A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which dec...A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which decrease drug penetration into the central nervous system and ultimately into tumors.It is noteworthy that the ABC transporters,ABCB1[known as P-glycoprotein(P-gp)]and ABCG2[known as breast cancer resistance protein(BCRP)],are overexpressed in brain tumors,including common gliomas.The co-presence of these transporters may negate the inhibition of either transporter,particularly if both transport the same anticancer drug.The cellular export of drugs by ABC transporters has been implicated in mediating resistance to anticancer drugs.However,the clinical relevance as a therapeutic target in human tumors remains a matter of contention.Although effective and clinically approved ABC transporter inhibitors could potentially overcome drug resistance,none are currently approved.Furthermore,the ABC transporter inhibitors in clinical trials produced low or no clinical efficacy,significant toxicities,and unsuitable pharmacokinetic profiles.Therefore,innovative approaches are needed to efficaciously and simultaneously inhibit these transporters to surmount anticancer drug resistance.This review emphasizes the clinical significance of ABC transporters in diminishing the efficacy of brain tumor treatments.The molecular alterations in BBB following brain tumor development,which are linked to various cancer therapies,are discussed.The overexpression of ABCB1 and ABCG2 at the BBB is discussed,potential strategies to decrease the export of chemotherapeutics by these transporters and the associated challenges and failures are discussed,and the implementation of novel approaches is considered.展开更多
The ATP-binding cassette transporters(ABC transporters)have been intensely studied over the past 50 years for their involvement in the multidrug resistance(MDR)phenotype,especially in cancer.They are frequently overex...The ATP-binding cassette transporters(ABC transporters)have been intensely studied over the past 50 years for their involvement in the multidrug resistance(MDR)phenotype,especially in cancer.They are frequently overexpressed in both naive and post-treatment tumors,and hinder effective chemotherapy by reducing drug accumulation in cancer cells.In the last decade however,several studies have established that ABC transporters have additional,fundamental roles in tumor biology;there is strong evidence that these proteins are involved in transporting tumor-enhancing molecules and/or in protein-protein interactions that impact cancer aggressiveness,progression,and patient prognosis.This review highlights these studies in relation to some well-described cancer hallmarks,in an effort to re-emphasize the need for further investigation into the physiological functions of ABC transporters that are critical for tum or development.Unraveling these new roles offers an opportunity to define new strategies and targets for therapy,which would include endogenous substrates or signaling pathways that regulate these proteins.展开更多
Stem cells intrigue. They have the ability to divide exponentially, recreate the stem cell compartment, as well as create differentiated cells to generate tissues. Therefore, they should be natural candidates to provi...Stem cells intrigue. They have the ability to divide exponentially, recreate the stem cell compartment, as well as create differentiated cells to generate tissues. Therefore, they should be natural candidates to provide a renewable source of cells for transplantation applied in regenerative medicine. Stem cells have the capacity to generate specific tissues or even whole organs like the blood, heart, or bones. A subgroup of stem cells, the neural stem cells （NSCs）, is characterized as a self-renewing population that generates neurons and glia of the developing brain. They can be isolated, genetically manipulated and differentiated in vitro and reintroduced into a developing, adult or a pathologically altered central nervous system. NSCs have been considered for use in cell replacement therapies in various neurodegenerative diseases such as Parkinson＇s disease and Alzheimer＇s disease. Characterization of genes with tightly controlled expression patterns during differentiation represents an approach to understanding the regulation of stem cell commitment. The regulation of stem cell biology by the ATP-binding cassette （ABC） transporters has emerged as an important new field of investigation. As a major focus of stem cell research is in the manipulation of cells to enable differentiation into a targeted cell population; in this review, we discuss recent literatures on ABC transporters and stem cells, and propose an integrated view on the role of the ABC transporters, especially ABCA2, ABCA3, ABCB 1 and ABCG2, in NSCs＇ proliferation, differentiation and regulation, along with comparisons to that in hematopoietic and other stem cells.展开更多
A recent study showed that erythromycin(ERY)exposure caused hormesis in a model alga(Raphidocelis subcapitata)where the growth was promoted at an environmentally realistic concentration(4μg/L)but inhibited at two hig...A recent study showed that erythromycin(ERY)exposure caused hormesis in a model alga(Raphidocelis subcapitata)where the growth was promoted at an environmentally realistic concentration(4μg/L)but inhibited at two higher concentrations(80 and 120μg/L),associated with opposite actions of certain signaling pathways(e.g.,xenobiotic metabolism,DNA replication).However,these transcriptional alterations remain to be investigated and verified at the metabolomic level.This study uncovered metabolomic profiles and detailed toxic mechanisms of ERY in R.subcapitata using untargetedmetabolomics.Themetabolomic analysis showed that metabolomic pathways including ABC transporters,fatty acid biosynthesis and purine metabolism were associated with growth promotion in algae treated with 4μg/L ERY.An overcompensation was possibly activated by the low level of ERY in algae where more resources were reallocated to efficiently restore the temporary impairments,ultimately leading to the outperformance of growth.By contrast,algal growth inhibition in the 80 and 120μg/L ERY treatments was likely attributed to the dysfunction of metabolomic pathways related to ABC transporters,energy metabolism and metabolism of nucleosides.Apart from binding of ERY to the 50S subunit of ribosomes to inhibit protein translation as in bacteria,the data presented here indicate that inhibition of protein translation and growth performance of algae by ERY may also result from the suppression of amino acid biosynthesis and aminoacyl-tRNA biosynthesis.This study provides novel insights into the dose-dependent toxicity of ERY on R.subcapitata.展开更多
