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BMSC-derived Exosomes Ameliorate Peritoneal Dialysis-associated Peritoneal Fibrosis via the Mir-27a-3p/TP53 Pathway

Current Medical Science 2024年第2期44卷 333-345页

作者： Jun-li ZHAO Lin ZHAO Qiu-nan ZHAN Miao LIU Ting ZHANG Wen-wen CHU Department of Nephrology Shanghai University of Medicine&Health Sciences Ailiated Zhoupu HospitalShanghai 201318China Orthopedic Department Guangming Traditional Chinese Medicine Hospital of Pudong New AreaShanghai 201399China

Objective:Peritoneal fibrosis(PF)is the main cause of declining efficiency and ultrafiltration failure of the peritoneum,which restricts the long-term application of peritoneal dialysis(PD).This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes(BMSC-Exos)on PF in response to PD.Methods:Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing.C57BL/6J mice were infused with 4.25%glucose-based peritoneal dialysis fluid(PDF)for 6 consecutive weeks to establish a PF model.A total of 36 mice were randomly divided into 6 groups:control group,1.5%PDF group,2.5%PDF group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Reverse transcription quantitative polymerase chain reaction(RT-qPCR)was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF.HE and Masson staining were performed to evaluate the extent of PF.The therapeutic potential of BMSC-Exos for PF was examined through pathological examination,RT-qPCR,Western blotting,and peritoneal function analyses.Epithelial-mesenchymal transition(EMT)of HMrSV5 was induced with 4.25%PDF.Cells were divided into control group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Cell Counting Kit-8 assay was used to measure cell viability,and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells.Results:Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs.The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos,but decreased in PD mice.We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice.Compared with the control mice,the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response,with markedly increas

关键词： peritoneal fibrosis bone marrow mesenchymal stem cell-derived exosomes miR-27a-3p TP53 epithelialmesenchymal transition

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Efficacy of physiological seawater nasal irrigation for the treatment of children with SARS-CoV-2 Omicron BA.2 variant infection:a randomized controlled trial

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World Journal of Pediatrics 2024年第5期20卷 461-469页

作者： Ji-Lei Lin Fen Zhang Yan-Bo Li Shu-Hua Yuan Jin-Hong Wu Jing Zhang Lei Zhang Yi He Jie Chen Yong Yin Department of Respiratory Medicine Shanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong University1678 Dongfang RoadPudong DistrictShanghaiChina University of British Columbia VancouverCanada Information Technology Department Shanghai Children’s Medical Center National Children’s Medical CenterSchool of MedicineShanghai Jiao Tong University1678 Dongfang RoadPudong DistrictShanghaiChina Department of Otorhinolaryngology Shanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong University1678 Dongfang RoadPudong DistrictShanghaiChina Department of Respiratory Medicine Sanya Women and Children’s Hospital Affiliated to Hainan Medical CollegeHainan Branch of Shanghai Children’s Medical CenterSanyaChina Department of Respiratory Medicine Linyi Maternal and Child Healthcare HospitalLinyiChina shanghai Children’s Medical Center Pediatric Medical Complex(pudong) ShanghaiChina Pediatric AI Clinical Application and Research Center Shanghai Children’s Medical CenterShanghaiChina

Background Saline nasal irrigation is an effective therapy for relieving common cold symptoms.This study aimed to investigate and explore the efficacy of physiological seawater nasal irrigation(PSNI)on children with mild and asymptomatic infection with Omicron.Methods This randomized controlled trial was conducted in shanghai,China,and 403 children with mild and asymptomatic infection with Omicron were included.These children were allocated into the PSNI group and the control group.The primary outcome was the duration of viral shedding(DVS),and the secondary outcome was the change in clinical symptoms.Results The median age of all participants was 5.59(6.26)years old.The DVS was significantly shorter in the PSNI group[2.40(1.13)]than in the control group[3.09(2.14)](P=0.014).The multivariable Cox regression model also showed that patients in the PSNI group had an increased probability of shorter DVS compared with patients in the control group[hazard ratio(HR),1.27;95%confidence interval(CI),1.04–1.55;P=0.017].Subgroup analysis suggested that the DVS of patients without full vaccination was significantly reduced in the PSNI group.The proportions of runny nose and stuffy nose were apparently reduced in the first three days in the PSNI group or the control group,but there was no evidence showing that PSNI contributes to the benefit compared with the control group.Conclusion PSNI can reduce the DVS of patients with mild and asymptomatic infection with SARS-CoV-2 Omicron BA.2 variant.

