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Anti-inflammatory pathways and alcoholic liver disease: Role of an adiponectin/interleukin-10/heme oxygenase-1 pathway

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World Journal of Gastroenterology 2010年第11期16卷 1330-1336页

作者： Palash Mandal Michele t Pritchard laura e Nagy Department of Pathobiology and Gastroenterology Cleveland ClinicLerner Research Institute/NE-40

the development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non-parenchymal cells in the liver. enhanced inflammation in the liver during ethanol exposure is an important contributor to injury. Kupffer cells, the resident macrophages in liver, are particularly critical to the onset of ethanol-induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharide via toll-like receptor 4. this sensitization enhances production of inflammatory mediators, such as tumor necrosis factor-α and reactive oxygen species, that contribute to hepatocyte dysfunction, necrosis, apoptosis, and fibrosis. Impaired resolution of the inflammatory process probably also contributes to ALD. the resolution of inflammation is an active, highly coordinated response that can potentially be manipulated via therapeutic interventions to treat chronic inflammatory diseases. Recent studies have identif ied an adiponectin/interleukin-10/heme oxygenase-1 (HO-1) pathway that is profoundly effective in dampening the enhanced activation of innate immune responses in primary cultures of Kupffer cells, as well as in an in vivo mouse model of chronic ethanol feeding. Importantly, induction of HO-1 also reduces ethanol-induced hepatocellular apoptosis in this in vivo model. Based on these data, we hypothesize that the development of therapeutic agents to regulate HO-1 and its downstream targets could be useful in enhancing the resolution of inflammation during ALD and preventing progression of early stages of liver injury.

关键词： Liver disease Alcohol Macrophages Hemeoxygenase-1 Inflammation

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Small heat shock protein B8:from cell functions to its involvement in diseases and potential therapeutic applications

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Neural Regeneration Research 2025年第10期20卷 2872-2886页

作者： Marta Chierichetti Riccardo Cristofani Valeria Crippa Veronica Ferrari Marta Cozzi elena Casarotto Paola Pramaggiore laura Cornaggia Guglielmo Patelli Ali Mohamed Margherita Piccolella Mariarita Galbiati Paola Rusmini Barbara tedesco Angelo Poletti Laboratory of experimental Biology Dipartimento di Scienze Farmacologiche e Biomolecolari“Rodolfo Paoletti”(DiSFeB)Universitàdegli Studi di MilanoMilanItaly

Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock ***8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation,cell division,and ***8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective *** line with this function,the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and *** cancer,HSPB8 has a dual role being capable of exerting either a pro-or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under ***,HSPB8 exerts a protective function in different diseases by modulating the inflammatory response,which characterizes not only neurodegenerative diseases,but also other chronic or acute conditions affecting the nervous system,such as multiple sclerosis and intracerebellar *** note,HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other *** is the case of cognitive impairment related to diabetes mellitus,in which HSPB8 exerts a protective activity by assuring mitochondrial *** review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions,focusing on the beneficial effects of its ***-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed,emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.

关键词： aggregation autophagy cancer chaperone chaperone-assisted selective autophagy cognitive impairment HSPB8 neuroinflammation neuromuscular diseases therapy

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Critiquing and Joining Intersections of Disaster,Conflict,and Peace Research

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International Journal of Disaster Risk Science 2020年第5期11卷 555-567页

作者： laura e.R.Peters Ilan Kelman College of earth.Ocean and Atmospheric SciencesOregon State UniversityCorvallis.OR 97331USA Institute for Risk and Disaster Reduction and Institute for Global HealthUniversity College LondonLondon WC1E 6BT.UK University of Agder.4630 Kristiansand Norway

Disaster research,conflict research,and peace research have rich and deep histories,yet they do not always fully intersect or learn from each other,even when they investigate if and how disasters lead to conflict or *** has tended to focus on investigating causal linkages between disaster(including those associated with climate change)and conflict,and disaster diplomacy emerged as a thread of explanatory research that investigates how and why disaster-related activities do and do not in fluence peace and ***,definitive conclusions on the disaster-conflict-peace nexus have evaded scientific consensus,in part due to conceptual,methodological,and interpretive differences among *** article highlights that this nexus would benefit from a more robust engagement with each field's foundational research that explores beyond binary and crude *** are concepts of destructive and constructive conflict;direct,structural,and cultural violence,and their relationships to vulnerability;negative and positive peace;and the ideals and realities of peacebuilding and conflict *** article demonstrates how integrated scholarship could open up and advance new lines of questioning,with implications for developing cohere nt research,policy,and *** article concludes by offering recommendations for how to better connect disaster,conflict,and peace research.

