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PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1913-1927页

作者： Hsiang-i Tsai Yanping Wu Rui huang Dandan Su Yingyi Wu Xiaoyan Liu Linglu Wang Zhanxue Xu Yuxin Pang Chong Sun Chao He Fan Shu Haitao Zhu Dongqing Wang Fang Cheng laiqiang huang Hongbo Chen School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityShenzhen 518107China Department of Medical Imaging the Affiliated Hospital of Jiangsu UniversityZhenjiang 212001China Department of Hematology Zhujiang HospitalSouthern Medical UniversityGuangzhou 510000China The Shenzhen Key Lab of Gene and Antibody Therapy Center for Biotechnology&BiomedicineDivision of Life and Health SciencesGraduate School at ShenzhenTsinghua UniversityShenzhen 518055China School of Traditional Medicine Materials Resource Guangdong Pharmaceutical UniversityYunfu 527322China Immune Regulation in Cancer German Cancer Research CenterHeidelberg 69120Germany

Mutations in the plant homeodomain-like finger protein 6(PHF6)gene are strongly associated with acute myeloid(AML)and T-cell acute lymphoblastic leukemia(T-ALL).In this study,we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus.The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci,resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription.The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner,thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription.The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci,resulting in an increase in rDNA transcription activity,the proliferation of in vitro leukemia cells,and the growth of in vivo mouse xenografts.Importantly,significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6.The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine,the drug that is most commonly used to treat AML.Collectively,we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia.

关键词： PHF6 SUV39H1 AML rDNA transcription Epigenetic CX5461 Methyltransferase Leukemia

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Raltitrexed as a synergistic hyperthermia chemotherapy drug screened in patient-derived colorectal cancer organoids

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Cancer Biology & Medicine 2021年第3期18卷 750-762页

作者： Lisi Zeng Quanxing Liao Haoran Zhao Shengwei Jiang Xianzi Yang Hongsheng Tang Qingjun He Xiansheng Yang Shuxian Fang Jinfu He Weiwen Cui laiqiang huang Shaohua Ma Shuzhong Cui Institute of Oncology Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou 510095China Department of Abdominal Surgery Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou 510095China Institute of Biopharmaceutical and Health Engineering Shenzhen International Graduate SchoolTsinghua UniversityShenzhen 518055China Tsinghua-Berkeley Shenzhen Institute(TBSI) Tsinghua UniversityShenzhen 518055China Shenzhen Key Laboratory of Gene and Antibody Therapy Tsinghua UniversityShenzhen 518055China Department of Medical Oncology Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou 510095China Department of Bioengineering University of CaliforniaBerkeley 94720USA

Objective:Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer.Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia;validate an index of the hyperthermia chemotherapy sensitization enhancement ratio(HCSER)to identify the chemotherapeutics most enhanced by hyperthermia;and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment.Methods:Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines.Cells from both sources were encapsulated in 3 D Matrigel droplets,which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres.The microspheres were seeded in 96-well plates,with each well containing a single microsphere that developed into an organoid after 7 days.The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37℃ as a control and 43℃ for 90 min to examine hyperthermia synergism.Cell viability was counted with 10%CCK8.Results:We successfully established a library of colorectal cancer organoids from 22 patient parental tumors.We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs.In 11 of the 22 patient organoids,raltitrexed had significant hyperthermia synergism,which was indexed as the highest HCSER score within each patient group.Conclusions:Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics.We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.

关键词： Colorectal cancer organoids hyperthermia chemotherapy sensitization enhancement ratio raltitrexed

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Dcalycinumines A-E,Alkaloids with Cytotoxic Activities of Nasopharyngeal Carcinoma Cells from Daphniphyllum calycinum

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Chinese Journal of Chemistry 2024年第1期42卷 35-42页

作者： Qing Tang Xiao-Yong Dai Qiang Lin Zhi-Peng Ling Yi-Kun Hao Tian-Xi Zhu Ji-Hui Zhang Yi-Bo Hou Yao-Lan Li Lai-Qiang huang Jing-Hao Wang Guo-Cai Wang Yu-Bo Zhang Guangdong Clinical Translational Centerfor Targeted Drug Department of PharmacologySchoolof MedicineJinan University GuangzhouGuangdong 510632China Institute of Traditional Chinese Medicine&Natural Products Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs ResearchCollegeof PharmacyJinan UniversityGuangzhouGuangdong511443China Institute of Biopharmaceutical and Health Engineering Shenzhen Key Laboratory of Gene and Antibody TherapyState Key Laboratory of Chemical OncogenomicsShenzhen International Graduate SchoolTsinghua UniversityShenzhenGuangdong 518055China The Guangzhou Key Laboratoryof Basic and Translational Research on Chronic Disease Department of PharmacyThe First Affiliated HospitalJinan UniversityGuangzhouGuangdong 510630China

