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The multidrug resistance transporter P-glycoprotein confers resistance to ferroptosis inducers

Cancer Drug Resistance 2023年第3期6卷 468-480页

作者： William J.E.Frye Lyn M.Huff JoséM.González Dalmasy paula salazar Rachel M.Carter Ryan T.Gensler Dominic Esposito Robert W.Robey Suresh V.Ambudkar Michael M.Gottesman Laboratory of Cell Biology Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA Protein Expression Laboratory Frederick National Laboratory for Cancer ResearchLeidos Biomedical ResearchIncFrederickMD 21704USA

Aim:Ferroptosis is a non-apoptotic form of cell death caused by lethal lipid *** small molecule ferroptosis inducers(FINs)have been reported,yet little information is available regarding their interaction with the ATP-binding cassette(ABC)transporters P-glycoprotein(P-gp,ABCB1)and *** thus sought to characterize the interactions of FINs with P-gp and ABCG2,which may provide information regarding oral bioavailability and brain penetration and predict drug-drug ***:Cytotoxicity assays with ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2 were used to determine the ability of the transporters to confer resistance to FINs;confirmatory studies were performed in OVCAR8 and NCI/ADR-RES *** ability of FINs to inhibit P-gp or ABCG2 was determined using the fluorescent substrates rhodamine 123 or purpuin-18,***:P-gp overexpression conferred resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin.P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of *** FINs ML-162,GPX inhibitor 26a,and PACMA31 at 10µM were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 *** inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 ***:Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the *** ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.

关键词： Ferroptosis drug resistance P-glycoprotein ABCG2

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Association between EGF +61A/G polymorphism and gastric cancer in Caucasians

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World Journal of Gastroenterology 2011年第4期17卷 488-492页

作者： Ana paula Araújo Bruno M Costa Ana L Pinto-Correia Maria Fragoso paula Ferreira Mário Dinis-Ribeiro Sandra Costa Rui M Reis Rui Medeiros Molecular Oncology Group Portuguese Institute of Oncology of Porto Life and Health Sciences Research Institute (ICVS) School of Health Sciences Oncology Department Portuguese Institute of Oncology of Porto Gastroenterology Department Portuguese Institute of Oncology of Porto Portugal Cintesis/Faculty of Medicine University of Porto Centro de Estudos em Biomedicina Health Sciences Faculty-Fernando Pessoa University Instituto de Ciencias Biomédicas de Abel salazar Abel Salazar Institute for the Biomedical Sciences

AIM: To investigate the association between epidermal growth factor (EGF) +61A/G polymorphism and susceptibility to gastric cancer, through a cross-sectional study. METHODS: Polymerase chain reaction resctriction fragment lenght polymorphism analyses were used to genotype EGF +61 in 207 patients with gastric lesions (162 patients with gastric adenocarcinomas, 45 with atrophy or intestinal metaplasia) and 984 controls. All subjects were Caucasian. RESULTS: Genotype distribution was 23.5% for GG and 76.5% for GA/AA in the control group, 18.4% for GG and 68.6% for GA/AA in the entire group with gastric lesions and 17.9% for GG and 82.1% for GA/AA in the group with gastric adenocarcinoma. No statistically significant associations were found between EGF +61 variants and risk for developing gastric cancer [odds ratios (OR) = 1.41, 95% confidence intervals (CI): 0.90-2.21, P = 0.116]. However, the stratification of individuals by gender revealed that males carrying A alleles (EGF +61A/G or AA) had an increased risk for developing gastric cancer as compared to GG homozygous males (OR = 1.55, 95% CI: 1.05-2.28, P = 0.021). CONCLUSION: In summary, we found that males who were A carriers for EGF +61 had an increased risk for developing gastric cancer. This result may be explained by the suggestion that women secrete less gastric acid than men.

