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Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

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Neural Regeneration Research 2025年第8期20卷 2325-2336页

作者： Yafan Bai Hui Ma Yue Zhang Jinfeng Li Xiaojuan Hou Yixin Yang Guyan Wang Yunfeng Li department of Anesthesiology Beijing Tongren HospitalCapital Medical UniversityBeijingChina Beijing Institute of Basic Medical Sciences BeijingChina Hebei North University ZhangjiakouHebei ProvinceChina Beijing Institute of Pharmacology and toxicology State Key Laboratory of Toxicology and Medical CountermeasuresBeijing Key Laboratory of NeuropsychopharmacologyBeijingChina

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary *** this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain *** experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain ***,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 ***,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain ***,YL-0919 effectively combated oxidative stress both in vivo and in *** protective effects of YL-0919 were partially inhibited by *** results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist ***-0919 may have potential as a new treatment for traumatic brain injury.

关键词： antidepressant drug blood-brain barrier cognitive function hypidone hydrochloride(YL-0919) neurological function nuclear factor-erythroid 2 related factor 2 oxidative stress sigma-1 receptor superoxide dismutase traumatic brain injury

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Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca_(ER)^(2+)perturbation in hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2023年第9期13卷 3744-3755页

作者： Yanan Li Keqin Li Ting Pan Qiaobo Xie Yuyao Cheng Xinfeng Wu Rui Xu Xiaohui Liu Li Liu Jiangming Gao Wenmin Yuan Xianjun Qu Shuxiang Cui department of toxicology and sanitary chemistry Beijing Key Laboratory of Environmental ToxicologySchool of Public HealthCapital Medical UniversityBeijing 100069China department of Pharmacology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China department of Pharmacology Marine Biomedical Research Institute of QingdaoQingdao 266071China

The well-known insulin-like growth factor 1(IGF1)/IGF-1 receptor(IGF-1R)signaling pathway is overexpressed in many tumors,and is thus an attractive target for cancer ***,results have often been disappointing due to crosstalk with other ***,we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma(HCC)cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2(SERCA2)*** response to ligand binding,IGF-1Rβis translocated into the ER byβ-arrestin2(β-arr2).Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ.SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ*** IGF-1Rβphosphorylates SERCA2 on Tyr^(990)to enhance its *** of SERCA2-Tyr^(990)disrupted the interaction of ER IGF-1Rβwith SERCA2,and therefore ER IGF-1Rβfailed to promote SERCA2 *** enhancement of SERCA2 activity triggered Ca_(ER)^(2+)perturbation,leading to an increase in *** blocked the interaction between SERCA2and ER IGF-1Rβand therefore SERCA2 activity,resulting in inhibition of HCC *** conclusion,the translocation of IGF-1R into the ER triggers Ca_(ER)^(2+)perturbation by enhancing SERCA2 activity through phosphorylating Tyr^(990)in HCC.

关键词： IGF-1R HCC Endoplasmic reticulum(ER) SERCA2 Ca_(ER)^(2+)perturbation βarrestin-2(β-arr2) SERCA2^(Y990) Thapsigargin

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Methylated and thiolated arsenic species for environmental and health research——A review on synthesis and characterization

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Journal of Environmental Sciences 2016年第11期28卷 7-27页

作者： William R.Cullen Qingqing Liu Xiufen Lu Anthony McKnight-Whitford Hanyong Peng Aleksandra Popowich Xiaowen Yan Qi Zhang Michael Fricke Hongsui Sun X.Chris Le department of chemistry University of British Columbia Division of Analytical and Environmental toxicology Department of Laboratory Medicine and Pathology University of Alberta department of chemistry University of Alberta

Hundreds of millions of people around the world are exposed to elevated concentrations of inorganic and organic arsenic compounds, increasing the risk of a wide range of health effects. Studies of the environmental fate and human health effects of arsenic require authentic arsenic compounds. We summarize here the synthesis and characterization of more than a dozen methylated and thiolated arsenic compounds that are not commercially available. We discuss the methods of synthesis for the following14 trivalent（Ⅲ） and pentavalent（） arsenic compounds： monomethylarsonous acid（MMA~Ⅲ）, dicysteinylmethyldithioarsenite（MMA~Ⅲ（Cys）_2）, monomethylarsonic acid（MMA~Ⅴ）,monomethylmonothioarsonic acid（MMMTAⅤ） or monothio-MMA~Ⅴ, monomethyldithioarsonic acid（MMDTA~Ⅴ） or dithio-MMA~Ⅴ, monomethyltrithioarsonate（MMTTA~Ⅴ） or trithio-MMA~Ⅴ,dimethylarsinous acid（DMA~Ⅲ）, dimethylarsino-glutathione（DMA~Ⅲ（SG））, dimethylarsinic acid（DMA~Ⅴ）, dimethylmonothioarsinic acid（DMMTA~Ⅴ） or monothio-DMAⅤ, dimethyldithioarsinic acid（DMDTA~Ⅴ） or dithio-DMA~Ⅴ, trimethylarsine oxide（TMAO~Ⅴ）, arsenobetaine（AsB）, and an arsenicin-A model compound. We have reviewed and compared the available methods,synthesized the arsenic compounds in our laboratories, and provided characterization information. On the basis of reaction yield, ease of synthesis and purification of product, safety considerations, and our experience, we recommend a method for the synthesis of each of these arsenic compounds.

