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1.
Nucleic Acids Res ; 52(D1): D1490-D1502, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37819041

RESUMO

The phenotypic and regulatory variability of drug transporter (DT) are vital for the understanding of drug responses, drug-drug interactions, multidrug resistances, and so on. The ADME property of a drug is collectively determined by multiple types of variability, such as: microbiota influence (MBI), transcriptional regulation (TSR), epigenetics regulation (EGR), exogenous modulation (EGM) and post-translational modification (PTM). However, no database has yet been available to comprehensively describe these valuable variabilities of DTs. In this study, a major update of VARIDT was therefore conducted, which gave 2072 MBIs, 10 610 TSRs, 46 748 EGRs, 12 209 EGMs and 10 255 PTMs. These variability data were closely related to the transportation of 585 approved and 301 clinical trial drugs for treating 572 diseases. Moreover, the majority of the DTs in this database were found with multiple variabilities, which allowed a collective consideration in determining the ADME properties of a drug. All in all, VARIDT 3.0 is expected to be a popular data repository that could become an essential complement to existing pharmaceutical databases, and is freely accessible without any login requirement at: https://idrblab.org/varidt/.


Assuntos
Bases de Dados de Proteínas , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Epigênese Genética , Regulação da Expressão Gênica , Processamento de Proteína Pós-Traducional , Preparações Farmacêuticas/metabolismo
2.
Nucleic Acids Res ; 52(D1): D1355-D1364, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37930837

RESUMO

The metabolic roadmap of drugs (MRD) is a comprehensive atlas for understanding the stepwise and sequential metabolism of certain drug in living organisms. It plays a vital role in lead optimization, personalized medication, and ADMET research. The MRD consists of three main components: (i) the sequential catalyses of drug and its metabolites by different drug-metabolizing enzymes (DMEs), (ii) a comprehensive collection of metabolic reactions along the entire MRD and (iii) a systematic description on efficacy & toxicity for all metabolites of a studied drug. However, there is no database available for describing the comprehensive metabolic roadmaps of drugs. Therefore, in this study, a major update of INTEDE was conducted, which provided the stepwise & sequential metabolic roadmaps for a total of 4701 drugs, and a total of 22 165 metabolic reactions containing 1088 DMEs and 18 882 drug metabolites. Additionally, the INTEDE 2.0 labeled the pharmacological properties (pharmacological activity or toxicity) of metabolites and provided their structural information. Furthermore, 3717 drug metabolism relationships were supplemented (from 7338 to 11 055). All in all, INTEDE 2.0 is highly expected to attract broad interests from related research community and serve as an essential supplement to existing pharmaceutical/biological/chemical databases. INTEDE 2.0 can now be accessible freely without any login requirement at: http://idrblab.org/intede/.


Assuntos
Bases de Dados de Compostos Químicos , Bases de Dados Factuais , Inativação Metabólica , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo
3.
Chem Rev ; 123(12): 7782-7853, 2023 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-37186942

RESUMO

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, and basic research. A plethora of chemical and genetic approaches have been devised to make antibodies accessible to more "undruggable" targets and equipped with new functions of illustrating or regulating biological processes more precisely. In this Review, in addition to introducing how naked antibodies and various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide conjugates, antibody-enzyme conjugates, etc.) work in therapeutic applications, special attention has been paid to how chemistry tools have helped to optimize the therapeutic outcome (i.e., with enhanced efficacy and reduced side effects) or facilitate the multifunctionalization of antibodies, with a focus on emerging fields such as targeted protein degradation, real-time live-cell imaging, catalytic labeling or decaging with spatiotemporal control as well as the engagement of antibodies inside cells. With advances in modern chemistry and biotechnology, well-designed antibodies and their derivatives via size miniaturization or multifunctionalization together with efficient delivery systems have emerged, which have gradually improved our understanding of important biological processes and paved the way to pursue novel targets for potential treatments of various diseases.


