Orthodontic forces have been reported to significantly increase nicotine-induced periodontal bone loss. At present, however, it is unknown, which further （side） effects can be expected during orthodontic treatment a...Orthodontic forces have been reported to significantly increase nicotine-induced periodontal bone loss. At present, however, it is unknown, which further （side） effects can be expected during orthodontic treatment at a nicotine exposure corresponding to that of an average European smoker. 63 male Fischer344 rats were randomized in three consecutive experiments of 21 animals each （A/B/C） to 3 experimental groups （7 rats, 112/3）. （A） cone-beam-computed tomography （CBCT）; （B） histology/serology; （C） reverse- transcription quantitative real-time polymerase chain reaction （RT-qPCR）/cotinine serology--（1） control; （2） orthodontic tooth movement （OTM） of the first and second upper left molar （NiTi closed coil spring, 0.25 N）; （3） OTM with 1.89 mg-kg- 1 per day s.c. of L（- ）-nicotine. After 14 days of OTM, serum cotinine and IL-6 concentration as well as orthodontically induced inflammatory root resorption （OIIRR）, osteoclast activity （histology）, orthodontic tooth movement velocity （CBCT, within 14 and 28 days of OTM） and relative gene expression of known inflammatory and osteoclast markers were quantified in the dental-periodontal tissue （RT-qPCR）. Animals exposed to nicotine showed significantly heightened serum cotinine and IL-6 levels corresponding to those of regular European smokers. Both the extent of root resorption, osteoclast activity, orthodontic tooth movement and gene expression of inflammatory and osteoclast markers were significantly increased compared to controls with and without OTM under the influence of nicotine. We conclude that apart from increased periodontal bone loss, a progression of dental root resorption and accelerated orthodontic tooth movement are to be anticipated during orthodontic therapy, if nicotine consumption is present. Thus patients should be informed about these risks and the necessity of nicotine abstinence during treatment.展开更多
Knowledge gaps in the biospeciation of potential metallodrugs may lead to the generalized assumption of their promiscuous reactivity and inherent toxicity,neglecting their pharmaceutical potential.Herein,we developed ...Knowledge gaps in the biospeciation of potential metallodrugs may lead to the generalized assumption of their promiscuous reactivity and inherent toxicity,neglecting their pharmaceutical potential.Herein,we developed a rapid and competitive LC-MS/MS assay to determine metalation dynamics of protein mixtures by metallodrugs.Specifically,the time-dependent reactivity of different metallodrugs,based on platinum(Ⅱ)(cisplatin,[Pt(ala)(ASA-But)Cl]),ruthenium(Ⅱ)([Ru(HQ)(Cym)Cl],[Ru(NHC)(Cym)Cl_(2)]),and iridium(Ⅲ)([Ir(HQ)(Cp^(*))Cl],[Ir(NHC)(Cp^(*))Cl_(2)]),towards an equimolar protein mixture was investigated.The assay revealed metal-dependent selectivity of adduct formation and subsequent deactivation by cellular detoxifying nucleophiles,e.g.glutathione(GSH).Online top-down fragmentation further enabled the localization of binding sites of metallodrugs on proteins in the same run,which could be directly related to complex speciation behaviour.The reactivity of Zeise’s salt derivative[Pt(ala)(ASA-But)Cl](ala=L-alanine;ASA-But=but-3-en-1-yl 2-acetoxybenzoate)with sulfur donor atoms was found to exceed all investigated compounds,including cisplatin.Ruthenium compounds preferred N-donor coordination,which resulted in a strong affinity towards histidine residues.Protein adducts of the somewhat redoxactive iridium compounds were quickly transformed into stable adducts with detoxifying nucleophiles,especially with GSH.This model system provides further evidence that metallodrug reactivity is more selective in competitive settings,as would be anticipated from exposure to single biomolecules.This implies that the intracellular selectivity of metallodrugs can be chemically tuned and that this aspect may be accounted for in future metallodrug design.Such design strategies will be supported by expanding the present competitive assay to more complex systems that better mimic physiological intra-and extracellular tumour microenvironments.展开更多
