrations in periodontitis patients. OSM decreased following non-surgical therapy. More longitudinal, randomized clinical controlled trials of are required to understand the modulation of OSM following periodontal treatment.
    • Glycogen Synthase Kinase 3-beta (GSK3beta) is a central regulator in the non-canonical NF-E2 Related Factor (Nrf2) antioxidant response

      Shelton, Phillip Michael; Jaiswal, Anil K. (2013)
      The stress response transcription factor Nrf2 is a master regulator of a battery of antioxidant and detoxification genes that promote cell survival. Classically defined as a chemoprevention factor, recent evidence has demonstrated that Nrf2 over-activation is found in many cancers and is associated with drug-radio-resistance, enhanced cell survival, and poor patient prognosis. Therefore, it is important to understand the molecular events that regulate its activity and how perturbations in cancer can facilitate over-activation of Nrf2. Glycogen synthase kinase-3 beta (GSK β) has emerged as a regulator of the non-canonical Nrf2 pathway by its ability to promote the degradation of Nrf2, both directly and indirectly through a mechanism involving the Src-A subfamily kinases. However, it remains ambiguous how GSK3β is regulated in the redox environment of the cell, and whether alterations in its activity can lead to increased activation of Nrf2. Herein, it is demonstrated that oxidative stress-induced activation of the PI3K/Akt pathway results in the phosphorylation of GSK3 β Ser-9, thereby inhibiting its activity. As a result, Nrf2 is able to become stabilized and induce the transcription of its defensive target genes. Subsequently, the coordinated action of the protein phosphatases PTEN, PP2A, and PP1 help to restore the activation of GSK3 β, and its ability to "shut off" the Nrf2 response. Moreover, the constitutive activation of the PI3K/Akt pathway, an event commonly found in cancers, leads to a sustained inhibition of GSK3 β, which consequently functions to drive Nrf2-mediated drug resistance and cell survival. In addition to its direct inhibition of Nrf2, GSK3 β also indirectly mediates the nuclear export and degradation of Nrf2 by triggering the nuclear translocation of the Src-A subfamily kinase members Src, Fyn, Yes, and Fgr. Surprisingly, the precise mechanism of how the Src-A subfamily translocates into the nucleus is unknown. In using Fyn kinase as a model, it is apparent that the Src homology 2 (SH2) and SH3 domains are necessary, however, the SH2 domain is sufficient for nuclear import due to a putative bipartite nuclear localization sequence in the SH2 domain. In summation, this thesis provides insight into the molecular mechanisms surrounding the ability of GSK3 β to inhibit Nrf2. Ultimately, we hope that the evidence presented within will provide translational applications to include the non-canonical GSK3 β/Nrf2 pathway as a therapeutic target in tumors harboring over-activation of Nrf2.
    • Immune Dysfunction in the Ts65Dn Mouse Model of Down Syndrome: Potential Role(s) of Reactive Oxygen Species (ROS) and Alterations in IL-7Ralpha Expression

      Lorenzo, Laureanne; Williams, Mark S., Ph.D. (2011)
      Down Syndrome (DS), a genetic disease caused by a triplication of chromosome 21, is characterized by increased markers of oxidative stress. In addition to cognitive defects, DS is characterized by hematologic disorders such as myelodysplastic syndrome, premature thymic involution and increased incidence of infections and leukemia. However, the potential causes of these defects have not been fully elucidated. The goal of this study was to examine hematopoietic stem cell, lymphoid progenitor cell, and mature lymphocyte function in DS using the Ts65Dn mouse model, which contains a segmental triplication of mouse chromosome 16 that is partially syntenic to human chromosome 21. Analysis of hematopoietic progenitor populations showed that Ts65Dn mice possessed fewer functional hematopoietic stem cells (HSC) and a significantly decreased percentage of bone marrow lymphoid progenitors. Increased reactive oxygen species (ROS) and markers of oxidative stress were detected in HSC populations and were associated with a loss of quiescence and increased apoptosis. Bone marrow progenitor, immature thymocyte, and mature lymphocyte populations expressed diminished levels of the IL-7Rα chain, which was associated with decreased proliferation and increased apoptosis. Modulating oxidative stress in vitro suggested that oxidative stress induced by diminished glutathione levels selectively leads to decreased IL-7Rα expression, and inhibits the survival of IL-7Rα expressing hematopoietic progenitors, potentially linking increased ROS and immunopathology. Other possible mechanisms identified in Ts65Dn mice that could induce diminished IL-7Rα expression in DS are increased microRNA expression and inhibition of the Notch pathway. The data suggest that hematopoietic stem cell, lymphoid progenitor cell, and mature lymphocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signaling may alter hematologic development in Ts65Dn mice. Therefore, the current study may support modulation of redox balance and IL-7Rα expression as possible therapeutic targets to treat immune dysfunction in DS and may provide a starting point for the manipulation of redox balance to modulate the immune response.
    • Negative Regulators of Nrf2 in the Early Response to Oxidative Stress

