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Kaempferol ameliorated levodopa-induced dyskinesia in experimental rats: A role of brain monoamines, cFOS, FosB, Parkin, Pdyn, TH, and p-JNK

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BIOCELL 2024年第3期48卷 513-523页

作者： PEI QIN MIAO LIU XIN WANG JIANHUA MA geriatrics department Chengde Central HospitalChengde067000China

Background:L-dopa(Levodopa)is well known for managing PD(Parkinson’s disease);however,its prolonged use caused dyskinesia(LID).Due to the varied presentation of LID,effective treatment options are scarce.Flavonoids reported their neuroprotective activity by ameliorating acetylcholinesterase,monoamine oxidase,and neuroinﬂammation.Kaempferol is anotherﬂavonoid bearing these potentials.Aim:To evaluate neuroprotective activity of kaempferol in dyskinetic rats.Methods:PD was developed in Sprague-Dawley rats by injecting combination of L-ascorbic acid(10µL)+6-OHDA(12µg)in medial forebrain bundle to induce neuronal damage in substantial nigra(SNr).LID was induced by administrating combination of L-dopa(20 mg/kg)+benserazide HCl(5 mg/kg)for 42 days.Rats were concomitantly treated with amantadine(40 mg/kg)or kaempferol(25,50,and 100 mg/kg,p.o.).Results:Kaempferol(50 and 100 mg/kg)markedly(p<0.05)inhibited LID-induced abnormal involuntary movements(AIMs)and alternation in motor function.Kaempferol administration considerably(p<0.05)inhibited reduced mitochondrial complex activities,serotonin and dopamine levels,Bcl-2,and Tyrosine hydroxylase protein expressions in SNr.Additionally,kaempferol considerably(p<0.05)attenuated increased cFOS,FosB,Parkin,and Pdyn mRNAs expressions,Bax,cleaved caspase-3,caspase-3,and pJNK proteins levels;DOPAC and 5-HIAA levels in SNr.A positive correlation was reported between cFOS,FosB,Parkin,Pdyn,apoptosis,and TH with AIMs.Conclusion:Kaempferol effectively attenuated L-dopa-induced AIMs and dyskinesia via amelioration of alterations in cFOS,FosB,Parkin,Pdyn,Tyrosine hydroxylase,and apoptosis in the brain SNr.

关键词： AIMs cFOS Kaempferol Levodopa-induced dyskinesia Pdyn

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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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Particularities of Anemia in the Elderly: Experience in a geriatrics department in Senegal

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Journal of Biosciences and Medicines 2023年第8期11卷 71-81页

作者： Assane Sall Massamba Bâ Pascal Tienin Babou Rokhaya Djajheté Dalahata Bâ Mamadou Coumé geriatrics department Fann/Dakar University Hospital Dakar Senegal

Background/Objective: Anemias are frequent conditions in geriatric practice. The etiologies are numerous, overlapping chronic and acute pathologies. it is also associated with high morbidity and mortality. In our context, few studies have addressed this issue, and none have been carried out in geriatric units with integrated geriatric dimensions. The aim of this study was to describe the particularities of anemia in old people in a geriatric short-stay service in Senegal. Materials and methods: This was a retrospective, descriptive study from 01 May 2019 to 31 December 2021, involving people aged 60 or over, hospitalized in the geriatrics department of Fann Hospital (Senegal) and presenting with anemia. Epidemiological, clinical and evolutionary characteristics were collected and analyzed using SPSS 24.0 software. Results: The prevalence of anemia was 32.3%. The mean age of our sample was 78.7 ± 8.5 years. Arterial high blood pressure (59.3%), diabetes mellitus (22.8%), prostate disease (12.3%) were the most frequent comorbidities. Clinical manifestations were dominated by physical asthenia (80%) and severe alteration of general condition (72%). The geriatric syndromes were essentially represented by the loss of Activities Daily Living (ADL) autonomy (65%), undernutrition (59%) and frailty (46%). The mean hemoglobin level was 8.4 g/dl ± 2.1. The main etiologies were infections (32.7%), chronic kidney disease (20.9%), iron deficiency (7.4%). The mean hospital stay was 8 days ± 3.7 days and the mortality rate was 19%. Conclusion: Anemia is a frequent occurrence in geriatric medicine, with a high morbidity and mortality rate;its expression is often atypical, with frequent geriatric syndromes;the etiologies are multiple and often interrelated, requiring an exhaustive and multidimensional approach.