基金the ReForM-A-research funding programme of the Faculty of Medicine(University of Regensburg)for their financial supportsupported by a ReForM-A grant from the ReForM research funding programme of the Faculty of Medicine of the University of Regensburg,Germany(Kirschneck 31 March 2015)the German Research Foundation(DFG)within the funding programme Open Access Publishing
文摘Orthodontic forces have been reported to significantly increase nicotine-induced periodontal bone loss. At present, however, it is unknown, which further （side） effects can be expected during orthodontic treatment at a nicotine exposure corresponding to that of an average European smoker. 63 male Fischer344 rats were randomized in three consecutive experiments of 21 animals each （A/B/C） to 3 experimental groups （7 rats, 112/3）. （A） cone-beam-computed tomography （CBCT）; （B） histology/serology; （C） reverse- transcription quantitative real-time polymerase chain reaction （RT-qPCR）/cotinine serology--（1） control; （2） orthodontic tooth movement （OTM） of the first and second upper left molar （NiTi closed coil spring, 0.25 N）; （3） OTM with 1.89 mg-kg- 1 per day s.c. of L（- ）-nicotine. After 14 days of OTM, serum cotinine and IL-6 concentration as well as orthodontically induced inflammatory root resorption （OIIRR）, osteoclast activity （histology）, orthodontic tooth movement velocity （CBCT, within 14 and 28 days of OTM） and relative gene expression of known inflammatory and osteoclast markers were quantified in the dental-periodontal tissue （RT-qPCR）. Animals exposed to nicotine showed significantly heightened serum cotinine and IL-6 levels corresponding to those of regular European smokers. Both the extent of root resorption, osteoclast activity, orthodontic tooth movement and gene expression of inflammatory and osteoclast markers were significantly increased compared to controls with and without OTM under the influence of nicotine. We conclude that apart from increased periodontal bone loss, a progression of dental root resorption and accelerated orthodontic tooth movement are to be anticipated during orthodontic therapy, if nicotine consumption is present. Thus patients should be informed about these risks and the necessity of nicotine abstinence during treatment.
基金funded by the Austrian Science Fund(FWF)under https://doi.org/10.55776/P37034.
文摘Knowledge gaps in the biospeciation of potential metallodrugs may lead to the generalized assumption of their promiscuous reactivity and inherent toxicity,neglecting their pharmaceutical potential.Herein,we developed a rapid and competitive LC-MS/MS assay to determine metalation dynamics of protein mixtures by metallodrugs.Specifically,the time-dependent reactivity of different metallodrugs,based on platinum(Ⅱ)(cisplatin,[Pt(ala)(ASA-But)Cl]),ruthenium(Ⅱ)([Ru(HQ)(Cym)Cl],[Ru(NHC)(Cym)Cl_(2)]),and iridium(Ⅲ)([Ir(HQ)(Cp^(*))Cl],[Ir(NHC)(Cp^(*))Cl_(2)]),towards an equimolar protein mixture was investigated.The assay revealed metal-dependent selectivity of adduct formation and subsequent deactivation by cellular detoxifying nucleophiles,e.g.glutathione(GSH).Online top-down fragmentation further enabled the localization of binding sites of metallodrugs on proteins in the same run,which could be directly related to complex speciation behaviour.The reactivity of Zeise’s salt derivative[Pt(ala)(ASA-But)Cl](ala=L-alanine;ASA-But=but-3-en-1-yl 2-acetoxybenzoate)with sulfur donor atoms was found to exceed all investigated compounds,including cisplatin.Ruthenium compounds preferred N-donor coordination,which resulted in a strong affinity towards histidine residues.Protein adducts of the somewhat redoxactive iridium compounds were quickly transformed into stable adducts with detoxifying nucleophiles,especially with GSH.This model system provides further evidence that metallodrug reactivity is more selective in competitive settings,as would be anticipated from exposure to single biomolecules.This implies that the intracellular selectivity of metallodrugs can be chemically tuned and that this aspect may be accounted for in future metallodrug design.Such design strategies will be supported by expanding the present competitive assay to more complex systems that better mimic physiological intra-and extracellular tumour microenvironments.
