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PubMed2000

CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA.

Human immunodeficiency virus type 1 (HIV-1) Tat interacts with cyclin T1 (CycT1), a regulatory partner of CDK9 in the positive transcription elongation factor (P-TEFb) complex, and binds cooperatively with CycT1 to TAR RNA to recruit P-TEFb and promote transcription elongation. We show here that Tat also stimulates phosphorylation of affinity-purified core RNA polymerase II and glutathione S-transferase-C-terminal-domain substrates by CycT1-CDK9, but not CycH-CDK7, in vitro. Interestingly, incubation of recombinant Tat-P-TEFb complexes with ATP enhanced binding to TAR RNA dramatically, and the C-terminal half of CycT1 masked binding of Tat to TAR RNA in the absence of ATP. ATP incubation lead to autophosphorylation of CDK9 at multiple C-terminal Ser and Thr residues, and full-length CycT1 (amino acids 728) [CycT1(1-728)], but not truncated CycT1(1-303), was also phosphorylated by CDK9. P-TEFb complexes containing a catalytically inactive CDK9 mutant (D167N) bound TAR RNA weakly and independently of ATP, as did a C-terminal truncated CDK9 mutant that was catalytically active but unable to undergo autophosphorylation. Analysis of different Tat proteins revealed that the 101-amino-acid SF2 HIV-1 Tat was unable to bind TAR with CycT1(1-303) in the absence of phosphorylated CDK9, whereas unphosphorylated CDK9 strongly blocked binding of HIV-2 Tat to TAR RNA in a manner that was reversed upon autophosphorylation. Replacement of CDK9 phosphorylation sites with negatively charged residues restored binding of CycT1(1-303)-D167N-Tat, and rendered D167N a more potent inhibitor of transcription in vitro. Taken together, these results demonstrate that CDK9 phosphorylation is required for high-affinity binding of Tat-P-TEFb to TAR RNA and that the state of P-TEFb phosphorylation may regulate Tat transactivation in vivo.

Adenosine Triphosphate↗

PubMed2005

HIV-1 TAR RNA: the target of molecular interactions between the virus and its host.

HIV-1 TAR RNA is the binding site of the viral protein Tat, the trans-activator of the HIV-1 LTR. It is present at the 5' end of all HIV-1 spliced and unspliced mRNAs in the nucleus as well as in the cytoplasm. It has a highly folded stem-bulge-loop structure, which also binds cellular proteins to form ribonucleoprotein complexes. The Tat-Cyclin T1-CDK9 complex is the main component in the trans-activation of HIV-1 and its affinity for TAR is regulated through Tat acetylation by histone acetyl transferases. Recent studies show that this complex is able to recruit other cellular partners to mediate efficient transcriptional elongation. TRBP, PKR and La bind directly to the TAR RNA structure and influence translation of HIV-1 in either positive or negative manners. Some mutations in TAR RNA severely impair HIV-1 trans-activation, translation and viral production, showing its functional importance. The overexpression or suppression of several TAR RNA-binding proteins has a strong impact on viral replication pointing out their major role in the viral life cycle. TAR RNA has been the target of drug development to inhibit viral replication. Recent data using small molecules or RNA-based technologies show that acting on the TAR RNA or on its viral and cellular binding factors effectively decreases virion production.

Acetyltransferases↗

PubMed2005

Thrombocytopenia-absent radius (tar) syndrome: a case with agenesis of corpus callosum, hypoplasia of cerebellar vermis and horseshoe kidney.

The thrombocytopenia-absent radius (TAR) syndrome (MIM 274000) is a congenital malformation syndrome characterised by bilateral absence of the radii with present thumbs, hypomegakaryocytic thrombocytopenia and a number of additional features including skeletal and cardiac anomalies. Mental retardation, reported in about 7% of patients, is usually secondary to intracranial hemorrhage. In 1994 there was a single report of a girl with TAR syndrome and hypoplasia of the cerebellar vermis and corpus callosum and in 2003 another case of TAR syndrome with cerebellar dysgenesis has been reported. In 2000 there was first report of horseshoe kidney in association with TAR syndrome followed by a clinical study of 34 cases with TAR syndrome in 2002 where horseshoe kidney was noted in two cases. Here we report of a girl with TAR syndrome, severe mental retardation, agenesis of corpus callosum, hypoplasia of cerebellar vermis and horseshoe kidney. There is no previous report of a child with TAR syndrome and all those associated anomalies in the same patient.

