AMPK:a target for drugs and natural products with effects on both diabetes and cancer

The AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy that appears to have arisen at an early stage during eukaryotic evolution. In 2001 it was shown to be activated by metformin, currently the major drug for treatment for type 2 diabetes. Although the known metabolic effects of AMPK activation are consistent with the idea that it mediates some of the therapeutic benefits of metformin, as discussed below it now appears unlikely that AMPK is the sole target of the drug. AMPK is also activated by several natural plant products derived from traditional medicines, and the mechanisms by which they activate AMPK are discussed. One of these is salicylate, probably the oldest medicinal agent known to humankind. The salicylate prodrug salsalate has been shown to improve metabolic parameters in subjects with insulin resistance and prediabetes, and whether this might be mediated in part by AMPK is discussed. Interestingly, there is evidence that both metformin and aspirin provide some protection against development of cancer in humans, and whether AMPK might be involved in these effects is also discussed

Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats.

To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats.For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp.Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP.Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo

Aqueous Extract of Terminalia chebula Induces Apoptosis in Lung Cancer Cells Via a Mechanism Involving Mitochondria-mediated Pathways

The current study was designed to evaluate the aqueous extract of Terminalia chebula activity, and the main pathway was detected on lung cancer by extracts of T. chebula. Aqueous extract of T. chebula was separated using a zeolite, and five fractions of T. chebula extract were obtained and analyzed by ultraviolet (UV) and infrared (IR) spectroscopy. Antiproliferative activity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) methods against human lung cancer (A549) and mouse lung cancer cell line LLC. T. chebula acts by regulating the Bcl-2 family protein-mediated mitochondrial pathway detected by western blot. Fraction 4 of the T. chebula extract showed much function and was thus studied further. Fraction 4 increased the activation of caspase-3, induced PARP cleavage, and promoted cytochrome c release into the cytoplasm. These data suggest that T. chebula acts by regulating the Bcl-2 family protein-mediated mitochondrial pathway and provide evidence that T. chebula deserves further investigation as a natural agent for treating and preventing cancer

Protocol for the acute lipid infusion study intervention (A). Blood glucose concentrations (B) and glucose infusion rates (C) in rats infused with saline or lipid and administered vehicle, TAK-242 or E5564.

<p>Values are means ± SEM, <i>n</i> = 6–9 rats/group. *Saline+Vehicle vs. Lipid+Vehicle; ^#Lipid+Vehicle vs. Lipid+TAK-242; ^◆Lipid+vehicle vs. Lipid+E5564, ^†Saline+Vehicle vs. Saline+E5564 (p<0.05).</p

Steady state glucose infusion rates (A), glucose disposal (B) and hepatic glucose production (C) in rats fed a HFD or a LFD and administered TAK-242 or vehicle for 10 wk.

<p>Values are means ± sem, <i>n</i> = 8–10 rats/group. *LFD+Vehicle vs. HFD+Vehicle, ^◆LFD+Vehicle vs. LFD+TAK-242, ^†suppression from basal (p<0.05). <i>Note</i>: <i>negative HGP values are an artifact and suggest complete suppression</i>.</p

Steady state glucose infusion rates (A), glucose disposal (B) and hepatic glucose production (C) in rats infused with saline or lipid and administered vehicle, TAK-242 or E5564.

<p>Values are means ± sem, <i>n</i> = 6–9 rats/group. *Saline+Vehicle vs. Lipid+Vehicle; ^#Lipid+Vehicle vs. Lipid+TAK-242; ^◆Lipid+Vehicle vs. Lipid+E5564, ^†suppression from basal (p<0.05). <i>Note</i>: <i>negative HGP values are an artifact and suggest complete suppression</i>.</p

Body weights (A) and energy intake (B) of rats fed a HFD or a LFD and administered TAK-242 or vehicle for 10 wk.

<p>Values are means ± sem, <i>n</i> = 8–10 rats/group. *LFD+Vehicle vs. HFD+Vehicle (p<0.05).</p