The plant pathogenic fungus Sclerotinia sclerotiorum is the causative agent of Sclerotinia stem rot(SSR)disease in most dicotyledons.Among the various proteins involved in drug efflux or substance transport,ATP-bindin...The plant pathogenic fungus Sclerotinia sclerotiorum is the causative agent of Sclerotinia stem rot(SSR)disease in most dicotyledons.Among the various proteins involved in drug efflux or substance transport,ATP-binding cassette(ABC)transporters constitute a superfamily of membrane-bound proteins that may play a crucial role in the survival of S.sclerotiorum.However,the expression patterns and functions of ABC transporter genes in S.sclerotiorum remain largely uncharacterized.This study characterized a highly expressed S.sclerotiorum ABC transporter gene during inoculation on host plants,Ss BMR1.Silencing Ss BMR1 resulted in a significant reduction in hyphal growth,infection cushion development,sclerotia formation,and virulence.Moreover,host-induced gene silencing(HIGS)of Ss BMR1 significantly enhanced plant resistance.Transcriptome and metabolomics analyses suggested that Ss BMR1 is involved in antioxidant and toxin transport,thereby influencing fungal defense and cell rescue mechanisms.In comparison to the wild-type strain,Ss BMR1 gene-silenced transformants exhibited a diminished response to extracellar oxidative stress and a decreased exporting of antioxidant glutathione.Tolerance assays further demonstrated the crucial role of Ss BMR1 in conferring resistance to the plant antifungal substances,camalexin and brassinin,as well as certain fungicides.Furthermore,Ss BMR1 gene-silenced transformants showed enhanced repression on virulence when sprayed with camalexin and brassinin on the leaves.Thus,Ss BMR1 likely contributes to virulence by facilitating the export of antioxidant and providing resistance against antifungal agents.The findings of this study provide valuable insights that could contribute to the development of novel management techniques for SSR.展开更多
Adenosine triphosphate(ATP)-binding cassette(ABC)transporter systems are divided into importers and exporters that facilitate the movement of diverse substrate molecules across the lipid bilayer,against the concentrat...Adenosine triphosphate(ATP)-binding cassette(ABC)transporter systems are divided into importers and exporters that facilitate the movement of diverse substrate molecules across the lipid bilayer,against the concentration gradient.These transporters comprise two highly conserved nucleotide-binding domains(NBDs)and two transmembrane domains(TMDs).Unlike ABC exporters,prokaryotic ABC importers require an additional substrate-binding protein(SBP)as a recognition site for specific substrate translocation.The discovery of a large number of ABC systems in bacterial pathogens revealed that these transporters are crucial for the establishment of bacterial infections.The existing literature has highlighted the roles of ABC transporters in bacterial growth,pathogenesis,and virulence.These roles include importing essential nutrients required for a variety of cellular processes and exporting outer membrane-associated virulence factors and antimicrobial substances.This review outlines the general structures and classification of ABC systems to provide a comprehensive view of the activities and roles of ABC transporters associated with bacterial virulence and pathogenesis during infection.展开更多
The remodeling of root architecture is a major developmental response of plants to phosphate （Pi） deficiency and is thought to enhance a plant＇s ability to forage for the available Pi in topsoil. The underlying mec...The remodeling of root architecture is a major developmental response of plants to phosphate （Pi） deficiency and is thought to enhance a plant＇s ability to forage for the available Pi in topsoil. The underlying mechanism controlling this response, however, is poorly understood. In this study, we identified an Arabidopsis mutant, hps 10 （hypersensitive to Pi starvation 10）, which is morphologically normal under Pi sufficient condition but shows increased inhibition of primary root growth and enhanced production of lateral roots under Pi defi- ciency, hpslO is a previously identified allele （als3-3） of the ALUMINUM SENSITIVE3 （ALS3） gene, which is involved in plant tolerance to aluminum toxicity. Our results show that ALS3 and its interacting protein AtSTAR1 form an ABC transporter complex in the tonoplast. This protein complex mediates a highly electro- genic transport in Xenopus oocytes. Under Pi deficiency, als3 accumulates higher levels of Fe3＋ in its roots than the wild type does. In Arabidopsis, LPR1 （LOW PHOSPHATE ROOT1） and LPR2 encode ferroxidases, which when mutated, reduce Fe3＋ accumulation in roots and cause root growth to be insensitive to Pi defi- ciency. Here, we provide compelling evidence showing that ALS3 cooperates with LPR1/2 to regulate Pi deficiency-induced remodeling of root architecture by modulating Fe homeostasis in roots.展开更多
The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases.The family of ATP-binding c...The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases.The family of ATP-binding cassette(ABC)transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers.These efflux transporters include P-glycoprotein(abcb1),‘breast cancer resistance protein'(abcg2)and the various‘multidrug resistance-associated proteins'(abccs).Understanding which efflux transporters are present at the blood-spinal cord,blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord tissue.Recent developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age,disease and environmental challenge.This means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that exist.In the present review,the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on:(i)protecting the spinal cord from adverse effects of systemically directed drugs,and(ii)limiting centrally directed drugs from accessing their active sites within the spinal cord.展开更多
Seed development is critical for plant reproduction and crop yield,with panicle seed-setting rate,grain-filling,and grain weight being key seed characteristics for yield improvement.However,few genes are known to regu...Seed development is critical for plant reproduction and crop yield,with panicle seed-setting rate,grain-filling,and grain weight being key seed characteristics for yield improvement.However,few genes are known to regulate grain filling.Here,we identify two adenosine triphosphate(ATP)-binding cassette(ABC)I-type transporter genes,OsABCI15 and OsABCI16,involved in rice grain-filling.Both genes are highly expressed in developing seeds,and their proteins are localized to the plasma membrane and cytosol.Interestingly,knockout of OsABCI15 and OsABCI16 results in a significant reduction in seed-setting rate,caused predominantly by the severe empty pericarp phenotype,which differs from the previously reported low seed-setting phenotype resulting from failed pollination.Further analysis indicates that OsABCI15 and OsABCI16 participate in ion homeostasis and likely export ions between filial tissues and maternal tissues during grain filling.Importantly,overexpression of OsABCI15 and OsABCI16 enhances the seed-setting rate and grain yield in transgenic plants and decreases ion accumulation in brown rice.Moreover,the OsABCI15/16 orthologues in maize exhibit a similar role in kernel development,as demonstrated by their disruption in transgenic maize.Therefore,ourfindings reveal the important roles of two ABC transporters in cereal grain filling,highlighting their value in crop yield improvement.展开更多
