The toxicological aspects as well as the immunosuppressive mechanism of 15-deoxyspergualin (DSP) were studied using BALB/c mice. Five-week-old animals were subcutaneously given phosphate-buffered saline (PBS; Group 1) or DSP at 0.5 (Group 2) to 5.0 mg (Group 4) per kg body weight daily for 1 to 3 months. They were sacrificed to obtain blood for hematology and liver function studies. The spleen, taken simultaneously, was histologically examined, the T cell surface markers of splenocytes were flow cytometrically measured, and their interleukin 2 (IL-2) production induced in vitro by Enterotoxin A (Ent A) was assayed using CTLL cells. Additionally, the in vitro effect of DSP on IL-2 generation and plaque forming cell (PFC) production was studied using splenocytes of non-treated mice. During the 3 months of treatment, the body weight slowly increased in Groups 1 and 2, while the body weight of the 2.5-mg DSP mouse group (Group 3) was significantly lower on days 28 and 56 of treatment compared with Group 1 of the same age (P less than 0.05). The administration of DSP at 5.0 mg/kg (Group 4) caused marked reduction in body weight of the animals. They were sacrificed on day 28 because of their worsening general condition. WBC and RBC counts decreased in Group 3 on days 57 and 93, and the platelet number increased on day 57. A liver function test was not affected by DSP treatment except for an elevated SGOT in Group 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Enhancement of methoxamine-induced contractile responses of rat ventricular muscle in streptozotocin-induced diabetes is associated with alpha1A adrenoceptor upregulation.

AIM: To clarify the time-related changes in cardiac function and the mechanism underlying the cardiac dysfunction present in diabetes mellitus, we studied mechanical responses induced by alpha(1)- and beta-adrenoceptors, the Ca(2+)-entry promoter Bay K 8644- and ryanodine (an agent known to inhibit Ca(2+) release from the sarcoplasmic reticulum) in papillary muscles from streptozotocin (STZ)-induced diabetic and age-matched control rats. METHODS: Male Wistar rats received a single injection of STZ (60 mg kg(-1)) via the tail vein to induce diabetes. For the mechanical studies, papillary muscle preparations were suspended in an organ bath and isometric contractions were measured in 1-, 4-, and 10-week STZ-induced diabetic and age-matched control rats. RESULTS: In 1-week diabetic rats, the contractions induced by isoproterenol, methoxamine and Bay K 8644 were unchanged (vs. age-matched controls). In 4-week diabetic rats, (a) the isoproterenol- and Bay K 8644-induced contractions were impaired, (b) sensitivity to ryanodine was reduced, whereas (c) the methoxamine-induced contraction was unchanged. In 10-week diabetic rats, the isoproterenol- and Bay K 8644-induced contractile responses were impaired and the sensitivity to ryanodine was reduced, but in sharp contrast the methoxamine-induced contraction was enhanced. Both the mRNA level for the alpha(1A) adrenoceptor (but not the alpha(1B) or alpha(1D) mRNAs) and alpha(1A) adrenoceptor protein were increased in 10-week diabetic rats (vs. age-matched controls). CONCLUSION: These results suggest that impairments of beta-adrenergic and Ca(2+)-handling mechanisms occur early in the development of cardiomyopathy in STZ-induced diabetic rats, and that this is followed by augmentation of alpha(1A) adrenoceptor-mediated inotropy due to alpha(1A) adrenoceptor upregulation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMedDate not supplied

Impairment of endothelium-dependent relaxation of superior mesenteric artery in genetically diabetic WBN/Kob rats.

The endothelium-dependent relaxation of superior mesenteric arteries of Wistar and genetically diabetic WBN/Kob rats was compared. Endothelium-dependent relaxation induced by acetylcholine (ACh) and A23187 was depressed in WBN/Kob rats. Relaxation induced by sodium nitroprusside, an endothelium-independent agent, in strips from WBN/Kob rats was similar to that in strips from Wistar rats. Indomethacin (5 x 10(-6) M) enhanced the relaxation responses to ACh in strips from both WBN/Kob and Wistar rats; however, endothelium-dependent relaxation induced by ACh remained attenuated in WBN/Kob rats. These results show that endothelium-dependent relaxation is impaired not only in thoracic aorta but also in superior mesenteric arteries in genetically diabetic rats.

