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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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Temperature-induced plasticity at cellular and organismal levels in the lizard Anolis carolinensis

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Integrative Zoology 2010年第3期5卷 208-217页

作者： rachel m.GOODmAN Tze P.HEAH Department of Ecology and Evolutionary Biology University of TennesseeKnoxvilleTennesseeUSA

Among ectotherms,individuals raised in cooler temperatures often have larger body size and/or larger cell *** current study tested whether geographic variation in cell size and plasticity for cell size exist in a terrestrial,ectothermic vertebrate,Anolis carolinensis Voigt,*** demonstrated temperature-induced plasticity in erythrocytes and epithelial cells of hatchlings lizards derived from the eggs of females sampled from four populations and incubated at multiple *** cells were produced in hatchlings from cooler treatments;however,hatchling body size was unaffected by ***,temperature-induced plasticity applies at the cellular,but not organismal,level in *** addition,reaction norms for cell size differed among *** was a latitudinal trend in cell size and in plasticity of cell size among our study *** two southernmost populations showed plasticity in cell size,whereas the two northernmost ones did *** suggest that selection pressure for larger cell size in northern,cooler environments has restricted plasticity in *** applied at the cellular level in response to variable incubation environments.

关键词： epithelium erythrocyte phenotypic plasticity reptile temperature

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The role of retinoic acid in the commitment to meiosis

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Asian Journal of Andrology 2021年第6期23卷 549-554页

作者： rachel L Gewiss m Christine Schleif michael D Griswold School of molecular Biosciences and Center for Reproductive Biology Washington State UniversityPullmanWA 99164USA

male meiosis is a complex process whereby spermatocytes undergo cell division to form haploid *** review focuses on the role of retinoic acid(RA)in meiosis,as well as several processes regulated by RA before cell entry into meiosis that are critical for proper meiotic entry and ***,we discuss RA metabolism in the testis as well as the roles of stimulated by retinoic acid gene 8(STRA8)and mEIOSIN,which are responsive to RA and are critical for *** assert that transcriptional regulation in the spermatogonia is critical for successful meiosis.

关键词： meiosis retinoic acid spermatogenesis testis

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BRCA mutated pancreatic cancer:A change is coming

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World Journal of Gastroenterology 2021年第17期27卷 1943-1958页

作者： michael N Rosen rachel A Goodwin michael m Vickers Faculty of medicine The University of OttawaOttawa K1H 8L6OntarioCanada The Ottawa Hospital Cancer Center The University of OttawaOttawa K1H 8L6OntarioCanada

Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced ***,patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast *** BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8%of patients with sporadic pancreatic *** patients with germline BRCA mutations,platinum-based chemotherapies and poly(ADP-ribose)polymerase inhibitors are effective treatment options which may offer survival *** review will focus on the molecular biology,epidemiology,and management of BRCA-mutated pancreatic ***-more,we will discuss future directions for this area of research and promising active areas of research.

关键词： Pancreatic cancer Systemic therapy Platinum chemotherapy BRCA Deoxyribonucleic acid repair Poly(ADP-ribose)polymerase inhibitors

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Regulation of enolase activation to promote neural protection and regeneration in spinal cord injury

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Neural Regeneration Research 2023年第7期18卷 1457-1462页

作者： Hannah mmcCoy rachel Polcyn Naren LBanik Azizul Haque Department of microbiology and Immunology Medical University of South CarolinaCharlestonSCUSA Department of Neurosurgery Medical University of South CarolinaCharlestonSCUSA Ralph H.Johnson Veterans Administration medical Center CharlestonSCUSA

Spinal cord injury(SCI)is a debilitating condition characterized by damage to the spinal cord resulting in loss of function,mobility,and sensation with no *** and Drug Administration-approved ***,a multifunctional glycolytic enzyme upregulated after SCI,promotes pro-and anti-inflammatory events and regulates functional recovery in *** is normally expressed in the cytosol,but the expression is upregulated at the cell surface following cellular injury,promoting glial cell activation and signal transduction pathway ***-induced microglia activation triggers pro-inflammatory mediators at the injury site,activating other immune cells and metabolic events,i.e.,Rho-associated kinase,contributing to the neuroinflammation found in *** surface expression also activates cathepsin X,resulting in cleavage of the C-terminal end of neuron-specific enolase(NSE)and non-neuronal enolase(NNE).Fully functional enolase is necessary as NSE/NNE C-terminal proteins activate many neurotrophic processes,i.e.,the plasminogen activation system,phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B,and mitogen-activated protein kinase/extracellular signal-regulated *** here suggest an enolase inhibitor,ENOblock,attenuates the activation of Rho-associated kinase,which may decrease glial cell activation and promote functional recovery following ***,ENOblock inhibits cathepsin X,which may help prevent the cleavage of the neurotrophic C-terminal protein allowing full plasminogen activation and phosphatidylinositol-4,5-bisphosphate 3-kinase/mitogen-activated protein kinase *** combined NSE/cathepsin X inhibition may serve as a potential therapeutic strategy for preventing neuroinflammation/degeneration and promoting neural cell regeneration and recovery following *** role of cell membrane-expressed enolase and associated metabolic events should be investigated to determine if the same strategies can be applied to other neu