Fivenovel Daphniphyllum alkaloids,named dcalycinumines A-E(1-4,6),andeight previously described Daphniphyllum alkaloids(5,7-13)were isolated from Daphniphyllum calycinum.Compound 1 is the first Daphniphyllum alkaloid possessing a highly rearranged 6/6/6/7/5/6 hexacyclic architecture with a unique 3-methyl-1-azabicyclo[4,4,0]decane ring system.Compound 2 represents a rare diamino Daphniphyllum alkaloid with an unprecedented 6/5/5/6/6/5 carbon skeleton featuring a unique 1-aza-6-azaspiro[4,5]decane unit,whereas 3 also represents a rare diamino Daphniphyllum alkaloid as a possible precursor of 2.Compound 4 is the second example of c-22-nor yuzurimine-type alkaloids.Their structures and absolute configurations were elucidated by HRESIMS,NMR spectroscopic analyses,EcD calculations,and single-crystal X-ray diffraction.Moreover,compound 1 showed remarkable antitumor activities,which could inhibit the proliferation,migration and invasion of nasopharyngeal carcinoma cells,and promoted nasopharyngeal carcinoma cells apoptosis.

关键词： Daphniphyllum calycinum Natural products Daphniphyllum alkaloid Structural elucidation Biological activity Apoptosis Nasopharyngealcarcinoma

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Associations of daily sedentary behavior,physical activity,and sleep with irritable bowel syndrome:A prospective analysis of 362,193 participants

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Journal of Sport and Health Science 2024年第1期13卷 72-80页

作者： Xu Gao Sifan Tian Ninghao huang Gang Sun Tao huang Department of Occupational and Environmental Health Sciences School of Public HealthPeking UniversityBeijing 100191China Department of Epidemiology and Biostatistics School of Public HealthPeking UniversityBeijing 100191China Department of Gastroenterology and Hepatology First Medical Center of People's Liberation Army General HospitalBeijing 100853China

Background:Irritable bowel syndrome(IBS)substantially affects quality of life and requires early prevention.This study aimed to elucidate the relationships between IBS and daily behaviors,including sedentary behavior(SB),physical activity(PA),and sleep.In particular,it seeks to identify healthy behaviors to reduce IBS risk,which previous studies have rarely addressed.Methods:Daily behaviors were retrieved from self-reported data of 362,193 eligible UK Biobank participants.Incident cases were determined by self-report or health care data according to RomeⅣcriteria.Results:A total of 345,388 participants were IBS-free at baseline,during a median follow-up of 8.45 years,19,885 incident IBS cases were recorded.When examined individually,SB and shorter(≤7 h/day)or longer(>7 h/day)sleep duration were each positively associated with increased IBS risk,and PA was associated with lower IBS risk.The isotemporal substitution model suggested that replacing SB with other activities could provide further protective effects against IBS risk.Among people sleeping≤7 h/day,replacing 1 h of SB with equivalent light PA,vigorous PA,or sleep was associated with 8.1%(95%confidence interval(95%CI):0.901-0.937),5.8%(95%CI:0.896-0.991),and 9.2%(95%CI:0.885-0.932)reduced IBS risk,respectively.For people sleeping>7 h/day,light and vigorous PA were associated with a 4.8%(95%CI:0.926-0.978)and a 12.0%(95%CI:0.815-0.949)lower IBS risk,respectively.These benefits were mostly independent of genetic risk for IBS.Conclusion:SB and unhealthy sleep duration are risk factors for IBS.A promising way to mitigate IBS risk for individuals sleeping≤7 h/day and for those sleeping>7 h/day appears to be by replacing SB with adequate sleep or vigorous PA,respectively,regardless of the genetic predisposition of IBS.

