Dynamic acetylation and deacetylation of nuclear histones is essential for regulating the access of chromosomal DNA to transcriptional machinery. The source of acetyl-CoA for histone acetylation in mammalian cell nuclei is not clearly known. We show that acetylcarnitine formed in mitochondria, is transported into cytosol by carnitine/acylcarnitine translocase, and then enters nucleus, where it is converted to acetyl-CoA by a nuclear carnitine acetyltransferase and becomes a source of acetyl groups for histone acetylation. Genetic deficiency of the translocase markedly reduced the mitochondrial acetylcarnitine dependent nuclear histone acetylation, indicating the significance of the carnitine-dependent mitochondrial acetyl group contribution to histone acetylation.

The antidiabetic effect of N. sativa seed ethanol extract (NSE) was assessed in Meriones shawi after development of diabetes. Meriones shawi were divided randomly into four groups: normal control, diabetic control, diabetic treated with NSE (2 g eq plant/kg) or with metformin (300 mg/kg) positive control, both administered by daily intragastric gavage for 4 weeks. Glycaemia and body weight were evaluated weekly. At study's end, an Oral Glucose Tolerance Test (OGTT) was performed to estimate insulin sensitivity. Upon sacrifice, plasma lipid profile, insulin, leptin, and adiponectin levels were assessed. ACC phosphorylation and Glut4 protein content were determined in liver and skeletal muscle. NSE animals showed a progressive normalization of glycaemia, albeit slower than that of metformin controls. Moreover, NSE increased insulinemia and HDL-cholesterol, compared to diabetic controls. Leptin and adiponectin were unchanged. NSE treatment decreased OGTT and tended to decrease liver and muscle triglyceride content. NSE stimulated muscle and liver ACC phosphorylation and increased muscle Glut4. These results confirm NSE's previously reported hypoglycaemic and hypolipidemic activity. More significantly, our data demonstrate that in vivo treatment with NSE exerts an insulin-sensitizing action by enhancing ACC phosphorylation, a major component of the insulin-independent AMPK signaling pathway, and by enhancing muscle Glut4 expression.

Activation of adenosine monophosphate-activated protein kinase by CSE and AA likely increases plasma membrane glucose transporters, resulting in elevated glucose uptake. In addition, the dysfunction of mitochondrial oxidative phosphorylation may enhance glycolysis and contribute to increased glucose uptake. These results collectively suggest that CSE may be a potential anti-diabetic nutraceutical.

Through ethnobotanical surveys, the CIHR Team in Aboriginal Antidiabetic Medicines identified 17 boreal forest plants stemming from the pharmacopeia of the Cree First Nations of Eeyou Istchee (James Bay region of Northern Quebec) that were used traditionally against diabetes symptoms. The leaves of Sarracenia purpurea (pitcher plant), one of the identified Cree plants, exhibited marked antidiabetic activity in vitro by stimulating glucose uptake in C2C12 mouse muscle cells and by reducing glucose production in H4IIE rat liver cells. Fractionation guided by glucose uptake in C2C12 cells resulted in the isolation of 11 compounds from this plant extract, including a new phenolic glycoside, flavonoid glycosides, and iridoids. Compounds 6 (isorhamnetin-3-O-glucoside), 8 [kaempferol-3-O-(6″-caffeoylglucoside], and 11 (quercetin-3-O-galactoside) potentiated glucose uptake in vitro, which suggests they represent active principles of S. purpurea (EC(50) values of 18.5, 13.8, and 60.5 μM, respectively). This is the first report of potentiation of glucose uptake by compounds 6 and 8, while compound 11 (isolated from Vaccinium vitis) was previously shown to enhance glucose uptake. Treatment of H4IIE liver cells with the new compound 1, 6'-O-caffeoylgoodyeroside, decreased hepatic glucose production by reducing glucose-6-phosphatase enzymatic activity (IC(50) = 13.6 μM), which would contribute to lowering glycemia and to the antidiabetic potential of S. purpurea.

In degenerative intervertebral discs (IVD), type X collagen (COL X) expression (associated with hypertrophic differentiation) and calcification has been demonstrated. Suppression of COL X expression and calcification during disc degeneration can be therapeutic. In the present study we investigated the potential of human parathyroid hormone 1-34 (PTH) in suppressing indicators of calcification potential (alkaline phosphatase (ALP), Ca 2+ , inorganic phosphate (Pi)), and COL X expression. Further, we sought to elucidate the mechanism of PTH action in annulus fibrosus (AF) and nucleus pulposus (NP) cells from human lumbar IVDs with moderate to advanced degeneration. Mitogen activated protein kinase (MAPK) signalling and alterations in the markers of calcification potential were analysed. PTH increased type II collagen (COL II) expression in AF (~200 %) and NP cells (~163 %) and decreased COL X levels both in AF and NP cells (~75 %). These changes in the expression of collagens were preceded by MAPK phosphorylation, which was increased in both AF and NP cells by PTH after 30 min. MAPK signalling inhibitor U0126 and protein kinase-A inhibitor H-89 DCH attenuated PTH stimulated COL II expression in both cell types. PTH decreased ALP activity and increased Ca 2+ release only in NP cells. The present study demonstrates that PTH can potentially retard IVD degeneration by stimulating matrix synthesis and suppressing markers of calcification potential in degenerated disc cells via both MAPK and PKA signalling pathways. Inhibition of further mineral deposition may therefore be a viable therapeutic option for improving the status of degenerating discs.

Bioassay-guided fractionation of a crude extract (80% EtOH in H(2)O) of stem bark of Sorbus decora led the isolation of three new pentacycle triterpenes (compounds 1-3). The structures of 1-3 were established on the basis of spectroscopic methods (IR, HREIMS, 1D and 2D NMR) as 23,28-dihydroxyursan-12-ene-3β-caffeate, 23,28-dihydroxylupan-20(29)-ene-3β-caffeate, and 3β,23,28-trihydroxy-12-ursene, respectively. Compound 2 significantly enhanced glucose uptake in C2C12 cells, but compounds 1 and 3 did not. In addition, triterpenoids 4-8, catechin, and epicatechin were also isolated. This is the first comprehensive report of the phytochemical constituents of S. decora since the initial study by Narashmachari and von Rudloff (1962) and includes evaluation of their antidiabetic activity.

These results demonstrate that knockdown of NPR-A up-regulates the expression of NPR-C, Giα proteins, and NPR-C-linked AC signalling and suggests a cross-talk between NPR-A and NPR-C.

The expression of type X collagen (COL X), a late-stage chondrocyte hypertrophy marker in human mesenchymal stem cells (MSCs) from osteoarthritis (OA) patients poses a major setback to current cartilage and intervertebral disc tissue engineering efforts. However, it is not yet clear whether COL X is expressed by all human bone marrow stem cells or if it is related to age, gender, site, disease status, or drug therapy. In the current study, we report that COL X expression is upregulated in MSCs from rabbits in a surgical instability model of OA (anterior cruciate ligament transection (ACLT)) when compared to control rabbit MSCs. Thus COL X expression in OA is a common phenomenon that is due to the disease process itself and not to other environmental factors. It is, therefore, critical to understand MSC phenotype in OA patients, as these cells are essential clinically for biological repair of cartilage lesions using autologous stem cells.