关键词： cathepsin X ENOblock enolase glia mitogen-activated protein kinase/extracellular signal-regulated kinase neurodegeneration neuroinflammation phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B Rho-associated protein kinase spinal cord injury

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On the effects of spatial resolution on effective distance measurement in digital landscapes

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Ecological Processes 2021年第1期10卷 659-677页

作者： rachel mundeli murekatete Takeshi Shirabe KTH Royal Institute of Technology School of Architecture and the Built EnvironmentTeknikringen 10A11428 StockholmSweden University of Rwanda College of Science and TechnologyCentre for Geographic Information Systems and Remote SensingKN 67 Street NyarugengeKigaliRwanda

Background:Connectivity is an important landscape attribute in ecological studies and conservation practices and is often expressed in terms of effective *** the cost of movement of an organism over a landscape is effectively represented by a raster surface,effective distances can be equated with the cost-weighted distance of least-cost *** is generally recognized that this measure is sensitive to the grid’s cell size,but little is known if it is always sensitive in the same way and to the same degree and if not,what makes it more(or less)*** conducted computational experiments with both synthetic and real landscape data,in which we generated and analyzed large samples of effective distances measured on cost surfaces of varying cell sizes derived from those *** particular focus was on the statistical behavior of the ratio—referred to as‘accuracy indicator’—of the effective distance measured on a lower-resolution cost surface to that measured on a higher-resolution cost ***:In the experiment with synthetic cost surfaces,the sample values of the accuracy indicator were generally clustered around 1,but slightly greater with the absence of linear sequences(or barriers)of high-cost or inadmissible cells and smaller with the presence of such *** latter tendency was more dominant,and both tendencies became more pronounced as the difference between the spatial resolutions of the associated cost surfaces *** two real satellite images(of different resolutions with fairly large discrepancies)were used as the basis of cost estimation,the variation of the accuracy indicator was found to be substantially large in the vicinity(1500 m)of the source but decreases quickly with an increase in distance from ***:Effective distances measured on lower-resolution cost surfaces are generally highly correlated with—and useful predictors of—effective distances measured on higher-resolution cost *** relationship t

关键词： Landscape connectivity Effective distance Raster-based least-cost path model Accuracy Spatial resolution

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The key piece of the airway remodeling puzzle revealed-LIGHT signaling in the lung

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Genes & Diseases 2023年第4期10卷 1131-1132页

作者： Ziyan rachel Chen Jim Hu Programmes in Translational medicine Research InstituteHospital for Sick ChildrenTorontoOntario M5G 0A4Canada Department of Laboratory medicine and Pathobiology University of TorontoTorontoOntario M5S 1A8Canada Department of Paediatrics University of TorontoTorontoOntario M5S 1A8Canada

Asthma is a chronic lung disease that primarily affects the lower respiratory tract in more than 300 million people *** is often triggered by exposure to certain substances or conditions,such as allergens or cold *** overreaction to the allergens causes inflammation and narrowing of the airway,which leads to episodic or persistent symptoms including shortness of breath,nocturnal cough,chest tightness,and wheezing.

