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Combination therapy using microwave ablation and d-mannose-chelated iron oxide nanoparticles inhibits hepatocellular carcinoma progression

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3475-3485页

作者： Rui Cui Luo Wang Dongyun Zhang Kun Zhang Jianping Dou Linan Dong Yixuan Zhang Jiapeng Wu Longfei Tan Jie Yu Ping Liang Department of Interventional Ultrasound PLA General HospitalBeijing 100853China Department of Medical Ultrasonics the Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China Laboratory of Controllable Preparation and App Department of Medical Ultrasound Shanghai Tenth People's HospitalTongji University School of MedicineShanghai 200072China Ultrasound Research and Education institute Tongji University School of MedicineShanghai 200072China Laboratory of Controllable Preparation and Application of Nanomaterials Key Laboratory of CryogenicsTechnical Institute of Physics and ChemistryChinese Academy of SciencesBeijing 100190China

Despite being a common therapy for hepatocellular carcinoma(HCC),insufficient thermal ablation can leave behind tumor residues that can cause recurrence.This is believed to augment M2 inflammatory macrophages that usually play a pro-tumorigenic role.To address this problem,we designed D-mannose-chelated iron oxide nanoparticles(man-IONPs) to polarize M2-like macrophages into the antitumor Ml phenotype.In vitro and in vivo experiments demonstrated that man-IONPs specifically targeted M2-like macrophages and accumulated in peri-ablation zones after macrophage infiltration was augmented under insufficient microwave ablation(MWA).The nanoparticles simultaneously induced polarization of pro-tumorigenic M2 macrophages into antitumor M1 phenotypes,enabling the transformation of the immunosuppressive microenvironment into an immunoactivating one.Post-MWA macrophage polarization exerted robust inhibitory effects on HCC progression in a well-established orthotopic liver cancer mouse model.Thus,combining thermal ablation with man-IONPs can salvage residual tumors after insufficient MWA.These results have strong potential for clinical translation.

关键词： Microwave ablation Hepatocellular carcinoma Iron oxide nanoparticle Macrophage polarization Targeted therapy

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P2X7 receptor blockade decreases inflammation,apoptosis,and enteric neuron loss during Clostridioides difficile toxin A-induced ileitis in mice

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World Journal of Gastroenterology 2022年第30期28卷 4075-4088页

作者： Ana A Q A Santos Deiziane V S Costa Danielle A Foschetti Antoniella S G Duarte Conceicao S Martins Pedro M G Soares Patricia Castelucci Gerly A C Brito Department of Morphology School of MedicineFederal University of CearaFortaleza 60430-170CearaBrazil Department of Physiology and Pharmacology School of MedicineFederal University of CearáFortaleza 60430-170CearaBrazil Department of Pathology and Legal medicine School of MedicineFederal University of CearaFortaleza 60430-170CearaBrazil Department of Morphology(UFC) Federal University of CearaFortaleza 60430-170CearaBrazil Department of Anatomy Institute of Biomedical SciencesUniversity of São PauloSao Paulo 05508-270Brazil Department of Morphology Federal University of CearaFortaleza 60140-170CearaBrazil

Clostridioides difficile(C.difficile)is the most common pathogen causing health care-associated infections.C.difficile TcdA and TcdB have been shown to activate enteric neurons;however,what population of these cells is more profoundly influenced and the mechanism underlying these effects remain unknown.AIM To characterize a specific population of TcdA-affected myenteric neurons and investigate the role of the P2X7 receptor in TcdA-induced ileal inflammation,cell death,and the changes in the enteric nervous system in mice.METHODS Swiss mice were used to model TcdA-induced ileitis in ileal loops exposed to TcdA(50μg/Loop)for 4 h.To investigate the role of the P2X7 receptor,Brilliant Blue G(50 mg/kg,i.p.),which is a nonspecific P2X7 receptor antagonist,or A438079(0.7μg/mouse,i.p.),which is a competitive P2X7 receptor antagonist,were injected one hour prior to TcdA challenge.Ileal samples were collected to analyze the expression of the P2X7 receptor(by quantitative real-time polymerase chain reaction and immunohistochemistry),the population of myenteric enteric neurons(immunofluorescence),histological damage,intestinal inflammation,cell death(terminal deoxynucleotidyltransferasemediated dUTP-biotin nick end labeling),neuronal loss,and S100B synthesis(immunohistochemistry).RESULTS TcdA upregulated(P<0.05)the expression of the P2X7 receptor gene in the ileal tissues,increasing the level of this receptor in myenteric neurons compared to that in control mice.Comparison with the control mice indicated that TcdA promoted(P<0.05)the loss of myenteric calretinin+(Calr)and choline acetyltransferase+neurons and increased the number of nitrergic+and Calr+neurons expressing the P2X7 receptor.Blockade of the P2X7 receptor decreased TcdAinduced intestinal damage,cytokine release[interleukin(IL)-1β,IL-6,IL-8,and tumor necrosis factor-α],cell death,enteric neuron loss,and S100B synthesis in the mouse ileum.CONCLUSION Our findings demonstrated that TcdA induced the upregulation of the P2X7 receptor,which promoted enteric neuron loss,