关键词： Anemia Geriatric Senegal

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Association between Gene Polymorphisms and SNP-SNP Interactions of the Matrix Metalloproteinase 2 Signaling Pathway and the Risk of Vascular Senescence

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Biomedical and Environmental Sciences 2024年第2期37卷 146-156页

作者： LIAO Zhen Yu YANG Shuo HU Song LIU Jia MAO Yong Jun SUN Shu Qin department of geriatrics the Affiliated Hospital of Qingdao UniversityQingdao 266000ShandongChina department of Critical Care Medicine the Affiliated Hospital of Qingdao UniversityQingdao 266000ShandongChina

Objective This study aimed to explore the association of single nucleotide polymorphisms(SNP)in the matrix metalloproteinase 2(MMP-2)signaling pathway and the risk of vascular senescence(VS).Methods In this cross-sectional study,between May and November 2022,peripheral venous blood of151 VS patients(case group)and 233 volunteers(control group)were collected.Fourteen SNPs were identified in five genes encoding the components of the MMP-2 signaling pathway,assessed through carotid-femoral pulse wave velocity(cf PWV),and analyzed using multivariate logistic regression.The multigene influence on the risk of VS was assessed using multifactor dimensionality reduction(MDR)and generalized multifactor dimensionality regression(GMDR)modeling.Results Within the multivariate logistic regression models,four SNPs were screened to have significant associations with VS:chemokine(C-C motif)ligand 2(CCL2)rs4586,MMP2 rs14070,MMP2rs7201,and MMP2 rs1053605.Carriers of the T/C genotype of MMP2 rs14070 had a 2.17-fold increased risk of developing VS compared with those of the C/C genotype,and those of the T/T genotype had a19.375-fold increased risk.CCL2 rs4586 and MMP-2 rs14070 exhibited the most significant interactions.Conclusion CCL2 rs4586,MMP-2 rs14070,MMP-2 rs7201,and MMP-2 rs1053605 polymorphisms were significantly associated with the risk of VS.

关键词： Vascular senescence Pulse wave velocity(PWV) Single nucleotide polymorphism(SNP) Matrix metalloproteinase 2(MMP-2) Extracellular matrix(ECM) Structural degradation Multifactor dimensionality reduction(MDR)

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CircPMS1 promotes proliferation of pulmonary artery smooth muscle cells,pulmonary microvascular endothelial cells,and pericytes under hypoxia

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Animal Models and Experimental Medicine 2024年第3期7卷 310-323页

作者： Xiaoyi Hu Shang Wang Hui Zhao Yaqin Wei Ruowang Duan Rong Jiang Wenhui Wu Qinhua Zhao Sugang Gong Lan Wang Jinming Liu Ping Yuan department of Cardio-Pulmonary Circulation Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina Institute of Bismuth Science University of Shanghai for Science and TechnologyShanghaiChina department of geriatrics Shanghai Institute of GeriatricsHuadong HospitalFudan UniversityShanghaiChina department of Anesthesiology Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina

Background:Circular RNAs(circRNAs)have been recognized as significant regulators of pulmonary hypertension(PH);however,the differential expression and function of circRNAs in different vascular cells under hypoxia remain unknown.Here,we identified co-differentially expressed circRNAs and determined their putative roles in the proliferation of pulmonary artery smooth muscle cells(PASMCs),pulmonary microvascular endothelial cells(PMECs),and pericytes(PCs)under hypoxia.Methods:Whole transcriptome sequencing was performed to analyze the differential expression of circRNAs in three different vascular cell types.Bioinformatic analysis was used to predict their putative biological function.Quantitative real-time polymerase chain reaction,Cell Counting Kit-8,and EdU Cell Proliferation assays were carried out to determine the role of circular postmeiotic segregation 1(circPMS1)as well as its potential sponge mechanism in PASMCs,PMECs,and PCs.Results:PASMCs,PMECs,and PCs exhibited 16,99,and 31 differentially expressed circRNAs under hypoxia,respectively.CircPMS1 was upregulated in PASMCs,PMECs,and PCs under hypoxia and enhanced the proliferation of vascular cells.CircPMS1may upregulate DEP domain containing 1(DEPDC1)and RNA polymerase II subunit D expression by targeting microRNA-432-5p(miR-432-5p)in PASMCs,upregulate MAX interactor 1(MXI1)expression by targeting miR-433-3p in PMECs,and upregulate zinc finger AN1-type containing 5(ZFAND5)expression by targeting miR-3613-5p in PCs.Conclusions:Our results suggest that circPMS1 promotes cell proliferation through the miR-432-5p/DEPDC1 or miR-432-5p/POL2D axis in PASMCs,through the miR-433-3p/MXI1 axis in PMECs,and through the miR-3613-5p/ZFAND5 axis in PCs,which provides putative targets for the early diagnosis and treatment of PH.

