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Pharmacological characterizationof synthetic cannabinoid MAM-2201：radioligand binding and abuse-related effects

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中国药理学与毒理学杂志 2017年第10期31卷 1016-1017页

作者： William e FANTeGROSSI Aaron JANOWSKY Amy J eSHLeMAN lauren N RUSSeLL Saki FUKUDA Jyoti GOGOI Cassandra PRIOLeAU Ambuja S BALe Srihari R TeLLA Merle G PAULe Takato HIRANITA Department of Pharmacology and Toxicology College of Medicine University of Arkansas for Medical Sciences AR 72207 Division of Neurotoxicology National Center for Toxicological Research Food and Drug Administration AR 72079 Departments of Psychiatry and Behavioral Neuroscience Oregon Health & Science University Portland OR 97239-3098 VA Portland Health Care System Portland OR 97239 Drug and Chemical evaluation Section Drug Enforcement Administration

OBJeCTIVe Over 30% of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic *** recent emergence of MAM-2201 on the illicit market is troubling because this drug has no precedent in either the scientific or patent literature,and appears to be a novel compound developed specifically as a "graymarket" drug of abuse bystructurally combining the known synthetic cannabinoids JWH-122 and *** is currently no published information regarding the pharmacology of *** The present studies characterized cannabinoid-like effects of MAM-2201 in vitro(interactions with cannabinoid type 1 receptors[CB1 Rs]) and in vivo(in mice and rats).ReSULTS In a radioligand binding assay using [3 H]CP55,940 in HeK cell membranes transfected with the CB1 R,MAM-2201(K i=5.4 nmol·L^(-1)),had higher binding affinity than WIN 55,212-2(K i=80 nmol·L^(-1)),and D9-THC(K i=8.3 nmol·L^(-1)).The e max values for MAM-2201 and WIN 55,212-2 in an assay of agonist inhibition of forskolin-stimulated c AMP were 85%(eC50=0.45 nmol·L^(-1)) and 95%,respectively,as compared with the D9-THC e max of 74%.In mice,MAM-2201(0.003-1.0 mg·kg^(-1),IP) produced dose-dependent cannabimimetic effects which were both more potent and more effective than those of ***-2201 and D9-THC dose-dependently produced hypothermia:eD50=0.287 and 25.4 mg·kg^(-1),analgesia:eD50=0.125 and 29.4 mg·kg^(-1),and catalepsy:eD50=0.301 and18.9 mg·kg^(-1) in adult male CD1 ***,MAM-2201 also elicited convulsant effects at a dose of 1.0 mg·kg^(-1) in 8/8 murine *** rats,MAM-2201 produced dose-dependent D9-THC-like interoceptive effects in subjects trained to discriminate 3.0 mg·kg^(-1)(IP) D9-THC from *** MAM-2201 binds CB1 Rs with high affinity and agonist efficacy,and functions as a potent cannabinoid agonist in vivo across several complementary measures of cannabinoid activity in two rodent species.

关键词： cannabinoid CB1 receptor behavior abuse liability

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

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Bone Research 2023年第4期11卷 737-750页

作者： Lindsey H.Remark Kevin Leclerc Malissa Ramsukh Ziyan Lin Sooyeon Lee Backialakshmi Dharmalingam lauren Gillinov Vasudev V.Nayak Paulo el Parente Margaux Sambon Pablo J.Atria Mohamed A.e.Ali Lukasz Witek Alesha B.Castillo Christopher Y.Park Ralf H.Adams aristotelis Tsirigos Sophie M.Morgani Philipp Leucht Department of Orthopaedic Surgery NYU Robert I.Grossman School of MedicineNew YorkNYUSA Applied Bioinformatics Laboratories NYU Grossman School of MedicineNew YorkNYUSA Institute of Comparative Molecular endocrinology Ulm UniversityUlmGermany Max Planck Institute for Molecular Biomedicine Department of Tissue Morphogenesisand University of MünsterFaculty of MedicineD-48149 MünsterGermany Department of Biochemistry and Molecular Biology University of Miami Miller School of MedicineMiamiFLUSA Department of Pathology NYU Robert I.Grossman School of MedicineNew YorkNYUSA Biomaterials Division New York University College of DentistryNew YorkNYUSA Hansjörg Wyss Department of Plastic Surgery NYU Grossman School of MedicineNew York UniversityNew YorkNYUSA Department of Biomedical engineering Tandon School of EngineeringNew York UniversityBrooklynNYUSA Department of Cell Biology NYU Robert I.Grossman School of MedicineNew YorkNYUSA

Skeletal stem and progenitor cells(SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

关键词： Notch skeletal elevated

In-depth examination of hyperproliferative healing in two breeds of Sus scrofa domesticus commonly used for research

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Animal Models and experimental Medicine 2021年第4期4卷 406-417页

