The PKD inhibitor CID755673 enhances cardiac function in <i>db/db</i> mice.

<p>(A) Physiological and cardiac morphological measures; (B) Representative M-mode and Doppler images; (C) LV Structural dimensions; (D) E:A ratio; (E) Deceleration time; (F) Ejection time; (G) Ejection fraction, and; (H) Fractional shortening in <i>db/db</i> mice treated with vehicle, 1mg/kg or 10mg/kg CID755673. Data represented are mean ± SEM, n = 7–8. † Denotes significantly different from vehicle mice (p<0.05). # Denotes significantly different from 1mg/kg CID755673-treated mice. Veh—vehicle; IVS—intraventricular septum thickness; LVID—left ventricular internal diameter; LVPW—left ventricular posterior wall thickness.</p

Acute CID755673 administration reduces PKD activity in a time and dose-dependent manner.

<p>(A) Representative western blots; (B) S916 PKD1 phosphorylation; (C) S916 PKD2 phosphorylation in the ventricles of wild type C57BL6 mice 1 hr after drug administration. (D) Representative western blots; (E) S916 PKD1 phosphorylation; (F) S916 PKD2 phosphorylation in the ventricles of wild type C57BL6 mice 4 hr after drug administration. Data represented are mean ± SEM, n = 3/group. * Denotes significantly different from vehicle-treated mice (p<0.05).</p

Assessment of PKD activation in <i>db/db</i> mice.

<p>(A) Representative western blots; (B) S916 PKD1 phosphorylation; (C) S916 PKD2 phosphorylation; (D) Representative western blots; (E) S23/24 cTn1 phosphorylation; (F) S498 HDAC5 phosphorylation in <i>db/-</i> and <i>db/db</i> mice in the fed or 4 hr fasted state, and; (G) Heat map of a PKD- dependent gene expression signature in 4 hr fasted <i>db/db</i> mice. Expression values are relative to <i>db/-</i> mice. Data represented are mean ± SEM, n = 7–8/group.</p

Cardiac dysfunction in <i>db/db</i> mice.

<p>(A) Physiological and cardiac morphological measures; (B) Representative M-mode and Doppler images; (C) LV Structural dimensions; (D) E:A ratio; (E) Deceleration time; (F) Ejection time; (G) Ejection fraction, and; (H) Fractional shortening in <i>db/-</i> and <i>db/db</i> mice. Data represented are mean ± SEM, n = 7–8/group. * Denotes significantly different from <i>db/-</i> mice (p<0.05). IVS—intraventricular septum thickness; LVID—left ventricular internal diameter; LVPW—left ventricular posterior wall thickness.</p

Assessment of PKD activation in CID755673-treated <i>db/db</i> mice.

<p>(A) Heat map of a PKD- dependent gene expression signature; (B) Representative western blots; (C) S23/24 cTn1 phosphorylation; (D) S498 HDAC5 phosphorylation; (E) KCNH2 gene expression in vehicle, 1mg/kg and 10mg/kg CID755673-treated <i>db/db</i> mice. Expression values are relative to <i>db/-</i> mice. Data represented are mean ± SEM, n = 7–8/group. * Denotes significantly different from vehicle-treated mice (p<0.05).</p

The use of a gene expression signature and connectivity map to repurpose drugs for bipolar disorder

<p><b>Objectives:</b> To create a gene expression signature (GES) to represent the biological effects of a combination of known drugs for bipolar disorder (BD) on cultured human neuronal cells (NT2-N) and rat brains, which also has evidence of differential expression in individuals with BD. To use the GES to identify new drugs for BD using Connectivity Map (CMap).<b>Methods:</b> NT2-N (<i>n</i> = 20) cells and rats (<i>n</i> = 8) were treated with a BD drug combination (lithium, valproate, quetiapine and lamotrigine) or vehicle for 24 and 6 h, respectively. Following next-generation sequencing, the differential expression of genes was assessed using edgeR in R. The derived GES was compared to differentially expressed genes in post-mortem brains of individuals with BD. The GES was then used in CMap analysis to identify similarly acting drugs.<b>Results:</b> A total of 88 genes showed evidence of differential expression in response to the drug combination in both models, and therefore comprised the GES. Six of these genes showed evidence of differential expression in post-mortem brains of individuals with BD. CMap analysis identified 10 compounds (camptothecin, chlorambucil, flupenthixol, valdecoxib, rescinnamine, GW-8510, cinnarizine, lomustine, mifepristone and nimesulide) acting similarly to the BD drug combination.<b>Conclusions:</b> This study shows that GES and CMap can be used as tools to repurpose drugs for BD.</p

Hepatic gene expression in <i>P</i>. <i>obesus</i> with NASH.

<p>Gene expression of markers of inflammation and fibrosis in livers of <i>P. obesus</i> with NASH, n = 8–9 per group. *p<0.05, **p<0.005.</p

PCR primer sequences.

<p>PCR primer sequences.</p

Hepatic lipid species in <i>P. obesus</i>.

<p>Thin layer chromatography analysis of hepatic lipid species in <i>P. obesus</i> fed either the standard diet or cholesterol-supplemented diet. Note that this technique is not quantitative, as equal amounts of lipid were analysed in each lane. CE = cholesterol esters, TAG = triacylglycerides, FFA = free fatty acids, PL = phospholipids.</p

Gene expression in livers of <i>P. obesus</i> fed the cholesterol-supplemented diet, expressed as fold difference relative to animals fed the standard diet.

<p>Gene expression in livers of <i>P. obesus</i> fed the cholesterol-supplemented diet, expressed as fold difference relative to animals fed the standard diet.</p