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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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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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Decline and fall of aging astrocytes:the human perspective

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Neural Regeneration Research 2025年第6期20卷 1713-1714页

作者： Alexei Verkhratsky Alexey Semyanov Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK department of Neurosciences University of the Basque Country UPV/EHU and CIBERNEDLeioaSpain department of Forensic Analytical toxicology School of Forensic MedicineChina Medical UniversityShenyangLiaoning ProvinceChina department of Stem Cell Biology State Research Institute Centre for Innovative MedicineVilniusLithuania International Collaborative Center on Big Science Plan for Purinergic Signalling Chengdu University of Traditional Chinese MedicineChengduSichuan ProvinceChina department of Physiology Jiaxing University College of MedicineJiaxingZhejiang ProvinceChina

“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.

关键词： aging teeth progressive

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Single-cell transcriptomic profiling reveals ZEB1-mediated regulation in microglial subtypes and the impact of exercise on neuroinflammatory responses

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Traditional Medicine Research 2025年第2期10卷 55-64页

作者： Jin-Fang Wu Yi-Sheng Chen Yu-Chun Xie department of Rehabilitation Medicine Jiangsu Province Geriatric HospitalNanjing 210024China Fujian Key Laboratory of Toxicant and Drug toxicology Medical CollegeNingde Normal UniversityNingde 352100China Central Laboratory Jiangsu Province Geriatric HospitalNanjing 210024China

Background:This study aims to identify distinct cellular subtypes within brain tissue using single-cell transcriptomic analysis,focusing on specific biomarkers that differentiate cell types and the effects of traditional and exercise ***:Four samples were analyzed:older control(OC),older exercise(OE),younger control(YC),and younger exercise(YE).Single-cell RNA sequencing was used to distinguish cellular subtypes through their biomarker *** visualization included violin and t-SNE plots to illustrate biomarker expression across cell clusters such as oligodendrocytes,microglia,and ***,BV2 cells were exposed to amyloid-beta fragments to simulate Alzheimer’s disease,assessing the impact of exercise-induced cellular ***:Distinct cellular subtypes were identified:oligodendrocytes(MBP,St18),microglia(Dock8),and astrocytes(Aqp4,Gpc5).Sample OE was predominantly oligodendrocytes,while YE had more astrocytes,inhibitory neurons,and Canal-Retzius *** showed a significant presence of Olfm3+ganglion ***1 gene knockout revealed changes in SMAD family gene expression,which regulate *** stress levels were also ***:This profiling enhances our understanding of brain cellular functions and interactions,potentially informing targeted therapies in neurological *** may influence brain cell immune responses and cell death pathways by regulating specific gene expressions,offering new insights for treating neuroinflammation and degeneration.

关键词： single-cell transcriptomics brain tissue cellular subtypes biomarker expression neuronal diversity

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Drug metabolism in drug discovery and development

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Acta Pharmaceutica Sinica B 2018年第5期8卷 721-732页

作者： Zhoupeng Zhang Wei Tang department of Pharmacokinetics Pharmacodynamics and Drug Metabolism Merck Sharp & Dohme Corp. Shanghai ChemPartners

Drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics(PK), pharmacodynamics(PD), and safety should be carefully considered. This communication provides an overview of common strategies in the area of drug metabolism for improving PK/PD and safety profiles of drug candidates; these include, but are not limited to, collaboration with medicinal chemists on structure–activity relationships(SAR) to overcome high clearance, using deuterium replacement to further optimize a lead, prodrug approaches to circumvent formulation and delivery difficulties, and addressing issues such as species differences in metabolism,drug–drug interactions(DDI) and formation of reactive metabolites.

关键词： Bioactivation Drug discovery and development Drug metabolism Metabolite Pharmacokinetics pharmacodynamics Safety Toxicity

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Photosafety testing of dermally-applied chemicals based on photochemical and cassette-dosing pharmacokinetic data

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Asian Journal of Pharmaceutical Sciences 2016年第1期11卷 237-238页

作者： Hiroto Ohtake Yukiko Suzuki Masashi Kato Yoshiki Seto Satomi Onoue department of Pharmacokinetics and pharmacodynamics School of Pharmaceutical Sciences University of Shizuoka

Drug-induced phototoxicity is elicited by exposure of skin and/or eyes to topical or systemic administration of chemicals,followed by exposure to *** photosafety testing,a new screening strategy,employing in vitro photochemical/photobiological and in vivo cassette-dosing pharmacokinetic(PK)studies,was proposed[1,2].The screening system provided reliable phototoxic predictions of tested chemicals at least within the same chemical series;however,the applicability of the proposed strategy is not fully understood.

关键词： Photosafety assessment Phototoxicity Photoreactivity Pharmacokinetics

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NANOG Alleviates the Damage of Human Hair Follicle Mesenchymal Stem Cells Caused by H_2O_2 through Activation of AKT Pathway

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Biomedical and Environmental Sciences 2019年第4期32卷 272-280页

作者： SHI Jia Hong ZUO Kui Yang ZHANG Ying Yao WANG Bo HAN Xing LIAN Ao Bo LIU Jin Yu department of toxicology School of Public HealthJilin University

Objective To explore the protective effect of NANOG against hydrogen peroxide(H_2O_2)-induced cell damage in the human hair follicle mesenchymal stem cells(hHF-MSCs). Methods NANOG was expressed from a lentiviral vector, pLVX-IRES-ZsGreen. NANOG hHF-MSCs and vector hHF-MSCs were treated with 400 μmol/L hydrogen peroxide(H_2O_2) for 2 h, the cell survival rate, cell morphology, ROS production, apoptosis and expression of AKT, ERK, and p21 were determined and compared. Results Our results showed that NANOG could activate AKT and upregulate the expression of p-AKT, but not p-ERK. When treated with 400 μmol/L H_2O_2, NANOG hHF-MSCs showed higher cell survival rate, lower ROS production and apoptosis, higher expression of p-AKT, higher ratio of p-AKT/AKT. Conclusion Our results suggest that NANOG could protect hHF-MSCs against cell damage caused by H_2O_2 through activating AKT signaling pathway.

