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METTL14 downregulation drives S100A4^(+)monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2176-2192页

作者： Yue-fan Wang Wen-li Zhang Zhi-xuan Li Yue Liu Jian Tan Hao-zan Yin Zhi-chao Zhang Xian-jie Piao Min-hao Ruan Zhi-hui Dai Si-jie Wang Chen-yang Mu Ji-hang Yuan Shu-han Sun Hui Liu Fu Yang The Third Department of Hepatic Surgery Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University200438 ShanghaiChina The Department of medical Genetics Naval Medical University200433 ShanghaiChina Translational Medicine Research Center Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital100048 BeijingChina The Department of Pharmaceutical Analysis School of PharmacyNaval Medical University200433 ShanghaiChina Key Laboratory of Biosafety Defense Ministry of Education200433 ShanghaiChina shanghai Key Laboratory of medical Biodefense 200433 ShanghaiChina

Without intervention,a considerable proportion of patients with metabolism‐associated fatty liver disease(MAFLD)will progress from simple steatosis to metabolism‐associated steatohepatitis(MASH),liver fibrosis,and even hepatocellular ***,the molecular mechanisms that control progressive MAFLD have yet to be fully ***,we unraveled that the expression of the N6-methyladenosine(m6A)methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD,whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation,liver injury,and ***,hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet(HFD).Notably,in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner,which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1^(+)Ccr2^(+)monocyte-derived macrophages(Mo-macs).In detail,Cx3cr1^(+)Ccr2^(+)Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells(HSCs)to promote liver *** experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1^(+)Ccr2^(+)*** of METTL14 or GLS2,or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and *** together,these findings indicate potential therapies for the treatment of MAFLD progression.

关键词： S100A4 MyD88 metabolism

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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 *** we revealed the immunosuppressive effect of folic acid by targeting splenic marginal zone B(MZB)*** 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 *** induced anergy of MZB cells by folic acid provides an immunological escaping window for *** 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 *** 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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Tissue adhesive,ROS scavenging and injectable PRP-based‘plasticine’for promoting cartilage repair

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Regenerative Biomaterials 2024年第1期3卷 94-107页

作者： Shiao Li Dawei Niu Haowei Fang Yancheng Chen Jinyan Li Kunxi Zhang Jingbo Yin Peiliang Fu Department of Orthopedics Shanghai Changzheng HospitalNaval Medical UniversityShanghai 200003P.R.China Department of Polymer Materials School of Materials Science and EngineeringShanghai UniversityShanghai 200444P.R.China

Platelet-rich plasma(PRP)that has various growth factors has been used clinically in cartilage ***,the short residence time and release time at the injury site limit its therapeutic *** present study fabricated a granular hydrogel that was assembled from gelatin microspheres and tannic acid through their abundant hydrogen *** microspheres with the gelatin concentration of 10wt%and the diameter distribution of 1-10 lm were used to assemble by tannic acid to form the granular hydrogel,which exhibited elasticity under low shear strain,but flowability under higher shear *** viscosity decreased with the increase in shear ***,the granular hydrogel exhibited self-healing feature during rheology ***,granular hydrogel carrying PRP not only exhibited well-performed injectability but also performed like a‘plasticine’that possessed good *** granular hydrogel showed tissue adhesion ability and reactive oxygen species scavenging *** hydrogel carrying PRP transplanted to full-thickness articular cartilage defects could integrate well with native cartilage,resulting in newly formed cartilage articular fully filled in defects and well-integrated with the native cartilage and subchondral *** unique features of the present granular hydrogel,including injectability,plasticity,porous structure,tissue adhesion and reactive oxygen species scavenging provided an ideal PRP carrier toward cartilage tissue engineering.

关键词： cartilage regeneration granular hydrogel gelatin tannic acid PRP

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Bromocriptine protects perilesional spinal cord neurons from lipotoxicity after spinal cord injury

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Neural Regeneration Research 2024年第5期19卷 1142-1149页

作者： Ying Peng Zhuoxuan Li Zhiyang Zhang Yinglun Chen Renyuan Wang Nixi Xu Yuanwu Cao Chang Jiang Zixian Chen Haodong Lin Trauma Center Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Orthopedics Zhongshan HospitalFudan UniversityShanghaiChina Department of Rehabilitation Medicine Shanghai Geriatric Medical CenterShanghaiChina

Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the ***,how lipids are metabolized by spinal cord neurons after spinal cord injury remains ***,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord *** found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in *** droplet accumulation could be induced by myelin debris in HT22 *** debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative *** oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell *** was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 *** function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord *** results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.

