PubMed Health⌕ Search

Biomedical subjects

S Shany

Publications and source records attributed to S Shany.

At least 19 recordsLinked to original sources
PubMed2005

Ultrasound-modulated light tomography assessment of osteoporosis.

We present a preliminary series of clinical experiments showing that ultrasound modulation of light in tissues allows tissue properties to be determined well inside the tissue. In this series of clinical experiments the optical scattering coefficient determined by the optical technique is compared with the bone density obtained by dual x-ray absorption. A correlation of 0.84 (p = 0.005) was found for a limited number of patients, showing the potential of this technique for the assessment of osteoporosis.

Feasibility Studies↗
PubMed2001

Regulation of TNF-alpha by 1alpha,25-dihydroxyvitamin D3 in human macrophages from CAPD patients.

BACKGROUND: We have previously reported that 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] accumulates in the dialysis fluid of uremic patients treated by continuous ambulatory peritoneal dialysis (CAPD). It has been reported that this metabolite regulates the production of cytokines by monocytes/macrophages. Since tumor necrosis factor-alpha (TNF-alpha) initiates an inflammatory cascade during peritonitis, the aim of the present study was to investigate the effect of 1alpha, 25(OH)2D3 on the production of TNF-alpha by human peritoneal macrophages (HPMs). METHODS: HPMs were obtained from patients on CAPD. Cells were incubated with various concentrations of 1alpha, 25(OH)2D3, 1alpha,24(S) dihydroxyvitamin D2 [1alpha,24(S)(OH)2D2] or 25-hydroxyvitamin D3 (25-OH-D3) for 16 hours. This was followed by lipopolysaccharide (LPS; 1 microg/mL) incubation for 2.5 to 6 hours. TNF-alpha protein production was determined by enzyme-linked immunosorbent assay. TNF-alpha mRNA was assayed by the reverse transcriptase-polymerase chain reaction procedure, using internal synthetic mRNA standards for quantitative results. RESULTS: Incubation of HPMs with 1alpha,25(OH)2D3 prior to stimulation with LPS dose dependently inhibited the expression of TNF-alpha on both mRNA and protein levels. Similar results were obtained with the less calcemic vitamin D2 analogue 1alpha,24(S)(OH)2D2. Incubation of HPMs with 25-OH-D3 also revealed a down-regulation of TNF-alpha expression. Since this down-regulatory effect was blocked by ketoconazole, it is likely that this effect was caused by the conversion of 25-OH-D3 into 1alpha,25(OH)2D3 by HPMs. CONCLUSIONS: 1alpha,25(OH)2D3 has a potent inhibitory effect on the production of TNF-alpha by LPS-activated HPMs. We hypothesize that 1alpha, 25(OH)2D3 may constitute a regulatory mechanism that, by controlling the intensity of the inflammatory response of the peritoneum, will moderate tissue damage during peritonitis.

Calcifediol↗
PubMed2000

Dietary treatment of hypercholesterolemia: do dietitians do it better? A randomized, controlled trial.

PURPOSE: Current guidelines of the National Cholesterol Education Program (NCEP) recommend initial dietary counseling by physicians for most patients with hypercholesterolemia; referral to a registered dietitian and lipid-lowering drugs are recommended only for patients who remain hypercholesterolemic. We evaluated the incremental value of detailed nutritional counseling by dietitians when added to general nutritional advice provided by physicians. SUBJECTS AND METHODS: Hypercholesterolemic patients detected during a cholesterol screening project were randomly assigned to receive dietary counseling by a physician only (70 patients) or by a physician and a registered dietitian (66 patients). Patients were observed for 1 year to determine compliance with NCEP guidelines. RESULTS: At 3 months, the mean (+/- SD) decrease in the serum low-density lipoprotein (LDL) cholesterol level was 7% +/- 11% in the physician group and 12% +/- 10% in the dietitian group (P <0.004). A decrease of 10% or more in the LDL cholesterol level was seen in 25 patients (36%) in the physician group and 43 patients (65%) in the dietitian group (P <0.001). Only 40 (29%) of the patients in both groups achieved their NCEP target goals at 3 months. The majority of these were low-risk patients with an LDL cholesterol target goal of 160 mg/dL. At 12 months, both groups lost about half of the beneficial effects on LDL cholesterol levels, and the difference between the two groups diminished. CONCLUSIONS: The short-term reduction in LDL cholesterol level achieved after counseling by dietitians is superior to that achieved by physicians. However, long-term compliance remains inadequate. For patients at high risk, consideration should be given to a more aggressive dietary approach and possibly earlier introduction of lipid-lowering medications.