关键词： Clostridioides difficile Clostridioides difficile toxin A P2X7 receptor Enteric nervous system Enteric neuron Enteric glia

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Correlations between Event-related Potentials with Pictures Recognition and WMS-RC Scores in Patients with Memory Disorder Caused by Severe Traumatic Brain Injury

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2008年第6期28卷 700-705页

作者：刘子龙刘良樊则兵陈晓瑞赵小红张玲莉饶广勋李海霞 Faculty of Forensic medicine Tongji Medical CollegeHuazhong University of Science and Technology Department of pediatrics Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology

This study explored the possibility of using event-related potentials （ERP） for the measurement of picture-recognition memory and examined its correlation with the Chinese Wechsler Memory Scale-revised （WMS-RC） in patients with memory disorder caused by severe traumatic brain injury （sTBI）. The subjects included 20 sTBI patients with memory disorder and 22 healthy individuals. Memory function was measured by using WMS-RC. Behavioral and ERP responses were recorded on-line during performance on a battery of picture recognition and the responses were analyzed off-line for recognition memory effects. Mean memory quotient （MQ） of patients with sTBI was significantly lower than that of the control group. Mean reaction time （RT） was significantly longer and the mean correctness rate （CR） of picture recognition was significantly lower in sTBI group than that of the controls. In controls, the main components of average ERP of picture recognition includes two positive-going waves, designated as P170 and P500, that appear 170 ms and 500 ms after stimulation when the subject could later successfully recall and recognize the pictures. P500 amplitude of target stimulus was significantly higher than that of non-target stimulus. Compared to controls, P500 responses of sTBI group were significantly delayed in latency （P〈0.001） and lower in amplitude （P〈0.001）. P500 latency showed significant negative correlation with MQ and the scores of ＂addition＂, ＂visual recognition＂, ＂picture recall＂, ＂visual reproduction＂ and ＂tactile memory＂ in WMS-RC. ERP of picture recognition provides a neurophysiological approach to directly assess memory impairment, and P500 may serve as a helpful index for memory disorder caused by sTBI in forensic practice.

关键词： picture recognition event-related potentials memory disorder severe traumatic braininjury

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Nature can still be the strongest help against aging and neurodegeneration:the sirtuins way

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Neural Regeneration Research 2023年第6期18卷 1271-1272页

作者： David Della-Morte Francesca Pacifici Department of Systems medicine University of Rome“Tor Vergata”RomeItaly Department of Human Sciences and Quality of Life Promotion San Raffaele Roma Open UniversityIRCCS San Raffaele RomaRomeItaly Department of Neurology and Evelyn F.McKnight Brain institute Miller School of MedicineUniversity of MiamiMiamiFLUSA

Unfortunately,ag ing is not a reversible phenomenon and the processes of senescence are unavoidable.However,the biological effects of aging may be turned back,and with those,it can be reduced risk of all age-related illnesses,such as cardiovascular diseases,cancer,diabetes,and neurodegenerative diseases,including Alzheimer’s disease(AD),and Parkinson’s diseases(PD).In the latest decades,scientists worldwide therefore have developed several strategies,either natural or pharmacological,to counteract aging phenomena,with the final goal to improve human life expectancy.The main scientific rationale beyond these strategies focuses on the opportunity to reduce chronic low-grade inflammation(inflammaging),the increase in oxidative stress damage,and the impairment in the immune system,all typical mechanisms of senescence(Verdaguer et al.,2012).

关键词： diseases aging inflammation

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Clinical Observation on 930 Child Epilepsy Cases Treated with Anti-epilepsy Capsules

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Journal of Traditional Chinese medicine 2003年第2期23卷 109-112页

作者：马融李少川李新民胡思源孙希焕刘玉珍张喜莲李向农马秀华王新中 Department of pediatrics First Affiliated Hospital of Tianjin College of Traditional Chinese MedicineTianjin 300193

1090 cases of child epilepsy were divided randomly into two groups: the treatment group (930 cases treated with anti-epilepsy capsules) and the control group (160 cases treated with luminal). The results showed that in the treatment group, 534 cases were markedly effective, 241 effective, 96 improved, 46 ineffective, and 13 aggravated, with a total effective rate of 83.33%; while in the control group, 64 cases were markedly effective, 19 effective, 38 improved, 29 ineffective, and 10 aggravated, with a total effective rate of 51.88%. The treatment group showed an obviously higher total effective rate than that in the control group (P<0.01). After treatment, cases in the two groups all had lower frequency of epilepsy attacks and shorter duration of each attack as compared with that before treatment (P<0.01), but the situation was obviously better in the treatment group. The anti-epilepsy capsules had very good effect on various types of epilepsy, especially on autonomic epilepsy and on epilepsies due to wind, phlegm, or terror as differentiated in TCM. After treatment, the recovery rate shown by EEG examination was 54.3% in the treatment group, while 38.4% in the control group, the former being obviously higher than the latter (P<0.01).

