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PubMed2004

Development of a validated liquid chromatography method for the simultaneous determination of eight fat-soluble vitamins in biological fluids after solid-phase extraction.

In the present study, a simple and rapid reversed-phase HPLC procedure has been developed for the simultaneous determination of eight fat-soluble vitamins (retinol, menadione, menaquinone, delta-tocopherol, cholecalciferol, alpha-tocopherol, alpha-tocopherol acetate and phylloquinone) in biological fluids: blood serum and urine. The analytical column, Phenomenex Luna C18 (150 mm x 4.6 mm) 3 microm, was operating at ambient temperature. Mobile phase consisted of a mixture of CH3OH-CH3CN delivered using a linear gradient, starting with a composition of 50-50% v/v and ending at 30-70% at a flow rate of 1.3 ml/min. Xanthophyll was used as internal standard (2 ng/microl). Detection and identification was performed using a photodiode array detector. Eluent monitoring was achieved at 280 nm for vitamins and 450 nm for the internal standard. However, quantitation was performed at maximum wavelength for each vitamin. Detection limits were found in the range of 1.4-6.6 ng per 20-microl injected samples, while linearity held up to 25 ng/microl. The statistical evaluation of the method was examined performing intra-day (n = 6) and inter-day calibration (n = 7) and was found to be satisfactory, with high accuracy and precision results. The biological fluids were treated using solid-phase extraction cartridges, to remove all endogenous interferences from sample matrix. The solid-phase extraction protocol was optimized in terms of retention and elution. High extraction recoveries from biological matrices: blood serum and urine, (average recovery ranging between 95 and 97.6% for blood serum and between 94.2 and 95.8% for urine) were achieved for the eight fat-soluble vitamins, using Cyclohexyl J.T. Baker SPE cartridges with methanol as eluent, requiring small volumes, 100 microl of blood serum and 100 microl of urine.

Chromatography, High Pressure Liquid↗
PubMed2004

Calcitriol derivatives with two different side chains at C-20. 24-hydroxy derivatives as metabolic products and molecular probes for VDR exploration.

We previously synthesized calcitriol derivatives with two identical side chains emanating at C-20, also known as gemini. In view of the evidence identifying C-24 hydroxylation as the first step in the in the metabolic cascade of calcitriol and gemini, stereochemical differentiation between the possible epimeric 20R- and 20S side-chain hydroxylated gemini became of interest. We now report the stereoselective synthesis of these compounds. Of these, 1,24(R),25-trihydroxy-21-(3-hydroxy-3-methyl-butyl)-20(R)-19-nor-cholecalciferol was identified as the main metabolic product of 19-nor-gemini. In general, higher doses of the 24-hydroxylated gemini compounds were required to increase blood calcium levels in mice and to suppress INF-gamma release in MLR.

Animals↗
PubMed2004

Role for tumor necrosis factor-alpha in UVB-induced conversion of 7-dehydrocholesterol to 1alpha,25-dihydroxyvitamin D3 in cultured keratinocytes.

UVB irradiation of cultured human keratinocytes induces both the conversion of 7-dehydrocholesterol (7-DHC) to calcitriol (1alpha,25(OH)(2)D(3)) and the release of tumor necrosis factor-alpha (TNF-alpha) in these cells. Calcitriol synthesis in human keratinocytes was reduced in the presence if a neutralizing polyclonal antibody directed against human TNF-alpha. On the other hand, we found a 1.7-fold higher stimulatory effect of UVB on liberation of TNF-alpha in cultured keratinocytes enriched with 7-DHC compared with irradiated cell cultures in absence of 7-DHC. These observations argue in favor of a synergetic relationship between generation of TNF-alpha and calcitriol in UVB irradiated keratinocytes. In addition, we found that TNF-alpha potently increases the conversion rate of Vitamin D(3) (cholecalciferol) to calcitriol in this cell system. The UVB-triggered formation of both TNF-alpha and calcitriol in cultured keratinocytes was wavelength-, time- and dose-dependent. Maximum formation of TNF-alpha and calcitriol was found at 300 nm and UVB doses of 30 mJ/cm2. The enhancement of both the formation of TNF-alpha and calcitriol in keratinocytes by UVB may be of relevance for regulation of growth and apoptosis in light-exposed epidermal cells and, in addition, may play a role in the UVB treatment of diseased skin including psoriasis.

