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Gene therapy for monogenic disorders: challenges, strategies, and perspectives

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Journal of Genetics and Genomics 2024年第2期51卷 133-143页

作者： Yi Zhang zhi-Ying wu Department of Medical Genetics and Center for Rare Diseases Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Department of Neurology Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Key Laboratory of Medical Neurobiology of Zhejiang Province HangzhouZhejiang 310009China

Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.

关键词： Gene therapy Monogenic diseases Geneediting Genedelivery Challenges

The physiological role of the unfolded protein response in the nervous system

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Neural Regeneration Research 2024年第11期19卷 2411-2420页

作者： Shuangchan wu Wensheng lin Department of Neuroscience University of MinnesotaMinneapolisMNUSA Institute for Translational Neuroscience University of MinnesotaMinneapolisMNUSA

The unfolded protein response(UPR)is a cellular stress response pathway activated when the endoplasmic reticulum,a crucial organelle for protein folding and modification,encounters an accumulation of unfolded or misfolded proteins.The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity,reducing protein biosynthesis,and promoting protein degradation.It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress.Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system.Here,we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions,and highlight the critical role of the UPR in brain development,memory storage,retinal cone development,myelination,and maintenance of myelin thickness.

关键词： myelin neuron oligodendrocyte Schwann cell unfolded protein response

Study of primordial deuterium abundance in Big Bang nucleosynthesis

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Nuclear Science and Techniques 2024年第3期35卷 208-215页

作者： zhi-lin Shen Jian-Jun He Key Laboratory of Beam Technology of Ministry of Education College of Nuclear Science and TechnologyBeijing Normal UniversityBeijing 100875China Institute of Radiation Technology Beijing Academy of Science and TechnologyBeijing 100875China

Big Bang nucleosynthesis(BBN)theory predicts the primordial abundances of the light elements^(2) H(referred to as deuterium,or D for short),^(3)He,^(4)He,and^(7) Li produced in the early universe.Among these,deuterium,the first nuclide produced by BBN,is a key primordial material for subsequent reactions.To date,the uncertainty in predicted deuterium abundance(D/H)remains larger than the observational precision.In this study,the Monte Carlo simulation code PRIMAT was used to investigate the sensitivity of 11 important BBN reactions to deuterium abundance.We found that the reaction rate uncertainties of the four reactions d(d,n)^(3)He,d(d,p)t,d(p,γ)^(3)He,and p(n,γ)d had the largest influence on the calculated D/H uncertainty.Currently,the calculated D/H uncertainty cannot reach observational precision even with the recent LUNA precise d(p,γ)^(3) He rate.From the nuclear physics aspect,there is still room to largely reduce the reaction-rate uncertainties;hence,further measurements of the important reactions involved in BBN are still necessary.A photodisintegration experiment will be conducted at the Shanghai Laser Electron Gamma Source Facility to precisely study the deuterium production reaction of p(n,γ)d.

关键词： Big Bang nucleosynthesis Abundance of deuterium Reaction cross section Reaction rate Monte Carlo method

Anesthesia,Anesthetics,and Postoperative Cognitive Dysfunction in Elderly Patients

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Current Medical Science 2024年第2期44卷 291-297页

作者： Hong-yu ZHU Jian-li YAN Min ZHANG Tian-yun XU Chen CHEN zhi-lin wu Department of Anesthesiology Linhe District People's HospitalBayannur 015000China Department of Neurosurgery Xinzhou District People's HospitalWuhan 430408China Department of Anesthesiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

Postoperative cognitive dysfunction(POCD)remains a major issue that worsens the prognosis of elderly surgery patients.This article reviews the current research on the effect of different anesthesia methods and commonly utilized anesthetics on the incidence of POCD in elderly patients,aiming to provide an understanding of the underlying mechanisms contributing to this condition and facilitate the development of more reasonable anesthesia protocols,ultimately reducing the incidence of POCD in elderly surgery patients.

