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Biomedical subjects

A K Verma

Publications and source records attributed to A K Verma.

At least 127 records · Page 7Linked to original sources
PubMed1986

Mouse skin tumor promoting activity of orange peel oil and d-limonene: a re-evaluation.

Orange peel oil has previously been shown to be a promoter of mouse skin tumors. It has been assumed that this activity is due to its major (95%) constituent, d-limonene. We have tested both orange peel oil and purified d-limonene as skin tumor promoters in a two-stage skin carcinogenesis model in which tumors were initiated with 7,12-dimethylbenz[a]-anthracene. We confirmed that topically applied orange peel oil is a very weak promoter of both skin papillomas and carcinomas. However, this promotional activity could not be accounted for by topically applied d-limonene. We thus feel that one or more minor components of orange peel oil has promotional activity. Neither orange peel oil nor d-limonene had promotional activity when given via the diet.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Modulation of mouse skin tumor promotion by dietary 13-cis-retinoic acid and alpha-difluoromethylornithine.

The effects of dietary supplementation of 13-cis-retinoic acid (13-cis-RA) and alpha-difluoromethylornithine (DFMO) in the drinking water on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation was determined. Administration of 13-cis-RA in the diet and DFMO in the drinking water was started 1 week and 2 days before the first TPA application to the dimethylbenz[a]anthracene-initiated skin of either female CD-1 or SENCAR mice, respectively. Dietary 13-cis-RA failed to inhibit both the tumor yield and the incidence; papillomas per mouse at 0, 5, 50, 100 and 200 mg/kg diet 13-cis-RA doses were 25, 30, 22, 28 and 25 respectively at 18 weeks of promotion treatment and at all doses 100% of the mice bore papillomas. However, dietary 13-cis-RA dramatically reduced the size of skin tumor promoted with TPA. 13-Cis-RA at doses of 5, 50, 100 and 200 mg/kg diet inhibited skin papillomas (greater than 4 mm diameter) per mouse by 28, 55, 76 and 93%, respectively. Retinoid treatment did not affect body weight gains and the survival was more than 80% in all groups. In accord with our previous findings, DFMO when given in drinking water, was a very effective inhibitor of mouse skin tumor promotion by TPA; DFMO at 0.25% concentration inhibited the number of papillomas by 50%. Inhibition of skin tumor promotion by combined treatments with dietary 13-cis-RA (100 mg/kg) and DFMO (0.25%) in the drinking water was possibly additive. The retinoid and DFMO preclude TPA-increased ornithine decarboxylase (ODC) activity and the accumulation of putrescine by differential effects on ODC, an enzyme associated with skin tumor promotion by TPA.

Animals↗
PubMed1986

Involvement of protein kinase C activation in ornithine decarboxylase gene expression in primary culture of newborn mouse epidermal cells and in skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.

The role of protein kinase C in ornithine decarboxylase (ODC; EC 4.1.1.17) gene expression in primary culture of newborn mouse epidermal cells (MEC) from BALB/c mice and in skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) in female CD-1 mice was determined. A time course and the dose-response curves of ODC induction paralleled that of ODC mRNA induction by TPA in MEC. TPA treatment did not elicit any change in the size of ODC mRNA. The magnitude of ODC induction was proportional to the amount of ODC mRNA increased by TPA. TPA (2 X 10(-7) M) failed to induce ODC activity in MEC plated in Ca2+-deprived medium; TPA induction of ODC could be resumed upon Ca2+ restoration in the medium. 1-Oleoyl-2-acetylglycerol, a membrane-permeable diacylglycerol which activates protein kinase C, induced at the same rate both ODC activity and the amount of ODC mRNA in MEC. Phospholipase C, which releases diacylglycerol from membrane phospholipids, also induced ODC activity; 0.02 units of phospholipase C per ml led to about a 50-fold increase in ODC activity at 6 h after treatment. Phospholipase A2 was ineffective. Phospholipase C-induced ODC activity correlated with an increased level of ODC mRNA. Furthermore, palmitoylcarnitine, an inhibitor of protein kinase C, inhibited epidermal ODC induction and the increased level of ODC mRNA by TPA. Also, palmitoylcarnitine inhibited skin tumor promotion by TPA; application of 3 mumol of palmitoylcarnitine in conjunction with each promotional treatment with 10 nmol of TPA to the initiated skin of female CD-1 mice inhibited tumor formation. Taken together, we conclude that activation of protein kinase C may be an early event in ODC gene transcription and skin tumor promotion by TPA.

Animals↗
PubMed1986

Brain edema.

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Blood-Brain Barrier↗
PubMed1985

Inhibition of ornithine decarboxylase activity by small doses of alpha-difluoromethylornithine.

