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Intranasal neprilysin rapidly eliminates amyloid-beta plaques, but causes plaque compensations: the explanation why the amyloid-beta cascade may fail?

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Neural Regeneration Research 2022年第9期17卷 1881-1884页

作者： Christian Humpel laboratory of Psychiatry and experimental Alzheimer’s Research Medical University of InnsbruckInnsbruckAustria

Neurodegenerative brain disorders are a major burden in our society,such as Alzheimer´s disease.In order to repair or prevent such diseases,drugs are designed which enter the brain,but the blood-brain barrier limits their entry and the search for alternative pathways is important.Recently,we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice.This review describes the anatomical structure of the intranasal pathway,explains the intranasal delivery of pure neprilysin,cell-loaded neprilysin(platelets)and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail.

关键词： amyloid-beta amyloid-beta degrading enzyme clear plaque collagen biomaterial intranasal neprilysin nose-to-brain

Post-infarct cardiac injury, protection and repair:roles of non-cardiomyocyte multicellular and acellular components

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Science China(Life Sciences) 2018年第3期61卷 266-276页

作者： Xiaojun Du experimental Cardiology laboratory Baker Heart and Diabetes Institute

Following myocardial infarction(MI), cardiomyocytes and infarct size are the focus of our attention when evaluating the extent of cardiac injury, efficacy of therapies or success in repairing the damaged heart by stem cell therapy. Numerous interventions have been shown by pre-clinical studies to be effective in limiting infarct size, and yet clinical trials designed accordingly have yielded disappointing outcomes. The ultimate goal of cardiac protection is to limit the adverse cardiac remodeling. Accumulating studies have revealed that post-infarct remodeling can be attenuated without infarct size limitation. To reconcile this, one needs to appreciate the significance of various cellular and acellular myocardial components that, like cardiomyocytes, undergo significant damage and dysfunction, which impact the ultimate cardiac injury and remodelling. Microvascular injury following ischemia-reperfusion may influence infarct size and promote inflammation. Myocardial injury evokes innate immunity with massive inflammatory infiltration that, although essential for the healing process, exacerbates myocardial injury and damage to extracellular matrix leading to dilative remodeling. It is also important to consider the multiple non-cardiomyocyte components in evaluating therapeutic efficacy. Current research indicates the pivotal role of these components in achieving cardiac regeneration by cell therapy. This review summarizes findings in this field, highlights a broad consideration of therapeutic targets,and recommends cardiac remodeling as the ultimate target.

关键词：细胞组成多细胞心脏梗塞损害部件修理保护

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The Journal of Biomedical Research 2016年第1期30卷 60-66页

作者： Mingzi Song Mingming Fang Liming Yu Yong Xu Departments of pathophysiology and Nursing Jiangsu Jiankang Vocational University Key laboratory of Cardiovascular Disease Department of PathophysiologyNanjing Medical University

Expression of P-selectin in injured or activated endothelia cells serves as a permissive step towards leukocyte recruitment and perpetuation of inflammation in the pathogenesis of atherosclerosis.P-selectin can be induced by pro-inflammatory stimuli via the transcription factor NF-κB,but the epigenetic mechanisms remain incompletely understood.Previously we reported that myocardin-related transcription factor A（MRTF-A）mediates the transactivation of a slew of adhesion molecules by oxidized low-density lipoprotein（oxLDL）,likely through a crosstalk with brahma-related gene 1（BRGl）,a chromatin remodeling protein.Here,we show that MRTF-A was both sufficient and necessary for the transactivation of P-selectin gene in endothelial cells treated with TNF-α.Depletion of MRTF-A using small interfering RNA（siRNA）abrogated the binding of BRGl on the P-selectin promoter.Overexpression of BRG1 up-regulated the activity of P-selectin promoter activity while BRGl knockdown attenuated P-selectin expression.Finally,BRGl silencing suppressed the accumulation of acetylated histone H3 and methylated histone H3K4,and altered the binding of NF-κB on the P-selectin promoter.Therefore,our data demonstrate an essential role for MRTF-A and BRGl in P-selectin transactivation in endothelial cells.

关键词： myocardin-related transcription factor A（MRTF-A） brahma-related gene 1（BRG1） P-selectin endothelial cell

Functionalization of in vivo tissue-engineered living biotubes enhance patency and endothelization without the requirement of systemic anticoagulant administration

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Bioactive Materials 2023年第8期26卷 292-305页

作者： Hongyu Yan Quhan Cheng Jianghua Si Songdi Wang Ye Wan Xin Kong Ting Wang Wenting Zheng Muhammad Rafique Xiaofeng Li Ju He Adam C.Midgley Yi Zhu Kai Wang Deling Kong a a Key laboratory of Bioactive Materials for the Ministry of Education College of Life SciencesNankai UniversityTianjin300071China Department of Ultrasound in Medicine Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200233China Tianjin Key laboratory of Urban Transport Emission Research College of Environmental Science and EngineeringNankai UniversityTianjin300071China State Key laboratory of experimental Hematology National Clinical Research Center for Blood DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin300020China Department of Vascular Surgery Tianjin First Central HospitalNankai UniversityTianjin300192China Department of Physiology and pathophysiology Tianjin Medical UniversityTianjin300070China