Calcitriol↗
PubMed2004

Cestrum diurnum leaf as a source of 1,25(OH)2 Vitamin D3 improves egg shell thickness.

A continuing concern of the poultry industry is the high incidence (12%) of egg losses in the laying house due to poor egg shell quality. Calcium (Ca) homeostasis is a key factor in egg shell formation. The economy of Ca utilisation is under the control of Vitamin D(3), particularly its active metabolite 1,25-dihydroxy cholecalciferol [1,25(OH)(2)D(3)]. Supplementation of 1,25(OH)(2)D(3) has been shown to increase specific gravity, shell thickness and shell weight of the egg. However, commercially available synthetic 1,25(OH)(2)D(3) is very expensive. Earlier studies from our Institute [Phytochemistry 37 (1994) 677] have identified a cheap, natural and rich source of 1,25(OH)(2)D(3) in the leaves of Cestrum diurnum (CD), a member of the Solanaceae family. In this study, CD leaves were explored as a source of 1,25(OH)(2)D(3) in the feed of layer birds to improve the egg shell thickness. Fifteen-week-old white leghorn layers were divided into four treatments of 60 birds each and as follows: (I) normal diet with Vitamin D(3), (II) normal diet with Vitamin D(3) + CD, (III) normal diet without Vitamin D(3) and, (IV) normal diet without Vitamin D(3) + CD powder. CD leaf powder was incorporated in to the feed at 0.3% level. The experimental feeding was continued up to 72 weeks of age of the birds. Weekly food intake and daily egg production were noted throughout the experimental period and the specific gravity of the eggs, feed consumed to lay one egg and egg shell thickness were determined. Incorporation of CD leaves in the feed had the maximal effect on all the parameters studied. The feed consumed to lay one egg was 20 g less than the control group. The specific gravity of the egg was higher by 0.005, than the control egg, indicating a 5% decrease in the breakage of eggs in CD fed chicks. Also there was a significant increase (P < 0.001) in egg shell thickness. The data suggest that incorporation of CD leaf powder in the feed of poultry layers increased the egg shell thickness, which in turn could decrease the economic loss due to breakage of eggs.

Animals↗
PubMed2005

Analogs of 1alpha,25-dihydroxyvitamin D(3) as novel inhibitors of renin biosynthesis.

The renin-angiotensin system (RAS) plays a central role in the pathogenesis of hypertension. Recently, we discovered that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] functions as a negative endocrine regulator of renin biosynthesis, which provides a molecular basis to explore the potential of Vitamin D analogs as renin inhibitors to control the RAS. To search for renin-inhibiting Vitamin D analogs, we screened 20 Vitamin D analog compounds using As4.1-hVDR cell (a juxtaglomerular cell line) culture by Northern blot and luciferase reporter assays. We found that the Gemini compounds, which have two side-chains at carbon-20 position, were particularly active in suppressing renin expression. Eight Gemini compounds were identified that were equally or 10- to 100-times more potent than 1,25(OH)(2)D(3) in renin inhibition. These Gemini compounds also potently stimulate 25-hydroxyvitamin D 24-hydroxylase expression in As4.1-hVDR cells. Administration of compound RO-27-5646 [1,25-dihydroxy-21-(3-methyl-3-hydroxy-butyl)-19-nor-cholecalciferol] in mice caused a marked reduction in renal renin mRNA expression without invoking severe hypercalcemia as seen in 1,25(OH)(2)D(3) treatment. These data establish in principle that Vitamin D analogs can indeed inhibit renin expression in vitro and in vivo, and support the notion that low calcemic Vitamin D analogs can potentially be used as therapeutic agents to control the RAS.

