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Inhibition of P-glycoprotein by two artemisinin derivatives

Natural Products and Bioprospecting 2012年第2期2卷 59-64页

作者： Babette STEGLICH Anne MAHRINGER Ying LI Gary H.POSNER Gert FRICKER thomas efferth Department of Pharmaceutical Biology Institute of Pharmacy and BiochemistryJohannes Gutenberg UniversityStaudinger Weg 5551 MainzGermany Institute of Pharmacy and Molecular Biotechnology Karl Ruprecht UniversityHeidelbergGermany Department of Synthetic Chemistry Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina Department of Chemistry Johns Hopkins UniversityBaltimore MDUSA

P-Glycoprotein/MDR1 represents an important component of the blood brain barrier and contributes to multidrug resistance.We investigated two derivatives of the anti-malarial artemisinin,SM616 and GHP-AJM-3/23,concerning their ability to interact with P-glycoprotein.The ability of the two compounds to inhibit P-glycoprotein(P-gp)activity was examined in sensitive CCRF-CEM and P-gp over-expressing and multidrug-resistant CEM/ADR5000 cells as well as in porcine brain capillary endothelial cells(PBCEC)by means of calcein-AM assays.Verapamil as well-known P-gp inhibitor was used as control drug.CEM/ADR5000 cells exhibited cross-resistance to GHP-AJM-3/23,but slight collateral sensitivity to SM616.Furthermore,SM616 inhibited calcein efflux both in CEM/ADR5000 and PBCEC,whereas GHP-AJM-3/23 did only increase calcein fluorescence in PBCEC,but not CEM/ADR5000.This may be explained by the fact that CEM/ADR5000 only express P-gp but not other ATP-binding cassette transporters,whereas PBCEC are known to express several ABC transporters and calcein is transported by more than one ABC transporter.Hence,SM616 may be the more specific P-gp inhibitor.In conclusion,the collateral sensitivity of SM616 as well as the inhibition of calcein efflux in both CEM/ADR5000 cells and PBCEC indicate that this compound may be a promising P-gp inhibitor to treat cancer therapy and to overcome the blood brain barrier.

关键词： blood brain barrier calcein multidrug resistance P-glycoprotein

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Growth inhibition of human acute lymphoblastic CCRF-CEM leukemia cells by medicinal plants of the West-Canadian Gwich’in Native Americans

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Natural Products and Bioprospecting 2012年第1期2卷 35-40页

作者： Katharina DEEG Tolga EICHHORN Gladys ALEXIE Nadine KRETSCHMER Kai ANDERSCH Rudolf BAUER thomas efferth Institute of Pharmacy and Molecular Biotechnology University of HeidelbergHeidelbergGermany Department of Pharmaceutical Biology Institute of Pharmacy and BiochemistryJohannes Gutenberg UniversityMainzGermany Fort McPerson Northwest TerritoriesCanada Institute of Pharmaceutical Sciences Department PharmacognosyKarl-Franzens UniversityGrazAustria Wilderness International Dresden(Germany)and Stony Plain(AlbertaCanada)

The Gwich’in,which belong to the Athapaskan language group of Native Americans live in the borderland between Alaska and Canada.We analyzed 29 medicinal plants of this tribe for their growth inhibitory activity against CCRF-CEM T-cell acute lymphoblastic leukemia(T-ALL)cells.The anti-leukemic activity of these plants has not been investigated as yet.Considering the poor cure rates of some ALL forms,there might be a great potential for medicinal plants as resource for natural products to treat T-ALL.We found that the hexane extracts of three plants revealed considerable growth inhibition on CCRF-CEM cells.The 50%inhibition concentrations(IC50)were 6.63±0.03μg/ml for Cladina mitis,8.65±0.38μg/ml for Picea mariana(needles),and 9.67±1.36μg/ml for Artemisia frigida.Further investigations are required to isolate the active constituents of these plants.

