OBJECTIVE： Though the initial etiologies of arthritis are multifactorial, clinically, patients share the prime complaints of the disease, pain. Here the authors assessed the analgesic and anti-inflammatory effects of...OBJECTIVE： Though the initial etiologies of arthritis are multifactorial, clinically, patients share the prime complaints of the disease, pain. Here the authors assessed the analgesic and anti-inflammatory effects of UP1304, a composite that contains a standardized blend of extracts from the rhizome of Curcuma /onga and the root bark of Morus a/ba, on rats with carrageenan-induced paw edema. METHODS： A plant library was screened for bradykinin receptor antagonists./n vivo, the anti- inflammatory and analgesic effects of the standardized composite, UP1304, were evaluated in rats with carrageenan-induced paw edema using oral dose ranges of 100-400 mg/kg. Ibuprofen, at a dose of 200 mg/kg, was used as a reference compound. In vitro, cycleoxygenase （COX） and lipoxygenase （LOX） inhibition assays were performed to evaluate the degree of inflammation. RESULTS： Statistically significant improvements in pain resistance and paw edema suppression were observed in animals treated with UP1304, when compared to vehicle-treated rats. Results from the highest dose of UP1304 （400 mg/kg） were similar to those achieved by ibuprofen treatment at 200 mg/kg. /n vitro, UP1304 showed dose-dependent inhibition of the enzymatic activities of COX and LOX. A half-maximal inhibitory concentration of 9.6 tJg/mL for bradykinin B1 inhibition was calculated for the organic extract of C./onga. Curcumin showed Ki values of 2.73 and 58 IJg/mL for bradykinin receptors B1 and B2, respectively. CONCLUSION： Data presented here suggest that UP1304, analgesic and anti-inflammatory agent of botanical origin, acted as a bradykinin receptor B1 and B2 antagonist, and inhibited COX and LOX enzyme activities. This compound should be considered for the management of symptoms associated with arthritis.展开更多
The aryl hydrocarbon receptor(AHR)is a ligand-dependent transcription factor of the bHLH/PAS protein family.In this review,we explore the multifaceted roles of AHR in both health and disease,tracing its recognition as...The aryl hydrocarbon receptor(AHR)is a ligand-dependent transcription factor of the bHLH/PAS protein family.In this review,we explore the multifaceted roles of AHR in both health and disease,tracing its recognition as a xenobiotic sensor and a central regulator of physiological homeostasis.We begin by recounting six decades of discoveries that have shaped our understanding of AHR,from its canonical function in environmental sensing to its critical roles in development,immune regulation,barrier tissue integrity,and host-microbe interactions.We detail recent structural breakthroughs that have illuminated the ligand-binding mechanisms and regulation of AHR,providing key insights into its activation and transcriptional control.We also highlight the diversity of AHR ligands,ranging from environmental toxins to microbial and dietary metabolites of tryptophan,and their contextdependent effects on AHR activation through the canonical pathway and noncanonical signaling mechanisms.We examine the involvement of AHR in pathologies such as cancer and autoimmune and inflammatory diseases and its potential as a therapeutic target.Finally,emphasis is placed on recent advances and future developments in drug design,aiming to develop modulators with clinical efficacy.This comprehensive synthesis underscores the dual role of AHR as a master integrator of both environmental and endogenous cues.Placing AHR within broader frameworks,such as the exposome,opens new avenues for therapeutic innovation and more effective strategies for disease prevention.展开更多
文摘OBJECTIVE： Though the initial etiologies of arthritis are multifactorial, clinically, patients share the prime complaints of the disease, pain. Here the authors assessed the analgesic and anti-inflammatory effects of UP1304, a composite that contains a standardized blend of extracts from the rhizome of Curcuma /onga and the root bark of Morus a/ba, on rats with carrageenan-induced paw edema. METHODS： A plant library was screened for bradykinin receptor antagonists./n vivo, the anti- inflammatory and analgesic effects of the standardized composite, UP1304, were evaluated in rats with carrageenan-induced paw edema using oral dose ranges of 100-400 mg/kg. Ibuprofen, at a dose of 200 mg/kg, was used as a reference compound. In vitro, cycleoxygenase （COX） and lipoxygenase （LOX） inhibition assays were performed to evaluate the degree of inflammation. RESULTS： Statistically significant improvements in pain resistance and paw edema suppression were observed in animals treated with UP1304, when compared to vehicle-treated rats. Results from the highest dose of UP1304 （400 mg/kg） were similar to those achieved by ibuprofen treatment at 200 mg/kg. /n vitro, UP1304 showed dose-dependent inhibition of the enzymatic activities of COX and LOX. A half-maximal inhibitory concentration of 9.6 tJg/mL for bradykinin B1 inhibition was calculated for the organic extract of C./onga. Curcumin showed Ki values of 2.73 and 58 IJg/mL for bradykinin receptors B1 and B2, respectively. CONCLUSION： Data presented here suggest that UP1304, analgesic and anti-inflammatory agent of botanical origin, acted as a bradykinin receptor B1 and B2 antagonist, and inhibited COX and LOX enzyme activities. This compound should be considered for the management of symptoms associated with arthritis.
