ACS Pharmacology and Translational Science最新文献

{"title":"Microsphere System Coloading Type I Collagen and Dexamethasone Sodium Phosphate for Osteoarthritis Therapy","authors":"Xianlan Chen,&nbsp;Lu Zhang,&nbsp;Yan Zheng,&nbsp;Haiyang Chi,&nbsp;Rongrong Zhao,&nbsp;Kang Hu,&nbsp;Jiashan Zhu,&nbsp;Mi Liu","doi":"10.1021/acsptsci.6c00389","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00389","url":null,"abstract":"<p>Knee osteoarthritis (KOA) has no effective nonsurgicaltreatment.Intra-articular therapy constitutes an effective localized intervention;however, persistent lymphatic drainage and synovial vascular exchangelead to rapid drug elimination. Encapsulating bioactive agents intomicrosphere delivery platforms enables localized intra-articular administration,with their scaffold-based spherical architecture serving as pharmaceuticaland cellular carriers or tissue engineering scaffolds, representinga highly promising therapeutic avenue for KOA. Herein, PLGA was employedto prepare microspheres and a sustained-release microsphere formulation(MPs PLGA DSP@COLI) was prepared for KOA therapeutics, co-encapsulatingtype I collagen (COLI) and dexamethasone sodium phosphate (DSP). Characterizationrevealed uniform particle size distribution, favorable dispersibility,and extended-release kinetics. Functional assessments demonstratedrobust anti-inflammatory efficacy and enhanced chondrocyte-mediatedextracellular matrix deposition. Histopathological and immunohistochemicalanalyses demonstrated preserved cartilage matrix integrity, augmentedCOLII synthesis, diminished inflammatory cellular infiltration, andmaintained homeostasis of cartilage matrix components, concomitantwith reduced OARSI and synovitis scores. These effects collectivelysuppressed synovial hyperplasia and inflammation and suggested potentialimprovement in joint conditions. Overall, MPs PLGA DSP@COLI combinesthe pharmacological anti-inflammatory properties of DSP with the extracellularmatrix-related biological functions of COLI, establishing an innovative“drug-device combination” therapeutic paradigm, whichrepresents a promising therapeutic strategy for KOA.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2910–2927"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes-Associated Cognitive Dysfunction: Pathophysiology, Molecular Mechanisms, and Emerging Therapeutic Strategies","authors":"Ravin Sarkar,&nbsp;Atul Kabra,&nbsp;Abdulaziz S. Saeedan,&nbsp;Mohd Nazam Ansari","doi":"10.1021/acsptsci.6c00440","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00440","url":null,"abstract":"<p>Diabetes-associated cognitive dysfunction (DACD), whichincludesmemory loss, executive dysfunction, attention, processing speed, andan increased risk of dementia, is a growing problem associated withdiabetes mellitus (DM), especially type 2 diabetes mellitus. Due toa significant increase in the global burden of diabetes and populationageing, DACD is becoming an important public health issue. This reviewprovides a comprehensive overview of the pathophysiology, molecularmechanisms, biomarkers, experimental models, and emerging therapeuticstrategies associated with DACD. At present, it is believed that themultiple mechanisms associated with chronic hyperglycemia, insulinresistance, oxidative stress, mitochondrial dysfunction, neuroinflammation,blood–brain barrier disruption, and microvascular injury allcontribute to the pathogenesis of DACD. These interrelated mechanismsare responsible for cognitive decline, synaptic dysfunction, and neuronaldamage. Experimental research has shown that specific molecular pathwayscontribute to the pathogenesis of DACD, such as AGE–RAGE signaling,nuclear factor-κB activation, PI3K/Akt dysregulation, and inflammatorycascades. Emerging biomarkers including neurofilament light (NfL)chain, phosphorylated tau (p-tau), neuroimaging markers, exosomes,metabolomic profiles, and transcriptomic signatures may improve earlydiagnosis and risk stratification. Several therapeutic approaches,including GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors,intranasal insulin, nanoparticle-based delivery systems, stem celltherapies, and bioactive compounds, have demonstrated promising neuroprotectiveeffects in preclinical studies, although clinical translation remainslimited. Finally, future studies should be directed toward the useof biomarker-driven diagnosis, clinically relevant disease models,and large-scale clinical studies in order to develop effective therapeuticinterventions. Understanding more of the mechanisms that underlieDACD could help inform the creation of precision medicine strategiesto prevent or delay diabetes-related cognitive decline.