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Biochemical mechanisms in drug-induced liver injury:Certainties and doubts

World Journal of Gastroenterology 2009年第39期15卷 4865-4876页

作者： Ignazio Grattagliano Leonilde Bonfrate Catia V Diogo Helen H wang david qh wang Piero Portincasa Clinica Medica "A.Murri" Dipartimento di Medicina Interna e Medicina PubblicaUniversity of Bari Medical School Department of Zoology Center for Neurosciences and Cell BiologyUniversity of Coimbra Department of Medicine Liver Center and Gastroenterology DivisionBeth Israel Deaconess Medical CenterHarvard Medical School and Harvard Digestive Diseases Center

Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

关键词： Adverse effects Apoptosis Drug toxicity Liver diseases Microsomes Mitochondria Necrosis

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Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells

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World Journal of Gastroenterology 2016年第26期22卷 6016-6026页

作者： Giulia Vecchione Elena Grasselli Adriana Voci Francesca Baldini Ignazio Grattagliano david qh wang Piero Portincasa Laura Vergani DISTAV Department of Earth Environment and Life Sciences University of Genova Department of Biomedical Sciences and Human Oncology University School of Medicine Department of Internal Medicine Division of Gastroenterology and Hepatology Saint Louis University School of Medicine

AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic ***: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric ***: Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB ***: We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.

关键词： Non-alcoholic fatty liver disease Steatotic hepatocytes Silybin Lipid metabolism Oxidative stress Lipid droplets Mitochondrial β -oxidation

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Therapy of gallstone disease:What it was,what it is,what it will be

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2012年第2期3卷 7-20页

作者： Piero Portincasa Agostino Di Ciaula Leonilde Bonfrate david qh wang Department of Biomedical Sciences and Human Oncology Clinica Medica "A.Murri"University of Bari Medical SchoolPiazza Giulio Cesare 11Policlinico70124 BariItaly Division of Internal Medicine Hospital of Bisceglievia Bovio 27970052 Bisceglie (Bari)Italy Division of Gastroenterology and Hepatology Department of Internal MedicineEdward Doisy Research CenterSaint Louis University School of MedicineSt.LouisMO 63104United States

Cholesterol gallstone disease is a common clinical condition influenced by genetic factors,increasing age,female gender,and metabolic *** laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones,new perspectives regarding medical therapy of cholelithiasis are currently under discussion,also taking into account the pathogenesis of gallstones,the natural history of the disease and the analysis of the overall costs of therapy.A careful selection of patients may lead to successful nonsurgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent *** classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations,suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe),or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis,might be proposed as additional approaches for treating cholesterol *** this review we discuss old,recent and future perspectives on medical treatment of cholesterol cholelithiasis.

关键词： Gallstones Dissolution therapy Cholecystectomy Bile acids Ezetimibe Statins Gallbladder Bile Nuclear receptors

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Quantification of perfluorinated compounds in atmospheric particulate shows potential connection with environmental event

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Journal of Environmental Sciences 2024年第2期136卷 237-247页

作者： Hua Tang Ying wang Shengling Si Hongli Li david Da Yong Chen National Institute of Metrology 18 BeisanhuandongluChaoyang DistrictBeijing 100029China School of Chemistry and Materials Science Nanjing Normal UniversityNanjing 210023China Si Chuan Zhong Ce Biao Wu Technology Co.Ltd. Sichuan 610052China Department of Chemistry University of British ColumbiaVancouver V6T 1Z1BCCanada

A method of quantification of perfluorinated compounds(PFCs)from atmospheric particulate matter(APM)is described.A single step pretreatment method,selective pressurized liquid extraction(SPLE),was developed to reduce the high matrix background and avoid contamination from commonly used multiple sample pretreatment *** effective sorbent was selected to purify the PFCs during SPLE,followed by liquid chromatography-tandem mass spectrometry(LC–MS/MS),for quantification of *** affecting the SPLE efficiency,including temperature,static extraction time,and number of extraction cycles used,were *** optimum conditions were found to be 120℃,10 min,and 3 cycles,***-MS/MS method was developed to obtain the optimal sensitivity specific to *** method detection limits(MDLs)were 0.006 to 0.48 ng/g for the PFCs studied and the linear response range was from 0.1 to 100 ng/*** ensure accurate values were obtained,each step of the experiment was evaluated and controlled to prevent *** optimized method was tested by performing spiking experiments in natural particulate matter matrices and good rates of recovery and reproducibility were obtained for all target ***,the method was successfully used to measure 16 PFCs in the APM samples collected in Beijing over five years from 2015 to *** is observed that some PFCs follow the trend of total PFC changes,and can be attributed to the environment influencing events and policy enforcement,while others don't seem to change as much with time of the year or from year to year.

