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Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation

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Liver Research 2020年第3期4卷 136-144页

作者： Xin Guo Bilian Zhu Hang Xu Honggui Li Boxiong Jiang Yina Wang Benrong Zheng Shannon Glaser Gianfranco Alpini Chaodong Wu Department of Nutrition Texas A&M UniversityCollege StationTXUSA Department of Nutrition and Food Hygiene School of Public HealthCheeloo College of MedicineShandong UniversityJinanChina Department of VIP Medical Service Center The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Medical Physiology Texas A&M University College of MedicineBryanTXUSA Hepatology and Gastroenterology MedicineIndiana UniversityIndianapolisINUSA Richard L.Roudebush VA Medical Center IndianapolisINUSA

Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be *** that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in ***:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD ***,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)*** latter were also fed an HFD and examined for NAFLD *** vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory ***:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT *** inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory *** NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT *** the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT ***:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induce

关键词： 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2) Hematopoietic cells Hepatic steatosis Inflammation Macrophages

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Argonaute(AGO)proteins play an essential role in mediating BMP9-induced osteogenic signaling in mesenchymal stem cells(MSCs)

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Genes & Diseases 2021年第6期8卷 918-930页

作者： Yukun Mao Na Ni Linjuan Huang Jiaming Fan Hao Wang Fang He Qing Liu Deyao Shi Kai Fu Mikhail Pakvasa William Wagstaff Andrew Blake Tucker Connie Chen Russell R.Reid Rex C.Haydon Sherwin H.Ho Michael J.Lee Tong-Chuan He Jian Yang Le Shen Lin Cai Hue H.Luu Departments of Spine Surgery and Musculoskeletal Tumor and NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanHubei Province430072PR China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and the School of Laboratory MedicineChongqing Medical UniversityChongqing400016PR China Departments of Nephrology and Obstetrics and GynecologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016PR China Department of Spine Surgery Second Xiangya HospitalCentral South UniversityChangshaHunan Province410011PR China Department of Orthopaedic Surgery Union Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei Province430022PR China Section of Plastic Surgery and Laboratory of Craniofacial Biology and Development and Section of Surgical ResearchDepartment of SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Biomedical Engineering Materials Research InstituteThe Huck Institutes of the Life SciencesThe Pennsylvania State UniversityUniversity ParkPA 16802USA

As multipotent progenitor cells,mesenchymal stem cells(MSCs)can renew themselves and give rise to multiple lineages including osteoblastic,chondrogenic and adipogenic ***’s previously shown that BMP9 is the most potent BMP and induces osteogenic and adipogenic differentiation of ***,the molecular mechanism through which BMP9 regulates MSC differentiation remains poorly *** evidence indicates that noncoding RNAs,especially microRNAs,may play important roles in regulating MSC differentiation and bone *** highly conserved RNA binding proteins,Argonaute(AGO)proteins are essential components of the multi-protein RNA-induced silencing complexes(RISCs),which are critical for small RNA ***,we investigate possible roles of AGO proteins in BMP9-induced lineage-specific differentiation of *** first found that BMP9 upregulated the expression of Ago1,Ago2 and Ago3 in *** engineering multiplex siRNA vectors that express multiple siRNAs targeting individual Ago genes or all four Ago genes,we found that silencing individual Ago expression led to a decrease in BMP9-induced early osteogenic marker alkaline phosphatase(ALP)activity in ***,we demonstrated that simultaneously silencing all four Ago genes significantly diminished BMP9-induced osteogenic and adipogenic differentiation of MSCs and matrix mineralization,and ectopic bone ***,our findings strongly indicate that AGO proteins and associated small RNA biogenesis pathway play an essential role in mediating BMP9-induced osteogenic differentiation of MSCs.

关键词： Argonaute(AGO)proteins BMP9 Bone formation Lineage-specific differentiation Mesenchymal stem cells miRNA biogenesis Osteogenic signaling

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Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

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Asian Journal of Urology 2016年第4期3卷 185-194页

作者： Cameron M.Armstrong Allen C.Gao Department of Urology University of CaliforniaDavisSacramentoCAUSA Comprehensive Cancer Center University of CaliforniaDavisSacramentoCAUSA VA Northern California Health Care System SacramentoCAUSA

The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and ***,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the *** the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been *** receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to *** regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current *** instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone ***1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment *** review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.

