Arthritis scores of (■) DBA/1 wild-type, (●) DBA/1 FcγR common γ-chain deficient, and (▲) DBA/1 FcγRIIB deficient mice

<p><b>Copyright information:</b></p><p>Taken from "The role and clinical implications of G6PI in experimental models of rheumatoid arthritis"</p><p>Arthritis Research & Therapy 2004;7(1):20-28.</p><p>Published online 30 Nov 2004</p><p>PMCID:PMC1064898.</p><p>Copyright © 2004 BioMed Central Ltd</p> Data are presented as mean clinical scores ± standard error of the mean only for those mice that developed arthritis. Arthritis incidence was 10/11 in DBA/1 wild-type, 8/24 in DBA/1 FcγR common γ-chain deficient, and 16/16 in DBA/1 FcγRIIB deficient mice. From [93], 2004. The American Association of Immunologists, Inc. Reprinted with permission

Detection of a Timing Channel in an UPPAAL Model of a Cyber-Manufacturing System

<p>Model of a cyber-manufacturing system for the UPPAAL model checker, including a mitigation of a timing channel.</p

Chemical Modification of the Multitarget Neuroprotective Compound Fisetin

Many factors are implicated in age-related central nervous system (CNS) disorders, making it unlikely that modulating only a single factor will provide effective treatment. Perhaps a better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Recently, we identified an orally active, neuroprotective, and cognition-enhancing molecule, the flavonoid fisetin, that is effective in several animal models of CNS disorders. Fisetin has direct antioxidant activity and can also increase the intracellular levels of glutathione (GSH), the major endogenous antioxidant. In addition, fisetin has both neurotrophic and anti-inflammatory activity. However, its relatively high EC₅₀ in cell based assays, low lipophilicity, high topological polar surface area (tPSA), and poor bioavailability suggest that there is room for medicinal chemical improvement. Here we describe a multitiered approach to screening that has allowed us to identify fisetin derivatives with significantly enhanced activity in an in vitro neuroprotection model while at the same time maintaining other key activities

Additional file 3: Table S3. of A novel Alzheimer’s disease drug candidate targeting inflammation and fatty acid metabolism

Metabolomic profile of plasma. This table includes the significantly changed metabolites found in the plasma between the AD and control groups, as well as the vehicle- and CAD-31-treated groups. (XLSX 16 kb

Additional file 2: Table S2. of A novel Alzheimer’s disease drug candidate targeting inflammation and fatty acid metabolism

Soluble and insoluble Aβ1–42 (pg/mg protein). (DOC 28 kb

Additional file 4: Table S4. of A novel Alzheimer’s disease drug candidate targeting inflammation and fatty acid metabolism

Metabolomic profile of cortex. This table includes the significantly changed metabolites found in the cortex between the AD and control groups, as well as the vehicle- and CAD-31-treated groups. (XLSX 17 kb

Metabolic Parameters at the end of the study.

<p>Statistical analysis by one-way ANOVA followed by Dunnett's post-hoc test to compare all groups against wild type. Data are mean ± SD of N = 5–7 per group.</p><p>* = P<0.001 vs. wild type.</p

Fisetin reduces MG-dependent protein glycation in the kidney and blood.

<p>(A) Kidneys were homogenized in PBS containing phosphatase and protease inhibitors and equal amounts of protein were analyzed by SDS-PAGE and Western blotting with an antibody to MG and actin as a loading control. The entire gel as shown was scanned and the total density normalized to actin. Four to 6 animals were used per group for quantifying band densities with 2 representative kidneys per group shown. (B) Either whole blood was assayed by Western blotting with an anti-MG antibody or kidney tissue with an anti-glyoxylase 1 antibody. The major MG-glycated protein in blood was hemoglobin (shown) and its loading control is total hemoglobin (α and β). Glyoxylase 1 expression was normalized to actin. (C) The activity of glyoxylase 1 was measured and is expressed in units. One unit is the amount of activity required to produce 1 mmole of S-D-lactoylglutathione/min/mg protein. ***(<i>p</i><0.001), **(<i>p</i><0.01) and *(<i>p</i><0.05) indicate significantly different from wild type or Akita alone as determined by ANOVA followed by Tukey's post test. (D) Exponentially dividing HT22 cells were exposed to 5 mM glutamic acid (GA) with or without 2 µM fisetin (Fis) for 8 h. The cells were lysed in SDS sample buffer and equal amounts of protein were analyzed by SDS-PAGE and Western blotting with an antibody to MG and actin as a loading control (n = 3). The kidney mesangial cell line MES13 was grown in 5 mM glucose (glu) (C is control) and some cells transferred to 25 mM glucose plus or minus 10 µM fisetin (Fis) for 8 h. The cells were lysed is SDS sample buffer and equal amounts of protein were analyzed by SDS-PAGE and Western blotting with an antibody to MG and actin as a loading control (n = 3). For both cell lines, the entire gels as shown were scanned and the total densities normalized to actin. Significant differences were determined by ANOVA followed by Tukey's post test. **<i>p</i><0.01; *** <i>p</i><0.001.</p

Fisetin reduces the consequences of diabetes in Akita mice.

<p>Male Akita mice were fed control diet or fisetin (0.05%) for 18 weeks beginning at 6 weeks of age. (A) Kidney hypertrophy was assessed by weighing the kidneys and normalizing the kidney weight to the relative weight of the mice. (B) Kidney function was assessed by measuring the albumin/creatinine ratio in the urine. Fisetin reduced diabetes-induced renal hypertrophy and albuminuria. Capillary lumen area, glomerular volume and PAS positive mesangial matrix area were increased in Akita mouse kidneys (E, F: +fisetin) compared with wild type mice (C, D: +fisetin). The increase in capillary lumen area (G) (<i>p</i><0.05) and glomerular volume in the Akita mouse kidneys was significantly different from controls (H) (<i>p</i><0.001) and was largely prevented by fisetin. The PAS positive area was also significantly increased in the Akita mouse kidneys (I) (<i>p</i><0.05) while this difference was not significant in the Akita + fisetin kidneys. All data are mean ± SD of <i>n</i> = 5–7/group. *(<i>p</i><0.05), **(<i>p</i><0.01), ***(<i>p</i><0.001) indicate significantly different from wild type or Akita alone as determined by ANOVA followed by Tukey's post test.</p

Fisetin reduces an experimental index of anxiety in Akita mice.

<p>Male Akita mice were fed control diet or fisetin (0.05%) diet for 18 weeks beginning at 6 weeks of age. Locomotor activity was measured in the open field test. Decreased locomotor activity is an indicator of elevated anxiety that is characteristic of diabetics in poor glycemic control. Fisetin restored (A) distance traveled and (B) time ambulatory to nearly control levels. All data are mean ± SD of <i>n</i> = 5–7/group. *(<i>p</i><0.05) and **(<i>p</i><0.01) indicate significantly different from wild type or Akita alone as determined by ANOVA followed by Tukey's post test.</p