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2688–2711"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Call for Papers: Natural Products in Pharmacology and Drug Development","authors":"Younis Baqi","doi":"10.1021/acsptsci.6c00545","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00545","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2658–2659"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Studying the Molecule, Assuming the Experience: The Pharmacology–Experience Asymmetry Framework for Psychedelic Research","authors":"Damián Pobihuszka","doi":"10.1021/acsptsci.6c00489","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00489","url":null,"abstract":"<p>Contemporary models of psychedelic action hold that clinicaloutcomesarise from an interaction between a pharmacologically induced brainstate and the lived experience that unfolds within it. Research effortis distributed very unevenly across those two domains: pharmacologicalvariables receive dose-finding trials, power calculations, and effect-sizeestimates, while the variables that shape experience are frequentlyunreported, rarely manipulated, and almost never compared. I arguethat this imbalance rests on a conceptual error about what is beingadministered, and propose that the object of psychedelic therapy isbest understood as the pharmacologically scaffolded experience. Onthat basis I describe the Pharmacology–Experience Asymmetryand develop a framework (PEAF) built on six postulates: the interventioncomprises two conceptually distinguishable components; therapeuticmechanisms span two partially differentiable domains; the elementsthat organize experience constitute a specifiable class of experientialinputs, with a taxonomy and a fixed-to-adaptive delivery axis; measurementeffort is asymmetrically distributed between domains; several currentconventions may represent crystallized methodological decisions ratherthan conclusions from comparative evidence; and investigative effortshould be approximately proportional to the causal weight attributedto each domain. I distinguish experiential inputs, process, and outcomes,examine why the asymmetry has persisted for six decades, and addressanticipated objections. Music serves as the illustrative case: a recentscoping review identified 19 papers from 10 studies across five decades,with one fully factorial design and one no-music arm, published in1970. Five testable predictions are derived, including one that requiresno new participants. Treating experiential inputs as tractable variablesrather than uncontrolled background would allow psychedelic researchto investigate them with methodological effort proportionate to thecausal weight assigned to experience by its own mechanistic models.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2991–2999"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Human Glucoregulatory Model for the Rational Design and Evaluation of Diabetes Therapeutics","authors":"Marco Machado,&nbsp;Sungyun Yang,&nbsp;Ali A. Alizadehmojarad,&nbsp;Michael S. Strano","doi":"10.1021/acsptsci.6c00356","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00356","url":null,"abstract":"<p>Diabetes mellitus remains a leadingcause of morbidity worldwide,motivating the development of novel diabetes therapeutics. Computationalglucoregulatory models that incorporate biochemical signaling andmechanisms have shown utility for preclinical evaluation and eventhe rational design of such interventions, potentially reducing theneed for animal experimentation. In this work, we expand upon ourIM³PACT 2.0 computational framework by applying it to humanclinical data and demonstrate its utility for translational predictionof glucose-responsive glucagon (GRG) therapeutic performance. Themodel was parameterized separately for healthy and type 1 diabetes(T1D) humans using a data-fitting procedure applied to clinical insulinand glucagon injection datasets. The resulting healthy model reproducesthe damped glucose recovery clinically observed following insulinadministration, characteristic of coupled insulin–glucagonregulation. Sensitivity analysis was performed to