关键词： anesthesia anesthetics postoperative cognitive dysfunction elderly patients

Advances in MET tyrosine kinase inhibitors in gastric cancer

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Cancer Biology & Medicine 2024年第6期21卷 484-498页

作者： Yifan Zhang lin Shen zhi Peng Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Department of Gastrointestinal Oncology Peking University Cancer Hospital & Institute State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Department of Gastrointestinal Oncology Peking University Cancer Hospital & Institute

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics, the management of gastric cancer calls for better-defined, biomarker-guided, molecular-based treatment strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types, including gastric cancer, and is associated with poor patient outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib, tepotinib, capmatinib, and crizotinib. Building on current knowledge, this review further discusses existing challenges in MET alterations testing, possible resistance mechanisms to MET inhibitors, and future directions of MET-targeting therapies.

关键词： Gastric cancer MET alterations MET testing MET tyrosine kinase inhibitors savolitinib

New phenylbutenoids and terpene glycosides from Ginkgo biloba leaves

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Chinese Journal of Natural Medicines 2024年第2期22卷 161-170页

作者： SUN Zeshi lin Shan wu zhi-Li DONG Hong-Yuan XU Xi-Ke LI Hui-Liang WANG Jinxin School of Pharmacy Second Military Medical UniversityShanghai 200433China State Key Laboratory of New Drug and Pharmaceutical Process Shanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 201203China

Our continued works on the chemical constituents of Ginkgo biloba(G.biloba)leaves has led to the isolation of two novel phenylbutenoids(1,2),along with five previously unidentified terpene glycosides(3−7).Among them,compounds 1 and 2 represent unique(Z)-phenylbutenoids,3−6 are megastigmane glycosides,and 7 is identified as a rare bilobanone glycoside(Fig.1).This study marks the first reported isolation of phenylbutenoid and bilobanone glycoside from G.biloba.The chemical structures of these compounds were elucidated through extensive spectroscopic analysis,including HR-ESI-MS and various 1D and 2D NMR experiments.Furthermore,the absolute configurations of these molecules were determined using Mosher’s method,ECD experiments,and Cu-KαX-ray crystallographic analyses.

关键词： Ginkgo biloba Phenylbutenoid Megastigmane glycoside Bilobanone glycoside

First-line immunotherapy for advanced non-small cell lung cancer:current progress and future prospects

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Cancer Biology & Medicine 2024年第2期21卷 117-124页

作者： Jingyi Wang lin wu The Second Department of Thoracic Oncology Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China Xiangya Lung Cancer Center Xiangya HospitalCentral South UniversityChangsha 410008China

Global Cancer Statistics 2022 reported the prevalence and high mortality rate of lung cancer.Notably,non-small cell lung cancer(NSCLC)accounts for the majority of the histologic types1.Precision therapy for lung cancer has progressed rapidly and immune checkpoint inhibitors(ICIs)have become a leading research topic.Indeed,ICI therapy has been shown to improve the prognosis of lung cancer patients.

关键词： lung cancer mortality

Auxiliary ball milling to prepare WS_(2)/graphene nanosheets composite for lithium-ion battery anode materials

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Tungsten 2024年第1期6卷 124-133页

作者： Yong-lin wu Jia-Bin Hong Wei-Xu Zhong Chun-Xiang Wang zhi-Feng Li Sydorov Dmytro Jiangxi Provincial Key Laboratory of Power Batteries and Materials Jiangxi University of Science and TechnologyGanzhou 341000China Faculty of Materials Metallurgy and Chemistry Jiangxi University of Science and TechnologyGanzhou 341000China Institute of Bioorganic Chemistry and Petrochemistry National Academy of Sciences of UkraineKiev 02160Ukraine