关键词： Selective pressurized liquid extraction Liquid chromatography-mass spectrometry Perfluorinated compounds Atmospheric particulate matter Pollution control

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A combined experimental and DEM investigation of grain interlocking in sheared granular assemblies

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Particuology 2024年第7期90卷 436-451页

作者： Rui Lu Qiang Luo Tengfei wang david P.Connolly Tao Xie School of Civil Engineering Southwest Jiaotong UniversityChengdu 610031China Key Laboratory of High-Speed Railway Engineering(Southwest Jiaotong University) Ministry of EducationChengdu 610031China School of Civil Engineering University of LeedsLeeds LS29JTUK Department of Civil Engineering McMaster UniversityHamiltonONCanada

Compacted granular material,integral to geotechnical engineering,undergoes translation,rotation,and interlocking when subject to shear displacements or external *** present study focuses on the interlocking of heterogeneous granular materials,a complex behavior influenced by gradation,compaction,and varying particle geometry,and has consequently received limited attention in existing *** address this research gap,we conducted an analysis on the effect of grain interlocking on the shear resistance of granular assemblies,using a combination of laboratory testing and the discrete element method(DEM).Initially,large-scale direct shear tests were conducted on gravel−sand mixes with varying degrees of compaction and normal *** of the mixes also underwent subsequent shear reversal to explore the differences in grain interlocking between the two shearing processes on the shear *** analyzing the laboratory results,a mesoscopic scale investigation was performed by replicating the test using discrete element *** facilitate this,granular particle geometries were measured using 3D laser scanning based on the physical lab ***,based on these scans,discrete element R-block and ball models were utilized to construct both the coarse and fine particles within the *** vibro-compaction was employed to regulate the degree of *** results indicate that an increase in vertical pressure,coupled with a zero dilatancy angle,results in a rising stress ratio,indicative of grain *** interlocking exhibits a positive correlation with both the coarse content and the degree of compaction,and varies depending on the shear *** interlocking progresses,the shear band,induced by particle movement,expands and is associated with reduced particle rotation near the shear *** study further reveals a consistent positive correlation between interlocking and the principal orientation angle of strong normal c

关键词： Granular material Interlocking Shear resistance Direct shear Discrete element method Vibro-compaction

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A silybin-phospholipids complex counteracts rat fatty liver degeneration and mitochondrial oxidative changes

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World Journal of Gastroenterology 2013年第20期19卷 3007-3017页

作者： Ignazio Grattagliano Catia V Diogo Maria Mastrodonato Ornella de Bari Michele Persichella david qh wang Adriana Liquori Domenico Ferri Maria Rosaria Carratù Paulo J Oliveira Piero Portincasa Section of Internal Medicine Department of Interdisciplinary MedicineUniversity of Bari70124 BariItaly Center for Neuroscience and Cell Biology Largo Marques de PombalUniversity of CoimbraP-3004-517 CoimbraPortugal Laboratory of Histology and Comparative Anatomy Department of Animal and Environmental BiologyUniversity of Bari70125 BariItaly Division of Gastroenterology and Hepatology Department of Internal MedicineEdward Doisy Research CenterSaint Louis University School of MedicineSaint LouisMO 63104United States Department of Pharmacology and Human Physiology University of Bari70124 BariItaly