Assuntos
Anticorpos , Imunoconjugados , Anticorpos/uso terapêutico , Imunoconjugados/uso terapêutico , Biotecnologia , Oligonucleotídeos
4.
Nucleic Acids Res ; 51(D1): D1288-D1299, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36243961

RESUMO

The efficacy and safety of drugs are widely known to be determined by their interactions with multiple molecules of pharmacological importance, and it is therefore essential to systematically depict the molecular atlas and pharma-information of studied drugs. However, our understanding of such information is neither comprehensive nor precise, which necessitates the construction of a new database providing a network containing a large number of drugs and their interacting molecules. Here, a new database describing the molecular atlas and pharma-information of drugs (DrugMAP) was therefore constructed. It provides a comprehensive list of interacting molecules for >30 000 drugs/drug candidates, gives the differential expression patterns for >5000 interacting molecules among different disease sites, ADME (absorption, distribution, metabolism and excretion)-relevant organs and physiological tissues, and weaves a comprehensive and precise network containing >200 000 interactions among drugs and molecules. With the great efforts made to clarify the complex mechanism underlying drug pharmacokinetics and pharmacodynamics and rapidly emerging interests in artificial intelligence (AI)-based network analyses, DrugMAP is expected to become an indispensable supplement to existing databases to facilitate drug discovery. It is now fully and freely accessible at: https://idrblab.org/drugmap/.


Assuntos
Inteligência Artificial , Descoberta de Drogas , Bases de Dados Factuais , Preparações Farmacêuticas , Atlas como Assunto
5.
Drug Metab Dispos ; 52(9): 997-1008, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-38960734

RESUMO

Hepatocellular carcinoma (HCC) is one of the most malignant tumors in the world. Inadequate efficacy of 5-fluorouracil (5-FU) on HCC could be related to low expression of human organic anion transporter 2 (OAT2). However, the knowledge of downregulation of OAT2 in HCC remains limited. We explored the underlying mechanism focusing on protein expression regulation and attempted to design a strategy to sensitize HCC cells to 5-FU. In this study, we revealed that the 1 bp to 300 bp region of OAT2 mRNA 3' untranslated region (UTR) reduced its protein expression and uptake activity in Li-7 and PLC/PRF/5 cells. Mechanistically, it was demonstrated that staphylococcal nuclease and Tudor domain containing 1 (SND1) bound at the 1 bp to 300 bp region of OAT2 mRNA 3' UTR, leading to a decrease in OAT2 protein expression. Enrichment analysis results indicated reduction of OAT2 might be mediated by translational inhibition. Furthermore, the knockdown of SND1 upregulated OAT2 protein expression and uptake activity. Based on this, decreasing SND1 expression enhanced 5-FU-caused G1/S phase arrest in Li-7 and PLC/PRF/5 cells, resulting in suppression of cell proliferation. Additionally, the knockdown of SND1 augmented the inhibitory effect of 5-FU on PLC/PRF/5 xenograft tumor growth in vivo by increasing OAT2 protein expression and accumulation of 5-FU in the tumor. Collectively, a combination of inhibition of SND1 with 5-FU might be a potential strategy to sensitize HCC cells to 5-FU from the perspective of restoring OAT2 protein level. SIGNIFICANCE STATEMENT: We investigated the regulatory mechanism of OAT2 protein expression in HCC cells and designed a strategy to sensitize them to 5-FU (OAT2 substrate) via restoring OAT2 protein level. It found that SND1, an RNA binding protein, regulated OAT2 protein expression by interacting with OAT2 mRNA 3' UTR 1-300 bp region. Through decreasing SND1, the antitumor effect of 5-FU on HCC was enhanced in vitro and in vivo, indicating that SND1 could be a potential target for sensitizing HCC cells to 5-FU.


Assuntos
Carcinoma Hepatocelular , Endonucleases , Fluoruracila , Neoplasias Hepáticas , Humanos , Fluoruracila/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Animais , Endonucleases/genética , Endonucleases/metabolismo , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Antimetabólitos Antineoplásicos/farmacologia , Camundongos Endogâmicos BALB C , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Proliferação de Células/efeitos dos fármacos , Regiões 3' não Traduzidas/genética , Masculino
6.
Drug Metab Dispos ; 52(8): 813-823, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38811154