关键词： Children Duration of viral shedding Omicron Physiological seawater nasal irrigation

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Efficacy and safety of Yiqi Peiyuan granules for improving the short-term prognosis of patients with acute kidney injury:A multicenter,double-blind,placebo-controlled,randomized trial

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Journal of Integrative Medicine 2024年第3期22卷 279-285页

作者： Jia-jia Wu Tian-yi Zhang Ying-hui Qi Min-yan Zhu Yan Fang Chao-jun Qi Li-ou Cao Ji-fang Lu Bo-han Lu Lu-min Tang Jian-xiao Shen Shan Mou Department of Nephrology Molecular Cell Lab for Kidney DiseaseShanghai Peritoneal Dialysis Research CenterUremia Diagnosis and Treatment CenterRenji Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghai 200127China Department of Nephrology Shanghai Pudong New Area Punan HospitalShanghai 200125China Department of Nephrology Ningbo Hangzhou Bay HospitalNingbo 315336Zhejiang ProvinceChina

Background:Yiqi Peiyuan(YQPY)prescription,a composite prescription of traditional Chinese medicine,has been used to prevent or delay the continued deterioration of renal function after acute kidney injury(AKI)in some institutions and has shown considerable efficacy.Objective:This is the first randomized controlled trial to assess efficacy and safety of YQPY for improving short-term prognosis in adult patients with AKI.Design,setting,participants and interventions:This is a prospective,double-blind,multicenter,randomized,and placebo-controlled clinical trial.A total of 144 enrolled participants were randomly allocated to two groups according to a randomization schedule.Participants,caregivers and investigators assessing the outcomes were blinded to group assignment.Patients in the YQPY group received 36 g YQPY granules twice a day for 28 days.Patients in the placebo group received a placebo in the same dose as the YQPY granules.Main outcome measures:The primary outcome was the change in the estimated glomerular filtration rate(eGFR)between baseline and after 4 and 24 weeks of treatment.The secondary outcomes were the change of serum creatinine(Scr)level between baseline and after treatment,and the incidence of endpoint events,defined as eGFR increasing by more than 25%above baseline,eGFR>75 mL/min per1.73 m2or the composite endpoint,which was defined as the sum of patients meeting either of the above criteria.Results:Data from a total of 114 patients(59 in the YQPY group and 55 in the control group)were analyzed.The mean changes in eGFR and Scr in weeks 4 and 24 had no difference between the two groups.In further subgroup analysis(22 in the YQPY group and 31 in the control group),the mean change in eGFR after treatment for 4 weeks was 27.39 mL/min per 1.73 m2in the YQPY group and 5.78 mL/min per1.73 m2in the placebo group,and the mean difference between groups was 21.61 mL/min per 1.73 m2(P<0.001).Thirteen(59.1%)patients in the YQPY group and 5(16.1%)in the placebo group reached the composite endpoints(P=0.002).Du

关键词： Chinese herbal medicine Randomized controlled trial Acute kidney injury Renal function

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mIgM-mediated splenic marginal zone B cells targeting of folic acid for immunological evasion

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Acta Pharmaceutica Sinica B 2024年第2期14卷 808-820页

作者： Huan Wang Zhuxuan Jiang Zhiwei Guo Gan Luo Tianhao Ding Changyou Zhan Department of Pharmacology School of Basic Medical Sciences&Department of PharmacyShanghai Pudong HospitalFudan UniversityShanghai 200032China Department of Pharmaceutical Sciences School of PharmacyNaval Medical UniversityShanghai 200433China shanghai Engineering Research Center for Synthetic Immunology Fudan UniversityShanghai 200032China