identify parameterscritical to describing glucose responses in the injection datasets,and a species comparison was performed that benchmarked human parametersagainst our previously validated rat model. Model performance wasevaluated using a series of simulated test injections, including dosesoutside the fitted dataset. This human model was then used to simulatethe translational therapeutic effect of a hydrogel-based compositemicroneedle (cMN) patch GRG, previously evaluated in streptozotocin-inducedT1D rats. A generalized parametric GRG design framework was subsequentlydeveloped, mapping the kinetic and drug-loading design space thatyields effective therapeutic performance in T1D humans. The parameterizedframework constitutes a validated in silico platform for the preclinicalevaluation and rational design of glucose-responsive glucagon therapeuticsin humans.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2889–2901"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zirconium-89 Labeling and Preliminary Evaluation of Simtuzumab as a Candidate Positron Emission Tomography (PET) Imaging Agent for Human Lysyl Oxidase-like 2 (LOXL2) in the Extracellular Matrix of Solid Tumors","authors":"Graham Ragland,&nbsp;Atchimnaidu Siriki,&nbsp;Kaustab Ghosh,&nbsp;Sarah Thau,&nbsp;Lucas Gonzalez,&nbsp;Nicholas Feinberg,&nbsp;Satish K. Chitneni","doi":"10.1021/acsptsci.6c00208","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00208","url":null,"abstract":"<p>Lysyl oxidase-like2 (LOXL2) is a copper-dependent enzymethatis involved in collagen and elastin cross-linking in the tumor extracellularmatrix (ECM) and contributes to tumor progression. Simtuzumab is aclinically evaluated humanized monoclonal antibody that binds to anallosteric binding site on LOXL2. Herein, we report radiolabelingand preliminary evaluation of simtuzumab labeled with zirconium-89(⁸⁹Zr, <em>t</em>_1/2: 3.3 days) forpositron emission tomography (PET) imaging of LOXL2 in the ECM oftumors. Simtuzumab was conjugated with desferrioxamine (DFO) and labeledwith ⁸⁹Zr in &gt;98% yield. Magnetic bead-based assay confirmedspecific binding of [⁸⁹Zr]Zr-DFO-simtuzumab to LOXL2. LOXL2expression levels and cell binding of [⁸⁹Zr]Zr-DFO-simtuzumabwere assessed in MIA PaCa-2 and HepG2 cell lines. Western blot analysisindicated higher LOXL2 expression in MIA PaCa-2 cells compared withHepG2 cells. Cell binding assays revealed minimal binding (&lt;0.5%)of [⁸⁹Zr]Zr-DFO-simtuzumab in both cell lines, reflectingthe lack of cell surface expression of LOXL2. Immunohistochemical(IHC) studies revealed primarily intracellular localization of LOXL2in the MIA PaCa-2 xenograft model, with minimal expression in HepG2xenografts in mice. microPET/CT imaging studies in mice bearing MIAPaCa-2 xenografts demonstrated low but visible uptake of [⁸⁹Zr]Zr-DFO-simtuzumab in tumors (6.2 ± 1.3% ID/g) at 96 h postinjection.Ex vivo biodistribution studies indicated higher uptake of the labeledconjugate in both xenograft tumor models relative to muscle, but nosignificant differences were observed in [⁸⁹Zr]Zr-DFO-simtuzumabuptake in the two tumor models, consistent with the low ECM-associatedLOXL2 in IHC staining. Overall, simtuzumab has been successfully labeledwith [⁸⁹Zr]Zr using DFO and characterized as a candidateimmunoPET tracer for LOXL2. However, additional studies are neededto further validate the labeled conjugate in tumor models with highLOXL2 expression in the ECM and to confirm LOXL2-specific ECM imagingin vivo by PET.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2795–2805"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabigerol Enhances Muscle Strength and Performance in Dexamethasone-Treated Mice","authors":"Izabel Feltrin Fabro,&nbsp;Tatyana Nery,&nbsp;Ana Paula Pinto de Araújo,&nbsp;Amanda Leite Bastos Pereira,&nbsp;Francielly Andressa Felipetti,&nbsp;Aderbal Silva Aguiar Jr","doi":"10.1021/acsptsci.6c00187","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00187","url":null,"abstract":"<p>Sarcopenia is a major clinical condition associated withagingand is characterized by progressive loss of skeletal muscle mass andfunction. Resistance training is an effective intervention to counteractmuscle atrophy; however, strategies that selectively enhance functionalperformance remain limited. Cannabigerol, a phytocannabinoid thatis not a CB1 receptor agonist and therefore lacks psychotomimeticactivity, has