Animals↗
PubMed2005

Vitamin D and skin cancer: a problem in gene regulation.

The skin is the major source of Vitamin D(3) (cholecalciferol), and ultraviolet light (UV) is critical for its formation. Keratinocytes, the major cell in the epidermis, can further convert Vitamin D(3) to its hormonal form, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] (calcitriol). 1,25(OH)(2)D(3) in turn stimulates the differentiation of keratinocytes, raising the hope that 1,25(OH)(2)D(3) may prevent the development of malignancies in these cells. Skin cancers (squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanomas) are the most common cancers afflicting humans. UV exposure is linked to the incidence of these cancers-UV is thus good and bad for epidermal health. Our focus is on the mechanisms by which 1,25(OH)(2)D(3) regulates the differentiation of keratinocytes, and how this regulation breaks down in transformed cells. Skin cancers produce 1,25(OH)(2)D(3), contain ample amounts of the Vitamin D receptor (VDR), and respond to 1,25(OH)(2)D(3) with respect to induction of the 24-hydroxylase, but fail to differentiate in response to 1,25(OH)(2)D(3). Why not? The explanation may lie in the overexpression of the DRIP complex, which by interfering with the normal transition from DRIP to SRC as coactivators of the VDR during differentiation, block the induction of genes required for 1,25(OH)(2)D(3)-induced differentiation.

Animals↗
PubMed2003

The Erlangen Fitness Osteoporosis Prevention Study: a controlled exercise trial in early postmenopausal women with low bone density-first-year results.

OBJECTIVE: To investigate the effect of a 2-year vigorous, combined high-impact, strength, and endurance training program on bone mineral density (BMD) determined by dual-energy x-ray absorptiometry (DXA), quantitative computed tomography (QCT), and ultrasound in early postmenopausal women with osteopenia. DESIGN: Nonrandomized controlled trial, reporting 1-year data. SETTING: Community. PARTICIPANTS: Early postmenopausal (1-8y postmenopausal) osteopenic women (DXA T score at lumbar spine or total hip between -1 and -2.5 standard deviations). The exercise group (n=59; mean age, 55.1+/-3.4y) and control group (n=41; mean age, 55.9+/-3.1y) were recruited from community registers. INTERVENTION: Fourteen months of exercise training, with 2 joint sessions and 2 additional home training sessions. Exercise and control groups were supplemented individually with calcium and cholecalciferol up to 1500mg of calcium and 500IU of vitamin D per day. MAIN OUTCOMES MEASURES: BMD at the lumbar spine and total hip measured by DXA, isometric maximum strength, and maximal oxygen consumption (VO2max) during a stepwise running test to exhaustion. RESULTS: Bone density increased significantly at the lumbar spine for the exercise group (1.3%, P<.001) and decreased in the control group (-1.2%, P<.01). Differences at the total hip (-0.3%, not significant vs -0.8%, P<.05) and the femoral neck (-0.8%, P<.05 vs -1.8%, P<.001) were nonsignificant. Changes in isometric maximum strength were significant for each region (grip strength, trunk flexors and extensors, hip flexors, leg adductors and abductors, arm flexors and extensors) in the exercise group (11%-39%) compared with nonrelevant changes (-1.1% to 3.9%) in the control group. Between-group differences were significant (P<.01-.001) for all strength parameters. VO2max increased significantly by 11% (P<.001) in the exercise group but decreased in the control group by 4% (P<.05) while showing significant between-group differences. CONCLUSION: High-intensity exercise training can have a positive influence on bone density in early postmenopausal osteopenic women.

Absorptiometry, Photon↗
PubMed1981

Calcium and phosphate metabolism in sarcoidosis with particular reference to parathyroid function.

