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Exosomes derived from microglia overexpressing miR-124-3p alleviate neuronal endoplasmic reticulum stress damage after repetitive mild traumatic brain injury

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Neural Regeneration Research 2024年第9期19卷 2010-2018页

作者： Yan Wang Dai Li Lan Zhang Zhenyu Yin Zhaoli Han Xintong Ge Meimei Li Jing Zhao Shishuang Zhang Yan Zuo Xiangyang Xiong Han Gao Qiang Liu Fanglian Chen Ping Lei Department of Geriatrics Tianjin Medical University General HospitalTianjinChina tianjin Geriatrics Institute Tianjin Medical University General HospitalTianjinChina tianjin Neurological Institute Tianjin Medical University General HospitalTianjinChina

We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.

关键词： apoptosis C/EBP homologous protein endoplasmic reticulum stress exosome inositol-requiring enzyme 1α microglia miR-124-3p neuron repetitive mild traumatic brain injury X-box binding protein 1

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Neoantigen cancer vaccines:a new star on the horizon

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Cancer Biology & Medicine 2024年第4期21卷 274-311页

作者： Xiaoling Li Jian You Liping Hong Weijiang Liu Peng Guo Xishan Hao Cell Biotechnology Laboratory Tianjin Cancer Hospital Airport HospitalTianjin 300308China National Clinical Research Center for Cancer Tianjin 300060China Haihe Laboratory of Synthetic Biology Tianjin 300090China Department of Thoracic Oncology Tianjin Cancer Hospital Airport HospitalTianjin 300308China Department of Thoracic Oncology Surgery Tianjin Medical University Cancer Institute&HospitalTianjin 300060China tianjin Medical University Cancer Institute&hospital Tianjin 300060China

Immunotherapy represents a promising strategy for cancer treatment that utilizes immune cells or drugs to activate the patient's own immune system and eliminate cancer cells.One of the most exciting advances within this field is the targeting of neoantigens,which are peptides derived from non-synonymous somatic mutations that are found exclusively within cancer cells and absent in normal cells.Although neoantigen-based therapeutic vaccines have not received approval for standard cancer treatment,early clinical trials have yielded encouraging outcomes as standalone monotherapy or when combined with checkpoint inhibitors.Progress made in high-throughput sequencing and bioinformatics have greatly facilitated the precise and efficient identification of neoantigens.Consequently,personalized neoantigen-based vaccines tailored to each patient have been developed that are capable of eliciting a robust and long-lasting immune response which effectively eliminates tumors and prevents recurrences.This review provides a concise overview consolidating the latest clinical advances in neoantigen-based therapeutic vaccines,and also discusses challenges and future perspectives for this innovative approach,particularly emphasizing the potential of neoantigen-based therapeutic vaccines to enhance clinical efficacy against advanced solid tumors.

关键词： Immunotherapy neoantigen cancer vaccine solid tumors high-throughput sequencing bioinformatics PDOs AI HLA TCR

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Immunomodulation of adipose-derived mesenchymal stem cells on peripheral blood mononuclear cells in colorectal cancer patients with COVID-19

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 2113-2122页

作者： Jun-Feng Wang Xiao-Xia Yang Jian Zhang Yan Zheng Fu-Qing Zhang Xiao-Feng Shi Yu-Liang Wang Department of Colorectal Oncology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China Department of Neurology Tianjin First Center HospitalTianjin 300192China Prosthodontics Studio Tianjin Stomatological HospitalTianjin 300041China Department of Clinical Laboratory Medicine Tianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin 300211China Department of Emergency Tianjin First Central HospitalTianjin 300192China

