It is suggested that individual differences in sensitivity to nicotine may help account for a number of anomalous findings uncovered in research on nicotine regulation. However, an examination of the literature reveals very little pertinent evidence. To demonstrate the existence of such differences, 124 male and female subjects were screened for responsiveness to nicotine by smoking a standard cigarette while their heart rates were continuously monitored for 5 minutes before, during, and after smoking. Puff analyses were also conducted to determine the amount of nicotine subjects obtained from cigarettes. Based on increases in heart rate of more than 10 or less than 8 beats per minute from baseline to smoking periods, subjects were categorized as responsive or nonresponsive. To assess stability of responsiveness over time, 20 responsive and 20 nonresponsive subjects were called back for a second session 1 week to 4 months later. At the second session, heart rates were again monitored before, during, and after smoking a standard cigarette. The data indicate that subjects maintained their relative degree of sensitivity to nicotine over time. The results are discussed in terms of Solomon's opponent process model and it is suggested that not all smokers are addicted to nicotine.
Journal of Photochemistry and Photobiology B: Biology
2017.0
Single stranded RNAs are biologically potent as they participate in various key cellular processes. The binding efficacy of two potent anticancer alkaloids, sanguinarine (here after SANG) and chelerythrine (here after CHEL), with single-stranded ribonucleic acids poly(rI), poly(rG), and poly(rC) were studied using spectroscopic and thermodynamic tools. Results reveal that both SANG and CHEL binds well with single stranded RNAs with affinity in the order poly(rI) > poly(rG) > poly(rC). CHEL showed slightly higher affinity compared to SANG with all the single stranded RNAs. Both SANG and CHEL showed association affinity of the lower 10(6) order with poly(rI), higher 10(5) order binding with poly(rG) and lower 10(5) order with poly(rC). The binding mode was partial intercalation due to the staking interaction between the bases and the alkaloids. The complexation of both the SANG and CHEL to the RNAs were mainly enthalpy driven and also favoured by entropy changes. Perturbation was observed in the RNA conformation due to binding of the alkaloids. In this present study we have deciphered the fundamental structural and calorimetric aspects of the interaction of the natural benzophenanthridine alkaloids with single stranded RNAs and these results may help to develop new generation alkaloid based therapeutics targeting single stranded RNAs.
The effects of hirsutine, an indole alkaloid from Uncaria rhynchophylla MIQ. JACKSON with antihypertensive, negative chronotropic and antiarrhythmic activity, and its C3 structural epimer, dihydrocorynantheine, on membrane potentials of rabbit sino-atrial node and guinea-pig right ventricle and left atrium were studied with microelectrode techniques. In sino-atrial node preparations, hirsutine and dihydrocorynantheine (0.1 microM to 10 microM) concentration-dependently increased cycle length, decreased slope of the pacemaker depolarization (phase 4 depolarization), decreased maximum rate of rise and prolonged action potential duration. In atrial and ventricular preparations, both compounds (0.1 microM to 30 microM) concentration-dependently decreased maximum rate of rise and prolonged action potential duration. These results indicate that hirsutine and dihydrocorynantheine have direct effects on the action potential of cardiac muscle through inhibition of multiple ion channels, which may explain their negative chronotropic and antiarrhythmic activity.
Several novel cell lines with variable resistance to Vinca alkaloids have been derived from the Caco-2 human colorectal carcinoma cell line. Parental Caco-2 cells were found by PCR analysis and immunofluorescence studies to produce a low amount of the mdr-1 gene product (P-glycoprotein) that may well be clinically significant. These cells, which were initially highly sensitive to desacetylvinblastine sulfate (DAVLB sulfate) were selected, without mutagenesis, through continuous culture with increasing concentrations of DAVLB sulfate over a 335-day period. This selection resulted in cell lines that displayed an mdr (multiple-drug-resistance) cross-resistance profile that could be reversed with agents such as verapamil and vindoline. During the selection process the amount of mdr-1 mRNA present, the extent of gene amplification and the amount of gp170 expressed all correlated well with the level of drug resistance. However, this correlation does not hold in the absence of selective pressure for the more resistant cell lines where gene amplification and the amount of P-glycoprotein present remained constant while the level of drug resistance and the amount of mdr-1 mRNA present declined. These cell lines are potential models for studying mdr-I gene expression and drug resistance in human epithelial malignancies.
