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PubMed1994

TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify.

Previous studies in our laboratory demonstrated messenger RNA for bone morphogenetic protein-2a in human calcified plaque, suggesting that arterial calcification is a regulated process, similar to osteogenesis. To further test this hypothesis, we have isolated and cloned a subpopulation of cells from bovine aortic media that show osteoblastic potential. These novel cells are primarily distinguished from smooth muscle cells by expression of a surface marker preliminarily identified as a modified form of the ganglioside sialyl-lactosylceramide (GM3). Osteoblastic potential was indicated by high levels of alkaline phosphatase and collagen I, expression of osteopontin and osteonectin (SPARC), and production of bone-specific osteocalcin and hydroxyapatite. Cultures of these cells were stimulated to form increased numbers of calcium-mineral-producing nodules by the oxysterol 25-hydroxycholesterol as well as by transforming growth factor-beta 1, both known to be present in atherosclerotic lesions. The stimulation of calcifying vascular cells in the artery wall by these two factors suggests a possible mechanism for the colocalization of calcification with atherosclerosis in vivo.

Alkaline Phosphatase↗
PubMed2002

Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol.

Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce cholesterol efflux, yet different mutations in ABCA1 result in different phenotypic effects in heterozygotes. For example, truncation mutations result in significantly lower HDL-C and apoliprotein A-I (apoA-I) levels in heterozygotes compared with nontruncation mutations, suggesting that truncation mutations may negatively affect the wild-type allele. To specifically test this hypothesis, we examined ABCA1 protein expression in response to 9-cis-retinoic acid (9-cis-RA) and 22-R-hydroxycholesterol (22-R-OH-Chol) in a collection of human fibroblasts representing eight different mutations and observed that truncation mutations blunted the response to oxysterol stimulation and dominantly suppressed induction of the remaining full-length allele to 5-10% of wild-type levels. mRNA levels between truncation and nontruncation mutations were comparable, suggesting that ABCA1 expression was suppressed at the protein level. Dominant negative activity of truncated ABCA1 was recapitulated in an in vitro model using transfected Cos-7 cells. Our results suggest that the severe reduction of HDL-C in patients with truncation mutations may be at least partly explained by dominant negative suppression of expression and activity of the remaining full-length ABCA1 allele. These data suggest that ABCA1 requires a physical association with itself or other molecules for normal function and has important pharmacogenetic implications for individuals with truncation mutations.

ATP Binding Cassette Transporter 1↗
PubMed1982

Metabolism of 25-hydroxycholesterol by rat luteal mitochondria and dispersed cells.

The metabolism of 25-hydroxycholesterol (25-OH-cholesterol) to progestins by mitochondria and dispersed cells prepared from ovaries of PMSG-hCG-primed rats was studied. Mitochondria converted [3H]25-OH-cholesterol into [3H]pregnenolone and [3H]progesterone. Unlabeled 25-OH-cholesterol also stimulated mitochondrial steroidogenesis in a dose-dependent, saturable fashion. A direct relationship between rates of steroid synthesis in the presence of 25-OH-cholesterol and mitochondrial cytochrome P-450 levels was found. Although steroid production and cytochrome P-450 content per milligram protein were higher in mitochrondia prepared from ovaries removed on day 8 post hCG than on either day 1 or day 14, steroid production per nanomole cytochrome P-450 was similar. Treatment of rats with hCG 1 h before killing significantly increased mitrochondrial steroid synthesis from endogenous substrate but had no effect on metabolism of 25-OH-cholesterol. Dispersed cells increased progestin production by 6-fold when incubated with 25-OH-cholesterol. The effects of 25-OH-cholesterol were dose dependent and saturable. While both LH and (Bu)2cAMP stimulated progestin synthesis from endogenous substrate, secretion of progestins with these agents reached levels only 60% of those observed in the presence of 25-OH-cholesterol. Neither LH nor (Bu)2cAMP altered the metabolism of the dydroxysterol by the cells nor did cycloheximide, which substantially inhibited progestin secretion in the absence of the hydroxysterol. However, animoglutethimide did block the stimulation of steroidogenesis by 25-OH-cholesterol. We conclude that 25-OH-cholesterol is an effective steroidogenic substrate for rat luteal tissue. With its use, information regarding the maximal capacity of luteal tissue to produce progestins in vitro can be obtained.

Aminoglutethimide↗
PubMed2005

Cytotoxic effect of 7beta-hydroxycholesterol on human NCI-H460 lung cancer cells.

