ABSTRACT
Complications associated with chronic kidney disease (CKD), which involves kidney inflammation, are a major health problem. Soy protein isolate (SPI) reportedly inhibits CKD exacerbation; however, its detailed action mechanism remains obscure. Therefore, the role of the polar lipid component of SPI in suppressing inflammation was investigated. Zucker fatty rats were divided into three groups and fed a diet containing casein, SPI, or casein + SPI ethanol extract (SPIEE) for 16 weeks. The isoflavones and phospholipids of SPIEE were evaluated for their anti-inflammatory effects. Rats in the SPI and casein + SPIEE groups showed reduced levels of the urinary N-acetyl-ß-d-glucosaminidase and renal IL-1ß mRNA (an inflammatory marker) compared with those in the casein group. In proximal tubular cells, genistein significantly inhibited monocyte chemoattractant protein-1 (MCP-1) expression induced by an IL-1ß stimulus. In macrophages, soybean phospholipids suppressed lipopolysaccharide-induced IL-1ß gene expression by inhibiting the phosphorylation of inhibitor κB and p65. Phosphatidylinositol (PI) was found to be essential for inhibition of IL-1ß expression. SPIEE inhibited the exacerbation of kidney disease. Genistein and soybean phospholipids, especially soybean-specific phospholipids containing PI, effectively inhibited the inflammatory spiral in vitro. Hence, daily soybean intake may be effective for inhibiting chronic inflammation and slowing kidney disease progression.
ABSTRACT
Recently, we developed a variety of phenformin derivatives as selective antitumor agents. Based on previous findings, this study evaluated a promising compound, 2-(2-chlorophenyl)ethylbiguanide (2-Cl-Phen), on the basis of stress responses in the human colon cancer cell line HT-29 under a serum- and glucose-deprived condition. 2-Cl-Phen triggered morphological changes such as shrinkage and plasma membrane disintegration, as well as a decrease in mitochondrial activity and an increase in LDH leakage. To understand intracellular issues relating to 2-Cl-Phen, this study focused on the expression levels of ER stress-inducible genes and several oncogenic genes. Serum and glucose deprivation significantly induced a variety of ER stress-inducible genes, but a 12-h treatment of 2-Cl-Phen down-regulated expression of several ER stress-related genes, with the exception of GADD153. Interestingly, the expression levels of ATF6α, GRP78, MANF, and CRELD2 mRNA were almost completely decreased by 2-Cl-Phen. This study also observed that a 24-h treatment of 2-Cl-Phen attenuated the expression levels of GRP78, GADD153, and c-Myc protein. The decrease in c-Myc protein occurred before the fluctuation of GRP78 protein, while the expression of c-Myc mRNA showed little change with cotreatment of serum and glucose deprivation with 2-Cl-Phen. To further understand the 2-Cl-Phen-induced down-regulation of ATF6-related genes, this study investigated the stability of ATF6α and GRP78 proteins using NanoLuc-tagged constructs. The expression levels of NanoLuc-tagged ATF6α and GRP78 were significantly down-regulated by 2-Cl-Phen in the presence or absence of the translation inhibitor cycloheximide. Taken together, our novel phenformin derivative 2-Cl-Phen has the unique characteristic of diminishing tumor adaptive responses, especially the expression of ATF6-related genes, as well as that of c-Myc protein, in a transcriptional and posttranscriptional manner under a serum- and glucose-deprived condition. Further characterization of cytotoxic mechanisms related to phenformin derivatives may give new insights into developing additional promising anticancer agents.