Fifty-six consecutive patients with sarcoidosis, 31 subacute and 25 chronic, were investigated for abnormalities of calcium and phosphate metabolism with particular reference to parathyroid function. No abnormality of serum calcium, phosphate, creatinine or alkaline phosphatase was found. Serum levels of 25-OH cholecalciferol were normal and parathyroid hormone levels were normal in all but one patient. Maximum renal tubular reabsorption capacities for calcium and phosphate (TmCa/GFR, TmP/GFR) in relation to glomerular filtration rate in the fasting state, were abnormal in some patients but this did not correlate with any other abnormality in parathyroid function. There was significant hypercalciuria (greater than 10 mmol calcium per 24 hours) in 7.5% of our patients and this is believed to be due to increased calcium flow.

Calcium↗
PubMed2000

Determination of eight water- and fat-soluble vitamins in multi-vitamin pharmaceutical formulations by high-performance liquid chromatography.

In the present work, a reversed-phase high-performance liquid chromatographic procedure has been developed for the determination of water-soluble vitamins (thiamine hydrochloride, pyridoxine hydrochloride, nicotinamide, riboflavin phosphoric ester and cyanocobalamine) and fat-soluble vitamins (retinol palmitate, cholecalciferol, alpha-tocopherol acetate) in multi-vitamin pharmaceutical formulations. The sample treatment proposed consists of a solid-phase extraction with C18 AR cartridges that allow the separation of fat-soluble vitamins, which were retained on the sorbent, from water-soluble vitamins. Afterwards, the water-soluble vitamins were analysed by HPLC on a Nova-Pack C18 (150x3.9 mm, 4 microm) analytical column, using CH3OH-0.05 M CH3COONH4 as mobile phase. The chromatographic analysis of the fat-soluble vitamins was carried out after their sequential elution with methanol and chloroform from C18 sorbent, on the above column. The mobile phase employed was MeOH-CH2CN (95:5, v/v) working at a flow-rate of 2 ml min(-1) in isocratic mode. The solid-phase extraction for these vitamins had been previously optimised. The experimental variables studied were: application volume, elution solvents and cleaning solutions. The UV-Vis detection of vitamins was made at 270 nm for all the water-soluble vitamins (362 nm for B12) and 285 nm for the water-soluble and fat-soluble vitamins present in real samples at different concentration levels. The accuracy of the method was tested obtaining an average recovery ranging between 78 and 116%.

Chromatography, High Pressure Liquid↗
PubMed2000

Contribution of diet to the dosing time-dependent change of vitamin D3-induced hypercalcemia in rats.

We have recently reported that the degree of hypercalcemia as an adverse effect induced by a single large-dose of active vitamin D3 varied with its dosing time without alteration in therapeutic effect for secondary hyperparathyroidism in patients with chronic renal failure. The present study was conducted to elucidate an effect of intestinal calcium (Ca) absorption on the chronopharmacological profiles of vitamin D3. 1, 25-dihydroxy-cholecalciferol (D3, 2 microg/kg) or vehicle alone was orally administered at two different times (2 and 14 hours after lights on; HALO) to male Wistar rats (n= 10) kept in rooms with a 12 h light-dark cycle. Blood samples for serum Ca concentration were taken before and 3, 6, 9, and 12 hours after the administration. Urine was collected for 6 hours after dosing. An identical protocol was repeated using the same animals after 16 hours fasting by a cross-over fashion. Under free-fed condition, basal concentration of serum Ca was higher at a resting period (lights on) than during an active period (lights off). Serum Ca reached its peak at 6 hours after dosing in both timings, while the value was significantly higher in the 2 HALO trial than in the 14 HALO trial. Area under the serum Ca concentration-time curve from 0 to 12 hours (AUC0-12h) and urinary excretion of Ca for 6 hours were also significantly higher in the 2 HALO trial than in the 14 HALO trial. When fasted, basal Ca concentration was reduced compared with the free-fed condition, while the daily variation was maintained. Serum Ca concentration profiles from 3 to 12 hours after dosing were not significantly different between the 2 HALO and 14 HALO trials. The AUC0-12h of serum Ca or its urinary excretion was not different between both trials. Serum concentrations of parathyroid hormone and total protein, measured before and 6 hours after the dosing were not affected by the dosing schedule. We have concluded that intestinal Ca absorption is a major factor for the chronopharmacological phenomenon of D3-induced hypercalcemia in intact rats, while intestinal and renal involvement may be relatively small in the mechanism of the intrinsic diurnal variation of serum Ca.