关键词： circular postmeiotic segregation 1 circular RNAs hypoxia pulmonary hypertension vascular cells

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Effect of cytochrome P4502C19(CYP2C19)gene polymorphism and clopidogrel reactivity on long term prognosis of patients with coronary heart disease after PCI

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Journal of Geriatric Cardiology 2024年第1期21卷 90-103页

作者： Cheng-Yan HU Yan-Ling WANG Zhen-Xing FAN Xi-Peng SUN Shuai WANG Zhi LIU department of geriatrics Fu Xing HospitalCapital Medical UniversityBeijingChina department of Cardiology Xuanwu Hospital Capital Medical UniversityBeijingChina Emergency department of Xuanwu Hospital Capital Medical UniversityBeijingChina

Objective To investigate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity and its association with longterm clinical outcome in patients with coronary heart disease(CHD)undergoing percutaneous coronary intervention(PCI).Methods In total,675 patients were enrolled.Based on the platelet inhibition rate,patients were categorized into two groups:clopidogrel low responsiveness(CLR)and normal clopidogrel responsiveness(NCR).The CLR group was divided into ticagrelor and clopidogrel group based on the antiplatelet drugs used in the follow-up treatment.Patients were classified into three groups(normal metabolizer,intermediate metabolizer,and poor metabolizer)based on the CYP2C19 genotype.We aimed to evaluate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity.The cumulative rates of 12-month all-cause deaths,major adverse cardiovascular events(MACCEs),and bleeding events were calculated.Results CLR was observed in 44.4%of the overall population.Significant differences were observed in the platelet inhibition rate of clopidogrel among the three metabolic genotypes(P0.05).Conclusions Low response to clopidogrel in CHD patients is correlated with CYP2C19 gene polymorphism.CYP2C19 genotyping combined with platelet reactivity is an independent predictor of 12-months MACCEs in patients with clopidogrel treatment after PCI,which is better than either test alone.

关键词： CYP2C19 drugs PCI

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Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer

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Chinese Medical Journal 2024年第2期137卷 209-221页

作者： Shi Qiu Yaqi Qiu Linghui Deng Ling Nie Liming Ge Xiaonan Zheng Di Jin Kun Jin Xianghong Zhou Xingyang Su Boyu Cai Jiakun Li Xiang Tu Lina Gong Liangren Liu Zhenhua Liu Yige Bao Jianzhong Ai Tianhai Lin Lu Yang Qiang Wei department of Urology Institute of UrologyNational Clinical Research Center for Geriatrics and Center of Biomedical Big DataWest China Hospital of Sichuan UniversityChengduSichuan 610041China department of Molecular Oncology Institute of Oncology Research(IOR)Oncology Institute of Southern Switzerland(IOSI)Bellinzona 6500Switzerland department of Science and Drug Technology University of TurinTurinItaly National Clinical Research Center of geriatrics The Center of Gerontology and GeriatricsWest China HospitalSichuan UniversityChengduSichuan 610000China department of Pathology West China HospitalSichuan UniversityChengduSichuan 610041China department of Pharmaceutics and Bioengineering School of Chemical EngineeringSichuan UniversityChengduSichuan 610000China

Background:Bladder cancer,characterized by a high potential of tumor recurrence,has high lifelong monitoring and treatment costs.To date,tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types.Nonetheless,the existence of soft tumor cells in bladder tumors remains elusive.Thus,our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods:The stiffness of bladder cancer cells was determined by atomic force microscopy(AFM).The modified microfluidic chip was utilized to separate soft cells,and the 3D Matrigel culture system was to maintain the softness of tumor cells.Expression patterns of integrinβ8(ITGB8),protein kinase B(AKT),and mammalian target of rapamycin(mTOR)were determined by Western blotting.Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59(TRIM59).The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models.Results:Using our newly designed microfluidic approach,we identified a small fraction of soft tumor cells in bladder cancer cells.More importantly,the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens,in which the number of soft tumor cells was associated with tumor relapse.Furthermore,we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells.Simultaneously,we detected a remarkable up-regulation in ITGB8,TRIM59,and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions:The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness.Meanwhile,the soft tumor cells become more sensitive to chemotherapy after stiffening,that offers new insights fo

关键词： Soft tumor cells 3D Matrigel Stemness Non-muscle invasive bladder neoplasms Microfluidic analytical techniques

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Appendiceal bleeding caused by vascular malformation: A case report

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World Journal of Clinical Cases 2024年第14期12卷 2457-2462页

作者： Qin Ma Jin-Jie Du department of General Surgery Fuling Hospital Affiliated to Chongqing UniversityChongqing 408000China department of geriatrics Fuling Hospital Affiliated to Chongqing UniversityChongqing 408000China

