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PubMed2004

Identification of a region in the vitamin D-binding protein that mediates its C5a chemotactic cofactor function.

The vitamin D-binding protein (DBP), also known as group-specific component or Gc-globulin, is a multifunctional plasma protein that can significantly enhance the leukocyte chemotactic activity to C5a and C5a des-Arg. DBP is a member of the albumin gene family and has a triple domain modular structure with extensive disulfide bonding that is characteristic of this protein family. The goal of this study was to identify a region in DBP that mediates the chemotactic cofactor function for C5a. Full-length and truncated versions of DBP (Gc-2 allele) were expressed in Escherichia coli using a glutathione S-transferase fusion protein expression system. The structure of the expressed proteins was confirmed by SDS-PAGE and immunoblotting, whereas protein function was verified by quantitating the binding of [(3)H]vitamin D. Dibutyryl cAMP-differentiated HL-60 cells were utilized to test purified natural DBP and recombinant expressed DBP (reDBP) for their ability to enhance chemotaxis and intracellular Ca(2+) flux to C5a. Natural and full-length reDBP (458 amino acid residues) as well as truncated reDBPs that contained the N-terminal domain I (domains I and II, residues 1-378; domain I, residues 1-191) significantly enhanced both cell movement and intracellular Ca(2+) concentrations in response to C5a. Progressive truncation of DBP domain I localized the chemotactic enhancing region between residues 126-175. Overlapping peptides corresponding to this region were synthesized, and results indicate that a 20-amino-acid sequence (residues 130-149, 5'-EAFRKDPKEYANQFMWEYST-3') in domain I of DBP is essential for its C5a chemotactic cofactor function.

Alleles↗
PubMed2005

Exposure to low concentrations of di-n-butyl phthalate during embryogenesis reduces survivability and impairs development of Xenopus laevis frogs.

Di-n-butyl phthalate (DBP) appears to be a ubiquitous environmental contaminant, as indicated by its presence in air, water, and soil worldwide (Giam et al., 1980; ATSDR, 2001; Peterson & Freeman, 1982) and the presence of its major metabolite, monobutyl phthalate (MBP), in random human urine samples (Blount et al., 2000). Studies indicate that exposure to a variety of endocrine-disrupting chemicals, such as DBP, may be partially responsible for reported global amphibian declines; if so, amphibians may serve as ecological harbingers for the future of human health. Therefore, this study was undertaken to investigate the effects of environmentally relevant concentrations of DBP on development in Xenopus laevis African clawed frogs. Developmental effects of DBP on Xenopus embryos were determined using the 96-h frog embryo teratogenesis assay-Xenopus (FETAX). Embryos (n = 300/group) were exposed from gastrulation (stage 8-11) through primary organogenesis (stage 46) to 0.1, 0.5, 1, 5, 10, or 15 ppm DBP dissolved in 0.01% dimethyl sulfoxide (DMSO), vehicle alone (0.01% DMSO; solvent control), or FETAX culture medium only (control; n = 600). At 96 h, mortalities for control, solvent control, and 0.1, 0.5, 1, 5, 10, and 15 ppm DBP were 5, 4, 6, 5, 5, 9, 18, and 52%, respectively; the incidence of developmental malformations in the surviving tadpoles was 7, 9, 15, 37, 51, 53, 90, and 100%. The average length of embryos was significantly lower in all DBP treatment groups. Thus, DBP significantly affected development of Xenopus embryos at low, environmentally relevant concentrations.

Abnormalities, Drug-Induced↗
PubMed1991

Exercise induced increase in diastolic blood pressure. Is it an indicator of coronary artery disease?

