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Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

Acta Pharmaceutica Sinica B 2021年第12期11卷 3869-3878页

作者： joseph L.jilek Kayla L.Frost Kevyn A.jacobus Wenxi He Erica L.Toth Michael Goedken Nathan J.Cherrington Department of Pharmacology&Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85724USA Rutgers Translational Sciences Rutgers UniversityPiscatawayNJ 08901USA

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is unknown.To test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and toxicity.NASH rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy rats.Likewise,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy rats.Renal copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP secretion.Hepatic CDDP accumulation increased 250%in NASH rats relative to healthy rats.Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was observed.These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.

关键词： Nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity

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Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in nonalcoholic steatohepatitis patients

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Acta Pharmaceutica Sinica B 2023年第1期13卷 1-28页

作者： Solène Marie Kayla L.Frost Raymond K.Hau Lucy Martinez-Guerrero jailyn M.Izu Cassandra M.Myers Stephen H.Wright Nathan J.Cherrington College of Pharmacy Department of Pharmacology&ToxicologyUniversity of ArizonaTucsonAZ 85721USA College of Medicine Department of PhysiologyUniversity of ArizonaTucsonAZ 85724USA

The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters.Non-alcoholic steatohepatitis(NASH)causes disease-specific alterations to the absorption,distribution,metabolism,and excretion(ADME)processes,including a decrease in protein expression of basolateral uptake transporters,an increase in efflux transporters,and modifications to enzyme activity.This can result in increased drug exposure and adverse drug reactions(ADRs).Our goal was to predict drugs that pose increased risks for ADRs in NASH patients.Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease,mainly non-alcoholic fatty liver disease(NAFLD),54 of which are known substrates of transporters and/or metabolizing enzymes.Since NASH is the progressive form of NAFLD but is most frequently undiagnosed,we identified other drugs at risk based on NASH-specific alterations to ADME processes.Here,we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH,based on their transport and/or metabolism processes.It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients,especially when eliminated through multiple pathways altered by the disease.Therefore,these results may inform clinicians regarding the selection of drugs for use in NASH patients.

关键词： Non-alcoholic steatohepatitis Hepatic elimination Transporter Enzyme Pharmacokinetics Drug-drug interaction Liver Adverse drug reaction

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Regulation of drug metabolism and toxicity by multiple factors of genetics,epigenetics,lncRNAs,gut microbiota,and diseases:a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations(MDO)

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Acta Pharmaceutica Sinica B 2017年第2期7卷 241-248页

作者： Ai-Ming Yu Magnus Ingelman-Sundberg Nathan J.Cherrington Lauren M.Aleksunes Ulrich M.Zanger Wen Xie Hyunyoung jeong Edward M.Morgan Peter j.Turnbaugh Curtis D.Klaassen Aadra P.Bhatt Matthew R.Redinbo Pengying Hao David j.Waxman Li Wang Xiao-bo Zhong Department of Biochemistry and Molecular Medicine School of MedicineUniversity of California at Davis Department of Physiology and Pharmacology Karolinska Institutet Department of Pharmaceutical Sciences College of PharmacyUniversity of Arizona Department of Pharmacology and Toxicology School of PharmacyRutgers University Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Eberhard Karls University Center of Pharmacogenomics and Department of Pharmaceutical Sciences School of PharmacyUniversity of Pittsburgh Department of Pharmacy Practice School of PharmacyUniversity of Illinois at Chicago Department of Pharmacology School of MedicineEmory University Department of Microbiology and Immunology and the George William Hooper Research Foundation University of California at San Francisco Department of Environmental and Occupational Health Sciences University of Washington Department of Chemistry University of North Carolina at Chapel Hill Department of Biology and Bioinformatics Program Boston University Department of Physiology and Neurobiology University of Connecticut Department of Pharmaceutical Sciences School of PharmacyUniversity of Connecticut

Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.

关键词： Drug metabolism and toxicity Genetics Epigenetics Gut microbiota Long non-coding RNAs Disease Personalized medication

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Use of donepezil for neurocognitive recovery after brain injury in adult and pediatric populations:a scoping review

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Neural Regeneration Research 2024年第8期19卷 1686-1695页

作者： Avery L.Miller nathan K.Evanson j.Michael Taylor University of Cincinnati College of Medicine CincinnatiOHUSA Department of Pediatrics University of CincinnatiCincinnatiOHUSA Department of Neurology and Rehabilitation Medicine University of CincinnatiCincinnatiOHUSA Division of Pediatric Rehabilitation Medicine Cincinnati Children’s Hospital Medical CenterCincinnatiOHUSA Division of Neurology Cincinnati Children’s Hospital Medical CenterCincinnatiOHUSA

There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients.Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury,but relatively less is known about the effect in pediatric populations.The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibito rs as a potential a djuvant treatment fo r neurocognitive decline in pediatric patients with traumatic brain injury.Investigators queried PubMed to identify literature published from database inception thro ugh june 2023 desc ribing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions.Based on preselected search criteria,340 unique papers we re selected for title and abstra ct screening.Thirty-two reco rds were reviewed in full after eliminating preclinical studies and pape rs outside the scope of the project.In adult traumatic brain injury,we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tole rated and shows both objective and patient-reported efficacy for reducing cognitive impairment.In children,3 pape rs report on 5 children recovering from traumatic brain injury,showing limited efficacy.An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group.Given its promise for efficacy in adults with traumatic brain injury and tole rability in pediatric patients,we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted.

