Detoxification of toxic herbs in TCM prescription based on modulation of efflux transporters

Traditional Chinese medicines(TCMs)have been used to prevent and treat various diseases for thousands of years.Promoting efficacy and reducing toxicity by the compatibility theory of TCMs has attracted increasing attention,especially for the toxicity of herbs.Studies have pointed out the interactions between the active compounds of herbs and transporters in the detoxification process of toxic compounds.Here,we summarize data on five toxic herbs commonly used in TCMs and their related efflux transporters to reduce toxicity to offer a scientific rationale for the compatibility principle of TCMs and provide guidance for the rational clinical use of TCMs.

Differential expression of breast cancer-resistance protein,lung resistance protein,and multidrug resistance protein 1 in retinas of streptozotocin-induced diabetic mice

AIM：To investigate the altering expression profiles of efflux transporters such as breast cancer-resistance protein（BCRP）,lung resistance protein（LRP）,and multidrug resistance protein 1（MDR1） at the inner blood-retinal barrier（BRB） during the development of early diabetic retinopathy（DR） and/or aging in mice.METHODS：Relative m RNA and protein expression profiles of these three efflux transporters in the retina during the development of early DR and/or aging in mice were examined.The differing expression profiles of Zonula occludens 1（ ZO-1） and vascular endothelial growth factor-A（ VEGFA） in the retina as well as the perfusion characterization of fluorescein isothiocyanate（FITC）-dextran and Evans blue were examined to evaluate the integrity of the inner BRB.RESULTS：There were significant alterations in these three efflux transporters＇ expression profiles in the m RNA and protein levels of the retina during the development of diabetes mellitus and/or aging.The development of early DR was confirmed by the expression profiles of ZO-1 and VEGFA in the retina as well as the compromised integrity of the inner BRB.CONCLUSION：The expression profiles of some efflux transporters such as BCRP,LRP,and MDR1 in mice retina during diabetic and/or aging conditions are tested,and the attenuated expression of BCRP,LRP,and MDR1 along with the breakdown of the inner BRB is found,which may be linked to the pathogenesis of early DR.

A chloride efflux transporter,BIG RICE GRAIN 1,is involved in mediating grain size and salt tolerance in rice

Grain size is determined by the size and number of cells in the grain.The regulation of grain size is crucial for improving crop yield;however,the genes and molecular mechanisms that control grain size remain elusive.Here,we report that a member of the detoxification efflux carrier/Multidrug and Toxic Compound Extrusion(DTX/MATE)family transporters,BIG RICE GRAIN 1(BIRG1),negatively influences grain size in rice(Oryza sativa L.).BIRG1 is highly expressed in reproductive organs and roots.In birg1 grain,the outer parenchyma layer cells of spikelet hulls are larger than in wild-type(WT)grains,but the cell number is unaltered.When expressed in Xenopus laevis oocytes,BIRG1 exhibits chloride efflux activity.Consistent with this role of BIRG1,the birg1 mutant shows reduced tolerance to salt stress at a toxic chloride level.Moreover,grains from birg1 plants contain a higher level of chloride than those of WT plants when grown under normal paddy field conditions,and the roots of birg1 accumulate more chloride than those of WT under saline conditions.Collectively,the data suggest that BIRG1 in rice functions as a chloride efflux transporter that is involved in mediating grain size and salt tolerance by controlling chloride homeostasis.