It has been previously reported that an increase in diastolic blood pressure greater than 15 mmHg comparing values at rest with those on treadmill exercise, with or without ST changes, enhances the probability of coronary artery disease. To investigate whether the diastolic blood pressure variation keeps its diagnostic value during upright bicycle exercise, we evaluated the diastolic blood pressure variations in 111 patients with angiographically documented coronary artery disease without previous myocardial infarction and in 53 patients with normal coronary arteries undergoing maximal stress testing on a bicycle ergometer. The sensitivity of diastolic blood pressure (DBP) variations to detect coronary artery disease was 66%, the specificity 32%, the positive predictive value 67%, the negative predictive value 31% and the predictive accuracy 55%. The respective values for ST depression were 83% (P less than 0.001 vs DBP variations), 53% (P less than 0.05 vs DBP variations), 64% (P less than 0.05 vs DBP variations) and 75% (P less than 0.001 vs DBP variations). Forty-nine of the 75 patients with multivessel coronary artery disease and 60 of the 89 patients without coronary artery disease or with single vessel disease had abnormal DBP variations (sensitivity 65; specificity 33%). The sensitivity of ST segment depression in predicting multivessel disease was 91% (P less than 0.001 vs DBP variations), and the specificity 42%. Thus, for bicycle ergometer exercise testing, ST segment depression seems to be more accurate than DBP variations in the diagnosis of coronary artery disease.

Adult↗
PubMed1980

Studies of blood pressure in schoolchildren (ages 6--19) and their parents in an integrated suburban school district.

Systolic blood pressure (SBP) and diastolic blood pressure (DBP), along with demographic and anthropometric variables were assessed in a biracial group of schoolchildren and parents in an integrated suburban school district: 682 schoolchildren, ages 6--19, including 268 white males, 236 white females, 85 black males and 93 black females; 362 adults, ages 20--64, including 142 white males, 159 white females, 20 black males and 41 black females. There were no significant black-white SBP or DBP differences in children, while SBP and DBP were higher in adult blacks than whites. Using multiple regression analysis, with BP as the dependent variable, SBP in children was significantly associated with pulse, weight, skinfold thickness, age and height; DBP was significantly associated with age, pulse, weight, and skinfold thickness. Race, sex, and education of the head of household did not significantly enter the multiple regression matrix for children's BP. Respectively, 29% and 22% of the variance of the children's SBP and DBP was accounted for by the measured variables. In adults, SBP was significantly related to weight, race, pulse, and age; DBP was significantly related to weight, race, age, and skinfold thickness. Respectively, 27% and 24% of the variance of the adults' SBP and DBP was accounted for by the measured variables. Covariance adjusted mean SBP and DBP were higher in hypertriglyceridemic than in hypotriglyceridemic children (p = 0.001), and were lower in hyperalpha-lipoproteinemic than hypoalpha-lipoproteinemic children (p less than or equal to 0.03). Children in an integrated school district may have shared behaviors, goals, and environments contributing to shared BP, while differing environmental factors may become amplified with age and life experience and contribute to higher BP in black adults.

Adolescent↗
PubMedDate not supplied

Expression of the synthetic gene of an artificial DDT-binding polypeptide in Escherichia coli.

This paper reports the expression of an artificial functional polypeptide in bacteria. The gene of a designed 24-residue DDT-binding polypeptide (DBP) was inserted between the BamHI and PstI cleavage sites of plasmid pUR291. The hybrid plasmid, pUR291-DBP, was cloned in Escherichia coli JM109. After induction by isopropyl-beta-D-thiogalactopyranoside a fusion protein was expressed in which DBP was linked to the COOH-terminus of beta-galactosidase. DBP, which is stable to trypsin, was obtained by tryptic digestion of the fusion protein and subsequent fractionation of the tryptic peptides by reversed-phase h.p.l.c. Recombinant and chemically synthesized DBP showed identical chromatographic properties, amino acid composition, and chymotryptic digestion patterns. Both the beta-galactosidase-DBP fusion and isolated recombinant DBP bound DDT. The fusion protein was 25 times as potent as the designed 24-residue DBP in activating a cytochrome P-450 model system using equimolar catalytic amounts of the two proteins.

Amino Acid Sequence↗
PubMed2005

Altered gene expression during rat Wolffian duct development following di(n-butyl) phthalate exposure.

