FBG and TC/HDL ratios in type 2 diabetes mellitus.

BACKGROUND: Presence of dyslipidemia, i.e. raised Total Cholesterol (TC) and decreased High Density Lipoproteins (HDL) is an established phenomenon in type 2 diabetes mellitus. Its relationship to the fasting blood sugar (FBG) level in both diabetics and non-diabetics has yet to be established. The present study aims to show such a relationship. METHODS: 150 subjects were selected and divided into two groups, one of 50 controls (non-diabetics), the other of 100 patients with type 2 diabetes mellitus. Their FBG levels were determined by enzyme oxidase method, and their TC and HDL levels were determined using a standard kit method. RESULTS: FBG and TC:HDL ratios were increased in the patient group (p = < 0.001). Comparison of FBG and TC:HDL ratios revealed a highly significant rise (p = < 0.001) in the patient group. FBG with TC:HDL ratios between both groups showed a positive correlation (r = 0.554). CONCLUSION: The results of the present study suggest an association between FBG and TC:HDL ratios, which may be a contributory factor to the increased prevalence of coronary artery disease in patients with type 2 diabetes mellitus.

Penetration enhancing effect of tetrahydrogeraniol on the percutaneous absorption of 5-fluorouracil from gels in excised rat skin.

Poly(acrylic acid) gels containing 5-fluorouracil (5-FU) and tetrahydrogeraniol (THG) were prepared and the effects of THG on 5-FU permeation across the excised rat skin were studied by in vitro methods. Experiments on in vitro permeation of 5-FU across the skin with vertical diffusion cells showed that addition of THG to the gels markedly enhanced the 5-FU permeability. Increasing the THG concentration in the gels to 8% proportionally increased the permeability of 5-FU. More than 12 h was required to reach a steady-state level of 5-FU after administration of 5-FU-THG gel topically. The permeability parameters such as flux, permeability coefficient and enhancement ratio were determined. The results indicated a maximum flux of 252.91+/-9.61 microgram/cm2 per h, and the enhancement ratio of 31.22+/-1.18 when the THG concentration was 8%. Synergistic effects of propylene glycol (PG) with THG were also investigated and a maximum flux of 256.81+/-9.15 microgram/cm2 per h, was obtained when the PG concentration was 5% and THG was 8%. The corresponding enhancement ratio was 31.71+/-1.13. These results suggest not only that THG would be very useful for increasing the skin permeability of 5-FU, but also that THG being a natural product might be useful for developing transdermal therapeutic systems for the delivery of practically unabsorbable drugs.

Synthesis and effect of two new penetration enhancers on the transdermal delivery of 5-fluorouracil through excised rat skin.

The tetrahydrogeraniol (THG) derivative, ethyl-(3,7-dimethyl octyl thio) acetate (EDOTA) was prepared by reacting tetrahydrogeranyl bromide (obtained by reaction of 40% hydrobromic acid and concentrated sulfuric acid) with ethyl 2-mercaptoacetate, while 3,7-dimethyl octyl propionate (DOP) was synthesized by a common esterification reaction by reacting THG with propionic acid in the presence of cyclohexane and concentrated sulfuric acid. The penetration-enhancing effect of the new enhancers were compared with THG and Azone in vitro using excised rat skin in modified Franz-type diffusion cells. 5-Fluorouracil (5-FU), a hydrophilic drug with poor skin permeability was used as a model permeant. Skin samples were pretreated with pure liquid enhancers for 12 h. 5-FU flux through the control and enhancer-treated skin increased linearly with its concentration in the receptor compartment. EDOTA and DOP interacted with the skin rapidly (< 2h), and the duration of action is at least 24 h. Significant differences were found in the flux values of 5-FU; EDOTA and DOP enhanced the permeability of the drug about 6-fold and 11-fold respectively. Increased partition coefficient and diffusion coefficient values were obtained by these enhancers. The results suggested that the amount of EDOTA and DOP in the skin, especially in the stratum corneum, may be related to their penetration-enhancing effect.

Effect of aspirin on induction of apoptosis in HT-29 human colon adenocarcinoma cells.

Aspirin (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal tumorigenesis. Apoptosis is a critical determinant of tissue mass homeostasis and may play a role in carcinogenesis. We studied the effect of ASA on the survival of a human colon cancer cell line using more sensitive methods than we had applied previously. ASA induced apoptosis in HT-29 colon adenocarcinoma cells at concentrations > or =1 mM as established by: (a) morphological changes consistent with apoptosis in cells examined by fluorescence microscopy and semi-thin cell sections, and (b) DNA strand breaks: 45% of the cells were TdT-mediated dUTP nick end labeling (TUNEL) positive at 3 mM at 72 hr, and 70% were positive by the comet assay. Electron microscopy also confirmed the induction of apoptosis by ASA. ASA-induced apoptosis was not associated with: (a) a ladder pattern on genomic DNA electrophoresis, or (b) a subdiploid peak on flow cytometry. Apoptotic bodies were virtually absent on standard morphological assessments and only a few were detected on semi-thin sections. For the above reasons, this apoptosis induced by ASA is "atypical," and the unusual features of ASA-induced apoptosis, besides their taxonomic value, may offer clues to the mechanisms that control the process of apoptosis or perhaps the cancer chemopreventive properties of this compound. These findings demonstrate that ASA induces apoptosis in human colon cancer cells, bolstering the hypothesis that apoptosis may be a mechanism by which NSAIDs inhibit colon carcinogenesis. These findings should be examined in animal and/or clinical research studies in vivo.

Curcumin, a natural plant phenolic food additive, inhibits cell proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-independent pathway.