AIM:To investigate the effectiveness of antioxidant compounds in modulating mitochondrial oxidative alterations and lipids accumulation in fatty ***:Silybin-phospholipid complex containing vitamin E(Realsil) was daily administered by gavage(one pouch diluted in 3 mL of water and containing 15 mg vitamin E and 47 mg silybin complexed with phospholipids) to rats fed a choline-deprived(CD) or a high fat diet [20% fat,containing 71% total calories as fat,11% as carbohydrate,and 18% as protein,high fat diet(HFD)] for 30 d and 60 d,*** control group was fed a normal semi-purified diet containing adequate levels of choline(35% total calories as fat,47% as carbohydrate,and 18% as protein).Circulating and hepatic redox active and nitrogen regulating molecules(thioredoxin,glutathione,glutathione peroxidase),NO metabolites(nitrosothiols,nitrotyrosine),lipid peroxides [malondialdehyde-thiobarbituric(MDA-TBA)],and pro-inflammatory keratins(K-18) were measured on days 0,7,14,30,and *** respiratory chain proteins and the extent of hepatic fatty infiltration were ***:Both diet regimens produced liver steatosis(50% and 25% of liver slices with CD and HFD,respectively) with no signs of necro-inflammation:fat infiltration ranged from large droplets at day 14 to disseminated and confluent vacuoles resulting in microvesicular steatosis at day 30(CD) and day 60(HFD).In plasma,thioredoxin and nitrosothiols were not significantly changed,while MDA-TBA,nitrotyrosine(from 6 ± 1 nmol/L to 14 ± 3 nmol/L day 30 CD,P < 0.001,and 12 ± 2 nmol/L day 60 HFD,P < 0.001),and K-18(from 198 ± 20 to 289 ± 21 U/L day 30 CD,P < 0.001,and 242 ± 23 U/L day 60 HFD,P < 0.001) levels increased significantly with ongoing *** the liver,glutathione was decreased(from 34.0 ± 1.3 to 25.3 ± 1.2 nmol/mg prot day 30 CD,P < 0.001,and 22.4 ± 2.4 nmol/mg prot day 60 HFD,P < 0.001),while thioredoxin and glutathione peroxidase were initially increased and then

关键词： Fatty liver Glutathione Lipid peroxidation Nitrosothiols Nitrotyrosine Thioredoxin

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General Optimal Trajectory Planning:Enabling Autonomous Vehicles with the Principle of Least Action

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Engineering 2024年第2期33卷 63-76页

作者： Heye Huang Yicong Liu Jinxin Liu Qisong Yang Jianqiang wang david Abbink Arkady Zgonnikov School of Vehicle and Mobility Tsinghua UniversityBeijing 100084China Department of Cognitive Robotics Faculty of MechanicalMaritime and Materials Engineering(3mE)Delft University of TechnologyDelft 2628Netherlands Department of Software Technology Faculty of Electrical EngineeringMathematics and Computer ScienceDelft University of TechnologyDelft 2628Netherlands Xi’an Institute of High-Technology Xi’an 710051China

This study presents a general optimal trajectory planning(GOTP)framework for autonomous vehicles(AVs)that can effectively avoid obstacles and guide AVs to complete driving tasks safely and ***,we employ the fifth-order Bezier curve to generate and smooth the reference path along the road *** coordinates are then transformed to achieve the curvature continuity of the generated *** the road constraints and vehicle dynamics,limited polynomial candidate trajectories are generated and smoothed in a curvilinear coordinate ***,in selecting the optimal trajectory,we develop a unified and auto-tune objective function based on the principle of least action by employing AVs to simulate drivers’behavior and summarizing their manipulation characteristics of“seeking benefits and avoiding losses.”Finally,by integrating the idea of receding-horizon optimization,the proposed framework is achieved by considering dynamic multi-performance objectives and selecting trajectories that satisfy feasibility,optimality,and *** simulations and experiments are performed,and the results demonstrate the framework’s feasibility and effectiveness,which avoids both dynamic and static obstacles and applies to various scenarios with multi-source interactive traffic ***,we prove that the proposed method can guarantee real-time planning and safety requirements compared to drivers’manipulation.

关键词： Autonomous vehicle Trajectory planning Multi-performance objectives Principle of least action

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Recent Progress of the Solar Wind Magnetosphere Ionosphere Link Explorer (SMILE) Mission

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空间科学学报 2024年第4期44卷 692-698页

作者： wang Chi ESCOUBET Philippe FORSYTH Colin LI Jing AGNOLON david State Key Laboratory of Space Weather National Space Science CenterChinese Academy of SciencesBeijing 100190 European Space Agency/European Space Research and Technology Centre Noordwijk 2201 AZ Mullard Space Science Laboratory University College LondonLondon RH56 NT

The SMILE(Solar wind Magnetosphere Ionosphere Link Explorer)mission is a joint space science mission between the Chinese Academy of Sciences(CAS)and the European Space Agency(ESA),aiming to understand the interaction of the solar wind with the Earth’s magnetosphere in a global *** of May 2024,the SMILE mission is in phase-D with an expected launch date of September *** report summarizes developments in the mission during the past two years.

