A double blind placebo controlled randomized trial of the effect of acute uric acid changes on inflammatory markers in humans: A pilot study

<div><p>Uric acid has been linked with increased risk of chronic disease such as cardiovascular disease and this association has been attributed to a pro-inflammatory effect. Indeed, observational studies have shown that high uric acid is associated with high level of pro-inflammatory cytokines in the blood. However, whether high uric acid directly affects inflammation or rather represents a parallel defensive antioxidant mechanism in response to pathology that causes inflammation is unknown. To determine whether acute increase or decrease uric acid levels affects inflammation in healthy individuals, a randomized, placebo-controlled, double blind clinical study of uric acid or rasburicase with 20 healthy volunteers in each treatment-placebo group was conducted at the National Institute on Aging (NIA) Clinical Research Unit (CRU) at Harbor Hospital in Baltimore, MD. Change in inflammatory response was assessed by administering an oral lipid tolerance before and after the treatment of uric acid, rasburicase and placebo. Following uric acid administration, there was an accentuated increase in IL-6 during the oral lipid tolerance test (P<0.001). No significant differences were observed after lowering of uric acid with rasburicase. No side effects were reported throughout the trial. In health individuals, acute increase in uric acid results in an increased IL-6 response when challenged with lipid load. Such effect of amplification of inflammatory response may explain the higher risk of chronic diseases observed in subclinical hyperuricemia in observational studies.</p><p>Trial Registration: ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01323335" target="_blank">NCT01323335</a></p></div

Changes in IL-6 levels during uric acid or rasburicase infusion and oral lipid tolerance test pre- and post- intervention.

<p>The level of IL-6 was measured at 0,2,4,6 and 8 hours during the oral lipid tolerance test a day before (A,D) and after (C,F) following the administration of uric acid (A-C) or rasburicase (D-F). During the intervention, IL-6 was measured at 0, 1, 2, 4, 8, 12, and 24* hours after the administration of 500mg of uric acid (B) or 0.15mg/kg of rasburicase (E). The effect of treatment (P_Tx), time (P_Time) and slope of change over time by treatment group (P_TxTime) from the mixed effect model is presented at the bottom of each figure. Differences in the postprandial pattern of IL-6 before and after treatment is displayed (C,F). The treatment group is displayed as triangles and the placebo group as the circles. The mean and standard errors are displayed. *The 24-hour time point after intervention is the baseline, or time 0 of the oral lipid tolerance test conducted the following day.</p

Changes in uric acid levels during uric acid or rasburicase administration.

<p>Concentrations of uric acid was measured at 0, 1, 2, 4, 8, 12, and 24 hours following the administration of 500mg uric acid (A) and 0.15 mg/kg rasburicase (B) is displayed. The treatment group is displayed as dotted line (uric acid or rasburicase) and the placebo group as the solid lines. Mean and standard errors are displayed.during uric acid infusion, there was a significant difference in the change in IL-18 (P_{treatment*time} = 0.0006; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181100#pone.0181100.s002" target="_blank">S2A Fig</a>) and CRP (P_{treatment*time} = 0.045; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181100#pone.0181100.s003" target="_blank">S3B Fig</a>) over time by treatment. For IL-18 the slope was more negative in the uric acid group compared to placebo group (β_{treatment*time12} = -36.2, P = 0.0002) at the 12^th hour. For CRP, at the 8^th and 12^th hour, there slope for uric acid group was lower than the placebo group (β_{treatment*time8} = -0.14, P = 0.04, β_{treatment*time8} = -0.18, P = 0.007). There were no significant differences in change of other markers by uric acid treatment group.</p

Characteristics of participants in the uric acid and rasburicase study.

<p>Characteristics of participants in the uric acid and rasburicase study.</p

Volcano plot of gene expression changes by rasburicase treatment.

<p>The level of gene expression was assessed at baseline and after 12 and 24 hours after infusion of 0.15mg/kg of rasburicase. The difference in gene expression by treatment group is displayed. The genes in the interferon signaling pathway that are significantly differentially expressed are shown (filled triangles).</p

COSORT flowchart for the uric acid and rasburicase study.