The cytotoxic activity of 7beta-hydroxycholesterol (7beta-OHC) was evaluated on human NCI-H460 lung cancer cells. 7beta-OHC decreased clonogenic survival of NCI-H460 in a dose dependent pattern. 7beta-OHC induced apoptosis in NCI-H460, with the characteristic features like increase in sub-G(1) hypodiploid (apoptotic) cells, and apoptotic body formation, as evidenced by flow cytometry and fluorescence microscope, respectively. Apoptosis was also associated with loss of mitochondrial transmembrane potential, and the activation of caspases 9 and 3. 7beta-OHC resulted in generation of reactive oxygen species (ROS) during apoptosis. On the whole, the results indicated that 7beta-OHC inhibited the proliferation of NCI-H460 cells through apoptosis via caspase activation.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

Cholesterol and 24S-hydroxycholesterol trafficking in Alzheimer's disease.

Cholesterol and the cholesterol oxide 24S-hydroxycholesterol (24S-HC) are highly enriched in the human CNS. Clinical, genetic, neurochemical and epidemiological evidence continue to support dysfunctional cholesterol metabolism as an important contributing factor driving the development and/or progression of Alzheimer's disease (AD) neuropathology. Cholesterol overabundance in the brain plasma membrane lipid- raft domains, appears to be fundamental to the generation of the more neurotoxic forms of amyloid-beta (Abeta) peptide from beta-amyloid holoprotein precursor. 24S-HC may have a pivotal role in promoting altered inflammatory signaling, apoptotic genetic responses and AD-type change. In clinical studies, cholesterol-lowering statins, nonsteroidal anti-inflammatory drugs, cholesterol absorption/transport inhibitors and related modulators of cholesterol trafficking have demonstrated some pharmacological benefit for the treatment of AD, but overall their efficacy at slowing the cognitive decline and the progression of AD remains controversial and open to question.

Alzheimer Disease↗
PubMed1985

Inhibition of sterol and DNA syntheses in phytohemagglutinin-stimulated human lymphocytes by 7 alpha-hydroxycholesterol.

Sterol and DNA syntheses were induced in human peripheral blood lymphocytes stimulated with phytohemagglutinin (PHA). DNA synthesis in the PHA-stimulated lymphocytes was suppressed by 7 alpha-hydroxycholesterol (7 alpha-HC). The maximum suppression of DNA synthesis was observed when 7 alpha-HC was added in the culture within 6 hr of PHA stimulation to the lymphocytes. However, as the concentration of fetal bovine serum (FBS) in the culture medium was increased, the inhibitory effect of 7 alpha-HC on the syntheses of sterol and DNA were decreased. Furthermore, low and high density lipoproteins completely reversed the inhibition of DNA synthesis by 7 alpha-HC. These results suggest that cholesterol is an essential requirement of lymphocyte blastogenesis regardless of whether the source of the sterol is exogenous or endogenous.

Cholesterol↗
PubMed1986

Steroidogenic effects of lipoproteins and 25-hydroxycholesterol on luteal and ovarian cells: a comparison of two pseudopregnant rat models.

Steroidogenesis was compared between luteal cells from immature pseudopregnant (PSP) rats induced by either 5 IU pregnant mare serum gonadotropin (PMSG) alone or 50 IU PMSG combined with 25 IU human chorionic gonadotropin (hCG). It was also determined whether differences in steroidogenesis existed when the entire ovary (ovarian cells) or just luteal cells from Day 4 PSP rats were exposed in vitro to lipoproteins or 25-hydroxycholesterol (25-OH chol). In the absence of luteinizing hormone (LH), basal steroid accumulation, especially progesterone (P4) was around fourfold greater in luteal cells from rats treated with PMSG alone than from rats receiving PMSG-hCG. However, serum P4 and LH were about fivefold greater in the latter group. It is therefore likely that net cellular cholesterol uptake per luteal cell is lower in the PMSG-hCG treated rats, but this is offset by a much greater mass and number of corpora lutea. Lipoproteins (HDL and LDL) and 25-OH chol stimulated in vitro luteal steroidogenesis from rats treated with PMSG alone or PMSG-hCG, and their responses were virtually identical. Therefore, luteal steroidogenesis in the rat always depends on exogenous cholesterol even though treatment in the preovulatory period with PMS or PMSG-hCG and serum LH and follicle-stimulating hormone (FSH) levels on Day 4 PSP are very different. When ovarian cells from PMSG-hCG treated rats were incubated with LH plus HDL or 25-OHP, the production of 20 alpha-DHP was considerably greater than luteal cell production which may be due to a contribution from nonluteal cells. Indeed, about 30% of the cells in the PMSG-hCG group represent nonluteal components as estimated by weight and deoxyribonucleic acid content.