Curcumin, the active ingredient of the rhizome of the plant turmeric (Curcuma longa Linn), a commonly used spice, prevents cancer in animal tumor models. Its mechanism of action is unknown; curcumin may act by inhibiting arachidonic acid metabolism. To explore the mechanism of curcumin's chemopreventive effect, we studied its role in proliferation and apoptosis in the HT-29 and HCT-15 human colon cancer cell lines. Curcumin dose-dependently reduced the proliferation rate of both cell lines, causing a 96% decrease by 48 hours. No apoptosis was detected. The antiproliferative effect was preceded by accumulation of the cells in the G2/M phase of cell cycle. The effect of curcumin was similar in both cell lines, which, however, differ in their ability to produce prostaglandins. We conclude that curcumin inhibits colon cancer cell proliferation in vitro mainly by accumulating cells in the G2/M phase and that this effect is independent of its ability to inhibit prostaglandin synthesis. The role of curcumin's antiproliferative effect in human colon cancer remains to be established.

Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway.

Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of and mortality from colon cancer. We observed that NSAIDs inhibit the proliferation rate, alter the cell cycle distribution, and induce apoptosis in colon cancer cell lines. We evaluated whether the inhibition by NSAIDs of prostaglandin (PG) synthesis is required for their effects on colon cancer cells by studying two human colon cancer cell lines: HCT-15 and HT-29. HCT-15, which lacks cyclooxygenase transcripts, does not produce PGs even when exogenously stimulated, whereas HT-29 produces PGE2, PGF2 alpha, and PGI2. HCT-15 and HT-29 cells, when treated for up to 72 hr with 200 microM sulindac sulfide (an active metabolite of sulindac) or 900 microM piroxicam, showed changes in proliferation, cell cycle phase distribution, and apoptosis. Treatment with PGE2, PGF2 alpha, and PGI2, following a variety of protocols, and at concentrations between 10(-6) and 10(-11) M, failed to reverse the effects of NSAIDs on these three parameters of cell growth. We concluded that NSAIDs inhibit the proliferation rate of the two colon cancer cell lines independent of their ability to inhibit PG synthesis. Thus, alternative mechanisms for their activity on tumor cell growth must be entertained. These observations may be relevant to the mechanism of colon tumor inhibition by NSAIDs.

The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells.

Eicosanoids have been implicated in colon carcinogenesis, but very little is known on the potential role of leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) in this process; such compounds are produced by colonocytes and tumor infiltrating leukocytes. We studied the effect of LTB4, LTB4 methyl ester, LTB5, 12(R)-HETE, 12(S)-HETE and 15(S)-HETE (10(-10), 10(-8), 10(-6) M) on the proliferation rate, the cell cycle distribution, and the rate of apoptosis in HT-29 and HCT-15 human colon carcinoma cells. Our data show that LTB4, a lipoxygenase product, increased the proliferation rate of both cell lines in a time- and concentration-dependent manner. In HT-29 cells the concentration-response curve was bell-shaped (maximal effect at 10(-8) M). The proliferative effects of LTB4 in HT-29 cells were inhibited by SC-41930, a competitive antagonist of LTB4, suggesting the existence of an LTB4 receptor in epithelial cells. The methyl ester of LTB4 stimulated the proliferation of these cells, but LTB5, an isomer of LTB4 derived from eicosapentaenoic acid, did not. Of the HETEs, only 12(R)-HETE, a P-450 product, stimulated the proliferation of both cell lines; the other HETEs, all lipoxygenase products, failed to affect the proliferation of these cells. None of these eicosanoids had any effect on cell cycle distribution or apoptosis in either cell line. Taken together with our previous data showing that PGs stimulate colon cancer cell proliferation (Qiao et al. (1995) Biochim. Biophys. Acta 1258, 215-223), these findings indicate that arachidonic acid products synthesized via at least three different pathways (cyclooxygenase, lipoxygenase, P-450) may not be able to modulate the growth of colon cancer, and suggest a potential role in human colon carcinogenesis for LTB4 and 12(R)-HETE.

Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo.

Eicosanoids have been implicated in colon carcinogenesis, but their role remains unclear. The levels of PGE2 are elevated in colon cancer tissues and in blood draining colon tumors. The effect of eicosanoids on the proliferation of colonic cells is unknown. We studied the effect of several prostaglandins (PGs) and leukotriene (LT)B4 on the proliferation rate of the human colon adenocarcinoma cell lines SW1116 and HT-29 and of 16,16-dimethyl PGE2 (dmPGE2) on the colon of BALB/c mice. PGs E2, F2 alpha, I2, the methyl ester of PGE2, dmPGE2, and LTB4 (10(-10), 10(-8), 10(-6) M), administered for up to 72 h, stimulated cell proliferation in SW1116 cells and all but PGF2 alpha and PGI2 stimulated proliferation in HT-29 cells. The proliferative effect was time- and concentration-dependent. However, in SW1116 cells the response to PGs was 'bell-shaped', being maximal at 10(-8) M, with the 10(-10) and 10(-6) M concentrations being less effective. In HT-29 cells, the addition of methyl groups to the PGE2 molecule increased the proliferative effect. None of these eicosanoids affected the distribution of these cells in the cell cycle or their rate of programmed cell death (apoptosis). dmPGE2 stimulated 3.6-fold the proliferation of colonocytes in normal BALB/c mice. This was determined by bivariate flow cytometric analysis of the expression of proliferating cell nuclear antigen (PCNA) in virtually pure populations of mouse colonocytes. dmPGE2 did not alter the cell cycle distribution of these cells. We conclude that several PGs as well as LTB4 stimulate the proliferation of human colon carcinoma cells in vitro, while dmPGE2 has a similar effect on mouse colonocytes in vivo. These findings raise the possibility that eicosanoids may contribute to colonic carcinogenesis by stimulating the proliferation rate of tumor cells in the colon.