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Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology:Implications for Alzheimer's disease therapy

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1707-1722页

作者： Chuanbin Yang Chengfu Su Ashok Iyaswamy Senthil Kumar Krishnamoorthi Zhou Zhu Sichang Yang Benjamin Chunkit Tong Jia Liu Sravan G.Sreenivasmurthy Xinjie Guan Yuxuan Kan Aston Jiaxi Wu alexis shiying huang Jieqiong Tan Kingho Cheung Juxian Song Min Li Mr.&Mrs.Ko Chi-Ming Centre for Parkinson’s Disease Research School of Chinese MedicineHong Kong Baptist UniversityHong Kong SARChina Department of Geriatrics Shenzhen People’s Hospital(the Second Clinical Medical CollegeJinan Universitythe First Affiliated HospitalSouthern University of Science and Technology)Shenzhen 518020China Institute for Research and Continuing Education Hong Kong Baptist UniversityShenzhen 518057China College of Pharmacy Henan University of Chinese MedicineZhengzhou 450000China Center for Medical Genetics and Hunan Key Laboratory of Animal Model for Human Diseases School of Life SciencesCentral South UniversityChangsha 410078China Medical College of Acupuncture-Moxibustion and Rehabilitation Guangzhou University of Chinese MedicineGuangzhou 510632China

Alzheimer's disease(AD),characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates,is the most common neurodegenerative disorder with limited therapeutic agents.Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates,and transcription factor EB(TFEB)is a master regulator of autophagy and lysosomal biogenesis.Thus,small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy.Here,we found that celastrol,an active ingredient isolated from the root extracts of Tripterygium wilfordii(Lei Gong Teng in Chinese)enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains.Importantly,celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice,two commonly used AD animal models.Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol.Overall,our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models.Therefore,Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.

关键词： TFEB Autophagy Lysosome biogenesis Alzheimer’s disease(AD) Tau Celastrol mTOR Therapeutic target

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Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts

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Journal of Genetics and Genomics 2024年第2期51卷 222-229页

作者： Wenbin huang shiying Zhang Jiuxiang Lin Yi Ding Nan Jiang Jieni Zhang Huaxiang Zhao Feng Chen Department of Orthodontics Peking University School and Hospital of StomatologyBeijing100081China Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research College of StomatologyXi’an Jiaotong UniversityXi’anShaanxi710004China Guangdong Provincial High-level Clinical Key Specialty Guangdong Province Engineering Research Center of Oral Disease Diagnosis and TreatmentDepartment of OrthodonticsStomatological CenterPeking University Shenzhen HospitalShenzhen Peking University-The Hong Kong University of Science and Technology Medical CenterShenzhenGuangdong 518036China Department of Physiology and Pathophysiology School of Basic Medical SciencesXi'an Jiaotong UniversityXi'anShaanxi710049China National Center for Stomatology National Clinical Research Center for Oral DiseasesNational Engineering Laboratory for Digital and Material Technology of StomatologyBeijing Key Laboratory for Digital StomatologyResearch Center of Engineering and Technology for Computerized Dentistry Ministry of HealthNMPA Key Laboratory for Dental MaterialsBeijing100101China Central Laboratory Peking University School and Hospital of StomatologyBeijing100081China

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb^(−/−) embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.

关键词： Or ofacial clefts FLNB Loss-of-function mutati on Cleft palate Filamin B Actin flannent Knockout mouse

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Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease

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中华医学杂志(英文版) 2024年第10期137卷 1207-1217页

作者： Pan Tianzhong Ding Peng huang Aijie Tang Baolin Song Kaidi Sun Guangyu Wu Yue Yang shiying Chen Xingchi Wang Dongyao Zhu Xiaoyu Department of Hematology The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China Anhui Provincial Key Laboratory of Blood Research and Applications Hefei Anhui China Blood and Cell Therapy Institute Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China

Background: With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation (UCBT), the correlation between immune reconstitution (IR) after UCBT and graft-versus-host disease (GVHD) has been reported successively, but reports on double-negative T (DNT) cell reconstitution and its association with acute GVHD (aGVHD) after UCBT are lacking.Methods: A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology, the First Affiliated Hospital of USTC, between August 2018 and June 2021. IR differences were compared between the patients with and without aGVHD.Results: The absolute number of DNT cells in the healthy Chinese population was 109 (70-157)/μL, accounting for 5.82 (3.98-8.19)% of lymphocytes. DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation. Importantly, the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year (F = 4.684,P = 0.039 andF = 5.583,P = 0.026, respectively). In addition, the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased, and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD (HR = 0.46, 95% confidence interval [CI]: 0.23-0.93;P = 0.031).Conclusions: Compared to the number of DNT cells in Chinese healthy people, the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow. In addition, the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.

