Naoko Kiyota

Astragalosides isolated from the root of Astragalus Radix inhibit the formation of advanced glycation end products.

Because advanced glycation end product (AGE) inhibitors such as pyridoxamine significantly inhibit the development of retinopathy and neuropathy in the streptozotocin-induced diabetic rat, treatment with AGE inhibitors is believed to be a potential strategy for the prevention of lifestyle-related diseases such as diabetic complications. A crude extract of Astragali Radix (AR; roots of Astragalus membranaceus ) inhibits the formation of N(epsilon)-(carboxymethyl)lysine (CML) and pentosidine during the incubation of bovine serum albumin with ribose. In the present study, compounds were isolated from AR that prevented CML and pentosidine formation. Astragalosides significantly inhibited the formation of both CML and pentosidine, and astragaloside V had the strongest inhibitory effect among all if the isolated compounds. These data suggest that AR and astragalosides may be a potentially useful strategy for the prevention of clinical diabetic complications by inhibiting AGEs.

Esculeogenin A, a New Tomato Sapogenol, Ameliorates Hyperlipidemia and Atherosclerosis in ApoE-Deficient Mice by Inhibiting ACAT

Objective—We recently identified esculeoside A, a new spirosolane-type glycoside, with a content in tomatoes that is 4-fold higher than that of lycopene. In the present study, we examined the effects of esculeoside A and esculeogenin A, a new aglycon of esculeoside A, on foam cell formation in vitro and atherogenesis in apoE-deficient mice. Methods and Results—Esculeogenin A significantly inhibited the accumulation of cholesterol ester (CE) induced by acetylated low density lipoprotein (acetyl-LDL) in human monocyte-derived macrophages (HMDM) in a dose-dependent manner without inhibiting triglyceride accumulation, however, it did not inhibit the association of acetyl-LDL to the cells. Esculeogenin A also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-coenzymeA (CoA): cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that esculeogenin A suppresses the activity of both ACAT-1 and ACAT-2. Furthermore, esculeogenin A prevented the expression of ACAT-1 protein, whereas that of SR-A and SR-BI was not suppressed. Oral administration of esculeoside A to apoE-deficient mice significantly reduced the levels of serum cholesterol, triglycerides, LDL-cholesterol, and the areas of atherosclerotic lesions without any detectable side effects. Conclusions—Our study provides the first evidence that purified esculeogenin A significantly suppresses the activity of ACAT protein and leads to reduction of atherogenesis.

Natural compounds containing a catechol group enhance the formation of Nε-(carboxymethyl)lysine of the Maillard reaction

Inhibition of advanced glycation end-product (AGE) formation is a potential strategy for the prevention of clinical diabetes complications. Screening for new AGE inhibitors revealed several natural compounds that inhibited the formation of N(ε)-(carboxymethyl)lysine (CML), a major antigenic AGE structure, whereas natural compounds containing a catechol group, such as gallic acid and epicatechin, significantly enhanced CML formation. A similar enhancing effect was also observed by culturing THP-1 macrophages in the presence of catechol compounds. Although 4-methylcatechol significantly enhanced CML formation from glycated HSA (gHSA), a model for Amadori proteins, analogues of catechol such as 5-methylresorcinol and methylhydroquinone showed no enhancing effect. Even though 1mM 4-methylcatechol, epicatechin, and gallic acid significantly enhanced CML formation from gHSA, it was significantly inhibited by decreasing their concentration. The enhancing effect of 1mM catechol compounds was inhibited in the presence of the glutathione peroxidase system, thus demonstrating that hydrogen peroxide generated from catechol compounds plays an important role in the enhancement of CML formation. Furthermore, administration of 500mg/kg/day epicatechin to STZ-induced diabetic mice for 45days enhanced CML accumulation at the surface area of gastric epithelial cells in the stomach. This study provides the first evidence that high amounts of catechol-containing structures enhance oxidative stress, thus leading to enhanced CML formation, and this phenomenon may explain the paradoxical effect that some flavonoids have on redox status.

Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting acyl-CoA: cholesterol acyl-transferase (ACAT)

It was previously revealed that esculeoside A, a new glycoalkaloid, and esculeogenin A, a new aglycon of esculeoside A, contained in ripe tomato ameliorate atherosclerosis in apoE-deficent mice. This study examined whether tomatidine, the aglycone of tomatine, which is a major tomato glycoalkaloid, also shows similar inhibitory effects on cholesterol ester (CE) accumulation in human monocyte-derived macrophages (HMDM) and atherogenesis in apoE-deficient mice. Tomatidine significantly inhibited the CE accumulation induced by acetylated LDL in HMDM in a dose-dependent manner. Tomatidine also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that tomatidine suppresses both ACAT-1 and ACAT-2 activities. Furthermore, the oral administration of tomatidine to apoE-deficient mice significantly reduced levels of serum cholesterol, LDL-cholesterol, and areas of atherosclerotic lesions. The study provides the first evidence that tomatidine significantly suppresses the activity of ACAT and leads to reduction of atherogenesis.

Some Natural Compounds EnhanceNɛ-(Carboxymethyl)lysine Formation

Since pyridoxamine, which traps intermediates in the Maillard reaction and lipid peroxidation reaction, significantly inhibits the development of retinopathy and neuropathy in the streptozotocin‐induced diabetic rat, treatment with advanced glycation end product inhibitors and antioxidants may be a potential strategy for the prevention of clinical diabetic complications. However, the paradoxical effect of green tea has been reported; although plasma hydroperoxide levels were ameliorated, the level of Nɛ‐(carboxyethyl)lysine (CML) in tendon and plasma was increased by the oral administration of green tea to diabetic rats. In the present study, we measured the effect of natural compounds on CML formation by enzyme‐linked immunosorbent assay. A significant amount of CML was observed when bovine serum albumin was incubated with ribose for 7 days. Under the same conditions, natural compounds, such as desgalactotigonin, showed inhibitory effects, whereas quercetin and acteoside enhanced CML formation, indicating that natural compounds contain both inhibitors and enhancers for CML formation.

Some Natural Compounds Enhance Nε-(Carboxymethyl)lysine Formation

Since pyridoxamine, which traps intermediates in the Maillard reaction and lipid peroxidation reaction, significantly inhibits the development of retinopathy and neuropathy in the streptozotocin‐induced diabetic rat, treatment with advanced glycation end product inhibitors and antioxidants may be a potential strategy for the prevention of clinical diabetic complications. However, the paradoxical effect of green tea has been reported; although plasma hydroperoxide levels were ameliorated, the level of Nɛ‐(carboxyethyl)lysine (CML) in tendon and plasma was increased by the oral administration of green tea to diabetic rats. In the present study, we measured the effect of natural compounds on CML formation by enzyme‐linked immunosorbent assay. A significant amount of CML was observed when bovine serum albumin was incubated with ribose for 7 days. Under the same conditions, natural compounds, such as desgalactotigonin, showed inhibitory effects, whereas quercetin and acteoside enhanced CML formation, indicating that natural compounds contain both inhibitors and enhancers for CML formation.

Some Natural Compounds EnhanceN ɛ‐(Carboxymethyl)lysine Formation

Since pyridoxamine, which traps intermediates in the Maillard reaction and lipid peroxidation reaction, significantly inhibits the development of retinopathy and neuropathy in the streptozotocin‐induced diabetic rat, treatment with advanced glycation end product inhibitors and antioxidants may be a potential strategy for the prevention of clinical diabetic complications. However, the paradoxical effect of green tea has been reported; although plasma hydroperoxide levels were ameliorated, the level of Nɛ‐(carboxyethyl)lysine (CML) in tendon and plasma was increased by the oral administration of green tea to diabetic rats. In the present study, we measured the effect of natural compounds on CML formation by enzyme‐linked immunosorbent assay. A significant amount of CML was observed when bovine serum albumin was incubated with ribose for 7 days. Under the same conditions, natural compounds, such as desgalactotigonin, showed inhibitory effects, whereas quercetin and acteoside enhanced CML formation, indicating that natural compounds contain both inhibitors and enhancers for CML formation.