The Effect of Metformin Treatment on CRBP-I Level and Cancer Development in the Liver of HBx Transgenic Mice.

Retinoids regulate not only various cell functions including proliferation and differentiation but also glucose and lipid metabolism. After we observed a marked up-regulation of cellular retinol-binding protein-I (CRBP-I) in the liver of hepatitis B virus x antigen (HBx)-transgenic (HBx Tg) mice which are prone to hepatocellular carcinoma (HCC) and fatty liver, we aimed to evaluate retinoid pathway, including genes for the retinoid physiology, CRBP-I protein expression, and retinoid levels, in the liver of HBx Tg mice. We also assessed the effect of chronic metformin treatment on HCC development in the mice. Many genes involved in hepatic retinoid physiology, including CRBP-I, were altered and the tissue levels of retinol and all-trans retinoic acid (ATRA) were elevated in the liver of HBx Tg mice compared to those of wild type (WT) control mice. CRBP-I protein expression in liver, but not in white adipose tissue, of HBx Tg mice was significantly elevated compared to WT control mice while CRBP-I protein expressions in the liver and WAT of high-fat fed obese and db/db mice were comparable to WT control mice. Chronic treatment of HBx Tg mice with metformin did not affect the incidence of HCC, but slightly increased hepatic CRBP-I level. In conclusion, hepatic CRBP-I level was markedly up-regulated in HCC-prone HBx Tg mice and neither hepatic CRBP-I nor the development of HCC was suppressed by metformin treatment.

CD26/DPP4 levels in peripheral blood and T cells in patients with type 2 diabetes mellitus.

CONTEXT: Dipeptidyl peptidase 4 (CD26/DPP4) is expressed on blood T cells and also circulates in a soluble form (sCD26/DPP4). OBJECTIVE: We aimed to evaluate blood T cell and circulating CD26/DPP4 and its association with metabolic parameters in patients with type 2 diabetes mellitus (T2DM). DESIGNS: We measured CD26/DPP4 expression (percentage of CD26(+) cells using flow cytometry) on CD4(+) and CD8(+) T cells, serum CD26/DPP4 level and activity, and various metabolic parameters in T2DM patients not on DPP4 inhibitor therapy (n = 148). Nondiabetic subjects (n = 50) were included as a control group. RESULTS: Compared with the healthy controls, CD26/DPP4 expression on CD4(+) T cells and CD8(+) T cells was higher in T2DM patients. Serum CD26/DPP4 levels and enzymatic activities were also higher in patients with T2DM than in the control group only when metformin and/or thiazolidinedione-treated T2DM patients were excluded; metformin and/or thiazolidinedione-treated T2DM patients had lower values compared with other T2DM patients. Various parameters in T2DM patients were related to CD26/DPP4 expression on the T cells (hemoglobin A1c), serum sCD26/DPP4 (hemoglobin A1c and insulin resistance assessed by updated homeostasis model assessment), and serum CD26/DPP4 activity (insulin resistance assessed by updated homeostasis model assessment, γ-glutamyl transferase, and alanine aminotransferase) by multivariate analyses. After active glucose control for 12 weeks in drug-naive T2DM patients (n = 50), CD26/DPP4 expression on blood T cells was significantly decreased. CONCLUSIONS: Our results suggest that the CD26/DPP4 level on blood T cells was associated with glucose control status in patients with T2DM.

Promotion effect of acankoreoside J, a lupane-triterpene in Acanthopanax koreanum, on hair growth.

This study was conducted to evaluate the effect of Acanthopanax koreanum and acankoreoside J from A. koreanum on the promotion of hair growth. When immortalized rat vibrissa dermal papilla cells were treated with extract of A. koreanum leaves, the proliferation of dermal papilla cells significantly increased. In particular, acankoreoside J among several components, isolated from A. koreanum leaves, markedly promoted the proliferation of the dermal papilla cells. When rat vibrissa follicles were treated with an acankoreoside J, the hair-fiber lengths of the vibrissa follicles increased significantly. We further investigated ß-catenin pathway and cell cycle regulation with respect to the effect of acankoreoside J on the proliferation of the dermal papilla cells. Treatment with acankoreoside J results in an increase of nuclear ß-catenin level, and up-regulation of cyclin D1, cyclin E and CDK2, whereas, the expression of p27(kip1) was down-regulated in the dermal papilla cells. Taken together, these results suggest that acankoreoside J, a lupane-triterpene of A. koreanum, has the potential of promoting hair growth by promoting cell cycle progression of the dermal papilla cells, through the increase of nuclear ß-catenin, along with the up-regulation of cyclin D1, cyclin E and CDK2, and down-regulation of p27(kip1).