RESUMO

Current therapeutic strategies for esophageal cancer (EC) patients have yielded limited improvements in survival rates. Recent research has highlighted the influence of drug metabolism enzymes on both drug response and EC development. Our study aims to identify specific drug metabolism enzymes regulated by histone acetylation and to elucidate its molecular and clinical features. CYP4F12 exhibited a notable upregulation subsequent to trichostatin A treatment as evidenced by RNA sequencing analysis conducted on the KYSE-150 cell line. The change in gene expression was associated with increased acetylation level of histone 3 K18 and K27 in the promoter. The regulation was dependent on p300. In silicon analysis of both The Cancer Genome Atlas esophageal carcinoma and GSE53624 dataset suggested a critical role of CYP4F12 in EC development, because CYP4F12 was downregulated in tumor tissues and predicted better disease-free survival. Gene ontology analysis has uncovered a robust correlation between CYP4F12 and processes related to cell migration, as well as its involvement in cytosine-mediated immune activities. Further investigation into the relationship between immune cells and CYP4F12 expression has indicated an increased level of B cell infiltration in samples with high CYP4F12 expression. CYP4F12 was also negatively correlated with the expression of inhibitory checkpoints. An accurate predictive nomogram model was established combining with clinical factors and CYP4F12 expression. In conclusion, CYP4F12 was crucial in EC development, and targeting CYP4F12 may improve the therapeutic efficacy of current treatment in EC patients. SIGNIFICANCE STATEMENT: CYP4F12 expression was downregulated in esophageal cancer (EC) patients and could be induced by trichostatin A. During EC development, CYP4F12 was linked to reduced cell migration and increased infiltration of B cells. CYP4F12 also is a biomarker as prognostic predictors and therapeutic guide in EC patients.


Assuntos
Neoplasias Esofágicas , Histonas , Humanos , Acetilação , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Família 4 do Citocromo P450/genética , Família 4 do Citocromo P450/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Ácidos Hidroxâmicos/farmacologia
7.
Pharmacol Res ; 207: 107332, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39089398

RESUMO

The endoplasmic reticulum (ER) plays a pivotal role in protein folding and secretion, Ca2+ storage, and lipid synthesis in eukaryotic cells. When the burden of protein synthesis and folding required to be handled exceeds the processing capacity of the ER, the accumulation of misfolded/unfolded proteins triggers ER stress. In response to short-term ER stress, the unfolded protein response (UPR) is activated to allow cells to survive. When ER stress is severe and sustained, it typically provokes cell death through multiple approaches. It is well documented that ER stress and metabolic deregulation are functionally intertwined, both are considered contributing factors to the pathogenesis of liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), ischemia/reperfusion (I/R) injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). Hepatocytes are rich in smooth and rough ER, which harbor metabolic enzymes that are capable of sensing alterations in various nutritional status and external stimuli. Extensive research has focused on the molecular mechanism linking ER stress with metabolic enzymes. The purpose of this review is to summarize the current knowledge regarding the effects of ER stress on metabolic enzymes in various liver diseases and to provide potential therapeutic strategies for chronic liver diseases via targeting UPR.


Assuntos
Estresse do Retículo Endoplasmático , Hepatopatias , Resposta a Proteínas não Dobradas , Humanos , Animais , Hepatopatias/metabolismo , Hepatopatias/enzimologia , Retículo Endoplasmático/metabolismo
8.
Nucleic Acids Res ; 50(D1): D1417-D1431, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34747471

RESUMO

The structural variability data of drug transporter (DT) are key for research on precision medicine and rational drug use. However, these valuable data are not sufficiently covered by the available databases. In this study, a major update of VARIDT (a database previously constructed to provide DTs' variability data) was thus described. First, the experimentally resolved structures of all DTs reported in the original VARIDT were discovered from PubMed and Protein Data Bank. Second, the structural variability data of each DT were collected by literature review, which included: (a) mutation-induced spatial variations in folded state, (b) difference among DT structures of human and model organisms, (c) outward/inward-facing DT conformations and (d) xenobiotics-driven alterations in the 3D complexes. Third, for those DTs without experimentally resolved structural variabilities, homology modeling was further applied as well-established protocol to enrich such valuable data. As a result, 145 mutation-induced spatial variations of 42 DTs, 1622 inter-species structures originating from 292 DTs, 118 outward/inward-facing conformations belonging to 59 DTs, and 822 xenobiotics-regulated structures in complex with 57 DTs were updated to VARIDT (https://idrblab.org/varidt/ and http://varidt.idrblab.net/). All in all, the newly collected structural variabilities will be indispensable for explaining drug sensitivity/selectivity, bridging preclinical research with clinical trial, revealing the mechanism underlying drug-drug interaction, and so on.


