Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More

Increasing interest has recently focused on determining whether several natural compounds, collectively referred to as nutraceuticals, may exert neuroprotective actions in the developing, adult, and aging nervous system. Quercetin, a polyphenol widely present in nature, has received the most attention in this regard. Several studies in vitro, in experimental animals and in humans, have provided supportive evidence for neuroprotective effects of quercetin, either against neurotoxic chemicals or in various models of neuronal injury and neurodegenerative diseases. The exact mechanisms of such protective effects remain elusive, though many hypotheses have been formulated. In addition to a possible direct antioxidant effect, quercetin may also act by stimulating cellular defenses against oxidative stress. Two such pathways include the induction of Nrf2-ARE and induction of the antioxidant/anti-inflammatory enzyme paraoxonase 2 (PON2). In addition, quercetin has been shown to activate sirtuins (SIRT1), to induce autophagy, and to act as a phytoestrogen, all mechanisms by which quercetin may provide its neuroprotection

Generation of bivalent chromatin domains during cell fate decisions

<p>Abstract</p> <p>Background</p> <p>In self-renewing, pluripotent cells, bivalent chromatin modification is thought to silence (H3K27me3) lineage control genes while 'poising' (H3K4me3) them for subsequent activation during differentiation, implying an important role for epigenetic modification in directing cell fate decisions. However, rather than representing an equivalently balanced epigenetic mark, the patterns and levels of histone modifications at bivalent genes can vary widely and the criteria for identifying this chromatin signature are poorly defined.</p> <p>Results</p> <p>Here, we initially show how chromatin status alters during lineage commitment and differentiation at a single well characterised bivalent locus. In addition we have determined how chromatin modifications at this locus change with gene expression in both ensemble and single cell analyses. We also show, on a global scale, how mRNA expression may be reflected in the ratio of H3K4me3/H3K27me3.</p> <p>Conclusions</p> <p>While truly 'poised' bivalently modified genes may exist, the original hypothesis that all bivalent genes are epigenetically premarked for subsequent expression might be oversimplistic. In fact, from the data presented in the present work, it is equally possible that many genes that appear to be bivalent in pluripotent and multipotent cells may simply be stochastically expressed at low levels in the process of multilineage priming. Although both situations could be considered to be forms of 'poising', the underlying mechanisms and the associated implications are clearly different.</p

Characterizing the Role of Paraoxonase 2 (PON2) in the Brain: Phenotypic Analysis and Modulating Factors

Thesis (Ph.D.)--University of Washington, 2021Paraoxonase 2 (PON2), one of three members of the paraoxonase gene family, is a ubiquitously expressed intracellular antioxidant enzyme. Primarily located at the inner mitochondrial membrane, it is thought to maintain redox homeostasis at the mitochondrial level and support proper cellular function. In the brain, PON2 is expressed highest in dopaminergic regions, such as the striatum and substantia nigra. In-vitro experiments with PON2 deficient primary cells have demonstrated it to be an important antioxidant in the brain, with deficient neural cells more sensitive to oxidative damage. In the general population, common polymorphisms known to affect the enzymatic activity of PON2 have been associated with increased risk for myocardial infarction as well as Alzheimer’s disease, highlighting a direct impact on human health. Despite evidence for PON2 as an important antioxidant in the brain with human health impacts, little attention has focused on the role of PON2 in the brain and what global effects deficiency may have. In my dissertation work, I further characterized PON2 deficiency in the brain to address important knowledge gaps. First, I characterized the developmental expression of PON2, demonstrating that PON2 is differentially expressed over early life development and suggests potential windows of susceptibility to oxidative damage in the developing and aging nervous system when PON2 expression is lowest. Second, I evaluated behavioral endpoints and transcript changes with RNA-Seq of three discrete regions (cerebral cortex, striatum, cerebellum) with PON2 deficiency, finding that PON2 deficient mice have motor deficits and significant changes to many RNA processing pathways. Additionally, PON2 deficiency abolishes sex-specific expression patterns observed in the brain. Building on previous work showing PON2 expression is highest in the dopaminergic regions and may play a role in the dopaminergic system, I compared the expression of key dopaminergic genes in wild type (WT) and PON2 deficient striatal tissue, finding that multiple dopaminergic pathway genes were impacted by PON2 deficiency at the transcript level. Quinpirole, a dopamine receptor 2 (DRD2) agonist, was able to significantly increase the expression of PON2 in-vitro, while fenoldopam, a dopamine receptor 1/5 (DRD1/5) agonist did not, suggesting PON2 plays a role in DRD2-specific signaling. Finally, I collected preliminary data suggesting PON2 deficiency impacts numerous targets relevant to neurodegenerative disease, supporting additional research in the aging nervous system. Taken together, the findings of this dissertation identify that PON2 deficiency has significant impacts on the brain at both a biochemical and phenotypic level. These results address important gaps in the literature regarding PON2 deficiency in the central nervous system and supports further avenues of study to analyze additional pathways and behavioral endpoints, as well as further investigation of PON2 polymorphisms in the population