关键词： Epidermal growth factor polymorphism Epidermal growth factor receptor Gastric cancer

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-765G > C COX-2 polymorphism may be a susceptibility marker for gastric adenocarcinoma in patients with atrophy or intestinal metaplasia

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World Journal of Gastroenterology 2006年第34期12卷 5473-5478页

作者： Carina Pereira Hugo Sousa paula Ferreira Maria Fragoso Luís Moreira-Dias Carlos Lopes Rui Medeiros Mário Dinis-Ribeiro Molecular Oncology Group Portuguese Institute of Oncology of Porto Portugal and ICBAS Abel Salazar Institute for the Biomedical Sciences Porto Portugal Oncology Department Portuguese Institute of Oncology of Porto Portugal Gastroenterology Department Portuguese Institute of Oncology of Porto Portugal and Cintesis / Faculty of Medicine University of Porto Porto Portugal

AIM： To investigate the relationship between the -765G 〉 C COX-2 polymorphism and the development of different gastric lesions： atrophy or intestinal metaplasia and gastric adenocarcinoma. METHODS： A cross-sectional study was performed involving 320 Portuguese individuals （210 without evidence of neoplastic disease, 73 patients with gastric adenocarcinomas and 37 with atrophy or intestinal metaplasia） using a PCR-RFLP method.RESULTS： -765C allele was overrepresented in the patients with gastric adenocarcinoma （51%） when compared either with the control group （38%） or patients with atrophy or intestinal metaplasia （27%）. Callele was found to be very common in our population （0.22）, and a multivariate logistic regression analysis revealed nearly 3-fold increased risk for the progression to gastric adenocarcinoma in patients with atrophy or intestinal metaplasia carrying the -765C allele （OR = 2.67, 95% CI = 1.03-6.93; P = 0.04）.CONCLUSION： -765C carrier status should be considered as another susceptibility marker for gastric adenocarcinoma development in patients with atrophy or intestinal metaplasia.

关键词： Gastric adenocarcinoma Atrophy Intestinal metaplasia COX-2 Polymorphism PCR-RFLP Pharmacogenomic

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Diagnosis and Objective Pain Assessment of Traditional Chinese Medicine May Be Useful to Demonstrate Specific Effects of Acupuncture in Low Back Pain: A Prospective, Randomized, Controlled and Single Blinded Pre-study

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Journal of Acupuncture and Tuina Science 2013年第3期11卷 155-159页

作者： Susana Seca paula Capelo Thomas Efferth Christoph Alexander Doenitz Sven Schroeder Ana Anjos Jorge Machado Henry Johannes Greten Institute of Biomedical Sciences Abel salazar (ICBAS) University of PortoPortoPortugal Heidelberg School of Chinese Medicine Heidelberg Germany University Hospital Center of Coimbra CoimbraPortugal Department of Pharmaceutical Biology Institute of Pharmacy and BiochemistryJohannes Gutenberg UniversityMainzGermany Institute of Biomedical Sciences Abel salazar (ICBAS) University of Porto Porto Portugal HanseMerkur Center for Traditional Chinese Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany Porto Biomechanics Laboratory (LABIOMEP) University of Porto Portugal German Society of Traditional Chinese Medicine Heidelberg Germany

Objective: To prove specific effects of acupuncture on chronic pain. It was speculated that the potential specific effectiveness of acupuncture could be better shown in more properly designed studies. Therefore, diagnoses of both Western medicine and traditional Chinese medicine (TCM) were used as inclusion criteria to allocate acupoints more precisely to the complaints of the patients. Secondly, objectively measurable parameters of pain relief in addition to usual Visual Analogue Scale (VAS) were chosen to quantify the effects of acupuncture. Methods: The study was prospective, randomized, controlled and single-blinded. Eighteen patients with chronic back pain and TCM diagnosis of a Taiyang/Yangming syndrome received one single session of acupuncture chosen according to TCM diagnosis or acupuncture on points outside the meridian system (controls). We evaluated pain via VAS and increased mobility via inclinometry of the back. Results: Although the sample size was small, there was a statistically significant improvement in pain and mobility in the intervention group (n=13), but not in the control group (n=5). The calculated sample size adequate power was lower for inclinometry than for VAS, indicating that VAS is less probable to discriminate acupuncture effects. Conclusion: Objectively measurable physical parameters such as the angle of flexion before and after acupuncture (inclinometry) may be more suitable to measure pain relief than subjective assessment by VAS in acupuncture studies. TCM diagnosis may be a helpful inclusion criterion in studies on acupuncture, so as to potentially allocate interventions better to the complaints of patients.