关键词： bromocriptine central nervous system cytosolic phospholipase A2 high-content screening lipid droplet lipid metabolism lipotoxicity mitogen-activated protein kinase spinal cord injury spinal cord neurons

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Risk evaluation for diabetic retinopathy in Chinese renalbiopsied type 2 diabetes mellitus patients

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International Journal of Ophthalmology(English edition) 2024年第7期17卷 1283-1291页

作者： Shou-Yue Huang Qi-Wei Hu Ze-Wei Zhang Ping-Yan Shen Qiong Zhang Department of Ophthalmology Ruijin Hospital Affiliated Medical SchoolShanghai Jiao Tong UniversityShanghai 200025China Department of Nephrology Ruijin Hospital Affiliated Medical SchoolShanghai Jiao Tong UniversityShanghai 200025China

AIM:To investigate diabetic retinopathy(DR)prevalence in Chinese renal-biopsied type 2 diabetes mellitus(T2DM)patients with kidney dysfunction,and to further evaluate its relationship with diabetic nephropathy(DN)incidence and the risk factors for DR development in this ***:A total of 84 renal-biopsied T2DM patients were *** and imaging examinations were employed for DR *** information and clinical measures along with renal histopathology were analyzed for comparisons between the DR and non-DR *** factors on DR development were analyzed with multiple logistic ***:DR prevalence was 50%in *** incidences of DN,non-diabetic renal disease(NDRD)and mixed-type pathology were 47.6%,19.0%and 33.3%in the DR group respectively,while 11.9%,83.3%and 4.8%in the non-DR *** blood pressure,ratio of urinary albumin to creatine ratio,urinary albumin,24-hours urinary protein,the incidence and severity of DN histopathology were found statistically increased in the DR *** logistic regression analysis showed histopathological DN incidence significantly increased the risk of DR development[odds ratio(OR)=21.664,95%confidential interval(CI)5.588 to 83.991,P<0.001 for DN,and OR=45.475,95%CI 6.949 to 297.611,P<0.001 for mixed-type,respectively,in reference to (NDRD)],wherein DN severity positively ***:Renal histopathological evidence indicates DN incidence and severity increases the risk of DR development in Chinese T2DM patients inexperienced of regular fundus examinations.

关键词： diabetic retinopathy diabetic nephropathy vision threatens renal biopsy vision screening

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Advanced rehabilitation in ischaemic stroke research

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Stroke & Vascular Neurology 2024年第4期9卷 328-343页

作者： Jixian Wang Yongfang Li Lin Qi Muyassar Mamtilahun Chang Liu Ze Liu Rubing Shi Shengju Wu Guo-Yuan Yang Department of Rehabilitation Medicine Ruijin HospitalShanghai Jiao Tong University School of MedicalShanghaiChina Med-X Research Institute and School of Biomedical Engineering Shanghai Jiao Tong UniversityShanghaiChina

At present,due to the rapid progress of treatment technology in the acute phase of ischaemic stroke,the mortality of patients has been greatly reduced but the number of disabled survivors is increasing,and most of them are elderly *** and rehabilitation therapists pay attention to develop all kinds of therapist techniques including physical therapy techniques,robot-assisted technology and artificial intelligence technology,and study the molecular,cellular or synergistic mechanisms of rehabilitation therapies to promote the effect of rehabilitation ***,we discussed different animal and in vitro models of ischaemic stroke for rehabilitation studies;the compound concept and technology of neurological rehabilitation;all kinds of biological mechanisms of physical therapy;the significance,assessment and efficacy of neurological rehabilitation;the application of brain–computer interface,rehabilitation robotic and non-invasive brain stimulation technology in stroke rehabilitation.

