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Decabromodiphenyl ether induces the chromosome association disorders of spermatocytes and deformation failures of spermatids in mice

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Journal of Environmental Sciences 2024年第4期138卷 531-542页

作者： Jinglong Xue Xiangyang Li Yafei Chi Leqiang Gao Yue Zhang Yan Wang Moxuan Zhao Jialiu Wei Zhixiong Shi Xianqing Zhou Department of Toxicology and Hygienic Chemistry School of Public HealthCapital Medical UniversityBeijing 100069China beijing key laboratory of Environmental Toxicology Capital Medical UniversityBeijing 100069China laboratory Animal Center Capital Medical UniversityBeijing 100069China key laboratory of cardiovascular Epidemiology&Department of Epidemiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China

The environmental presence of decabromodiphenyl ether(BDE-209),which is toxic to the male reproductive system,is widespread.The current study investigated its mechanism of toxicity in mice.The results showed,that BDE-209 induced DNA damage,decreased the expression of the promoter of meiosis spermatogenesis-and oogenesis-specific basic helix-loop-helix 1(Sohlh1),meiosis related-factors Lethal(3)malignant brain tumor like 2(L3MBTL2),PIWI-like protein 2(MILI),Cyclin-dependent kinase 2(CDK2),Cyclin A,synaptonemal complex protein 1(SYCP1)and synaptonemal complex protein 3(SYCP3),and caused spermatogenic cell apoptosis,resulting in a decrease in sperm quantity and quality.Furthermore,BDE-209 downregulated the levels of anaphase-promoting complex/cyclosome(APC/C),increased the expression of PIWI-like protein 1(MIWI)in the cytoplasm of elongating spermatids,and decreased the nuclear levels of RING finger protein 8(RNF8),ubiquitinated(ub)-H2A/ub-H2B,and Protamine 1(PRM1)/Protamine 2(PRM2),while increasing H2A/H2B nuclear levels in spermatids.The reproductive toxicity was persistent for 50 days following the withdrawal of BDE-209 exposure.The results suggested that BDE-209 inhibits the initiation of meiosis by decreasing the expression of Sohlh1.Furthermore,the reduced expression of L3MBTL2 inhibited the formation of chromosomal synaptonemal complexes by depressing the expression of meiosis regulators affecting the meiotic progression and also inhibited histone ubiquitination preventing the replacement of histones by protamines,by preventing RNF8 from entering nuclei,which affected the evolution of spermatids into mature sperm.

关键词： BDE-209 Meiosis L3MBTL2 Sperm RNF8 Histone ubiquitination

m^(6)A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

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Frontiers of Medicine 2024年第3期18卷 499-515页

作者： Han Wu Weitao Jiang Ping Pang Wei Si Xue Kong Xinyue Zhang Yuting Xiong Chunlei Wang Feng Zhang Jinglun Song Yang Yang Linghua Zeng Kuiwu Liu Yingqiong Jia Zhuo Wang Jiaming Ju Hongtao Diao Yu Bian Baofeng Yang Department of Pharmacology(National key laboratory of Frigid Zone cardiovascular Diseases the State-Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin150081China

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction(MI)can lead to heart failure.RNA N6-methyladenosine(m^(6)A)methylation has been shown to play a pivotal role in the occurrence and development of many illnesses.In investigating the biological function of the m^(6)A reader YTHDF1 in cardiac fibrosis,adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts,and MI surgery in vivo and transforming growth factor-β(TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models.Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis,whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development.Mechanistically,zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter.YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway,thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis.Consistently,our data indicated that YTHDF1 was involved in activation,proliferation,and migration to participate in cardiac fibrosis in vitro.Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

关键词： cardiac fibrosis YTHDF1 AXL ZBED6 heart failure

Home Blood Pressure Monitoring and Its Association With Blood Pressure Control Among Hypertensive Patients With High cardiovascular Risk in China

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Cardiology Discovery 2024年第1期4卷 15-22页

作者： Jiaying Li Aoxi Tian Jiamin Liu Jinzhuo Ge Yue Peng Xiaoming Su Jing Li National Clinical research Center for cardiovascular Diseases National Health Commission Key Laboratory of Clinical Research for Cardiovascular MedicationsState Key Laboratory of Cardiovascular DiseaseFuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeNational Center for Cardiovascular DiseasesBeijing 100037China