关键词： SMILE Soft X-ray Imager Ultra-Violet Imager Light Ion Analyzer Magnetometer

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Development of T cell antigen-based human coronavirus vaccinesagainst nAb-escaping SARS-CoV-2 variants

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Science Bulletin 2024年第15期69卷 2456-2470页

作者： Hao Zhou Ping Leng Yang wang Kaiwen Yang Chen Li david M.Ojcius Pengfei wang Shibo Jiang College of Medical Technology Chengdu University of Traditional Chinese MedicineChengdu 611137China Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine Chongqing Traditional Chinese Medicine HospitalChongqing 400016China Shanghai Pudong Hospital Fudan University Pudong Medical CenterShanghai Institute of Infectious Disease and BiosecuritySchool of Life SciencesFudan UniversityShanghai 200438China Department of Biomedical Sciences University of the PaciﬁcArthur Dugoni School of DentistrySan FranciscoCA 94115USA Key Laboratory of Medical Molecular Virology of Ministry of Education/Ministry of Health/Chinese Academy of Medical Sciences Shanghai Institute of Infectious Disease and BiosecuritySchool of Basic Medical SciencesFudan UniversityShanghai 200032China

Currently approved vaccines have been successful in preventing the severity of COVID-19 and hospitalization. These vaccines primarily induce humoral immune responses;however, highly transmissible and mutated variants, such as the Omicron variant, weaken the neutralization potential of the vaccines, thus,raising serious concerns about their efficacy. Additionally, while neutralizing antibodies(nAbs) tend to wane more rapidly than cell-mediated immunity, long-lasting T cells typically prevent severe viral illness by directly killing infected cells or aiding other immune cells. Importantly, T cells are more cross-reactive than antibodies, thus, highly mutated variants are less likely to escape lasting broadly cross-reactive T cell immunity. Therefore, T cell antigen-based human coronavirus(HCoV) vaccines with the potential to serve as a supplementary weapon to combat emerging SARS-CoV-2 variants with resistance to n Abs are urgently needed. Alternatively, T cell antigens could also be included in B cell antigen-based vaccines to strengthen vaccine efficacy. This review summarizes recent advancements in research and development of vaccines containing T cell antigens or both T and B cell antigens derived from proteins of SARS-CoV-2 variants and/or other HCo Vs based on different vaccine platforms.

关键词： COVID-19 Immune escape Omicron variant SARS-CoV-2 T cell antigen-based vaccine

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Numerical Study of Flow Features Around Submerged Circular and Square Piles at Flat and Scoured Beds Using OpenFOAM

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Journal of Ocean University of China 2024年第4期23卷 897-914页

作者： wang Chaolin WU Guoxiang wang Dianhe DU Shengtao ZHANG Zhiyong JIN Heng ZHU david Z. LIANG Bingchen Donghai Academy School of Civil&Environmental Engineering and Geography ScienceNingbo UniversityNingbo 315211China Key Laboratory of Estuary and Coast of Zhejiang Province and Zhejiang Institute of Hydraulics and EstuaryHangzhou 310020China Shandong Provincial Key Laboratory of Ocean Engineering and College of EngineeringOcean University of ChinaQingdao 266100China Shandong Water Conservancy Vocational College Rizhao 276826China School of Mechanical and Energy Engineering Ningbotech UniversityNingbo 315211China

Elucidating the flow features around piles in local scouring processes is crucial for studies of local scouring mechanisms and scour depth *** study details the flow turbulence characteristics of two submerged piles that are determined by solving the Navier-Stokes equations with the improved delayed detached eddy simulation *** model is verified by comparing experimental and numerical results for hydrodynamic parameters with the literature for both square-crossing piles(SCPs)and circular-crossing piles(CCPs).Original topographies of flat and scoured beds(i.e.,the initial and equilibrium scouring stages)are based on experimental results obtained by the authors in the present *** and CCP flow features in the scouring process are *** results indicate that during the scouring process,the time-averaged drag coefficient and root mean square(rms)of the lift coefficient increase linearly in the CCP test,while the rms of the lift coefficient in the SCP test decreases ***,the minimum pressure coefficient is always located in the upstream corners in the SCP case but moves from 72.5°to 79.5°when the scour hole is completely developed in the CCP *** flow behind the pile,which is generated by separated boundary layers above the top face of the pile,can reach the sand bed and turn the separated shear layers into patches of small vortices in the near-wake ***,the high shear stress zones are mainly at the scour edges under scoured-bed conditions.

关键词： flat bed scoured bed local scour OpenFOAM bed shear stress

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