Vascular regeneration and patency maintenance,without anticoagulant administration,represent key developmental trends to enhance small-diameter vascular grafts(SDVG)performance.In vivo engineered autologous biotubes have emerged as SDVG candidates with pro-regenerative properties.However,mechanical failure coupled with thrombus formation hinder translational prospects of biotubes as SDVGs.Previously fabricated poly(ε-caprolactone)skeleton-reinforced biotubes(PBs)circumvented mechanical issues and achieved vascular regeneration,but orally administered anticoagulants were required.Here,highly efficient and biocompatible functional modifications were introduced to living cells on PB lumens.The 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(DMPE)-PEG-conjugated anti-coagulant bivalirudin(DPB)and DMPE-PEG-conjugated endothelial progenitor cell(EPC)-binding TPS-peptide(DPT)modifications possessed functionality conducive to promoting vascular graft patency.Co-modification of DPB and DPT swiftly attained luminal saturation without influencing cell viability.DPB repellent of non-specific proteins,DPB inhibition of thrombus formation,and DPB protection against functional masking of DPT’s EPC-capture by blood components,which promoted patency and rapid endothelialization in rat and canine artery implantation models without anticoagulant administration.This strategy offers a safe,facile,and fast technical approach to convey additional functionalization to living cells within tissue-engineered constructs.

关键词： In vivo tissue-engineering Biotube Living tissue modification Anticoagulation Rapid endothelialization

experimental evidence of obesity as a risk factor for severe acute pancreatitis

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World Journal of Gastroenterology 2009年第42期15卷 5260-5265页

作者： Jean-Louis Frossard Pierre Lescuyer Catherine M Pastor Service of Gastroenterology Geneva University HospitalsGeneva 1205Switzerland laboratory of pathophysiology and molecular imaging Geneva University HospitalsGeneva 1205Switzerland Service of Genetics and Central laboratory Geneva University HospitalsGeneva 1205Switzerland

The incidence of acute pancreatitis,an inflammation of the pancreas,is increasing worldwide.Pancreatic injury is mild in 80%-90% of patients who recover without complications.The remaining patients may develop a severe disease with local complications such as acinar cell necrosis,abscess and remote organ injury including lung injury.The early prediction of the severity of the disease is an important goal for physicians in management of patients with acute pancreatitis in order to optimize the therapy and to prevent organ dysfunction and local complications.For that purpose,multiple clinical scale scores have been applied to patients with acute pancreatitis.Recently,a new problem has emerged:the increased severity of the disease in obese patients.However,the mechanisms by which obesity increases the severity of acute pancreatitis are unclear.Several hypotheses have been suggested:(1) obese patients have an increased inflammation within the pancreas;(2) obese patients have an increased accumulation of fat within and around the pancreas where necrosis is often located;(3) increase in both peri-and intra-pancreatic fat and inflammatory cells explain the high incidence of pancreatic inflammation and necrosis in obese patients;(4) hepatic dysfunction associated with obesity might enhance the systemic inflammatory response by altering the detoxification of inflammatory mediators;and(5) ventilation/perfusion mismatch leading to hypoxia associated with a low pancreatic flow might reduce the pancreatic oxygenation and further enhance pancreatic injury.Recent experimental investigations also show an increased mortality and morbidity in obese rodents with acute pancreatitis and the implication of the adipokines lep-tin and adiponectin.Such models are important to investigate whether the inflammatory response of the disease is enhanced by obesity.It is exciting to speculate that manipulation of the adipokine milieu has the potential to influence the severity of acute pancreatitis.

关键词：急性胰腺炎治疗临床检查

Can mouse models mimic sporadic Alzheimer’s disease?

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Neural Regeneration Research 2020年第3期15卷 401-406页

作者： Bettina M.Foidl Christian Humpel laboratory of Psychiatry and experimental Alzheimer’s Research Medical University of Innsbruck

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder and the most common form of dementia worldwide.As age is the main risk factor,>97%of all AD cases are of sporadic origin,potentiated by various risk factors associated with life style and starting at an age>60 years.Only<3%of AD cases are of genetic origin caused by mutations in the amyloid precursor protein or Presenilins 1 or 2,and symptoms already start at an age<30 years.In order to study progression of AD,as well as therapeutic strategies,mouse models are state-of-the-art.So far many transgenic mouse models have been developed and used,with mutations in the APP or presenilin or combinations(3×Tg,5×Tg).However,such transgenic mouse models more likely mimic the genetic form of AD and no information can be given how sporadic forms develop.Several risk genes,such as Apolipoprotein E4 and TREM-2 enhance the risk of sporadic AD,but also many risk factors associated with life style(e.g.,diabetes,hypercholesterolemia,stress)may play a role.In this review we discuss the current situation regarding AD mouse models,and the problems to develop a sporadic mouse model of AD.