Di(n-butyl) phthalate (DBP) is a common plasticizer and solvent that disrupts androgen-dependent male reproductive development in rats. In utero exposure to 500 mg/kg/day DBP on gestation days (GD) 12 to 21 decreases androgen biosynthetic enzymes, resulting in decreased fetal testicular testosterone levels. One consequence of prenatal DBP exposure is malformed epididymides in adult rats. Reduced fetal testosterone levels may be responsible for the malformation, since testosterone is required for Wolffian duct stabilization and their development into epididymides. Currently, little is understood about the molecular mechanisms of Wolffian duct differentiation. The objective of this study was to identify changes in gene expression associated with altered morphology of the proximal Wolffian duct following in utero exposure to DBP. Pregnant Crl:CD(R) (SD) rats were gavaged with corn oil vehicle or 500 mg/kg/day DBP from GD 12 to GD 19 or 21. There were only small morphological differences between control and DBP-exposed Wolffian ducts on GD 19. On GD 21, 89% of male fetuses in the DBP dose group showed marked underdevelopment of Wolffian ducts, characterized by decreased coiling. RNA was isolated from Wolffian ducts on GD 19 and 21. Together with empirical information, cDNA microarrays were used to help identify candidate genes that could be associated with the morphological changes observed on GD 21. These candidate genes were analyzed by real-time RT-PCR. Changes in mRNA expression were observed in genes within the insulin-like growth factor (IGF) pathway, the matrix metalloproteinase (MMP) family, the extracellular matrix, and in other developmentally conserved signaling pathways. On GD 19, immunolocalization of IGF-1 receptor protein demonstrated an increase in cytoplasmic expression in the mesenchymal and epithelial cells. There was also a variable decrease in androgen receptor protein in ductal epithelial cells on GD 19. This study provides insight into the effects of antiandrogens on the molecular mechanisms involved in Wolffian duct development. The altered morphology and changes in gene expression following DBP exposure are suggestive of altered paracrine interactions between ductal epithelial cells and the surrounding mesenchyme during Wolffian duct differentiation due to lowered testosterone production.

Animals↗
PubMed2005

Exposure in utero to di(n-butyl) phthalate alters the vimentin cytoskeleton of fetal rat Sertoli cells and disrupts Sertoli cell-gonocyte contact.

Di(n-butyl) phthalate (DBP) is commonly used in personal care products and as a plasticizer to soften consumer plastic products. Male rats exposed to DBP in utero have malformations of the male reproductive tract and testicular atrophy characterized by degeneration of seminiferous epithelium and decreased sperm production. In the fetal testis, in utero exposure to DBP reportedly resulted in reduced testosterone levels, Leydig cell aggregates, and multinucleated gonocytes (MNG). We investigated whether exposure in utero to DBP affects rat fetal Sertoli cells and compromises interactions between Sertoli and germ cells in the developing testis. Histological examination showed that MNG occurred at low frequency in the normal fetal rat testis. Exposure in utero at the dose level of DBP above estimated environmental or occupational human exposure levels significantly increased the number of these abnormal germ cells. Postnatally, MNG exhibited aberrant mitoses and were detected at the basal lamina. MNG were not apoptotic in the fetal and postnatal rat testes, as indicated by TUNEL. Sertoli cells in DBP-exposed fetal testis had retracted apical processes, altered organization of the vimentin cytoskeleton, and abnormal cell-cell contacts with gonocytes. The effect of DBP on Sertoli cell morphology at the level of light microscopy was reversed after birth and cessation of exposure. Our data indicate that fetal Sertoli cells are targeted by exposure in utero to DBP and suggest that abnormal interactions between Sertoli and germ cells during fetal life play a role in the development of MNG.

Animals↗
PubMed1992

The influence of ambulatory blood pressure monitoring on the design and interpretation of trials in hypertension.

OBJECTIVE: To describe the reproducibility of diastolic blood pressure (DBP) measurement by clinic and ambulatory monitoring and to evaluate the effects of this reproducibility on the design and interpretation of clinical trials in hypertension research. DESIGN: Prospective single-blind study of repeat measurement reproducibility of blood pressure recording. SETTING: Tertiary referral hospital hypertension clinic. PATIENTS: One hundred untreated mild-to-moderate hypertensive subjects taking 1 month of single-blind placebo. MAIN OUTCOME MEASURES: A single clinic measurement of DBP was poorly reproducible and the results for single DBP estimates taken out of a daytime ambulatory recording were similar. Average ambulatory DBP was much more reproducible, although this improvement depended upon the averaging of many measurements taken throughout the day. CONCLUSIONS: Ambulatory monitoring would decrease antihypertensive trial size by a factor of four or halve the size of detectable DBP difference between treatments. The use of poorly reproducible DBP measurements such as single clinic readings may have led to an underestimation of the risks of minor degrees of blood pressure elevation because of a 'regression dilution' bias. For single clinic DBP readings, we calculate this underestimation to be as much as 69%, and for average ambulatory DBP approximately 20%.