关键词： Prostate cancer Castration resistant prostate cancer Enzalutamide Abiraterone Docetaxel Drug resistance

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Multifaceted signaling regulators of chondrogenesis:Implications in cartilage regeneration and tissue engineering

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Genes & Diseases 2015年第4期2卷 307-327页

作者： Jordan D.Green Viktor Tollemar Mark Dougherty Zhengjian Yan Liangjun Yin Jixing Ye Zachary Collier Maryam K.Mohammed Rex C.Haydon Hue H.Luu Richard Kang Michael J.Lee Sherwin H.Ho Tong-Chuan He Lewis L.Shi Aravind Athiviraham The University of Chicago Pritzker School of Medicine ChicagoIL 60637USA Department of Orthopaedic Surgery and Rehabilitation Medicine The University of Chicago Medical CenterChicagoIL 60637USA Department of Orthopaedic Surgery The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China School of Bioengineering Chongqing UniversityChongqingChina

Defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity and avascular *** surgical treatment options do not ensure consistent regeneration of hyaline cartilage in favor of fibrous ***,we review the current understanding of the most important biological regulators of chondrogenesis and their interactions,to provide insight into potential applications for cartilage tissue *** include various signaling pathways,including fibroblast growth factors(FGFs),transforming growth factor b(TGF-b)/bone morphogenic proteins(BMPs),Wnt/b-catenin,Hedgehog,Notch,hypoxia,and angiogenic signaling *** and epigenetic regulation of chondrogenesis will also be *** in our understanding of these signaling pathways have led to promising advances in cartilage regeneration and tissue engineering.

关键词： BMPs Cartilage Cell signaling Chondrogenesis FGF Regenerative medicine

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Cold adaptation does not alter ATP homeostasis during cold exposure in Drosophila melanogaster

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Integrative Zoology 2018年第4期13卷 471-481页

作者： Caroline M.WILLIAMS James R.ROCCA Arthur S.EDISON David B.ALLISON Theodore J.MORGAN Daniel A.HAHN Department of Integrative Biology University of CaliforniaBerkeleyCaliforniaUSA Departments of Entomology and Nematology University of FloridaGainesvilleFloridaUSA Biochemistry University of FloridaGainesvilleFloridaUSA Advanced Magnetic Resonance Imaging and Spectroscopy Facility McKnight Brain InstituteUniversity of FloridaGainesvilleFloridaUSA Departments of Genetics and Biochemistry Complex Carbohydrate Research CenterUniversity of GeorgiaAthensGeorgiaUSA Department of Epidemiology and Biostatistics School of Public HealthIndiana University BloomingtonBloomingtonIndianaUSA Division of Biology Kansas State UniversityManhattanKansasUSA

In insects and other ectotherms,cold temperatures cause a coma resulting from loss of neuromuscular function,during which ionic and metabolic homeostasis are progressively *** adaptation improves homeostasis during cold exposure,but the ultimate targets of selection are still an open *** acclimation and adaptation remodels mitochondrial metabolism in insects,suggesting that aerobic energy production during cold exposure could be a target of ***,we test the hypothesis that cold adaptation improves the ability to maintain rates of aerobic energy production during cold exposure by using^(31)P NMR on live *** lines of Drosophila melanogaster artificially selected for fast and slow recovery from a cold coma,we show that cold exposure does not lower ATP levels and that cold adaptation does not alter aerobic ATP production during cold ***-hardy and cold-susceptible lines both experienced a brief transition to anaerobic metabolism during cooling,but this was rapidly reversed during cold exposure,suggesting that oxidative phosphorylation was sufficient to meet energy demands below the critical thermal minimum,even in cold-susceptible *** thus reject the hypothesis that performance under mild low temperatures is set by aerobic ATP supply limitations in ***,excluding oxygen and capacity limitation as a weak link in energy *** work suggests that the modulations to mitochondrial metabolism resulting from cold acclimation or adaptation may arise from selection on a biosynthetic product(s)of those pathways rather than selection on ATP supply during cold exposure.