Objective:Home blood pressure monitoring(HBPM)is viewed as a facilitating factor in the initial diagnosis and long-term management of treated hypertension.However,evidence remains scarce about the effectiveness of HBPM use in the real world.This study aimed to examine the associations of HBPM use with blood pressure(BP)control and medication adherence.Methods:This prospective cohort study included hypertensive patients with high cardiovascular risk who were aged≥50 years.At baseline,information about types of BP monitor,frequency of HBPM,perception of anti-hypertensive treatment,and measured office BP were collected.During the 1-year follow-up(visits at 1,2,3,6,and 12 months),information on medication adherence was collected at each visit.The 2 major outcomes were BP control at baseline and medication adherence during the 1-year follow-up.A log-binomial regression model was used to examine the association between frequency of HBPM and outcomes,stratified by the perceptions of anti-hypertensive treatment.Results:A total of 5,363 hypertensive patients were included in the analysis.The age was(64.6±7.2)years,and 41.2%(2,208)were female.Of the total patients,85.9%(4,606)had a home BP monitor and 47.8%(2,564)had an incorrect perception of anti-hypertensive treatment.Overall,24.2%(1,299)of patients monitored their BP daily,37.6%(2,015)weekly,17.3%(926)monthly,and 20.9%(1,123)less than monthly.At baseline,the systolic BP and diastolic BP were(146.6±10.8)mmHg and(81.9±10.6)mmHg,respectively,and 28.5%(1,527)of patients had their BP controlled.Regardless of whether the patients had correct or incorrect perceptions of anti-hypertensive treatment,there is no significant association between HBPM frequency and BP control at baseline.During the 1-year follow-up,23.9%(1,280)of patients had non-adherence to medications at least once.In patients with an incorrect perception of anti-hypertensive treatment,those monitoring BP most frequently(daily)had the highest non-adherence rate(29.9%,175/585).Compared with those monitoring their

关键词： Hypertension Home blood pressure monitoring Blood pressure control Medication adherence

Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway

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Science China(Life Sciences) 2024年第4期67卷 663-679页

作者： Yanfang Liu Yan Wang Bing Liu Wenzhong Liu Yuanyuan Ma Yiren Cao Shi Yan Panpan Zhang Lixin Zhou Qimin Zhan Nan Wu key laboratory of Carcinogenesis and Translational research(Ministry of Education/beijing) Department of Thoracic Surgery IIPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of Carcinogenesis and Translational research(Ministry of Education/beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of Carcinogenesis and Translational research(Ministry of Education/beijing) Department of Thoracic Oncology IIPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of Carcinogenesis and Translational research(Ministry of Education) Department of PathologyPeking University Cancer Hospital and InstituteBeijing 100142China Peking University International Cancer Institute Beijing 100191China Institute of Cancer research Shenzhen Bay LaboratoryShenzhen 518132China

Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of chemoresistance.By analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 188 NSCLC tumor samples,using comprehensive identification of RNA-binding proteins by mass spectrometry(ChIRP-MS)assays,as well as RNA immunoprecipitation(RIP)and RNA pull-down analyses,we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based chemotherapy.The expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of chemoresistance.LncRNA16 binds to HBB and promotes HBB accumulation by inhibiting autophagy.LncRNA16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the mitochondria.Importantly,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in vivo.Overall,lncRNA16 is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.

关键词： chemoresistance lncRNARNA interference ROs chemosensitizer

Bioengineered skin organoids:from development to applications

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Military Medical research 2024年第3期11卷 449-466页

作者： Zi-Xuan Hong Shun-Tian Zhu Hao Li Jing-Zhi Luo Yu Yang Yang An Xi Wang Kai Wang Department of Physiology and Pathophysiology School of Basic Medical SciencesState Key Laboratory of Vascular Homeostasis and RemodelingPeking UniversityBeijing 100191China Department of Hepatopancreatobiliary Surgery the Third Affiliated Hospital of Soochow UniversityChangzhou 213000JiangsuChina Department of Plastic Surgery Peking University Third HospitalBeijing 100191China Clinical Stem Cell research Center Peking University Third HospitalBeijing 100191China State key laboratory of cardiovascular Disease Fuwai HospitalBeijing 100037China beijing key laboratory of Metabolic Disorder Related cardiovascular Disease Capital Medical UniversityBeijing 100050China

Signifcant advancements have been made in recent years in the development of highly sophisticated skin organoids.Serving as three-dimensional(3D)models that mimic human skin,these organoids have evolved into complex structures and are increasingly recognized as efective alternatives to traditional culture models and human skin due to their ability to overcome the limitations of two-dimensional(2D)systems and ethical concerns.The inherent plasticity of skin organoids allows for their construction into physiological and pathological models,enabling the study of skin development and dynamic changes.This review provides an overview of the pivotal work in the progression from 3D layered epidermis to cyst-like skin organoids with appendages.Furthermore,it highlights the latest advancements in organoid construction facilitated by state-of-the-art engineering techniques,such as 3D printing and microfuidic devices.The review also summarizes and discusses the diverse applications of skin organoids in developmental biology,disease modelling,regenerative medicine,and personalized medicine,while considering their prospects and limitations.