关键词： stimulation mortality acute

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Effects of dietary intervention on human diseases:molecular mechanisms and therapeutic potential

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1389-1422页

作者： Yu-Ling Xiao Yue Gong Ying-Jia Qi Zhi-Ming Shao Yi-Zhou Jiang Key Laboratory of Breast Cancer in shanghai Department of Breast SurgeryFudan University Shanghai Cancer CenterShanghaiChina Department of Oncology Shanghai Medical CollegeFudanUniversityShanghai200032China

Diet,serving as a vital source of nutrients,exerts a profound influence on human health and disease ***,dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases,autoimmune diseases,cardiovascular diseases,and metabolic *** interventions have demonstrated substantial potential in modulating metabolism,disease trajectory,and therapeutic *** reprogramming is a hallmark of malignant progression,and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer *** intake,as a key environmental factor,can influence tumor *** evidence indicates that dietary interventions might affect the nutrient availability in tumors,thereby increasing the efficacy of cancer ***,the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is *** encouraging results,the mechanisms underlying diet-based therapeutic strategies remain largely unexplored,often resulting in underutilization in disease *** this review,we aim to illuminate the potential effects of various dietary interventions,including calorie restriction,fasting-mimicking diet,ketogenic diet,protein restriction diet,high-salt diet,high-fat diet,and high-fiber diet,on cancer and the aforementioned *** explore the multifaceted impacts of these dietary interventions,encompassing their immunomodulatory effects,other biological impacts,and underlying molecular *** review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.

关键词： diseases metabolism potential

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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 *** this dichotomy in mind,it is extremely important to find ways to preserve celastrol’s efficacy while reducing or preventing its ***:In this study,insulin-resistant Hep G2(IR-Hep G2)cells were prepared using palmitic acid and used for in vitro ***-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 *** 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 ***:Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-Hep G2 *** downregulated glutathione peroxidase 4(GPX4)m *** docking models predicted that solute carrier family 7 member 11(SLC7A11)and GPX4 were covalently bound by ***,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 ***:One potential mechanism of celastrol’s cytotoxicity is the induction of ferroptosis,which can be alleviated by treatment with ferroptosis *** 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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The anti-inflammatory effects of exercise on autoimmune diseases:A 20-year systematic review

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Journal of Sport and Health Science 2024年第3期13卷 353-367,I0001页

作者： Beibei Luo Dao Xiang Xiaorong Ji Xuan Chen Rui Li Shuxin Zhang Yujun Meng David C.Nieman Peijie Chen School of Exercise and Health Shanghai University of SportShanghai 200438China shanghai Key Laboratory of Human Performance Shanghai University of SportShanghai 200438China Department of Diving and Hyperbaric Medicine Naval Medical CenterShanghai 200433China National Key Laboratory of Immunity and Inflammation Naval Medical UniversityShanghai 200433China Human Performance Laboratory Appalachian State UniversityNorth Carolina Research CampusKannapolisNC 28081USA Research Institute for Doping Control Shanghai University of SportShanghai 200438China

Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune *** aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune ***:PubMed,Web of Science,and Embase databases were systematically reviewed for related studies published between January 1,2003,and August 31,*** randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were *** quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk ***:A total of 14,565 records were *** screening the titles,abstracts,and full texts,87 were eligible for the systematic *** studies were conducted in 25 different countries and included a total of 2779 participants(patients with autoimmune disease,in exercise or control groups).Overall,the evidence suggests that inflammation-related markers such as C-reactive protein,interleukin 6,and tumor necrosis factor a were reduced by regular exercise *** exercise interventions combined with multiple exercise modes were associated with greater ***:Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory *** systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune *** patients with autoimmune disease can safely adopt moderate exercise training protocols,but changes in inflammation biomarkers will be modest at *** exercise interventions are ineffective or even modestly but transiently pro-inflammatory.

关键词： Autoimmune diseases Cytokines Inflammation Physical activity Training

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Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

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Zoological Research 2024年第3期45卷 506-517页

作者： Xilei Peng Haonan Dong Lixing Zhang Suling Liu Fudan university shanghai Cancer Center&Institutes of Biomedical Sciences/State Key Laboratory of Genetic Engineering/Cancer Institutes/Department of Oncology/Key Laboratory of Breast Cancer in shanghai/shanghai Key Laboratory of medical Epigenetics/shanghai Key Laboratory of Radiation Oncology/International Co-laboratory of medical Epigenetics and Metabolism Ministry of Science and Technology/Shanghai Medical College/Fudan UniversityShanghai 200032China

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and *** cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and *** have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast *** tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ***,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer *** this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory ***,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during ***,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

关键词： Breast cancer Metastasis Cancer stem cell Ecosystem Tumor microenvironment Mouse model

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