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miR-181b promotes angiogenesis and neurological function recovery after ischemic stroke

Neural Regeneration Research 2023年第9期18卷 1983-1989页

作者： Li-Xia Xue Lin-Yuan shu Hong-Mei Wang Kai-Li Lu Li-Gang Huang Jing-Yan Xiang Zhi Geng Yu-Wu Zhao Hao Chen Department of Neurology Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Emergency medicine Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Neurosurgery Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina

Promotion of new blood vessel formation is a new strategy for treating ischemic stroke.Non-coding miRNAs have been recently considered potential therapeutic targets for ischemic stroke.miR-181b has been shown to promote angiogenesis in hypoxia and traumatic brain injury model,while its effect on ischemic stroke remains elusive.In this study,we found that overexpression of miR-181b in brain microvascular endothelial cells subjected to oxygen-glucose deprivation in vitro restored cell prolife ration and enhanced angiogenesis.In rat models of focal cerebral ischemia,ove rexpression of miR-181b reduced infarction volume,promoted angiogenesis in ischemic penumbra,and improved neurological function.We further investigated the molecular mechanism by which miR-181b participates in angiogenesis after ischemic stroke and found that miR-181b directly bound to the 3’-UTR of phosphatase and tensin homolog(PTEN) mRNA to induce PTEN downregulation,leading to activation of the protein kinase B(Akt) pathway,upregulated expression of vascular endothelial growth facto rs,down-regulated expression of endostatin,and promoted angiogenesis.Taken togethe r,these results indicate that exogenous miR-181b exhibits neuroprotective effects on ischemic stro ke through activating the PTEN/Akt signal pathway and promoting angiogenesis.

关键词： Akt angiogenesis endostatin ischemic stroke middle cerebral artery occlusion miR-181b neurological function recovery oxygen-glucose deprivation PTEN vascular endothelial growth factor

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Inhibiting phosphatase and actin regulator 1 expression is neuroprotective in the context of traumatic brain injury

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Neural Regeneration Research 2023年第7期18卷 1578-1583页

作者： Yao Jing Lin Zhang shi-Wen Chen Yan Guo shi-Ming Ju Fang Yuan Hao Chen Dian-Xu Yang Heng-Li Tian Zhi-Ming Xu Jun Ding Department of Neurosurgery Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina

studies have found that the phosphatase actin regulatory factor 1 expression can be related to stroke,but it remains unclear whether changes in phosphatase actin regulatory factor 1 expression also play a role in traumatic brain injury.In this study we found that,in a mouse model of traumatic brain injury induced by controlled cortical impact,phosphatase actin regulatory factor 1 expression is increased in endothelial cells,neurons,astrocytes,and microglia.When we overexpressed phosphatase actin regulatory factor 1 by injection an adeno-associated virus vector into the contused area in the traumatic brain injury mice,the water content of the brain tissue increased.However,when phosphatase actin regulatory factor 1 was knocked down,the water content decreased.We also found that inhibiting phosphatase actin regulatory factor 1 expression regulated the nuclear factor kappa B signaling pathway,decreased blood-brain barrier permeability,reduced aquaporin 4 and intercellular adhesion molecule 1 expression,inhibited neuroinflammation,and neuronal apoptosis,thereby improving neurological function.The findings from this study indicate that phosphatase actin regulatory factor 1 may be a potential therapeutic target for traumatic brain injury.

关键词： apoptosis aquaporin 4 blood brain barrier intercellular adhesion molecule 1 neuroinflammation nuclear factor kappa B occludin phosphatase and actin regulator-1 traumatic brain injury zonula occludens 1

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Insulin sensitivity,βcell function,and adverse pregnancy outcomes in women with gestational diabetes

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Chinese Medical Journal 2022年第21期135卷 2541-2546页

作者： Yun shen Yanwei Zheng Yingying su susu Jiang Xiaojing Ma Jiangshan Hu Changbin Li Yajuan Huang Yincheng Teng Yuqian Bao Minfang Tao Jian Zhou Department of Endocrinology and Metabolism Shanghai Clinical Center for DiabetesShanghai Sixth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200233China Department of Gynecology and Obstetrics Shanghai Sixth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200233China shanghai Diabetes Institute Shanghai Key Laboratory of Diabetes MellitusShanghai Sixth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200233China