Abnormalities, Multiple↗

PubMed1979

Tar gel-phototherapy for psoriasis. Combined therapy with suberythemogenic doses of fluorescent sunlamp ultraviolet radiation.

To determine the efficacy of suberythemogenic ultraviolet phototherapy in conjunction with administration of a tar gel (SEUV TG), patients with widespread psoriasis were treated by application of a tar gel preparation followed after 12 hours by suberythemogenic doses of fluorescent sunlamp irradiation. In paired comparison studies, therapeutic effects of the following treatments were evaluated: SEUV-TG, a more conventional erythemogenic tar gel phototherapy regimen (modified Goeckerman), the tar gel alone, and SEUV irradiation following application of gel vehicle. Response to therapy was monitored with a severity score system. In patients with psoriasis responsive to phototherapy, smaller quantities of UV energy administered in combination with a tar gel were at least as effective as larger erythemogenic doses. Production of erythema with fluorescent sunlamp radiation does not appear to be necessary to improve psoriasis. Both UV radiation and tar gel have beneficial effects on psoriasis, but the combination is superior.

Adolescent↗

PubMed1976

Reactions to cigarettes as a function of nicotine and "tar".

Experiments carried out to examine the effects of nicotine and "tar" on the extent of and subjective reactions to cigarette smoking. It was confirmed that smokers rate commercial, low-nicotine cigarettes as less "strong" and less "satisfying" than their usual brands. Since such cigarettes deliver reduced amounts of tar as well as of nicotine, an experiment to distinguish between the two was carried out with special cigarettes. Ratings of "strength" were directly related to nicotine but were not affected by tar. The numbers of cigarettes smoked fell slightly as their estimated delivery of nicotine increased, but tar had no effect on this index. The urinary excretion of nicotine was correlated with the rated yields of nicotine for the different cigarettes, but there was also evidence that subjects tended to adjust their manner of smoking so as to titrate their doses of nicotine. The results are interpreted as indicating a role for nicotine, but not for tar, in the maintenance of cigarette smoking behavior, and as support for the view that less harmful cigarettes should have a high yield of nicotine relative to tar.

Adult↗

PubMed1986

Tar yields of cigarettes and the risk of oesophageal cancer.

The relationship between cigarettes with varying tar yields and the risk of oesophageal cancer was evaluated using data from a hospital-based case-control study conducted in Northern Italy on 129 histologically confirmed cases and 426 controls with acute, non-neoplastic of digestive diseases unrelated to tobacco or alcohol consumption. Compared with never-smokers, the relative risks of developing cancer of the oesophagus were 2.9 for subjects who smoked mainly middle- or low-tar (less than 22 mg) cigarettes and 8.9 for those smoking high-tar cigarettes (greater than or equal to 22 mg). The difference between the two categories was evident among ever-smokers and only current smokers, was not explained by adjustment for the major covariates of interest (social class, alcohol consumption and dietary indicators), and persisted when allowance was made for duration of smoking and number of cigarettes smoked per day by means of multiple regression analysis. The present findings suggest that the relation between tar deliveries of cigarettes and risk may be even more marked for oesophageal than for lung cancer. Further, they have important public health implications, in consideration of the current relatively high tar yields of Italian cigarettes, particularly in a few areas of north-eastern Italy where death certification rates from cancer of the oesophagus are among the highest in Europe. Nonetheless, in this study, smokers of prevalently low- to mid-tar cigarettes still did experience a significantly higher oesophageal cancer risk than life-long non-smokers.

Adult↗

PubMed1994

Cigarette tar promotes neutrophil-induced DNA damage in cultured lung cells.