关键词： cytotoxicity herbs leukemia medicinal plants pharmacognosy

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量化中医学中“寒”与“热”的初步临床研究(英文)

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中西医结合学报 2012年第5期10卷 532-537页

作者： Christoph A.Doenitz Ana Anjos thomas efferth Tobias Greten Henry J.Greten Institute of Biomedical Sciences(ICBAS) University of PortoLargo Professor Abel Salzar 24099-030 PortoPortugal German Society of Traditional Chinese Medicine 69126 HeidelbergGermany Heidelberg School of Chinese Medicine 69126 HeidelbergGermany Department of Pharmaceutical Biology Institute of Pharmacy and BiochemistryUniversity of MainzMainzGermany

目的:本研究探讨通过测量微循环相关指标客观衡量针刺效果的可能性,中医寒证针刺治疗前毛细血管灌注状态的意义,以及微循环相关指标在未来中医诊断中的意义。方法:本研究为前瞻性、非对照、不设盲临床研究。研究共纳入32例股骨骨折手术... 详细信息

目的:本研究探讨通过测量微循环相关指标客观衡量针刺效果的可能性,中医寒证针刺治疗前毛细血管灌注状态的意义,以及微循环相关指标在未来中医诊断中的意义。方法:本研究为前瞻性、非对照、不设盲临床研究。研究共纳入32例股骨骨折手术后的老年患者。这些患者均接受施于胃经梁丘穴的"豹斑点刺"针刺治疗。针刺治疗前后使用白光光谱学及激光多普勒测量微循环相关指标如血流速率、血流量、血红蛋白含量、氧饱和度等。结果:股骨骨折后,根据血流量的不同,患者被分为两组,即高灌注组和低灌注组。低灌注组的毛细血管血流量及血流速率在针刺治疗后明显增加,而高灌注组则无明显改变。如果不考虑患者在针刺治疗前的灌注状态,则统计分析表明所有患者针刺治疗前后的灌注状态均无明显改变,因此针刺的作用可能被患者的异质性所掩盖。结论:微循环相关指标对于客观衡量针刺的治疗效果及描述针刺治疗前的营养性功能以均衡比较组之间的差异有重要意义。在本试验中,局部寒证(腿部的毛细血管低灌注)可以通过针刺补气血的胃经梁丘穴得到显著改善,而在热证组(毛细血管高灌注)未见明显改变。未来的研究可以通过将中医营养参数测量的营养状态与中医诊断中的主要证候相联系而得到更多结论。

关键词：针刺疗法微循环股骨骨折中医学说血流速度血红蛋白类临床试验

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气功缓解物理治疗师职业倦怠的初步研究(英文)

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中西医结合学报 2012年第11期10卷 1233-1239页

作者： Joāo Pedro Saganha Christoph Doenitz Tobias Greten thomas efferth Henry J. Greten Institute of Biomedical Sciences University of Porto German Society of Traditional Chinese Medicine Heidelberg School of Chinese Medicine Department of Pharmaceutical Biology Institute of Pharmacy and Biochemistry University of Mainz

目的:本研究探讨物理治疗师发生职业倦怠的普遍性,了解气功疗法是否可以有效地缓解这类情况,并为今后更深入的研究提供初步的数据。方法:物理治疗师们在试验前先完成一份人口调查问卷以及职业倦怠问卷,然后选择那些在最重要的量表维度... 详细信息

目的:本研究探讨物理治疗师发生职业倦怠的普遍性,了解气功疗法是否可以有效地缓解这类情况,并为今后更深入的研究提供初步的数据。方法:物理治疗师们在试验前先完成一份人口调查问卷以及职业倦怠问卷,然后选择那些在最重要的量表维度中显示职业倦怠水平最高的物理治疗师分为干预组和对照组。8个干预组成员需完成一个由海德堡中医学院研发的特定的气功介入,另外8个对照组成员则被排在等待名单中。在为期3周的治疗或等待后,再一次对两组人员进行职业倦怠问卷调查,并比较前后两次的结果。结果:对106个物理治疗师(36名男性,70名女性)的职业倦怠问卷结果显示,52人(49%)存在情绪疲劳,36人(33.9%)存在自我感觉丧失,33人(31.2%)成就感降低,而在这33人中有4人(3.8%)存在严重的工作倦怠情绪,29人(27.4%)则处于中等程度倦怠。气功治疗干预组的情绪疲劳分量表的平均值从38.0下降到31.4,而对照组的均值从33.9上升到37.9,两组数据差异具有统计学意义(P =0.023)。气功治疗使自我感觉丧失分量表的平均值从10.8降低到6.8,而在对照组中则从7.3上升到10.6,干预组与对照组之间的差异同样具有统计学意义(P =0.013)。关于成就感的分量表,两组数据之间的差异不明显。结论:气功可以有效改善职业倦怠的症状,此类气功是自我控制工作倦怠感的有效途径。每天仅需2次,每次5min的练习就能取得一定的效果。本次试验的结果也为今后进行更大范围的盲法、对照、随访试验设计奠定了基础。