Promotion effect of norgalanthamine, a component of Crinum asiaticum, on hair growth.

This study was conducted to evaluate the effect of Crinum asiaticum, a plant native to Jeju Island, Korea, on the promotion of hair growth. When rat vibrissa follicles were treated with a 95% ethanol (EtOH) extract of C. asiaticum, the hair-fiber lengths of the vibrissa follicles increased significantly. In addition, after daily topical application of the EtOH extract of C. asiaticum onto the back of C57BL/6 mice, anagen progression of the hair shaft was induced. Moreover, the extract increased the proliferation of immortalized vibrissa dermal papilla cells. When the vibrissa follicles in the anagen phase were treated with the extract, immunohistochemical analysis revealed that the extract was found to increase the expression of proliferating cell nuclear antigen (PCNA) in the bulb region of the 7-day cultured follicles. In particular, norgalanthamine, a principal of the extract, showed activity that increased the hair-fiber lengths of vibrissa follicles and the proliferation of dermal papilla cells. These results suggest that norgalanthamine, a principal of C. asiaticum, has the potential to promote hair growth via the proliferation of dermal papilla.

Promotion effect of Schisandra nigra on the growth of hair.

This study was conducted to evaluate the effect of Schisandra nigra, a plant native to Jeju Island, South Korea, on the promotion of hair growth. When rat vibrissa follicles were treated with 85% ethanol (EtOH) extract of S. nigra, the hair-fiber lengths of the vibrissa follicles increased significantly. In addition, after topical application of the EtOH extract of S. nigra onto the back of C57BL/6 mice every other day, anagen progression of the hair shaft was induced. Moreover, the extract increased both the expression of proliferating cell nuclear antigen (PCNA) in the bulb matrix region and the proliferation of immortalized vibrissa dermal papilla cells. In order to determine the mechanism by which S. nigra promotes hair growth, we examined its relationship with the transforming growth factor-beta2 (TGF-beta2) signal pathway, which is known to be a regulator of catagen induction. When the vibrissa follicles in the anagen phase were treated with S. nigra extract for 7 days, the expression of TGF-beta2 in the bulb matrix region was found to be lower than that of the control follicles that were expected to be in the anagen-catagen transition phase. These results suggest that S. nigra extract has the potential to promote hair growth via down regulation of TGF-beta2 and the proliferation of dermal papilla.

Effect of KIOM-79 against mitochondrial damage induced by streptozotocin in pancreatic beta-cells.

The present study examined the effects of KIOM-79 on streptozotocin (STZ)-induced mitochondrial oxidative stress in rat pancreatic beta-cells (RINm5F). KIOM-79 is a mixture of plant extracts from parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix, and Euphorbiae radix. A marked increase in mitochondrial reactive oxygen species (ROS) was observed in STZ induced diabetic cells, which returned to control conditions after KIOM-79 treatment. Mitochondrial manganese superoxide dismutase (Mn SOD) activity and its protein expression were downregulated by STZ treatment but upregulated by KIOM-79 treatment. In addition, KIOM-79 treatment restored the loss of the mitochondrial membrane potential (Deltapsi) produced by STZ treatment. KIOM-79 induced an increase in Bcl-2 and a decrease in phospho Bcl-2 and Bax, which are related to permeability of the mitochondrial membrane. Further, KIOM-79 inhibited the translocation of cytochrome c from the mitochondria to the cytosol and elevated the ATP level, which was reduced by STZ treatment. These results suggest that KIOM-79 exhibits a protective effect through activation of antioxidant defense mechanisms and by attenuation of mitochondrial dysfunction in STZ-induced diabetic cells.

Protective effect of butin against hydrogen peroxide-induced apoptosis by scavenging reactive oxygen species and activating antioxidant enzymes.