20-alpha-Dihydroprogesterone↗
PubMed1999

Suppression of rat liver tumorigenesis by 25-hydroxycholesterol and all-trans retinoic acid: differentiation therapy for hepatocellular carcinoma.

To determine whether differentiation therapy is useful in treating patients with hepatoma, we assayed the effects of 25-hydroxycholesterol (25-OH) and/or all-trans retinoic acid (ATRA) on rat AH136B ascites hepatoma cells. Flow cytometric DNA analysis showed that treatment of cells with 25-OH alone induced entry into the sub-G1 phase in a dose-dependent manner. While ATRA alone was ineffective, it enhanced the activity of 25-OH. Condensed and fragmented nuclei occurred mainly in cells treated with 25-OH (4 microg/ml). When cells treated with 25-OH (4 microg/ml), or 25-OH (4 microg/ml) + ATRA (1 microM) were transplanted into Donryu rats, we found that tumor development was completely inhibited; in contrast, rats administered the methanol-treated AH136B cells developed tumors. These findings suggest that AH136B cells in the sub-G1 phase can not recover tumorigenicity, and that the administration of a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, such as 25-OH, and ATRA may be effective in treating patients with hepatoma.

Animals↗
PubMed1976

Identification of 17-methyl-18-norandrosta-5,13(17-dien-3beta-ol, the C19 fragment formed by adrenal side chain cleavage of a 20-aryl analog of (20S)-20-hydroxycholesterol.

Incubation of (20R)-20-phenyl-5-pregnene-3beta,20-diol, an aromatic analog of (23S)-20-hydroxycholesterol, with an adrenal mitochondrial preparation leads to the formation of four compounds: pregnenolone, phenol, a C8 ketone, acetophenone, and a nonpolar C19 compound. This latter compound has now been identified by reverse isotope dilution analysis and by gas chromatography/mass spectrometry as 17-methyl-18-norandrosta-5,13(17)-dien-3beta-ol. From these results it is evident that enzymatic fission of the C-17,20 bond of this synthetic derivative occurs. On the other hand, when (20S)-20-hydroxy[21-14C]cholesterol was used as substrate, the analogous cleavage did not take place. Thus, substitution of an aromatic group on C-20 facilitates side chain cleavage between that carbon atom and the nucleus whereas neither of the naturally occuring precursors, cholesterol or its 20-hydroxylated counterpart, are metabolized to a C8 fragment.

Adrenal Glands↗
PubMedDate not supplied

Antitumor activity and induction of apoptosis by water-soluble derivatives of 7 beta-hydroxycholesterol in human colon carcinoma cell lines.

At present, cancer therapy of solid tumors, such as lung and colorectal cancer, is unsatisfactory. Recently, oxygenated sterols have shown selective cytotoxicity against tumor cells. In this study, the cytotoxicity of 7 beta-hydroxycholesterol (7 beta HC) and two water-soluble derivatives of 7 beta HC, i.e. 7 beta HC-bis-hemisuccinate [disodium salt] (7 beta HC-HS) and 7 beta HC-bis-hemisuccinate-diethanolaminoate (7 beta HC-EA), was determined in DLD-1, KM20L2, HCT-116, HT-29 and SW620 colon carcinoma cell lines using a cell count assay. IC50 values of the two water-soluble derivatives were, on the whole, comparable to 7 beta HC lying in the range of 3-10 microM. In addition, the water-soluble derivatives were able to induce apoptosis in the examined DLD-1 and KM20L2 colon carcinoma cell lines in contrast to the parent compound 7 beta HC, as shown by DNA fragmentation, by the cleavage of DNA repair enzyme poly(ADP) ribose polymerase (PARP), and by the proteolytic cleavage of caspase-3 (CPP32). Due to the improved water-solubility of 7 beta HC-HS and 7 beta HC-EA and their promising antitumor activity in vitro, animal studies in suitable tumor models are warranted.

Antineoplastic Agents↗
PubMedDate not supplied

[level of 7alpha-hydroxycholesterol in blood plasma as an indicator of cholesterol catabolism in hyperlipidemia and with hypolipidemic therapy].