Background: The potential impact of β cell function and insulin sensitivity on adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM) remains uncertain. We aimed to investigate the association between β cell dysfunction, insulin resistance, and the composite adverse pregnancy outcomes.Methods: This observational study included 482 women diagnosed with GDM during pregnancy. Quantitative metrics on β cell function and insulin sensitivity during pregnancy were calculated using traditional equations. The association of β cell dysfunction and insulin resistance with the risk of the composite adverse pregnancy outcomes was investigated using multivariable-adjusted logistic regression models.Results: Multivariable-adjusted odds ratios (ORs) of adverse pregnancy outcomes across quartiles of homeostatic model assessment for insulin resistance (HOMA-IR) were 1.00, 0.95, 1.34, and 2.25, respectively (P for trend = 0.011). When HOMA-IR was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 1.34 (95% confidence interval 1.16-1.56) for each 1-unit increase in HOMA-IR. Multivariable-adjusted ORs of adverse pregnancy outcomes across quartiles of homeostatic model assessment for β cell function (HOMA-β) were 1.00, 0.51, 0.60, and 0.53, respectively (P for trend = 0.068). When HOMA-β was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 0.57 (95% CI 0.24-0.90) for each 1-unit increase in HOMA-β. However, other quantitative metrics were not associated with the composite adverse pregnancy outcomes.Conclusions: We demonstrated a significant association of β cell function and insulin sensitivity with the risk of adverse pregnancy outcomes. We have provided additional evidence on the early identification of adverse pregnancy outcomes besides the glycemic values.

关键词： βcell function Insulin sensitivity Adverse pregnancy outcomes

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Cell cycle exit and neuronal differentiation 1-engineered embryonic neural stem cells enhance neuronal differentiation and neurobehavioral recovery after experimental traumatic brain injury

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Neural Regeneration Research 2022年第1期17卷 130-136页

作者： Ren Wang Dian-Xu Yang Ying-Liang Liu Jun Ding Yan Guo Wan-Hai Ding Heng-Li Tian Fang Yuan Department of Neurosurgery Shanghai Jiao Tong University Affiliated Sixth People’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Department of Neurosurgery Shanghai Tenth People’s HospitalTongji UniversityShanghaiChina

Our previous study showed that cell cycle exit and neuronal differentiation 1(CEND1)may participate in neural stem cell cycle exit and oriented differentiation.However,whether CEND1-transfected neural stem cells can improve the prognosis of traumatic brain injury remained unclear.In this study,we performed quantitative proteomic analysis and found that after traumatic brain injury,CEND1 expression was downregulated in mouse brain tissue.Three days after traumatic brain injury,we transplanted CEND1-transfected neural stem cells into the area surrounding the injury site.We found that at 5 weeks after traumatic brain injury,transplantation of CEND1-transfected neural stem cells markedly alleviated brain atrophy and greatly improved neurological function.In vivo and in vitro results indicate that CEND1 overexpression inhibited the proliferation of neural stem cells,but significantly promoted their neuronal differentiation.Additionally,CEND1 overexpression reduced protein levels of Notch1 and cyclin D1,but increased levels of p21 in CEND1-transfected neural stem cells.Treatment with CEND1-transfected neural stem cells was superior to similar treatment without CEND1 transfection.These findings suggest that transplantation of CEND1-transfected neural stem cells is a promising cell therapy for traumatic brain injury.This study was approved by the Animal Ethics Committee of the school of Biomedical Engineering of shanghai jiao tong university,China(approval No.2016034)on November 25,2016.

