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Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis:Implications for bone health

World Journal of Stem Cells 2024年第4期16卷 389-409页

作者： Ling-Ling Wang Zhan-Jin Lu Shun-Kui Luo Yun Li Zhe Yang Hong-Yun Lu Department of Gerontology The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000Guangdong ProvinceChina Department of Endocrinology and Metabolism The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000Guangdong ProvinceChina guangdong provincial key laboratory of Biomedical Imaging The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000Guangdong ProvinceChina Department of Endocrinology and Metabolism Zhuhai People’s Hospital(Zhuhai Clinical Medical College of Jinan Universitythe First Hospital Affiliated with Medical College of Macao University of Science and Technology)Zhuhai 519000Guangdong ProvinceChina

BACKGROUND Osteoporosis(OP)has become a major public health problem *** OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing *** the bone marrow(BM)niche,bone mesenchymal stem cells(BMSCs)are exposed to a hypoxic ***,a few studies have demonstrated that hypoxiainducible factor 2alpha(HIF-2α)is involved in BMSC osteogenic differentiation,but the molecular mechanism involved has not been *** To investigate the effect of HIF-2αon the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells(HSCs)in the BM niche on the progression of *** Mice with BMSC-specific HIF-2αknockout(Prx1-Cre;Hif-2αfl/fl mice)were used for in vivo *** quantification was performed on mice of two genotypes with three interventions:Bilateral ovariectomy,semilethal irradiation,and dexamethasone ***,the hematopoietic function of HSCs in the BM niche was compared between the two mouse *** vitro,the HIF-2αagonist roxadustat and the HIF-2αinhibitor PT2399 were used to investigate the function of HIF-2αin BMSC osteogenic and adipogenic ***,we investigated the effect of HIF-2αon BMSCs via treatment with the mechanistic target of rapamycin(mTOR)agonist MHY1485 and the mTOR inhibitor *** The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention *** vitro,Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2αagonist roxadustat,and after 7 d of BMSC adipogenic differentiation,the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased;in addition,after 14 d of osteogenic differentiation,BMSCs treated with roxadusta

关键词： Hypoxia-inducible factor-2α Bone marrow niche Bone mesenchymal stem cells Osteoporosis Osteogenic/adipogenic differentiation Mechanistic target of rapamycin signaling pathway

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Comparison of the early curative effect in patients undergoing mechanical vs. bioprosthetic aortic valve replacement with concomitant annuloplasty by the Nicks procedure

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South China Journal of Cardiology 2024年第1期25卷 29-37页

作者：吴浩向鸿谟王露朱平 guangdong Cardiovascular Institute Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouGuangdong 510100China guangdong provincial key laboratory of Pathogenesis Targeted Prevention and Treatment of Heart DiseaseGuangzhou Key Laboratory of Cardiac Pathogenesis and PreventionGuangzhouGuangdong 510100China

Background The probability of prosthesis-patient mismatch(PPM)is high in aortic valve replacement surgery for small aortic valve annulus,which increases the postoperative prosthetic valve transvalvular pressure *** aortic annuloplasty is a commonly applied surgical procedure,but there is currently no uniform standard or guideline on the type of prosthetic valve that should be used during ***,this study aimed to analyze whether there was any difference in the short-term prognosis between the choice of mechanical valves and bioprosthetic valves during aortic valve replacement surgery with concomitant aortic annuloplasty by the Nicks *** A retrospective analysis was conducted based on the clinical data from 55 patients undergoing aortic valve replacement surgery with concomitant annuloplasty by the Nicks procedure at the Cardiac Surgery Department of guangdong provincial People’s Hospital from November 2021 to December *** this study,all patients received aortic annuloplasty by the Nicks *** these patients,30 were in the mechanical valve group,while the other 25 were in the bioprosthetic valve *** including left ventricular end-diastolic/endsystolic diameters,left ventricular ejection fraction,interventricular septal thickness,left ventricular posterior wall thickness,transvalvular pressure gradient,left ventricular fractional shortening,and left ventricular mass index were collected 1 week preoperatively and 1 week and 3 months *** on gender,age,body surface area,types of perioperative complications,operation time,complication rates,and outcomes was also *** Among the 55 patients enrolled in this study,4 *** main causes of death included postoperative low cardiac output syndrome,severe pulmonary infection,and multi-organ ***,there was a statistically significant difference in left ventricular end-diastolic diameter between the mechanical valv

关键词： Valve replacement Small aortic annulus Nicks procedure Prosthesis-patient mismatch Mechani-cal valve Bioprosthetic valve

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High-density lipoprotein regulates angiogenesis by affecting autophagy via miRNA-181a-5p