Activity Cycles↗
PubMedDate not supplied

Chemoprevention of mammary carcinogenesis by 1alpha-hydroxyvitamin D5, a synthetic analog of Vitamin D.

Numerous analogs of Vitamin D have been synthesized in recent years with the hope of generating a compound that retains the anticarcinogenic activity of Vitamin D without causing any toxicity. We synthesized such an analog, 1alpha-hydroxy-24-ethylcholecalciferol [1alpha-hydroxyvitamin D(5) or 1alpha(OH)D(5)], and showed that it was tolerated by rats and mice at a much higher dose than 1alpha,25 dihydroxy cholecalciferol [1alpha,25(OH)(2)D(3)]. This property makes it a prime candidate for chemoprevention studies. In the mouse mammary gland organ culture (MMOC), 1alpha(OH)D(5) inhibited carcinogen-induced development of both mammary alveolar and ductal lesions. In vivo carcinogenesis study showed statistically significant reduction of tumor incidence and multiplicity in N-methyl-N-nitrosourea (MNU)-treated rats that were fed 25-50 microg 1alpha(OH)D(5)/kg diet. There were no adverse effects on plasma calcium concentrations. In order to determine if the effect of 1alpha(OH)D(5) would be selective in suppressing proliferation of transformed cells, its effects on cell growth and proliferation were compared between BT474 (cancer) and MCF12F (non-tumorigenic) human breast epithelial cells. Results showed that 1alpha(OH)D(5) induced apoptosis and cell cycle G1 phase arrest in BT474 breast cancer cells without having any effects on proliferation of the MCF12F cells. In addition, in MMOC it had no growth inhibitory effects on normal epithelial cell proliferation in the absence of carcinogen. Similarly, non-tumorigenic human breast epithelial cells in explant culture did not respond to 1alpha(OH)D(5), whereas treatment with 1alpha(OH)D(5) induced cell death in the explants of cancer tissue. These results collectively indicate that 1alpha(OH)D(5) selectively induced apoptosis only in transformed cells but not in normal breast epithelial cells. Interestingly, the growth inhibitory effects of 1alpha(OH)D(5) were observed in Vitamin D receptor positive (VDR(+)) breast cancer cells, but not in highly metastatic VDR(-) breast cancer cells, such as MDA-MB-435 and MDA-MB-231, suggesting that 1alpha(OH)D(5) action may be mediated, in part, by VDR.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

Alendronate for treatment of renal transplant patients with osteoporosis.

UNLABELLED: Osteoporosis is a frequent complication after renal transplantation. Some workers have shown that bisphosphonates may be effective to prevent and treat corticosteroid-induced osteoporosis in these patients. In this study we report our experience with administration of the biphosphonate alendronate to treat renal transplanted patients with established osteoporosis. MATERIALS AND METHODS: Twelve to 24 months after transplantation (9 women, 5 men) 14 renal transplant patient were treated with alendronate and 12 patients (7 women, 5 men) were untreated. All patients displayed an iPTH <240 pg/mL and a bone mineral density (BMD) t-score <-2.5. All patients received cyclosporine and prednisone therapy. Biochemical measurements, BMD, and X-rays of the lumbar spine were measured during study. Patients in the treatment group received alendronate 10 mg/d (po) and vitamin D plus calcium (800 UI cholecalciferol and 2.5 g of CaCO(3)) per day while those in the control group only received vitamin D plus calcium, at the same dose. RESULTS: There was no difference in mean age, weight, time after transplantation, or immunosuppression between the treatment and control groups. There were no significant differences in the biochemical parameters during the study period. Over the 1-year study period, patients receiving alendronate displayed a greater increase in BMD. Lumbar spine BMD increased 4.3 +/- 6.1% in the treatment group versus 0.55 +/- 5.30% in controls. Femoral neck BMD increased 10.3 +/- 11.9% and 2.2 +/- 5.7%, respectively, in the treatment and control groups. Patients receiving alendronate frequently experienced intestinal disconfort. CONCLUSIONS: The bisphosphonate alendronate is effective to treat renal transplant patients suffering from established osteporosis.

