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Large animal models for Huntington's disease research

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Zoological Research 2024年第2期45卷 275-283页

作者： Bofeng Han Weien liang xiao-jiang li Shihua li Sen Yan Zhuchi Tu Guangdong-Hongkong-Macao CNS Regeneration Institute of Jinan University Key Laboratory of CNS Regeneration(Jinan University)-Ministry of EducationGuangdong Key Laboratory of Non-Human Primate ResearchGuangzhouGuangdong 510632China Department of Pathophysiology School of MedicineJinan UniversityGuangzhouGuangdong 510632China

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

关键词： Huntington's disease Large animal models Sheep Non-human primates Transgenic pigs

Genetically modified non-human primate models for research on neurodegenerative diseases

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Zoological Research 2024年第2期45卷 263-274页

作者： Ming-Tian Pan Han Zhang xiao-jiang li Xiang-Yu Guo Guangdong Key Laboratory of Non-human Primate Research Guangdong-Hongkong-Macao Institute of CNS RegenerationJinan UniversityGuangzhouGuangdong 510632China

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

关键词： Neurodegeneration Non-human primate Macaque monkey Animal model Gene modification

Comparative analysis of primate and pig cells reveals primate-specific PINK1 expression and phosphorylation

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Zoological Research 2024年第2期45卷 242-252页

作者： Xiu-Sheng Chen Rui Han Yan-Ting liu Wei Huang Qi Wang Xin Xiong Ying Zhang Jian-Guo Zhao Shi-Hua li xiao-jiang li Wei-li Yang Guangdong Key Laboratory of Non-human Primate Research Key Laboratory of CNS Regeneration(Ministry of Education)GHM Institute of CNS RegenerationJinan UniversityGuangzhouGuangdong 510632China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China University of Chinese Academy of Sciences Beijing 100049China

PTEN-induced putative kinase 1(PINK1),a mitochondrial kinase that phosphorylates Parkin and other proteins,plays a crucial role in mitophagy and protection against neurodegeneration.Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson's disease.However,there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration.Additionally,PINK1 knockout pigs(Sus scrofa)do not appear to exhibit neurodegeneration.In our recent work involving non-human primates,we found that PINK1 is selectively expressed in primate brains,while absent in rodent brains.To extend this to other species,we used multiple antibodies to examine the expression of PINK1 in pig tissues.In contrast to tissues from cynomolgus monkeys(Macaca fascicularis),our data did not convincingly demonstrate detectable PINK1expression in pig tissues.Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation,as observed in cultured monkey cells.A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain.Consistently,PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD.These findings provide new evidence that PINK1expression is specific to primates,underscoring the importance of non-human primates in investigating PINK1function and pathology related to PINK1 deficiency.

关键词： PINK1 Parkin Mitochondria Phosphorylation Non-human primates Pigs

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Unconventional Fluorescent and Multi-responsive Polysiloxane:Synthesis,Characterization and Biological Applications

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Chinese Journal of Polymer Science 2024年第5期42卷 579-590,I0006页

作者： xiao-Di li Shu-Sheng li Xu-Bao jiang xiao-li Zhu Xiang Zheng Kong College of Chemistry and Chemical Engineering University of JinanJinan250022China College of Chemical Engineering Tianjin UniversityTianjin300072China Foshan(Southern China)Institute for New Materials Foshan528200China

Owing to their high significance in fundamental study and diverse applications,stimuli-responsive and fluorescent polymers,particularly those with cluster-triggered emission(CTE)featured by non-conjugated chromophores,have drawn tremendous attention in recent years.In this work,fluorescent and multi-responsive polysiloxane(FRPS)was synthesized by hydrolytic condensation polymerization of 3-aminopropyl methyl diethoxysilane(APMS)with 3-(N-isopropyl propionamide)iminopropyl methyl diethoxysilane(APMS-NIP),which was formed in situ through aza-Michael addition between APMS and N-isopropyl acrylamide.FRPS was not only highly sensitive to temperature,pH and CO_(2) in water,but also showed an enhanced and stimuli-adjustable fluorescence emission.The effects of monomer feeding,pH and CO_(2) on its lower critical solution temperature and fluorescent property were investigated.FRPS fluorescence emission was ascribed to CTE mechanism.In addition,FRPS was shown to be highly potential as physiological indicator for cell imaging,and for controlled release and trace detection of doxorubicin.This study provides therefore a type of stimuli-responsive and fluorescent material for potential applications in biomedical fields,and it is also of great significance for understanding of the fluorescence mechanism of polysiloxane-based stimuli-responsive polymers.

