5-(tetradecyloxy)-2-furoic acid (TOFA)は細胞周期阻害とアポトーシス誘導により胆管細胞癌の増殖を抑える

熊本大

Shikonin Induces ROS-Dependent Apoptosis Via Mitochondria Depolarization and ER Stress in Adult T Cell Leukemia/Lymphoma

Adult T cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy that develops in some elderly human T-cell leukemia virus (HTVL-1) carriers. ATLL has a poor prognosis despite conventional and targeted therapies, and a new safe and efficient therapy is required. Here, we examined the anti-ATLL effect of Shikonin (SHK), a naphthoquinone derivative that has shown several anti-cancer activities. SHK induced apoptosis of ATLL cells accompanied by generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and induction of endoplasmic reticulum (ER) stress. Treatment with a ROS scavenger, N-acetylcysteine (NAC), blocked both loss of mitochondrial membrane potential and ER stress, and prevented apoptosis of ATLL cells, indicating that ROS is an upstream trigger of SHK-induced apoptosis of ATLL cells through disruption of the mitochondrial membrane potential and ER stress. In an ATLL xenografted mouse model, SHK treatment suppressed tumor growth without significant adverse effects. These results suggest that SHK could be a potent anti-reagent against ATLL

Proteomic analysis of kidney in rats chronically exposed to monosodium glutamate.

Chronic monosodium glutamate (MSG) intake causes kidney dysfunction and renal oxidative stress in the animal model. To gain insight into the renal changes induced by MSG, proteomic analysis of the kidneys was performed.Six week old male Wistar rats were given drinking water with or without MSG (2 mg/g body weight, n = 10 per group) for 9 months. Kidneys were removed, frozen, and stored at -75°C. After protein extraction, 2-D gel electrophoresis was performed and renal proteome profiles were examined with Colloidal Coomassie Brilliant Blue staining. Statistically significant protein spots (ANOVA, p<0.05) with 1.2-fold difference were excised and analyzed by LC-MS. Proteomic data were confirmed by immunohistochemistry and Western blot analyses.The differential image analysis showed 157 changed spots, of which 71 spots were higher and 86 spots were lower in the MSG-treated group compared with those in the control group. Eight statistically significant and differentially expressed proteins were identified: glutathione S-transferase class-pi, heat shock cognate 71 kDa, phosphoserine phosphatase, phosphoglycerate kinase, cytosolic glycerol-3-phosphate dehydrogenase, 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase, α-ketoglutarate dehydrogenase and succinyl-CoA ligase.The identified proteins are mainly related to oxidative stress and metabolism. They provide a valuable clue to explore the mechanism of renal handling and toxicity on chronic MSG intake

Two-dimensional gel electrophoresis of rat kidney lysate; Coomassie blue-stained gels from control (a) and MSG-treated rats (b).

<p>Proteins were resolved on 7 cm pH 3–11 IEF strips (NL) followed by SDS-PAGE (12%). The differentially expressed spots detected by the image Master 2D Platinum 7.0 software are circled. The gels shown are representative of three independent experiments.</p

Proposed model of MSG-induced ROS production in rat kidney.

<p>The higher level of glutamate on chronic MSG intake accelerates TCA cycle. The increased level of α-KGDH may stimulate ROS production hence oxidative stress occurs in the kidney of the MSG-treated rats.</p

Western blot analysis of α-ketoglutarate dehydrogenase (α-KGDH) and glutathione S-transferase P (GSTP) in the kidney tissues of control and MSG treated groups (A), Quantitative analysis indicated that α-KGDH expression was significantly higher in the kidney of the MSG-treated group than that of control (B), whereas, GSTP expression was found significantly lower than that of control (C).

<p>The blots shown are representative of two independent experiments. C1–C5 and T1–T5 indicate animals in the control and MSG-treated groups, respectively.</p

List of renal proteins with significantly altered expression after long term chronic MSG treatment.

<p>List of renal proteins with significantly altered expression after long term chronic MSG treatment.</p

Pancreatic function in control and MSG-treated groups as measured by (A) insulin levels at 1, 3, 6, and 9 months (mean ± SEM) and (B) oral glucose tolerance test (OGTT) at 9 months(mean ± SD).

<p>Pancreatic function in control and MSG-treated groups as measured by (A) insulin levels at 1, 3, 6, and 9 months (mean ± SEM) and (B) oral glucose tolerance test (OGTT) at 9 months(mean ± SD).</p

Monosodium Glutamate Induces Changes in Hepatic and Renal Metabolic Profiles and Gut Microbiome of Wistar Rats

The short- and long-term consumption of monosodium glutamate (MSG) increases urinary pH but the effects on the metabolic pathways in the liver, kidney and the gut microbiota remain unknown. To address this issue, we investigated adult male Wistar rats allocated to receive drinking water with or without 1 g% MSG for 2 weeks (n = 10, each). We performed a Nuclear Magnetic Resonance (NMR) spectroscopy-based metabolomic study of the jejunum, liver, and kidneys, while faecal samples were collected for bacterial DNA extraction to investigate the gut microbiota using 16S rRNA gene sequencing. We observed significant changes in the liver of MSG-treated rats compared to controls in the levels of glucose, pyridoxine, leucine, isoleucine, valine, alanine, kynurenate, and nicotinamide. Among kidney metabolites, the level of trimethylamine (TMA) was increased, and pyridoxine was decreased after MSG-treatment. Sequencing of the 16S rRNA gene revealed that MSG-treated rats had increased Firmicutes, the gut bacteria associated with TMA metabolism, along with decreased Bifidobacterium species. Our data support the impact of MSG consumption on liver and kidney metabolism. Based on the gut microbiome changes, we speculate that TMA and its metabolites such as trimethylamine-N-oxide (TMAO) may be mediators of the effects of MSG on the kidney health

Islet size (um²) distribution in control and MSG-treated groups at 1, 3, 6, and 9 months.

<p>Islet size (um²) distribution in control and MSG-treated groups at 1, 3, 6, and 9 months.</p