We have investigated the ability of aqueous cigarette tar extracts to promote human polymorphonuclear leukocyte (PMNL)- and hydrogen peroxide (H2O2)-induced DNA single-strand breaks (DNA-SSB) in cultured human lung cells. Tar extract itself did not cause any DNA-SSB formation, whereas PMNL (activated with phorbol myristate acetate (PMA)) and H2O2 both caused a small but significant DNA-SSB formation on their own. On the other hand, if cells were first treated with tar extract and then exposed to PMA-activated PMNL or H2O2, the DNA-SSB formation increased considerably. Pretreatment with iron-loaded tar extracts caused a greater increase after PMNL exposure than pretreatment with regular tar extracts. No DNA-SSB formation was found if catalase was present during the PMNL exposure, indicating that H2O2 was important for the PMNL-induced DNA damage. These findings suggest that cigarette tar promotes neutrophil-induced DNA damage in human lung cells and that this effect can be further potentiated by iron. This can be of importance in explaining the carcinogenic effects of cigarette smoking and the increased risk of lung cancer among asbestos workers and iron miners who smoke.

Bronchi↗

PubMed1993

Evaluation of the relationship between PAH content and mutagenic activity of fumes from roofing and paving asphalts and coal tar pitch.

Fume condensates from asphalt and coal tar pitch were evaluated to determine if polycyclic aromatic hydrocarbon (PAH) composition, crude oil source, or temperature at which the fume was generated correlated with mutagenic activity. The fume condensates were tested for mutagenic activity using a modified Ames Test. Benzo[a]pyrene (BP) and other PAHs were detected in all samples. The concentration of BP in coal tar pitch was 18,100 ppm while the concentration in asphalt was less than 6 ppm. Coal tar fumes contained between two and three orders of magnitude more BP, as well as other PAH species, than asphalt fumes. Coal tar fume condensates were also approximately 100 times more mutagenic than those of asphalt. Generation temperature, crude oil source, and/or process conditions affected the PAH concentrations but not the mutagenicity in roofing asphalt fume condensates. With paving asphalt fumes, PAH content and mutagenicity varied with crude oil source but not with processing conditions; due to limited data, it was not possible to determine the effect of generation temperature. Coal tar pitch fumes generated at 316 degrees C contained significantly higher concentrations of PAHs than those generated at 232 degrees C and the mutagenic activity generally paralleled the PAH content. A subset of the paving asphalts demonstrated good correlation between mutagenicity and three- to seven-ring PAH content. These results indicate that asphalt fumes are far less mutagenic than coal tar fumes. Asphalt fumes differ in their ability to induce mutagenic activity, and, most likely, in their potential carcinogenicity.

Air Pollutants, Occupational↗

PubMed1989

Effect of smoked tobacco tar on the growth, cytolytic action, DNA synthesis, and gene expression of herpes simplex virus.

Previous experiments have shown that topical application of smoked tobacco tar condensate to HSV-infected oral mucosae of mice promotes neoplastic changes. Although HSV is an oncogenic virus, the virus must be inactivated and lose its cytolytic activity to be oncogenic in vitro and in vivo. Therefore, we investigated the effect of the water-extractable components of smoked tobacco tar condensate (smoked tobacco tar extract) on the growth, cytolytic activity, DNA synthesis, and gene expression of type 1 herpes simplex virus (HSV-1). Diluted tar extracts in tissue culture medium markedly inhibited the replication and cytolytic activity of HSV-1 in vitro. The smoked tobacco tar extract also notably inhibited the synthesis of viral DNA and late gene expression in a dose-dependent manner. The synthesis of alpha- and beta-classes of viral proteins was not affected by the extract. Therefore, it is probable that the smoked tobacco tar extract inhibits the synthesis of viral DNA directly rather than indirectly by depressing early gene expression.

Animals↗

PubMed1988

Smoking and lung cancer: risk as a function of cigarette tar content.