关键词： acetylcholinesterase inhibitor adult cognition donepezil pediatrics traumatic brain injury

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The skeletal muscle fiber periphery:A nexus of mTOR-related anabolism

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运动医学与健康科学(英文) 2023年第1期5卷 10-19页

作者： Cassidy T.Tinline-Goodfellow Matthew j.Lees nathan Hodson Faculty of Kinesiology and Physical Education University of TorontoCanada Institute of Sport Manchester Metropolitan UniversityManchesterUnited Kingdom Department of Sport and Exercise Sciences Manchester Metropolitan UniversityManchesterUnited Kingdom

Skeletal muscle anabolism is driven by numerous stimuli such as growth factors,nutrients(i.e.,amino acids,glucose),and mechanical stress.These stimuli are integrated by the mechanistic target of rapamycin(mTOR)complex 1(mTORC1)signal transduction cascade.In recent years,work from our laboratory and elsewhere has sought to unravel the molecular mechanisms underpinning the mTOR-related activation of muscle protein synthesis(MPS),as well as the spatial regulation of these mechanisms within the skeletal muscle cell.These studies have suggested that the skeletal muscle fiber periphery is a region of central importance in anabolism(i.e.,growth/MPS).Indeed,the fiber periphery is replete with the substrates,molecular machinery,and translational apparatus necessary to facilitate MPS.This review provides a summary of the mechanisms underpinning the mTOR-associated activation of MPS from cell,rodent,and human studies.It also presents an overview of the spatial regulation of mTORC1 in response to anabolic stimuli and outlines the factors that distinguish the periphery of the cell as a highly notable region of skeletal muscle for the induction of MPS.Future research should seek to further explore the nutrient-induced activation of mTORC1 at the periphery of skeletal muscle fibers.

关键词： Skeletal muscle mTOR Periphery Muscle protein synthesis Hypertrophy Translation

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数据驱动建模及科学计算

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2017年

作者： (美)j. nathan Kutz

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A narrative review of ocular surface disease considerations in the management of glaucoma

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Annals of Eye Science 2023年第3期8卷 33-40页

作者： nathan j.Arboleda Wen-jeng(Melissa)Yao Alex Theventhiran Gene Kim Department of Ophthalmology&Visual Sciences Albert Einstein College of MedicineMontefiore Medical CenterGreene Medical Arts Pavilion-Henkind InstituteBronxNYUSA

s from those searches were screened for relevance to our review topics.Publications were included if the subjects included glaucoma patients,and if ocular surface outcomes were described.Non-English papers were excluded.Key Content and Findings:Topical glaucoma medications frequently cause adverse effects on the ocular surface,both through direct action of the medications themselves as well as through toxicity from their associated preservatives.Optimization of the ocular surface may improve medication compliance rates.Traditional surgical treatments for glaucoma,such as trabeculectomy,can exacerbate OSD by disrupting the ocular surface but can also reduce the need for chronic medications.Optimization of ocular surface health is imperative in reducing trabeculectomy complication rates,while also potentially reducing the need for trabeculectomy in patients that are able to achieve intraocular pressure control through improved drop tolerability.The introduction of MIGS represents a promising alternative to existing therapies and has been shown to alleviate the overall medication burden.It would be reasonable to assume that decreasing the medication burden could reduce OSD prevalence and severity.However,more research is needed to directly assess the extent of improvement seen after MIGS.Conclusions:A comprehensive understanding of the importance of OSD in medical and surgical management of glaucoma is essential in optimizing patient care and improving outcomes.

关键词： Glaucoma ocular surface disease(OSD) dry eye minimally invasive glaucoma surgery(MIGS) trabeculectomy

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Validating neural networks for spectroscopic classification on a universal synthetic dataset

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npj Computational Materials 2023年第1期9卷 1325-1336页

作者： jan Schuetzke nathan j.Szymanski Markus Reischl Institute for Automation and Applied Informatics Karlsruhe Institute of TechnologyKarlsruhe 76131Germany Department of Materials Science&Engineering Lawrence Berkeley National LaboratoryBerkeleyCA 94720USA Department of Materials Science&Engineering UC BerkeleyBerkeleyCA 94720USA

To aid the development of machine learning models for automated spectroscopic data classification,we created a universal synthetic dataset for the validation of their performance.The dataset mimics the characteristic appearance of experimental measurements from techniques such as X-ray diffraction,nuclear magnetic resonance,and Raman spectroscopy among others.We applied eight neural network architectures to classify artificial spectra,evaluating their ability to handle common experimental artifacts.While all models achieved over 98%accuracy on the synthetic dataset,misclassifications occurred when spectra had overlapping peaks or intensities.We found that non-linear activation functions,specifically ReLU in the fully-connected layers,were crucial for distinguishing between these classes,while adding more sophisticated components,such as residual blocks or normalization layers,provided no performance benefit.Based on these findings,we summarize key design principles for neural networks in spectroscopic data classification and publicly share all scripts used in this study.