The induction of ornithine decarboxylase (ODC) appears to be an important aspect of carcinogenesis. Agents which inhibit ODC have been shown to preclude cancer formation in many organ systems. We studied the dose and dose schedule of alpha-difluoromethylornithine (DFMO), a suicide inhibitor of ODC, needed to effectively inhibit ODC activity in mice. Our data demonstrate that doses many-fold lower than comparable maximal tolerated doses in humans can inhibit ODC activity in mice. In addition, a simplified, once daily dosage of DFMO appears adequate.

Animals↗
PubMed1985

Inhibition of phorbol ester-caused synthesis of mouse epidermal ornithine decarboxylase by retinoic acid.

The mechanisms by which topically applied retinoic acid to mouse skin inhibits tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced epidermal ornithine decarboxylase activity were analyzed. Retinoic acid inhibition of the induction of epidermal ornithine decarboxylic activity was not the result of nonspecific cytotoxicity, production of a soluble inhibitor of ornithine decarboxylase, or direct effect on its activity. In addition, inhibition of TPA-caused increased ornithine decarboxylase activity does not appear to be due to enhanced degradation and/or post-translational modification of ornithine decarboxylase by transglutaminase-mediated putrescine incorporation. We found that retinoic acid inhibits the synthesis of ornithine decarboxylase caused by TPA. Application of 10 nmol TPA to mouse skin led to a dramatic induction of epidermal ornithine decarboxylase activity which was paralled by increased [3H]difluoromethylornithine binding and an increased incorporation of [35S]methionine into the enzyme. Application of 17 nmol retinoic acid 1 h prior to application of 10 nmol TPA to skin resulted in inhibition of the induction of activity which accompanied inhibition of [3H]difluoromethylornithine binding and [35S]methionine incorporation into ornithine decarboxylase protein as determined by the tube-gel electrophoresis of the enzyme immunoprecipitated with monoclonal antibodies to it. Inhibition of ornithine decarboxylase synthesis was not the result of the inhibitory effect of retinoic acid on general protein synthesis. The results indicate that retinoic acid possibly inhibits TPA-caused synthesis of ornithine decarboxylase protein selectively.

Acyltransferases↗
PubMed1985

Evidence against involvement of the human erythrocyte plasma membrane Ca2+-ATPase in Ca2+-dependent K+ transport.

Two tests were performed to assess the relationship between the Ca2+-activated K+ channel and the Ca2+-pumping ATPase in human erythrocytes. Antibodies against the purified ATPase inhibited the ATPase in resealed erythrocytes, but had no effect on the K+ channel (as assessed by Rb+ efflux). Reconstituted liposomes containing the purified active Ca2+-pumping ATPase showed no Ca2+-activated Rb+ influx. Both of these results suggest that some molecule other than the Ca2+-ATPase is responsible for the K+ channel.

Antibodies↗
PubMed1985

Hyperthermia and polyamine biosynthesis: decreased ornithine decarboxylase induction in skin and kidney after heat shock.

The effect of hyperthermia treatments on ornithine decarboxylase (ODC) induction in mouse tissue was determined both in vitro and in vivo. In vitro, the addition of 12-0-tetradecanoylphorbol-13-acetate (TPA) to adult mouse skin pieces incubated at 37 degrees C in serum-free MEM led to a dramatic increase in epidermal ODC activity 5 hours following treatment. In contrast, incubation temperatures of 40 degrees C for the entire 5 hour incubation period rendered the skin pieces unresponsive to TPA for ODC induction. This inhibition of ODC induction was not the result of thermal skin kill, inactivation of TPA, or a general effect on epidermal protein synthesis. The inhibition of ODC induction could be reversed by switching the incubation temperature back to 37 degrees C. In vivo, raising the core body temperature in male mice to 41 degrees C for 1 hour resulted in a 78% decrease in kidney ODC activity. The kidney DNA synthesis and protein synthesis remained unaltered following the whole body hyperthermia treatments.

Animals↗
PubMed1985

Dose and schedule of oral retinoic acid and indomethacin needed to effectively inhibit phorbol ester-induced epidermal ornithine decarboxylase activity.

Currently there is no well-defined biological parameter or marker to help define agents, doses, and dose schedules for human cancer chemoprevention trials. Induction of ornithine decarboxylase, the rate limiting enzyme in the polyamine biosynthetic pathway, has been shown to be an essential aspect of mouse skin tumor promotion. Supplementary information suggest that this enzyme is an important aspect of carcinogenesis in other organ systems and in other animals (including humans). We have developed an assay system which effectively measured tumor promoter (TPA)-induced ornithine decarboxylase activity on 3-4 mm skin samples from mice and humans. Using this system we evaluated the doses and dose schedules of retinoic acid and indomethacin needed to effectively inhibit ornithine decarboxylase activity. Our data suggest that the doses and schedules of these compounds needed to inhibit ornithine decarboxylase activity would be toxic in humans.

