Effects of 17-DMAG on survival rate of rats after LPS administration.

<p>17-DMAG (17D; 5 mg/kg) was given 20 h or 0 min prior to LPS initiation (30 mg/kg/4 h). Quercetin (Q; 300 mg/kg, i.p.), an HSP70 inhibitor, was given 6 h prior to LPS initiation. Data are shown as mean± SEM. *P < 0.05 vs. the sham group; ^#P < 0.05 vs. the LPS group, ⁺P < 0.05 vs.17D+LPS group; n = 5–20.</p

Effects of 17-DMAG (17D) on mean arterial blood pressure (MAP) in LPS induced endotoxemic rats.

<p>17-DMAG (17D; 5 mg/kg) was given 20 h or 0 min prior to LPS initiation (30 mg/kg/4 h). Quercetin (Q; 300 mg/kg, i.p.), an HSP70 inhibitor, was given 6 h prior to LPS initiation. Values are expressed as mean±SEM. Animal number in each group is shown in the parenthesis. *P < 0.05 vs. sham group, ^# P < 0.05 vs. LPS group.</p

Effects of 17-DMAG (17D) on iNOS protein expression in hearts (A), lungs (B), and livers (C) of rats 6 h after LPS administration.

<p>Q: quercetin; Values are expressed as mean±SEM. *P < 0.05 vs. sham group; ^#P < 0.05 vs. LPS group; ⁺P < 0.05 vs.17D+LPS group.</p

The Role of Heat Shock Protein 70 in the Protective Effect of YC-1 on β-Amyloid-Induced Toxicity in Differentiated PC12 Cells

<div><p>Neurodegenerative brain disorders such as Alzheimer’s disease (AD) have been well investigated. However, significant methods for the treatment of the progression of AD are unavailable currently. Heat shock protein 70 (Hsp70) plays important roles in neural protection from stress by assisting cellular protein folding. In this study, we investigated the effect and the molecular mechanism of YC-1, an activator of guanylyl cyclase (GC), on Aβ_25–35-induced cytotoxicity in differentiated PC12 cells. The results of this study showed that Aβ_25–35 (10 µM) significantly increased p25 protein production in a pattern that was consistent with the increase in μ-calpain expression. Moreover, Aβ_25–35 significantly increased tau hyperphosphorylation and induced differentiated PC12 cell death. YC-1 (0.5–10 µM) prevented the cell death induced by Aβ_25–35. In addition, YC-1 (1, 10 µM) significantly blocked Aβ_25–35-induced μ-calpain expression and decreased the formation of p25 and tau hyperphosphorylation. Moreover, YC-1 (5–20 µM) alone or combined with Aβ_25–35 (10 µM) significantly increased the expression of Hsp70 in differentiated PC12 cells. The neuroprotective effect of YC-1 was significantly attenuated by an Hsp70 inhibitor (quercetin, 50 µM) or in PC12 cells transfected with an Hsp70 small interfering RNA. However, pretreatment of cells with the GC inhibitor ODQ (10 µM) did not affect the neuroprotective effect of YC-1 against Aβ_25–35 in differentiated PC12 cells. These results suggest that the neuroprotective effect of YC-1 against Aβ_25–35-induced toxicity is mainly mediated by the induction of Hsp70. Thus, YC-1 is a potential agent against AD.</p></div

Effects of 17-DMAG (17D) on the plasma concentrations of nitric oxide (NO) metabolites (A), TNF-α (B), IL-6 (C), and phosphorylated NF-κB p65 (pp65) protein expression in lungs (D) after rats subjected to LPS administration.

<p>The level of TNF-α was detected 2 h after LPS initiation; NO metabolites, IL-6, and pp65 levels were detected after 6 h. Q: quercetin; Values are expressed as mean±SEM. Animal number in each group is shown in the parenthesis. *P < 0.05 vs. sham group; ^#P < 0.05 vs. LPS group. ⁺P < 0.05 vs.17D+LPS group.</p

Effects of 17-DMAG (17D) on LPS-induced cardiac caspase 3 activity.

<p>Q: quercetin; Values are expressed as mean±SEM. Animal number in each group is shown in the parenthesis. *P < 0.05 vs. sham group; ^#P < 0.05 vs. LPS group; ⁺P < 0.05 vs.17D+LPS group.</p

Effects of 17-DMAG (17D) on the levels of superoxide anion production (A) and reduced glutathione (B) in hearts of rats 6 h after LPS administration.

<p>Q: quercetin; Values are expressed as mean±SEM. *P < 0.05 vs. sham group; ^#P < 0.05 vs. LPS group.</p

Effects of 17-DMAG (17D) on prothrombin time (A), platelet count (B) and PAI-1 protein expression in lungs (C) 6 h after LPS administration.

<p>Q: quercetin; Values are expressed as mean±SEM. Animal number in each group is shown in the parenthesis. *P < 0.05 vs. sham group; ^#P < 0.05 vs. LPS group.</p

YC-1 enhanced the expression of Hsp70 in differentiated PC12 cells.

<p>(A) Effect of YC-1 (0.1–20 µM) on the expression of Hsp70 in differentiated PC12 cells. Differentiated PC12 cells were incubated with different concentrations of YC-1 (0.1–20 µM) for 24 h and the expression levels of Hsp70 were determined by Western blotting. (B) Effect of YC-1 (10 µM) on the time-course changes in the expression of Hsp70 in differentiated PC12 cells. (C) Effect of YC-1 (10 µM) alone and/or with Aβ_25–35 (10 µM) on the expression of Hsp70 in differentiated PC12 cells. Differentiated PC12 cells were incubated with YC-1 (10 µM) in the presence of Aβ_25–35 (10 µM) for 24 h. All data shown represent the mean ± SD (n  = 5). *<i>P</i><0.05 vs. control; ^#<i>P</i><0.05 vs. Aβ_25–35-treated cells.</p

Hsp70 inhibition attenuated the neuroprotection mediated by YC-1 in differentiated PC12 cells.

<p>Western blotting detection of the expression of Hsp70 and p25 in differentiated PC12 cells transfected with an Hsp70 siRNA for 36 h and treated with Aβ_25–35 (10 µM) and YC-1 (10 µM). Representative Western blotting data are shown in (A). (B) and (C) are bar graphs of the expression of Hsp70 and p25, respectively. All data shown represent the mean ± SD (n  = 3). *<i>P</i><0.05 vs. control; ^#<i>P</i><0.05 vs. cells treated similarly but without Hsp70 siRNA transfection.</p