The effect of micronized fenofibrate (Lipanthyl 200 M, Laboratoire Fournier, France, in dose 200 mg per day) on the serum level of 7 alpha-hydroxycholesterol (7 alpha-(OH)C) was studied in 10 men (aged 31-60 years) with hyperlipidemia (total C > 6.5 mmol/l). The levels of 7 alpha-(OH)C as well as that of total C, LDL C, VLDL C and HDL C and triglycerides (Tg) were measured before Lipanthyl 200 M treatment (point 0) and after 1, 2 and 3 months of the drug administration. The content of 7 alpha-(OH)C was determined by the reversed phase HPLC after the enzymatic conversion of serum 7 alpha-(OH)C to 7 alpha-(OH)-4-cholesten-3-one in cholesterol oxidase reaction. 7 beta-(OH)C was used as the internal recovery standard. Lipanthyl treatment resulted in considerable reduction of total C, VLDL C and LDL C levels and 7 alpha-(OH)C content. After the second and third months of therapy serum levels of 7 alpha-(OH)C were significantly reduced from 1.3 +/- 0.1 to 0.8 +/- 0.2 and 0.7 +/- 0.1 mumol/l; (P < 0.02). The decrease of 7 alpha-(OH)C content was associated with the decrease in Tg and VLDL C levels. Thus, our data suggest that the level of 7 alpha-(OH)C of in human serum may be used as an indicator of intensity of cholesterol oxidation into bile acids.

Adult↗
PubMed2001

Influence of 7beta-hydroxycholesterol on glutathione status and nitric oxide production in macrophages: in vitro studies.

Incubation of murine peritoneal macrophages with 7beta-hydroxycholesterol (7beta-OH) for 24 hr led to dose-dependent reduction in cellular glutathione content as well as nitrite levels in the medium. Treatment with an inorganic form of selenium, sodium selenite which is a potent antioxidant, elevated the cellular glutathione levels and decreased nitrite levels. Our results suggest that 7beta-OH may exert its pro-atherogenic effect by inhibiting glutathione synthesis and nitric oxide production by macrophages present in the arterial wall and thus, impair the cellular antioxidant defense system.

Animals↗
PubMedDate not supplied

Effects of combinations of 7beta-hydroxycholesterol and anticancer drugs or ionizing radiation on the proliferation of cultured tumor cells.

Oxysterols compose a large class of natural substances endowed in a number of cases with marked antiproliferative and cytotoxic activities. The consequences of treatments combining 7beta-hydroxycholesterol (7beta-OHC) or XG-142 (a galactose-linked hydrosoluble derivative of 7beta-OHC) with drugs used in cancer chemotherapy or gamma radiation has been evaluated upon a variety of tumor cell lines: Hep-G2, U937, K562 cells, its adriamycin-resistant variant K562 Adr+ and RDM4. Proliferation was assessed by the Uptiblue assay and the [3H]Thymidine incorporation test. Results indicated that 7beta-OHC increased the sensitivity of tumor cells to adriamycin, VP-16, 5-FU and bleomycin to various degrees. 7beta-OHC was found to reinforce the susceptibility of K562 adriamycin-resistant cells to this drug. In RDM4 cells, an enhanced radiosensitivity by 7beta-OHC was also obtained, whereas XG-142 was less efficient in provoking such an effect.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Effect of cholesterol and 7-beta hydroxycholesterol on glutathione status and nitric oxide production in murine peritoneal macrophages.

Present study was conducted to observe the effect of cholesterol and oxidized cholesterol (7beta-hydroxycholesterol,7beta-OH) on the nitric oxide (NO) production and the redox ratio by lipopolysaccharide-stimulated macrophages. Dose-dependent decrease in NO levels was seen with both cholesterol and 7beta-OH at different incubation intervals (6,12,18,24 hr) and concentrations (2.5,5,7.5microg/ml). On comparison, a significant decrease in the NO was observed at 24 hr interval in 7beta-OH exposed cells with all respective concentrations of cholesterol. Incubation with 7beta-OH also resulted in significant increase in levels of oxidized glutathione (GSSG) and decrease in reduced glutathione (GSH), while cholesterol showed no effect on GSSG levels. Moreover, GSH levels were lowered only at highest concentration (7.5microg/ml), and at longer incubation intervals (18,24 hr) with cholesterol exposure. This altered the redox status in both cholesterol/7beta-OH treated macrophages. Increased redox ratio and decreased NO levels indicated increased oxidative stress and decreased vasodilation by 7beta-OH compared to cholesterol.

Animals↗
PubMedDate not supplied

7beta-hydroxycholesterol blocked at C-3-OH inhibits growth of rat glioblastoma in vivo: comparison between 7beta-hydroxycholesteryl-3beta (ester)-oleate and 7beta-hydroxycholesteryl-3-beta-O (ether)-oleyl.