关键词： Umbilical cord blood transplantation Graft-versus-host disease Immune reconstitution Double negative T Hematological Malignancies Treg cell Breg cell

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Natural variation of an autophagy-family gene among rice subspecies affects grain size and weight

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The Crop Journal 2024年第1期12卷 121-132页

作者： shiying huang Peng Wang Caijing Li Qingwen Zhou Tao huang Yicong Cai Qin Cheng Hui Wang Qi Zhong Zhihao Chen Liping Chen Haohua He Jianmin Bian Key Laboratory of Crop Physiology Ecology and Genetic BreedingMinistry of Education.Jiangxi Agricultural UniversityNanchang 330045JiangxiChina Weill Cornell Medical Immunology and Microbiology1300 York AvenueBox 62New YorkNY 10065USA

Elucidating the genetic basis of natural variation in grain size and weight among rice varieties can help breeders develop high-yielding varieties.We identified a novel gene,GW3a(Grain Weight 3a)(LOC_Os03g27350),that affects rice grain size and weight.gw3a mutants showed higher total starch content and dry matter accumulation than the wild type(WT),Nipponbare,suggesting that GW3a negatively regulates grain size and weight.Moreover,our study found that GW3a interacted with OsATG8 by cleaving it,suggesting that GW3a may be involved in the assembly of autophagosomes and starch degradation in plants.The haplotype analysis of GW3a showed functional differences between indica and japonica rice.Taken together,we conclude that GW3a is expressed in the autophagosome pathway regulating starch metabolism in rice,affecting yield-related traits,such as grain size,grain weight and thousand grain weight(TGW).Our findings also shed new light on autophagy-mediated yield trait regulation,proposing a possible strategy for the genetic improvement of high-yield germplasm in rice.

关键词： Grain size GW3a Autophagy Starch content

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Identification and characterization of chemical constituents in Mahuang Guizhi Decoction and their metabolites in rat plasma and brain by UPLC-Q-TOF/MS

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Chinese Herbal Medicines 2024年第3期16卷 466-480页

作者： Ping Wei shiying huang Juan Yang Mo Zhao Qiugu Chen Xiaoyu Deng Jianping Chen Yisheng Li Pingshan District Maternal & Child Healthcare Hospital of Shenzhen Pingshan General Hospital of Southern Medical University Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation Shenzhen Traditional Chinese Medicine HospitalThe Fourth Clinical Medical College of Guangzhou University of Chinese Medicine Shenzhen Longgang Otorhinolaryngology Hospital

Objective:Mahuang Guizhi Decoction(MGD),an essential herbal pair in traditional Chinese medicine,is able to release cold,fever and asthma,mainly containing alkaloids,flavonoids,phenylpropanoids and amino acids.However,the absorption and distribution of these four category compounds in vivo still remained unclearly.Methods:In our research,we utilized UPLC-Q-TOF-MS technique to identify the constituents within MGD,as well as the prototypes of MGD and their metabolites absorbed in plasma and brain.We further profiled the drug-time curve of prototypes and metabolites of MGD both in plasma and brain.Results:Our results showed that 105 constituents were characterized in MGD.Thirty of them could be absorbed into blood,and ten of them could be distributed into brain.We also discovered eight new bio-transformed metabolites in blood,and a half of which could pass through the blood-brain barrier.In addition,all components detected in vivo could be absorbed and distributed immediately.Conclusion:These findings provide an approachable method to analyze the potential bio-active compounds in MGD and their in vivo behaviors,which could promote the efficacious material basis study of MGD and the security of clinical utilization.

关键词： chemical constituents Mahuag Guizhi Decoction metabolites rat plasma and brain UPLC-Q-TOF-MS

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Multimodality management for chronic subdural hematoma in China: protocol and characteristics of an ambidirectional, nationwide, multicenter registry study

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中华神经外科杂志(英文) 2024年第2期10卷 1-10页

