Toshio Norikura

Anticancer activities of thelephantin O and vialinin A isolated from Thelephora aurantiotincta.

Thelephora aurantiotincta is an edible mushroom belonging to the genus Thelephora; it grows in symbiosis with pine trees. Recently, phytochemical investigations have revealed that the genus Thelephora is an abundant source of p-terphenyl derivatives. However, their bioactivity has not yet been well characterized. In screening for natural materials with anticancer activity, a T. aurantiotincta ethanol extract (TAE) was found to decrease cell viability in human hepatocellular carcinoma cells (HepG2). In this study, a new p-terphenyl derivative, thelephantin O, and a known compound, vialinin A, were isolated as the principal bioactive components of TAE. These compounds decreased cell viability in HepG2 and human colonic carcinoma cells (Caco2), but not in noncancerous human hepatocytes. This is the first report of the isolation from T. aurantiotincta of selective cytotoxic agents against cancer cells.

Total Synthesis of Pectenotoxin‐2

Pectenotoxin-2 (PTX2) is a shellfish toxin and has a non-anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non-anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin-2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone-mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring-closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid-catalyzed isomerization of anomeric PTX2b. [6,6]-Spiroacetal pectenotoxin-2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2≫PTX2b>PTX2c.

Lignophenols Decrease Oleate-Induced Apolipoprotein-B Secretion in HepG2 Cells

Lignin is one of the components in the plant cell wall, after cellulose, making up 20-30% of the global plant biomass. Lignophenols (LPs) are derivatives of lignin with high phenolic function and antioxidant properties. However, their medicinal property is not well characterised. Apolipoprotein-B (apo-B) is an essential component in very low-density lipoprotein, and high levels of serum apolipoprotein-B (apo-B) are a major factor for coronary heart disease. In this study, we examined the effect of lignophenols on apo-B secretion in HepG2 cells. HepG2 cells were treated with varying concentrations of LPs and 0.8 mm sodium oleate. LPs decreased oleate-induced apo-B secretion in a dose-dependent manner. LPs also decreased oleate-induced microsomal triglyceride transfer protein (MTTP) mRNA expression and cellular total cholesterol, suggesting that lipid bioavailability and lipidation of lipoprotein are likely involved in the decreased secretion of apo-B. Furthermore, LPs decreased oleate-induced mature sterol regulatory element binding protein 2 (SREBP-2), a transcription factor that activates cholesterol biosynthesis. This is the first study to show that LPs can decrease oleate-induced apo-B secretion in HepG2 cells. The modulations of MTTP mRNA expression, cellular total cholesterol metabolism and mature SREBP-2 expression may be important factors in the regulation of apo-B secretion by LPs.

Lignin-derived lignophenols attenuate oxidative and inflammatory damage to the kidney in streptozotocin-induced diabetic rats

Abstract This study investigated the effects of lignin-derived lignophenols (LPs) on the oxidative stress and infiltration of macrophages in the kidney of streptozotocin (STZ)-induced diabetic rats. The diabetic rats were divided into four groups with 0%, 0.11%, 0.33% and 1.0% LP diets. The vehicle-injected controls were given a commercial diet. At 5 weeks, superoxide (O2−) production, macrophage kinetics, the degree of fibrosis in glomeruli and mRNA expression for monocyte chemoattractant protein-1 (MCP-1) were examined. The NADPH-stimulated O2− levels in the kidney of the diabetic rats treated with 1.0% LP were significantly lower than those in untreated diabetic rats. The number of macrophages, levels of MCP-1 mRNA expression and degree of glomerular fibrosis increased in untreated LP and these levels were significantly lower in 1.0%LP-treated rats. The results suggested that LPs suppress the excess oxidative stress, the infiltration and activation of macrophages and the glomerular expansion in STZ-induced diabetic kidneys.

Maternal low-protein diet suppresses vascular and renal endothelial nitric oxide synthase phosphorylation in rat offspring independent of a postnatal fructose diet.

We investigated the effects of a postnatal fructose diet on the programmed hypertension and vascular and renal dysfunction in offspring from dams exposed to protein restriction. Pregnant Wistar rats were fed control and low-protein diets during the gestation and suckling periods. From the end of lactation, male offspring received standard chow or a 60% fructose diet: a control diet in the gestation and suckling periods and a control diet from the end of lactation, control-on-control (CC), 60% fructose diet-on-control (CF), control-on-low-protein diet (LPC) and 60% fructose diet-on-low-protein diet (LPF). The systolic blood pressure (SBP) was measured during treatment. At postnatal days 94-101, urinary 24 h nitrate/nitrite (NO x ) content, protein levels of endothelial nitric oxide synthase (eNOS) and mRNA levels of endothelin-1 (ET-1), and NAD(P)H oxidase subunits in the aorta and kidney were examined. The SBP at postnatal days 97-101 increased in CF (137 ± 2 mmHg, P < 0.05), LPC (135 ± 1 mmHg, P < 0.05) and LPF (141 ± 2 mmHg, P < 0.05), compared with CC (124 ± 1 mmHg). The urinary NO x contents and eNOS phosphorylation in the aorta and kidney of CF, LPC and LPF decreased when compared with CC. In the aorta, the mRNA levels of NAD(P)H oxidase subunits p47phox in LPC and ET-1 in LPC and LPF increased. These results indicate that maternal protein restriction elevated the blood pressure, the downregulated nitric oxide production and eNOS phosphorylation, whereas the postnatal fructose diet made no significant difference to these alterations.

Maternal green tea polyphenol intake during lactation attenuates kidney injury in high-fat-diet-fed male offspring programmed by maternal protein restriction in rats

Maternal malnutrition is known to increase the risk of obesity in offspring. We investigated whether green tea extract (GTE) intake during lactation affects obesity-related fibrosis and inflammation in the kidney of high-fat-diet-fed adult offspring of protein-restricted-diet-fed dams during pregnancy and lactation. Pregnant Wistar rats received diets containing 20% (normal-protein, NP) or 8% (low-protein, LP) casein, and they received 0%-, 0.12%- or 0.24%-GTE-containing LP diets (LP/LP, LP/LGT and LP/HGT, respectively) during lactation. At weaning, the pups that received a diet providing 13% (normal-fat, NF) or 45% (high-fat, HF) energy from fat were divided into five groups: NP/NP/NF, LP/LP/NF, LP/LP/HF, LP/LGT/HF and LP/HGT/HF. At week 45, the degree of fibrosis; macrophage infiltration; protein expression levels of TGF-β; and mRNA levels of TNF-α, DNMT, UHRF1 and histone lysine methyltransferase (G9a) in the kidneys of male offspring were examined. The area of fibrosis and TGF-βlevels increased in the LP/LP/HF group. Conversely, the fibrotic areas and TGF-β levels in the LP/HGT/HF group decreased (33% and 31%, respectively) compared with those in the LP/LP/HF group. The number of macrophages and mRNA levels of TNF-α in the LP/HGT/HF group decreased (34% and 29%, respectively) compared with those in the LP/LP/HF group. DNMT1, UHRF1 and G9a mRNA levels in the LP/HGT/HF group decreased compared with those in the LP/LP/HF group. In conclusion, GTE intake during lactation attenuated tubulointerstitial fibrosis and macrophage infiltration by down-regulating epigenetic modulators such as DNMT1, UHRF1 and G9a in the kidney of HF-diet-fed adult offspring programmed by maternal protein restriction.