关键词： Arsenic standards Speciation analysis Arsenic metabolites Sulphur-containing arsenic species Synthetic chemistry of arsenic Pentavalent and trivalent methylarsenicals

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An Overview of Adverse Outcome Pathway Links between PM_(2.5)Exposure and Cardiac Developmental Toxicity

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Environment & Health 2024年第3期2卷 105-113页

作者： Chen Liang Ruiyang Ding Qinglin Sun Shiqian Liu Zhiwei Sun Junchao Duan department of toxicology and sanitary chemistry School of Public HealthCapital Medical UniversityBeijing 100069China Beijing Key Laboratory of Environmental toxicology Capital Medical UniversityBeijing 100069China

Fine particulate matter(PM_(2.5))is a significant risk factor for birth *** the first and most important organ to develop during embryogenesis,the heart’s potential susceptibility to PM_(2.5)has attracted growing *** several studies supporting the cardiac developmental toxicity of PM_(2.5),the diverse study types,models,and end points have prevented the integration of *** this Review,we present an adverse outcome pathway framework to elucidate the association between PM_(2.5)-induced molecular initiating events and adverse cardiac developmental *** of the aryl hydrocarbon receptor(AhR)and excessive generation of reactive oxygen species(ROS)were considered as molecular initiating *** excessive production of ROS induced oxidative stress,endoplasmic reticulum stress,DNA damage,and inflammation,resulting in *** activation of the AhR inhibited the Wnt/β-catenin pathway and then suppressed cardiomyocyte *** cardiomyocyte differentiation and persistent apoptosis resulted in abnormalities in the cardiac structure and *** of the aforementioned events have been identified as key events(KEs).The culmination of these KEs ultimately led to the adverse outcome,an increased morbidity of congenital heart defects(CHDs).This work contributes to understanding the causes of CHDs and promotes the safety evaluation of PM_(2.5).

关键词： fine particulate matter adverse outcome pathways cardiac developmental toxicity congenital heart defects reactive oxygen species aryl hydrocarbon receptor

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Decoding the genetic program of micronucleus formation: linking chromosomal instability to human disease

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Signal Transduction and Targeted Therapy 2024年第7期9卷 2840-2842页

作者： Jörg Fahrer Division of Food chemistry and toxicology Department of ChemistryRPTU Kaiserslautern-Landau67663 KaiserslauternGermany

A recent study by Adams and colleagues published in Nature unveiled more than one hundred genes that are involved in micronucleus formation,1 which is a biomarker for genomic instability and associated with aging,cancer,and other disorders.2 As an outstanding achievement,the authors identified DSCC1(DNA Replication And Sister Chromatid Cohesion 1)as a critical gene protecting against early developmental defects,genomic instability,reduced proliferative capacity,cohesinopathy-related phenotypes,and tumor development in vivo.

关键词： chromosomal linking Replication

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Benefits and risks associated with consumption of Great Lakes fish containing omega-3 fatty acids and polychlorinated biphenyls(PCBs)

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Journal of Environmental Sciences 2016年第3期28卷 1-5页

作者： Rebecca E.Paliwoda Ashley M.Newbigging Zhixin Wang X.Chris Le department of chemistry University of Alberta Division of Analytical and Environmental toxicology Department of Laboratory Medicine and PathologyUniversity of Alberta

Introduction Assessment of environmental health effects arising from exposure to multiple substances is often very *** is particularly true when humans are exposed to a mixture that contains both beneficial and harmfu... 详细信息

关键词： Environmental epidemiology Polychlorinated biphenyls(PCBs) Omega-3 fatty acids Thyroid cancer Dietary exposure Food contamination New York fishermen

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Arsenobetaine:the ongoing mystery

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National Science Review 2016年第4期3卷 451-458页

作者： Aleksandra Popowich Qi Zhang X.Chris Le department of chemistry University of Alberta Division of Analytical and Environmental toxicology Department of Laboratory Medicine and PathologyUniversity of Alberta

Arsenobetaine(As B) is a non-toxic organoarsenical identiied as a major arsenic species in marine animals and a number of terrestrial *** its irst identiication nearly 40 years ago,numerous studies investigating the biosynthesis and function of As B have been carried out,although molecular mechanisms have not been fully *** and how is As B formed? Why do marine animals acquire high concentrations of As B? his review briely summarizes the current progress of As B research toward understanding its origin,function and the putative pathways for its *** paper also suggests potential future studies in the atempt to solve the As B mystery.