Metals and Paraoxonases

The paraoxonases (PONs) are a three-gene family which includes PON1, PON2, and PON3. PON1 and PON3 are synthesized primarily in the liver and a portion is secreted in the plasma, where they are associated with high-density lipoproteins (HDLs), while PON2 is an intracellular enzyme, expressed in most tissues and organs, including the brain. PON1 received its name from its ability to hydrolyze paraoxon, the active metabolite of the organophosphorus (OP) insecticide parathion, and also more efficiently hydrolyzes the active metabolites of several other OPs. PON2 and PON3 do not have OP-esterase activity, but all PONs are lactonases and are capable of hydrolyzing a variety of lactones, including certain drugs, endogenous compounds, and quorum-sensing signals of pathogenic bacteria. In addition, all PONs exert potent antioxidant effects. PONs play important roles in cardiovascular diseases and other oxidative stress-related diseases, modulate susceptibility to infection, and may provide neuroprotection (PON2). Hence, significant attention has been devoted to their modulation by a variety of dietary, pharmacological, lifestyle, or environmental factors. A number of metals have been shown in in vitro, animal, and human studies to mostly negatively modulate expression of PONs, particularly PON1, the most studied in this regard. In addition, different levels of expression of PONs may affect susceptibility to toxicity and neurotoxicity of metals due to their aforementioned antioxidant properties

Natalizumab stabilizes physical, cognitive, MRI, and OCT markers of disease activity: A prospective, non-randomized pilot study

<div><p>Natalizumab is an effective therapy for multiple sclerosis (MS). Its effectiveness has been demonstrated in several clinical and imaging studies. The objective of this study was to further demonstrate the efficacy of natalizumab using a comprehensive battery of clinical and imaging markers in the same cohort of patients followed longitudinally, hence capturing the multi-faceted nature of the MS disease process. A prospective, open-label, pilot study of 20 MS patients treated with natalizumab was conducted. High resolution MRI, Symbol-Digit Modalities Test (SDMT), and Optical Coherence Tomography (OCT) scans were obtained at baseline, 48, and 96 weeks. 15 patients completed the study. Natalizumab treatment decreased Expanded Disability Status Scale score (EDSS) and no change in SDMT, Brain Parenchymal Fraction (BPF), or any of the OCT markers of retinal degeneration was observed. Thalamic and whole brain volume as assessed by Percentage Brain Volume Change (PBVC) showed continuous deterioration. Higher baseline T2 lesion load correlated with increased rate of PBVC at 96-weeks (r = 0.566, R² = 0.320, p = 0.035) and thalamic volume loss (r = -0.586, R² = 0.344, p = 0.027). Most patients, 93%, achieved no evidence of disease activity (NEDA) at 2 years, likely due to early disease duration and lower initial baseline lesion load. This study further demonstrates stabilization of clinical and imaging markers of disease activity during natalizumab treatment.</p></div

Higher baseline T2 lesion volume correlates with thalamic volume loss over 96 weeks.

<p>Higher baseline T2 lesion volume correlates with thalamic volume loss over 96 weeks.</p

TREND flow diagram describing the number of patients the trial screened, enrolled, allocated, completed and discontinued the intervention.

<p>TREND flow diagram describing the number of patients the trial screened, enrolled, allocated, completed and discontinued the intervention.</p

Longitudinal clinical and imaging metrics over 96-week treatment period.

<p>Longitudinal clinical and imaging metrics over 96-week treatment period.</p

Baseline characteristics of study cohort.

<p>Baseline characteristics of study cohort.</p