emerged as a potential modulator of neuromuscular function,although its role in skeletal muscle adaptation remains poorly understood.Here, we investigated the effects of resistance exercise and cannabigerol,alone and in combination, in a dexamethasone-induced model of muscleatrophy in mice. Animals received dexamethasone (20 mg/kg, i.p.) for12 days and were subsequently subjected to a 4-week ladder-based resistanceexercise protocol. Cannabigerol (10 mg/kg, i.p.) was administeredon training days. Resistance exercise restored muscle morphology andimproved fatigue resistance. In contrast, cannabigerol acted mainlyon neuromuscular performance, increasing muscle power while producingonly a small increase in fiber cross-sectional area. Cannabigerolpotentiated training-induced power output, increasing performanceby ∼55% in the first week and up to ∼87% after 4 weekscompared to exercise alone. In addition, cannabigerol increased peakgrip strength (∼10%) and lowered post-exercise blood lactatein sedentary animals (∼48%). These findings show that resistanceexercise and cannabigerol exert complementary effects on skeletalmuscle─exercise promoting structural recovery and cannabigerolenhancing neuromuscular performance and lowering post-exercise lactate─andsupport further investigation of cannabigerol as an adjunct to exercisein glucocorticoid-induced muscle atrophy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2772–2782"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational Pharmacokinetic and Pharmacodynamic Evaluation of Mefloquine Against Plasmodium falciparum Using a Hollow Fiber Infection Model","authors":"Sabiha R. Mim,&nbsp;Kiana Pica,&nbsp;Lili Liu,&nbsp;Yanan Zang,&nbsp;Yinzhi Lang,&nbsp;Jürgen B. Bulitta,&nbsp;Francine Johansson Azeredo","doi":"10.1021/acsptsci.6c00482","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00482","url":null,"abstract":"<p>This study establisheda plastic-based hollow fiber infectionmodel(HFIM) to reproduce human-like mefloquine exposure and quantify antimalarialpharmacodynamics (PD) against blood-stage <em>Plasmodium falciparum</em>. Asynchronized ring-stage 3D7 parasites were maintained in the extracapillaryspace under continuous-flow culture conditions that supported sustainedgrowth across two consecutive 48 h intraerythrocytic life cycles.The observed parasitemia dynamics were comparable in static and dynamicdrug-free controls. Target total plasma concentration time profilesfor intravenous mefloquine were generated using a pharmacokinetic(PK) simulation study based on previously reported compartmental modelsfrom adult malaria patients and subsequently implemented in the HFIMthrough programmed dilution to mimic first-order elimination, withdosing simulated as a 100 mg intravenous (IV) bolus every 24 h for3 days. The HFIM exposure profile maintained clinically relevant peakconcentrations with the long clinical PK half-life of mefloquine.Under these dynamic exposure conditions, mefloquine produced sustainedsuppression of parasitemia across successive life cycles relativeto both control conditions, consistent with concentration-driven blood-stageactivity. The estimated IC50 was 0.03 mg/L. Together, this study demonstratedthat the commonly used plastic-based HFIM can simulate clinicallyrelevant PK profiles and characterize the antimalarial PD againstblood-stage <em>P. falciparum</em>. This addresses limitationsof static in vitro assays and reduces the reliance on animal models,where preclinical-to-clinical concordance can be poor. Thereby, HFIMprovides a promising framework for optimizing antimalarial dosingstrategies. Future studies will extend this approach to rational evaluationof combination therapies using PK/PD-guided regimen design to improveclinical relevance.