<p>COSORT flowchart for the uric acid and rasburicase study.</p

Presentation_1_Nicotinamide adenine dinucleotide supplementation drives gut microbiota variation in Alzheimer’s mouse model.pdf

Alzheimer’s disease (AD) is the most common neurodegenerative disease. Growing evidence suggests an important role for gut dysbiosis and gut microbiota-host interactions in aging and neurodegeneration. Our previous works have demonstrated that supplementation with the nicotinamide adenine dinucleotide (NAD+) precursor, nicotinamide riboside (NR), reduced the brain features of AD, including neuroinflammation, deoxyribonucleic acid (DNA) damage, synaptic dysfunction, and cognitive impairment. However, the impact of NR administration on the intestinal microbiota of AD remains unknown. In this study, we investigated the relationship between gut microbiota and NR treatment in APP/PS1 transgenic (AD) mice. Compared with wild type (WT) mice, the gut microbiota diversity in AD mice was lower and the microbiota composition and enterotype were significantly different. Moreover, there were gender differences in gut microbiome between female and male AD mice. After supplementation with NR for 8 weeks, the decreased diversity and perturbated microbial compositions were normalized in AD mice. This included the species Oscillospira, Butyricicoccus, Desulfovibrio, Bifidobacterium, Olsenella, Adlercreutzia, Bacteroides, Akkermansia, and Lactobacillus. Our results indicate an interplay between NR and host-microbiota in APP/PS1 mice, suggesting that the effect of NR on gut dysbiosis may be an important component in its therapeutic functions in AD.</p

Enhanced Upregulation of CRH mRNA Expression in the Nucleus Accumbens of Male Rats after a Second Injection of Methamphetamine Given Thirty Days Later

<div><p>Methamphetamine (METH) is a widely abused amphetamine analog. Few studies have investigated the molecular effects of METH exposure in adult animals. Herein, we determined the consequences of an injection of METH (10 mg/kg) on transcriptional effects of a second METH (2.5 mg/kg) injection given one month later. We thus measured gene expression by microarray analyses in the nucleus accumbens (NAc) of 4 groups of rats euthanized 2 hours after the second injection: saline-pretreated followed by saline-challenged (SS) or METH-challenged (SM); and METH-pretreated followed by saline-challenged (MS) or METH-challenged (MM). Microarray analyses revealed that METH (2.5 mg/kg) produced acute changes (1.8-fold; <i>P</i><0.01) in the expression of 412 (352 upregulated, 60 down-regulated) transcripts including cocaine and amphetamine regulated transcript, corticotropin-releasing hormone (<i>Crh</i>), oxytocin (<i>Oxt</i>), and vasopressin (<i>Avp</i>) that were upregulated. Injection of METH (10 mg/kg) altered the expression of 503 (338 upregulated, 165 down-regulated) transcripts measured one month later (MS group). These genes also included <i>Cart</i> and <i>Crh</i>. The MM group showed altered expression of 766 (565 upregulated, 201 down-regulated) transcripts including <i>Avp</i>, <i>Cart</i>, and <i>Crh</i>. The METH-induced increased <i>Crh</i> expression was enhanced in the MM group in comparison to SM and MS groups. Quantitative PCR confirmed the METH-induced changes in mRNA levels. Therefore, a single injection of METH produced long-lasting changes in gene expression in the rodent NAc. The long-term increases in <i>Crh</i>, <i>Cart</i>, and <i>Avp</i> mRNA expression suggest that METH exposure produced prolonged activation of the endogenous stress system. The METH-induced changes in oxytocin expression also suggest the possibility that this neuropeptide might play a significant role in the neuroplastic and affiliative effects of this drug.</p></div

NSAIDs reduce the growth of HEY xenografts in nude mice.

<p>HEY cells (1.5×10⁶) were injected subcutaneously into both flanks of nude mice. A) Mice were randomized into 2 groups: control or diclofenac (18 mg/kg). Treatment was started three days after cell injection and was administered intraperitoneally twice a week for 4 weeks. Tumors were measured twice a week, starting at week 1. The control group (only PBS) consisted of 6 mice that developed 12 tumors in total; the diclofenac group (18 mg/kg) consisted of 6 mice that developed a total of 11 tumors. Values represent means ± standard errors. Statistical significance is represented as * p<0.05. B) Mice were randomized into 2 groups: control or indomethacin (2.5 mg/kg). Treatment was started the day after cell injection and was given daily in drinking water for 6 weeks. Tumors were measured twice a week, starting at week 3. The control group (only water) consisted of 5 mice that developed 9 tumors in total; the indomethacin group (2.5 mg/kg) consisted of 5 mice that developed a total of 5 tumors. Values represent means ± standard errors. Statistical significance is represented as * p<0.05.</p

Diclofenac and Indomethacin promote cell cycle arrest and apoptosis in ovarian cancer cells.

<p>A) HEY, OVCAR5 and UCI-101 cells were treated for 24 hours with 300 µM diclofenac or indomethacin. Cells were labeled with propidium iodide and analyzed in a FACS Caliber Flow Cytometer. Image shown is representative of 4 experiments. B) Cells were treated for 48 or 96 hours with 300 µM diclofenac or indomethacin. Apoptosis and DNA content were assayed by BrdU and propidium iodide staining using Apo-BrdU kit. Cells in upper quadrant box (P3 gate) represent the apoptotic population.</p