      Kaspar, James William; Jaiswal, Anil K. (2011)
      Uncontrolled levels of oxidative stress have been implicated in causing a variety of diseases, including neurodegenerative disorders and cancer. The complex signaling pathways that combat oxidative stress are clinically relevant targets for development of safe and effective methods for treatment of these ailments. Enhancement of these pathways in various disease states could decrease the levels of oxidative stress and improve the status of patients with different afflictions. The NF-E2 related factor 2 (Nrf2) signaling pathway could be a therapeutic target for preventing oxidative stress related diseases. Nrf2 is a basic leucine zipper transcription factor that binds antioxidant response elements (AREs) located in promoters of antioxidant genes. Nrf2 regulates expression and induction of cytoprotective genes in response to oxidative stress. Several negative regulators of Nrf2 have been elucidated and may be potential targets for therapies to enhance the protective abilities of Nrf2. They may also be manipulated to decrease the activity of Nrf2 in specific diseases where Nrf2 exhibits harmful effects. The main focus of this thesis is the regulation and cellular signaling of the negative regulators of Nrf2 including INrf2, Cul3, Rbx1, Bach1, and Fyn. The molecular mechanisms triggered in the early response of cells to oxidative stress are not well understood. The present studies demonstrate that within 0.5 hours of antioxidant or xenobiotic treatment, the negative regulators of Nrf2 export out of the nucleus allowing Nrf2 unimpeded movement to the ARE. Mutation of tyrosine residues in the negative regulators stymied nuclear export suggesting tyrosine phosphorylation controls nuclear export. Furthermore, mutant negative regulators interfered with the ability of Nrf2 to activate defensive genes. This study also found that Nrf2 is able to control the regulation of some of its other negative regulators including Cul3 and Rbx1. Thus, the pre-induction regulation of Nrf2 is controlled by the nuclear export of the negative regulators allowing for activation of defensive gene expression. In summation, the work done in this thesis provides insights into the mechanisms by which Nrf2 activity is tightly controlled during oxidative stress. Negative regulators of Nrf2 may be prime targets for preventing diseases caused by chronic oxidative stress.
    • Prefrontal Cortical Fast-Spiking Interneurons in Healthy Animals and in a Developmental Model of Schizophrenia