作者： Liu Tao Zhao Zhihao huang Jinhao Zhu Xide Chen Weiliang Lin Kun Yu Yunhu Li Zhanying Fan Yibing Liu Mingqi Nie Meng Liu Xuanhui Gao Chuang Quan Wei Qian Yu Wu Chenrui Yuan Jiangyuan Wu Di Lv Chuanxiang Dong shiying Mi Liang Tian Yu Tian Ye Zhang Jianning Jiang Rongcai Department of Neurosurgery Tianjin Medical University General Hospital Tianjin China Ministry of Education Tianjin Neurological Institute Key Laboratory of Post Neuro-injury Neuro-repair and Regeneration in Central Nervous System Tianjin Medical University General Hospital Tianjin China Department of Neurosurgery Linyi People’s Hospital Shandong China Department of Neurosurgery Haining People’s Hospital Zhejiang China Department of Neurosurgery Fujian Provincial Hospital Fujian China Department of Clinical Research Center for Neurological Disease the People’s Hospital of HongHuaGang District of ZunYi Guizhou China Department of Neurosurgery Kailuan General Hospital Hebei China Department of Neurosurgery Tianjin First Central Hospital Tianjin China Department of Neurosurgery The First Hospital of Jilin University Changchun China

Background Despite its prevalence, there is ongoing debate regarding the optimal management strategy for chronic subdural hematoma (CSDH), reflecting the variability in clinical presentation and treatment outcomes. This ambidirectional, nationwide, multicenter registry study aims to assess the efficacy and safety of multimodality treatment approaches for CSDH in the Chinese population.Methods/design A multicenter cohort of CSDH patients from 59 participating hospitals in mainland China was enrolled in this study. The treatment modalities encompassed a range of options and baseline demographics, clinical characteristics, radiographic findings, and surgical techniques were documented. Clinical outcomes, including hematoma resolution, recurrence rates, neurological status, and complications, were assessed at regular intervals during treatment, 3 months, 6 months, 1 year, and 2 years follow-up.Result Between March 2022 and August 2023, a comprehensive cohort comprising 2173 individuals who met the criterion was assembled across 59 participating clinical sites. Of those patients, 81.1% were male, exhibiting an average age of 70.12 ± 14.53 years. A historical record of trauma was documented in 48.0% of cases, while headache constituted the predominant clinical presentation in 58.1% of patients. The foremost surgical modality employed was the burr hole (61.3%), with conservative management accounting for 25.6% of cases. Notably, a favorable clinical prognosis was observed in 88.9% of CSDH patients at 3 months, and the recurrence rate was found to be 2.4%.Conclusion This registry study provides critical insights into the multimodality treatment of CSDH in China, offering a foundation for advancing clinical practices, optimizing patient management, and ultimately, improving the quality of life for individuals suffering from this challenging neurosurgical condition.Trial registration ChiCTR2200057179

关键词： Chronic subdural hematoma Multimodality therapy Outcome Recurrence

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传统髹漆工艺在革制品中的应用探究

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皮革科学与工程 2024年第1期34卷 114-118页

作者：陈崟江诗颖黄少青泉州师范学院福建泉州362000 泉州职业技术大学福建泉州362000

髹漆工艺是古老的中华传统文化手艺,兼具独特的艺术价值及文化价值。文章通过介绍髹漆工艺技法及特点,从髹漆工艺在革制品设计应用中所涉及的技法、形态、局限性等方面综合考量,阐述二者相结合的可能性与操作方法,探索传统髹漆工艺在当... 详细信息

髹漆工艺是古老的中华传统文化手艺,兼具独特的艺术价值及文化价值。文章通过介绍髹漆工艺技法及特点,从髹漆工艺在革制品设计应用中所涉及的技法、形态、局限性等方面综合考量,阐述二者相结合的可能性与操作方法,探索传统髹漆工艺在当代可创新应用的发展方向,以期为传统髹漆工艺与革制品设计结合提供参考,挖掘新的发展道路,促进传统手工艺市场化、艺术化和生态化转型。

关键词：髹漆工艺革制品传统手工艺漆艺

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自贡地区不同年龄阶段妊娠早期妇女甲状腺功能指标参考区间的建立

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暨南大学学报（自然科学与医学版） 2024年第1期45卷 71-76页

作者：黄世莹付玉刘伟平自贡市第一人民医院检验科四川自贡643000

目的:采用间接法建立四川自贡地区健康妊娠早期妇女不同年龄阶段甲状腺激素测定的参考区间,为临床诊断和治疗提供依据。方法:选取自贡市第一人民医院妇产科建档的2019年1月至2021年12月健康妊娠早期妇女的数据,共1518例。根据孕妇年龄分... 详细信息