Animals↗

PubMedDate not supplied

Ultrastructure of glomerular basement membrane in active heymann nephritis rats revealed by tissue-negative staining method.

Recently, we have developed a tissue-negative staining method, and successfully visualized fine meshwork structure of the glomerular basement membrane (GBM). To clarify the mechanism of proteinuria in active Heymann nephritis, we performed tissue-negative staining and investigated the ultrastructural alterations of the GBM. Active Heymann nephritis, the animal model of human membranous nephropathy, was induced in Lewis rats by the injection of proximal tubular brush border antigen, i.e. Fx1A. Urinary protein excretion was measured and histological studies were performed over 15 weeks following the Fx1A injection. Proteinuria developed at 10 weeks after injection (38.2 +/- 7.4 mg/day) and progressively increased (160.2 +/- 20.6 mg/day at 15 weeks). Capillary fine deposits of IgG and C3 were seen by immunofluorescence, and subepithelial electron dense deposits (EDD) by transmission electron microscopy (TEM). Using the tissue-negative staining method, regular meshwork structure consisted of fine fibrils and pores (2.5 +/- 0.7 nm in short dimension) was observed in the GBM of control rats. At 10 and 15 weeks after injection, the GBM, directly facing the endothelial side of EDD, contained enlarged pores and nephrotic tunnels. Mean values of the short dimension of enlarged pores were 2.9 +/- 0.5 nm at 10 weeks and 3.1 +/- 0.4 nm at 15 weeks, which were significantly larger than that of control rats (p < 0.01). The rest area of the GBM, including newly produced GBM covering the epithelial side of EDD, had no significant difference in size of the pores from control GBM and no tunnels. Although there was no significant difference in the size of enlarged pores between 10 and 15 weeks, the percentage area of GBM with impaired size barrier increased at 15 weeks (51.4 +/- 8.1%) compared with 10 weeks (24.0 +/- 8.3%) and related to severity of proteinuria. The density of the tunnels also increased at 15 weeks. In conclusion, immune deposits may affect the GBM biosynthesis and induce the defect of size barrier of the GBM, which is responsible for proteinuria in active Heymann nephritis.

Animals↗

PubMedDate not supplied

Cycloprodigiosin hydrochloride, a H+/Cl- symporter, induces apoptosis in human colon cancer cell lines in vitro.

Recently, we reported that cycloprodigiosin hydrochloride (cPrG.HCl), a novel H+/Cl- symporter, induces acidification of the cytosol and leads to apoptosis on rat and human liver cancer cells. In the present study, the effects of cPrG.HCl, a H+/Cl- symporter, were examined in colon cancer cell lines in vitro. In the MTT assay, cPrG.HCl inhibited the growth of two colon cancer cell lines (WiDr and SW480) in a dose- and time-dependent manner. The cPrG.HCl treatment of both types of cells induced apoptosis as confirmed by the appearance of a sub-G1 population and intranucleosomal DNA fragmentation. In addition, cPrG.HCl lowered pHi (below pH 6.8) respectively. Therefore, these results suggest that cPrG.HCl may be useful for the treatment of colon cancer cells.

Antiporters↗

PubMedDate not supplied

Relationship between radical intensity and biological activity of cacao husk extracts.

The relationship between radical intensity and biological activity of cacao husk extracts was investigated. Electron spin resonance (ESR) spectroscopy demonstrated that the radical intensity of hexane, acetone, methanol and 70% methanol extracts increased with water-solubility. Several fractions of these husk extracts, separated by different column chromatographies, significantly inhibited the cytopathic effect of human immunodeficiency virus (HIV) infection in parallel with their radical intensity. However, their cytotoxic activity against human leukemic and carcinoma cell lines is not always correlated with their radical intensity. Water-soluble and lipophilic compounds might induce cytotoxic activity by different mechanisms.