      Lewis, Eastman; O'Donnell, Patricio (2014)
      Schizophrenia is a serious mental illness from which approximately 1% of the world's population suffers. Current treatments are effective against positive symptoms such as hallucinations and delusions, but do little to ameliorate the cognitive deficits which are a devastating component of the disease. A current hypothesis is that hypofunction of cortical fast spiking interneurons (FSI) is an important substrate of these deficits. However, the mechanisms producing this hypofunction are unclear. Based on the observation that NMDA receptor antagonists like ketamine are psychotomimetic and produce a disinhibited cortex, it has been suggested that hypofunctional NMDA receptors may underlie the hypothesized deficit in FSI function. Recently, this has been called into question based on the observation that NMDA receptors contribute minimally to synaptic responses in adult FSI. Here we tested whether adult FSI express functional NMDA receptors in the adult rat cortex. We found that while only a subset of FSI express NMDA receptors at synaptic locations, all FSI express functional NMDA receptors at some location. In light of this, the hypothesis that hypofunctional NMDA receptors on FSI contribute to cortical disinhibition and cognitive symptoms in schizophrenia should not be disregarded. As schizophrenia is a developmental disorder with late adolescent or early adult onset, it is important to understand possible links between early-life abnormalities and adult-onset symptoms. In a second set of experiments, we used the neonatal ventral hippocampal lesion (NVHL) model of schizophrenia to test the possibility that developmental oxidative stress could provide a link between neonatal insults and cortical dysfunction in adulthood. Indeed, we found evidence that developmental oxidative stress causes electrophysiological deficits in the adult NVHL cortex. This implicates oxidative stress as a link between early-life insults and adult-onset psychiatric disorders. Furthermore, this indicates that developmental antioxidant treatment may be beneficial for individuals at high risk for developing schizophrenia.
    • Sex dependent Mitochondrial Mechanisms of Neonatal Cerebral Hypoxic-ischemic Encephalopathy

      Demarest, Tyler G.; Fiskum, Gary (2016)
      Many neurodevelopmental disorders are sex-biased, with males being particularly susceptible to central nervous system (CNS) abnormalities, but mechanisms underlying the sex-biased susceptibility are unclear. Neonatal hypoxic-ischemic encephalopathy (HIE) is one such disorder affecting 1.5-2/1000 live term births that contributes to lifelong cognitive and motor impairments, with males being at a greater risk for these adverse outcomes. Moreover, sex differences in neurobehavioral outcome are observed following the Rice-Vannucci (1981) rodent model of neonatal hypoxic-ischemia (HI). The unilateral carotid artery ligation in this model of HI results in an ipsilateral infarct, and a contralateral "hypoxia-only" hemisphere. Mitochondrial dysfunction is a common feature of CNS injury with increasing evidence suggesting marked sex differences in mitochondrial metabolism of humans and rodents. Following HI, mitochondrial bioenergetic dysfunction contributes to an extended secondary energy failure lasting days or weeks, making it a prime neuroprotective target. Acetyl-L-Carnitine (ALCAR) is neuroprotective following neurotrauma in juvenile and adult animal models; ALCAR is hypothesized to function as an alternative biofuel, antioxidant or by promoting mitochondrial biogenesis but the exact mechanism of neuroprotection is unclear. Emerging evidence suggests that mechanisms implicated in the pathophysiology of CNS injury are also sex dependent including oxidative phosphorylation, oxidative stress, antioxidant defense systems, mitochondrial biogenesis, autophagy and cell death signaling pathways. Therefore, these studies tested the hypotheses that following HIE: mitochondrial function, oxidative stress, antioxidant responses, mitochondrial quality control and cell death are sex dependent, and that ALCAR administration protects against these pathophysiological mechanisms. We observed that complex I mitochondrial respiration is impaired significantly more in males than females, which is associated with increased protein oxidation, impairment of mitochondrial glutathione peroxidase (GPx) activity, and decreased GPx4 immunoreactivity in male, but not female brain. Females have a higher level of reduced glutathione (GSH) than males in shams, decreased GSH, and increased non-mitochondrial GPx activity following HI in both cerebral hemispheres. There is no increase in protein oxidation in the female brain after HI. Furthermore, we find that ALCAR reduces protein oxidation in males following HI. Moreover, we determined mitochondrial fragmentation occurs, to different extents, in both sexes 24 hours after HI. Female mitochondria in the contralateral hemisphere are degraded by mitophagy while male mitochondrial proteins are tagged for removal but the mitophagy machinery is impaired, resulting in an accumulation of damaged mitochondria in the male brain following injury. Finally, we determined that there is significant neuronal cell death in both hemispheres in the male brain following HI, while neuronal death occurs exclusively in the ipsilateral hemisphere of the female brain. These sex-dependent mitochondrial mechanisms further the understanding of a sexually dimorphic neonatal brain injury and will aid in the advancement of sex-specific therapeutic development.