ABC transporters form the largest of all transporter families, and their structural study has made tremen- dous progress over recent years. However, despite such advances, the precise mechanisms that determine the ene...ABC transporters form the largest of all transporter families, and their structural study has made tremen- dous progress over recent years. However, despite such advances, the precise mechanisms that determine the energy-coupling between ATP hydrolysis and the con- formational changes following substrate binding remain to be elucidated. Here, we present our thermodynamic analysis for both ABC importers and exporters, and introduce the two new concepts of differential-binding energy and elastic conformational energy into the dis- cussion. We hope that the structural analysis of ABC transporters will henceforth take thermodynamic aspects of transport mechanisms into account as well.展开更多
Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and ...Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies.Unfortunately,with traditional drug discovery approaches,only echinocandins was approved by FDA as a new class of antifungals in the past two decades.Drug efflux is one of the major contributors to multi-drug resistance,the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance.In this study,we combined structure-based virtual screening and whole-cell based mechanism study,identified a natural product,beauvericin(BEA)as a drug efflux pump modulator,which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette(ABC)transporters;meantime,BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species(ROS).It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole(KTC)and could cure the murine model of disseminated candidiasis.Toxicity evaluation of BEA,including acute toxicity test,Ames test,and hERG(human ether-a-go-go-related gene)test promised that BEA can be harnessed for treatment of candidiasis,especially the candidiasis caused by ABC overexpressed multi-drug resistant C.albicans.展开更多
Utilizing transporter-mediated drug delivery to achieve effective oral absorption emerges as a promising strategy.Researchers have been concentrated on discovering solutions to the issues of low solubility and poor pe...Utilizing transporter-mediated drug delivery to achieve effective oral absorption emerges as a promising strategy.Researchers have been concentrated on discovering solutions to the issues of low solubility and poor permeability of insoluble drugs,whereas,current reports have revealed that drug transporter proteins are abundantly expressed in the mucosa of intestinal epithelial cells,and that their mediated drug absorption effectively improved the bioavailability of orally administered drugs.There are two main categories based on the transporter mechanism,which include the family of ATP-binding cassette(ABC)transporters with efflux effects that reduce drug bioavailability and the family of solute carriers(SLC)transporters with uptake effects that promote drug absorption,respectively.Thus,we review studies of intestinal transporter-mediated delivery of drugs to enhance oral absorption,including the types of intestinal transporters,distribution characteristics,and strategies for enhancing oral absorption using transporter-mediated drug delivery systems are summarized,with the aim of providing important theoretical references for the development of intestinal-targeted delivery system.展开更多
Pesticide resistance greatly limits control efficacy after the long-term application of pesticides.The two-spottedspider mite,Tetranychus urticae Koch,is a notorious agricultural pest worldwide that is resistant to va...Pesticide resistance greatly limits control efficacy after the long-term application of pesticides.The two-spottedspider mite,Tetranychus urticae Koch,is a notorious agricultural pest worldwide that is resistant to various pesticides,including abamectin.While some studies of abamectin resistance have investigated target resistance related toglutamate-gated chloride channels(GluCls),studies on the metabolic resistance mechanisms are still limited.In this study,we identified an ABCC subfamily gene,Tu ABCC4,that was overexpressed in resistant populations of T.urticae,based on the analysis of previously obtained transcriptomic and RNA-seq data.No consistent nonsynonymousmutations in the Tu ABCC4 gene were found between the susceptible and resistant populations,although Tu ABCC4expression was significantly increased in all the resistant populations that were studied.Synergistic experiments withthe inhibitor verapamil and gene expression analysis of the susceptible and resistant populations confirmed the key roleof Tu ABCC4 in abamectin resistance.In addition,an increase in the expression of the Tu ABCC4 gene was shown byRNA interference and genetic association analysis to be closely related to the resistance of T.urticae to abamectin.Inconclusion,overexpression of Tu ABCC4 was shown to be involved in abamectin resistance in T.urticae.These resultscan help us to better understand the molecular basis of pest resistance to abamectin.展开更多
Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters poten...Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles,including targeted distribution,improved clinical efficacy and low adverse reaction.In this review,we summarize the tissue-specific expression,transport functions and substrates profiles of the major influx and efflux transporters,including solute carrier（SLC） superfamily and adenosine triphosphate（ATP）-binding cassette（ABC） superfamily.Moreover,we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties.Lastly,we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.展开更多
Multidrug resistance （MDR） is a major problem in cancer chemotherapy. One of the best known mechanisms of MDR is the elevated expression of ATP-binding cassette （ABC） transporters. While some members of human ABC ...Multidrug resistance （MDR） is a major problem in cancer chemotherapy. One of the best known mechanisms of MDR is the elevated expression of ATP-binding cassette （ABC） transporters. While some members of human ABC transporters have been shown to cause drug resistance with elevated expression, it is not yet known whether the over-expression of other members could also contribute to drug resistance in many model cancer cell lines and clinics. The recent development ofmicroarrays and quantitative PCR arrays for expression profiling analysis of ABC transporters has helped address these issues. In this article, various arrays with limited or full list of ABC transporter genes and their use in identifying ABC transporter genes in drug resistance and chemo-sensitivity prediction will be reviewed.展开更多
The World Health Organisation recommends exclusive breastfeeding for the first six months of an infant’s life and in combination with solid food thereafter. This recommendation was introduced based on research showin...The World Health Organisation recommends exclusive breastfeeding for the first six months of an infant’s life and in combination with solid food thereafter. This recommendation was introduced based on research showing numerous health benefits of breastfeeding for both the mother and the infant. However, there is always concern regarding the transfer of medications from mother to their breastfed baby via milk. Pharma-cokinetic properties of a drug are usually used to pre-dict its transferability into breast milk. Although most drugs are compatible with breastfeeding, cases of toxic drug exposure have been reported. This is thought to be due to active transport mechanisms whereby effux transporter proteins expressed in the epithelial cells of the mammary gland actively secrete drugs into milk. An example of such effux transporters including the breast cancer resistance protein which is strongly induced during lactation and this could result in contamination of milk with the substrates of this transporter which may place the suckling infant at risk of toxicity. Furthermore, there is little known about the substrate specifcity of most effux transporters as we have highlighted in this review. There also exists some degree of contradiction between in vivo and in vitro studies which makes it difficult to conclusively predict outcomes and drug-drug interactions.展开更多