The hypothesis of reduction in lung cancer risk associated with the adoption of low-tar cigarettes was examined in a subset of subjects from a population-based, case-control study of incident primary lung cancer among New Jersey white men. Risk was related to time-weighted average tar levels of cigarettes smoked in 1973-1980. Unadjusted estimates of risk were significantly low for the lowest tar (less than 14 mg/cig) smokers [odds ratio = 0.53 (0.29,0.97)] compared with the highest (21.1-28 mg/cig). However, adjustment by age and total pack-years rendered the risk reduction insignificant. Of note was the finding that cases who smoked low-tar cigarettes compensated for reducing tar by increasing the number of cigarettes they smoked by almost half a pack per day from the years 1963-1972 to 1973-1980, while in the same period controls and high-tar cigarette smoking cases did not increase the numbers smoked.

Humans↗

PubMed1988

1-Hydroxypyrene as an indicator of the mutagenicity of coal tar after activation with human liver preparations.

Liver S9 fractions were prepared from male Wistar rats, either non-induced or induced with Aroclor 1254 and from 5 human kidney transplant donors. The preparations were compared for their ability to metabolize the premutagens present in coal tar to mutagenic metabolites in the Salmonella mutagenicity assay towards strain TA98. Low levels of mutagenicity of coal tar were seen with human S9 preparations. The differences between the S9 mix of the 5 donors in capacity to activate premutagens were approximately 6-fold. The activation of coal tar by rat liver S9 preparations was higher than by the human S9 preparations. The metabolic conversion of pyrene in coal tar to 1-hydroxypyrene by the same human S9 preparations was determined in a parallel assay. 3 human preparations showed a high correlation between the formation of 1-hydroxypyrene and bioactivation of coal tar to mutagenic metabolites. The slope values of the individual regression lines were equal, suggesting that 1-hydroxypyrene is a good indicator for the activation of premutagens present in coal tar.

Animals↗

PubMed2005

Molecular characterisation of birch bark tar by headspace solid-phase microextraction gas chromatography-mass spectrometry: a new way for identifying archaeological glues.

To develop an analytical methodology, as non-destructive as possible, suitable for the identification of natural substances from archaeological origin, we studied the potentiality of solid-phase microextraction (SPME) for analysing birch bark tar, an adhesive commonly used during ancient times. First of all, birch bark tars were produced by a controlled heating of birch bark. The two kinds of samples obtained using different processes of fabrication, one at liquid state, the second one at solid state, were then analysed by headspace HS-SPME-GC-MS. Different conditions of sample treatment were tested (two different fibre coatings, various times and temperatures of extraction) in order to suggest optimal conditions for the analysis of birch bark tar. Both samples were shown to be rich in volatile organic components. Two main groups of constituents, namely phenolic compounds issued from lignin or tannin known to be present in bark and sesquiterpenoid hydrocarbons, secondary metabolites largely distributed in the plant kingdom, were detected for the first time in birch bark tar. HS-SPME-GC-MS appears thus to be a very efficient method for investigating the volatiles emitted by plant tars and could be further used for the study of birch bark tar samples issued from archaeological context.

Adhesives↗

PubMed1997

Effects of varying marijuana potency on deposition of tar and delta9-THC in the lung during smoking.

To determine whether smoking more, compared to less, potent marijuana (MJ) cigarettes to a desired level of intoxication ("high") reduces pulmonary exposure to noxious smoke components, in 10 habitual smokers of MJ, we measured respiratory delivery and deposition of tar and delta9-tetrahydrocannabinol (THC), carboxyhemoglobin (COHb) boost, smoking topography, including cumulative puff volume (CPV) and breathholding time, change in heart rate (deltaHR) and "high" during ad lib smoking of 0, 1.77, and 3.95% MJ cigarettes on 3 separate days. At each session, subjects had access to only a single MJ cigarette. On average, smoking topography and COHb boost did not differ across the different strengths of MJ, while THC delivery, as well as HR, were significantly greater (p < 0.01) and tar deposition significantly less (p < 0.03) for 3.95% than 1.77% MJ. Although individual adaptations in smoking topography for 3.95% compared to 1.77% MJ were highly variable, three subjects with the lowest 3.95% MJ:1.77% MJ ratios for CPV also displayed the lowest 3.95% MJ:1.77% MJ ratios for tar deposition. In vitro studies using a standardized smoking technique revealed a mean 25% lower tar yield from 3.95% than 1.77% MJ (p < 0.05), but no difference between 1.77% and 0% marijuana. Under the conditions of this study, we conclude that tar delivery is reduced relative to THC content in a minority of subjects, and this reduction appears to be due to a reduced intake of smoke (decreased CPV) and/or a reduced tar yield from the stronger MJ preparation.