Legumain-induced intracerebrally crosslinked vesicles for suppressing efflux transport of Alzheimer’s disease multi-drug nanosystem

Brain barrier is both a protective permeability hurdle and a limitation site where therapeutic agents are excluded to enter the target region.Designing drug vehicle to overcome this notorious barrier bottle is challenging.Herein,we construct a stimuli-responsive self-assembled nanovesicle that delivers water-soluble drugs to prevent the efflux transport of brain barriers by responding to the endogenously occurring signals in Alzheimer’s disease(AD)brain microenvironment.Once stimuli-responsive vesicles are accumulated in intracerebrally,the intrinsically occurring legumain endopeptidase cleaves the Ac-Ala-Ala-Asn-Cys-Asp(AK)short peptide on the drug vesicles to expose the 1,2 thiol amino group to cyclize with the cyano groups on 2-cyano-6-aminobenzothiazole(CABT)of the chaperone vesicles,thus triggering the formation of cross-linked micrometre-scale vesicles.Such a structural alteration completely prevents further brain barriers efflux.The superior neuroprotective capacity of cross-linked vesicles is validated in senescence accelerated mouse prone 8(SAMP8).This smart multi-drug delivery vesicle is promising to serve as a powerful system for AD treatment and can be adapted for the therapy of other central nervous system(CNS)disorders.

Taxane resistance in castration-resistant prostate cancer: mechanisms and therapeutic strategies

Despite its good initial response and significant survival benefit in patients with castrationresistant prostate cancer(CRPC), taxane therapy inevitably encounters drug resistance in all patients.Deep understandings of taxane resistant mechanisms can significantly facilitate the development of new therapeutic strategies to overcome taxane resistance and improve CRPC patient survival. Multiple pathways of resistance have been identified as potentially crucial areas of intervention. First, taxane resistant tumor cells typically have mutated microtubule binding sites, varying tubulin isotype expression,and upregulation of efflux transporters. These mechanisms contribute to reducing binding affinity and availability of taxanes. Second, taxane resistant tumors have increased stem cell like characteristics,indicating higher potential for further mutation in response to therapy. Third, the androgen receptor pathway is instrumental in the proliferation of CRPC and multiple hypotheses leading to this pathway reactivation have been reported. The connection of this pathway to the AKT pathway has received significant attention due to the upregulation of phosphorylated AKT in CRPC. This review highlights recent advances in elucidating taxane resistant mechanisms and summarizes potential therapeutic strategies for improved treatment of CRPC.

Pharmacokinetic aspects and in vitro–in vivo correlation potential for lipid-based formulations

Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract.These formulations offer multiple advantages such as reduction in food effect and inter-individual variability,ease of preparation,and the possibility of manufacturing using common excipients available in the market.Despite these advantages,very few products are available in the present market,perhaps due to limited knowledge in the in vitro tests(for prediction of in vivo fate)and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration.The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations,their pharmacokinetic aspects and in vitro in vivo correlation(IVIVC)perspectives.Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion,bioavailability enhancement mechanisms,impact of excipients on efflux transporters,and lymphatic transport are discussed with examples.In addition,various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation,in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.

Cellular arsenic transport pathways in mammals

Natural contamination of drinking water with arsenic results in the exposure of millions of people world-wide to unacceptable levels of this metalloid. This is a serious global health problem because arsenic is a Group 1（proven） human carcinogen and chronic exposure is known to cause skin, lung, and bladder tumors. Furthermore, arsenic exposure can result in a myriad of other adverse health effects including diseases of the cardiovascular,respiratory, neurological, reproductive, and endocrine systems. In addition to chronic environmental exposure to arsenic, arsenic trioxide is approved for the clinical treatment of acute promyelocytic leukemia, and is in clinical trials for other hematological malignancies as well as solid tumors. Considerable inter-individual variability in susceptibility to arsenic-induced disease and toxicity exists, and the reasons for such differences are incompletely understood. Transport pathways that influence the cellular uptake and export of arsenic contribute to regulating its cellular, tissue, and ultimately body levels. In the current review, membrane proteins（including phosphate transporters, aquaglyceroporin channels, solute carrier proteins, and ATP-binding cassette transporters） shown experimentally to contribute to the passage of inorganic, methylated, and/or glutathionylated arsenic species across cellular membranes are discussed. Furthermore, what is known about arsenic transporters in organs involved in absorption, distribution, and metabolism and how transport pathways contribute to arsenic elimination are described.