关键词： spectroscopic adding classify

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Autologous treatment for ALS with implication for broad neuroprotection

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Translational Neurodegeneration 2022年第1期11卷 718-736页

作者： Daehwan Kim Subin Kim Ashley Sung Neetika Patel nathan Wong Michael j.Conboy Irina M.Conboy Department of Bioengineering and QB3 Institute University of CaliforniaBerkeleyCA 94720USA

Background: Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of motor neurons (MNs), leading to paralysis, respiratory failure and death within 2-5 years of diagnosis. The exact mechanisms of sporadic ALS, which comprises 90% of all cases, remain unknown. In familial ALS, mutations in superoxide dismutase (SOD1) cause 10% of cases. Methods: ALS patient-derived human-induced pluripotent stem cells (ALS hiPSCs, harboring the SOD1AV4 mutation), were differentiated to MNs (ALS-MNs). The neuroprotective effects of conditioned medium (CM) of hESCs (H9), wt hiPSCs (WTC-11) and the ALS iPSCs, on MN apoptosis and viability, formation and maintenance of neurites, mitochon-drial activity and expression of inflammatory genes, were examined. For in vivo studies, 200 μl of CM from the ALS iPSCs (CS07 and CS053) was injected subcutaneously into the ALS model mice (transgenic for the human SOD1G93A mutation). Animal agility and strength, muscle innervation and mass, neurological score, onset of paralysis and lifes-pan of the ALS mice were assayed. After observing significant disease-modifying effects, the CM was characterized biochemically by fractionation, comparative proteomics, and epigenetic screens for the dependence on pluripotency. CM of fibroblasts that were differentiated from the wt hiPSCs lacked any neuroprotective activity and was used as a negative control throughout the studies. Results: The secretome of PSCs including the ALS patient iPSCs was neuroprotective in the H2O2 model. In the model with pathogenic SOD1 mutation, ALS iPSC-CM attenuated all examined hallmarks of ALS pathology, rescued human ALS-MNs from denervation and death, restored mitochondrial health, and reduced the expression of inflam-matory genes. The ALS iPSC-CM also improved neuro-muscular health and function, and delayed paralysis and mor-bidity in ALS mice. Compared side by side, cyclosporine (CsA), a mitochondrial membrane blocker that prevents the leakage of mitochondrial DNA, failed to avert the death of ALS-MNs, al

关键词： Neurodegeneration Amyotrophic lateral sclerosis SOD1 mutation Pluripotent stem cells Secretome

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Click and bioorthogonal hyaluronic acid hydrogels as an ultra-tunable platform for the investigation of cell-material interactions

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Bioactive Materials 2023年第6期24卷 438-449页

作者： nathan Lagneau Pierre Tournier Boris Halgand François Loll Yves Maugars jérôme Guicheux Catherine Le Visage Vianney Delplace Nantes Université OnirisCHU NantesINSERMRegenerative Medicine and SkeletonRMeSUMR 1229F-44000France

The cellular microenvironment plays a major role in the biological functions of cells.Thus,biomaterials,especially hydrogels,which can be design to mimic the cellular microenvironment,are being increasingly used for cell encapsulation,delivery,and 3D culture,with the hope of controlling cell functions.Yet,much remains to be understood about the effects of cell-material interactions,and advanced synthetic strategies need to be developed to independently control the mechanical and biochemical properties of hydrogels.To address this challenge,we designed a new hyaluronic acid(HA)-based hydrogel platform using a click and bioorthogonal strain-promoted azide-alkyne cycloaddition(SPAAC)reaction.This approach facilitates the synthesis of hydrogels that are easy to synthesize and sterilize,have minimal swelling,are stable long term,and are cytocompatible.It provides bioorthogonal HA gels over an uncommonly large range of stiffness(0.5-45 kPa),all forming within 1-15 min.More importantly,our approach offers a versatile one-pot procedure to independently tune the hydrogel composition(e.g.,polymer and adhesive peptides).Using this platform,we investigate the independent effects of polymer type,stiffness,and adhesion on the secretory properties of human adipose-derived stromal cells(hASCs)and demonstrate that HA can enhance the secretion of immunomodulatory factors by hASCs.

关键词： Hydrogels Click and bioorthogonal chemistry Hyaluronic acid Mesenchymal stromal cells Cell-material interactions Secretome

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