Objective：ATP-binding cassette transporters（ABC） A1 and G1 play an important role in mediating cholesterol efflux and preventing macrophage foam cell formation. In this study, we examined the regulation of ABC tran...Objective：ATP-binding cassette transporters（ABC） A1 and G1 play an important role in mediating cholesterol efflux and preventing macrophage foam cell formation. In this study, we examined the regulation of ABC transporters by high glucose in human vascular smooth muscle cells（VSMCs）, the other precursor of foam cells. Methods：Incubation of human VSMCs with D-glucose（5 to 30 mM） for 1 to 7 days in the presence or absence of antioxidant and nuclear factor（NF）- κ B inhibitors, the expressions of ABCA1 and ABCG1 were analyzed by real time PCR and Western blotting. Results：High glucose decreased ABCG1 mRNA and protein expression in cultured VSMCs, whereas the expression of ABCA1 was not significantly decreased. Down-regulation of ABCG1 mRNA expression by high glucose was abolished by antioxidant N-acetyl-L-cysteine（NAC） and NF- κ B inhibitors, BAY 11-7085 and tosyl-phenylalanine chloromethyl-ketone（TPCK）. Conclusion：High glucose suppresses the expression of ABCG1 in VSMCs, which is the possible mechanism of VSMC derived foam cell transformation.展开更多
Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have sh...Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.展开更多
Multidrug resistance protein 5 (MRP5/ABCC5) is a 161 kDa member of the super family of ATP-binding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidr...Multidrug resistance protein 5 (MRP5/ABCC5) is a 161 kDa member of the super family of ATP-binding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively e?uxing anticancer drugs. ABCC5 has also been identified as an efflux transporter of cGMP (cyclic guanosine monophosphate). Elevated intracellular levels of cGMP in cancer cells have been implicated in several clinical studies, that may induce apoptosis, and as a result many different cancer cells seem to overcome this deleterious effect by increased efflux of cGMP through ABCC5. Thus inhibition of ABCC5 may have cytotoxic effects mediated through cGMP and it will also increase the intracellular concentration of other drugs that are aimed for the treatment of cancer which are otherwise exported out of the cells. Considering the functional importance and lack of X-ray crystal structure of ABCC5, present work was undertaken to construct 3D structure of protein using homology modeling protocol of YASARA structure (V. 16.3.28). In this study, five different ABC templates (PDB ID’s: 4F4C, 4Q9H, 4M1M, 4M2T and 4KSD) were used for homology modeling. Five models were constructed on each template and a hybrid model was built using all five templates. All models were refined and ranked as per their overall Z-score. The top ranked ABBC5 model was based on template 4Q9H that had 91.2% of residues in allowed regions as revealed by PROCHECK-NMR and the QMEAN score was 0.54 which indicated a reliable model. The results of the study and the proposed model can be further used for elucidating the structural and functional aspects of ABCC5 and to gain more insights to the molecular basis of ABCC5 inhibition through docking studies.展开更多
The use of synthetic pesticides carries a significant risk of pests developing resistance,leading to decreased pesticide effectiveness.ATP-binding cassette(ABC)transporters,especially the ABCC subfamily members,have b...The use of synthetic pesticides carries a significant risk of pests developing resistance,leading to decreased pesticide effectiveness.ATP-binding cassette(ABC)transporters,especially the ABCC subfamily members,have been suggested to act as efflux pumps for various pesticides,thereby contributing to pesticide resistance.So far,the identification of potential pesticide substrates of insect ABC transporters is most often based on the quantification of transcript in arthropods.Here,we screened and identified the potential pesticide substrates of ABCC-9C from Tribolium castaneum based on an in vitro ATPase activity assay.Together with affinity evaluation-,cytotoxicity analysis-,and RNA interference-based bioactivity tests,we revealed that the insecticides,carbofuran,and buprofezin,are potential substrates of TcABCC-9C.Additionally,we identified an amphipathic translocation channel in the transmembrane domain of TcABCC-9C formed by 8 transmembrane helices.Molecular docking suggested that both carbofuran and buprofezin bind at the same site within the translocation channel via hydrophobic interactions.These findings indicate that TcABCC-9C might play a critical role in multi-pesticide resistance,providing a potential target for managing pesticide resistance and laying the groundwork for future pest control strategies.Given the conservations among ABCC subfamily members,the experimental model we developed in this study can be also applied to identify the potential substrates of other ABCC transporters,as well as to predict insecticide resistance mediated by ABCC transporters.展开更多
基金supported by Arkansas Bioscience Institute funds (ABI-GR020025) from University of Arkansas for Medical Sciences
文摘A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which decrease drug penetration into the central nervous system and ultimately into tumors.It is noteworthy that the ABC transporters,ABCB1[known as P-glycoprotein(P-gp)]and ABCG2[known as breast cancer resistance protein(BCRP)],are overexpressed in brain tumors,including common gliomas.The co-presence of these transporters may negate the inhibition of either transporter,particularly if both transport the same anticancer drug.The cellular export of drugs by ABC transporters has been implicated in mediating resistance to anticancer drugs.However,the clinical relevance as a therapeutic target in human tumors remains a matter of contention.Although effective and clinically approved ABC transporter inhibitors could potentially overcome drug resistance,none are currently approved.Furthermore,the ABC transporter inhibitors in clinical trials produced low or no clinical efficacy,significant toxicities,and unsuitable pharmacokinetic profiles.Therefore,innovative approaches are needed to efficaciously and simultaneously inhibit these transporters to surmount anticancer drug resistance.This review emphasizes the clinical significance of ABC transporters in diminishing the efficacy of brain tumor treatments.The molecular alterations in BBB following brain tumor development,which are linked to various cancer therapies,are discussed.The overexpression of ABCB1 and ABCG2 at the BBB is discussed,potential strategies to decrease the export of chemotherapeutics by these transporters and the associated challenges and failures are discussed,and the implementation of novel approaches is considered.
