2019 - Vol. 2
|Oleanolic Acid-3-(1′2′Orthoacetate-Glucoside)-28-Glucoside Alleviates Methylmercury Toxicity in Vitro and in Vivo||Vol.2, No.4, p.56-60|
|Ryosuke Nakamura , Tatsuya Shirahata , Tatsuya Katsumi , Naruki Konishi , Yasukazu Takanezawa , Yuka Ohshiro , Shimpei Uraguchi , Yoshinori Kobayashi , Masako Kiyono|
|Received: July 27, 2019|
|Accepted: August 14, 2019|
|Released: August 29, 2019|
|Abstract||Full Text PDF[1M]|
Methylmercury (MeHg) is one of the most toxic environmental pollutants and causes serious health hazards worldwide. Recently, we demonstrated that oleanolic acid (OA) 3-glucoside (OA3Glu), a saponin derivative in which glucose is bound to the C3 position of OA, has anti-MeHg activity by suppressing Hg accumulation in organs of mice. In this study, we examined the anti-MeHg activity of OA-3-(1′2′orthoacetate-Glu)-28-Glu in which glucose is bound to the C3 position of OA in a different binding form from that in OA3Glu. We found that OA-3-(1′2′orthoacetate-Glu)-28-Glu suppressed cellular MeHg uptake and improved cell viability upon exposure to MeHg in Caco-2 cells. To verify the in vivo anti-MeHg activities of OA-3-(1′2′orthoacetate-Glu)-28-Glu, mice were orally administered MeHg (0.02, 1.0, or 5.0 mg·kg−1·d−1), with or without OA-3-(1′2′orthoacetate-Glu)-28-Glu. The mice cotreated with 0.02 mg·kg−1·d−1 MeHg and OA-3-(1′2′orthoacetate-Glu)-28-Glu showed significantly lower Hg content in the liver and kidney than those treated with MeHg alone. In addition, interleukin (IL)-1β and IL-6 levels in the brain of mice cotreated with 5.0 mg·kg−1·d−1 MeHg and OA-3-(1′2′orthoacetate-Glu)-28-Glu were significantly lower than those of mice treated with MeHg alone. These results suggested that OA-3-(1′2′orthoacetate-Glu)-28-Glu had potential as an anti-MeHg accumulation compound, owing to its ability to suppress MeHg distribution into organs especially under low-level MeHg exposure condition. Taken together, it was suggested that glucose binding to the C3 position of OA is important for anti-MeHg activity of OA saponin derivatives.
|Two Modes of Toxicity of Lipid Nanoparticles Containing a pH-Sensitive Cationic Lipid on Human A375 and A375-SM Melanoma Cell Lines||Vol.2, No.4, p.48-55|
|Ahmed Y. AlBaloul , Yusuke Sato , Nako Maishi , Kyoko Hida , Hideyoshi Harashima|
|Received: May 10, 2019|
|Accepted: August 02, 2019|
|Released: August 28, 2019|
|Abstract||Full Text PDF[1M]|
Melanomas are one of the most aggressive form of skin cancer and are resistant to many cancer therapies. Lipid nanoparticles (LNPs) containing a pH-sensitive cationic lipid, YSK05 (YSK05-LNPs), for delivering short interfering RNA (siRNA) were found to strongly triggers in vitro toxicity in human A375 and A375-SM melanoma cell lines regardless of gene silencing. Assessing the localization of the toxicity was done by controlling the cellular uptake of the YSK05-LNPs that contained different polyethyleneglycol (PEG)-lipid. The YSK05-LNPs exhibited consistent dose- and time-dependent toxicity, independent of their cellular uptake, indicating that the toxicity is triggered by an interaction between the YSK05-LNPs and the cell surface. Treatment with free YSK05 resulted in only time-dependent toxicity. These results suggest that the YSK05-LNPs trigger two modes of action; a fast-acting component that is related to the LNP formulation and a slow-acting mode, which is related to the YSK05 lipid itself. Necrosis was determined to be the cause of cell death, as evidenced by the results of Annexin V assays, which are specific for confirming lipid-based toxicity. These findings indicate that these YSK05-LNPs have substantial potential for use as an antimelanoma agent as both an RNA interference-based drug and as a chemotherapeutic drug.
|Prostaglandin-Modulated Interaction of Thymic Progenitor Cells with Blood Vessels during Estradiol-Induced Thymic Involution||Vol.2, No.4, p.39-47|
|Nurhanani Razali , Io Horikawa , Hirofumi Hohjoh , Chihiro Yoshikawa , Hiroshi Hasegawa|
|Received: July 10, 2019|
|Accepted: July 13, 2019|
|Released: August 01, 2019|
|Abstract||Full Text PDF[6M]|
Thymic involution-associated disfunction of thymus is implicated in aging, microbial infection, pregnancy, improper nutrition, and etc., therefore it is clinically important especially in aged societies. Excess administration of estradiol to male mice is known to induce thymic involution and used as a mouse model of thymic involution, whereas the mechanisms of which have not been well understood. Here we examined the role of prostanoids in the estradiol-induced thymic involution in mice. The administration of 17β-estradiol for 7 consecutive days induced thymic involution. In the involute thymus, the expression of mRNAs for some synthetic enzymes of prostanoids, including Ptgs1, Ptgs2, Ptgds, Hpgds, Ptges1, and Tbxas, are upregulated. In order to examine the roles of prostanoids in the thymic involution, we treated the mice with an NSAID, etodolac, following 17β-estradiol-administration. The etodolac-treatment partially inhibited the estradiol-induced reduction of thymic size and disorganization of the boundary between thymic cortex and medulla, as indicated by keratin 5 expression as well as by localization of innate immune cells. CD34-positive thymic progenitor cells localized near the blood vessels in the estradiol-administered thymus, although they were more dispersed by the etodolac-treatment. The association of CD34-positive cells with blood vessels is known to be mediated by E- and P-selectins, whose expressions were also regulated by estradiol-administration in an etodolac-sensitive manner. These results indicated the role of prostanoids in the histological change of thymus during estradiol-induced thymic involution.