关键词： Polysiloxane Multi-responsiveness Cluster-triggered emission Cell imaging Controlled drug release

Effect of Maternal DEHP Exposure on lipid Metabolism in Adult Male Rats and the Antagonistic Effect of Genistein

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Biomedical and Environmental Sciences 2024年第3期37卷 315-319页

作者： ZHANG Yun Bo li jiang li TIAN Jie NA xiao lin Department of Environmental Hygiene Public Health CollegeHarbin Medical UniversityHarbin 150081HeilongjiangChina

lipid metabolism refers to the biochemical processes involved in synthesising,storing,utilising,and breaking down lipids in living organisms.lipids are essential for various physiological functions,including energy storage,insulation,protection of organs,and the formation of cell membranes.Aberrations in lipid metabolism can lead to a number of health issues,such as atherosclerosis,obesity,and type 2 diabetes,etc.[1].Environmental factors,genetics,and lifestyle factors are some of the factors that can contribute to the development of dyslipidemia.Currently,there is a growing academic interest in the impact of environmental factors.

关键词： lipid metabolism organs

Unconventional Fluorescent and Multi-responsive Polyethyleneimine with LCST and UCST Behavior:Synthesis,Characterization and Biological Applications

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Chinese Journal of Polymer Science 2024年第6期42卷 826-837页

作者： Feng-Ming Yin li-li Wu Shu-Sheng li xiao-Na Pan xiao-li Zhu Xu-Bao jiang Xiang Zheng Kong College of Chemistry and Chemical Engineering University of JinanJinan250022China Shandong Institute for Product Quality Inspection Jinan250102China College of Chemical Engineering Tianjin UniversityTianjin300072China

Non-aromatic fluorescent and multi-responsive materials,exhibiting inherent fluorescence emission and controlled phase change,have garnered significant attention in recent years.However,the underlying interaction between their fluorescent properties and phase transition remains unclear.In this study,we synthesized a series of catalyst-free aza-Michael addition-based polyethyleneimine(RFPEI)materials by reacting polyethyleneimine(PEI)with N-isopropyl acrylamide(NIPAM).The resulting RFPEI was comprehensively characterized,and demonstrated dual-phase transition behavior(LCST and UCST)in water,which could be finely tuned by adjusting its composition or external factors such as pH.Notably,upon UV irradiation(365 nm),RFPEI exhibited strong fluorescence emission.We further investigated the effects of NIPAM grafting percentage to PEI,polymer concentration,and pH on the LCST/UCST and fluorescent properties of RFPEI aqueous solutions.Moreover,we showcased the great potential of RFPEI as a versatile tool for physiological cell imaging,trace detection,and controlled release of doxorubicin.Our study presents a novel class of stimuli-responsive fluorescent materials with promising applications in the field of biomedicine.

关键词： Polyethyleneimine Multi-responsiveness Intrinsic fluorescence emission Cell imaging Controlled drug release

Ginsenoside Rd Induces Differentiation of Myeloid Leukemia Cells via Regulating ERK/GSK-3β Signaling Pathway

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Chinese Journal of Integrative Medicine 2024年第7期30卷 588-599页

作者： jiang Yu-xia ZHAO Yan-na YU xiao-ling YIN li-ming Department of Hematology Tongde Hospital of Zhejiang Province Institute of Hematology Research the First Affiliated Hospital of Zhejiang Chinese Medical University(Zhejiang Provincial Hospital of Chinese Medicine)

Objective: To investigate the role of ginsenoside Rd（GRd） in acute myeloid leukemia（AML） cell differentiation. Methods: AML cells were treated with GRd（25, 50, 100 and 200 μg/mL）, retinoic acid（RA, 0.1g/L） and PD98059（20 mg/mL） for 72 h, cell survival was detected by methylthiazolyldiphenyl-tetrazolium bromide and colony formation assays, and cell cycle was detected by flow cytometry. Cell morphology and differentiation were observed by Wright-Giemsa staining, peroxidase chemical staining and cellular immunochemistry assay, respectively. The protein expression levels of GATA binding protein 1（GATA-1）, purine rich Box-1（PU.1）, phosphorylated-extracellular signal-related kinase（p-ERK）, ERK, phosphorylated-glycogen synthase kinase-3β（p-GSK3β）, GSK3β and signal transducer and activator of transcription 1（STAT1） were detected by Western blot. Thirty-six mice were randomly divided into 3 groups using a random number table: model control group（non-treated）, GRd group [treated with 200 mg/（kg·d） GRd] and homoharringtonine（HTT） group [treated with 1 mg/（kg·d） HTT]. A tumor-bearing nude mouse model was established, and tumor weight and volume were recorded. Changes of subcutaneous tumor tissue were observed after hematoxylin and eosin staining. WT1 and GATA-1 expressions were detected by immunohistochemical staining. Results: The cell survival was inhibited by GRd in a dose-dependent manner and GRd caused G0/G1cell arrest（Plicited upregulation of p-ERK, p-GSK-3β and STAT1 expressions in cells, and reversed the effects of PD98059 on inhibiting the expressions of peroxidase, GATA-1 and PU.1（P<0.05）. After GRd treatment, tumor weight and volume of mice were decreased, and tumor cells underwent massive apoptosis and necrosis（P<0.05）. WT1 level was decreased, and GATA-1 level was significantly increased in subcutaneous tumor