关键词： Low Back Pain Traditional Chinese Medicine Acupuncture Therapy Sham Acupuncture Randomized Controlled Trial

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How Growth Ability of Multidrug-Resistant Escherichia coli Is Affected by Abiotic Stress Factors

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Open Journal of Preventive Medicine 2014年第5期4卷 250-256页

作者： Lucinda Janete Bessa Vania Filipa Dias Angelo Mendes paula Martins-Costa Helena Ramos Paulo Martins da Costa CIIMAR—Interdisciplinary Center for Marine and Environmental Research University of PortoPortoPortugal ICBAS—Institute Abel salazar for the Biomedical Sciences University of PortoPortoPortugal FCUP—Faculty of Sciences University of PortoPortoPortugal Servico de Microbiologia Centro Hospitalar do PortoHospital Geral de Santo AntonioPortoPortugal

The ability of multidrug-resistant Escherichia coli to adapt and grow in a wide range of different environmental conditions may be crucial to the global spread of antimicrobial resistance. The aim of this study was to evaluate the survival ability of 54 multidrug-resistant E. coli strains, isolated from three different biotopes (clinical setting, gull intestine, river water) when subjected to variations in pH (from 3 to 11) and salinity (from 0.5% to 6% of NaCl) and to nutrient deprivation. The growth of each isolate as well as of a reference strain was assessed during 168 h in every varying condition. Slight variations in the growth ability under some abiotic stress factors were recorded among the isolates from the different biotopes. Multidrug-resistant isolates from gull feces were found to be the more tolerant to environmental abiotic changes, while isolates from river water were the less tolerant. In addition, it was notorious that the carriage of antimicrobial resistance has a clear fitness cost in comparison with the susceptible (reference) strain, highlighting the necessity of reducing the selective pressure exerted by antibiotics. This study underlines the ecological hardness of multidrug-resistant E. coli isolates with a consequent ability to reach and colonize new host and environments.

关键词： Escherichia coli Multidrug Resistance Nutrient Deprivation pH Salinity

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Expression and activity of heterologous hydroxyisocaproate dehydrogenases in Synechocystis *** 6803ΔhoxYH

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Engineering Microbiology 2022年第1期2卷 1-7页

作者： Valentina Jurka Christoph K.Winkler Silvan Poschenrieder Paulo Oliveira Catarina C.Pacheco Eunice A.Ferreira Florian Weissensteiner Piera De Santis Selin Kara Robert Kourist paula Tamagnini Wolfgang Kroutil a Institute of Chemistry University of GrazNAWI GrazHeinrichstrasse 288010 GrazAustria i3S–Instituto de Investigação e Inovação em Saúde Universidade do Porto4200-135 PortoPortugal IBMC–Instituto de Biologia Molecular e Celular Universidade do Porto4200-135 PortoPortugal Departamento de Biologia Faculdade de CiênciasUniversidade do Porto4169-007 PortoPortugal ICBAS–Instituto de Ciências Biomédicas Abel salazar Universidade do Porto4050-313 PortoPortugal Aarhus University Department of EngineeringBiological and Chemical Engineering SectionBiocatalysis and Bioprocessing GroupGustav Wieds Vej 10DK 8000 AarhusDenmark Institute of Molecular Biotechnology Graz University of Technology8010 GrazAustria Field of Excellence BioHealth University of Graz8010 GrazAustria BioTechMed Graz 8010 GrazAustria.

Exploiting light to drive redox reactions is currently a hot topic since light is considered as an environmentally friendly source of ***,cyanobacteria,which can use light e.g.,for generating NADPH,are in the focus of ***,it has been shown that various heterologous redox enzymes could be expressed in these *** we demonstrated the successful inducer-free expression of𝛼-keto-acid dehydroge-nases(L-HicDH and D-HicDH)from Lactobacillus confusus DSM 20196 and Lactobacillus paracasei DSM 20008 in Synechocystis *** 6803ΔhoxYH mutant using replicative *** the L-HicDH showed poor activity limited by the amount of expressed enzyme,the D-HicDH was applied both in vivo and in vitro,transforming the selected𝛼-keto acids to the corresponding optically pure(R)-𝛼-hydroxy acids(ee>99%)in up to 53%and 90%conversion,respectively.

关键词： Cyanobacteria Biocatalysis Photobiotransformation Synechocystis sp.PCC 6803 Hydroxyisocaproate dehydrogenase Ketoacid dehydrogenase

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