Effect of osthole on advanced glycation end products-induced renal tubular hypertrophy and role of klotho in its mechanism of action.

BACKGROUND: Osthole has been widely reported to have pharmacological activities such as anti-cancer, anti-inflammation and anti-hyperlipidemic effects. Klotho was identified as an anti-senescence protein in a variety of tissues. Loss of klotho has been associated with chronic kidney disease. However, potential roles and molecular events for osthole and klotho in diabetic nephropathy remain unclear. PURPOSE: In the current study, we undertook to study the effect of osthole on klotho expression in advanced glycation end products (AGE)-cultured human renal proximal tubular cells, and to investigate the molecular mechanisms of osthole and exogenous klotho against AGE-induced renal tubular hypertrophy. METHODS: Cell viability was elucidated by MTT assay. Protein expression was measured by Western blotting. mRNA level was analyzed by real-time PCR. Cellular hypertrophy growth was evaluated by hypertrophy index. Relative cell size was detected by flow cytometry. RESULTS: We found that raising the ambient AGE concentration causes a dose-dependent decrease in klotho synthesis. Osthole significantly increased AGE-inhibited klotho mRNA and protein expression. Osthole and exogenous klotho treatments significantly attenuated AGE-induced Janus kinase 2 (JAK2)-signal transducers and activators of transcription 1 (STAT1) and STAT3 activation. Moreover, protein levels of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 were augmented by osthole and exogenous klotho. The abilities of osthole and exogenous klotho to reverse AGE-induced cellular hypertrophy were verified by the observation that osthole and exogenous klotho inhibited p21Waf1/Cip1/collagen IV/RAGE expression, total protein content, and cell size. CONCLUSION: Consequently, we found that osthole attenuated AGE-induced renal tubular hypertrophy via induction of klotho expression and suppression of the JAK2-STAT1/STAT3 signaling. These results also showed that klotho might be used as a unique molecular target for the treatment of diabetic nephropathy.

Antidiabetic, Antihyperlipidemic, and Antioxidant Activities of Mulberry Lees Fermented Products in Diabetic Mice.

Mulberry lees are the sediment in the bottom of the barrel, which can be obtained from the processing of mulberry wine, and they are considered as low-value byproducts. In this study, mulberry lees were extracted with ethanol, and then fermented with Monascus pilosus to obtain fermented products (M × M). Male ICR mice were diabetes induced by STZ, and then oral administration of fermented products. The results showed that fermented products could reduce 31.9% to 47.9% plasma glucose, 25.8% to 48.2% total cholesterol, and 16.7% to 25% triglyceride levels in diabetic mice, and it can greatly lower the malondialdehyde (MDA) content by 26.4% to 59.7% but raise antioxidant enzyme activity in the liver of the mice. Moreover, fermented products not only could reduce AST and ALT activity of the diabetic mice, thereby alleviating liver inflammation, but also lowered the urea nitrogen and creatinine levels, improved glomerulus volume, and reduced swelling and inflammation in the kidneys. It was concluded that mulberry lees fermented products could be served as a value-added resource for human health.

Cinnamaldehyde and nitric oxide attenuate advanced glycation end products-induced the Jak/STAT signaling in human renal tubular cells.

Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. It possesses anti-diabetic properties in vitro and in vivo and has anti-inflammatory and anti-cancer effects. To explore whether cinnamaldehyde was linked to altered advanced glycation end products (AGE)-mediated diabetic nephropathy, the molecular mechanisms of cinnamaldehyde responsible for inhibition of AGE-reduced nitric oxide (NO) bioactivity in human renal proximal tubular cells were examined. We found that raising the ambient AGE concentration causes a dose-dependent decrease in NO generation. Cinnamaldehyde significantly reverses AGE-inhibited NO generation and induces high levels of cGMP synthesis and PKG activation. Treatments with cinnamaldehyde, the NO donor S-nitroso-N-acetylpenicillamine, and the JAK2 inhibitor AG490 markedly attenuated AGE-inhibited NOS protein levels and NO generation. Moreover, AGE-induced the JAK2-STAT1/STAT3 activation, RAGE/p27(Kip1) /collagen IV protein levels, and cellular hypertrophy were reversed by cinnamaldehyde. The ability of cinnamaldehyde to suppress STAT activation was also verified by the observation that it significantly increased SCOS-3 protein level. These findings indicate for the first time that in the presence of cinnamaldehyde, the suppression of AGE-induced biological responses is probably mediated by inactivating the JAK2-STAT1/STAT3 cascade or activating the NO pathway.

Antimutagenic and antiproliferative effects of roasted and defatted peanut dregs on human leukemic U937 and HL-60 cells.

The antimutagenic effects on Salmonella typhimurium TA98 and TA100 strains and antiproliferative effects on leukemia cell lines (U937 and HL-60) of peanut protein isolate (PPI), peanut protein isolate enzyme hydrolysate (PPIEH), roasted and defatted peanut dregs (RDPD), and roasted and defatted peanut dregs enzyme hydrolysate (RDPDEH) were investigated. The antimutagenic effects on B(a)P and 4-NQO toward the TA98 and TA100 strains were found to follow a diminishing order: RDPD > RDPDEH >> PPI = PPIEH with dose-dependency. Antiproliferative effects on leukemia cells U937 and HL-60 were also detected. RDPD was found to be the most effective of all the peanut preparations. At 100 microg/mL concentration, RDPD inhibited the proliferation of U937 and HL-60 cells by 56% and 52%, respectively. We propose to consider RDPD and RDPDEH in the development of natural chemotherapeutic or chemopreventive dietary supplements against leukemia and to upgrade the utilization of these by-products in peanut oil production.