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| 1 | Biochemical mechanisms in drug-induced liver injury:Certainties and doubts显示文摘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 O2 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 Ca2+-dependent ATPase,reduced capability to sequester Ca2+ 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. | Ignazio Grattagliano Leonilde Bonfrate Catia V Diogo Helen H Wang David QH Wang Piero Portincasa | 2009 | World Journal of Gastroenterology2009，15，39： | 30 |
| 2 | Macrophage secretory products induce an inflammatory phenotype in hepatocytes显示文摘AIM:To investigate the influence of macrophages on hepatocyte phenotype and function.METHODS:Macrophages were differentiated from THP-1 monocytes via phorbol myristate acetate stimulation and the effects of monocyte or macrophageconditioned medium on HepG2 mRNA and protein expression determined.The in vivo relevance of these findings was confirmed using liver biopsies from 147 patients with hepatitis C virus(HCV)infection.RESULTS:Conditioned media from macrophages,but not monocytes,induced a transient morphological change in hepatocytes associated with upregulation of vimentin(7.8±2.5-fold,P=0.045)and transforming growth factor(TGF)-β1(2.6±0.2-fold,P<0.001)and downregulation of epithelial cadherin(1.7±0.02-fold,P=0.017)mRNA expression.Microarray analysis revealed significant upregulation of lipocalin-2(17-fold,P <0.001)and pathways associated with inflammation,and substantial downregulation of pathways related to hepatocyte function.In patients with chronic HCV,realtime polymerase chain reaction and immunohistochemistry confirmed an increase in lipocalin-2 mRNA(F0 1.0 ±0.3,F1 2.2±0.2,F2 3.0±9.3,F3/4 4.0±0.8,P= 0.003)and protein expression(F1 1.0±0.5,F2 1.3± 0.4,F3/4 3.6±0.4,P=0.014)with increasing liver injury.High performance liquid chromatography-tandem mass spectrometry analysis identified elevated levels of matrix metalloproteinase(MMP)-9 in macrophageconditioned medium,and a chemical inhibitor of MMP-9 attenuated the change in morphology and mRNA expression of TGF-β1(2.9±0.2 vs 1.04±0.1,P<0.001) in macrophage-conditioned media treated HepG2 cells.In patients with chronic HCV infection,hepatic mRNA expression of CD163(F0 1.0±0.2,F1/2 2.8±0.3,F3/4 5.3±1.0,P=0.001)and MMP-9(F0 1.0±0.4,F1/2 2.8±0.3,F3/4 4.1±0.8,P=0.011)was significantly associated with increasing stage of fibrosis.CONCLUSION:Secreted macrophage products alter the phenotype and function of hepatocytes,with increased expression of inflammatory mediators,suggesting that hepatocytes actively participate in liver injury. | Michelle Melino Victoria L Gadd Gene V Walker Richard Skoien Helen D Barrie Dinesh Jothimani Leigh Horsfall Alun Jones Matthew J Sweet Gethin P Thomas Andrew D Clouston Julie R Jonsson Elizabeth E Powell | 2012 | World Journal of Gastroenterology2012，18，15： | 3 |
| 3 | Social support in later life : examining the roles of childhood and adulthood cognition 显示文摘 | Bourne V J Helen C Fox B | 2007 | Personal Individ Dif- fer2007，43，： | 1 |
| 4 | 基于G-蛋白偶联受体激酶2抑制剂治疗心力衰竭的合理药物设计(英文)显示文摘G protein-coupled receptors(GPCRs)convert extracellular stimuli in the form of hormones,odorants and light into profound changes in cell homeostasis.Their timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained signaling.Seven GPCR kinases(GRKs)phosphorylate and regulate the activity of most of the^800 GPCRs in the human genome.Although GRKs normally play an adaptive role,in conditions such as chronic heart failure they are overexpressed and linked to disease progression.GRK2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy,respectively.Our lab has determined atomic structures representing all three vertebrate GRK subfamilies,and is now in the midst of a campaign to develop selective inhibitors of these enzymes using structure-based rational design.We have identified the FDA approved drug paroxetine as a selective GRK2 inhibitor,determined the crystal structure of the GRK2·paroxetine complex and,in collaboration with the Koch lab,showed that the drug improves contractility in myocytes and,most impressively,recovery in postmyocardial infarcted mice.Since then,we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for GRK5.Using a'hybrid'inhibitor design approach we have generated GRK selective chemical probes that exhibit improved potency and stability and are able to increase inotropy and dampen the hypertrophic response in cardiomyocytes and small animal models.Structural analysis has revealed the molecular basis for selectivity and potency in many of these compounds,allowing for the design of future generations of GRK chemical probes. | John J TESMER Helen V WALDSCHMIDT Marie C CATO Renee BOULEY Osvaldo CRUZ-RODRIGUEZ Scott D LARSEN | 2017 | 中国药理学与毒理学杂志2017，31，10： | 1 |
| 5 | Measurement of specific Ig A in faecal extracts and intestinal lavage fluid for monitoring of mucosal immune responses显示文摘 | Harleen M S Tom H K Helene V | 2000 | J Immun Meth2000，239，6： | 1 |