目的:采用间接法建立四川自贡地区健康妊娠早期妇女不同年龄阶段甲状腺激素测定的参考区间,为临床诊断和治疗提供依据。方法:选取自贡市第一人民医院妇产科建档的2019年1月至2021年12月健康妊娠早期妇女的数据,共1518例。根据孕妇年龄分为A组(34岁)3组,以2.5%至97.5%的百分位点数所在区域作为参考区间。对3个年龄阶段目标人群的促甲状腺激素(TSH)、总三碘甲状腺原氨酸(TT3)、总甲状腺素(TT4)、血清游离三碘甲状腺原氨酸(FT3)和血清游离甲状腺素(FT4)这5项甲状腺激素数据进行统计分析。结果:不同年龄妊娠早期妇女的TSH、FT3和FT4这3项指标之间无统计学差异,3组年龄合并的参考区间分别为TSH(0.12~3.81 mIU/L)、FT3(2.20~5.03 pmol/L)、FT4(4.79~16.13 pmol/L);不同年龄的TT3、TT4水平有统计学差异,其中年龄小于26岁的妊娠早期妇女的TT3、TT4的参考区间分别为1.04~2.78 nmol/L和91.80~204.88 nmol/L,而年龄大于26岁的妊娠早期妇女的TT3、TT4的参考区间分别为1.04~2.55 nmol/L和82.70~190.00 nmol/L。各指标年龄组A、B、C组与非妊娠组比较,差异均有统计学意义(P<0.05)。结论:建立的自贡地区不同年龄阶段妊娠早期妇女甲状腺激素5项指标参考区间,可为临床疾病诊断、治疗和预后判断提供参考。

关键词：促甲状腺激素甲状腺激素妊娠期妇女参考区间间接法

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涉农高职院校乡村振兴人才培养质量评价中存在的问题与对策——湖南省为例

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南方农机 2024年第6期55卷 179-182页

作者：黄仕英长沙商贸旅游职业技术学院湖南长沙410116

随着乡村振兴战略的全面推进,涉农高职院校在培养乡村振兴人才方面扮演着重要角色。然而,现阶段一些涉农高职院校在乡村振兴人才培养过程中还存在不足,导致乡村振兴人才培养效率不高,质量无法得到保障。基于此,笔者以湖南省为例,通过对... 详细信息

随着乡村振兴战略的全面推进,涉农高职院校在培养乡村振兴人才方面扮演着重要角色。然而,现阶段一些涉农高职院校在乡村振兴人才培养过程中还存在不足,导致乡村振兴人才培养效率不高,质量无法得到保障。基于此,笔者以湖南省为例,通过对湖南省目前涉农高职院校师资质量、培养过程质量、在校生质量和毕业生质量等多个维度进行剖析后,提出应进一步完善涉农高职院校乡村振兴人才培养质量评价体系,涉农高职院校乡村振兴人才培养质量评价体系要从教师培训与实践经验、培养目标的设立及产教融合、多维度评估学生综合素质、毕业生跟踪服务等方面设计更加合理的质量评价指标,以提高涉农高职院校人才培养质量,为乡村振兴战略贡献力量。

关键词：涉农高职院校乡村振兴人才培养

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典型钢铁冶炼场地重金属污染空间分布特征及风险评价

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环境污染与防治 2024年第1期46卷 104-110页

作者：黄波涛钱诗颖叶文娟上海市环境科学研究院上海200233

以上海某关停钢铁冶炼厂为研究对象,结合专业判断布点法与系统布点法布设83个土壤点位,采集表、中、深层共249个土壤样品,分析As、Pb、Cd、Ni、Hg、Cu这6种重金属的分布特征、污染状况、潜在生态风险及健康风险。结果表明,As、Pb出现部... 详细信息

以上海某关停钢铁冶炼厂为研究对象,结合专业判断布点法与系统布点法布设83个土壤点位,采集表、中、深层共249个土壤样品,分析As、Pb、Cd、Ni、Hg、Cu这6种重金属的分布特征、污染状况、潜在生态风险及健康风险。结果表明,As、Pb出现部分样品超标,Cd、Pb为强变异,其他重金属变异程度中等;重金属平均含量在垂向上呈现自上而下逐渐降低的趋势,且最高值均分布在表层,累积区域主要为扒渣厂房、钢渣处理区和废钢配料间;地累积指数评价结果显示,Cd和Pb的污染相对较为严重,重污染及以上的样品比例分别为8.43%、3.61%。潜在生态风险评价结果显示,场地整体的生态风险较高,Cd为主要贡献因子,较强风险及以上的样品占比高达51.81%;人体健康风险评价结果显示,Pb、As和Cd可能对人体产生一定的健康风险,因此有必要开展土壤的风险管控或修复以保证场地的再开发利用。

关键词：钢铁冶炼场地重金属污染空间分布生态风险健康风险评价

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