Adult↗
PubMed1997

Trough-to-peak ratio and circadian blood pressure profile after treatment with once-daily extended-release diltiazem, 240 mg, in patients with mild-to-moderate essential hypertension.

Once-daily diltiazem extended-release 240 mg (Lacerol-HTA Retard) was evaluated for safety, efficacy, and trough-to-peak ratio in a multicenter open study by using 24-h blood pressure (BP) monitoring in mild-to-moderate essential hypertension. After a 4-week washout period, 30 patients (17 men, 13 women) aged 25-76 years, showing a mean daytime diastolic BP (DBP) >90 mm Hg, were treated with diltiazem-ER, 240 mg, given once daily for 8 weeks. Ambulatory BP monitoring was obtained at the end of a 4-week placebo run-in period and during the last week of treatment. A significant reduction of the mean values of clinical BP [161.6 +/- 16.2 to 151.2 +/- 15.6 mm Hg; p < 0.01 for systolic BP (SBP); and 101.1 +/- 4.8 to 93.3 +/- 9.2 mm Hg; p < 0.001 for DBP] was observed at the end of treatment in the group of 30 patients, with no significant changes in heart rate (77.1 +/- 9.9 to 73.1 +/- 11.1 beats/min; p = NS). Likewise, mean values of 24-h SBP, DBP, SBP-load, and DBP-load were significantly reduced. In the group of 21 responders, the average reduction at peak was -18.6 +/- 12.9 mm Hg for SBP and -14.7 +/- 9.5 mm Hg for DBP. The residual effect at trough was -12.2 +/- 14.7 and -8.1 +/- 10 mm Hg, respectively. The trough-to-peak ratio was estimated as 0.66 for SBP and 0.55 for DBP. Long-term variability expressed as the mean standard deviation of BP for the 24-h period was reduced in responders (16.2 +/- 4.3 to 14.6 +/- 2.7 mm Hg for SBP; p = 0.0395; and 12.1 +/- 2.7 to 10.7 +/- 2.5 mm Hg for DBP; p = 0.0019), although no changes were observed in the variation coefficient (10.58-10.57% for SBP and 12.88-12.87% for DBP). We conclude that once-daily diltiazem-ER, 240 mg, was effective and well tolerated. Blood pressure was controlled over the entire period of 24 h, preserving the circadian profile and reducing long-term variability in responders. The significant reduction of both BP values and long-term variability may have implications involving protection from end-organ damage in essential hypertension.

Adult↗
PubMed2003

Validation of the ROSSMAX blood pressure measuring monitor according to the European Society of Hypertension International Protocol for Validation of Blood Pressure Measuring Devices in Adults.

BACKGROUND: It is now accepted that blood pressure measuring devices should be subjected to an independent evaluation of their accuracy before they are marketed for clinical use. The results of validation of the ROSSMAX Blood Pressure Measuring Monitor for self-measurement according to the European Society of Hypertension International Protocol for Validation of Blood Pressure Measuring Devices in Adults are presented in this paper. POPULATION: Thirty-three subjects were recruited from among staff and patients at Beaumont Hospital, Dublin, Ireland. METHODS: The ROSSMAX monitor was connected to the Sphygmocorder, an audiovisual system for validation, which records blood pressure on tape and video for later analysis. Nine sequential same-arm measurements between the device and a standard mercury sphygmomanometer were recorded using the Sphygmocorder. RESULTS: In phase 1, the ROSSMAX monitor produced 21 measurements within 5 mmHg, 31 within 10 mmHg and 38 within 15 mmHg for systolic blood pressure (SBP), and 36 within 5 mmHg, 43 within 10 mmHg and 45 within 15 mmHg for diastolic blood pressure (DBP). The mean differences were -5.6 (10.2) [mean (SD)] mmHg for SBP and -0.5 (4.5) mmHg for DBP. The ROSSMAX monitor failed to meet any of the criteria for SBP but comfortably passed all of the criteria for DBP. In phase 2.1, the ROSSMAX monitor had 51 measurements within 5 mmHg, 73 within 10 mmHg and 86 within 15 mmHg for SBP, and 71 measurements within 5 mmHg, 93 within 10 mmHg and 98 within 15 mmHg for DBP. The mean differences were -4.5. (9.5) mmHg for SBP and -1.8 (5.0) mmHg for DBP. The ROSSMAX monitor failed to meet any of the criteria for SBP but comfortably passed all of the criteria for DBP. In phase 2.2, 16 subjects had at least two of the differences lying within 5 mmHg and 10 subjects had no differences within 5 mmHg for SBP; 26 subjects had at least two of the differences falling within 5 mmHg and three subjects no differences within 5 mmHg for DBP. The ROSSMAX monitor failed to meet the criteria for SBP but passed the criteria for DBP. CONCLUSIONS: The ROSSMAX monitor cannot be recommended for clinical use in an adult population because it records SBP inaccurately.