基金This work was funded by Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro(FAPERJ),Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior(CAPES)and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)from the Brazilian government and the Institute of Primate Research,Kenya(IPR).
文摘The ATP-binding cassette transporters(ABC transporters)have been intensely studied over the past 50 years for their involvement in the multidrug resistance(MDR)phenotype,especially in cancer.They are frequently overexpressed in both naive and post-treatment tumors,and hinder effective chemotherapy by reducing drug accumulation in cancer cells.In the last decade however,several studies have established that ABC transporters have additional,fundamental roles in tumor biology;there is strong evidence that these proteins are involved in transporting tumor-enhancing molecules and/or in protein-protein interactions that impact cancer aggressiveness,progression,and patient prognosis.This review highlights these studies in relation to some well-described cancer hallmarks,in an effort to re-emphasize the need for further investigation into the physiological functions of ABC transporters that are critical for tum or development.Unraveling these new roles offers an opportunity to define new strategies and targets for therapy,which would include endogenous substrates or signaling pathways that regulate these proteins.
文摘Stem cells intrigue. They have the ability to divide exponentially, recreate the stem cell compartment, as well as create differentiated cells to generate tissues. Therefore, they should be natural candidates to provide a renewable source of cells for transplantation applied in regenerative medicine. Stem cells have the capacity to generate specific tissues or even whole organs like the blood, heart, or bones. A subgroup of stem cells, the neural stem cells （NSCs）, is characterized as a self-renewing population that generates neurons and glia of the developing brain. They can be isolated, genetically manipulated and differentiated in vitro and reintroduced into a developing, adult or a pathologically altered central nervous system. NSCs have been considered for use in cell replacement therapies in various neurodegenerative diseases such as Parkinson＇s disease and Alzheimer＇s disease. Characterization of genes with tightly controlled expression patterns during differentiation represents an approach to understanding the regulation of stem cell commitment. The regulation of stem cell biology by the ATP-binding cassette （ABC） transporters has emerged as an important new field of investigation. As a major focus of stem cell research is in the manipulation of cells to enable differentiation into a targeted cell population; in this review, we discuss recent literatures on ABC transporters and stem cells, and propose an integrated view on the role of the ABC transporters, especially ABCA2, ABCA3, ABCB 1 and ABCG2, in NSCs＇ proliferation, differentiation and regulation, along with comparisons to that in hematopoietic and other stem cells.
基金supported by the National Natural Science Foundation of China (No. 42101077)The Key Research and Development Program of Shaan Xi Province (No. 2020SF-387)ShaanXi Thousand Talent Program for Young Outstanding Scientists (No. 334041900007)
文摘A recent study showed that erythromycin(ERY)exposure caused hormesis in a model alga(Raphidocelis subcapitata)where the growth was promoted at an environmentally realistic concentration(4μg/L)but inhibited at two higher concentrations(80 and 120μg/L),associated with opposite actions of certain signaling pathways(e.g.,xenobiotic metabolism,DNA replication).However,these transcriptional alterations remain to be investigated and verified at the metabolomic level.This study uncovered metabolomic profiles and detailed toxic mechanisms of ERY in R.subcapitata using untargetedmetabolomics.Themetabolomic analysis showed that metabolomic pathways including ABC transporters,fatty acid biosynthesis and purine metabolism were associated with growth promotion in algae treated with 4μg/L ERY.An overcompensation was possibly activated by the low level of ERY in algae where more resources were reallocated to efficiently restore the temporary impairments,ultimately leading to the outperformance of growth.By contrast,algal growth inhibition in the 80 and 120μg/L ERY treatments was likely attributed to the dysfunction of metabolomic pathways related to ABC transporters,energy metabolism and metabolism of nucleosides.Apart from binding of ERY to the 50S subunit of ribosomes to inhibit protein translation as in bacteria,the data presented here indicate that inhibition of protein translation and growth performance of algae by ERY may also result from the suppression of amino acid biosynthesis and aminoacyl-tRNA biosynthesis.This study provides novel insights into the dose-dependent toxicity of ERY on R.subcapitata.