关键词：气功厌倦,职业性物理治疗技术生物反馈试点项目

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气功对学习横笛儿童焦虑和心理应激功能的影响(英文)

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中西医结合学报 2012年第8期10卷 858-865页

作者： Claudia Maria Sousa Mario Gonalves Jorge Machado thomas efferth Tobias Greten Petra Froeschen Henry J. Greten Institute of Biomedical Sciences University of Porto German Society of Traditional Chinese Medicine Heidelberg School of Chinese Medicine Department of Pharmaceutical Biology Institute of Pharmacy and Biochemistry University of Mainz

目的:基于病例治疗,对气功疗效是否可以用生理测量指标和心理评分量化这一命题进行研究。方法:研究设计为前瞻性干预对照研究。气功组纳入8名儿童,接受为期7周的"白球"气功训练,每周2次,每次30min。对照组纳入8名儿童不接受气功训练。... 详细信息

目的:基于病例治疗,对气功疗效是否可以用生理测量指标和心理评分量化这一命题进行研究。方法:研究设计为前瞻性干预对照研究。气功组纳入8名儿童,接受为期7周的"白球"气功训练,每周2次,每次30min。对照组纳入8名儿童不接受气功训练。使用针对儿童的"抑郁、焦虑和压力量表"衡量焦虑的主观感受。此外,在研究开始和结束时分别测量两组儿童的唾液中皮质醇水平、心率变化、血压、斜方肌肌电图、反应时间等指标。结果:与对照组比较,气功组在心率指标方面显著降低。虽然在其他指标方面两组之间无显著差异,但是气功组在唾液中皮质醇水平、斜方肌肌电图及血压等指标方面的效应量更大。在焦虑主观感受、唾液中皮质醇水平和心率指标方面,气功组相对较低。结论:"白球"气功可以显著降低学习乐器表演的儿童的心率。基于本研究8/8的样本量,气功也有减轻焦虑和降低血压的作用。对于今后将要开展的量化气功疗效的研究,可以增大样本量,研究其他焦虑感增加的环境下年轻人的情况,设置合理的对照干预措施,解决设盲的问题,测量其他可能会受到气功治疗影响的指标,以及比较气功与其他可以降低焦虑的方法的疗效。

关键词：气功中医学说焦虑应激音乐可行性研究

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Theory and classification of mass extinction causation

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National Science Review 2024年第1期11卷 16-36页

作者： thomas J.Algeo Jun Shen State Key Laboratory of Biogeology and Environmental Geology China University of Geosciences—Wuhan State Key Laboratory of Geological Processes and Mineral Resources China University of Geosciences—Wuhan Department of Geosciences University of Cincinnati