关键词： airway lung inflammation

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Soil fungal and prokaryotic community structure exhibits differential short-term responses to timber harvest in the Pacific Northwest

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Pedosphere 2020年第1期30卷 109-125页

作者： rachel E.DANIELSON megan L.mCGINNIS Scott m.HOLUB David D.mYROLD Department of Crop and Soil Science Oregon State UniversityCorvallis OR 97331-7306(USA) United State Forest Service Helena-Lewis and Clark National Forest2880 Skyway DriveHelena MT 59602(USA) Weyerhaeuser Company PO Box 275Springfield OR 97477(USA) Department of Land Airand Water ResourcesUniversity of CaliforniaDavis CA 95616USA

Conventional clear-cut timber harvest is a widespread industrial practice across the Pacific Northwest;however,information regarding how these practices impact soil microbial community structure at the regional scale is *** evidence of consistent and substantial impact of harvest on soil microbial functional profiles across the region(despite a range of environmental conditions),the objective of this study was to determine the extent to which harvest also influences the structure of prokaryotic and fungal soil microbial communities,and how generalized these trends are throughout the geographic *** soil samples were collected one year before and after harvest across nine second-growth Douglas-fir forests in the Pacific *** community DNA was extracted from the soils,and high-throughput targeted gene sequencing of the 16 S r RNA gene for prokaryotes and the internal transcribed spacer(ITS)gene for fungi was *** diversity was consistently and significantly higher after harvest;it was moderately so for fungal communities(+14.6%),but only marginally so for prokaryotic communities(+2.0%).Similarly,on average,a greater proportion of the variation in the community structure of fungi(20.1%)at each site was associated with forest harvest compared to that of prokaryotes(13.2%).Overall,the greatest influence of timber harvest on soil microbial communities appeared to be a relative depletion of ectomycorrhizal fungi,with a concomitant enrichment of saprotrophic *** the short-term responses of soil microbial communities across the region,particularly those of tree root-associated symbionts,may aid our understanding of the role soil microbial communities play in ecological succession.

关键词： clear-cut Douglas-fir forest ectomycorrhizal fungi forest soil microbial community microbial diversity root-associated symbiont saprotrophic fungi

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Eat more natural dietary fiber and whole grains to minimize liver disease risk

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Hepatobiliary Surgery and Nutrition 2022年第4期11卷 601-604页

作者： rachel m.Golonka Beng San Yeoh matam Vijay-Kumar Department of Physiology and Pharmacology University of Toledo College of Medicine and Life SciencesToledoOHUSA

Nutritional habits in the United States have dramatically changed since the Industrial Revolution in the 18th ***,not every‘advancement’from then to now has improved human dietary habits and *** is evident from the rising epidemic of nutritional insufficiencies associated with the increasing prevalence of age-related diseases(1).Work from Dennis Burkett in the late 1960s was one of the first to hypothesize that refinement of grains and removal of dietary fiber could explain the regional dichotomy in disease incidence(2).

关键词： fiber refinement grains

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Advances in targeted nanotherapeutics： From bioconjugation to biomimicry

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Nano Research 2018年第10期11卷 4999-5016页

作者： Danielle m. Valcourt Jenna Harris rachel S. Riley megan Dang Jianxin Wang Emily S. Day 161 Colburn L ab Department of Biomedical Engineering University of Delaware Newark DE 19716 USA 201 DuPont Hall Department of Materials Science & Engineering University o f Delaware Newark DE 79716 USA 4701 Ogletown Stanton Road Helen F. Graham Cancer Center & Research Institute Newark DE 19713 USA

Since the emergence of cancer nanomedicine, researchers have had intense interest in developing nanoparticles （NPs） that can specifically target diseased sites while avoiding healthy tissue to mitigate the off-target effects seen with conventional treatments like chemotherapy. Initial endeavors focused on the bioconjugation of targeting agents to NPs, and more recently, researchers have begun to develop biomimetic NP platforms that can avoid immune recognition to maximally accumulate in tumors. In this review, we describe the advantages and limitations of each of these targeting strategies. First, we review developments in bioconjugation strategies, where NPs are coated with biomolecules such as antibodies, aptamers, peptides, and small molecules to enable cell-specific binding. While bioconjugated NPs offer many exciting features and have improved pharmacokinetics and biodistribution relative to unmodified NPs, they are still recognized by the body as ＂foreign＂, resulting in their clearance by the mononuclear phagocytic system （mPS）. To overcome this limitation, researchers have recently begun to investigate biomimetic approaches that can hide NPs from immune recognition and reduce clearance by the mPS. These biomimetic NPs fall into two distinct categories： synthetic NPs that present naturally occurring structures, and NPs that are completely disguised by natural structures. Overall bioconjugated and biomimetic NPs have substantial potential to improve upon conventional treatments by reducing off-target effects through site-specific delivery. and they show great promise for future standards of care. Here, we provide a summary of each strategy, discuss considerations for their design moving forward, and highlight their potential clinical impact on cancer therapy.

关键词： targeting nanoparticles cancer biomimicry bioconjugation delivery

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