Folic acid is a fully oxidized synthetic folate with high bioavailability and stability which has been extensively prescribed to prevent congenital disabilities.Here we revealed the immunosuppressive effect of folic acid by targeting splenic marginal zone B(MZB)cells.Folic acid demonstrates avid binding with the Fc domain of immunoglobulin M(IgM),targeting IgM positive MZB cells in vivo to destabilize IgM-B cell receptor(BCR)complex and block immune responses.The induced anergy of MZB cells by folic acid provides an immunological escaping window for antigens.Covalent conjugation of folic acid with therapeutic proteins and antibodies induces immunological evasion to mitigate the production of anti-drug antibodies,which is a major obstacle to the long-term treatment of biologics by reducing curative effects and/or causing adverse reactions.Folic acid acts as a safe and effective immunosuppressant via IgM-mediated MZB cells targeting to boost the clinical outcomes of biologics by inhibiting the production of anti-drug antibodies,and also holds the potential to treat other indications that adverse immune responses need to be transiently shut off.

关键词： Membrane-bound IgM Anti-drugantibodies Bcell anergy Folic acid Marginal zoneBcells Bcell receptor Biologics Targeting

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Development and validation of a nomogram to predict allograft survival after pediatric liver transplantation

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World Journal of Pediatrics 2024年第3期20卷 239-249页

作者： Guang-Xiang Gu Shu-Ting Pan Yi-Chen Fan Chen Chen Qiang Xia Department of Liver Surgery Renji HospitalShanghai Jiaotong University School of MedicineNo.160 Pujian RoadPudong New DistrictShanghai 200128China Department of Liver Transplantation Sun Yet-Sen Memorial HospitalSun Yat-Sen UniversityNo.107 Yanjiang West RoadGuangzhou 510080China Clinical Center for Investigation Renji HospitalShanghai Jiaotong University School of MedicineShanghaiChina Department of Anesthesiology Renji HospitalShanghai Jiaotong University School of MedicineShanghaiChina

Background Liver transplantation is the main treatment for cholestatic liver disease and some metabolic liver diseases in children.However,no accurate prediction model to determine the survival probability of grafts prior to surgery exists.This study aimed to develop an effective prognostic model for allograft survival after pediatric liver transplantation.Methods This retrospective cohort study included 2032 patients who underwent pediatric liver transplantation between January 1,2006,and January 1,2020.A nomogram was developed using Cox regression and validated based on bootstrap sampling.Predictive and discriminatory accuracies were determined using the concordance index and visualized using calibration curves;net benefits were calculated for model comparison.An online Shiny application was developed for easy access to the model.Results Multivariable analysis demonstrated that preoperative diagnosis,recipient age,body weight,graft type,preoperative total bilirubin,interleukin-1β,portal venous blood flow direction,spleen thickness,and the presence of heart disease and cholangitis were independent factors for survival,all of which were selected in the nomogram.Calibration of the nomogram indicated that the 1-,3-,and 5-year predicted survival rates agreed with the actual survival rate.The concordance indices for graft survival at 1,3,and 5 years were 0.776,0.757,and 0.753,respectively,which were significantly higher than those of the Pediatric End-Stage Liver Disease and Child-Pugh scoring systems.The allograft dysfunction risk of a recipient could be easily predicted using the following URL:https://aspelt.***.io/ASPELT/l Conclusion The allograft survival after pediatric liver transplantation(ASPELT)score model can effectively predict the graft survival rate after liver transplantation in children,providing a simple and convenient evaluation method for clinicians and patients.

关键词： Allograft survival Nomogram Pediatric liver transplantation

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温针灸结合推拿治疗颈性眩晕伴焦虑状态的疗效观察

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Journal of Acupuncture and Tuina Science 2024年第3期22卷 239-245页

作者：顾尤胡嘉威严月华潘国良董晓薇曾亮孔谐和(译) shanghai pudong hospital/pudong hospital Affiliated to Fudan University Shanghai 201399China 不详

目的:观察温针灸加推拿治疗对颈性眩晕伴焦虑患者临床症状和焦虑状态的影响。方法:将70例颈性眩晕伴焦虑状态的患者采用随机数字表法分成观察组和对照组,每组35例。在疾病宣教基础上,观察组予温针灸加推拿治疗,每周3次,对照组予甲磺酸... 详细信息