基金received financial support from the Natural Science Foundation of Chongqing,China(CSTB2023NSCQMSX0355)the Fundamental Research Funds for the Central Universities,China(SWU120075)the National Natural Science Foundation of China(32372077)。
文摘The plant pathogenic fungus Sclerotinia sclerotiorum is the causative agent of Sclerotinia stem rot(SSR)disease in most dicotyledons.Among the various proteins involved in drug efflux or substance transport,ATP-binding cassette(ABC)transporters constitute a superfamily of membrane-bound proteins that may play a crucial role in the survival of S.sclerotiorum.However,the expression patterns and functions of ABC transporter genes in S.sclerotiorum remain largely uncharacterized.This study characterized a highly expressed S.sclerotiorum ABC transporter gene during inoculation on host plants,Ss BMR1.Silencing Ss BMR1 resulted in a significant reduction in hyphal growth,infection cushion development,sclerotia formation,and virulence.Moreover,host-induced gene silencing(HIGS)of Ss BMR1 significantly enhanced plant resistance.Transcriptome and metabolomics analyses suggested that Ss BMR1 is involved in antioxidant and toxin transport,thereby influencing fungal defense and cell rescue mechanisms.In comparison to the wild-type strain,Ss BMR1 gene-silenced transformants exhibited a diminished response to extracellar oxidative stress and a decreased exporting of antioxidant glutathione.Tolerance assays further demonstrated the crucial role of Ss BMR1 in conferring resistance to the plant antifungal substances,camalexin and brassinin,as well as certain fungicides.Furthermore,Ss BMR1 gene-silenced transformants showed enhanced repression on virulence when sprayed with camalexin and brassinin on the leaves.Thus,Ss BMR1 likely contributes to virulence by facilitating the export of antioxidant and providing resistance against antifungal agents.The findings of this study provide valuable insights that could contribute to the development of novel management techniques for SSR.
基金supported by the Universiti Kebangsaan Malaysia under the Research University Grant(No.GUP-2020-030)awarded to Sylvia CHIENG.
文摘Adenosine triphosphate(ATP)-binding cassette(ABC)transporter systems are divided into importers and exporters that facilitate the movement of diverse substrate molecules across the lipid bilayer,against the concentration gradient.These transporters comprise two highly conserved nucleotide-binding domains(NBDs)and two transmembrane domains(TMDs).Unlike ABC exporters,prokaryotic ABC importers require an additional substrate-binding protein(SBP)as a recognition site for specific substrate translocation.The discovery of a large number of ABC systems in bacterial pathogens revealed that these transporters are crucial for the establishment of bacterial infections.The existing literature has highlighted the roles of ABC transporters in bacterial growth,pathogenesis,and virulence.These roles include importing essential nutrients required for a variety of cellular processes and exporting outer membrane-associated virulence factors and antimicrobial substances.This review outlines the general structures and classification of ABC systems to provide a comprehensive view of the activities and roles of ABC transporters associated with bacterial virulence and pathogenesis during infection.
文摘The remodeling of root architecture is a major developmental response of plants to phosphate （Pi） deficiency and is thought to enhance a plant＇s ability to forage for the available Pi in topsoil. The underlying mechanism controlling this response, however, is poorly understood. In this study, we identified an Arabidopsis mutant, hps 10 （hypersensitive to Pi starvation 10）, which is morphologically normal under Pi sufficient condition but shows increased inhibition of primary root growth and enhanced production of lateral roots under Pi defi- ciency, hpslO is a previously identified allele （als3-3） of the ALUMINUM SENSITIVE3 （ALS3） gene, which is involved in plant tolerance to aluminum toxicity. Our results show that ALS3 and its interacting protein AtSTAR1 form an ABC transporter complex in the tonoplast. This protein complex mediates a highly electro- genic transport in Xenopus oocytes. Under Pi deficiency, als3 accumulates higher levels of Fe3＋ in its roots than the wild type does. In Arabidopsis, LPR1 （LOW PHOSPHATE ROOT1） and LPR2 encode ferroxidases, which when mutated, reduce Fe3＋ accumulation in roots and cause root growth to be insensitive to Pi defi- ciency. Here, we provide compelling evidence showing that ALS3 cooperates with LPR1/2 to regulate Pi deficiency-induced remodeling of root architecture by modulating Fe homeostasis in roots.
文摘The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases.The family of ATP-binding cassette(ABC)transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers.These efflux transporters include P-glycoprotein(abcb1),‘breast cancer resistance protein'(abcg2)and the various‘multidrug resistance-associated proteins'(abccs).Understanding which efflux transporters are present at the blood-spinal cord,blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord tissue.Recent developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age,disease and environmental challenge.This means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that exist.In the present review,the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on:(i)protecting the spinal cord from adverse effects of systemically directed drugs,and(ii)limiting centrally directed drugs from accessing their active sites within the spinal cord.
基金the National Natural Science Foundation of China(32100206 and 32072037)the Research Programs from Jiangsu Government(BE2022336)+1 种基金the Project of Zhongshan Biological Breeding Laboratory(BM2022008-02)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)and the Key Scientific Research Project of the Higher Education Institution in Jiangsu Province(No.20KJA210002).
文摘Seed development is critical for plant reproduction and crop yield,with panicle seed-setting rate,grain-filling,and grain weight being key seed characteristics for yield improvement.However,few genes are known to regulate grain filling.Here,we identify two adenosine triphosphate(ATP)-binding cassette(ABC)I-type transporter genes,OsABCI15 and OsABCI16,involved in rice grain-filling.Both genes are highly expressed in developing seeds,and their proteins are localized to the plasma membrane and cytosol.Interestingly,knockout of OsABCI15 and OsABCI16 results in a significant reduction in seed-setting rate,caused predominantly by the severe empty pericarp phenotype,which differs from the previously reported low seed-setting phenotype resulting from failed pollination.Further analysis indicates that OsABCI15 and OsABCI16 participate in ion homeostasis and likely export ions between filial tissues and maternal tissues during grain filling.Importantly,overexpression of OsABCI15 and OsABCI16 enhances the seed-setting rate and grain yield in transgenic plants and decreases ion accumulation in brown rice.Moreover,the OsABCI15/16 orthologues in maize exhibit a similar role in kernel development,as demonstrated by their disruption in transgenic maize.Therefore,ourfindings reveal the important roles of two ABC transporters in cereal grain filling,highlighting their value in crop yield improvement.