Assuntos
Transporte Biológico/genética , Bases de Dados Factuais , Bases de Dados de Produtos Farmacêuticos , Humanos , Mutação/genética , Relação Estrutura-Atividade , Xenobióticos/química , Xenobióticos/classificação , Xenobióticos/uso terapêutico
9.
Angew Chem Int Ed Engl ; 63(18): e202319232, 2024 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-38472118

RESUMO

Cell-surface proteins are important drug targets but historically have posed big challenges for the complete elimination of their functions. Herein, we report antibody-peptide conjugates (Ab-CMAs) in which a peptide targeting chaperone-mediated autophagy (CMA) was conjugated with commercially available monoclonal antibodies for specific cell-surface protein degradation by taking advantage of lysosomal degradation pathways. Unique features of Ab-CMAs, including cell-surface receptor- and E3 ligase-independent degradation, feasibility towards different cell-surface proteins (e.g., epidermal growth factor receptor (EGFR), programmed cell death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2)) by a simple change of the antibody, and successful tumor inhibition in vivo, make them attractive protein degraders for biomedical research and therapeutic applications. As the first example employing CMA to degrade proteins from the outside in, our findings may also shed new light on CMA, a degradation pathway typically targeting cytosolic proteins.


Assuntos
Autofagia Mediada por Chaperonas , Neoplasias , Humanos , Autofagia/fisiologia , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Peptídeos/metabolismo , Lisossomos/metabolismo
10.
Small ; 19(35): e2301132, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37127881

RESUMO

Accurate quantification and dynamic expression profiling of mitochondrial RNA (mtRNA for short) are critical for illustrating their cellular functions. However, there lack methods for precise detection of mtRNA in situ due to the delivery restrictions and complicated cellular interferences. Herein, a dual-color imaging system featured with signal amplification and normalization capability for quantitative analysis of specific mtRNA is established. As a proof-of-concept example, an enzyme-free hairpin DNA cascade amplifier fine-tailored to specifically recognize mtRNA encoding NADH dehydrogenase subunit 6 (ND6) is employed as the signal output module and integrated into the biodegradable mitochondria-targeting black phosphorus nanosheet (BP-PEI-TPP) to monitor spatial-temporal dynamics of ND6 mtRNA. An internal reference module targeting ß-actin mRNA is sent to the cytoplasm via BP-PEI for signal normalization, facilitating mtRNA quantification inside living cells with a degree of specificity and sensitivity as high as reverse transcription-quantitative polymerase chain reaction (RT-qPCR). With negligible cytotoxicity, this noninvasive "RT-qPCR mimic" can accurately indicate target mtRNA levels across different cells, providing a new strategy for precise analysis of subcellular RNAs in living systems.


Assuntos
Mitocôndrias , RNA , Humanos , RNA Mitocondrial/metabolismo , Mitocôndrias/metabolismo , RNA Mensageiro/metabolismo , Citoplasma/metabolismo
11.
Drug Metab Dispos ; 51(10): 1316-1323, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37295948

RESUMO

The ATP-binding cassette (ABC) and solute carrier (SLC) transporters are critical determinants of drug disposition, clinical efficacy, and toxicity as they specifically mediate the influx and efflux of various substrates and drugs. ABC transporters can modulate the pharmacokinetics of many drugs via mediating the translocation of drugs across biologic membranes. SLC transporters are important drug targets involved in the uptake of a broad range of compounds across the membrane. However, high-resolution experimental structures have been reported for a very limited number of transporters, which limits the study of their physiologic functions. In this review, we collected structural information on ABC and SLC transporters and described the application of computational methods in structure prediction. Taking P-glycoprotein (ABCB1) and serotonin transporter (SLC6A4) as examples, we assessed the pivotal role of structure in transport mechanisms, details of ligand-receptor interactions, drug selectivity, the molecular mechanisms of drug-drug interactions, and differences caused by genetic polymorphisms. The data collected contributes toward safer and more effective pharmacological treatments. SIGNIFICANCE STATEMENT: The experimental structure of ATP-binding cassette and solute carrier transporters was collected, and the application of computational methods in structure prediction was described. P-glycoprotein and serotonin transporter were used as examples to reveal the pivotal role of structure in transport mechanisms, drug selectivity, the molecular mechanisms of drug-drug interactions, and differences caused by genetic polymorphisms.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Proteínas da Membrana Plasmática de Transporte de Serotonina , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/fisiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Trifosfato de Adenosina
12.
Drug Metab Dispos ; 51(11): 1499-1507, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37643881