Adult↗
PubMed1992

Differential effects of endothelin-1 on the vasorelaxant properties of benzopyran and non-benzopyran potassium channel openers.

1. The effects of endothelin-1 (ET-1) on the vasorelaxant properties of structurally different potassium channel openers (PCOs), BRL-38227, Ro 31-6930, SDZ PCO 400, EMD-52692, RP-49356 and pinacidil, were studied. 2. All PCOs evoked concentration-related relaxations of ET-1 (10 nM) or KCl (20 mM) contracted rat isolated aortic rings denuded of endothelium. BRL-38227, EMD 52692, SDZ PCO 400 and Ro 31-6930 were 11-42 times less potent in relaxing contractions to ET-1 than KCl. In contrast, this differential potency was not observed with RP-49356 or pinacidil. 3. BRL-38227 (0.06-3.0 microM), RP-49356 (0.3-3.0 microM) and pinacidil (0.3-3.0 microM) displaced KCl concentration-response curves to the right of controls, without modifying the maximum response. A subcontractile concentration of ET-1 (0.1 nM) prevented the inhibitory effects of low concentrations of BRL-38227 (0.06-0.1 microM) on KCl responses, but failed to modify those to RP-49356, pinacidil or high concentrations of BRL-38227 (0.3-3.0 microM). The inhibitory effects of BRL-38227 (0.1 microM) were also not changed by ET-3 (1.0 nM) or angiotensin II (0.1 nM). 4. In anaesthetized spontaneously hypertensive rats (SHR), cumulative bolus intravenous administrations of BRL-38227 (1-1000 micrograms kg-1, i.v.), Ro 31-6930 (1-1000 micrograms kg-1, i.v.), RP-49356 (10-1000 micrograms kg-1, i.v.) or nitrendipine (0.1-30 micrograms kg-1, i.v.) produced dose-dependent falls in diastolic blood pressure (DBP).ET-1 (i.v.) evoked a transient fall in DBP (1 pg kg- = 58 + 1 mmHg) which returnedto pre-administration levels within 4 min.5. Pretreatment of anaesthetized SHR with ET-l (1 pg kg-', i.v.) significantly increased the ED,5 (dose to evoke a 15% fall in DBP) values for BRL-38227 and Ro 31-6930. However, ET-l failed to modify the ED,5 values for RP-49356 or nitrendipine. The ED50 values for all of the vasodilators studied were not modified by ET-1.6. Infusion of BRL-38227 (2 pgkg-'min-', i.v.) or RP-49356 (4 pgkg-'min', i.v.) to anaesthetized SHR evoked dose-related falls in DBP, with a corresponding increase in descending aortic blood flow (DABF) and a decrease in total lower body vascular resistance (TLBVR). Pretreatment with ET-1 (1 ptg kg-', i.v.) significantly attenuated the decreases in DBP and TLBVR observed with low doses of BRL-38227, but not RP-49356 or high doses of BRL-38227. In contrast, ET-3 (3 pig kg-, i.v.) failed to modify the effects of BRL-38227 on DBP or TLBVR.7. In conscious SHR, the fall in DBP to BRL-38227 (30 pgkg-', p.o.) was significantly reduced following ET-1 (1 pig kg-', i.a.) treatment. ET-1 (1 pg kg-', i.a.) pretreatment, however, failed to modify the decrease in DBP induced by an equieffective oral dose of RP-49356 (1001pgkg-1).8. In conclusion, ET-1 selectively attenuated the vasorelaxant effects of the potassium channel opener,BRL-38227 and other substituted benzopyrans. The results are compatible with the hypothesis that benzopyran PCOs and ET-1 have affinity for a site that does not recognise RP-49356 or pinacidil. Thus,ET-l can differentiate between structurally unrelated potassium channel openers. The cardiovascular effects of some, but not all, PCOs might be radically modified in the clinical setting by elevated endogenous levels of ET-1 associated with certain diseased states.