| 6 | Steroids in intractable childhood epilepsy: Clinical experience and review of the literature 显示文摘 | Helene V Paul B Gunnar B | 2005 | Seizure2005，14，6： | 1 |
| 7 | Upstream stimulatory factor-2 (USF2) activity is required for glucose stimulation of L-Pyruvate kinase promoter activity in single living islet β-cells 显示文摘 | Helen J Kennedy B V lmran R | 1997 | JBC1997，272，20： | 1 |
| 8 | Intake, digestibility, and ruminal degradability of shredded hay显示文摘 | Helene Petit V Savoie P et ol | 1994 | J Dairy Sci1994，77，： | 1 |
| 9 | Pilot study assessing functional outcome of tibial pilon fractures using the VSTORM method显示文摘 | Lewis JA Helen V Ian P | 2013 | Injury2013，44，8： | 1 |
| 10 | Diabetes and advanced glycoxidation end products显示文摘 | Huebschmann G Regensteiner JG Helen V | 2006 | Diabet Care2006，29，： | 1 |
| 11 | Further improvement of the critical charge model for the theoretical evaluation of the breakdown voltage of conductor bundle-toplane gaps显示文摘 | Alexandrov G N Podporkyn G V Helene Menemenlis | 1980 | IEEE Trans on Power Apparatus and Systems1980，99，2： | 1 |
| 12 | Genomic structure, promoter analysis and expression of the porcine( Sus scrofa) TLR4 gene 显示文摘 | Anne V Thomas A D Broers Helene F Vandegaart | 2006 | Molecular Immunology2006，，43： | 1 |
| 13 | The ice test versus the rest test in myasthenia gravis显示文摘 | Kenneth C Kubis Helen V Danesh-Meyer Peter J Savino Robert C Sergott | 2000 | Ophthalmology2000，，11： | 1 |
| 14 | Measurement of specific IgA in faecal extracts and intestinal lavage fluid for monitoring of mucosal immune responses显示文摘 | Harleen M S Tom H K Helene V | 2000 | J Immun Meth2000，239，： | 1 |
| 15 | Tranexamic acid for intracerebral haemorrhage within 2 hours of onset: protocol of a phase Ⅱ randomised placebo-controlled double-blind multicentre trial显示文摘Rationale Haematoma growth is common early after intracerebral haemorrhage(ICH),and is a key determinant of outcome.Tranexamic acid,a widely available antifibrinolytic agent with an excellent safety profile,may reduce haematoma growth.Methods and design Stopping intracerebral haemorrhage with tranexamic acid for hyperacute onset presentation including mobile stroke units(STOP-MSU)is a phase Ⅱ double-blind,randomised,placebo-controlled,multicentre,international investigator-led clinical trial,conducted within the estimand statistical framework.Hypothesis In patients with spontaneous ICH,treatment with tranexamic acid within 2 hours of onset will reduce haematoma expansion compared with placebo.Sample size estimates A sample size of 180 patients(90 in each arm)would be required to detect an absolute difference in the primary outcome of 20%(placebo 39%vs treatment 19%)under a two-tailed significance level of 0.05.An adaptive sample size re-estimation based on the outcomes of 144 patients will allow a possible increase to a prespecified maximum of 326 patients.Intervention Participants will receive 1 g intravenous tranexamic acid over 10 min,followed by 1 g intravenous tranexamic acid over 8 hours;or matching placebo.Primary efficacy measure The primary efficacy measure is the proportion of patients with haematoma growth by 24±6 hours,defined as either≥33%relative increase or≥6 mL absolute increase in haematoma volume between baseline and follow-up CT scan.Discussion We describe the rationale and protocol of STOP-MSU,a phase Ⅱ trial of tranexamic acid in patients with ICH within 2 hours from onset,based in participating mobile stroke units and emergency departments. | Nawaf Yassi Henry Zhao Leonid Churilov Bruce C V Campbell Teddy Wu Henry Ma Andrew Cheung Timothy Kleinig Helen Brown Philip Choi Jiann-Shing Jeng Annemarei Ranta Hao-Kuang Wang Geoffrey C Cloud Rohan Grimley Darshan Shah Neil Spratt Der-Yang Cho Karim Mahawish Lauren Sanders John Worthington Ben Clissold Atte Meretoja Vignan Yogendrakumar Mai Duy Ton Duc Phuc Dang Nguyen Thai My Phuong Huy-Thang Nguyen Chung Y Hsu Gagan Sharma Peter J Mitchell Bernard Yan Mark W Parsons Christopher Levi Geoffrey A Donnan Stephen M Davis | 2022 | Stroke & Vascular Neurology2022，7，2： | 1 |
| 16 | Effects of Fe^3+ and Ag^+ Ions on the Photocatalytic Degradation of Sucrose in Water显示文摘 | Veronica V Helen T Rose A | 2001 | Catalysis Today2001，68，： | 1 |
| 17 | Reduction of the need for phase unwrapping in radar interferometry显示文摘 | Didier M Helene V Mart R | 1996 | IEEE Trans on Geoscience and Re mote Sensing1996，34，2： | 1 |
| 18 | Non-linear fitting of mechanical data for efficacy determination of single versus double bundle achilles tendon grafts for PCL reconstructions显示文摘 | Antonio V Helen K Deante L | 2002 | Bio Medical Materials and Engineering2002，12，3： | 1 |
| 19 | Specific inhibition of human immunodeficiency virus type 1 (HIV-1) integration in cell culture:putative inhibitors of HIV-1 integrase显示文摘 | Nick V Raman K Helen H | 2001 | AAC2001，45，9： | 1 |
| 20 | Brain regulation of feeding behavior and food intake in fish显示文摘 | LIN X W HELENE V YUWARAJ N | 2000 | Comparative Biochemistry and Physiology Part A2000，126，： | 1 |
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