关键词： Alzheimer’s disease beta-amyloid cerebral amyloid angiopathy cognitive impairment sporadic and genetic mouse models tau vascular risk factors

Protein inhibitor of activated STAT 4(PIAS4) regulates liver fibrosis through modulating SMAD3 activity

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The Journal of Biomedical Research 2016年第6期30卷 496-501页

作者： Huihui Xu Zhiwen Fan Wenfang Tian Yong Xu Key laboratory of Cardiovascular Disease and Molecular Intervention Department of PathophysiologyNanjing Medical University

Excessive fibrogenesis disrupts normal liver structure,impairs liver function,and precipitates the development of cirrhosis,an irreversible end-stage liver disease.A host of factors including nutrition surplus contribute to liver fibrosis but the underlying mechanism is not fully understood.In the present study,we investigated the involvement of protein inhibitor for activated stat 4（PIAS4）in liver fibrosis in a mouse model of non-alcoholic steatohepatitis（NASH）.We report that PIAS4 silencing using short hairpin RNA（shRNA）attenuated high-fat high-carbohydrate（HFHC）diet induced liver fibrosis in mice.Quantitative PCR and Western blotting analyses confirmed that PIAS4 knockdown downregulated a panel of pro-fibrogenic genes including type I and type III collagens,smooth muscle actin,and tissue inhibitors of metalloproteinase.Mechanistically,PIAS4 silencing blocked the recruitment of SMAD3,a potent pro-fibrogenic transcription factor,to the promoter regions of pro-fibrogenic genes and dampened SMAD3 acetylation likely by upregulating SIRT1 expression.In conclusion,PIAS4 may contribute to liver fibrosis by modulating SIRT1-dependent SMAD3 acetylation.

关键词： liver fibrosis PIAS4 SMAD3 acetylation transcriptional regulation

Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice

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Cellular & Molecular Immunology 2019年第11期16卷 878-886页

作者： Xianhong Du Zhuanchang Wu Yong Xu Yuan Liu Wen Liu Tixiao Wang Chunyang Li Cuijuan Zhang Fan Yi Lifen Gao Xiaohong Liang Chunhong Ma Key laboratory for experimental Teratology of Ministry of Education Department of ImmunologyShandong University School of Basic Medical ScienceJinanShandong 250012PR China Department of Radiation Oncology Qilu Hospital of Shandong UniversityJinanShandongPR China Key laboratory for experimental Teratology of Ministry of Education Department of Histology and EmbryologyShandong University School of Basic Medical ScienceJinanShandongPR China Institute of Pathology and pathophysiology Shandong University School of MedicineJinanPR China Key laboratory of Infection and Immunity of Shandong Province School of Basic Medical SciencesShandong UniversityJinanChina

As an immune checkpoint,Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver diseases.However,the precise roles of Tim-3 in nonalcoholic steatohepatitis(NASH)remain unstated.In the current study,we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet(MCD)-induced NASH mice.The results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice,including F4/80^(+)CD11b^(+),F4/80^(+)CD68^(+),and F4/80^(+)CD169^(+)macrophages.Remarkably,Tim-3 knockout(KO)significantly accelerated MCD-induced liver steatosis,displaying higher serum ALT,larger hepatic vacuolation,more liver lipid deposition,and more severe liver fibrosis.Moreover,compared with wild-type C57BL/6 mice,Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2,NLRP3,and caspase-1 p20 together with increased generation of IL-1βand IL-18 in livers.In vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species(ROS)and related downstream pro-inflammatory cytokine secretion of IL-1βand IL-18 in macrophages.Exogenous administration of N-Acetyl-L-cysteine(NAC),a small molecular inhibitor of ROS,remarkably suppressed caspase-1 p20 expression and IL-1βand IL-18 production in livers of Tim-3 KO mice,thus significantly reducing the severity of steatohepatitis induced by MCD.In conclusion,Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.

关键词： macrophage NASH ROS Tim-3

Small scale adeno-associated virusvector production for preclinical gene delivery based on chloroform precipitation

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Neural Regeneration Research 2022年第1期17卷 99-100页

作者： Marcus Davidsson Andreas Heuer Molecular Neuromodulation Department of Experimental Medical SciencesLund UniversityLundSweden Behavioural Neuroscience laboratory Department of Experimental Medical SciencesLund UniversityLundSweden

Gene therapy aims to introduce genetic information into a cell-type of interest to replace,correct,silence,or modify defective genes.Gene therapy in its broadest sense can theoretically prevent,halt,or cure any condition that affects mankind.In addition to that,the introduction and/or manipulation of genes is one of the major research areas in biological sciences,aimed to deepen our knowledge on how biological systems work.Scientific advances have made it possible to induce changes ranging from manipulations of large stretches of the genome to the change of single nucleotides.The gold-standard vehicles to bring this genetic information into the target cells are viral vectors.

关键词： replace Small mankind