Huperzine A, a promising therapeutic agent for Alzheimer's disease, was examined for its potential to antagonize the deleterious neurochemical, structural, and cognitive effects of infusing beta-amyloid protein-(1-40) into the cerebral ventricles of rats. Daily intraperitoneal administration of huperzine A for 12 consecutive days produced significant reversals of the beta-amyloid-induced deficit in learning a water maze task. This treatment also reduced the loss of choline acetyltransferase activity in cerebral cortex, and the neuronal degeneration induced by beta-amyloid protein-(1-40). In addition, huperzine A partly reversed the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax and P53 proteins and reduced the apoptosis that normally followed beta-amyloid injection. The present findings confirm that huperzine A can alleviate the cognitive dysfunction induced by intracerebroventricular infusion of beta-amyloid protein-(1-40) in rats. The beneficial effects are not confined to the cholinergic system, but also include favorable changes in the expression of apoptosis-related proteins and in the extent of apoptosis in widespread regions of the brain.
A room-temperature Ni-catalyzed reductive approach to homocoupling of unactivated primary, secondary, and tertiary alkyl bromides is described. The catalytic system can be easily generated from air-stable and cheap materials and demonstrates broad functional group tolerance, thus allowing facile access to useful dimeric triterpene and lignan-like molecules. Moreover, the dimerization of tertiary bromide 6 1, efficiently establishes sterically hindered vicinal quaternary carbons (C3a and C3a'), which is a key linkage of intriguing bispyrrolo[2,3-b] indoline alkaloids, thereby enabling us to complete the total syntheses of racemic chimonanthine (9) and folicanthine (10). In addition, this dimerization method can be expanded to the highly stereoselective synthesis of bisperhydrofuro[2,3-b]furan (5a) and the dimeric spiroketal 5b, signifying the involvement of possible radical species.
Tobacco-specific alkaloids and nitrosamines are important biomarkers for the estimation of tobacco use and human exposure to tobacco-specific nitrosamines that can be monitored by wastewater analysis. Thus far their analysis has used solid phase extraction, which is costly and time-consuming. In this study, we developed a direct injection liquid chromatography-tandem mass spectrometry method for the quantification of two tobaccospecific alkaloids and five nitrosamines in wastewater. The method achieved excellent linearity (R2 > 0.99) for all analytes, with calibration ranging from 0.10 to 800 ng/L. Method limits of detection and quantification were 0.17 ng/L (N-nitrosonornicotine, NNN) and 1.0 ng/L (N-nitrosoanatabine (NAT) and NNN), with acceptable accuracy (100 % +/- 20 %) and precision (+/- 15 %). Analyte loss during filtration was < 15 %, and the relative matrix effect was < 10 %. The method was applied to 43 pooled wastewater samples collected from three wastewater treatment plants in Australia between 2017 and 2021. Anabasine and anatabine were detected in all samples at concentrations of 5.0 - 33 ng/L and 12 - 41 ng/L, respectively. Three of the five tobacco-specific nitrosamines (NAT, NNN, and (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL)) were detected, in < 50 % of the wastewater samples, with concentrations nearly ten times lower than the tobacco alkaloids (< 1.0 - 6.2 ng/L). In-sewer stability of the nitrosamines was also assessed in this study, with four (NAT, NNAL, NNN, and N-nitrosoanabasine (NAB)) being stable (i.e. < 20 % transformation over 12 h in both control reactor (CR) and rising main reactor (RM) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being moderately stable (< 40 % loss over 12 h in RM). This direct injection method provides a high-throughput approach in simultaneous investigation of tobacco use and assessment of public exposure to tobacco-specific nitrosamines.