RESUMO

Human UDP-glucuronosyltransferases (UGTs) play a pivotal role as prominent phase II metabolic enzymes, mediating the glucuronidation of both endobiotics and xenobiotics. Dimerization greatly modulates the enzymatic activities of UGTs. In this study, we examined the influence of three mutations (H35A, H268Y, and N68A/N315A) and four truncations (signal peptide, single transmembrane helix, cytosolic tail, and di-lysine motif) in UGT2B7 on its heterodimerization with wild-type UGT1A9, using a Bac-to-Bac expression system. We employed quantitative fluorescence resonance energy transfer (FRET) techniques and co-immunoprecipitation assays to evaluate the formation of heterodimers between UGT1A9 and UGT2B7 allozymes. Furthermore, we evaluated the glucuronidation activities of the heterodimers using zidovudine and propofol as substrates for UGT2B7 and UGT1A9, respectively. Our findings revealed that the histidine residue at codon 35 was involved in the dimeric interaction, as evidenced by the FRET efficiencies and catalytic activities. Interestingly, the signal peptide and single transmembrane helix domain of UGT2B7 had no impact on the protein-protein interaction. These results provide valuable insights for a comprehensive understanding of UGT1A9/UGT2B7 heterodimer formation and its association with glucuronidation activity. SIGNIFICANCE STATEMENT: Our findings revealed that the H35A mutation in UGT2B7 affected the affinity of protein-protein interaction, leading to discernable variations in fluorescence resonance energy transfer efficiencies and catalytic activity. Furthermore, the signal peptide and single transmembrane helix domain of UGT2B7 did not influence heterodimer formation. These results provide valuable insights into the combined effects of polymorphisms and protein-protein interactions on the catalytic activity of UGT1A9 and UGT2B7, enhancing our understanding of UGT dimerization and its impact on metabolite formation.

13.
Pharm Res ; 40(9): 2177-2194, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37610618

RESUMO

PURPOSE: 5-fluorouracil (5-FU) and its prodrug capecitabine are commonly prescribed anti-tumor medications. We aimed to establish physiologically based pharmacokinetic (PBPK) models of capecitabine-metabolites and 5-FU-metabolites to describe their pharmacokinetics in tumor and plasma of cancer patients with liver impairment. METHODS: Models including the cancer compartment were developed in PK-Sim® and MoBi® and evaluated by R programming language with 25 oral capecitabine and 18 intravenous 5-FU studies for cancer patients with and without liver impairment. RESULTS: The PBPK models were constructed successfully as most simulated Cmax and AUClast were within two-fold error of observed values. The simulated alterations of tumor 5-FU Cmax and AUClast in cancer patients with severe liver injury compared with normal liver function were 1.956 and 3.676 after oral administration of capecitabine, but no significant alteration was observed after intravenous injection of 5-FU. Besides, 5-FU concentration in tumor tissue increases with higher tumor blood flow but not tumor size. Sensitivity analysis revealed that dihydropyrimidine dehydrogenase (DPD) and other metabolic enzymes' activity, capecitabine intestinal permeability and plasma protein scale factor played a vital role in tumor and plasma 5-FU pharmacokinetics. CONCLUSIONS: PBPK model prediction suggests no dosage adaption of capecitabine or 5-FU is required for cancer patients with hepatic impairment but it would be reduced when the toxic reaction is observed. Furthermore, tumor blood flow rate rather than tumor size is critical for 5-FU concentration in tumor. In summary, these models could predict pharmacokinetics of 5-FU in tumor in cancer patients with varying characteristics in different scenarios.