Adult↗
PubMed2000

Cord leptin level and fetal macrosomia.

OBJECTIVE: To determine the relationships among serum leptin, insulin-like growth factor-I, and insulin levels in large for gestational age (LGA) infants. METHODS: Serum samples were collected from maternal veins and umbilical arteries of 52 consecutive, term, LGA neonates of nondiabetic mothers. Maternal and neonatal serum samples were analyzed for levels of leptin, insulin-like growth factor-I, and insulin by specific radioimmunoassays. Multiple regression analysis was used to determine independent risk factors for fetal macrosomia. RESULTS: The independent risk factor significantly associated with fetal macrosomia was umbilical cord leptin concentration (P <.01, beta = 0.59). There was a statistically significant correlation between umbilical cord leptin and insulin-like growth factor-I levels and birth weight (r = 0.51, P <.01; r = 0.37, P <.01; respectively). The correlation between umbilical cord insulin levels and birth weight was not statistically significant (r = 0.06, P =.63), nor was that between maternal body mass index and birth weight (r = 0.09, P =.50). CONCLUSION: Our data showed that umbilical cord leptin concentration was an independent risk factor for fetal macrosomia.

Adult↗
PubMed2000

Estrogen controls expression and bioresponse of 1,25-dihydroxyvitamin D receptors in the rat colon.

Estrogen receptors are extensively expressed in the gastrointestinal tract, however their physiological role is not clear yet. Estrogen and 1,25-dihydroxyvitamin D [1,25(OH)2D3] apparently share common activities in the intestine such as growth-suppressing effects on the colonic mucosa and positively influence intestinal calcium absorption. In view of our previous studies showing up-regulation of vitamin D receptors (VDR) in the duodenal mucosa and in osteoblasts, the present study was designed to address a possible interaction between estrogen and the vitamin D endocrine system in the colonic mucosa. Three groups of female rats were studied: sham operated ('Sham'), ovariectomized ('OVX'), and ovariectomized estrogen-treated ('OVX+E'). VDR gene expression was assessed by Northern blot analysis, VDR protein expression was assessed by ligand-binding assays, and Western-blotting. Endogenous 1,25(OH)2D3 bioactivity in colonic mucosal extracts was assessed by alkaline phosphatase activity and calbindin-9kD mRNA expression. Northern blots revealed marked increase in band intensity corresponding with the VDR mRNA product in 'Sham' or 'OVX+E' vs. 'OVX'. In ligand-binding experiments, 1,25(OH)2D3 was shown to bind specifically to a single class of receptors in extracts obtained from each of the groups (Kd--0.03 nM). The maximal VDR binding capacity of colonic mucosal extracts was 203 +/- 23 fmol/mg protein in 'Sham', 362 +/- 41 in 'OVX+E' and 102 +/- 15 in 'OVX' ('Sham' or 'OVX+E' vs. 'OVX', p < 0.001). Western-blot analysis also revealed higher VDR protein expression in the estrogen-exposed animals. Alkaline phosphatase activity and calbindin-9kD mRNA expression were significantly higher in colonic mucosal extracts from estrogen-exposed rats. Estrogen increases VDR gene transcript level, protein expression and endogenous 1,25(OH)2D3 bioactivity in colonic mucosa, which may suggest that some of the estrogen activities in the colonic mucosa, such as its growth-suppressing effect, could be mediated, at least in part, by an increase in colonic mucosa responsiveness to endogenous 1,25(OH)2D3.

Animals↗
PubMed2000

A protective role of dietary vitamin D3 in rat colon carcinogenesis.

