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Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

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Acta Pharmaceutica Sinica B 2016年第5期6卷 492-503页

作者： Xi-Ling Jiang Hong-Wu Shen Donald E.Mager Stephan Schmidt Ai-Ming Yu Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical SciencesUniversity at BuffaloThe State University of New York Department of Pharmaceutics Center for Pharmacometrics and Systems PharmacologyUniversity of Florida Department of Biochemistry & Molecular Medicine UC Davis School of Medicine2700 Stockton Boulevard

We have shown recently that concurrent harmaline,a monoamine oxidase-A inhibitor(MAOI),potentiates serotonin(5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine(5-Me O-DMT)-induced *** objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic(PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in *** thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback ***-induced hypothermia and 5-Me O-DMT–elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1 Areceptor and thermogenesis via the stimulation of 5-HT2 Areceptor,*** serotonergic 5-Me O-DMT–induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic *** PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on5-Me O-DMT and harmaline PK properties,and drug- and stress-induced simple hypo/hyperthermic and complex biphasic ***,the modeling results revealed a 4-fold decrease of apparent SC_(50) value(1.88–0.496 mmol/L) for 5-Me O-DMT when harmaline was co-administered,providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-Me ODMT–induced *** addition,the hyperpyrexia caused by toxic dose combinations of harmaline and 5-Me O-DMT were linked to the increased systemic exposure to harmaline rather than5-Me O-DMT,although the body temperature profiles were mispredicted by the *** results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.

关键词： PK/PD model Thermoregulation Indolealkylamine Serotonin Monoamine oxidase-A inhibitor Stress

The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4523-4534页

作者： Rebecca R.Florke Gee Andrew D.Huber Jing Wu Richa Bajpai Allister J.Loughran Shondra M.Pruett-Miller Taosheng Chen Department of Chemical Biology and Therapeutics St.Jude Children's Research HospitalMemphisTN 38105USA Graduate School of Biomedical Sciences St.Jude Children's Research HospitalMemphisTN 38105USA Center for Advanced Genome Engineering and Department of Cell and Molecular Biology St.Jude Children's Research HospitalMemphisTN 38105USA

Pregnane X receptor(PXR)is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes[e.g.,cytochrome P4503A4(CYP3A4)]and *** the regulation of PXR target genes is well-characterized,less is known about the regulation of PXR protein *** screening an RNAi library,we identified the F-box-only protein 44(FBXO44)as a novel E3ligase for *** abundance increases upon knockdown of FBXO44,and,inversely,decreases upon overexpression of *** analysis revealed that FBXO44 interacts with PXR,leading to its ubiquitination and proteasomal degradation,and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional *** summary,FBXO44 regulates PXR protein abundance,which has downstream consequences for CYP3A4 levels and drug-drug *** results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3ubiquitin ligase activities will affect PXR-mediated drug metabolism.

关键词： PXR FBXO44 Ubiquitination Proteasomal degradation CYP3A4 Drug-drug interactions E3 ligase Nuclear receptor

ZBTB7A governs estrogen receptor alpha expression in breast cancer

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Journal of Molecular Cell Biology 2018年第4期10卷 273-284页

作者： Mary Ellen Molloy Monika Lewinska Amanda K. Williamson Thanh Thao Nguyen Gamze Kuser-Abali Lu Gong Jiawei Yan John B. Little Pier Paolo Pandolfi Zhi-Min Yuan Department of Environmental health John B. Little Center for Radiation Sciences Harvard T.H. Chan School of Public Health Boston MA 02215 USA Biotech Research and Innovation Centre Department of Health and Medical Sciences University of Copenhagen Copenhagen Denmark Cancer Genetics Program Beth Israel Deaconess Cancer Center Departments of Medicine and Pathology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA 02215 USA

