Background Obesity‐induced insulin resistance is the major determinant of metabolic syndrome, which precedes the development of type 2 diabetes mellitus.11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is considered a potential therapeutic target in the treatment of type 2 diabetes mellitus, while the potential mechanism is not very clearly identified. Methods In vitro cultured 3T3‐L1 pre‐adipocytes, prednisone and over‐expressed 11β‐HSD1 were used to induce insulin resistance. Type 2 diabetes mellitus mouse models were treated with 11β‐HSD1 inhibitor PF00195715 and JNK inhibitor C66 by gavage, respectively. Results Stimulation of prednisone or over‐expressed 11β‐HSD1 significantly disturbed insulin signal pathway, decreased AKT phosphorylation and led to insulin resistance, while these effects were reversed by PF00195715 and C66. Either C66 or DN‐JNK significantly attenuated the 11β‐HSD1 over‐expression induced insulin resistance, indicating a mediated role of JNK. Oral administration with either PF00195715 or C66 in mouse models remarkably relieved insulin resistance and type 2 diabetes mellitus. Conclusion 11β‐HSD1 mediates insulin resistance and type 2 diabetes mellitus through JNK activation.
Prostate cancer is the most commonly diagnosed malignancy among men. The Discovery of new agents for the treatment of prostate cancer is urgently needed. Compound WZ35, a novel analog of the natural product curcumin, exhibited good anti-prostate cancer activity, with an IC50 of 2.2 μM in PC-3 cells. However, the underlying mechanism of WZ35 against prostate cancer cells is still unclear. Human prostate cancer PC-3 cells and DU145 cells were treated with WZ35 for further proliferation, apoptosis, cell cycle, and mechanism analyses. NAC and CHOP siRNA were used to validate the role of ROS and ER stress, respectively, in the anti-cancer actions of WZ35. Our results show that WZ35 exhibited much higher cell growth inhibition than curcumin by inducing ER stress-dependent cell apoptosis in human prostate cells. The reduction of CHOP expression by siRNA partially abrogated WZ35-induced cell apoptosis. WZ35 also dose-dependently induced cell cycle arrest in the G2/M phase. Furthermore, we found that WZ35 treatment for 30 min significantly induced reactive oxygen species (ROS) production in PC-3 cells. Co-treatment with the ROS scavenger NAC completely abrogated the induction of WZ35 on cell apoptosis, ER stress activation, and cell cycle arrest, indicating an upstream role of ROS generation in mediating the anti-cancer effect of WZ35. Taken together, this work presents the novel anticancer candidate WZ35 for the treatment of prostate cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human prostate cancer treatment.
Nature Communications 8: Article number: 13997 (2017); Published: 3 January 2017; Updated: 19 March 2018 The original version of this Article contained an error in the Methods section entitled ‘Fatty acid-albumin complex’, where the bovine serum albumin concentration of the 5 mM palmitic acid solution used for in vitro experiments was incorrectly reported as being 28 μM, and should have read 627 μM.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)