Alendronate↗
PubMed1995

1,25-Dihydroxy-16-ene-23-yne-vitamin D3 and prostate cancer cell proliferation in vivo.

OBJECTIVES: 1,25-Dihydroxyvitamin D can inhibit the proliferation of prostate cancer cells, but its clinical use is limited by hypercalcemia. We examined the effects of a "noncalcemic" vitamin D analogue, 1,25-Dihydroxy-16-ene-23-yne-cholecalciferol (16-23-D3), on the proliferation of human prostate cancer cells in a mouse model. METHODS: Twenty-four athymic nude mice were inoculated with human prostate carcinoma cells from the PC-3 cell line. Twelve mice (experimental group) received injections of 1.6 micrograms of 16-23-D3 on alternate days over a 22-day period. Twelve mice (control group) received sham injections. Tumor volumes, pathologic findings, and terminal serum calcium levels were compared between groups. RESULTS: The relative increase in tumor volume was significantly lower in the experimental than in the control group in the first interval following treatment (P < 0.01). Mean tumor volumes in the experimental group were approximately 15% smaller than in the control group. Serum calcium levels did not differ between groups. CONCLUSIONS: 16-23-D3 showed modest antiproliferative effects on prostate cancer cells in this model without evidence of drug-induced hypercalcemia. These findings support the concept that vitamin D analogues can inhibit the proliferation of human prostate cancer cells in vivo.

Adenocarcinoma↗
PubMed1976

Prevention of vitamin-D deficiency in Asians.

Asian families living in Glasgow were studied between December, 1973, and June, 1974. One group of families served as a control; their mean serum-25-hydroxy-vitamin-D (25-hydroxy-cholecalciferol and 25-hydroxyergocalciferol) remained low, being 5-1 +/- 0-8 (S.E.M.) ng/ml at the end of the study. A second group was given 3000 units of vitamin D2 in a capsule weekly; this raised the mean concentration of 25-hydroxy-vitamin-D to 18-1 +/- 2-9 ng/ml. The variable effectiveness of this supplement was attributable to some subjects not taking the capsules regularly. The third group of families was provided with chupatty flour fortified with vitamin D(6000 units per kg). This increased mean serum-25-hydroxy-vitamin-D very uniformly to a mean value of 19-5 +/- 1-2 ng/ml. It is concluded that vitamin-D deficiency in Asian immigrants could be substantially reduced by fortification of chupatty flour with vitamin D.

Adolescent↗
PubMed2002

Ischaemic heart failure: a new explanation of its cause and preventability.

When the heart contracts, it compresses its own arteries, so that blood flow in the coronary circulation comes to a standstill during systole. The heart must be supplied with blood from an auxiliary supply during diastole. The auxiliary pump is the aorta and its branches. When the stroke volume is injected into the aorta, it is overfilled and distended, storing energy in stretched elastic tissues. During diastole the contraction of these tissues maintains diastolic pressure. The hardest working organ in the body, the heart, therefore is supplied with blood only intermittently and only at diastolic pressure. In addition a layer of calcium tends to accumulate in the aorta, deteriorating its elasticity. It is suggested that this auxiliary pump is the weakest link in the circulatory system. If it fails, the heart dies of ischaemia. The calcium requirements of the body vary greatly in various age groups; 99% of the calcium content of the adult body is in the skeleton, which is complete by the age of 32 years. After that calcium requirements decrease. Catering for such varying calcium needs the gut to be impermeable to calcium. A special substance, 1,25,-dihydroxycholecalciferol, secreted by the liver and kidneys is needed to transfer calcium through the intestinal wall. When calcium needs are satisfied, the synthesis of cholecalciferol is discontinued, and the calcium in food in the intestines is excreted. To cater for the other extreme, when the calcification of the infant skeleton needs much calcium, nature produces a special nutrient, milk, not only rich in calcium, but containing a substance promoting its transference through the intestinal wall. The human habit of consuming the milk of another species is harmful because it invalidates the natural expedient of limiting calcium intake when it is not needed. The calcium excess resulting from milk consumption tends to calcify the aorta, deteriorating its elasticity, resulting in lower diastolic pressure. When that becomes inadequate, the heart dies of ischaemia.