Assuntos
Antimetabólitos Antineoplásicos , Neoplasias , Humanos , Capecitabina/uso terapêutico , Desoxicitidina , Fluoruracila , Neoplasias/tratamento farmacológico
14.
Analyst ; 148(3): 556-561, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36562478

RESUMO

A novel method for detecting miRNA has been developed using a combination of duplex-specific nuclease signal amplification (DSNSA) and a catalytic hairpin assembly (CHA). In this work, a biotinylated trigger release (BTR) probe with a biotin group at the 3'-end and a CHA reaction sequence trigger as an initiator (catalyst I) at the 5'-end was designed to hybridize target miRNA. The DSN enzyme was introduced to initiate the DSNSA. The miRNA was released to consume more BTR probes and amplify the signals. Subsequently, streptavidin-coated magnetic beads (SA-MBs) were added to the DSNSA reaction solution to remove excess BTR probes that did not hybridize with miRNA, which would then separate BTR probes and catalyst-I, to ensure detection with high selectivity and sensitivity. The catalyst-I remaining in the solution could trigger the CHA reaction to enable signal amplification in the second step. The developed method exhibits a sensitive detection limit and excellent selectivity in identifying a high sequence homology among family members.


Assuntos
Técnicas Biossensoriais , MicroRNAs , Técnicas Biossensoriais/métodos , MicroRNAs/genética , Catálise , Biotina , Estreptavidina , Endonucleases , Limite de Detecção
15.
Nucleic Acids Res ; 49(D1): D1233-D1243, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33045737

RESUMO

Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.


Assuntos
Bases de Dados Factuais , Drogas em Investigação/metabolismo , Enzimas/metabolismo , Inativação Metabólica/genética , Medicamentos sob Prescrição/metabolismo , Processamento de Proteína Pós-Traducional , Xenobióticos/metabolismo , Bactérias/enzimologia , Metilação de DNA , Enzimas/classificação , Fungos/enzimologia , Histonas/genética , Histonas/metabolismo , Humanos , Internet , Taxa de Depuração Metabólica , Microbiota/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Software
16.
Drug Metab Dispos ; 50(1): 76-85, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34426411

RESUMO

With the rapid progress in pharmaceutical experiments and clinical investigations, extensive knowledge of drug transporters (DTs) has accumulated, which is valuable data for the understanding of drug metabolism and disposition. However, such data are largely dispersed in the literature, which hampers its utility and significantly limits its possibility for comprehensive analysis. A variety of databases have, therefore, been constructed to provide DT-related data, and they were reviewed in this study. First, several knowledge bases providing data regarding clinically important drugs and their corresponding transporters were discussed, which constituted the most important resources of DT-centered data. Second, some databases describing the general transporters and their functional families were reviewed. Third, various databases offering transporter information as part of their entire data collection were described. Finally, customized database functions that are available to facilitate DT-related research were discussed. This review provided an overview of the whole collection of DT-related databases, which might facilitate research on precision medicine and rational drug use. SIGNIFICANCE STATEMENT: A collection of well established databases related to drug transporters were comprehensively reviewed, which were organized according to their importance in drug absorption, distribution, metabolism, and excretion research. These databases could collectively contribute to the research on rational drug use.


Assuntos
Proteínas de Transporte/metabolismo , Bases de Dados Factuais , Bases de Dados Genéticas , Preparações Farmacêuticas/metabolismo , Farmacocinética , Animais , Proteínas de Transporte/genética , Humanos , Taxa de Depuração Metabólica , Distribuição Tecidual
17.
Chem Res Toxicol ; 35(3): 422-430, 2022 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-35147423

RESUMO

Hand-foot syndrome (HFS) is a major adverse reaction to capecitabine (CAP). The exact pathogenesis of this disease remains unclear. In this study, metabolomics combined with cell RNA sequencing was used to study the mechanisms of CAP-induced HFS. The murine model of HFS was constructed by intragastric administration of CAP or its metabolites. Quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays were used to verify the mechanisms. Metabolomics showed the phosphatidylinositol signaling pathway and amino acid and fatty acid metabolism to be the major metabolic alterations related to the occurrence of HFS. Transcriptomics profiles further revealed that the cytokine-cytokine receptor interaction, IL17 signaling pathway, Toll-like receptor signaling pathway, arachidonic acid metabolism, MAPK signaling pathway, and JAK-STAT3 signaling pathway were the vital steps in skin toxicity induced by CAP or its metabolites. We also verified that the inflammation mechanisms were primarily mediated by the abnormal expression of interleukin (IL) 6 or IL8 and not exclusively by COX-2 overexpression. Finally, the P38 MAPK, NF-κB, and JAK-STAT3 signaling pathways, which mediate high levels of expression of IL6 or IL8, were identified as potential pathways underlying CAP-induced HFS.