关键词： arsenic arsenobetaine arsenocholine arsenosugars biosynthesis arsenic metabolism speciation

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Switching off DNA repair—how colorectal cancer evades targeted therapies through adaptive mutability

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Signal Transduction and Targeted Therapy 2020年第1期5卷 2343-2344页

作者： Jörg Fahrer Division of Food chemistry and toxicology Department of ChemistryTechnical University of Kaiserslautern67663 KaiserslauternGermany

A very recent study by Russo et *** in Science demonstrates that colorectal cancer(CRC)cells adapt to targeted therapies by downregulating DNA repair at the expense of an increased mutation frequency and microsatellite instability(MSI).1 The authors intriguingly showed that CRC cells are capable of activating stress-induced mutagenesis similar to unicellular organisms in a transient and controlled manner,allowing them to survive under targeted therapies(Fig.1).

关键词： targeted colorectal al

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Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-Ⅰ

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Acta Pharmaceutica Sinica B 2023年第7期13卷 2963-2975页

作者： Qiaobo Xie Yanyan Chu Wenmin Yuan Yanan Li Keqin Li Xinfeng Wu Xiaohui Liu Rui Xu Shuxiang Cui Xianjun Qu department of Pharmacology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Ocean University of China School of Medicine and PharmacyQingdao 266075China Marine Biomedical Research Institute of Qingdao Qingdao 266075China department of toxicology and sanitary chemistry Beijing Key Laboratory of Environmental ToxicologySchool of Public HealthCapital Medical UniversityBeijing 100069China

Insulin-like growth factor-1 receptor(IGF-1R) has been made an attractive anticancer target due to its overexpression in ***,targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream ***,we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of *** active β-arrestin-2 scaffolds this disobliging signaling to talk with *** response to ligands,IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250,opening the middle loop(Leu130-Cys141) to the RING domain of MEX3A through the conformational changes of β*** models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of *** assay of the mutants βarr2Y64Aand βarr2Y250Afurther confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of *** truncated-βarr2 and the peptide ATQAIRIF,which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes,thus blocking the IGF-1R-triggered RIG-I *** of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I ***(I:C) could reverse anti-PD-L1 insensitivity by recovery of *** summary,we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

关键词： IGF-1R RIG-Iβ-Arrestin-2(βarr2) K48-linked ubiquitination MEX3A Anti-PD-L1

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Vascular endothelial growth factor:a double-edged sword in the development of white matter lesions

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Neural Regeneration Research 2025年第1期20卷 191-192页

作者： Narek Manukjan Daniel Fulton Zubair Ahmed WMatthijs Blankesteijn Sébastien Foulquier department of Pharmacology and toxicology Maastricht UniversityMaastrichtThe Netherlands CARIM-School for Cardiovascular Diseases Maastricht UniversityMaastrichtThe Netherlands Neuroscience and Ophthalmology Institute of Inflammation and AgeingUniversity of BirminghamEdgbastonBirminghamUK Centre for Trauma Sciences Research University of BirminghamEdgbastonBirminghamUK MHeNs-School for Mental Health and Neuroscience Maastricht UniversityMaastrichtThe Netherlands department of Neurology Maastricht University Medical CenterMaastrichtThe Netherlands

As the population ages,the burden of age-related diseases becomes ***,over 55 million people suffer from dementia worldwide,with Alzheimer’s disease being the most common ***,it is becoming clearer that underlying vascular pathology such as cerebral small vessel disease(cSVD)may be a more detrimental cause for dementia(Cuadrado-Godia et al.,2018).It is estimated that 10%-30%of the elderly population and 35%-90%of all dementia patients exhibit signs of *** term cSVD refers to pathology affecting the small vessels of the brain,which can lead to lacunar cerebral infarcts,enlarged perivascular spaces,and cortical hemorrhages(Cuadrado-Godia et al.,2018).CSVD is often associated with cognitive decline,gait problems,and dementia(Cuadrado-Godia et al.,2018).

关键词： pathology becoming white

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