Adult↗
PubMed1989

Hypercalcemia.

Elevated serum calcium occurs relatively uncommonly in dogs and rarely in cats. Hypercalcemia can serve as a marker of disease that enables diagnosis but may also contribute to development of lesions and the clinical signs of disease. Specific clinical signs do not necessarily accompany hypercalcemia, and its presence will frequently be unsuspected. Fortuitous hypercalcemia is often discovered after a review of serum biochemical profile results. This article emphasizes malignancy-associated hypercalcemia and the emergence of cholecalciferol rodenticide toxicity as an important cause of hypercalcemia, as well as its treatment.

Animals↗
PubMedDate not supplied

Vitamin-D dependent 9 kDa calcium-binding protein gene: cDNA cloning, mRNA distribution and regulation.

Cholecalciferol (calcitriol) the active hormonal form of vitamin D induces the synthesis of at least two intracellular calcium-binding proteins (Ka = 10(6) M-1), the cholecalcins (CaBP) in mammals. We used the synthesis of these proteins to study the genomic steroid-like action of vitamin D. The 9 kDa CaBP is mainly concentrated in the duodenum while 28 kDa CaBP is located in the kidney and cerebellum. Complementary DNA copies of rat intestinal 9 kDa CaBP mRNA were cloned in E. coli. The deduced amino acid sequence for 9 kDa CaBP contains two 'EF hand' domains corresponding to calcium-binding sites I and II. The homology observed suggests, after comparison with the structures of other intracellular CaBPs, that rat 9 kDa CaBP mRNA contains the remains of an untranslated calcium-binding site III-like structure seen in 28 kDa CaBP from kidney and cerebellum of rat. Northern blots showed that the cDNA sequence hybridizes to a homogeneous 500-600 nucleotide mRNA species from rat duodenum. Larger mRNA species encoding 28 kDa CaBP were undetectable in rat kidney and cerebellum even under low stringency conditions. These findings demonstrate that there is no cross-hybridization between 9 kDa and 28 kDa CaBP mRNAs, and Southern analysis indicates that there are distinct genes coding for each rat cholecalcin. The cDNA probe was used to analyze the specific 9 kDa CaBP gene expression along the intestine of growing rats and during gestation and fetal development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Selenium, calcium channel blockers, and cancer risk--the Yin and Yang of apoptosis?

It is increasingly clear that apoptosis plays a crucial role in the promotional phase of cancer development. Initiated pre-neoplastic clones in rat liver experience a high rate of apoptosis, and this rate has an important impact on the survival and growth of these clones. Suppression of apoptosis appears to be a universal property of cancer promoters, suggesting conversely that agents which inhibit cancer induction during the promotional phase increase the rate of apoptosis in initiated cells. Modulation of apoptosis is a likely explanation for recent striking evidence that use of calcium channel blockers substantially increases, whereas supplemental selenium substantially decreases, human cancer incidence. Non-genotoxic measures which are likely to upregulate apoptosis in pre-neoplastic/neoplastic cells--and thus may be useful in prevention and/or therapy--include selenium, retinoids/carotenoids, green tea polyphenols, caloric restriction, downregulation of IGF-I activity, high-dose tamoxifen and other protein kinase C antagonists, withdrawal or blockade of trophic hormones, isoflavones, limonene, vitamin D and cholecalciferol analogs, dietary fiber/sodium butyrate, hyperthermia, benzaldehyde derivatives, and creatine.

Animals↗