BACKGROUND Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells(ADSCs)are an effective therapeutic approach for managing coronavirus disease 2019(COVID-19);however,further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors(TFs)and cytokine release in peripheral blood mononuclear cells(PBMCs).AIM To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer(CRC)patients with severe COVID-19(CRC^(+)patients).METHODS PBMCs from CRC^(+)patients(PBMCs-C+)and age-matched CRC patients(PBMCs-C)were stimulated and cultured in the presence/absence of ADSCs.The mRNA levels of T-box TF TBX21(T-bet),GATA binding protein 3(GATA-3),RAR-related orphan receptor C(RORC),and forkhead box P3(FoxP3)in the PBMCs were determined by reverse transcriptase-polymerase chain reaction.Culture supernatants were evaluated for levels of interferon gamma(IFN-γ),interleukin 4(IL-4),IL-17A,and transforming growth factor beta 1(TGF-β1)using an enzyme-linked immunosorbent assay.RESULTS Compared with PBMCs-C,PBMCs-C+exhibited higher mRNA levels of T-bet and RORC,and increased levels of IFN-γ and IL-17A.Additionally,a significant decrease in FoxP3 mRNA and TGF-β1,as well as an increase in Tbet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios were observed in PBMCs-C+.Furthermore,ADSCs significantly induced a functional regulatory T cell(Treg)subset,as evidenced by an increase in FoxP3 mRNA and TGF-β1 release levels.This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC,release of IFN-γ and IL-17A,and T-bet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios,compared with the PBMCs-C+alone.CONCLUSION The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+,favoring Treg responses.Thus,ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond

关键词： Colorectal cancer COVID-19 Adipose-derived mesenchymal stem cells T helper cell Immunomodulation

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Symmetry of upper eyelid after unilateral blepharoptosis repair with minimally invasive conjoint fascial sheath suspension technique

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International Journal of Ophthalmology(English edition) 2024年第1期17卷 53-60页

作者： Yianzhu Liu Wenli Chen Xia Chen tianjin Eye hospital Tianjin 300020China tianjin Key Lab of Ophthalmology and Visual Science Tianjin 300020China

AIM:To investigate the symmetry of upper eyelid in patients with unilateral mild and moderate blepharoptosis who underwent unilateral minimally invasive combined fascia sheath(CFS)suspension.METHODS:A retrospective study of patients who underwent unilateral minimally invasive CFS suspension surgery between January 2018 and December 2021.Inclusion criteria included unilateral mild and moderate ptosis,good levator muscle function(>9 mm)and follow-up of at least 6mo.Pre-and post-operative symmetry was graded subjectively for marginal reflex distance 1(MRD1),tarsal platform show(TPS)and eyebrow fat span(BFS).A t-test was used to evaluate MRD1,TPS and BFS asymmetry by calculating delta values.The Bézier curve tool of the Image J software was used to extract the upper eyelid contours,where the symmetry was measured by the percentage of overlapping curvatures(POC).RESULTS:Totally 105 patients(105 eyelids)were included(mild group,n=84;moderate group,n=21).Postoperatively,all patients increased MRD1 and decreased TPS in the ptotic eye while maintaining unchanged BFS.The asymmetric delta value for MRD1 was measured to be 1.48±0.86 preoperatively,and it decreased to 0.58±0.67 postoperatively in all cases(P=0.0004).In patients with mild ptosis,the asymmetry value of TPS fell significantly from 1.15±0.62 to 0.68±0.38(P=0.0187).The symmetry of the upper eyelid contour increased in all subgroups of patients,with a POC of 59.39%±13.45%preoperatively and POC of 78.29%±13.80%postoperatively.CONCLUSION:Minimally invasive CFS suspension is proved to be an effective means of improving the symmetry of unilateral ptosis in terms of MRD1(all subgroups),POC(all subgroups)and TPS(only mild group),whereas BFS is unaffected.

关键词： symmetry unilateral blepharoptosis minimally invasive combined fascia sheath suspension

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Circ_0003855 involvement of esophageal cancer progression through miR-622/FLOT1

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Oncology Research 2024年第5期32卷 925-931页

作者： JINGJING TIAN XIBAO HU XINRONG ZHANG Department of Gastroenterology Tianjin Nankai HospitalTianjin300100China Department of Digestive Medicine First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjin300100China

To confirm the relationship between Circ_0003855 and EC,we purchased the Human esophageal carcinoma cell line Eca109 and normal human esophageal epithelial cells HEEC,and the expression levels of Circ_0003855,miR-622,and FLOT1 were detected.The results show that Circ_0003855 and FLOT1 were highly expressed in Eca109 cells,while miR-622 was lowly expressed(p0.05).Synthesizing the results of these experiments above,we believe that interfering with the expression of Circ_0003855 can inhibit the activity of EC cells,and its mechanism is related to miR-622 and FLOT1.