The aim of the present work was to gain insight into a putative anticancer effect of dietary vitamin D3 (cholecalciferol) in a rat model of colon carcinogenesis. Male rats were assigned to three different dietary groups. The dietary regimens were based on a standard murine-defined diet (AIN-76A) or a stress diet containing 20% fat, reduced Ca2+ concentration, a high phosphorus-to-Ca2+ ratio, and either low or high vitamin D3 content. Colorectal cancer was induced by administration of the procarcinogen 1,2-dimethylhydrazine (DMH). Blood Ca2+, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and 25-hydroxyvitamin D3 [25(OH)D3] levels were measured in DMH-treated rats and in respective weight- and age-matched dietary control groups. Colonic epithelial proliferation was assessed by determining thymidine kinase (TK) activity, bromodeoxyuridine (BrdUrd) incorporation into crypt cell DNA, and the mean labeling index along the colonic crypt continuum. Maintenance of rats on the stress diet either unmodified or supplemented with vitamin D3 in the absence of carcinogen treatment provoked a time-dependent rise in colonic TK activity and hyperproliferation of colonic epithelium. DMH treatment of rats maintained on the standard diet caused a marked increase in the proliferative indexes of colonic epithelium and in expansion of the crypt proliferative compartment. TK activity and the crypt mitotic zone were significantly augmented in the animal group fed the stress diet. Supplementary vitamin D3 abrogated the stress diet-enhanced colonic responses to the carcinogenic insult. Colon tumor multiplicity was fourfold higher in animals fed the stress diet than in animals maintained on a standard diet. The marked rise in colonic tumor multiplicity and adenocarcinoma incidence in rats fed the stress diet was obliterated by supplemental dietary vitamin D3. Cumulatively, the present results indicate that dietary vitamin D3 impedes the neoplastic process in murine large intestine and strengthen the view that inappropriate changes in dietary components and micronutrients are contributory determinants of colorectal cancer.

1,2-Dimethylhydrazine↗
PubMed2000

Soluble polysaccharide and biomass of red microalga Porphyridium sp. alter intestinal morphology and reduce serum cholesterol in rats.

The present study investigated the effects of the red microalga Porphyridium sp. on gastrointestinal physiology and lipid metabolism in male Sprague-Dawley rats. Diets containing dietary fibre from pelleted red microalgal cells (biomass) or their sulfated polysaccharide, pectin or cellulose (control) were fed to rats for a period of 30 d. All three fibre-supplemented diets increased the length of both the small intestine and colon, with a significantly greater effect in rats fed the algal polysaccharide. The polysaccharide also increased mucosa and muscularis cross-sectional area of the jejunum, and caused hypertrophy in the muscularis layer. The algal biomass significantly lowered gastrointestinal transit time by 44% in comparison with the control rats. Serum and mucosal cholecystokinin levels were lower in rats on the pectin and polysaccharide diets, while cholecystokinin levels in rats fed algal biomass were not different from those in the control animals. In comparison with the control diet, all the experimental diets significantly lowered serum cholesterol levels (22-29%). Feeding of non-fermentable algal polysaccharide or biomass significantly increased faecal weight and bile acid excretion compared with pectin-fed or control rats. The algal polysaccharide and biomass were thus shown to be potent hypocholesterolaemic agents active at low concentrations in the diet. Both metabolic and morphological changes were observed following consumption of algae, suggesting several possible mechanisms by which the alga affects lipid metabolism. The results presented in the present study encourage the use of red microalga as a functional food.

Analysis of Variance↗
PubMed1999

In colorectal carcinoma patients, serum vitamin D levels vary according to stage of the carcinoma.

BACKGROUND: Epidemiologic studies have demonstrated an inverse correlation between dietary calcium and vitamin D intake and the incidence of colorectal carcinoma. Elevated serum levels of 25-hydroxyvitamin D3 (25-OH-D3) are associated with a major reduction in the incidence of this neoplasm. The reduction in tumor size and number induced by calcium supplements in an experimental carcinogenesis model was neutralized by vitamin D3 deficiency. To the authors' knowledge, vitamin D serum levels have never been determined previously in colorectal carcinoma patients. They compared serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 25-OH-D3, and parathyroid hormone (PTH) levels of colorectal carcinoma patients with those of healthy controls. METHODS: Serum 1,25(OH)2D3, 25-OH-D3, and PTH levels were determined in 84 colorectal carcinoma patients (10 with Stage I, 29 with Stage II, 25 with Stage III, and 20 with Stage IV) and 30 healthy controls, all of whom were normocalcemic and not taking calcium or vitamin D supplements. RESULTS: 25-OH-D3 serum levels were higher in cancer patients than controls, irrespective of stage. Serum 1,25(OH)2D3 decreased with advancing stage: 73 +/- 18, 48 +/- 16, 39 +/- 12, 34 +/- 13, and 75 +/- 20 pg/mL in Stages I, II, III, IV, and controls, respectively. There was a corresponding increase in serum PTH levels: 58.0 +/- 9.4, 73.7 +/- 14.4, 79.0 +/- 21.3, 100.4 +/- 30.9, and 51.2 +/- 3.9 pg/mL in Stages I, II, III, IV, and controls, respectively. Serum vitamin D metabolite levels did not correlate with gender, age, tumor localization, or histologic grade. CONCLUSIONS: An inverse correlation between serum levels of the active metabolite of vitamin D and colorectal carcinoma stage has been demonstrated for the first time, to the authors' knowledge, in colorectal carcinoma patients. Because 1,25(OH)2D3 has been shown to inhibit proliferation of colonic epithelial cells, decreased serum levels may facilitate the growth of colorectal carcinoma and influence its biologic behavior.