文摘ABC transporters form the largest of all transporter families, and their structural study has made tremen- dous progress over recent years. However, despite such advances, the precise mechanisms that determine the energy-coupling between ATP hydrolysis and the con- formational changes following substrate binding remain to be elucidated. Here, we present our thermodynamic analysis for both ABC importers and exporters, and introduce the two new concepts of differential-binding energy and elastic conformational energy into the dis- cussion. We hope that the structural analysis of ABC transporters will henceforth take thermodynamic aspects of transport mechanisms into account as well.
基金the National Program on Key Basic Research Project(973program,2013CB734000)in part by grants from the National Natural Science Foundation of China[31670052,31430002,31320103911,31400090,81302678 and 31125002]+2 种基金the Ministry of Science and Tech-nology of the People’s Republic of China[2011ZX09102-011-11,2013ZX10005004-005]China Ocean Mineral Resources R&D Association(Grant No.DY125-15-T-07)the European Union’s Seventh Framework Programme(FP7/2007-2013)under grant agreement no.312184.
文摘Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies.Unfortunately,with traditional drug discovery approaches,only echinocandins was approved by FDA as a new class of antifungals in the past two decades.Drug efflux is one of the major contributors to multi-drug resistance,the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance.In this study,we combined structure-based virtual screening and whole-cell based mechanism study,identified a natural product,beauvericin(BEA)as a drug efflux pump modulator,which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette(ABC)transporters;meantime,BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species(ROS).It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole(KTC)and could cure the murine model of disseminated candidiasis.Toxicity evaluation of BEA,including acute toxicity test,Ames test,and hERG(human ether-a-go-go-related gene)test promised that BEA can be harnessed for treatment of candidiasis,especially the candidiasis caused by ABC overexpressed multi-drug resistant C.albicans.
基金funded by the National Natural Science Foundation of China(No.82304730)the Project of Academic and Technical Leaders in Major Disciplines in Jiangxi Province(No.20212BCJL23060)+3 种基金the Natural Science Foundation of Jiangxi Province(No.20232BAB216128)the Project of Jiangxi Provincial Department of Education(No.GJJ2200977)the Jiangxi University of Chinese Medicine Science and Technology Innovation Team Development Program(Nos.CXTD-22004,CXTD-22008)the PhD Startup Foundation of Affiliated Hospital of Jiangxi University of Chinese Medicine(No.23KYQDZJ02).
文摘Utilizing transporter-mediated drug delivery to achieve effective oral absorption emerges as a promising strategy.Researchers have been concentrated on discovering solutions to the issues of low solubility and poor permeability of insoluble drugs,whereas,current reports have revealed that drug transporter proteins are abundantly expressed in the mucosa of intestinal epithelial cells,and that their mediated drug absorption effectively improved the bioavailability of orally administered drugs.There are two main categories based on the transporter mechanism,which include the family of ATP-binding cassette(ABC)transporters with efflux effects that reduce drug bioavailability and the family of solute carriers(SLC)transporters with uptake effects that promote drug absorption,respectively.Thus,we review studies of intestinal transporter-mediated delivery of drugs to enhance oral absorption,including the types of intestinal transporters,distribution characteristics,and strategies for enhancing oral absorption using transporter-mediated drug delivery systems are summarized,with the aim of providing important theoretical references for the development of intestinal-targeted delivery system.
基金supported by the National Natural Science Foundation of China(32072458 and 32221004)the National Key R&D Program of China(2022YFD1602403)+2 种基金the Beijing Agriculture Innovation Consortium,China(BAIC04-2024)the earmarked fund for China Agriculture Research System(CARS-23)the Beijing Key Laboratory for Pest Control and Sustainable Cultivation of Vegetables,China。
文摘Pesticide resistance greatly limits control efficacy after the long-term application of pesticides.The two-spottedspider mite,Tetranychus urticae Koch,is a notorious agricultural pest worldwide that is resistant to various pesticides,including abamectin.While some studies of abamectin resistance have investigated target resistance related toglutamate-gated chloride channels(GluCls),studies on the metabolic resistance mechanisms are still limited.In this study,we identified an ABCC subfamily gene,Tu ABCC4,that was overexpressed in resistant populations of T.urticae,based on the analysis of previously obtained transcriptomic and RNA-seq data.No consistent nonsynonymousmutations in the Tu ABCC4 gene were found between the susceptible and resistant populations,although Tu ABCC4expression was significantly increased in all the resistant populations that were studied.Synergistic experiments withthe inhibitor verapamil and gene expression analysis of the susceptible and resistant populations confirmed the key roleof Tu ABCC4 in abamectin resistance.In addition,an increase in the expression of the Tu ABCC4 gene was shown byRNA interference and genetic association analysis to be closely related to the resistance of T.urticae to abamectin.Inconclusion,overexpression of Tu ABCC4 was shown to be involved in abamectin resistance in T.urticae.These resultscan help us to better understand the molecular basis of pest resistance to abamectin.
基金National Science and Technology Major Project(Grant No. 2012ZX09506001-004)
文摘Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles,including targeted distribution,improved clinical efficacy and low adverse reaction.In this review,we summarize the tissue-specific expression,transport functions and substrates profiles of the major influx and efflux transporters,including solute carrier（SLC） superfamily and adenosine triphosphate（ATP）-binding cassette（ABC） superfamily.Moreover,we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties.Lastly,we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.