作者： Colton H.Funkhouser Liam D.Kirkpatrick Robert D.Smith lauren T.Moffatt Jeffrey W.Shupp Bonnie C.Carney Firefighters'Burn and Surgical Research Laboratory MedStar Health Research InstituteWashingtonDistrict of ColumbiaUSA Department of Biochemistry and Molecular and Cellular Biology Georgetown University Medical CenterWashingtonDistrict of ColumbiaUSA Department of Surgery Georgetown University School of MedicineWashingtonDistrict of ColumbiaUSA The Burn Center Department of SurgeryMedStar Washington Hospital CenterWashingtonDistrict of ColumbiaUSA

Background:Wound healing can result in various outcomes,including hypertrophic scar(HTS).Pigs serve as models to study wound healing as their skin shares physi-ologic similarity with ***(Yk)and Duroc(Dc)pigs have been used to mimic normal and abnormal wound healing,*** reason behind this differential healing phenotype was explored ***:excisional wounds were made on Dc and Yk pigs and were sampled and imaged for 98 *** arrays were used to determine differential gene *** Scar Scale(VSS)scores were ***-epithelialization was analyzed.H&e,Mason's trichrome,and immunostains were used to determine cellularity,col-lagen content,and blood vessel density,***:Yk wounds heal to a“port wine”HTS,resembling scarring in Fitzpatrick skin types(FST)*** wounds heal to a dyspigmented,non-pliable HTS,resembling scarring in FST *** expression during wound healing was differentially regulated versus uninjured skin in 40/80 genes,15 of which differed between *** scars had a higher VSS score at all time *** and Dc wounds had equivalent re-epithelialization,collagen disorganization,and blood vessel ***:Our findings demonstrate that Dc and Yk pigs can produce *** creation and healing were consistent among breeds,and differences in gene expression were not sufficient to explain differences in resulting scar *** pig breeds should be used in animal models to investigate novel therapeutics to provide insight into a treatment's effectiveness on various skin types.

关键词： animal models burns Fitzpatrick skin type hypertrophic scar wound healing

Inflammatory conversion of quiescent osteoblasts by metastatic breast cancer cells through peRKl/2 aggravates cancer-induced bone destruction

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Bone Research 2021年第4期9卷 557-570页

作者： Jungho Back Minh Nam Nguyen Lu Li Saelim Lee Inkyu Lee Fancheng Chen lauren Gillinov Yeon-Ho Chung Kareme D.Alder Hyuk-Kwon Kwon Kristin e.Yu Christopher M.Dussik Ziehen Hao Michael J.Flores Yoseph Kim Izuchukwu K.Ibe Alana M.Munger Sung Wook Seo Francis Y.Lee Department of Orthopaedics&Rehabilitation Yale UniversitySchool of MedicineNew HavenCTUSA Research Center for Genetics and Reproductive Health School of MedicineVietnam National University Ho Chi Minh CityLinh Trung WardThu Due DistrictHo Chi Minh CityVietnam Department of Rehabilitation Medicine Renji HospitalSchool of MedicineShanghai JiaoTong UniversityShanghaiChina College of Medicine Dankook UniversityCheonanRepublic of Korea Department of Life Science Chung-Ang UniversitySeoulRepublic of Korea Shanghai Medical College Fudan UniversityShanghai CityChina Department of emergency&Trauma Changhai HospitalNavy Medical UniversityShanghaiChina Biomedical engineering Johns Hopkins UniversityBaltimoreMDUSA Department of Orthopedic Surgery Samsung Medical CenterSungkyunkwan University School of MedicineSeoulGangnam-guRepublic of Korea

Disruption of bone homeostasis caused by metastatic osteolytic breast cancer cells increases inflammatory osteolysis and decreases bone formation,thereby predisposing patients to pathological fracture and cancer *** of osteoblast function induces skeletal diseases due to the disruption of bone *** observed increased activation of peRK1/2 in osteolytic breast cancer cells and osteoblasts in human pathological specimens with aggressive osteolytic breast cancer *** confirmed that osteolytic breast cancers with high expression of peRK1/2 disrupt bone homeostasis via osteoblastic eRK1/2 activation at the bone-breast cancer *** process of inflammatory osteolysis modulates eRK1/2 activation in osteoblasts and breast cancer cells through dominant-negative MeK1 expression and constitutively active MeK1 expression to promote cancer growth within ***,an FDA-approved MeK inhibitor,not only reduced breast cancer-induced bone destruction but also dramatically reduced cancer growth in bone by inhibiting the inflammatory skeletal *** together,these findings suggest that eRK1/2 activation in both breast cancer cells and osteoblasts is required for osteolytic breast cancer-induced inflammatory osteolysis and that eRK1/2 pathway inhibitors may represent a promising adjuvant therapy for patients with aggressive osteolytic breast cancers by altering the shared cancer and bone microenvironment.

关键词： peRK1/2 breast homeostasis