Adult↗

PubMed1999

Effect of filter vent blocking on carbon monoxide exposure from selected lower tar cigarette brands.

Two studies were conducted to determine the effect of blocking filter vents on carbon monoxide (CO) exposure under ad lib smoking conditions. In Study 1, 12 daily cigarette smokers smoked cigarettes from the brands Now (1 mg tar by the FTC Method) and Marlboro Lights (10 mg tar) under each of two vent-blocking conditions (unblocked and finger blocked). Blocking filter vents with fingers led to an 85% increase in CO for the brand Now, but had no added effect on CO exposure from the Marlboro Lights. In Study 2, another 12 daily cigarette smokers smoked cigarettes from each of four additional brands: Carlton (1 mg tar), Now (2 mg tar), Virginia Slims Ultra-lights (5 mg tar), and Virginia Slims Lights (8 mg tar). Blocking filter vents with the lips caused all four brands to produce equal CO exposures. Blocking vents increased smokers' exposure to CO by 239% when smoking Carltons and by 44% when smoking Nows. No significant increases in CO with blocking were found for either of the Virginia Slims brands. These results suggest that the degree to which a brand is ventilated determines whether that brand is susceptible to increased CO yields as a result of vent blocking.

Administration, Inhalation↗

PubMed2000

A double blind, randomized, controlled clinical trial to assess the efficacy of a new coal tar preparation (Exorex) in the treatment of chronic, plaque type psoriasis.

Exorex is a new topical formulation for the treatment of psoriasis; it contains 1% coal tar and a synthetic analogue resembling components identified in banana skin (a complex of esterified essential fatty acids). To determine whether the esterified essential fatty acid complex confers any therapeutic advantage over coal tar alone, patients with chronic plaque psoriasis (n = 20) were entered into a double-blind, randomized, right/left comparison of Exorex, and Exorex without the essential fatty acid component (known hereafter as coal tar control) for 8 weeks. Target plaques were scored (0-4) for erythema, desquamation and infiltration at day 0 and at 2 week intervals throughout the study. No significant differences were detected between Exorex and coal tar control with respect to changes in the summed scores at baseline and following 8 weeks of treatment (mean difference in summed score changes from baseline between Exorex and coal tar control 0.2, 95% confidence interval - 0.44 to 0.84; P = 0.52) or in the area under the response-time curve (P = 0.16). Mean percentage improvement in summed scores of target plaques were 53.9% (SE = 4%) and 56.1% (SE = 4.9%) for Exorex and coal tar control, respectively. Results suggest that the complex of esterified essential fatty acids is not exerting any clinically important therapeutic effect in the treatment of chronic plaque psoriasis.

Administration, Topical↗

PubMed2003

Calcipotriol versus coal tar: a prospective randomized study in stable plaque psoriasis.