关键词： chill coma energetics insect oxygen limitation thermal tolerance

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Developing macromolecular therapeutics:the future drug-of-choice

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Frontiers of Chemical Science and Engineering 2010年第1期4卷 10-17页

作者： Huining HE Weibing DONG Junbo GONG Jingkang WANG Victor C.YANG Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency Tianjin UniversityTianjin 300072China State Key Laboratory of Chemical Engineering Tianjin UniversityTianjin 300072China School of Chemical Engineering Tianjin UniversityTianjin 300072China Department of Pharmaceutical Sciences College of PharmacyUniversity of Michigan428 Church StreetAnn ArborMI 48109-1065USA

Macromolecular drugs including peptides,proteins,antibodies,polysaccharides and nucleic acids have been widely used for therapy of major diseases such as carcinoma and AIDS as well as cardiovascular and neurodegenerative disorders among other medical *** to their unmatched properties of high selectivity and efficiency,macromolecular drugs have been recognized as the drug-of-choice of the *** worldwide progress on macromolecular therapeutics still remains in the infant stage and is therefore wide open for equalground competition,R&D related to macromolecular drugs should be considered as the main point of focus in China in setting up its strategic plans in pharmaceutical *** this article,research strategies and drug delivery approaches that should be adopted to enhance the therapeutic effects of macromolecular drugs are *** addition,comments concerning how to implement such strategies to excel from competition in this challenging research field,such as the design of innovative and highly effective delivery systems of macromolecular drugs with self-owned intellectual property rights,are provided.

关键词： macromolecular drugs drug delivery systems therapeutic efficacy

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Exacerbation of chronic inflammatory diseases by infectious agents:Fact or fiction?

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World Journal of Diabetes 2010年第2期1卷 27-35页

作者： Bernhard Kaltenboeck Department of Pathobiology College of Veterinary MedicineAuburn University

Chronic inflammatory diseases caused by obesity represent critical public health concerns worldwide. In these diseases such as metabolic syndrome,diabetes and atherosclerosis,adipose tissue acts as an endocrine organ that releases large quantities of inflammatory mediators into *** classically recognized effectors on the development of obesity and resultant conditions,infection has attracted attention as an enhancer of chronic inflammatory *** diseases have long been associated with obesity,metabolic syndrome,diabetes and ***,the infectious hypothesis for chronic inflammatory diseases has been challenged by inconclusive clinical ***,the large body of evidence accumulated over decades on the association of infectious diseases with obesity,diabetes and cardiovascular disease should not be ***,re-formulation of hypothesesof the mechanisms by which microbes affect obesityassociated diseases may be required with an emphasis on the early events in the progression of such diseases and the multifactorial nature of pathogen-host *** review focuses on pathogens that directly promote obesity and on pathogens that cause chronic infections and thereby enhance metabolic diseases in obese patients.A new perspective on the interaction between infections and obesity-related diseases may improve management of chronic inflammatory diseases that rank high among global threats to human health.

关键词： Chronic inflammatory diseases Obesity Diabetes Adenovirus-36 Chlamydia pneumoniae

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Neural EGF-like protein 1(NELL-1):Signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine

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Genes & Diseases 2017年第3期4卷 127-137页

作者： Mikhail Pakvasa Alex Alverdy Sami Mostafa Eric Wang Lucy Fu Alexander Li Leonardo Oliveira Aravind Athiviraham Michael J.Lee Jennifer Moriatis Wolf Tong-Chuan He Guillermo A.Ameer Russell R.Reid The University of Chicago Pritzker School of MedicineChicagoIL 60637USA Laboratory of Craniofacial Biology and Development Section of Plastic and Reconstructive SurgeryDepartment of SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Rosalind Franklin University Chicago Medical SchoolNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Biomedical Engineering Northwestern UniversityEvanstonIL 60208USA Center for Advanced Regenerative Engineering Northwestern UniversityEvanstonIL 60208USA Department of Surgery Feinberg School of MedicineNorthwestern UniversityChicagoIL 60611USA

Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects,two problems associated with significant *** differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth *** EGF Like-Like molecule 1(NELL-1)is a secreted glycoprotein that has proven,both in vitro and in vivo,to be a potent osteo-inductive ***,it has been shown to repress adipogenic differentiation and ***-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein(BMP)2 and9,and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of *** we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering.

关键词： Bone tissue engineering Mesenchymal stem cells NELL-1 NEL-like protein 1 Osteogenic differentiation

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MACMIC Reveals A Dual Role of CTCF in Epigenetic Regulation of Cell Identity Genes

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Genomics, Proteomics & Bioinformatics 2021年第1期19卷 140-153页