Theory regarding the causation of mass extinctions is in need of systematization, which is the focus of this contribution. Every mass extinction has both an ultimate cause, i.e. the trigger that leads to various climato-environmental changes, and one or more proximate cause(s), i.e. the specific climato-environmental changes that result in elevated biotic mortality. With regard to ultimate causes, strong cases can be made that bolide(i.e. meteor) impacts, large igneous province(LIP) eruptions and bioevolutionary events have each triggered one or more of the Phanerozoic Big Five mass extinctions, and that tectono-oceanic changes have triggered some second-order extinction events. Apart from bolide impacts, other astronomical triggers(e.***.solar flares, gamma bursts and supernova explosions) remain entirely in the realm of speculation. With regard to proximate mechanisms, most extinctions are related to either carbon-release or carbon-burial processes, the former being associated with climatic warming, ocean acidification, reduced marine productivity and lower carbonate δ13C values, and the latter with climatic cooling, increased marine productivity and higher carbonate δ13C values. Environmental parameters such as marine redox conditions and terrestrial weathering intensity do not show consistent relationships with carbon-cycle changes.In this context, mass extinction causation can be usefully classified using a matrix of ultimate and proximate factors. Among the Big Five mass extinctions, the end-Cretaceous biocrisis is an example of a bolide-triggered carbon-release event, the end-Permian and end-Triassic biocrises are examples of LIP-triggered carbon-release events, and the Late Ordovician and Late Devonian biocrises are examples of bioevolution-triggered carbon-burial events. Whereas the bolide-impact and LIP-eruption mechanisms appear to invariably cause carbon release, bioevolutionary triggers can result in variable carbon-cycle changes, e.g. carbon burial during the Late Ordovician and Late Devonian events,

关键词： biocrisis ultimate cause proximate cause bolide large igneous province bioevolutionary event

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Insights into carbon dioxide sequestration into coal seams through coupled gas flow-adsorption-deformation modelling

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Journal of Rock Mechanics and Geotechnical Engineering 2024年第1期16卷 26-40页

作者： Hywel thomas Min Chen Geoenvironmental Research Centre Cardiff School of EngineeringCardiff UniversityQueen’s BuildingsThe ParadeNewport RoadCardiffCF243AAUK Key Laboratory of Marine Geology Tongji UniversityShanghai200092China

Injecting carbon dioxide(CO_(2))into coal seams may unlock substantial carbon sequestration potential.Since the coal acts like a carbon filter,it can preferentially absorb significant amounts of CO_(2).To explore this further,desorption of the adsorbed gas due to pressure drop is investigated in this paper,to achieve an improved understanding of the long-term fate of injected CO_(2) during post-injection period.This paper presents a dual porosity model coupling gas flow,adsorption and geomechanics for studying coupled processes and effectiveness of CO_(2) sequestration in coals.A new adsorption?desorption model derived based on thermodynamics is incorporated,particularly,the desorption hysteresis is considered.The reliability of the proposed adsorption-desorption isotherm is examined via validation tests.It is indicated that occurrence of desorption hysteresis is attributed to the adsorption-induced pore deformation.After injection ceases,the injected gas continues to propagate further from the injection well,while the pressure in the vicinity of the injection well experiences a significant drop.Although the adsorbed gas near the well also decreases,this decrease is less compared to that in pressure because of desorption hysteresis.The unceasing spread of CO_(2) and drops of pressure and adsorbed gas depend on the degree of desorption hysteresis and heterogeneity of coals,which should be considered when designing CO_(2) sequestration into coal seams.

关键词： CO_(2)geological storage Coal seam Adsorption Desorption hysteresis

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CLASSIFICATIONS OF DUPIN HYPERSURFACES IN LIE SPHERE GEOMETRY

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Acta Mathematica Scientia 2024年第1期44卷 1-36页

作者： thomas E.CECIL Department of Mathematics and Computer Science College of the Holy CrossWorcesterMA01610USA

This is a survey of local and global classification results concerning Dupin hypersurfaces in S^(n)(or R^(n))that have been obtained in the context of Lie sphere geometry.The emphasis is on results that relate Dupin hypersurfaces to isoparametric hypersurfaces in spheres.Along with these classification results,many important concepts from Lie sphere geometry,such as curvature spheres,Lie curvatures,and Legendre lifts of submanifolds of S^(n)(or R^(n)),are described in detail.The paper also contains several important constructions of Dupin hypersurfaces with certain special properties.