关键词： Circ_0003855 miR-622 FLOT1 Esophageal cancer Cell proliferation

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Clinical outcome and prognostic factors of T4N0M0 colon cancer after R0 resection:A retrospective study

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1869-1877页

作者： Bang Liu Zhao-Xiong Zhang Xin-Yang Nie Wei-Lin Sun Yong-Jia Yan Wei-Hua Fu Department of General Surgery Tianjin Medical University General HospitalTianjin Medical UniversityTianjin 300052China

BACKGROUND Paradoxically,patients with T4N0M0(stage II,no lymph node metastasis)colon cancer have a worse prognosis than those with T2N1-2M0(stage III).However,no previous report has addressed this issue.AIM To screen prognostic risk factors for T4N0M0 colon cancer and construct a prognostic nomogram model for these patients.METHODS Two hundred patients with T4N0M0 colon cancer were treated at tianjin Medical University General hospital between January 2017 and December 2021,of which 112 patients were assigned to the training cohort,and the remaining 88 patients were assigned to the validation cohort.Differences between the training and validation groups were analyzed.The training cohort was subjected to multi-variate analysis to select prognostic risk factors for T4N0M0 colon cancer,followed by the construction of a nomogram model.RESULTS The 3-year overall survival(OS)rates were 86.2%and 74.4%for the training and validation cohorts,respectively.Enterostomy(P=0.000),T stage(P=0.001),right hemicolon(P=0.025),irregular review(P=0.040),and carbohydrate antigen 199(CA199)(P=0.011)were independent risk factors of OS in patients with T4N0M0 colon cancer.A nomogram model with good concordance and accuracy was constructed.CONCLUSION Enterostomy,T stage,right hemicolon,irregular review,and CA199 were independent risk factors for OS in patients with T4N0M0 colon cancer.The nomogram model exhibited good agreement and accuracy.

关键词： T4N0M0 colon cancer Prognosis Multivariate analysis Nomogram Colon cancer

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Single-cell RNA sequencing reveals abnormal transcriptome signature of erythroid progenitors in pure red cell aplasia

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Genes & Diseases 2024年第1期11卷 49-52页

作者： Yumei Liu Haiyue Niu Jie Ren Zhiqin Wang Li Yan Limin Xing Zonghong Shao Rong Fu Zhigang Cai Huaquan Wang Department of Hematology Tianjin Medical University General HospitalTianjin 300052China School of Basic Medical Sciences Tianjin Medical UniversityTianjin 300070China

Pure red cell aplasia(PRCA)is a bone marrow failure syndrome characterized by severe anemia,reticulocytopenia,selective reduction,and even the absence of bone marrow erythroid precursors,while leukocyte and platelet counts are normal.1 Acquired PRCA can be divided into primary and secondary.Both are mediated by immune responses.Reduction in the quantity and dysfunction of committed erythroid progenitors(EPs),including burst forming uniterythroid(BFU-E)and colony forming unit-erythroid(CFU-E),may be the source of reduced erythropoiesis and needs to be elucidated.

关键词： progenitor anemia leukocyte

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Establishment and validation of an adherence prediction system for lifestyle interventions in non-alcoholic fatty liver disease

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World Journal of Gastroenterology 2024年第10期30卷 1393-1404页

作者： Ming-Hui Zeng Qi-Yu Shi Liang Xu Yu-Qiang Mi Clinical School of the Second People’s hospital Tianjin Medical UniversityTianjin 300192China Department of Gastroenterology Cangzhou People’s HospitalCangzhou 061000Hebei ProvinceChina Department of Hepatology Tianjin Second People’s HospitalTianjin 300192China tianjin Research Institute of Liver Diseases Tianjin 300192China

