Anti-tumor promoting effects of multiflorane-type triterpenoids and cytotoxic activity of karounidiol against human cancer cell lines.

Forty-nine multiflorane-type triterpenoids consisting of 11 compounds isolated from the seeds of Trichosanthes kirilowii (Cucurbitaceae) and 38 of their derivatives have been evaluated for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in Raji cells as a primary screening test for anti-tumor promoters. All of the compounds tested showed an inhibitory effect against EBV-EA activation, and among which 43 were revealed to possess remarkable activity with potencies either comparable to or stronger than that of glycyrrhetic acid, a known natural anti-tumor promoter. Their structure-activity relationship is discussed. Evaluation of the cytotoxic activity of karounidiol (27) against human cancer cell lines exhibited cytotoxicity especially against a human renal cancer.

Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro.

Osteoblasts and adipocytes are derived from common bone marrow stromal cells that play crucial roles in the generation of osteoclasts. Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) induces adipogenic differentiation of stromal cells; however, whether this would affect osteoblast/osteoclast differentiation is unknown. Thus, we examined the effects of the thiazolidinedione (TZD) class of antidiabetic agents that activate PPARgamma on osteoblast/osteoclast differentiation using mouse whole bone marrow cell culture. As reported, all TZDs we tested (troglitazone, pioglitazone, and BRL 49653) markedly increased the number of Oil Red O-positive adipocytes and the expression of adipsin and PPARgamma 2. 1alpha,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] did not affect adipogenic differentiation induced by TZDs. TZDs did not affect alkaline phosphatase activity, an early marker of osteoblastic differentiation, despite their marked adipogenic effects. TZDs decreased the number of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells induced by 1,25-(OH)2D3 or PTH. Troglitazone dose dependently inhibited basal and 1,25-(OH)2D3- and PTH-induced bone resorption as assessed by pit formation assay. Interleukin-11 blocked the induction by troglitazone of adipogenesis, but had no effect on the inhibition of osteoclast-like cell formation. These results indicate that TZDs are potent inhibitors of bone resorption in vitro. Inhibitory effects of TZDs on osteoclastic bone resorption was not osteotropic factor specific and did not appear to be related to their adipogenic effects. Thus, TZDs may suppress bone resorption in diabetic patients and prevent bone loss.

Short-term treatment with troglitazone decreases bone turnover in patients with type 2 diabetes mellitus.

Poorly controlled type 2 or non-insulin dependent diabetes mellitus (NIDDM) patients exhibit high bone turnover, which decelerate with treatment according to the degree of improvement in glycemic control. In adults, higher bone turnover results in rapid bone loss. Therefore, deceleration of bone turnover is beneficial for bone. Troglitazone (Tro), a new anti-diabetic drug, is a thiazolidinedione (TZD) which promotes adipocyte differentiation by activating peroxisome proliferator activated receptor gamma (PPARgamma). Because, in the bone marrow, adipocytes and osteoblasts originate in common mesenchymal stem cells that are also essential for osteoclastogenesis, TZDs may directly affect bone metabolism. Thus, we examined the effects of Tro on metabolic bone markers in type 2 DM patients. Tro (400 mg/day) was administered to 33 type 2 DM patients for four weeks. The day before and four weeks after starting Tro, serum and urine samples were collected after overnight fasting. Metabolic bone markers and glycemic indices were assessed. As bone resorption markers, urinary free and total deoxypyridinoline as well as urinary collagen type I C-terminal telopeptide were measured; as bone formation markers, serum bone type and total alkaline phosphatase (BALP and ALP) levels along with osteocalcin (OC) were used. No significant changes in fasting plasma glucose or HbA1c levels were observed in our short-term treatment with Tro. All the bone resorption markers, BALP and ALP were significantly decreased. OC was not significantly changed. The discrepant changes of OC from all the other metabolic bone markers suggest limitation of the use of OC as a reliable bone formation marker in diabetics. Our results that Tro decreased metabolic bone markers before significantly improving glucose metabolism suggest that it has direct effects on bone and decreased bone turnover. TZDs may spare bone mass in NIDDM subjects through its dual effects on glucose and bone metabolism.

[Disorders of gonadal function in hypothalamic-pituitary diseases].