The antioxidant property of butin was investigated for cytoprotective effect against H(2)O(2)-induced cell damage. This compound showed intracellular reactive oxygen species (ROS) scavenging, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, inhibition of lipid peroxidation, and DNA damage. This radical scavenging activity of butin protected cell damage exposed to H(2)O(2). Also, butin reduced the apoptotic cells induced by H(2)O(2), as demonstrated by the decreased DNA fragmentation, apoptotic body formation, and caspase 3 activity. In addition, butin restored the activity and protein expression of cellular antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT) in H(2)O(2)-treated cells. Taken together, these findings suggest that butin protected cells against H(2)O(2)-induced cell damage via antioxidant property.

The Effects of Crinum asiaticum on the Apoptosis Induction and the Reversal of Multidrug Resistance in HL-60/MX2.

The present study investigated the anti-proliferative and chemosensitizing effects of Crinum asiaticum var. japonicum against multi-drug resistant (MDR) cancer cells. The 80% methanol extract, chloroform (CHCI3) fraction and butanol (BuOH) fraction of C asiaticum inhibited the growth of mitoxantrone (MX) resistant HL-60 (HL-60/MX2) cells. When HL-60/MX2 cells were treated with the CHCI3 and BuOH fractions, DNA ladder and sub-G1 hypodiploid cells were observed. Furthermore, the fractions reduced Bcl-2 mRNA levels, whereas Bax mRNA levels were increased. These results suggest that the inhibitory effect of C. asiaticum on the growth of the HL-60/MX2 cells might arise from the induction of apoptosis. Treatment of HL-60/MX2 cells with the fractions markedly decreased the mRNA levels of the multi-drug resistance protein-1 and breast cancer resistance protein. The CHCI3 fraction and hexane fraction increased MX accumulation in HL-60/MX2 cells. These results imply that the CHCI3 fraction of C asiaticum plays a pivotal role as a chemosensitizer. We suggest that components of C asiaticum might have a therapeutic potential for the treatment of MDR leukemia.

Caffeic acid protects hydrogen peroxide induced cell damage in WI-38 human lung fibroblast cells.

Cytoprotective effect of caffeic acid (3,4-dihydroxy cinnamic acid) on human lung fibroblast (WI-38) cells against hydrogen peroxide induced damage was investigated. Caffeic acid was found to scavenge intracellular reactive oxygen species, and 1,1-diphenyl-2-picrylhydrazyl radical, and thus prevented lipid peroxidation. The caffeic acid protected cell damage of WI-38 cells exposed to hydrogen peroxide (H(2)O(2)), via the activation of extracellular signal regulated kinase protein. Caffeic acid increased the activity of catalase and its protein expression. Hence, from the present study, it is suggestive that caffeic acid protects WI-38 cells against H2O2 damage by enhancing the cellular antioxidant activity.

The cytotoxicity of Scytosiphon lomentaria against HL-60 promyelocytic leukemia cells.

This study examined the cytotoxicity of Scytosiphon lomentaria, using various cancer cell lines. The ethyl acetate (EtOAc) fraction of this alga showed the cytotoxicity to leukemia cells, including HL-60. When HL-60 cells were treated with its EtOAc fraction, several apoptotic characteristics, such as DNA fragmentation, chromatin condensation, and an increase of the population of sub-G1 hypodiploid cells, were observed. Moreover, the EtOAc fraction decreased c-Myc expression in a dose-dependent manner. In order to understand the mechanism of apoptosis induction by S. lomentaria, we examined the changes of Bcl-2 and Bax protein expression levels. The EtOAc fraction reduced Bcl-2, an antiapoptotic protein, but increased Bax, a proapoptotic protein, in a dose-dependent manner. When we examined the activation of caspase-3, an effector of apoptosis, the expression of the active form (19 kDa) of caspase-3 increased, and the increase of their activities was demonstrated by the cleavage of poly (ADP-ribose) polymerase, a substrate of caspase-3, to 85 kDa. The results suggest that the inhibitory effect of S. lomentaria on the growth of HL-60 appears to arise from the induction of apoptosis by way of the down-regulation of Bcl-2 and the activation of caspase.