关键词：儿童癫痫中医药疗法临床疗效

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Appraisal of the Quality and Contents of Clinical Practice Guidelines for Hypertension Management in Chinese medicine: A Systematic Review

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Chinese Journal of Integrative medicine 2018年第7期24卷 545-550页

作者： YUWEN Ya HAN Xue-jie WENG Wei-liang ZHAO Xue-yao LIU Yu-qi LI Wei-qiang LIU Da-sheng WANG Yan-ping LU Ai-ping institute of Basic Research in Clinical medicine China Academy of Chinese Medical Sciences institute of Clinical Pharmacology Xiyuan HospitalChina Academy of Chinese Medical Sciences Chinese medicine College Ningxia Medical University School of Chinese medicine Hong Kong Baptist University

Objective： To evaluate the quality and consistency of recommendations in the clinical practice guidelines（CPGs） for hypertension in Chinese medicine（CM）. Methods： CM CPGs were identified from 5 electronic databases and hand searches through related handbooks published from January 1990 to December 2013. Three reviewers independently appraised the CPGs based on the Appraisal of Guidelines for Research and Evaluation（AGREE Ⅱ） instrument, and compared the CPGs＇ recommendations on CM syndrome pattern classification and treatment. Results： Five CM CPGs for hypertension were included. The quality score of the evidence-based（EB） guideline was higher than those of the consensus-based with no explicit consideration of evidence-based（CB-EB） and the consensus-based（CB） guidelines. Three out of five patterns in the CPGs were recommended by the EB guideline. Tianma Gouteng Formula（天麻钩藤复方） in the EB guideline was recommended mostly for hypertension patients with pattern of ascendant hyperactivity of Gan（Liver）-yang and pattern of yin deficiency with yang hyperactivity in the CPGs. Acupuncture and massage were recommended for Grade Ⅰ and Grade Ⅱ hypertension with severe symptoms weakening the quality of life in the EB guideline. For Grade Ⅰ and Grade Ⅱ hypertension, CM could be used alone, while for Grade Ⅲ hypertension, they should be used in combination with Western medicines. Conclusion： The quality of EB guideline was higher than those of CB and CB-EB CPGs in CM for hypertension and CM should be prescribed alone or combined with Western medicines based on the grade of hypertension.

关键词： hypertension Chinese medicine clinical practice guideline systematic review syndrome pattern

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Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations

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药学学报:英文版 2023年第6期13卷 2715-2735页

作者： Pengyun Li Changkai Jia Zhiya Fan Xiaotong Hu Wenjuan Zhang Ke Liu Shiyang Sun Haoxin Guo Ning Yang Maoxiang Zhu Xiaomei Zhuang Junhai Xiao Zhibing Zheng Song Li National Engineering Research Center for Strategic Drugs Beijing Institute of Pharmacology and Toxicology InstitutionBeijing 100850China State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China National Center for Protein Sciences(Beijing) Beijing Institute of LifeomicsState Key Laboratory of ProteomicsBeijing Proteome Research CenterBeijing 102206China Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation MedicineBeijing 100850China

Various c-mesenchymal-to-epithelial transition(c-MET) inhibitors are effective in the treatment of non-small cell lung cancer;however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras(PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC_(50) values and achieved picomolar DC_(50) values and>99% of maximum degradation(D_(max)) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion.Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^(Y1230H) and c-MET^(D1228N) mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

关键词： Cancer therapy Drug design c-MET Proteolysis targeting chimeras(PROTACs) Drug resistance

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Interaction between neutrophil extracellular traps and cardiomyocytes contributes to atrial fibrillation progression

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Signal Transduction and Targeted Therapy 2023年第8期8卷 3849-3861页