关键词： ginsenoside Rd myeloid leukemia survival differentiation extracellular signal-related kinase signaling pathway

Impacts of Water-Sediment Regulation Scheme on Chromophoric Dissolved Organic Matter in the Lower Yellow River

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Journal of Ocean University of China 2024年第2期23卷 455-466页

作者： liU xiao jiang Xueyan liU Qian SUI Juanjuan ZOU li Key Laboratory of Marine Chemistry Theory and Technology of Ministry of Education Ocean University of ChinaQingdao 266100China College of Chemistry and Chemical Engineering Ocean University of ChinaQingdao 266100China School of Earth Sciences University of BristolBristolBS81RJUK North China Sea Environmental Monitoring Center State Oceanic AdministrationQingdao 266033China Key Laboratory of Ecological Prewarning Protection and Restoration of Bohai SeaMinistry of Natural ResourcesQingdao 266033China Key Laboratory of Marine Environment and Ecology of Ministry of Education Ocean University of ChinaQingdao 266100China College of Environmental Science and Engineering Ocean University of ChinaQingdao 266100China

As a river with more than 3000 reservoirs in its watershed,the Yellow River has been affected by dams not only on the sediment load,but also on the water quality.Water-sediment regulation scheme(WSRS),which has been carried out annually in the Yellow River since 2002,is a typical human activity affecting river water quality.Chromophoric dissolved organic matter(CDOM)in river is susceptible to changes in ecological and environmental conditions as well as human activities.Here,we report variations in dissolved organic carbon concentrations,compositions and sources of CDOM in time series samples in the lower Yellow River during WSRS.In addition,a parallel factor fluorescence analysis(PARAFAC)method is applied to identify different fluorescent components in water samples during WRSR,showing four major components including tryptophan-like component(C1),microbial humic-like component(C2),terrestrial humic-like component(C3)and tyrosine-like component(C4).In general,C1 increased after water regulation,while C2 and C3 increased after sediment regulation,indicating that the water and sediment released by the dam have different effects on CDOM compositions.Under the impacts of the dam,source of CDOM in the lower Yellow River is mainly autochthonous related to microbial activities,and is regulated by the terrestrial input during WSRS period.Sediment resuspension inhibits microbial activities and reduces the production of autochthonous CDOM.Overall,human activities especially WSRS,as exemplified here,significantly alter the quality and quantity of CDOM in the lower Yellow River,affecting CDOM dynamics and biogeochemical processes in the estuarine environment.

关键词： chromophoric dissolved organic matter(CDOM) water-sediment regulation scheme(WSRS) Yellow River optical properties

Elemene Antitumor Drugs Development Based on "Molecular Compatibility Theory" and Clinical Application: A Retrospective and Prospective Outlook

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Chinese Journal of Integrative Medicine 2024年第1期30卷 62-74页

作者： jiang xiao-ying SHI li-ping ZHU Jun-long BAI Ren-ren XIE Tian School of Pharmacy Hangzhou Normal UniversityHangzhou(311121)China Key Laboratory of Elemene Class Anti-cancer Chinese Medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhou(311121)China Good Clinical Practice Center Affliliated Hospital of Nanjing University of Chinese MedicineNanjing(210000)China

Elemene, derived from Curcuma wenyujin, one of the "8 famous genuine medicinal materials of Zhejiang province," exhibits remarkable antitumor activity. It has gained wide recognition in clinical practice for effectiveness on tumors. Dr. XIE Tian introduced the innovative concept of "molecular compatibility theory" by combining Chinese medicine principles, specifically the "monarch, minister, assistant, and envoy" theory, with modern biomedical technology. This groundbreaking approach, along with a systematic analysis of Chinese medicine and modern biomedical knowledge, led to the development of elemene nanoliposome formulations. These novel formulations offer numerous advantages, including low toxicity, well-defined composition, synergistic effects on multiple targets, and excellent biocompatibility. Following the principles of the "molecular compatibility theory", further exploration of cancer treatment strategies and methods based on elemene was undertaken. This comprehensive review consolidates the current understanding of elemene's potential antitumor mechanisms, recent clinical investigations, advancements in drug delivery systems, and structural modifications. The ultimate goal of this review is to establish a solid theoretical foundation for researchers, empowering them to develop more effective antitumor drugs based on the principles of "molecular compatibility theory".

关键词： molecular compatibility theory Chinese integrative medicine elemene antitumor activity drug delivery structural modification