关键词： Irritable bowel syndrome Isotemporal substitution model Physical activity Sedentary behavior Sleep

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Fast Blood Oxygenation through Hemocompatible Asymmetric Polymer of Intrinsic Microporosity Membranes

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Research 2024年第1期2023卷 261-270页

作者： Xinxi huang Junping huang Pengcheng Su Wanbin Li Guangdong Key Laboratory of Environmental Pollution and Health School of EnvironmentJinan UniversityGuangzhou 511443China

Membrane technology has attracted considerable attention for chemical and medical applications,among others.Artificial organs play important roles in medical science.A membrane oxygenator,also known as artificial lung,can replenish O_(2) and remove CO_(2) of blood to maintain the metabolism of patients with cardiopulmonary failure.However,the membrane,a key component,is subjected to inferior gas transport property,leakage propensity,and insufficient hemocompatibility.In this study,we report efficient blood oxygenation by using an asymmetric nanoporous membrane that is fabricated using the classic nonsolvent-induced phase separation method for polymer of intrinsic microporosity-1.The intrinsic superhydrophobic nanopores and asymmetric configuration endow the membrane with water impermeability and gas ultrapermeability,up to 3,500 and 1,100 gas permeation units for CO_(2) and O_(2),respectively.Moreover,the rational hydrophobic–hydrophilic nature,electronegativity,and smoothness of the surface enable the substantially restricted protein adsorption,platelet adhesion and activation,hemolysis,and thrombosis for the membrane.Importantly,during blood oxygenation,the asymmetric nanoporous membrane shows no thrombus formation and plasma leakage and exhibits fast O_(2) and CO_(2) transport processes with exchange rates of 20 to 60 and 100 to 350 ml m^(−2) min^(−1),respectively,which are 2 to 6 times higher than those of conventional membranes.The concepts reported here offer an alternative route to fabricate high-performance membranes and expand the possibilities of nanoporous materials for membrane-based artificial organs.

关键词： porosity asymmetric Oxygen

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A thermodynamic perspective on electrode poisoning in solid oxide fuel cells

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International Journal of Minerals,Metallurgy and Materials 2024年第6期31卷 1449-1455页

作者： Kevin huang Department of Mechanical Engineering University of South CarolinaColumbiaUSA

A critical challenge to the commercialization of clean and high-efficiency solid oxide fuel cell(SOFC)technology is the insuf-ficient stack lifespan caused by a variety of degradation mechanisms,which are associated with cell components and chemical feedstocks.Cell components related degradation refers to thermal/chemical/electrochemical deterioration of cell materials under operating conditions,whereas the latter regards impurities in feedstocks of oxidant(air)and reductant(fuel).This article provides a thermodynamic perspective on the understanding of the impurities-induced degradation mechanisms in SOFCs.The discussion focuses on using thermodynamic ana-lysis to elucidate poisoning mechanisms in cathodes by impurity species such as Cr,CO_(2),H_(2)O,and SO_(2) and in the anode by species such as S(or H_(2)S),SiO_(2),and P_(2)(or PH_(3)).The author hopes the presented fundamental insights can provide a theoretical foundation for search-ing for better technical solutions to address the critical degradation challenges.

关键词： impurities air fuel reaction activity

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In situ direct reprogramming of astrocytes to neurons via polypyrimidine tract-binding protein 1 knockdown in a mouse model of ischemic stroke

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Neural Regeneration Research 2024年第10期19卷 2240-2248页

作者： Meng Yuan Yao Tang Tianwen huang Lining Ke En huang Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province Fujian Medical UniversityFuzhouFujian ProvinceChina Department of Human Anatomy School of Basic Medical SciencesFujian Medical UniversityFuzhouFujian ProvinceChina Scientific Research Center School of Basic Medical SciencesFujian Medical UniversityFuzhouFujian ProvinceChina Department of Neurology Fujian Medical University Union HospitalFuzhouFujian ProvinceChina Fujian Key Laboratory of Vascular Aging Fujian Medical UniversityFuzhouFujian ProvinceChina

In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.e B-GFAP-sh PTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-sh PTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment.

关键词： astrocyte in situ direct reprogramming ischemic stroke miR-30 based shRNA neuron polypyrimidine tract-binding protein 1 transdifferentiation

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Recurrent malignant hyperthermia after scoliosis correction surgery

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World Journal of Emergency Medicine 2024年第1期15卷 70-72页

作者： Junfeng Su Man huang Department of General Intensive Care Unit the Second Affi liated Hospital of Zhejiang University School of MedicineHangzhou 310052China Key Laboratory of Early Warning and Intervention of Multiple Organ Failure Ministry of Education of the People's Republic of ChinaHangzhou 310052China

Malignant hyperthermia(MH)is a genetic disorder of skeletal muscle cells that affects muscle cytoplasmic calcium homeostasis,with high mortality and low morbidity.Generally,it presents with non-specific signs of a hypermetabolic response,including high fever,tachycardia,and elevated end-tidal carbon dioxide(ETCO_(2)).The successful treatment lies in the timely recognition and early use of dantrolene.[1]As an inhibitor of Ca2+release through ryanodine receptor(RYR)channels,the skeletal muscle relaxant dantrolene has proven to be both a valuable experimental probe of intracellular Ca2+signaling and a lifesaving treatment for MH.[2]Dominant mutations in the skeletal muscle RYR1 gene are well-recognized causes of both malignant hyperthermia susceptibility(MHS)and central core disease(CCD).