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Science China(Life Sciences) 2024年第2期67卷 286-300页

作者： Bi-Ang Kang Hua-Ming Li Ya-Ting Chen Meng-Jie Deng Yan Li Yue-Ming Peng Jian-Jun Gao Zhi-Wei Mo Jia-Guo Zhou Zhi-Jun Ou Jing-Song Ou Division of Cardiac Surgery Cardiovascular Diseases InstituteThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China National-guangdong Joint Engineering laboratory for Diagnosis and Treatment of Vascular Diseases Guangzhou 510080China NHC key laboratory of Assisted Circulation(Sun Yat-sen University) Guangzhou 510080China guangdong provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases Guangzhou 510080China Division of Vascular Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of pharmacology Cardiac and Cerebral Vascular Research CenterZhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China Division of Hypertension and Vascular Diseases Department of CardiologyCardiovascular Diseases InstituteThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China guangdong provincial key laboratory of Brain Function and Disease Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China

We previously demonstrated that normal high-density lipoprotein(nHDL)can promote angiogenesis,whereas HDL from patients with coronary artery disease(d HDL)is dysfunctional and impairs *** plays a critical role in angiogenesis,and HDL regulates ***,it is unclear whether n HDL and d HDL regulate angiogenesis by affecting *** cells(ECs)were treated with n HDL and d HDL with or without an autophagy ***,endothelial nitric oxide synthase(e NOS)expression,miRNA expression,nitric oxide(NO)production,superoxide anion(O2^(·-))generation,EC migration,and tube formation were evaluated.n HDL suppressed the expression of miR-181a-5p,which promotes autophagy and the expression of e NOS,resulting in NO production and the inhibition of O2^(·-)generation,and ultimately increasing in EC migration and tube formation.d HDL showed opposite effects compared to n HDL and ultimately inhibited EC migration and tube *** found that autophagy-related protein 5(ATG5)was a direct target of ***5 silencing or miR-181a-5p mimic inhibited n HDL-induced autophagy,e NOS expression,NO production,EC migration,tube formation,and enhanced O2^(·-)generation,whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of d ***5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null(LDLr^(-/-))mice when compared to C57BL/6 ***5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr^(-/-)*** together,nHDL was able to stimulate autophagy by suppressing miR-181a-5p,subsequently increasing e NOS expression,which generated NO and promoted *** contrast,d HDL inhibited angiogenesis,at least partially,by increasing miR-181a-5p expression,which decreased autophagy and e NOS expression,resulting in a decrease in NO production and an increase in O2^(·-)*** findings reveal a nov

关键词： high-density lipoprotein angiogenesis autophagy ATG5 miRNA endothelial nitric oxide synthase

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Identification of novel drug targets for diabetic retinopathy:proteome-wide mendelian randomization and colocalization analyses

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Eye Science 2024年第1期1卷 26-44页

作者：杨少鹏朱梓瑜刘日乾黄文勇王伟 State key laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceGuangdong Provincial Clinical Research Center for Ocular DiseasesGuangzhou 510060China Hainan Eye Hospital and key laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityHaikou 570100China

Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic *** analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been ***:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma *** data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European *** instrumental variables were identified using multiple *** the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with *** MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR *** systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically ***:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative *** each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR *** proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)wer

关键词： plasma proteome mendelian randomization therapeutic targets genome-wide analysis study colocalization analysis diabetic retinopathy

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Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer

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Cancer Biology & Medicine 2024年第1期21卷 83-103页

作者： Yumei Wang Haiyan Wang Wei Shao Yuhui Chen Yu Gui Chao Hu Xiaohong Yi Lijun Huang Shasha Li Dong Wang School of Basic Medical Sciences State Key Laboratory of Southwestern Chinese Medicine ResourcesChengdu University of Traditional Chinese MedicineChengdu 611137China Department of Pathology School of MedicineQinghai UniversityXining 810001China Omics Biosciences Inc Beijing 100871China laboratory of Integrative Medicine Clinical Research Center for BreastState Key Laboratory of BiotherapyWest China HospitalSichuan University and Collaborative Innovation CenterChengdu 610041China State key laboratory of Southwestern Chinese Medicine Resources School of PharmacyChengdu University of Traditional Chinese MedicineChengdu 611137China Department of Endocrinology and Metabolism Guangdong Provincial Key Laboratory of Diabetology&Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity ResearchMedical Center for Comprehensive Weight ControlThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China

Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain *** is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic ***:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic ***,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast ***:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific *** discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and ***,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene ***,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast ***:Our work deciphered the extensive regulation among hundreds of epigenetic *** identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.

关键词： Epigenetic regulators breast cancer regulatory network HTS^(2)

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