基金supported by Inserm,CNRS,the University of Montpellier,the French National Research Agency(ANR),grant No.ANR-23-CE34-0006-01(SYNERGY)the French Agency for Food,Environmental and Occupational Health&Safety(ANSES),grant No.EST-24-013(AHRtox)+7 种基金kindly supported by the Fraunhofer Cluster of Excellence Immune-Mediated Diseases(grant CIMD_CED-AhR)the German Federal Ministry of Education and Research(grant CED-AhR)the National Institutes of Health Grant ES028244(GHP).B.P.L.is currently supported,in part,by grants P30ES001247,R01ES030300 and R01ES036197 from the US National Institute of Environmental Health Science,National Institutes of Health.P.M.-Athe European Union’s Horizon 2020 research and innovation program under grant agreement number 951921NORTE2030-FEDER-01777300-SCALE-ImmunoHUB2030 supported by Norte Portugal Regional Operational Programme(NORTE 2030),under the PORTUGAL 2030 Partnership Agreement,through the European Regional Development Fund(FEDER),and COMPETE2030-FEDER-00693400supported by FEDER and national Funds(Fundação para a Ciência e Tecnologia,FCT),operation number 15824 relative to applications to MPr-2023-12support from the German Research Foundation(SFB1389 UNITE-Glioblastoma,project No.404521405)and the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(grant agreement number 101045257,CancAHR)supported by the Deutsche Forschungsgemeinschaft,grants ES 103/11-1,HA 7346/5-1 and HA 7346/6-1.
文摘The aryl hydrocarbon receptor(AHR)is a ligand-dependent transcription factor of the bHLH/PAS protein family.In this review,we explore the multifaceted roles of AHR in both health and disease,tracing its recognition as a xenobiotic sensor and a central regulator of physiological homeostasis.We begin by recounting six decades of discoveries that have shaped our understanding of AHR,from its canonical function in environmental sensing to its critical roles in development,immune regulation,barrier tissue integrity,and host-microbe interactions.We detail recent structural breakthroughs that have illuminated the ligand-binding mechanisms and regulation of AHR,providing key insights into its activation and transcriptional control.We also highlight the diversity of AHR ligands,ranging from environmental toxins to microbial and dietary metabolites of tryptophan,and their contextdependent effects on AHR activation through the canonical pathway and noncanonical signaling mechanisms.We examine the involvement of AHR in pathologies such as cancer and autoimmune and inflammatory diseases and its potential as a therapeutic target.Finally,emphasis is placed on recent advances and future developments in drug design,aiming to develop modulators with clinical efficacy.This comprehensive synthesis underscores the dual role of AHR as a master integrator of both environmental and endogenous cues.Placing AHR within broader frameworks,such as the exposome,opens new avenues for therapeutic innovation and more effective strategies for disease prevention.