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is the most common liver disease worldwide,affecting about 1/4th of the global population and causing a huge global economic burden.To date,no drugs have been approved for the treatment of NAFLD,making the correction of unhealthy lifestyles the principle method of treatment.Identifying patients with poor adherence to lifestyle correction and attempting to improve their adherence are therefore very important.AIM To develop and validate a scale that can rapidly assess the adherence of patients with NAFLD to lifestyle interventions.METHODS The Exercise and Diet Adherence Scale(EDAS)was designed based on com-pilation using the Delphi method,and its reliability was subsequently evaluated.Demographic and laboratory indicators were measured,and patients completed the EDAS questionnaire at baseline and after 6 months.The efficacy of the EDAS was evaluated in the initial cohort.Subsequently,the efficacy of the EDAS was internally verified in a validation cohort.RESULTS The EDAS consisted of 33 items in six dimensions,with a total of 165 points.Total EDAS score correlated significantly with daily number of exercise and daily reduction in calorie intake(P500 kacl/d),(sensitivity/specificity was 100.0%/75.8%),while patients score below 97 could nearly rule out the possibility of daily exercise(sensitivity/specificity was 89.5%/44.4%).Total EDAS scores≥116,97-115,and<97 points were indicative of good,average,and poor adherence,respectively,to diet and exercise recommendations.CONCLUSION The EDAS can reliably assess the adherence of patients with NAFLD to lifestyle interventions and have clinical application in this population.

关键词： Fatty liver Lifestyle intervention Behavioral change Patient adherence Compliance

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Regulation of specific abnormal calcium signals in the hippocampal CA1 and primary cortex M1 alleviates the progression of temporal lobe epilepsy

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Neural Regeneration Research 2024年第2期19卷 425-433页

作者： Feng Chen Xi Dong Zhenhuan Wang Tongrui Wu Liangpeng Wei Yuanyuan Li Kai Zhang Zengguang Ma Chao Tian Jing Li Jingyu Zhao Wei Zhang Aili Liu Hui Shen Laboratory of Neurobiology School of Biomedical EngineeringTianjin Medical UniversityTianjinChina Institute for Translational Neuroscience the Second Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina Institute for Translational Brain Research Fudan UniversityShanghaiChina Department of Radiology the Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingJiangsu ProvinceChina Innovative Institute of Chinese Medicine and Pharmacy Shandong University of Traditional Chinese MedicineJinanChina Department of Anesthesiology Tianjin Medical University General HospitalTianjinChina Department of Orthopaedics Tianjin Medical University General HospitalTianjinChina tianjin Eye hospital Tianjin Eye InstituteTianjin Key Lab of Ophthalmology and Visual ScienceTianjinChina Laboratory of Neurobiology School of Basic Medical SciencesTianjin Medical UniversityTianjinChina

Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and is not fully understood.Intracellular calcium dynamics have been implicated in temporal lobe epilepsy.However,the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown,and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice.In this study,we used a multichannel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process.We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes.In particular,cortical spreading depression,which has recently been frequently used to represent the continuously and substantially increased calcium signals,was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from gradeⅡto gradeⅤ.However,vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures.Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to gradeⅠepisodes.In addition,the latency of cortical spreading depression was prolonged,and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced.Intriguingly,it was possible to rescue the altered intracellular calcium dynamics.Via simultaneous analysis of calcium signals and epileptic behaviors,we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced,and that the end-point behaviors of temporal lobe epilepsy were improved.Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to diff

关键词： Ca^(2+) calcium signals chemogenetic methods hippocampus primary motor cortex pyramidal neurons temporal lobe epilepsy

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Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease

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Neural Regeneration Research 2024年第3期19卷 619-628页

作者： Jun Chang Yujiao Li Xiaoqian Shan Xi Chen Xuhe Yan Jianwei Liu Lan Zhao First Teaching hospital of tianjin University of Traditional Chinese Medicine TianjinChina National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion TianjinChina tianjin University of Traditional Chinese Medicine TianjinChina

Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.

关键词： Alzheimer’s disease amyloid-β cell therapy extracellular vesicle neural stem cell synaptic plasticity tau

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