关键词： cell cycle exit and neuronal differentiation 1 cyclin D1 embryonic neural stem cells neuronal differentiation genetic engineering overexpression mice Notch1 p21 traumatic brain injury

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Efficacy of interleukin-17 inhibitors on radiographic progression in psoriatic arthritis:A systematic review and meta-analysis

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Chinese Medical Journal 2024年第4期137卷 473-475页

作者： Han-Lei Jiang Yu Du Qiang tong sheng-Ming Dai Department of Rheumatology and Immunology Shanghai Sixth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200233China

To the Editor:Psoriatic arthritis(PsA)is a highly heterogeneous inflammatory arthritis.It occurs in up to 30%of patients with psoriasis and can have severe impacts on peripheral joints,spine,tendon insertions,and fingers. ^([1])Radiographic progression is currently the preferred method for assessing structural damage of PsA. ^([2])Biologic treatment options for PsA include tumor necrosis factor-αinhibitors(TNFi),interleukin-12/23 inhibitors,and interleukin-17(IL-17)inhibitors.The therapeutic effects of IL-17 inhibitors on structural damage were not consistent over multiple trials.Therefore,a systematic review and meta-analysis of the available randomized controlled trials(RCTs)was conducted to quantify the overall effect of IL-17 inhibitors on structural damage in PsA.This study was registered with PROsPERO(No.CRD42022301774).

关键词： damage analysis inhibitors

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EGFR-targeted and gemcitabine-incorporated chemogene for combinatorial pancreatic cancer treatment

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Nano Research 2024年第2期17卷 848-857页

作者： Miao Xie Qiushuang Zhang Yuanyuan Guo Lijuan Zhu Xinyuan Zhu Chuan Zhang school of Chemistry and Chemical Engineering Frontiers Science Center for Transformative MoleculesInstitute of Molecular MedicineSixth people’s HospitalSchool of MedicineShanghai Key Laboratory for Molecular Engineering of Chiral DrugsShanghai Jiao Tong UniversityShanghai 200240China Department of Radiology Shanghai Jiao Tong University Affiliated Sixth People’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200233China Institute of Molecular medicine Shanghai Jiao Tong University Affiliated Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China

Pancreatic cancer stands out as a recognized intractable tumor due to its high malignancy and mortality rates,which are largely attributed to the insensitivity of current clinical chemotherapies or multidrug-resistance.Combinatorial chemo and gene therapy that integrates different therapeutic targets,may increase the chemosensitivity of pancreatic cancer and synergistically enhance the antitumor efficacy.However,conventional co-delivery of gene and chemo drugs is intensively dependent on complex nanoparticle delivery systems,thus would be limited by unstable drug packaging,nonspecific biodistribution,and biosafety problem.Herein,we rationally designed an epidermal growth factor-receptor(EGFR)-targeted and gemcitabine-incorporated oligonucleotide(termed as chemogene)with anti-Bcl-2 sequence,which achieves simple and precise integration of gemcitabine into a gene regulative agent,as well as the EGFR-targeted delivery for pancreatic cancer therapy.Through solid-phase synthesis,gemcitabine,as the first-line chemodrug for pancreatic cancer,is introduced to the antisense oligonucleotide to replace all cytosine nucleosides to obtain the gemcitabine-integrated chemogene(Ge-AsO^(Bcl-2)).Thereafter,Ge-AsO^(Bcl-2)is covalently coupled with EGFR nanobody to construct the final targeted chemogene without any exogenous carriers.Notably,this nanobody-conjugated chemogene exhibits remarkable tumor targeting capability and antitumor effects both in vitro and in vivo,which initiates a first step toward the application of combinatorial chemo and gene therapy for future pancreatic cancer treatment.

关键词： antisense oligonucleotide chemogene nanobody drug delivery system pancreatic cancer

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Laponite intercalated biomimetic multilayer coating prevents glucocorticoids induced orthopedic implant failure

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Bioactive Materials 2023年第4期22卷 60-73页

作者： Zhe Liu Qian Tang Ruo-Tao Liu Ming-Zhao Yu Hao Peng Chang-Qing Zhang Zhen-Zhong Zhu Xiao-Juan Wei Department of Orthopedic surgery Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine600 Yishan RoadShanghai200233China Institute of Microsurgery on Extremities Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine600 Yishan RoadShanghai200233China