Animals↗
PubMed2002

Antiandrogenic effects of dibutyl phthalate and its metabolite, monobutyl phthalate, in rats.

Developmental toxicity following administration of dibutyl phthalate (DBP) and its major metabolite, monobutyl phthalate (MBuP), by gavage was determined in Wistar rats. DBP on days 0-8 of pregnancy induced an increase in the incidence of preimplantation loss at 1250 mg/kg and higher and postimplantation loss at 750 mg/kg and higher. MBuP on days 0-8 of pregnancy produced an increase in the incidence of pre- and postimplantation loss at 1000 mg/kg. DBP on days 7-15 of pregnancy caused an increase in the incidence of fetuses with malformations at 750 mg/kg. MBuP on days 7-15 of pregnancy produced an increased incidence of fetuses with malformations at 500 mg/kg and higher. DBP on days 15-17 of pregnancy resulted in a decrease in the anogenital distance (AGD) of male fetuses and increase in the incidence of fetuses with undescended testes at 500 mg/kg and higher. MBuP on days 15-17 of pregnancy caused a decreased male AGD and increased incidence of fetuses with undescended testes at 250 mg/kg and higher. No effect of DBP and MBuP on the AGD was found in female offspring. The spectrum of fetal malformations, dependence of gestational days of treatment on the manifestation of teratogenicity, and alterations in development of the male reproductive system observed after administration of DBP were in good agreement with those observed after administration of MBuP. These findings suggest that MBuP may be responsible for the induction of developmental toxic effects of DBP. The doses that produced a decrease in the AGD and undescended testes in male offspring were lower than those producing maternal toxicity, fetal malformations after administration during major organogenesis, and embryonic loss. The male reproductive system may be more susceptible than other organ systems to DBP and MBuP toxicity after maternal exposure.

Androgen Antagonists↗
PubMed2004

Efficacy and safety of telmisartan vs. losartan in control of mild-to-moderate hypertension: a multicentre, randomised, double-blind study.

This multicentre, randomised, double-blind, double-dummy, parallel-group study compared the efficacy and safety of telmisartan with those of losartan after 8 weeks' treatment. In total, 330 patients with mild-to-moderate hypertension (systolic blood pressure [SBP] <180 mmHg; diastolic blood pressure [DBP] 95-109 mmHg) were randomly assigned to receive once-daily treatment with telmisartan 40 mg (n = 164) or losartan 50 mg (n = 166). After 4 weeks' treatment, if a patient's DBP was > or = 90 mmHg, the dose was increased to telmisartan 80 mg or losartan 100 mg, respectively. The results show that mean trough seated blood pressure was reduced significantly more in the telmisartan group than that in the losartan group (SBP 12.5 mmHg vs. 9.4 mmHg, p = 0.037; DBP 10.9 mmHg vs. 9.3 mmHg, p = 0.030). The overall DBP response rate (reduction from baseline in mean seated DBP > or = 10 mmHg and/or a mean seated DBP <90 mmHg) at the end of the study in the telmisartan group was higher than that in losartan group (70.1% vs. 58.7%, p = 0.020). At both the low and high doses, the DBP response rates for telmisartan were significantly higher than those for losartan (telmisartan 40 mg vs. losartan 50 mg: 46.3% vs. 32.5%, p = 0.010; telmisartan 80 mg vs. losartan 100 mg: 79.3% vs. 65.3%, p = 0.008). Adverse events with the two treatments were comparable (telmisartan vs. losartan 23.2% vs. 22.9%, p = 0.952). Most events were mild in intensity and abated within 72 h. Thus, telmisartan 40 mg or 80 mg administered once daily can reduce SBP and DBP effectively and safely.