文摘Multidrug resistance （MDR） is a major problem in cancer chemotherapy. One of the best known mechanisms of MDR is the elevated expression of ATP-binding cassette （ABC） transporters. While some members of human ABC transporters have been shown to cause drug resistance with elevated expression, it is not yet known whether the over-expression of other members could also contribute to drug resistance in many model cancer cell lines and clinics. The recent development ofmicroarrays and quantitative PCR arrays for expression profiling analysis of ABC transporters has helped address these issues. In this article, various arrays with limited or full list of ABC transporter genes and their use in identifying ABC transporter genes in drug resistance and chemo-sensitivity prediction will be reviewed.
文摘The World Health Organisation recommends exclusive breastfeeding for the first six months of an infant’s life and in combination with solid food thereafter. This recommendation was introduced based on research showing numerous health benefits of breastfeeding for both the mother and the infant. However, there is always concern regarding the transfer of medications from mother to their breastfed baby via milk. Pharma-cokinetic properties of a drug are usually used to pre-dict its transferability into breast milk. Although most drugs are compatible with breastfeeding, cases of toxic drug exposure have been reported. This is thought to be due to active transport mechanisms whereby effux transporter proteins expressed in the epithelial cells of the mammary gland actively secrete drugs into milk. An example of such effux transporters including the breast cancer resistance protein which is strongly induced during lactation and this could result in contamination of milk with the substrates of this transporter which may place the suckling infant at risk of toxicity. Furthermore, there is little known about the substrate specifcity of most effux transporters as we have highlighted in this review. There also exists some degree of contradiction between in vivo and in vitro studies which makes it difficult to conclusively predict outcomes and drug-drug interactions.
基金supported by the National Natural Science Foundation of China(No.30570732),NCET-04-197"985 Project"of Ministry of Education,Study on molecular mechanism of vascular-related diseases and on gene function.
文摘Objective：ATP-binding cassette transporters（ABC） A1 and G1 play an important role in mediating cholesterol efflux and preventing macrophage foam cell formation. In this study, we examined the regulation of ABC transporters by high glucose in human vascular smooth muscle cells（VSMCs）, the other precursor of foam cells. Methods：Incubation of human VSMCs with D-glucose（5 to 30 mM） for 1 to 7 days in the presence or absence of antioxidant and nuclear factor（NF）- κ B inhibitors, the expressions of ABCA1 and ABCG1 were analyzed by real time PCR and Western blotting. Results：High glucose decreased ABCG1 mRNA and protein expression in cultured VSMCs, whereas the expression of ABCA1 was not significantly decreased. Down-regulation of ABCG1 mRNA expression by high glucose was abolished by antioxidant N-acetyl-L-cysteine（NAC） and NF- κ B inhibitors, BAY 11-7085 and tosyl-phenylalanine chloromethyl-ketone（TPCK）. Conclusion：High glucose suppresses the expression of ABCG1 in VSMCs, which is the possible mechanism of VSMC derived foam cell transformation.
文摘Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.
文摘Multidrug resistance protein 5 (MRP5/ABCC5) is a 161 kDa member of the super family of ATP-binding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively e?uxing anticancer drugs. ABCC5 has also been identified as an efflux transporter of cGMP (cyclic guanosine monophosphate). Elevated intracellular levels of cGMP in cancer cells have been implicated in several clinical studies, that may induce apoptosis, and as a result many different cancer cells seem to overcome this deleterious effect by increased efflux of cGMP through ABCC5. Thus inhibition of ABCC5 may have cytotoxic effects mediated through cGMP and it will also increase the intracellular concentration of other drugs that are aimed for the treatment of cancer which are otherwise exported out of the cells. Considering the functional importance and lack of X-ray crystal structure of ABCC5, present work was undertaken to construct 3D structure of protein using homology modeling protocol of YASARA structure (V. 16.3.28). In this study, five different ABC templates (PDB ID’s: 4F4C, 4Q9H, 4M1M, 4M2T and 4KSD) were used for homology modeling. Five models were constructed on each template and a hybrid model was built using all five templates. All models were refined and ranked as per their overall Z-score. The top ranked ABBC5 model was based on template 4Q9H that had 91.2% of residues in allowed regions as revealed by PROCHECK-NMR and the QMEAN score was 0.54 which indicated a reliable model. The results of the study and the proposed model can be further used for elucidating the structural and functional aspects of ABCC5 and to gain more insights to the molecular basis of ABCC5 inhibition through docking studies.
基金supported by the National Natural Science Foundation of China(32161133010)the National Key Research and Development Program of China(2022YFD1700200)+1 种基金the Special Funds for Science Technology Innovation and Industrial Development of Shenzhen Dapeng New District(PT202101-02)the Shenzhen Science and Technology Program(KQTD20180411143628272).
文摘The use of synthetic pesticides carries a significant risk of pests developing resistance,leading to decreased pesticide effectiveness.ATP-binding cassette(ABC)transporters,especially the ABCC subfamily members,have been suggested to act as efflux pumps for various pesticides,thereby contributing to pesticide resistance.So far,the identification of potential pesticide substrates of insect ABC transporters is most often based on the quantification of transcript in arthropods.Here,we screened and identified the potential pesticide substrates of ABCC-9C from Tribolium castaneum based on an in vitro ATPase activity assay.Together with affinity evaluation-,cytotoxicity analysis-,and RNA interference-based bioactivity tests,we revealed that the insecticides,carbofuran,and buprofezin,are potential substrates of TcABCC-9C.Additionally,we identified an amphipathic translocation channel in the transmembrane domain of TcABCC-9C formed by 8 transmembrane helices.Molecular docking suggested that both carbofuran and buprofezin bind at the same site within the translocation channel via hydrophobic interactions.These findings indicate that TcABCC-9C might play a critical role in multi-pesticide resistance,providing a potential target for managing pesticide resistance and laying the groundwork for future pest control strategies.Given the conservations among ABCC subfamily members,the experimental model we developed in this study can be also applied to identify the potential substrates of other ABCC transporters,as well as to predict insecticide resistance mediated by ABCC transporters.