关键词： hyperthermia malignant elevated

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Aberrant protamination in sperm correlates to anomalous nuclear and cytoplasmic architectures in infertile males with sperm dysmorphology

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Asian Journal of Andrology 2024年第2期26卷 183-188页

作者： Huan Jiang Chu-Jie huang Department of Reproductive Endocrinology Longgang District Maternity&Child Healthcare Hospital of Shenzhen City(Longgang Maternity and Child Institute of Shantou University Medical College)Shenzhen 518172China Institute of Reproductive Immunology College of Life Science and TechnologyJinan UniversityGuangzhou 510632China

Aberrant sperm protamination is linked to sperm dysmorphology and nuclear chromatin condensation.Yet,its effects on sperm cytoplasmic maturation remain largely unexplored.The relationships of protamines,sperm morphology,DNA damage,and cytoplasmic remodeling were illustrated in this study to provide fresh perspectives on the mechanisms of male infertility.A total of 205 infertile males were allocated into 5 groups according to the percentage of spermatozoa exhibiting abnormal morphology within their samples.Sperm concentration,motility,abnormal sperm morphology,cytoplasmic droplets(CDs),and excess residual cytoplasm(ERC)were analyzed according to the World Health Organization manual(2010).Sperm nuclear vacuoles(NVs)were determined by propidium iodide(PI)staining.Sperm protamine expressions(P1 and P2)were detected by western blot.DNA damage was measured by acridine orange test(AOT)to calculate the proportion of sperm with single-strand DNA breaks(SSBs).Our data showed that sperm concentration and motility in infertile males significantly decreased with the severity of abnormal sperm morphology(both P<0.01).P1 level,P1/P2 ratio,and SSB rate increased with the severity of sperm dysmorphology,whilst the P2 level decreased(all P

关键词： abnormal sperm morphology excess residual cytoplasm male infertility protamines sperm DNA damage sperm nuclear vacuoles

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Mechanism of acupuncture in attenuating cerebral ischaemia-reperfusion injury based on nuclear receptor coactivator 4 mediated ferritinophagy

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Journal of Traditional Chinese Medicine 2024年第2期44卷 345-352页

作者： ZHANG Xinchang huang Zheng huang Peiyan YANG Mengning ZHANG Zhihui NI Guangxia College of Acupuncture-Moxibustion and Tuina Nanjing University of Chinese MedicineNanjing 210023China Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese MedicineNanjing 210023China

OBJECTIVE:To explore the effect of acupuncture treatment on cerebral ischaemia-reperfusion injury(CIRI)and reveal the underlying mechanism of the effect based on nuclear receptor coactivator 4(NCOA4)mediated ferritinophagy.METHODS:Sprague-Dawley male rats were divided into four groups:the sham group,model group,acupuncture group,and sham acupuncture group.After 2 h of middle cerebral artery occlusion(MCAO),reperfusion was performed for 24 h to induce CIRI.The rats were treated with acupuncture at the Neiguan(PC6)and Shuigou(GV26)acupoints.Their neurological function was evaluated by taking their Bederson scores at 2 h after ischaemia and 24 h after reperfusion.Triphenyltetrazolium chloride staining was applied to assess the cerebral infarct volume at 24 h after reperfusion.The malondialdehyde(MDA)and ferrous iron(Fe^(2+))levels were observed after 24 h of reperfusion using an assay kit.Western blotting was performed to detect the expression of NCOA4 and ferritin heavy chain 1(FTH1)at 24 h after reperfusion.Moreover,the colocalization of ferritin with neurons,NCOA4 with microtubule-associated protein 1 light chain 3(LC3),and NCOA4 with ferritin was visualized using immunofluorescence staining.RESULTS:Acupuncture significantly improved neurological function and decreased cerebral infarct volume in the acupuncture group.Following CIRI,the expression of NCOA4,LC3 and FTH1 was increased,which enhanced ferritinophagy and induced an inappropriate accumulation of Fe^(2+)and MDA in the ischaemic brain.However,acupuncture dramatically downregulated the expression of NCOA4,LC3 and FTH1,inhibited the overactivation of ferritinophagy,and decreased the levels of MDA and Fe^(2+).CONCLUSIONS:Acupuncture can inhibit NCOA4-mediated ferritinophagy and protect neurons against CIRI in a rat model.

关键词： acupuncture ferritinophagy ferroptosis ferritin nuclear receptor coactivator 4 cerebral ischaemia-reperfusion injury

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