Adolescent↗
PubMed2007

Curcumin and kolaviron ameliorate di-n-butylphthalate-induced testicular damage in rats.

The present study was carried out to evaluate the ameliorative effects of kolaviron (a biflavonoid from the seeds of Garcinia kola) and curcumin (from the rhizome, Curcuma longa L.) on the di-n-butylphthalate (DBP)-induced testicular damage in rats. Administration of DBP to rats at a dose of 2 g/kg for 9 days significantly decreased the relative testicular weights compared to the controls, while the weights of other organs remained unaffected. Curcumin or kolaviron did not affect all the organ weights of the animals. While only DBP treatment significantly increased the testicular malondialdehyde level and gamma-glutamyl transferase activity (gamma-GT), it markedly decreased glutathione level, the testicular catalase, glucose-6-phosphate dehydrogenase, superoxide dismutase, sperm gamma-GT activities and serum testosterone level compared to the control group. Data on cauda epididymal sperm count and live/dead ratio were not significantly affected in the DBP-treated rats. Alone, DBP treatment resulted in a 66% decrease in spermatozoa motility and a 77% increase in abnormal spermatozoa in comparison to control. DBP-treated rats showed marked degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. The DBP-induced injuries in biochemical, spermatological parameters and histological structure of testis were recovered by treatment with kolaviron or curcumin. The pattern in the behaviour of these compounds might be correlated with their structural variations. Our results indicate that kolaviron and curcumin protect against testicular oxidative damage induced by DBP. The chemoprotective effects of these compounds may be due to their intrinsic antioxidant properties and as such may prove useful in combating phthalate-induced reproductive toxicity.

Animals↗
PubMed1998

Decorin-binding protein of Borrelia burgdorferi is encoded within a two-gene operon and is protective in the murine model of Lyme borreliosis.

Isolated outer membranes of Borrelia burgdorferi were used in immunoblotting experiments with sera from immune mice to identify new putative Lyme disease vaccine candidates. One immunoreactive polypeptide migrated on polyacrylamide gels just proximal to outer surface protein C and comigrated with [3H]palmitate-labeled polypeptides. A degenerate oligonucleotide primer based upon internal amino acid sequence information was used to detect the corresponding gene within a B. burgdorferi total genomic library. The relevant open reading frame (ORF) encoded a polypeptide comprised of a 24-amino-acid putative signal peptide terminated by LLISC, a probable consensus sequence for lipoprotein modification, and a mature protein of 163 amino acids. Immunoblots of a recombinant fusion protein corresponding to this ORF supported the idea that the encoded protein was a previously reported decorin-binding protein (DBP) of B. burgdorferi N40 (B. P. Guo, S. J. Norris, L. C. Rosenberg, and M. Höök, Infect. Immun. 63:3467-3472, 1995). However, further DNA sequencing revealed the presence of a second ORF, designated ORF-1, whose termination codon was 119 bp upstream of the dbp gene. ORF-1 also encoded a putative lipoprotein with a mature length of 167 amino acids. Northern blots, Southern blots, and primer extension analyses indicated that ORF-1 and dbp comprised a two-gene operon located on the 49-kb linear plasmid. Both proteins, which were 40% identical and 56% similar, partitioned into Triton X-114 detergent extracts of B. burgdorferi isolated outer membranes. Mice infected with B. burgdorferi produced high titers of antibodies against the ORF-1-encoded protein and DBP during both early and later stages of chronic infection. Both DBP and the ORF-1-encoded protein were sensitive to proteinase K treatment of intact borreliae, suggesting that they were surface exposed. In active immunization experiments, 78% of mice immunized with recombinant DBP were immune to challenge. While it is not clear whether the two lipoproteins encoded by the ORF-1-dbp operon have analogous decorin-binding functions in vivo, the combined studies implicate DBP as a new candidate for a human Lyme disease vaccine.

Adhesins, Bacterial↗
PubMed1977

Adenovirus type 2 coded single-stranded DNA binding protein: in vivo phosphorylation and modification.