Assuntos
Síndrome Mão-Pé , NF-kappa B , Animais , Capecitabina/efeitos adversos , Síndrome Mão-Pé/etiologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Camundongos , NF-kappa B/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Pharmacol Res ; 177: 106101, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35104632

RESUMO

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths in the world. The downregulation of farnesoid X receptor (FXR) is frequently founded in CRC patients. The current study found that the decreased expression of FXR in colorectal cancer leads to disorders of bile acids (BAs) metabolism. The altered BAs profile shaped distinct intestinal flora and positively regulated secretory immunoglobulin A (sIgA). The dual regulation of BAs and sIgA enhanced adhesion and biofilm formation of enterotoxigenic Bacteroides fragilis (ETBF), which has a colorectal tumorigenesis effect. The abundance of ETBF increased significantly in intestinal mucosa of colitis-associated cancer (CAC) mice, and finally promoted the development of colorectal cancer. This study suggests that downregulation of FXR in CRC results in BAs dysregulation, and BAs have strong effects on sIgA and gut flora. The elevated BAs concentration and altered gut microbiome are risk factors for CRC.


Assuntos
Infecções Bacterianas , Neoplasias Colorretais , Animais , Bacteroides fragilis/metabolismo , Ácidos e Sais Biliares/metabolismo , Carcinogênese , Transformação Celular Neoplásica , Regulação para Baixo , Humanos , Imunoglobulina A Secretora/metabolismo , Camundongos
19.
Analyst ; 147(22): 4986-4990, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36214814

RESUMO

Polynucleotide kinase (PNK), a bifunctional enzyme with 5'-kinase and 3'-phosphatase activities, plays an important role in DNA repair and is associated with various diseases. Here, we developed a primer-free, sensitive, and isothermal quantitative assay to detect PNK activity. In the presence of PNK, the 3'-phosphate group of the substrate was digested with 3'-OH, initiating the amplification reaction. Elongated dsDNA binds to the dsDNA-specific fluorescent dye EvaGreen, leading to a significant enhancement in fluorescence intensity. The limit of detection (LOD) of this method was 7.7 × 10-7 U µL-1, which is comparable or even superior to that of previously reported methods. This approach also showed good quantitative ability in complex cell lysates, indicating potential for biological sample analysis. Additionally, this facile and sensitive assay can be used to screen for PNK inhibitors. The proposed method provides a promising platform for sensitive PNK activity monitoring and inhibition screening for drug discovery and clinical treatment.


Assuntos
Técnicas Biossensoriais , Polinucleotídeo 5'-Hidroxiquinase , Polinucleotídeo 5'-Hidroxiquinase/análise , Bacteriófago T4 , Espectrometria de Fluorescência/métodos , Limite de Detecção , Fosfatos , Técnicas Biossensoriais/métodos
20.
Nucleic Acids Res ; 48(D1): D1042-D1050, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31495872

RESUMO

The absorption, distribution and excretion of drugs are largely determined by their transporters (DTs), the variability of which has thus attracted considerable attention. There are three aspects of variability: epigenetic regulation and genetic polymorphism, species/tissue/disease-specific DT abundances, and exogenous factors modulating DT activity. The variability data of each aspect are essential for clinical study, and a collective consideration among multiple aspects becomes crucial in precision medicine. However, no database is constructed to provide the comprehensive data of all aspects of DT variability. Herein, the Variability of Drug Transporter Database (VARIDT) was introduced to provide such data. First, 177 and 146 DTs were confirmed, for the first time, by the transporting drugs approved and in clinical/preclinical, respectively. Second, for the confirmed DTs, VARIDT comprehensively collected all aspects of their variability (23 947 DNA methylations, 7317 noncoding RNA/histone regulations, 1278 genetic polymorphisms, differential abundance profiles of 257 DTs in 21 781 patients/healthy individuals, expression of 245 DTs in 67 tissues of human/model organism, 1225 exogenous factors altering the activity of 148 DTs), which allowed mutual connection between any aspects. Due to huge amount of accumulated data, VARIDT made it possible to generalize characteristics to reveal disease etiology and optimize clinical treatment, and is freely accessible at: https://db.idrblab.org/varidt/ and http://varidt.idrblab.net/.

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