Implant failure,which is commonly associated with failure of osseointegration and peri-implant infection,is a severe complication of orthopedic surgery.In particular,the survival rate of implants is significantly decreased in patients using long-term glucocorticoids(GCs).However,the exact molecular mechanism underlying GCs-induced implant loosening,as well as preventive strategies for these patients,is unclear.To address this problem,we performed RNA-sequencing and found that WNT16 was correlated with GCs-induced osteopenia(LogFC=-5.17,pspired by the concept of“organic-inorganic”hybrid,we theorized to introduce a bioactive two-dimensional nanosheet into a layer-by-layer(LbL)self-assembly coating to construct a customized implant that targets WNT16.After screening commercially available nanosheets,laponite(LAP)was identified as a cost-effective rescuer for GCs-induced WNT16 inhibition,which was then intercalated into LbL deposition system consisting of quaternized chitosan(QCs)and hyaluronic acid(HA).The hybrid coating(QCs/HA/LAP)showed micrometer thickness and improved hydrophilicity and interface roughness.Furthermore,QCs/HA/LAP coated polyetheretherketone(PEEK)implant enhanced cell viability,adhesion,and osteogenic differentiation of bone marrow mesenchymal stem cells(BMsCs),and promoted osteointegration of PEEK in GCs-treated rats by targeting the WNT16/β-catenin axis.The assembled QCs has proven antibacterial properties,and the hybrid coating exerted potent detrimental effects against methicillin-resistant staphylococcus aureus(MRsA)and Escherichia coli(E.coli),both in vitro and in vivo.Taken together,these results suggest that QCs/HA/LAP coating has great potential for use in implants customization,and has synergistic pro-osteogenic and antibacterial effects that help prevent implant failure in GCs-treated patients.

关键词： Layer-by-layer self-assembly Organic-inorganic hybrid Glucocorticoid Osseointegration Antibacterial

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Photoacoustic image-guided corpus cavernosum intratunical injection of adipose stem cell-derived exosomes loaded polydopamine thermosensitive hydrogel for erectile dysfunction treatment

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Bioactive Materials 2022年第3期7卷 147-156页

作者： Li Liang Yi shen Zhifeng Dong Xin Gu Department of Respiratory and Critical Care medicine Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080China Bio-ID Center School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai200240China Department of Cardiology Shanghai Sixth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai200233China Department of Urology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of Medicine201999China

stem cell-derived exosomes(sC-EXO)was an emerging therapeutic agent in regenerative medicine.Intratunical injection of sC-EXO is considered as a prospective approach for erectile dysfunction(ED)treatment.However,high vascularization of cavernous body makes effective retention a major challenge for sC-EXO intratunical injection.In this study,a Polydopamine nanoparticles(PDNPs)incorporated poly(ethylene glycol)-poly(ε-caprolactone-co-lactide)(PDNPs-PELA)thermosensitive hydrogels were fabricated by a facile in situ polymerization for intratunical administration of adipose stem cell-derived exosomes(EXO).The hydrogels exhibited sol-gel transition at body temperature.Moreover,the in-situ polymerization of PDNPs using poly(ethylene glycol)-poly(ε-caprolactone-co-lactide)(PELA)block copolymer as a template was found to be more stable dispersion in the gel system.After being encapsulated into the hydrogel,EXO shows sustained release behavior within two weeks.In vivo animal experiments revealed that exosomes released from hydrogel lead to the healing of endothelial cells and neurons,increase of the cavity’s pressure,thereby restoring the erectile function.In particular,since the PDNPs in thermosensitive gels have excellent photoacoustic performance,the hydrogel can be accurately delivered into the tunica albuginea by the guidance of real-time photoacoustic imaging.These results suggest that the as-prepared PDNPs-PELA has a promising future as an injectable exosome carrier for ED treatment.