The adenovirus type 2-coded single-stranded DNA binding protein (DBP) was shown to be a phosphoprotein and to exist in at least two forms that differ in mobility by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. After a 30-min pulse with [35S]methionine or 32PO4, 35S- or 32P-labeled DBP had a nominal molecular weight of 74,000 whereas after a 30-min label followed by a 20-h chase, 35S- and 32P-labeled DBP had a nominal molecular weight of 77,000. Both large and small forms of 35S- and 32P-labeled DBP bound to single-stranded DNA-cellulose columns and were eluted by 0.4 to 0.6 M NaCl; both forms also were immunoprecipitated by antiserum against adenovirus type 1-simian virus 40-induced tumor cells (this antiserum contains antibodies against DBP) and by monospecific antiserum against 95 to 99% purified DBP. With highly purified 32P-DBP labeled 7 to 10 h postinfection, it was shown that the 32P radioactivity was firmly associated with protein material (i.e., not contaminating nucleic acids or phospholipids) and had properties expected of a phosphoester of an amino acid; paper electrophoresis of acid hydrolysates of this preparation identified phosphoserine but not phosphothreonine. Phosphoserine but not phosphothreonine was also identified in acid hydrolysates of another preparation of 32P-DBP labeled for 30 min, chased for 20 h, and then immunoprecipitated by adenovirus type 1-simian virus 40 antiserum.

Adenoviruses, Human↗
PubMed1990

Conserved region 3 of the adenovirus type 5 DNA-binding protein is important for interaction with single-stranded DNA.

The adenovirus-encoded single-stranded DNA-binding protein (DBP) functions in viral DNA replication and several aspects of RNA metabolism. Previous studies (G. A. M. Neale and G. R. Kitchingman, J. Biol. Chem. 264:3153-3159, 1989) have defined three highly conserved regions in the carboxy-terminal domain of the protein (amino acids 178 to 186, 322 to 330, and 464 to 475) that may be involved in the binding of the protein to single-stranded DNA. We examined the role of conserved region 3 (464 to 475) by constructing nine classes of point mutants with from one to four amino acid changes. The point mutants were tested for their ability to assist adeno-associated virus DNA replication. All nine differed from wild-type DBP; seven were essentially nonfunctional, whereas two had 55 and 145%, respectively, of the wild-type DBP helper activity. Three of the mutants were found to be temperature sensitive, with significantly greater helper activity at 33 degrees C than at 37 degrees C. All nine mutants produced essentially wild-type levels of protein. One monoclonal antibody against the DBP, termed 2/4, did not immunoprecipitate the mutant DBPs as well as wild-type DBP, indicating either that the antibody recognized sequences around CR3 or that the conformation of the protein around the epitope recognized by 2/4 had changed. Two of the three temperature-sensitive DBP mutants bound to single-stranded DNA-cellulose with the same affinity as wild-type DBP at 4 degrees C; the remaining mutants all showed reduced affinity. These results demonstrated that many of the residues within conserved region 3 of the DBP are important for interaction of the protein with nucleic acid.

Adenoviruses, Human↗
PubMed1994

Helix-destabilizing properties of the adenovirus DNA-binding protein.

The adenovirus DNA-binding protein (DBP) is a multifunctional protein that is essential for viral DNA replication. DBP binds both single-stranded and double-stranded DNA as well as RNA in a sequence-independent manner. Previous studies showed that DBP does not promote melting of duplex poly(dA-dT) in contrast to prokaryotic single-strand-binding proteins. However, here we show that DBP can displace oligonucleotides annealed to single-stranded M13 DNA. Depending upon the DBP concentration, strands of at least 200 nucleotides can be unwound. Although unwinding of short (17-bp), fully duplex DNA is facilitated by DBP, unwinding of larger (28-bp) duplexes is only possible if single-stranded protruding ends are present. These protruding ends must be at least 4 nucleotides long for optimal unwinding, and both 5' and 3' single-stranded overhangs suffice. DBP-promoted strand displacement is sensitive to MgCl2 and NaCl and not dependent upon ATP. Our results suggest that DBP, through formation of a protein chain on the displaced strand, may destabilize duplex DNA ahead of the replication fork, thereby assisting in strand displacement during replication.

Adenoviridae↗