作者： Li He Ruiqi Liu Honghua Yue Xiaoxin Zhang Xiaohui Pan Yutao Sun Jun Shi Guonian Zhu Chaoyi Qin Yingqiang Guo Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory West China HospitalSichuan UniversityChengdu 610041 SichuanChina Department of Plastic and Burn Surgery West China HospitalSichuan UniversityChengduChina West China Center of Excellence for Pancreatitis Institute of Integrated Traditional Chinese and Western MedicineWest China HospitalSichuan UniversityChengduChina Department of Endocrinology&Metabolism West China HospitalSichuan UniversityChengduChina Department of Pulmonary and Critical Care medicine and institute of Respiratory Health West China HospitalSichuan UniversityChengduChina

Atrial fibrillation(AF)is a frequent arrhythmia associated with cardiovascular morbidity and mortality.Neutrophil extracellular traps(NETs)are DNA fragments with cytoplasm proteins released from neutrophils,which are involved in various cardiovascular diseases.To elucidate the role of NETs in AF,we investigated the effect of NETs on AF progression and the secretion of NETs in AF.Results showed that:NETs induced the autophagic apoptosis of cardiomyocytes,and NETs also led to mitochondrial injury by promoting mitochondrial depolarization and ROS production.Ongoing tachy-pacing led to the structural loss of cardiomyocytes and provided potent stimuli to induce NETs secretion from neutrophils.In the meanwhile,increased Ang II in AF facilitated NETs formation through the upregulation of AKT phosphorylation,while it could not directly initiate NETosis as the autophagy was not induced.In vivo,DNase I was administrated to abrogate NETs formation,and AF-related fibrosis was ameliorated as expected.Correspondingly,the duration of the induced AF was reduced.Our study addresses the formation mechanism of NETs in AF and demonstrates the lethal effects of NETs on cardiomyocytes through the induction of mitochondrial injury and autophagic cell death,which comprehensively describes the positive feedback comprised of NETs and stimuli secreted by cardiomyocytes that sustains the progression of AF and AF related fibrosis.

关键词： cardiomyocytes fibrillation cardiovascular

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Noninvasive Fibrosis Assessment in Chronic Hepatitis C Infection: An Update

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Journal of Clinical and Translational Hepatology 2023年第5期11卷 1228-1238页

作者： Kristina Bojanic Mirta Sudaric Bogojevic Sonja Vukadin Renata Sikora Gordana Ivanac Nikola Raguz Lucic Martina Smolic Ashraf ATabll George YWu Robert Smolic Faculty of Dental medicine and Health Osijek Josip Juraj Strossmayer University of OsijekOsijekCroatia Faculty of medicine Osijek Josip Juraj Strossmayer University of OsijekOsijekCroatia Health Center Osijek-Baranja County OsijekCroatia Department of Biology Josip Juraj Strossmayer University of OsijekOsijekCroatia University Hospital Dubrava ZagrebCroatia School of medicine University of ZagrebZagrebCroatia Microbial Biotechnology Department Biotechnology Research InstituteNational Research CenterGizaEgypt Egypt Center for Research and Regenerative medicine(ECRRM) CairoEgypt University of Connecticut Health Center FarmingtonCTUSA

Liver biopsy is historically the gold standard for liver fibrosis assessment of chronic hepatitis C patients.However,with the introduction and validation of noninvasive tests(NITs)to evaluate advanced fibrosis,and the direct-acting antiviral agents for treatment of chronic hepatitis C virus(HCV),the role of NITs have become even more complex.There is now need for longitudinal monitoring and elucidation of cutoff values for prediction of liver-related complication after sustained virological response.The aim of this report is to provide a critical overview of the various NITs available for the assessment of liver fibrosis in HCV patients.

关键词： Hepatitis C virus Fibrosis Noninvasive serum fibrosis markers Transient elastography Shear wave elastography Magnetic resonance elastography Steatohepatitis

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World Journal of Gastroenterology 2022年第30期28卷 4231-4234页

作者： Manuel Muro Aurelia Collados-Ros Isabel Legaz Immunology Service Instituto Murciano de investigación biosanitaria(IMIB)Hospital Clínico Universitario Virgen de la Arrixaca(HCUVA)Murcia 30120Spain Department of Legal and Forensic medicine Biomedical Research Institute(IMIB)Regional Campus of International Excellence“Campus Mare Nostrum”Faculty of MedicineUniversity of MurciaMurcia 30100Spain

Alcohol intake is a risk factor for cancer development and metastatic disease progression.Extracellular vesicle(EV)-mediated interorgan communication is assumed to be significant in boosting tumorigenic pathways and disease progression.Recent research indicates that exosomes have a variety of roles in the development of cancer during pathophysiological conditions.The involvement of EV signaling during cancer progression in the alcohol environment is unknown.Therefore,understanding communication networks and the role of EVs as biomarkers can contribute significantly to developing strategies to address the serious public health problems associated with alcohol consumption and cancer.

关键词： Exosomes Liver metastasis Alcohol-associated liver disease Cancer

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