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2983–2990"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective Effects of the Phytocystatin CaneCPI-5 on Periodontal Ligament Cell Osteogenic Activity and Alveolar Bone Loss under Inflammatory Challenge","authors":"Maria Eduarda Scordamaia Lopes,&nbsp;Angélica Letícia Reis Pavanelli,&nbsp;Sâmmea Martins Vieira,&nbsp;Gisele Faria,&nbsp;Flávio Henrique Silva,&nbsp;Sigrun Eick,&nbsp;Andressa V. B. Nogueira,&nbsp;James Deschner,&nbsp;Joni Augusto Cirelli","doi":"10.1021/acsptsci.6c00363","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00363","url":null,"abstract":"<p>Periodontal diseaseis characterized by a chronic inflammatoryenvironment that compromises the regenerative capacity of periodontaltissues, particularly by impairing the osteogenic potential of periodontalligament cells. Phytocystatins have emerged as bioactive moleculeswith potential regenerative and immunomodulatory properties; however,their effects on periodontal tissues under inflammatory conditionsremain unexplored. In this study, we investigated the effects of CaneCPI-5on the osteogenic behavior of human periodontal ligament cells (hPDLCs)under basal and inflammatory conditions in vitro, as well as its impacton alveolar bone preservation and periodontal tissue responses ina murine model of experimental periodontitis. In vitro, CaneCPI-5promoted the expression of osteogenic markers and supported mineralizedmatrix formation under basal conditions. Notably, CaneCPI-5 preservedosteogenic gene expression and mineral deposition in hPDLCs exposedto <em>Filifactor alocis</em>, indicating asustained osteogenic response despite inflammatory stimulation. Invivo, treatment with CaneCPI-5 significantly attenuated alveolar boneloss, increased bone mineral density and bone volume fraction, andwas associated with histological features indicative of a more preservedperiodontal tissue architecture compared with untreated disease controls.Stereometric analyses further revealed reduced inflammatory cell infiltrationand vascular density, alongside increased fibroblast presence andextracellular matrix components in treated animals. Collectively,these findings demonstrate that CaneCPI-5 supports osteogenic activityand contributes to periodontal tissue preservation in inflammatorysettings. The convergence of in vitro and in vivo data suggests thatCaneCPI-5 may be a promising bioactive molecule for the developmentof adjunctive regenerative strategies to mitigate inflammation-associatedperiodontal tissue destruction.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2902–2909"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Diverse Endogenous Metabolic and Signaling Pathways by UDP-Glucuronosyltransferases (UGTs) Revealed by Metabolomics of Knockout Mice","authors":"Kian Falah,&nbsp;Jiarun Liu,&nbsp;Nghia Nguyen,&nbsp;Shujuan Chen,&nbsp;Robert H. Tukey,&nbsp;Sanjay K. Nigam","doi":"10.1021/acsptsci.6c00197","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00197","url":null,"abstract":"<p>Uridine 5′-diphospho-glucuronosyltransferase (UGT)enzymesplay a critical role in hepatic and other metabolism of endogenousand exogenous small molecules. The addition of glucuronic acid viaUGT increases the polarity and subsequent solubility of small molecules,helping direct them for biliary excretion and renal excretion by organicanion transporter OAT3 (SLC22A8). Mutations in UGTs are associatedwith disorders in biliary metabolism (e.g., Gilbert’s syndrome,Crigler-Najjar syndrome). Here, we used comprehensive serum metabolomicprofiling of pan <em>Ugt1</em>-knockout (<em>Ugt1^–/–</em>) mice to define the metabolic consequencesof UGT deficiency. All 7 knockout mice exhibited markedly elevatedbilirubin (mean = 5.96 mg/dL). Partial Least Squares DiscriminantAnalysis (PLS-DA) showed clear separation between <em>Ugt1^–/–</em> and wild type (WT), and volcanoplots revealed significant endogenous metabolite alterations. Theseincluded upregulation of numerous bilirubin degradation products aswell as major disturbances in lipid and amino acid metabolism. Inparticular, pathway enrichment analyses identified disruptions infatty acid biosynthesis, glycine-serine metabolism, heme breakdown,porphyrin metabolism, and β-oxidation of fatty acids. Thus,the UGT1 proteins regulate different aspects of endogenous metabolismand signaling. Consistent with this notion, there were increases inliver expression of several nuclear receptors (e.g., HNF4a, PPARa,PXR) involved in metabolic signaling. These results support the remotesensing and signaling theory (RSST), which proposes that UGT1 proteinsplay a key role in organ crosstalk via routing small molecules betweenthe liver and kidney, with glucuronidated molecules being mainly directedto the multispecific SLC kidney transporter OAT3. We propose thatthis glucuronidation-regulated RSST loop is essential to signalingalong the gut-liver-kidney axis.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2535–2543"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}