关键词： Dupin hypersurfaces isoparametric hypersurfaces Lie sphere geometry Lie sphere transformations Lie curvatures

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EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors

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Signal Transduction and Targeted Therapy 2024年第2期9卷 679-692页

作者： Keith Al-Hasani Safiya Naina Marikar Harikrishnan Kaipananickal Scott Maxwell Jun Okabe Ishant Khurana thomas Karagiannis Julia J.Liang Lina Mariana thomas Loudovaris thomas Kay Assam El-Osta Epigenetics in Human Health and Disease Program Baker Heart and Diabetes Institute75 Commercial RoadMelbourne 3004 VICAustralia Department of Diabetes Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia Epigenetics in Human Health and Disease Laboratory Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia School of Science STEM CollegeRMIT UniversityMelbourne 3001 VICAustralia Immunology and Diabetes Unit St Vincent’s Institute of Medical ResearchFitzroy 3065 VICAustralia Department of Medicine and Therapeutics The Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and Obesity Prince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32-Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongSha TinHong Kong SAR Biomedical Laboratory Science Department of TechnologyFaculty of HealthUniversity College CopenhagenCopenhagenDenmark

β-cells are a type of endocrine cell found in pancreatic islets that synthesize,store and release insulin.In type 1 diabetes(T1D),T-cells of the immune system selectively destroy the insulin-producingβ-cells.Destruction of these cells leads to a lifelong dependence on exogenous insulin administration for survival.Consequently,there is an urgent need to identify novel therapies that stimulateβ-cell growth and induceβ-cell function.We and others have shown that pancreatic ductal progenitor cells are a promising source for regeneratingβ-cells for T1D owing to their inherent differentiation capacity.Default transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 methyltransferase.In the present study,we show that transient stimulation of exocrine cells,derived from juvenile and adult T1D donors to the FDAapproved EZH2 inhibitors GSK126 and Tazemetostat(Taz)influence a phenotypic shift towards aβ-like cell identity.The transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin modification.Targeting EZH2 is fundamental toβ-cell regenerative potential.Reprogrammed pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex vivo.These pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration ofβ-like cell function.

关键词： EZH2 struction inhibitors

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B-cell and antibody responses to SARS-CoV-2:infection,vaccination,and hybrid immunity

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Cellular & Molecular Immunology 2024年第2期21卷 144-158页

作者： Dennis Lapuente thomas H.Winkler Matthias Tenbusch Institut für klinische und molekulare Virologie Universitätsklinikum Erlangen und Friedrich-Alexander-Universität(FAU)Erlangen-NürnbergSchlossgarten 491054 ErlangenGermany Department of Biology Division of GeneticsNikolaus-Fiebiger-Center for Molecular MedicineFriedrich-Alexander-Universität Erlangen-Nürnberg(FAU)ErlangenGermany Medical Immunology Campus Erlangen Friedrich-Alexander-Universität(FAU)Erlangen-NürnbergSchlossplatz 191054 ErlangenGermany

The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)in 2019 prompted scientific,medical,and biotech communities to investigate infection-and vaccine-induced immune responses in the context of this pathogen.B-cell and antibody responses are at the center of these investigations,as neutralizing antibodies(nAbs)are an important correlate of protection(COP)from infection and the primary target of SARS-CoV-2 vaccine modalities.In addition to absolute levels,nAb longevity,neutralization breadth,immunoglobulin isotype and subtype composition,and presence at mucosal sites have become important topics for scientists and health policy makers.The recent pandemic was and still is a unique setting in which to study de novo and memory B-cell(MBC)and antibody responses in the dynamic interplay of infection-and vaccine-induced immunity.It also provided an opportunity to explore new vaccine platforms,such as mRNA or adenoviral vector vaccines,in unprecedented cohort sizes.Combined with the technological advances of recent years,this situation has provided detailed mechanistic insights into the development of B-cell and antibody responses but also revealed some unexpected findings.In this review,we summarize the key findings of the last 2.5 years regarding infection-and vaccine-induced B-cell immunity,which we believe are of significant value not only in the context of SARS-CoV-2 but also for future vaccination approaches in endemic and pandemic settings.

关键词： SARS-CoV-2 neutralizing antibodies memory responses vaccines IgG4

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