A novel nano-WS_(2)/graphene nanosheets(GNSs)composite is obtained by ball milling with xylitol as auxiliary agent and hightemperature sintering.Xylitol improves the shear force during ball milling and well overcomes the van der Waals interactions between the interlayer of graphite and WS_(2).Through high-temperature calcination,GNSs and WS_(2) nanosheets can form tight interface contact.The produced WS_(2)/GNSs composites can be used as anode materials for lithium-ion batteries,while maintaining a high reversible specific capacity of 705 mAh·g^(-1)with the capacity retention of 95%at a current density of 250 mA·g^(-1)after 200 cycles,mainly because WS_(2)/GNSs composites have a higher Li^(+)diffusion coefficient of 2.2×10^(-9)cm^(2)·s^(-1)and a higher specific surface area of 70.10 m^(2)·g^(-1).As a result,the xylitol-assisted ball milling method designed in this work is suitable for extended preparation of peeling of two-dimensional layer materials into nanosheets.

关键词： Lithium-ion battery Anode material WS_(2) Graphene nanosheets Auxiliary ball milling

Polysaccharide of Alocasia cucullata Exerts Antitumor Effect by Regulating Bcl-2, Caspase-3 and ERK1/2 Expressions during Long-Time Administration

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Chinese Journal of Integrative Medicine 2024年第1期30卷 52-61页

作者： ZHOU Qi-chun XIAO Shi-lin lin Ru-kun LI Chan CHEN zhi-jie CHEN Yi-fei LUO Chao-hua MO zhi-xian lin Ying-bo School of Traditional Chinese Medicine Southern Medical UniversityGuangzhou(510515)China Clinical and Basic Research Team of TCM Prevention and Treatment of Non-Small Cell Lung Cancer the Second Clinical College of Guangzhou University of Chinese MedicineGuangzhou(510120)China Department of Chinese Medicine Zhujiang Hospital Affiliated to Southern Medical UniversityGuangzhou(510282)China Department of Pharmacy Jiangmen Central HospitalJiangmen(529000)China

Objective: To study the in vitro and in vivo antitumor effects of the polysaccharide of Alocasia cucullata(PAC) and the underlying mechanism. Methods: B16F10 and 4T1 cells were cultured with PAC of 40 μg/m L, and PAC was withdrawn after 40 days of administration. The cell viability was detected by cell counting kit-8. The expression of Bcl-2 and Caspase-3 proteins were detected by Western blot and the expressions of ERK1/2 mRNA were detected by quantitative real-time polymerase chain reaction(qRT-PCR). A mouse melanoma model was established to study the effect of PAC during long-time administration. Mice were divided into 3 treatment groups: control group treated with normal saline, positive control group(LNT group) treated with lentinan at 100 mg/(kg·d), and PAC group treated with PAC at 120 mg/(kg·d). The pathological changes of tumor tissues were observed by hematoxylin-eosin staining. The cell apoptosis of tumor tissues was detected by TUNEL staining. Bcl-2 and Caspase-3 protein expressions were detected by immunohistochemistry, and the expressions of ERK1/2, JNK1 and p38 mRNA were detected by qRT-PCR. Results: In vitro, no strong inhibitory effects of PAC were found in various tumor cells after 48 or 72 h of administration. Interestingly however, after 40 days of cultivation under PAC, an inhibitory effect on B16F10 cells was found. Correspondingly, the long-time administration of PAC led to downregulation of Bcl-2 protein(P <0.05), up-regulation of Caspase-3 protein(P<0.05) and ERK1 mRNA(P<0.05) in B16F10 cells. The above results were verified by in vivo experiments. In addition, viability of B16F10 cells under long-time administration culture in vitro decreased after drug withdrawal, and similar results were also observed in 4T1 cells. Conclusions: Long-time administration of PAC can significantly inhibit viability and promote apoptosis of tumor cells, and had obvious antitumor effect in tumor-bearing mice.

关键词： polysaccharide of Alocasia cucullata tumor cells Bcl-2 Caspase-3 ERK1/2 Chinese medicine