Hypothalmic-pituitary-gonadal hormones are regulated by number of factors including GnRH, LH and FSH, and gonadal hormones. They are regulated also by pituitary prolactin, activin and inhibin. Hypogonadism is divided into primary and secondary hypogonadism. Secondary hypogonadism is caused by various lesions involving either the hypothalmus or the pituitary. In this paper, etiology, diagnosis and treatment of the secondary hypogonadism are described. The most frequent causes of hypothamic hypogonadism are hypothalamic tumors, such as germinoma. As the pituitary hypogonadism, pituitary tumors, and Sheehan's syndrome are most common disorders. Diagnosis of the secondary hypogonadism is made based on the diagnostic criteria established by The Research Group of the Japanese Ministry of Health and Welfare. The criteria includes signs and symptoms in addition to laboratory examinations such as measurement of serum gonadotropin, sex steroid and LH-RH test. First choice of the treatment of hyothalmic hypogondism is continuous pulsatile injection of synthetic LH-RH. In the pituitary hypogonadism, hCG, hMG, estrogen and testosterone or the combination of these are applied depending upon the age and other factors of the patients.

Enantioseparation of beta-blockers labelled with a chiral fluorescent reagent, R (-)-DBD-PyNCS, by reversed-phase liquid chromatography.

A fluorescent chiral tagging reagent, 4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfony l)-2,1, 3-benzoxadiazole [R(-)-DBD-PyNCS], has been used for the liquid chromatographic resolution of racemic pairs of beta-blockers. The reagents reacts with beta-blockers at 65 degrees C for 90 min in aqueous acetonitrile containing 0.05% triethylamine to produce the corresponding pair of diastereomers. No racemization occurs during the tagging reaction under these conditions. From results of the time-course study of oxprenolol the reactivities of the enantiomers of beta-blockers with R(-)-DBD-PyNCS are comparable. The optimum excitation and emission wavelengths of the resulting derivatives were ca. 460 and 550 nm, respectively. The derivatives of beta-blockers were efficiently resolved by a reversed-phase column with water-acetonitrile containing 0.1% trifluoroacetic acid as the eluent. The resolution (Rs) values of the diastereomers derived from 10 beta-blockers were in the range of 1.54-4.80. The Rs value for timolol was 0.643. The detection limits (signal-to-noise ratio of 2) were one or two orders of magnitude lower with beta-blockers having the iso-propylamino structure (15-300 fmol) than with those having the tert-butylamino structure (1.25-8.00 pmol). The proposed procedure was applied to the determination of R(+)- and S(-)-propranolol in rat plasma and saliva after oral administration of R(+)-propranolol hydrochloride or S(-)-propranolol hydrochloride.

Grain Growth Rates of MgSiO3 Perovskite and Periclase Under Lower Mantle Conditions

The grain growth rates of MgSiO3 perovskite and periclase in aggregates have been determined at 25 gigapascals and 1573 to 2173 kelvin. The average grain size (G) was fitted to the rate equation, and the grain growth rates of perovskite and periclase were G10.6 = 1 x 10(-57.4) t exp(-320.8/RT) and G10.8 = 1 x 10(-62.3) t exp(-247.0/RT), respectively, where t is the time, R is the gas constant, and T is the absolute temperature. These growth rates provide insight into the mechanism for grain growth in minerals relevant to the Earth's lower mantle that will ultimately help define the rheology of the lower mantle.

[Endocrine disorders associated with impaired glucose tolerance].

Endocrine disorders associated with diabetes mellitus are described. When blood glucose control deteriorates, observed endocrine abnormalities are as follows. 1) Blood GH levels increase. This elevation is small but enough to disturb insulin secretion and glucose metabolism. Plama insulin-like growth factor-1 levels decrease in spite of their strong relation with diabetic retinopathy. 2) Blood thyroid hormones show the similarity with low T3 syndrome. 3) Hyporeninemic hypoaldosteronism occurs especially with patients who have hypertension or moderate diabetic complications. 4) Plasma pancreatic glucagon levels are elevated. Amino acids induce hypersecretion but hypoglycemia fails to response normally. Glucose administration shows impaired inhibition or paradoxical hypersecretion. 5) Other plasma levels of pancreatic hormones such as gastrin, secretin, motilin and somatostatin are usually elevated.

Newtonian dislocation creep in quartzites: implications for the rheology of the lower crust.

Mechanical and microstructural evidence indicates that a natural and a synthetic quartzite deformed by Newtonian dislocation (Harper-Dorn) creep at temperatures higher than 1073 K and stresses lower than 300 megapascals. The observation of this creep in these materials suggests that the lower crust may flow like a Newtonian viscous fluid by a dislocation mechanism at stresses much smaller than those previously postulated.

Absorption effects on total-internal-reflection fluorescence spectroscopy.

A theoretical consideration is made for transverse-electric polarization vectors of a transmitted field in an optically absorbing sample to derive a fluorescence intensity formula as a function of the absorption index of the sample as well as incident and observation angles in total-internal-reflection fluorescence spectroscopy. These equations are experimentally confirmed. It is shown that the angular spectrum of fluorescence intensity is the Laplace transformation of the effective penetration depth, even for the absorbing sample. High resolution of the depth profile is expected for an absorbing sample compared with a nonabsorbing one.