Aged↗
PubMed1999

Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa.

Menopause and estrogen deficiency are associated with apparent intestinal resistance to vitamin D, which can be reversed by estrogen replacement. The in vivo influence of estrogens on duodenal vitamin D receptor (VDR) was studied in three groups of rats: ovariectomized (OVX), sham-operated, and ovariectomized rats treated daily with estrogen (40 microg/kg BW) for 2 weeks (OVX + E). Estrogen administration to OVX rats resulted in a 2-fold increase in VDR messenger RNA transcripts. 1,25(OH)2D3 was shown to bind specifically to one class of receptors in duodenal mucosal extracts, with a dissociation constant of 0.03 nM. Binding was significantly increased in duodenal extracts from OVX + E rats, compared with OVX rats (735 +/- 81 vs. 295 +/- 26 fmol/mg protein; P < 0.001); a comparable, 1.5- to 2-fold increase in VDR protein expression was observed in Western blot analyzes of the duodenal mucosa. Markers of VDR activity were increased in estrogen-exposed rats: calbindin-9k messenger RNA transcript content was 1.4- to 1.6-fold higher, and alkaline phosphatase activity was 1.4- to 3-fold higher in sham-operated and OVX + E, respectively, compared with OVX. 25(OH)D, 1,25(OH)2D, or PTH levels were not altered by estrogen treatment. Cumulatively, these findings suggest that estrogen up-regulates VDR expression in the duodenal mucosa and concurrently increases the responsiveness to endogenous 1,25(OH)2D. Modulation of intestinal VDR activity by estrogen, and subsequent influence on intestinal calcium absorption, could be one of the major protective mechanisms of estrogen against osteoporosis.

Alkaline Phosphatase↗
PubMed1999

The protective effect of estrogen against chemically induced murine colon carcinogenesis is associated with decreased CpG island methylation and increased mRNA and protein expression of the colonic vitamin D receptor.

Epidemiological studies suggest that estrogen prevents neoplastic transformation in the intestinal mucosa. Estrogen was shown to increase the expression of vitamin D receptors (VDR) in a variety of tissues. 1,25-Dihydroxyvitamin D [1,25-(OH)2D] and several of its analogues are known as potent antineoplastic and prodifferentiative in many cell types, including colon-derived cells. The present study was designed to examine the effect of estradiol (E2) on dimethylhydrazine (DMH)-induced colon cancer in rats, and the possibility that E2 may exert its protective effect on the colon through modulation of the vitamin D-endocrine system. The in vivo effect of E2 on DMH-induced colorectal cancer was studied in four groups of ovariectomized female rats: (I) untreated control, (II) E2 treated, (III) DMH treated, and (IV) combined E2 and DMH treated. Significantly higher uterine weights and higher colonic estrogen receptor content confirmed the effectiveness of ovariectomy and E2 replacement. The number of malignant tumors in group IV was 2.3+/-1.1 (mean +/- SE) per rat, compared with 8.1+/-1.9 in group III (P < 0.001). Exposure to estrogen was associated with a marked increase in VDR mRNA content and VDR protein expression in the normal colonic mucosa. In tumor extracts VDR protein expression was considerably lower compared with normal mucosa. Estrogen treatment did not affect serum levels of 25(OH)D, 1,25(OH)2D, and PTH. Significant CpG island methylation in the VDR gene was observed in colonic tissue DNA harvested from rats treated with DMH, but not in colonic mucosae from rats treated with DMH + E2. The highest frequency of CpG methylation in the VDR gene was detected in DNA extracted from cancer tissue rims. In summary, the protective effect of estrogen against chemically induced colonic carcinogenesis is associated with reduced methylation of the VDR gene and with upregulation of both VDR gene transcription and protein expression. We suggest that estrogen may interfere with the process of CpG DNA methylation in the colonic mucosa to prevent silencing of the VDR gene. Increased VDR activity could be one of the mechanisms by which estrogen protects against neoplastic transformation in the colon.