ZBTB7A, a member of the POZ/BTB and Krüppel （POK） family of transcription factors, has been shown to have a context-dependent role in cancer development and progression. The role of ZBTB7A in estrogen receptor alpha （ERα）-positive breast cancer is largely unknown. Approximately 70% of breast cancers are classified as ERα-positive. ERα carries out the biological effects of estrogen and its expression level dictates response to endocrine therapies and prognosis for breast cancer patients. In this study, we find that ZBTB7A transcriptionally regulates ERα expression in ERα-positive breast cancer cell lines by binding to the ESR1 promoter leading to increased transcription of ERα. Inhibition of ZBTB7A in ERα-positive cells results in decreased estrogen responsiveness as demonstrated by diminished estrogen-response element-driven luciferase reporter activity, induction of estrogen target genes, and estrogen-stimulated growth. We also report that ERα potentiates ZBTB7A expression via a post-translational mechanism, suggesting the presence of a positive feedback loop between ZBTB7A and ERα, conferring sensitivity to estrogen in breast cancer. Clinically, we find that ZBTB7A and ERα are often co-expressed in breast cancers and that high ZBTB7A expression correlates with improved overall and relapse-free survival for breast cancer patients. Importantly, high ZBTB7A expression predicts a more favorable outcome for patients treated with endocrine therapies. Together, these findings demonstrate that ZBTB7A contributes to the transcriptional program maintaining ERα expression and potentially an endocrine therapy-responsive phenotype in breast cancer.

关键词： ZBTB7A ERα breast cancer endocrine therapies

Transcriptional regulators dictate innate lymphoid cell fates

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Protein & Cell 2017年第4期8卷 242-254页

作者： Chao Zhong Jinfang Zhu Molecular and Cellular Immunoregulation Unit Laboratory of Immunology National Institute of Allergy and Infec Diseases National Institutes of Health Bethesda MD 20892 USA institute of Systems Biomedicine School of Basic Medical Sciences Peking University Health Science Center Beijing 100191 China

Research on innate lymphoid cells （ILC） has recently been a fast paced topic of immunological research. As ILCs are able to produce signature Th cytokine, ILCs have garnered considerable attention and have been described to represent the innate counterpart of the CD4＋ T helper （Th） cells. The development and function of ILCs are precisely regulated by a network of crucial tran- scription factors, which are also involved in the devel- opment or differentiation of conventional natural killer （cNK） cells and T cells. In this review, we will summarize the key transcriptional regulators and their functions through each phases of ILC development. With the phase of ILC lineage commitment, we will focus in particular on the roles of the transcription regulators Id2 and GATA-3, which in collaboration with other transcriptional factors, are critically involved in the generation of ILC fate determined progenitors. Once an ILC lineage has been established, several other transcription factors are required for the specification and functional regulation of distinct mature ILC subsets. Thus, a comprehensive understanding of the interactions and regulatory mech- anisms mediated by these transcription factors will help us to further understand how ILCs exert their helper-like functions and bridge the innate and adaptive immunity.

关键词： innate lymphoid cell transcription factors,GATA-3 Id2

A silent two-photon imaging system for studying in vivo auditory neuronal functions

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Light(Science & Applications) 2022年第5期11卷 888-900页

作者： Xindong Song Yueqi Guo Chenggang Chen Xiaoqin Wang Laboratory of Auditory Neurophysiology Department of Biomedical EngineeringJohns Hopkins University School of MedicineBaltimoreMD 21205USA

Two-photon laser-scanning microscopy has become an essential tool for imaging neuronal functions in vivo and has been applied to different parts of the neural system,including the auditory ***,many components of a two-photon microscope,such as galvanometer-based laser scanners,generate mechanical vibrations and thus acoustic artifacts,making it difficult to interpret auditory responses from recorded ***,we report the development of a silent two-photon imaging system and its applications in the common marmoset(Callithrix Jacchus),a non-human primate species sharing a similar hearing range with *** utilizing an orthogonal pair of acoustooptical deflectors(AODs),full-frame raster scanning at video rate was achieved without introducing mechanical *** depth can be optically controlled by adjusting the chirping speed on the AODs without any mechanical motion along the ***,all other sound-generating components of the system were acoustically isolated,leaving the noise floor of the working system below the marmoset’s hearing *** with the system in awake marmosets revealed many auditory cortex neurons that exhibited maximal responses at low sound levels,which were not possible to study using traditional two-photon imaging *** is the first demonstration of a silent two-photon imaging system that is capable of imaging auditory neuronal functions in vivo without acoustic *** capacity opens new opportunities for a better understanding of auditory functions in the brain and helps isolate animal behavior from microscope-generated acoustic interference.