作者： Guangyu Wang Bo Xia Man Zhou Jie Lv Dongyu Zhao Yanqiang Li Yiwen Bu Xin Wang John P.Cooke Qi Cao Min Gyu Lee Lili Zhang Kaifu Chen Center for Bioinformatics and Computational Biology Department of Cardiovascular SciencesInstitute for Academic MedicineHouston Methodist Research InstituteHoustonTX 77030USA Center for Cardiovascular Regeneration Department of Cardiovascular SciencesInstitute for Academic MedicineHouston Methodist Research InstituteHoustonTX 77030USA Department of Cardiothoracic Surgeries Weill Cornell Medical CollegeCornell UniversityNew YorkNY 10065USA Houston Methodist Institute for Academic Medicine Houston Methodist Research InstituteHoustonTX 77030USA Basic and Translational Research Division Department of CardiologyBoston Children’s HospitalBostonMA 02115USA Department of Pediatrics Harvard Medical SchoolBostonMA 02115USA Department of Urology Feinberg School of MedicineNorthwestern UniversityChicagoIL 60611USA Robert H.Lurie Comprehensive Cancer Center Feinberg School of MedicineNorthwestern UniversityChicagoIL 60611USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA 不详

Numerous studies of relationship between epigenomic features have focused on their strong correlation across the genome,likely because such relationship can be easily identified by many established methods for correlation ***,two features with little correlation may still colocalize at many genomic sites to implement important *** is no bioinformatic tool for researchers to specifically identify such feature ***,we develop a method to identify feature pairs in which two features have maximal colocalization minimal correlation(MACMIC)across the *** MACMIC analysis of 3306 feature pairs in 16 human cell types,we reveal a dual role of CCCTC-binding factor(CTCF)in epigenetic regulation of cell identity *** super-enhancers are associated with activation of target genes,only a subset of super-enhancers colocalized with CTCF regulate cell identity *** super-enhancers colocalized with CTCF,CTCF is required for the active marker H3 K27 ac in cell types requiring the activation,and also required for the repressive marker H3 K27 me3 in other cell types requiring *** work demonstrates the biological utility of the MACMIC analysis and reveals a key role for CTCF in epigenetic regulation of cell *** code for MACMIC is available at https://***/bxia888/MACMIC.

关键词： Mutual information Correlation CCCTC-binding factor H3K27ac H3K27me3

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Macrophage-derived matrix metalloproteinase-1 enhances aortic aneurysm formation in transgenic rabbits

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The Journal of Biomedical Research 2019年第4期33卷 271-279页

作者： Manabu Niimi Kazutoshi Nishijima Shuji Kitajima Fumikazu Matsuhisa Kaneo Satoh Hirokazu Yamazaki Jifeng Zhang Y. Eugene Chen Jianglin Fan Department of Molecular Pathology Graduate School of MedicineUniversity of YamanashiYamanashi 409-3898Japan Animal Research Laboratory Bioscience Education-Research Support CenterAkita UniversityAkita 010-8502Japan Analytical Research Center for Experimental Sciences Saga UniversitySaga 840-8502Japan Department of Laboratory Medicine Graduate School of MedicineUniversity of YamanashiYamanashi 409-3898Japan Center for Advanced Models for Translational Sciences and Therapeutics University of Michigan Medical CenterAnn ArborMI 48109USA School of Biotechnology and Health Sciences Wuyi UniversityJiangmenGuangdong 529020China

Increased expression of matrix metalloproteinase-1(MMP-1)has been observed in the lesions of atherosclerosis and aneurysms;however,it is not fully understood whether macrophage-derived MMP-1 affects these *** investigate whether macrophage-derived MMP-1 participates in the development of vascular diseases,we generated transgenic(Tg)rabbits expressing human MMP-1 in the monocyte/macrophage lineage under the control of the human scavenger receptor enhancer/*** rabbits exhibited no visible abnormalities throughout their *** blotting analysis revealed that the amount of MMP-1 proteins in the conditioned media secreted from peritoneal macrophages of Tg rabbits was up to 3-fold higher than that in non-Tg *** the first experiment,Tg and non-Tg rabbits were fed a cholesterol diet for 16 weeks,and aortic and coronary atherosclerosis were *** gross lesion area of aortic atherosclerosis in Tg rabbits was not significantly different from that in non-Tg rabbits,but Tg rabbits had marked destruction of the medial elastic lamina of the aortic lesions on microscopic *** the second experiment,we generated aortic aneurysms by incubating with *** with non-Tg rabbits,Tg rabbits exhibited a significantly greater aortic *** macrophage-derived MMP-1 led to increased medial destruction in both aortic atherosclerosis and *** results demonstrate that MMP-1 plays a different role in the pathogenesis of atherosclerosis and aneurysms.

关键词： matrix metalloproteinase-1 macrophage atherosclerosis aneurysm transgenic rabbit

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