Administration, Oral↗
PubMed1985

Tumor promoter 12-O-tetradecanoylphorbol-13-acetate receptors in normal human transitional epithelial cells.

As a prelude to study the promotion with TPA of in vitro transformation of human urothelial cells (HUC) in culture, we characterized tumor promoter TPA receptors in primary cultures of HUC. [3H]TPA bound specifically to intact living HUC; maximum specific binding was attained in approximately 30 min at 37 degrees C. [3H]TPA bound to HUC in a saturable and competitive manner. Scatchard analysis of specific binding to intact cells displayed a single slope corresponding to an equilibrium dissociation constant (Kd) of 0.56 nM; at saturation TPA-binding capacity was 2.37 pmol/10(6) HUC (1.43 X 10(6) sites per cell). [3H]TPA bound specifically and with high affinity to the particulate fractions of HUC; binding was both saturable and reversible. Saturation of the specific binding of [3H]TPA occurred at approximately 1 nM at 4 degrees C. Scatchard analysis of specific binding to the particulate fraction displayed a single slope corresponding to a Kd of 1.08 nM; at saturation TPA-binding capacity was 2.05 pmol/mg protein (750 000 molecules per HUC). [3H]TPA binding was inhibited by the biologically active phorbol ester, phorbol didecanoate, whereas inactive phorbol did not compete for TPA binding. Binding was not affected by sodium saccharin, epidermal growth factor, retinoic acid or dexamethasone. [3H]TPA bound specifically to the HUC cytosolic fraction but only in the presence of calcium and phosphatidylserine. Calcium-activated and phospholipid-sensitive protein kinase activity was detected in HUC fractions. These results indicate the presence of high-affinity specific receptors for TPA in HUC.

Caenorhabditis elegans Proteins↗
PubMed1985

Acute ascending motor paralysis due to rabies: a clinicopathological report.

An unusual presentation of a not so uncommon disease is described. Practical difficulties in arriving at a diagnosis of paralytic rabies are discussed. An enquiry of exposure and suspicion of rabies in atypical Landry's paralysis is stressed. The importance of autopsy to confirm either of the diagnoses is emphasized.

Acute Disease↗
PubMed1985

Inhibition of phorbol ester--induced human epidermal ornithine decarboxylase activity by oral compounds: a possible role in human chemoprevention studies.

Extensive animal data have suggested that, in some systems, the induction of ornithine decarboxylase (ODC) is an essential, although not sufficient, aspect of tumor promotion and that compounds that inhibit ODC can inhibit tumor formation. Using fasting human volunteers, we report that human epidermal and dermal ODC are consistently induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in a manner similar to that seen in mouse skin. There is a marked intersubject variation in TPA-induced epidermal ODC activity levels. Orally administered compounds significantly inhibited TPA-caused human epidermal ODC induction. These data may be useful in the further development of drugs, doses, and dose schedules for use in human cancer chemoprevention studies.

Adult↗
PubMed1985

In vitro induction of human skin ornithine decarboxylase by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

A method was developed for the in vitro induction by 12-O-tetradecanoylphorbol-13-acetate (TPA) of ornithine decarboxylase (ODC) activity in human skin punch biopsy samples. Addition of TPA to 1 ml serum-free minimum essential medium containing a single 3-mm human skin punch biopsy sample obtained from a surgical specimen resulted in an induction of ODC activity with a peak activity at 5 hours after TPA addition. In vitro induction of human epidermal ODC activity was dependent on the TPA concentration in the medium; about a twofold increase in ODC activity was observed 6 hours after the addition of 0.1 microM TPA, and about a fivefold increase in ODC activity was observed with 1 microM TPA. TPA also caused about a fivefold to sixfold increase in ODC activity in 3-mm skin punch biopsy samples from healthy volunteers. Human skin punch biopsy samples remained responsive to TPA induction of ODC activity even when stored in serum-free medium at 4 degrees C for 24 hours. A similar degree of induction of ODC activity by TPA was observed whether whole unfractionated human epidermis or a soluble epidermal extract was used for ODC assays. Increased ODC activity was the result of the increase in enzymatically active ODC protein, quantitated by a [3H]difluoromethylornithine-binding assay. Thus human skin, like mouse skin, is responsive to TPA for ODC induction.

Amputation, Surgical↗