Animals↗
PubMed1998

Increase of serum lipoprotein (a) levels during growth hormone therapy in normal short children.

UNLABELLED: We studied the effect of growth hormone (GH) therapy on serum lipoprotein levels and the atherogenic index in short children without GH deficiency. Fasting blood samples were collected from ten (eight males) normal, short, prepubertal children, aged 6-12 years, before, during a 1-year course of GH therapy (0.1 IU/Kg/day), and 3 months after the cessation of GH administration. An increase in serum lipoprotein(a) [Lp(a)] levels of (mean% +/- SEM) 43 +/- 14, 58 +/- 18, 61 +/- 17 above the baseline levels was noted at 3 months (P < 0.05), 6 months (P < 0.01), and 1-year (P < 0.01) respectively after the beginning of GH administration. (ANOVA, P < 0.01). An inverse relationship between baseline serum Lp(a) concentrations and the percentage increment in Lp(a) after 9 months of GH therapy (r = -0.65, P < 0.05) was observed. GH therapy over a period of 1 year had no effect on plasma cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein cholesterol [HDL-C] concentrations and the atherogenic index. Three months after the cessation of GH therapy, serum Lp(a) levels were not significantly different from the pre-treatment values. CONCLUSIONS: Serum Lp(a) concentrations remained above pretreatment values during a 1-year period of GH treatment in short children without GH deficiency and declined shortly after cessation of therapy. Since GH therapy for short children without GH deficiency usually continues for several years, we suggest that serum Lp(a) levels should be determined and followed regularly in such children under prolonged GH therapy.

Analysis of Variance↗
PubMed1998

Gorging and plasma HDL-cholesterol--the Ramadan model.

OBJECTIVES: To evaluate the effect of a single evening meal (gorging) on plasma lipids and lipoproteins in normal individuals observing the Ramadan Fast. During the Ramadan month, Muslims refrain from food and liquids during the day and eat a large meal after sundown. DESIGN: Sequential measurement of plasma lipids and lipoproteins in Muslims observing the Ramadan Fast and non-fasting individuals. SETTING: The study was conducted in the Bedouin town of Rahat, in the northern Negev area of Israel. SUBJECTS: Twenty-two healthy subjects who fasted during Ramadan and 16 non-fasting laboratory workers, were studied before Ramadan, at week 1, 2 and 4 of the Ramadan month, and again four weeks after the end of Ramadan. RESULTS: Plasma high-density lipoprotein cholesterol (HDL) rose significantly (P < 0.001) at the week 4 measurement, returning to basal levels 4 weeks after the end of Ramadan. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL), very-low density lipoprotein cholesterol (VLDL), and lipoprotein (a) [Lp(a)] did not change significantly. CONCLUSIONS: Plasma HDL increased by 23% after four weeks of gorging. The dietary change did not affect the composition of other lipoproteins, such as LDL, VLDL or Lp(a), other plasma biochemical parameters, or BMI. Prolonged gorging, well tolerated by all individuals, is a very effective non-pharmacological method to increase plasma HDL-cholesterol.

Adult↗
PubMed1997

Whey deionization method of infant formula affects plasma lipids.

BACKGROUND: Casein has proved to be hypercholesterolemic. According to results of previous studies, the casein-to-whey ratio in infant formula influences plasma lipid profile. This study explored whether different methods of whey deionization also affect levels of plasma lipids. METHODS: Two types of a whey-predominant (whey 60%:casein 40%) formula which differed only in the methods used for whey deionization (ultrafiltration or electrodialysis), were fed to healthy newborn infants for 60 days, using a prospective, double-blind, randomized design. Formulas were otherwise identical in composition. RESULTS: Groups were similar in gestational age, gender, birth weight, and growth parameters. Evaluation of fasting plasma levels after 60 days revealed significantly higher values of total cholesterol (p < 0.001) and low-density lipoprotein cholesterol (p < 0.001) in infants fed ultrafiltrated whey compared with the same values in infants fed electrodialyzed whey. Plasma levels in the two groups of very low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides revealed no statistically significant differences. CONCLUSIONS: Plasma lipid profile in infancy is influenced by dietary protein, not only by the casein-to-whey ratio, but also by the method of whey deionization.