目的:观察温针灸加推拿治疗对颈性眩晕伴焦虑患者临床症状和焦虑状态的影响。方法:将70例颈性眩晕伴焦虑状态的患者采用随机数字表法分成观察组和对照组,每组35例。在疾病宣教基础上,观察组予温针灸加推拿治疗,每周3次,对照组予甲磺酸倍他司汀片口服,每日3次。两组均治疗4周。观察两组治疗后颈性眩晕评估量表(ESCV)、焦虑自评量表(SAS)和汉密尔顿焦虑量表(HAMA)的评分变化。结果:研究过程中观察组有1例因不能配合治疗而脱落。观察组总有效率和愈显率分别为94.1%和50.0%,对照组分别为88.6%和8.6%,两组总有效率和愈显率差异均有统计学意义(P<0.05)。治疗后,两组患者的ESCV、SAS和HAMA评分均较治疗前明显下降(P<0.01),且观察组各项评分低于对照组(P<0.01或P<0.05)。结论:温针灸结合推拿能显著改善颈性眩晕伴焦虑状态患者的临床症状。

关键词：温针疗法推拿按摩眩晕焦虑身心共病随机对照试验

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Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells

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Journal of Integrative Medicine 2024年第3期22卷 286-294页

作者： Jia-jia Liu Xue Zhang Bang-lan Cai Man-man Qi Yong-bin Chi Bin Peng Deng-hai Zhang School of Medicine Shanghai UniversityShanghai 200444China shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases Shanghai Pudong Gongli HospitalSecondary Military Medical UniversityShanghai 200135China School of Basic Medicine Ningxia Medical UniversityYinchuan 750004Ningxia Hui Autonomous RegionChina

Objective:Research has shown that celastrol can effectively treat a variety of diseases,yet when passing a certain dosage threshold,celastrol becomes toxic,causing complications such as liver and kidney damage and erythrocytopenia,among others.With this dichotomy in mind,it is extremely important to find ways to preserve celastrol’s efficacy while reducing or preventing its toxicity.Methods:In this study,insulin-resistant Hep G2(IR-Hep G2)cells were prepared using palmitic acid and used for in vitro experiments.IR-Hep G2 cells were treated with celastrol alone or in combination with Nacetylcysteine(NAC)or ferrostatin-1(Fer-1)for 12,24 or 48 h,at a range of doses.Cell counting kit-8assay,Western blotting,quantitative reverse transcription-polymerase chain reaction,glucose consumption assessment,and flow cytometry were performed to measure celastrol’s cytotoxicity and whether the cell death was linked to ferroptosis.Results:Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-Hep G2 cells.Celastrol downregulated glutathione peroxidase 4(GPX4)m RNA.Molecular docking models predicted that solute carrier family 7 member 11(SLC7A11)and GPX4 were covalently bound by celastrol.Importantly,we found for the first time that the application of ferroptosis inhibitors(especially NAC)was able to reduce celastrol’s toxicity while preserving its ability to improve insulin sensitivity in IR-Hep G2 cells.Conclusion:One potential mechanism of celastrol’s cytotoxicity is the induction of ferroptosis,which can be alleviated by treatment with ferroptosis inhibitors.These findings provide a new strategy to block celastrol’s toxicity while preserving its therapeutic effects.

关键词： Celastrol Insulin resistance Ferroptosis N-Acetylcysteine Palmitic acid Molecular docking

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A BBS4 mutation causes autosomal dominant polycystic liver disease

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Genes & Diseases 2024年第1期11卷 72-75页

作者： Yalu Cui Wenping Xu Jinpei Liu Shuqing Liu Wei Huang Yihai Shi Xin Zhang Cuihua Lu Weifen Xie Department of Gastroenterology Changzheng HospitalNaval Medical UniversityShanghai 200003China Department of Gastroenterology Gongli Hospital of Shanghai Pudong New AreaShanghai 200135China Department of Gastroenterology Affiliated Hospital of Nantong UniversityNantong UniversityNantongJiangsu 226001China

Autosomal dominant polycystic liver disease(ADPLD)refers to a condition characterized by the presence of numerous cholangiocytes-lined and fluid-filled cysts in the liver and the absence of polycystic kidney disease.1 Although patients with ADPLD may be asymptomatic,some patients suffer from abdominal pain,gastroesophageal reflux,and nausea,because of hepatomegaly.