关键词： Skin organoid Organoid generation Skin appendage Tissue engineering Disease modelling Regenerative medicine

Association of acute glycemic parameters at admission with cardiovascular mortality in the oldest old with acute myocardial infarction

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Journal of Geriatric Cardiology 2024年第3期21卷 349-358页

作者： Hui-Hui LIU Meng ZHANG Yuan-Lin GUO Cheng-Gang ZHU Na-Qiong WU Ying GAO Rui-Xia XU Jie QIAN Ke-Fei DOU Jian-Jun LI Cardiometabolic Center State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesNational Clinical Research Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

OBJECTIVES Stress-related glycemic indicators,including admission blood glucose(ABG),stress-hyperglycemia ratio(SHR),and glycemic gap(GG),have been associated with worse outcomes after acute myocardial infarction(AMI).However,data regarding their prognostic value in the oldest old with AMI are unavailable.Therefore,this study aimed to investigate the association of stress-related glycemic indicators with short-and long-term cardiovascular mortality(CVM)in the oldest old(≥80 years)with AMI.METHODS In this prospective study,a total of 933 consecutive old patients with AMI admitted to FuWai hospital(beijing,China)were enrolled.On admission,ABG,SHR,and GG were assessed and all participants were classified according to their quartiles.Kaplan-Meier,restricted cubic splines(RCS),and multivariate Cox regression analyses were performed to evaluate the association between these glycemic indicators and CVM within 30 days and long-term follow-up.RESULTS During an average of 1954 patient-years of follow-up,a total of 250 cardiovascular deaths were recorded.Kaplan-Meier analyses showed the lowest CVM in quartile 1 of ABG and in quartile 2 of SHR and GG.After adjusting for potential covariates,patients in quartile 4 of ABG,SHR,and GG had a respective 1.67-fold(95%CI:1.03-2.69;P=0.036),1.80-fold(95%CI:1.16-2.79;P=0.009),and 1.78-fold(95%CI:1.14-2.79;P=0.011)higher risk of long-term CVM risk compared to those in the reference groups(quartile 1 of ABG and quartile 2 of SHR and GG).Furthermore,RCS suggested a J-shaped relationship of ABG and a Ushaped association of SHR and GG with long-term CVM.Additionally,we observed similar associations of these acute glycemic parameters with 30-day CVM.CONCLUSIONS Our data first indicated that SHR and GG consistently had a U-shaped association with both 30-day and longterm CVM among the oldest old with AMI,suggesting that they may be useful for risk stratification in this special population.

关键词： admitted infarction shaped

Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

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Science China(Life Sciences) 2024年第2期67卷 301-319页

作者： Xiaoli Tang Hong Liu Rongjia Rao Yafei Huang Mengqi Dong Miaomiao Xu Shanshan Feng Xun Shi Li Wang Zengwu Wang Bingying Zhou State key laboratory of cardiovascular Disease Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100037China Department of Epidemiology Cardiovascular Institute and Fuwai HospitalChinese Academy of Medical Science&Peking Union Medical CollegeBeijing 100037China Shenzhen key laboratory of cardiovascular Disease Fuwai Hospital Chinese Academy of Medical SciencesShenzhenShenzhen 518020China

Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity,posing a serious threat to pharmaceutical industries and patients’lives.However,mitochondrial toxicity testing is not incorporated into routine cardiac safety screening procedures.To accurately model native human cardiomyocytes,we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes(h PCMs)to a nucleoside analog,remdesivir(RDV).Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in h PCMs.Accordingly,action potential duration was elongated in h PCMs,reflecting clinical incidences of RDV-induced QT prolongation.In a screen for mitochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced cardiotoxicity.Our study demonstrates the utility of h PCMs in the detection of clinically relevant cardiac toxicities,and offers a framework for h PCM-based high-throughput screening of cardioprotective agents.

关键词： remdesivir mitochondrial toxicity cardiotoxicity human primary cardiomyocytes high-throughput screening

Blood pressure targets in patients with chronic kidney disease:Comments and controversies

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Chinese Medical Journal 2024年第3期137卷 270-272页

作者： Ying Zheng Guangyan Cai Xiangmei Chen Department of Nephrology First Medical Center of Chinese PLA General HospitalNational Key Laboratory of Kidney DiseasesNational Clinical Research Center for Kidney DiseasesBeijing Key Laboratory of Kidney Disease ResearchBeijing 100853China

According to the Global Burden of Disease Study 2017,there are 132 million patients with chronic kidney disease(CKD)in China,^([1])and the prevalence of hypertension in Chinese patients with CKD(67.3%)is significantly higher than that in the general population(23.2%).^([2,3])CKD is both a cause and a consequence of hypertension,and these two conditions form a vicious cycle that leads to the high prevalence rate of hypertension in patients with CKD.Uncontrolled hypertension accelerates the deterioration of renal function,which significantly increases the risk of developing end-stage renal disease(ESRD),as well as cardiovascular and cerebrovascular diseases,leading to poor patient outcomes.

关键词： patients Blood hypertension

Genomic characterization of peritoneal lavage cytology-positive gastric cancer

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Chinese Journal of Cancer research 2024年第1期36卷 66-77页

作者： Zhouqiao Wu Tingfei Gu Changxian Xiong Jinyao Shi Jingpu Wang Ting Guo Xiaofang Xing Fei Pang Ning He Rulin Miao Fei Shan Yuan Zhou Ziyu Li Jiafu Ji key laboratory of Carcinogenesis and Translational research(Ministry of Education/beijing) Gastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China Department of Biomedical Informatics Department of Physiology and PathophysiologyCenter for Noncoding RNA MedicineMOE Key Lab of Cardiovascular SciencesSchool of Basic Medical SciencesPeking UniversityBeijing 100191China State key laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China

Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer.Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer.Results: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

关键词： Cytology gastric carcinoma peritoneal metastasis whole exome sequencing