BACKGROUND: It was previously demonstrated that the 7beta-hydroxycholesteryl-3beta(ester)-oleate (7beta-ester) possesses antitumor properties against the experimental rat C6 glioblastoma. The effect of an analog of this molecule, 7beta-hydroxycholesterol-3beta-O(ether)-oleyl (7beta-ether), was investigated. MATERIALS AND METHODS: Liposomes containing no oxysterol (control), 7beta-ether or 7beta-ester were injected into tumors induced by C6 cells in rat brain cortex. At defined times, the animals were sacrificed, the tumors stained with cresyl violet and their volumes measured by densitometry. Oxysterol clearance was assessed by quantification from lipid extraction of treated tumors. RESULTS: The clearance of the new compound was slower than that of the 7beta-ester form. The 7beta-ether and 7beta-ester forms displayed similar antitumor activities against 3-day-old tumors. In contrast, the 7beta-ether form was more active on well-developed glioblastoma: 75 nmol inhibited tumor growth by 70% compared to controls, while the 7beta-ester had no effect under such conditions. The 7beta-ether form had a cytostatic rather than a cytotoxic effect. In addition, the composition of the liposomes did not affect the antitumor activity. CONCLUSION: Only blockade of the C-3-OH group is required for the antitumor effect of this kind of oxysterol. It is suggested that the absence of "etherases" enhances the antitumor activity of this type of compound. Thus, an original therapeutic approach for glioblastoma treatment may be envisaged with such compounds.

Animals↗
PubMedDate not supplied

Antitumor activity of oxysterols. Effect of two water-soluble monophosphoric acid diesters of 7 beta-hydroxycholesterol on mastocytoma P815 in vivo.

Oxysterols, a family of naturally occurring products, have been shown to possess several biological activities. In particular, they are more toxic towards tumor cells than towards normal cells. In addition, they markedly modify immune cell responses. To carry out in vivo studies, we have synthesized phosphodiesters of 7 beta-hydroxycholesterol (JB69 and XA29). These water-soluble prodrugs have a similar toxicity to their parent compound under in vitro conditions. When administered intraperitoneally to mice bearing the P815 mastocytoma, they induced significant increases in life span. The results depend on the administration protocol. Under appropriate conditions, 20 to 40% of treated mice recover completely. This, together with their immunological effect, suggests that these oxysterols should be considered to be agents for immunochemotherapeutic investigations. By their ability to inhibit HMG CoA reductase, they may prevent the biosynthesis of prenyl groups whose coupling to oncogenes is responsible for the biological activity expression of the latter. Several indications are compatible with an effect on the cell membrane. Our recent studies have shown Protein Kinase C to be a target of oxysterols. On the basis of results obtained by our group and by others, we believe that oxysterols may form a new class of antitumor agents.

Animals↗
PubMedDate not supplied

Extracellular calcium and luteinizing hormone effects on 22-hydroxycholesterol used for testosterone production in mouse Leydig cells.

The effect of extracellular calcium on testosterone synthesis in response to luteinizing hormone (LH) or 22-hydroxycholesterol (22-OH-C) by isolated adult mouse Leydig cells was studied. Leydig cells were isolated by linear density gradient centrifugation. The cells were incubated in minimum essential medium with or without calcium (1.36 mmol/L) in an atmosphere of 95% air and 5% carbon dioxide at 37 degrees C for 3 hours with or without LH (10 ng/sample), or with or without 22-OH-C (10 mumol/L). Testosterone production in response to LH was significantly lower (P less than 0.02) in the absence of extracellular calcium and in the presence of verapamil (10 mumol/L), a calcium channel blocking agent. Extracellular calcium did not significantly (P greater than 0.05) affect testosterone production in cells incubated with 22-OH-C in either the presence or absence of LH. The results suggest that steps in steroidogenesis from 22-OH-C to testosterone are unaffected by extracellular calcium content and that extracellular calcium affects the use of intracellular cholesterol by the cholesterol side-chain cleavage enzyme.

Animals↗
PubMed1989

Cholic acid synthesis from 26-hydroxycholesterol and 3-hydroxy-5-cholestenoic acid in the rabbit.

Intravenous administration of 26-hydroxycholesterol to the rabbit with a bile fistula yielded cholic acid in proportions (84 and 86%) not significantly different from that derived from cholesterol. By contrast, the naturally occurring C27 bile acid 3 beta-hydroxy-5-cholestenoic acid yielded not more than 8% cholic acid. Thus initial 26-hydroxylation of cholesterol followed by 7-alpha-hydroxylation can provide sufficient amounts of cholic acid to be considered a quantitatively significant pathway for bile acid synthesis, and in addition it is the only pathway that can be the source of the circulating levels of C24 and C27 monohydroxy bile acids.

Animals↗