关键词： NANOG homeobox protein Hair follicles Mesenchymal stem cells Hydrogen peroxide AKT

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Polysaccharides from Tricholoma matsutake and Lentinus edodes enhance 5-fluorouracil-mediated H22 cell growth inhibition

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Journal of Traditional Chinese Medicine 2014年第3期34卷 309-316页

作者： Ming Ren Lingyan Ye Xiaoshi Hao Zhixing Ren Shuping Ren Kun Xu Juan Li department of toxicology School of Public Health Jilin University

OBJECTIVE： Few studies have investigated the ef- fects produced by combinations of polysaccharides and chemotherapeutic drugs in cancer treatment. We hypothesized that a combination of polysaccha- rides （COP） from Lentinus edodes and Tricholoma matsutake would improve the efficacy of 5-fluoro- uracil （5-FU）-mediated inhibition of H22 cell growth. METHODS： Mice were injected H22 cells and then treated with either 5-FU, polysaccharides from Tri- choloma matsutake （PTM）, polysaccharides from Lentinus edodes （PL）, PTM ＋ PL, 5-FU ＋ PTM, 5-FU ＋ PL, or 5-FU ＋ COR The tumor weight and volume, and splenic CD4 ＋ and CD8 ＋ T cell frequencies, were determined. Additionally, splenic natural killer （NK） cell and cytotoxic T lymphocyte （CTL） activities were assessed and the serum levels of tumor necro- sis factor-a （TNF-a）, Interleukin-2 （IL-2）, and Interfer- on-y （IFN-y） were measured. RESULTS： Compared with mice from the control,5-FU, PL, PTM, PTM ＋ PL, 5-FU ＋ PL, and 5-FU ＋ PTM groups, mice treated with 5-FU ＋ COP showed：（a） significantly reduced tumor weight and volume （P〈 0.05）, （b） significantly higher serum levels of TNF-α, IL-2, and IFN-y （P〈0.05）, （c） significantly increased CD4＋ and CD8＋ 1 cell frequencies in the spleen （P〈 0.05）, and （d） significantly increased splenic NK cell and CTL activities （P〈0.05）. The tumor weight and volume in mice treated with 5-FU＋PL or 5-FU＋PTM were significantly reduced compared with mice treated with 5-FU alone （P〈0.05）. Serum levels of TNF-α, 11.-2, and IFN-y, frequencies of CD4 ＋ and CD8＋ T cells in the spleen, and splenic NK and CTL activities were also significantly increased in mice treated with 5-FU＋PL or 5-FU＋PTM compared with mice treated with 5-FU alone （P〈0.05）. CONCLUSION： Polysaccharides from Lentinus edodes and Tricholoma matsutake could enhance the efficacy of 5-FU-mediated H22 cell growth inhi- bition.

关键词： Polysaccharides Immunomodulation Shiitake mushrooms Tricholoma matsutake Fluoro-uracil Growth inhibitors

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Effect of extract of Abrus precatorius on blood glucose concentration of alloxan induced diabetic Albino Wistar Rats

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Asian Pacific Journal of Tropical Medicine 2009年第6期2卷 16-17页

作者： Georgewill OA Georgewill UO department of Pharmacology and toxicology

Objective:To evaluate the effect of extract of Abrus precatorius on blood glucose of alloxan induced albino wistar ***:Experimental animals received daily oral administration of extract of Abrus precatorius for 14 *** effect of 200 mg/kg dose was studied during the treatment ***:There was a significant reduction in blood glucose concentration(P < 0.05) with the mean blood glucose of the different groups as 5.0±0.3 for normal control,7.0±0.4 for diabetic control group and 4.0±0.2 for diabetic treated group. Conclusion:The findings of this study suggest that extract of Abrus precatorius has hypoglycemic effect.

关键词： Abrus precatorius Hypoglycemia Diabetes Hyperglycemia

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PBPK modeling and simulation in drug research and development

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Acta Pharmaceutica Sinica B 2016年第5期6卷 430-440页

作者： Xiaomei Zhuang Chuang Lu State Key Laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology department of DMPK BiogenInc.

Physiologically based pharmacokinetic(PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical *** can also explore the effects of various physiologic parameters such as age,ethnicity,or disease status on human pharmacokinetics,as well as guide dose and dose regiment selection and aid drug–drug interaction risk *** modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry,and has become an integral tool in drug discovery and *** this mini-review,the concept and methodology of PBPK modeling are briefly *** case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and *** case studies are from our own work and the literature for better understanding of the absorption,distribution,metabolism and excretion(ADME) of a drug candidate,and the applications to increase efficiency,reduce the need for animal studies,and perhaps to replace clinical *** regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

关键词： PBPK PK prediction Absorption Metabolism Drug–drug interaction Special population

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