BACKGROUND: Topical therapies are the first line of treatment for patients with stable plaque psoriasis (SPP) affecting a limited body surface area. Very few trials comparing newer agents, such as 0.005% topical calcipotriol, with conventional modes of therapy, such as coal tar ointment, have been reported. METHODS: A prospective, right-left randomized, investigator-blinded study with a 12-week treatment period and an 8-week follow-up period was performed. Thirty-six patients with nearly bilaterally symmetrical SPP lesions on the limbs were instructed to apply 5% coal tar ointment overnight on one side once daily and 0.005% calcipotriol ointment on the other side twice a day. All patients were advised to expose both sides to the sun for 2 h every day. Psoriatic lesions and progress during treatment were evaluated using the severity (0-3) scale of erythema, scaling and induration (ESI score). Evaluation was carried out every 2 weeks during the treatment period and monthly during follow-up. At the end of 12 weeks, patients with > 75% reduction in the ESI score were considered to be markedly improved, those with 51-75% reduction to be moderately improved, those with 26-50% reduction to be minimally improved and those with < 25% to be non-responders. Self-assessment by the patients regarding the efficacy and acceptability of the two modalities was on a five-point scale. Serum calcium, serum phosphate, total and differential serum proteins, 24-h urinary calcium and phosphate were monitored both at baseline and after completion of therapy. RESULTS: Thirty of the 36 recruited patients completed the study. The difference in clinical response between the two sides was statistically significant at 4, 6 and 8 weeks, with the percentage reduction in ESI score with calcipotriol being 65.7 +/- 12.2% compared with 45.8 +/- 16.6% with coal tar at 8 weeks (P < 0.01, t = 6.4). However, the difference in clinical response at 10 and 12 weeks between the two sides was not significant, with a mean reduction of 71.9 +/- 13.3% in ESI score on the calcipotriol-treated side compared with 69.4 +/- 15.4% with coal tar ointment (P > 0.05). In the follow-up period of 8 weeks, recurrence of lesions was noted in 10% of patients treated with calcipotriol compared with 16.7% in those treated with coal tar after an average period of 6 +/- 1.2 and 5 +/- 1.3 weeks, respectively (P > 0.05). CONCLUSIONS: It was found that 0.005% calcipotriol ointment produced a faster initial response and had better cosmetic acceptability in patients, although after a long period of treatment, i.e. 12 weeks, 5% coal tar ointment had comparable efficacy. There was no statistically significant difference in the relapse rates between the two modalities.

Administration, Topical↗

PubMedDate not supplied

A study on the mutagenicity of tobacco smoke from low-tar cigarettes.

A series of 16 low-tar cigarettes, yielding from 1 to 10 mg of tar, were smoked on a modified cigarette smoking machine that collected both mainstream (MS, inhaled) smoke and sidestream (SS, between puffs) smoke. The SS smoke is the major contributor to environmental tobacco smoke. The collected MS and SS smoke condensates were evaluated for mutagenicity by the Ames test and compared with MS and SS smoke condensates from a high-tar cigarette. Both MS and SS condensates of low-tar cigarettes (LTCs) were tested with the Salmonella strains TA1538 and TA100. Except for three cigarettes, the MS smoke mutagenicities of the LTC smoke condensates were significantly reduced (about 30%) when compared with a control, high-tar (23-mg) cigarette. Opposite results were obtained for the SS smoke condensates, which were more mutagenic (about 20%) than the SS smoke condensate of the high-tar cigarette. Thus, LTC mainstream smoke may be less hazardous to the LTC smoker, whereas LTC sidestream may emit more mutagenic compounds into environmental tobacco smoke, which, through passive inhalation, could affect both smokers and nonsmokers.

Humans↗

PubMed1982

Induction of neonatal rat skin and liver aryl hydrocarbon hydroxylase by coal tar and its constituents.

Topical application of coal tar solution (USP) to neonatal rats resulted in the induction of skin and liver aryl hydrocarbon hydroxylase (AHH) activities. Furthermore indirect exposure of the animals to coal tar vapors resulted in induction of the enzyme in skin and liver. Cutaneous application of coal tar to pregnant rats resulted in induction of skin and liver AHH activity in both mothers and prenatal rats. Among several defined constituents of coal tar tested benzo(a)pyrene (BP), anthracene and acridine were found to have measurable induction effects on neonatal rat skin and liver AHH. These studies indicate that therapeutic coal tar solution as well as selected defined chemical constituents of coal tar are capable of altering the activity of AHH in skin and liver.

Acridines↗