PMID- 28632169 OWN - NLM STAT- MEDLINE DCOM- 20180417 LR - 20220317 IS - 1660-3397 (Electronic) IS - 1660-3397 (Linking) VI - 15 IP - 6 DP - 2017 Jun 20 TI - The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 beta-Cells. LID - 10.3390/md15060185 [doi] LID - 185 AB - Astaxanthin, an antioxidant agent, can protect pancreatic beta-cells of db/db mice from glucotoxicity and resolve chronic inflammation in adipose tissue. Nonetheless, the effects of astaxanthin on free-fatty-acid-induced inflammation and cellular stress in beta-cells remain to be demonstrated. Meanwhile, palmitate enhances the secretion of pro-inflammatory adipokines monocyte chemoattractant protein-1 (MCP-1) and VEGF(120) (vascular endothelial growth factor). We therefore investigated the influence of astaxanthin on palmitate-stimulated MCP-1 and VEGF(120) secretion in mouse insulinoma (MIN6) pancreatic beta-cells. Furthermore, whether astaxanthin prevents cellular stress in MIN6 cells was also assessed. Pre-treatment with astaxanthin or with N-acetyl-cysteine (NAC) which is an antioxidant drug, significantly attenuated the palmitate-induced MCP-1 release through downregulation of phosphorylated c-Jun NH(2)-terminal protein kinase (JNK) pathways, and suppressed VEGF(120) through the PI3K/Akt pathways relative to the cells stimulated with palmitate alone. In addition, palmitate significantly upregulated homologous protein (CHOP) and anti-glucose-regulated protein (GRP78), which are endoplasmic reticulum (ER) stress markers, in MIN6 cells. On the other hand, astaxanthin attenuated the increased CHOP content, but further up-regulated palmitate-stimulated GRP78 protein expression. By contrast, NAC had no effects on either CHOP or GRP78 enhancement induced by palmitate in MIN6 cells. In conclusion, astaxanthin diminishes the palmitate-stimulated increase in MCP-1 secretion via the downregulation of JNK pathways in MIN6 cells, and affects VEGF(120) secretion through PI3K/Akt pathways. Moreover, astaxanthin can prevent not only oxidative stress caused endogenously by palmitate but also ER stress, which NAC fails to attenuate, via upregulation of GRP78, an ER chaperon. FAU - Kitahara, Atsuko AU - Kitahara A AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. kitahara@ks.kyorin-u.ac.jp. FAU - Takahashi, Kazuto AU - Takahashi K AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. kazuto_ta@ks.kyorin-u.ac.jp. FAU - Morita, Naru AU - Morita N AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. n-morita@ks.kyorin-u.ac.jp. FAU - Murashima, Toshitaka AU - Murashima T AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. mtosh@ka3.so-net.ne.jp. FAU - Onuma, Hirohisa AU - Onuma H AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. onuma@ks.kyorin-u.ac.jp. FAU - Sumitani, Yoshikazu AU - Sumitani Y AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. sumitani@ks.kyorin-u.ac.jp. FAU - Tanaka, Toshiaki AU - Tanaka T AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. toshiaki@ks.kyorin-u.ac.jp. FAU - Kondo, Takuma AU - Kondo T AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. takkon808@gmail.com. FAU - Hosaka, Toshio AU - Hosaka T AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. toshio.hosaka@outlook.com. FAU - Ishida, Hitoshi AU - Ishida H AD - Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. ishida@ks.kyorin-u.ac.jp. LA - eng PT - Journal Article DEP - 20170620 PL - Switzerland TA - Mar Drugs JT - Marine drugs JID - 101213729 RN - 0 (Chemokine CCL2) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Hspa5 protein, mouse) RN - 0 (Palmitates) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0 (Xanthophylls) RN - 8XPW32PR7I (astaxanthine) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM MH - Acetylcysteine/pharmacology MH - Animals MH - Cell Line, Tumor MH - Chemokine CCL2/metabolism MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/*drug effects MH - MAP Kinase Signaling System/drug effects MH - Mice MH - Oxidative Stress/*drug effects MH - Palmitates/antagonists & inhibitors/*pharmacology MH - Vascular Endothelial Growth Factor A/metabolism MH - Xanthophylls/pharmacology PMC - PMC5484135 OTO - NOTNLM OT - astaxanthin OT - palmitate OT - pancreatic beta-cell COIS- The authors declare no conflict of interest. EDAT- 2017/06/21 06:00 MHDA- 2018/04/18 06:00 PMCR- 2017/06/01 CRDT- 2017/06/21 06:00 PHST- 2017/05/15 00:00 [received] PHST- 2017/06/10 00:00 [revised] PHST- 2017/06/14 00:00 [accepted] PHST- 2017/06/21 06:00 [entrez] PHST- 2017/06/21 06:00 [pubmed] PHST- 2018/04/18 06:00 [medline] PHST- 2017/06/01 00:00 [pmc-release] AID - md15060185 [pii] AID - marinedrugs-15-00185 [pii] AID - 10.3390/md15060185 [doi] PST - epublish SO - Mar Drugs. 2017 Jun 20;15(6):185. doi: 10.3390/md15060185.