Cholesterol↗
PubMed1996

Short-term growth hormone therapy increases serum lipoprotein (a) levels in normal short children without growth hormone deficiency.

We investigated the short-term effect of GH (0.1 IU/kg/day) on serum lipoprotein (a) [Lp(a)] in 8 normal short children aged 6-12 years. GH increased serum Lp(a) concentrations in all the children studied. An increase to 107 +/- 5, 161.6 +/- 14.7 and 152.5 +/- 18.5% (mean +/- SE) of baseline levels was observed after 2 (p = NS), 6 (p < 0.01) and 12 weeks (p < 0.05), respectively. Our results suggest that GH therapy may pose a significant influence on Lp(a) serum levels in non-GH-deficient short children.

Body Height↗
PubMed1996

Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients.

To evaluate the effect of dietary fiber supplements on levothyroxine (T4) bioavailability in hypothyroid patients, dietary fiber-containing supplementation was withheld from patients requiring disproportionately high doses of T4, in whom a dietary history revealed ingestion of a dietary fiber supplement. The dose of T4 was maintained at a constant level. Serum thyrotropin (TSH) was assessed before and after removal of the dietary fiber supplements. T4 requirements, reflected by either decreased serum TSH or by decreased T4 dose, was observed in conjunction with decreased dietary fiber intake compared with T4 requirement during increased dietary fiber intake. In vitro experiments carried out to determine the mechanism of interaction between dietary fiber and T4 revealed dose dependent, nonspecific adsorption of levothyroxine by wheat bran. These results indicate a decrease in T4 bioavailability by dietary fiber through a mechanism involving nonspecific adsorption of T4 to dietary fibers. Increased intake of dietary fiber may account for the need for larger than expected doses of T4 in some hypothyroid patients.

Adsorption↗
PubMed1995

Coordinate regulation of nitric oxide and 1,25-dihydroxyvitamin D production in the avian myelomonocytic cell line HD-11.

Cells of the monocyte/macrophage lineage are capable of both nitric oxide (NO) and 1,25-dihydroxyvitamin D [1, 25-(OH)2D] production through expression of inducible nitric oxide synthase (iNOS) and a putative 25-hydroxyvitamin D (25-OHD)-1-hydroxylase, respectively. We have recently reported that 1,25-(OH)2D synthesis in the chick myelomonocytic cell line HD-11 is restricted by inhibition of iNOS. In the current set of experiments, measuring nitrite, a stable water-soluble secreted metabolite of NO as an index of iNOS activity and 1,25-(OH)2D3 in lipid extracts of cells incubated with 200 nM 25-OHD3 as an index of 1-hydroxylase activity, we demonstrate that NO and 1,25-(OH)2D production by HD-11 cells are temporally related, induced by the same kinds of activating agents, and coordinately regulated. NO and 1,25-(OH)2D3 production by HD-11 cells was stimulated severalfold by the macrophage stimulators interferon-gamma and lipopolysaccharide and by an autologous, nonlipid, heat-labile factor with an apparent molecular mass approximately 10,000 daltons. As expected NO synthesis was 1) dependent upon the presence of L-arginine in the extracellular medium, 2) subject to significant stimulation by Nw-hydroxy-L-arginine, an L-arginine-derived intermediate in NO biosynthesis, and by sodium nitroprusside, a non-L-arginine-dependent source of intracellular NO, and 3) inhibited by Nw-nitro-L-arginine methyl ester, a competitive inhibitor of iNOS. At high NO production rates, induced either by high-dose lipopolysaccharide or by sodium nitroprusside exposure, there was an apparent downturn in 1,25-(OH)2D3 synthesis, suggesting functional dependence of the 1-hydroxylase on NO but ultimate inhibition of 1,25-(OH)2D3 synthetic capacity at high levels of intracellular NO production. On the basis of these results we postulate that the macrophage 25-OHD-1-hydroxylation reaction may be dependent on iNOS-generated NO as a soluble source of electrons and regulated in an autocrine mode by a macrophage-derived NO stimulatory factor and NO itself.

Amino Acid Oxidoreductases↗