Anti-HIV Agents↗

PubMedDate not supplied

Cytotoxicity and differentiation-inducing activity of phenothiazine and benzo[a]phenothiazine derivatives.

The effects of 13 phenothiazines, and 8 benzo[a]phenothiazines on the growth and differentiation of various human cultured cell lines were investigated. Perphenazine dimaleate and chlorpromazine hydrochloride were more cytotoxic against human normal fibroblasts and glioma cells than 19 other related compounds. The differentiation of three human myelogenous leukemic cell lines (ML-1, U-937, THP-1) into maturing monocytes/macrophages was potently induced by 12H- benzo[a]phenothiazine and 5-oxo-5H-benzo[a]phenothiazine. The differentiation--inducing activity of phenothiazine, and other benzo[a]phenothiazine derivatives was much less, and that of phenothiazine derivatives without the benzyl group was undetectable. Simultaneous treatment with 12H- benzo[a]phenothiazine and tumor necrosis factor produced additive, but not synergistic differentiation--induction of these cells.

Cell Differentiation↗

PubMedDate not supplied

Metabolic fate of alclometasone dipropionate in rats, rabbits, and mice. Metabolic products and pathway following subcutaneous administration.

The metabolic fate of alclometasone dipropionate (ADP or S-3460) has been studied in rats, rabbits, and mice, with consideration of their interspecies differences. Several reference compounds related to ADP were synthesized for the determination and identification of the metabolites. After sc administration of 14C-labeled ADP, the metabolites in plasma, bile, and urine were separated and analyzed using TLC-ARG (autoradiography) and HPLC in comparison with the reference compounds. The metabolites identified, fully or tentatively, by MS and 1H-NMR totaled 11. The metabolic transformations were: hydrolysis of the side chain esters, dehydrochlorination leading to the formation of delta 6-double bond, 6 beta-hydroxylation, 6 beta, 7 beta-epoxides from 6 beta-hydroxylated metabolites, side chain oxidation to 21-oic and 20-oic acids in the 6 beta-hydroxylated metabolites, and conjugation to glucuronides and sulfates. The metabolic pathway, postulated on the basis of the identified and quantitated metabolites, was a rapid hydrolysis of 21-ester of ADP to the corresponding alcohol, M-1, after systemic uptake. This M-1 was a main metabolite in plasma of animals studied, and due to its relatively longer life time in the media, it seemed to allow a variety of metabolism to occur, giving the oxidative and conjugative metabolites mentioned above.

Adenosine Diphosphate↗

PubMedDate not supplied

Interaction of chlorpromazine with DNA.

The mechanism of the potential anticancer agent chlorpromazine hydrochloride (CPZ) with DNA was investigated by the techniques of high-performance liquid chromatography (HPLC), viscosity and Raman spectroscopy. It has been suggested from HPLC work that DNA nucleotides (except nucleosides) from either a CPZ-DNA system or a CPZ-nucleotide system. Furthermore, the shear stress of the viscosity of the CPZ-DNA system and the CPZ-nucleotide systems ware shown to be apparently the higher increasing than that of DNA and nucleotide alone. These systems had non-Newtonian properties for the formation of the CPZ-DNA and the CPZ-nucleotide systems under experimental conditions. The Raman spectra showed a dramatic difference at 982 cm-1 due to the symmetric P-O stretching vibration of the PO4(2-) group between dGMP and the CPZ-dGMP system.

Antineoplastic Agents↗

PubMedDate not supplied

Raman spectra of methyl substituted benz[c]acridines and their complex with DNA.

Raman spectra of methyl substituted benz[c]acridines (BAc) in the solid state were recorded. Their assignments were proposed for the frequencies of Raman spectra observed. The purpose of this work was to elucidate the mechanisms of interaction between BAc and DNA in vitro. For the DNA-BAc complex, the data show that BAc interact not only with the bases pair, but also with the sugar-phosphate site of DNA within the interbinding process.

Acridines↗

PubMedDate not supplied

[Doughnut sign in brain scanning (author's transl)].

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Adolescent↗

PubMedDate not supplied

Thrombosis of prosthetic heart valve: surgical treatment.

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Adult↗