BACKGROUND Acute lower gastrointestinal bleeding(LGIB)is a common occurrence in clinical practice.However,appendiceal bleeding is an extremely rare condition that can easily be overlooked and misdiagnosed.The preoperative detection of appen-diceal bleeding often poses challenges due to the lack of related guidelines and consensus,resulting in controversial treatment approaches.CASE SUMMARY We presented a case of a 33-year-old female who complained of hematochezia that had lasted for 1 d.Colonoscopy revealed continuous bleeding in the appen-diceal orifice.A laparoscopic appendectomy was performed immediately,and a pulsating blood vessel was observed in the mesangium of the appendix,accor-dingly,active bleeding into the appendicular lumen was considered.Pathological examination revealed numerous hyperplastic vessels in the appendiceal mucosa and dilated capillary vessels.CONCLUSION The preoperative detection of appendiceal bleeding is often challenging,colo-noscopy is extremely important,bowel preparation is not routinely recommend-ed for patients with acute LGIB or only low-dose bowel preparation is recom-mended.Laparoscopic appendectomy is the most appropriate treatment for appendiceal bleeding.

关键词： Lower gastrointestinal bleeding Appendiceal bleeding Colonoscopy Vas-cular malformation Laparoscopic appendectomy Case report

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Use of Rats Mesenchymal Stem Cells Modified with mHCN2 Gene to Create Biologic Pacemakers

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2010年第4期30卷 447-452页

作者：马金张存泰黄深王国强全小庆 department of geriatrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

The possibility of rats mesenchymal stem cells (MSCs) modified with murine hyperpolarization-activated cyclic nucleotide-gated 2 (mHCN2) gene as biological pacemakers in vitro was studied. The cultured MSCs were transfected with pIRES2-EGFP plasmid carrying enhanced green fluorescent protein (EGFP) gene and mHCN2 gene. The identification using restriction enzyme and sequencing indicated that the mHCN2 gene was inserted to the pIRES2-EGFP. Green fluorescence could be seen in MSCs after transfection for 24–48 h. The expression of mHCN2 mRNA and protein in the transfected cells was detected by RT-PCR and Western blot, and the quantity of mHCN2 mRNA and protein expression in transfected MSCs was 5.31 times and 7.55 times higher than that of the non-transfected MSCs respectively (P<0.05, P<0.05). IHCN2 was recorded by whole-cell patch clamp method. The effect of Cs+, a specific blocker of pacemaker current, was measured after perfusion by patch clamp. The results of inward current indicated that there was no inward current recording in non-transfected MSCs and a large voltage-dependent inward and Cs+-sensitive current activated on hyperpolarizations presented in the transfected MSCs. IHCN2 was fully activated around–140 mV with an activation threshold of –60 mV. The midpoint (V50) was –95.1±0.9 mV (n=9). The study demonstrates that mHCN2 mRNA and protein can be expressed and the currents of HCN2 channels can be detected in genetically modified MSCs. The gene-modified MSCs present a novel method for pacemaker genes into the heart or other electrical syncytia.

关键词： stem cells gene therapy hyperpolarization-activated cyclic nucleotide-gated pacemaker current

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The Elevated Expression of Osteopontin and NF-κB in Human Aortic Aneurysms and Its Implication

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2011年第5期31卷 602-607页

作者：糜涛聂斌张存泰周洪莲 department of geriatrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

The expression and significance of osteopontin （OPN） and NF-κB in patients with thoracic aortic aneurysm （TAA） and abdominal aortic aneurysm （AAA） were investigated. Thirteen TAA specimens, 20 AAA specimens and 6 normal aortic specimens were collected. The expression of OPN, nuclear factor-κB P65 （NF-κB P65）, urokinase plasminogen activator （uPA）, matrix metalloproteinase-2 （MMP-2） and matrix metalloproteinase-9 （MMP-9） were detected by using immunohisto-chemistry and Western blotting was employed to determine the expression of OPN and NF-κB P65. Immunohistochemical results showed that the expression of OPN, NF-κB P65, uPA, MMP-2 and MMP-9 was positive in all TAA and AAA specimens and negative in normal specimens, with the difference being statistically significant （P〈0.05）. There was no difference in the expression between TAA and AAA specimens （P〉0.05）. Correlation analysis revealed that there existed a positive correlation between the expression of OPN and that of NF-κB P65, uPA, MMP-2 and MMP-9 and between the expression of NF-κB P65 and that of uPA, MMP-2, MMP-9 （P〈0.05）. Western blotting demonstrated that OPN and NF-κB P65 were positive in AAA and TAA specimens, and negative in normal specimens with the differences being statistically significant （P〈0.05）. There were no statistically significant differences in the expression of OPN and NF-κB P65 between AAA and TAA specimens （P〉0.05）. It was concluded that OPN and NF-κB P65 were involved in the pathogenesis of TAA and AAA. OPN can up-regulate the expression of MMP and uPA via NF-κB signaling pathway thereby accelerating the degradation of extracellular matrix and playing an important role in the pathogenesis and development of TAA and AAA.

关键词： aortic aneurysm osteopontin NF-κB matrix metalloproteinase

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