关键词： system utilizing generating

Materials advancements for the safety and patency of implantable cardiovascular devices

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Nano Research 2024年第10期17卷 8977-8989页

作者： Zulmari Silva Pedraza Bo Liu Xudong Wang Department of Materials Science and Engineering University of Wisconsin−MadisonMadisonWisconsin 53706USA Departments of Cell and Regenerative Biology University of Wisconsin-MadisonMadisonWisconsin 53705USA

Implantable cardiovascular devices have revolutionized the management of cardiovascular diseases,significantly enhancing patients’quality of *** the increasing demand of cardiac implantable electronic devices,the imperative for novel device development is *** review article first elaborates the mechanisms underlying foreign body response and infection,elucidating the complex interplay between implanted constructs and host *** discussion then focuses on current advancements in materials science and engineering aimed at mitigating these *** innovations,such as drugeluting materials,surface modifications,and biomimetic materials,are explored as strategies to modulate these responses and to prevent fibrotic or thrombotic complications and ***,future directions in materials development for implantable cardiovascular devices are *** addressing safety and patency concerns through innovative material strategies,this article aims to guide the research and development of advanced materials for both current and future cardiovascular implantable devices,ultimately improving patient outcomes and advancing cardiovascular disease treatment.

关键词： biomaterials implantable devices cardiovascular diseases implantable materials

Characterization and of Ralstonia TAL-Like DNA-Binding Specificities Effectors

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Molecular Plant 2013年第4期6卷 1318-1330页

作者： Lixin Li Ahmed Atef Agnieszka Piatek Zahir Ali Marek Piatek Mustapha Aouida Altanbadralt Sharakuu Ali Mahjoub Guangchao Wang Suhail Khan Nina V. Fedoroff Jian-Kang Zhu Magdy M. Mahfouz Center for Desert Agriculture King Abdullah University of Science and Technology Thuwal 23955-6900 Kingdom of Saudi Arabia Department of Biological Sciences Faculty of Sciences King Abdulaziz University PO Box 80203 Jeddah 21589 Kingdom of Saudi Arabia Imaging Core Laboratory King Abdullah University of Science and Technology Thuwal 23955-6900 Kingdom of Saudi Arabia Department of Horticulture and Landscape Architecture Purdue University West Lafayette IN 47907 USA

Transcription activator-like effectors （TALEs） from Xanthomonas sp. have been used as customizable DNA- binding modules for genome-engineering applications, Ralstonia solanacearum TALE-like proteins （RTLs） exhibit similar structural features to TALEs, including a central DNA-binding domain composed of 35 amino acid-long repeats. Here, we characterize the RTLs and show that they localize in the plant cell nucleus, mediate DNA binding, and might function as transcriptional activators. RTLs have a unique DNA-binding architecture and are enriched in repeat variable di-residues （RVDs）, which determine repeat DNA-binding specificities. We determined the DNA-binding specificities for the RVD sequences ND, HN, NP, and NT. The RVD ND mediates highly specific interactions with C nucleotide, HN interacts spe- cifically with A and G nucleotides, and NP binds to C, A, and G nucleotides. Moreover, we developed a highly efficient repeat assembly approach for engineering RTL effectors. Taken together, our data demonstrate that RTLs are unique DNA-targeting modules that are excellent alternatives to be tailored to bind to user-selected DNA sequences for targeted genomic and epigenomic modifications. These findings will facilitate research concerning RTL molecular biology and RTL roles in the pathogenicity of Ralstonia spp.

关键词： Ralstonia solanacearum genome engineering TAL effectors TALE activators and repressors TALE nucleases (TALENs) targeted genome modifications.

