查看更多>>摘要：Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease (NAFLD) and its progressive stage,nonalcoholic steatohepatitis (NASH).Traditional herbal medicines (THM) have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and mechanisms.In modern times,NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and progression.THM have garnered increased attention for providing therapeutic candidates for treating NAFLD.In this review,a new model called "multiple organs-multiple hits" is proposed to explain mechanisms of NASH progression.Against this proposed model,the effects and mechanisms of the frequently-studied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed,among which silymarin and berberine are already under U.S.FDA-sanctioned phase 4 clinical studies.Furthermore,experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are discussed.The opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are high-lighted.Increasing mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.
查看更多>>摘要：Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism.The gut microbiome,the collection of microorganisms in the gastrointestinal tract,can alter the metabolic outcome of pharmaceuticals,environmental toxicants,and heavy metals,thereby changing their pharmacokinetics.Direct chemical modification of xenobiotics by the gut microbiome,either through the intestinal tract or re-entering the gut via enterohepatic circulation,can lead to increased metabolism or bioactivation,depending on the enzymatic activity within the microbial niche.Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways.Additionally,the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins,supporting the protective mucosal layer,and/or directly sequestering chemicals.Lastly,host gene expression is regulated by the microbiome,including CYP450s,multi-drug resistance proteins,and the transcription factors that regulate them.While the microbiome affects the host and pharmacokinetics of the xenobiotic,xenobiotics can also influence the viability and metabolism of the microbiome.Our understanding of the complex interconnectedness between host,microbiome,and metabolism will advance with new modeling systems,technology development and refinement,and mechanistic studies focused on the contribution of human and microbial metabolism.
查看更多>>摘要：Sepsis is an infection-induced systemic inflammatory syndrome.The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways.When sepsis occurs,the expression and activity of many inflammatory cytokines are markedly affected.Xenobiotic receptors are chemical-sensing transcription factors that play essential roles in the transcriptional regulation of drug-metabolizing enzymes (DMEs).Xenobiotic receptors mediate the functional crosstalk between sepsis and drug metabolism because the inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs.Xenobiotic receptors in turn may affect the clinical outcomes of sepsis.This review focuses on the sepsis-induced inflammatory response and xenobiotic receptors such as pregnane X receptor (PXR),aryl hydrocarbon receptor (AHR),glucocorticoid receptor (GR),and constitutive androstane receptor (CAR),DMEs such as CYP1A,CYP2B6,CYP2C9,and CYP3A4,and drug transporters such as p-glycoprotein (P-gp),and muitidrug resistance-associated protein (MRPs) that are affected by sepsis.Understanding the xenobiotic receptor-mediated effect of sepsis on drug metabolism will help to improve the safe use of drugs in sepsis patients and the development of new xenobiotic receptor-based therapeutic strategies for sepsis.
查看更多>>摘要：The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance.P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover.Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD).Herein,on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies,we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance.We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury,or viral hepatitis;(ii)discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates;and (iii) detail the pathophysiological consequences of disrupted P450 ERAD,contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.
查看更多>>摘要：Solute carrier (SLC) transporters meditate many essential physiological functions,including nutrient uptake,ion influx/efflux,and waste disposal.In its protective role against tumors and infections,the mammalian immune system coordinates complex signals to support the proliferation,differentiation,and effector function of individual cell subsets.Recent research in this area has yielded surprising findings on the roles of solute carrier transporters,which were discovered to regulate lymphocyte signaling and control their differentiation,function,and fate by modulating diverse metabolic pathways and balanced levels of different metabolites.In this review,we present current information mainly on glucose transporters,amino-acid transporters,and metal ion transporters,which are critically important for mediating immune cell homeostasis in many different pathological conditions.
查看更多>>摘要：Cancer cells reprogram their gene expression to promote growth,survival,proliferation,and invasiveness.The unique expression of certain uptake transporters in cancers and their innate function to concentrate small molecular substrates in cells make them ideal targets for selective delivering imaging and therapeutic agents into cancer cells.In this review,we focus on several solute carrier (SLC) transporters known to be involved in transporting clinically used radiopharmaceutical agents into cancer cells,including the sodium/iodine symporter (NIS),norepinephrine transporter (NET),glucose transporter 1 (GLUT1),and monocarboxylate transporters (MCTs).The molecular and functional characteristics of these transporters are reviewed with special emphasis on their specific expressions in cancers and interaction with imaging or theranostic agents [e.g.,I-123,I-131,123I-iobenguane (mIBG),18F-fluorodeoxyglucose (18F-FDG) and 13C pyruvate].Current clinical applications and research areas of these transporters in cancer diagnosis and treatment are discussed.Finally,we offer our views on emerging opportunities and challenges in targeting transporters for cancer imaging and treatment.By analyzing the few clinically successful examples,we hope much interest can be garnered in cancer research towards uptake transporters and their potential applications in cancer diagnosis and treatment.
查看更多>>摘要：Cytochrome P450 1A (CYP1A),one of the major CYP subfamily in humans,not only metabolizes xenobiotics including clinical drugs and pollutants in the environment,but also mediates the biotransformation of important endogenous substances.In particular,some single nucleotide polymorphisms (SNPs) for CYP1A genes may affect the metabolic ability of endogenous substances,leading to some physiological or pathological changes in humans.This review first summarizes the metabolism of endogenous substances by CYP1A,and then introduces the research progress of CYP1A SNPs,especially the research related to human diseases.Finally,the relationship between SNPs and diseases is discussed.In addition,potential animal models for CYP1A gene editing are summarized.In conclusion,CYP1A plays an important role in maintaining the health in the body.
查看更多>>摘要：Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters.Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability (pharmacokinetics,or PK) and therapeutic efficacy (pharmacodynamics,or PD) of drugs.Recent studies have suggested that the long non-coding RNAs (lncRNAs) are highly relevant to drug metabolism and drug resistance,including chemo-resistance in cancers,through the regulation of drug metabolism and disposition related genes.This review summarizes the regulation of enzymes,transporters,or regulatory proteins involved in drug metabolism by lncRNAs,with a particular emphasis on drug metabolism and chemo-resistance in cancer patients.The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related lncRNAs are also proposed.Understanding the role of lncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms,but also enable the discovery of lncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients,including cancer patients.
查看更多>>摘要：Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations.While regulation of genes related to cell growth,survival,and death has been extensively studied,much less is known on the regulation of drug-metabolizing enzymes (DMEs) by oncogenic signaling.Here,a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phases I and II of xenobiotic metabolism.Comparably few data are available with respect to DME regulation by p53-dependent signaling,telomerase expression or altered chromatin remodeling.By contrast,DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase (MAPK) cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth,demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negative-regulatory effects of MAPK signaling.Mechanistic studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver tumors.Observations of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.
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