关键词： Photoacoustic imaging Exosomes Thermosensitive gel Intratunical injection Erectile dysfunction

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Expression profiles of circulating tRNA-derived small RNAs and their potential role in diabetes

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BIOCELL 2023年第7期47卷 1645-1650页

作者： JING JIN XIE LI TING QIU LEI sONG YUANYUE CUI GUANGYA ZHANG sHU LI WENCHENG ZHAO Department of Ophthalmology Shanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghai200127China Department of Ophthalmology Shanghai General HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200080China Department of Endocrinology Shanghai Ninth People’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200011China Department of Cardiology Shanghai Sixth People’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200233China Department of Medical Oncology Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China

This work aimed to reveal the expression profiles of tRNA-derived small RNAs(tsRNAs)in diabetes.Methods:Thirty-five diabetes patients and thirty-three controls were enrolled.The serum samples of 4 diabetes patients and 4 controls were subjected to tRF and tiRNA polymerase chain reaction(PCR)Array analysis.Then quantitative PCR(qPCR)validation was performed on all the samples.Bioinformatics analyses were conducted to explore their functions.Results:We found 115 tsRNAs that significantly differed between the two groups.3′tiR-080-ProTGG(mt)was selected for further qPCR validation in all participants,and it was significantly decreased in diabetes patients compared with controls.Bioinformatics analysis indicated that 3′tiR-080-ProTGG(mt)may play regulatory roles via the cyclic adenosine monophosphate(cAMP)signaling pathway in the pathogenesis and progression of diabetes.Conclusion:Hence,we report that circulating tsRNAs are dysregulated that could be involved in the pathogenesis of diabetes.

关键词： Diabetes Noncoding RNAs tRF tiRNA

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Prevalence of psoriatic arthritis in Chinese population with psoriasis:A multicenter study conducted by experienced rheumatologists

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Chinese Medical Journal 2023年第12期136卷 1439-1447页

作者： Hua Zhang Miao Chen Ran Cui Xia Li Kexiang Yan Lihong Chen Zhenghua Zhang Ning Yu Xinling Bi Hui Deng Yangfeng Ding Qiong Huang sheng-Ming Dai Department of Rheumatology and Immunology Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200233China Department of Dermatology Ruijin HospitalShanghai Jiao Tong University School of Medicine School of MedicineShanghai 200025China Department of Dermatology Huashan HospitalFudan UniversityShanghai Institute of DermatologyShanghai 200040China Department of Dermatology Shanghai Skin Disease HospitalShanghai 200050China Institute of Psoriasis of tongji university Shanghai 200092China Department of Dermatology Changhai HospitalNaval Medical UniversityShanghai 200433China Department of Dermatology Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200233China

Background:Reports on the prevalence of psoriatic arthritis(PsA)among Chinese patients with psoriasis are very limited.This study,conducted by rheumatologists,estimated the prevalence of PsA in a large number of Chinese patients with psoriasis.Methods:Consecutive patients with a confirmed diagnosis of psoriasis attending nine dermatology clinics in five hospitals were recruited.All psoriasis patients were asked to complete a questionnaire comprising 16 questions to identify possible cases of PsA.All patients with one or more positive answers to the questionnaire were evaluated by two experienced rheumatologists.Results:A total of 2434 psoriasis patients,including 1561 males and 873 females,were enrolled.Both the questionnaire and rheumatologists’examinations were completed in the dermatology clinics.The results identified 252 patients with PsA,comprising 168 males and 84 females.The overall prevalence of PsA among psoriasis patients was 10.4%(95%confidence interval[95%CI],9.1%-11.7%).By sex,the prevalence was 10.8%(95%CI,9.2%-12.5%)for males and 9.6%(95%CI,7.7%-11.9%)for females and there was no significant sex difference in the prevalence of PsA(P=0.38).Of the 252 PsA patients,125(49.6%,95%CI,41.3%-59.1%)were newly diagnosed by rheumatologists.Consequently,the prevalence of undiagnosed PsA among psoriasis patients was 5.2%(95%CI,4.4%-6.2%).Conclusion:The prevalence of PsA in the Chinese population with psoriasis is about 10.4%,which is almost double that of previous reports in the Chinese population,but lower than that in Caucasians.

关键词： Psoriatic arthritis Prevalence Epidemiology Underdiagnosis screening tool

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