Locomotor analysis identifies early compensatory changes during disease progression and subgroup classification in a mouse model of amyotrophic lateral sclerosis

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Neural Regeneration Research 2017年第10期12卷 1664-1679页

作者： Melissa M.Haulcomb Rena M.Meadows Whitney M.Miller Kathryn P.Mc Millan Me Kenzie J.Hilsmeyer Xuefu Wang Wesley T.Beaulieu Stephanie L.Dickinson Todd J.Brown Virginia M.Sanders Kathryn J.Jones Department of Anatomy and Cell Biology Indiana University School of MedicineIndianapolisINUSA Research and Development Service Roudebush Veterans Administration Medical CenterIndianapolisINUSA Program in Medical Neurosciences Indiana University School of MedicineIndianapolisINUSA Department of Statistics Indiana UniversityBloomingtonINUSA Department of Epidemiology and Biostatistics Indiana UniversityBloomingtonINUSA Department of Cancer Biology and Genetics The Ohio State University Wexner Medical CenterColumbusOHUSA

Amyotrophic lateral sclerosis is a motoneuron degenerative disease that is challenging to diagnose and presents with considerable variability in *** identification and enhanced understanding of symptomatic patterns could aid in diagnosis and provide an avenue for monitoring disease *** of the m SOD1 G93 A mouse model provides control of the confounding environmental factors and genetic heterogeneity seen in amyotrophic lateral sclerosis patients,while investigating underlying disease-induced *** the present study,we performed a longitudinal behavioral assessment paradigm and identified an early hindlimb symptom,resembling the common gait abnormality foot drop,along with an accompanying forelimb compensatory mechanism in the m SOD1 G93 A *** these initial changes,m SOD1 mice displayed a temporary hindlimb compensatory mechanism resembling an exaggerated steppage *** the disease progressed,these compensatory mechanisms were not sufficient to sustain fundamental locomotor parameters and more severe deficits *** next applied these initial findings to investigate the inherent variability in B6 SJL m SOD1 G93 A *** identified four behavioral variables that,when combined in a cluster analysis,identified two subpopulations with different disease progression rates：a fast progression group and a slow progression *** behavioral assessment paradigm,with its analytical approaches,provides a method for monitoring disease progression and detecting m SOD1 subgroups with different disease *** affords researchers an opportunity to search for genetic modifiers or other factors that likely enhance or slow disease *** factors are possible therapeutic targets with the potential to slow disease progression and provide insight into the underlying pathology and disease mechanisms.

关键词： nerve regeneration amyotrophic lateral sclerosis motoneuron degenerative disease locomotor disease progression disease variability SOD1 mouse neural regeneration

Intragroup social dynamics vary with the presence of neighbors in a cooperatively breeding fish

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Current Zoology 2019年第1期65卷 21-31页

作者： Jennifer K. Hellmann Ian M. Hamilton Department of Evolution Ecology and Organismal Biology The Ohio State University Columbus OH 43210 USA Department of Mathematics The Ohio State University Columbus OH 43210 USA Jennifer K. Hellmann Department of Animal Biology School of Integrative Biology University of Illinois Urbana-Champaign 505 S Goodwin Ave Urbana IL 61801 USA

Conflict is an in here nt part of social life in group-living species. Group members may mediate conflict through submissive and affiliative behaviors, which can reduce aggression, stabilize dominance hierarchies, and foster group cohesion. The frequency and resolution of within-group conflict may vary with the presenee of neighboring groups. Neighbors can threaten the territory or resources of the whole group, promoting behaviors that foster within-group cohesion. However, neighbors may also foster conflict of interests among group members: opportunities for subordinate dispersal may alter conflict among dominants and subordinates while opportunities for extrapair reproduction may increase conflict between mates. To understand how neighbors mediate within-group conflict in the cooperatively breeding fish Neolamprologus pulcher, we measured behavioral dynamics and social network structure in isolated groups, groups recently exposed to neighbors, and groups with established neighbors. Aggression and submission between the dominant male and female pair were high in isolated groups, but dominant aggression was directly primarily at subordinates when groups had neighbors. This suggests that neighbors attenuate conflict between mates and foster conflict between dominants and subordinates. Further, aggression and submission between similarly sized group members were most frequent when groups had neighbors, suggesting that neighbors induce rank-related conflict. We found relatively little change in within-group affiliative networks across treatments, suggesting that the presence of neighbors does not alter behaviors associated with promoting group cohesion. Collectively, these results provide some of the first empirical insights into the extent to which intragroup behavioral networks are mediated by intergroup interactions and the broader social context.

关键词： affiliation colony conflict exponential random graph model Neolamprologus pulcher network