关键词： liver polycystic patients

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Targeting proprotein convertase subtilisin/kexin type 9(PCSK9):from bench to bedside

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Signal Transduction and Targeted Therapy 2024年第2期9卷 509-557页

作者： Xuhui Bao Yongjun Liang Hanman Chang Tianji Cai Baijie Feng Konstantin Gordon Yuekun Zhu Hailian Shi Yundong He Liyi Xie Institute of Therapeutic Cancer Vaccines Fudan University Pudong Medical CenterShanghaiChina shanghai Key Laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghaiChina Department of Oncology Fudan University Pudong Medical CenterShanghaiChina Center for Clinical Research Fudan University Pudong Medical CenterShanghaiChina Clinical Research Center for Cell-based Immunotherapy Fudan UniversityShanghaiChina Department of Pathology Duke University Medical CenterDurhamNCUSA Center for Medical Research and Innovation Fudan University Pudong Medical CenterShanghaiChina Institute for Food Safety and Health Illinois Institute of TechnologyChicagoILUSA Department of Sociology University of MacaoTaipaMacaoChina Medical Institute Peoples’Friendship University of RussiaMoscowRussia A.Tsyb Medical Radiological Research Center ObninskRussia Department of Colorectal Surgery The First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineZhangjiang Hi-tech ParkShanghaiChina Department of Radiation Oncology Fudan University Shanghai Cancer CenterShanghaiChina Department of Oncology Shanghai Medical CollegeFudan UniversityShanghaiChina

Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9,extending beyond CVD to emphasize its significance in diverse physiological and pathological states,including liver diseases,infectious diseases,autoimmune disorders,and notably,cancer.Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors(LDLRs),elucidating its substantial impact on cholesterol homeostasis and cardiovascular health.It also details the evolution of PCSK9-targeted therapies,translating foundational bench discoveries into bedside applications for optimized patient care.The advent and clinical approval of innovative PCSK9 inhibitory therapies(PCSK9-iTs),including three monoclonal antibodies(Evolocumab,Alirocumab,and Tafolecimab)and one small interfering RNA(siRNA,Inclisiran),have marked a significant breakthrough in cardiovascular medicine.These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia,reducing cardiovascular risks,and have showcased profound value in clinical applications,offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders.Furthermore,emerging research,inclusive of our findings,unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment.This review also highlights PCSK9’s aberrant expression in various cancer forms,its association with cancer prognosis,and its crucial roles in carcinogenesis and cancer immunity.In conclusion,this synthesized review integrates existing knowledge and novel insights on PCSK9,providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders.It emphasizes the clinical

关键词： PCSK9 metabolism convert

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Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1412-1427页

作者： Jianpei Xu Yinzhe Sun Yang You Yuwen Zhang Dan Huang Songlei Zhou Yipu Liu Shiqiang Tong Fenfen Ma Qingxiang Song Chengxiang Dai Suke Li Jigang Lei Zhihua Wang Xiaoling Gao Jun Chen shanghai pudong hospital&Department of Pharmaceutics School of PharmacyFudan UniversityShanghai 201203China Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China Department of Pharmacology and Chemical Biology State Key Laboratory of Oncogenes and Related GenesShanghai Universities Collaborative Innovation Center for Translational MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Emergency Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China Institute of Science and Technology for Brain-Inspired Intelligence&Department of Neurology Fudan UniversityShanghai 201203China Department of Rehabilitation Medicine Huashan HospitalFudan UniversityShanghai 201203China Daxing Research Institute University of Science and Technology BeijingBiomedical Industry BaseZhongguancun Science and Technology ParkBeijing 102600China Cellular Biomedicine Group Inc. Shanghai 201210China

Mesenchymal stem cells(MSCs)experience substantial viability issues in the stroke infarct region,limiting their therapeutic efficacy and clinical translation.High levels of deadly reactive oxygen radicals(ROS)and proinflammatory cytokines(PC)in the infarct milieu kill transplanted MSCs,whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs’viability.Based on the intrinsic hormesis effects in cellular biology,we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy.This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer.In this system,extracellular ROSscavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a microlivable niche at the level of a single MSC for transplantation.Meanwhile,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing.The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days.This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.

关键词： Ischemic stroke Mesenchymal stem cell Cell engineering Hormesis effect Bioorthogonal chemistry Microglia Reactive oxygen spices Proinflammatory cytokines

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