关键词： Climate change Conflict research Disaster diplomacy Disaster risk reduction Peace research

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A modified intron of VRt2 drives glume and grain elongation in wheat

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Molecular Plant 2021年第9期14卷 1421-1423页

作者： laura e.Dixon Scott A.Boden Faculty of Biological Sciences University of LeedsLeeds LS29JTUK School of Agriculture Food and WineWaite Research InstituteUniversity of AdelaideGlen OsmondSA 5064Australia

Yield is a complex trait that is determined predominantly by the number,size,and weight of grain produced by a plant,which are all in fluenced by multiple genes and environ mental *** cereals,grain size is in flue need by envir on mental signals including nutrient availability and temperature,and by variation for genes that control the dimensions of a grain or the size of floral organs(e.g.,Heang and Sassa,2012;Brinton et al.,2017;Adamski et al.,2021;Liu et al.,2021;Xiao et al.,2021).three recent studies have investigated subspecies of tetrapioid and hexapioid wheat that produce Ion ger grains,which form in florets that contain elongated floral structures(Adamski et al.,2021;Liu et al.,2021;Xiao et al.,2021);their findings provide new understanding of the genes controlling floret architecture,which could be used by breeders to enhance grain size and yield.

关键词： grain organs wheat

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Immunological mechanisms and therapeutic targets of fatty liver diseases

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Cellular & Molecular Immunology 2021年第1期18卷 73-91页

作者： Hua Wang Wajahat Mehal laura e.Nagy Yaron Rotman Department of Oncology the First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina InfIammation and Immune Mediated Diseases Laboratory of Anhui Province HefeiAnhuiChina West Haven VA Medical Center West Haven CT and Yale University School of MedicineNew HavenCTUSA Department of Inflammation and Immunity Cleveland ClinicClevelandOHUSA Department of Gastroenterology and Hepatology Center for Liver Disease ResearchCleveland ClinicClevelandOHUSA Department of Molecular Medicine Case Western Reserve UniversityClevelandOHUSA Liver and energy Metabolism Section Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA

Alcoholic liver disease(ALD)and nonalcoholic fatty liver disease(NAFLD)are the two major types of chronic liver disease *** processes play key roles in the pathogeneses of fatty liver diseases,and continuous inflammation promotes the progression of alcoholic steatohepatitis(ASH)and nonalcoholic steatohepatitis(NASH).Although both ALD and NAFLD are closely related to inflammation,their respective developmental mechanisms differ to some ***,we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and *** cell types in the liver,including macrophages,neutrophils,other immune cell types and hepatocytes,are involved in fatty liver disease *** addition,microRNAs(miRNAs),extracellular vesicles(eVs),and complement also contribute to the inflammatory process,as does intertissue crosstalk between the liver and the intestine,adipose tissue,and the nervous *** point out that inflammation also plays important roles in promoting liver repair and controlling bacterial *** the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

关键词： ALD NAFLD inflammation cytokine target immune

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Virtual drug design： Skpl-Skp2 inhibition targets cancer stem cells

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Asian Journal of Andrology 2013年第6期15卷 717-718页

作者： laura e Pascal Zhou Wang Department of Urology University of Pittsburgh School of Medicine Pittsburgh PA 15232 USA University of Pittsburgh Cancer Institute University of Pittsburgh School of Medicine Pittsburgh PA 15232 USA Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA 15232 USA

the dysregulation of pathways regulat-ing cellular function is a frequent hall-mark of cancer and the development of specific pathway inhibitors that alter tumor growth and progression are the focus of multiple recent studies. e3 ubiquitin ligases are a large group of diverse protein enzymes that specifically target proteins for dear- ance, and their importance to normal cel-lular function is illustrated in the many diseases associated with their loss of func- tion or inappropriate targeting. S-phase kinase-associated protein 2 （Skp2） is an F box protein that plays critical roles in cell-cycle progression, senescence, metabolism, and acts as an Skpl-Cullin-l-F box （SCF） ubiquitin ligase substrate recognition fac-tor. Overexpression of Skp2 is associated with poor prognosis and metastasis in many cancers and is a well validated drug target. In a recent report, Chart et al. have iden-tified an Skp2 inhibitor that selectively impairs Skp2 e3 ligase activity using an integrated virtual high-throughput drug screening and experimental validation approach. this Skp2 inhibitor restricts cancer stemness and potentiates sensitivity to chemotherapeutic agents in multiple ani-mal tumor models. these findings identify a new novel small molecule that targets the Skp2 and reduces tumor growth by attenu-ating aerobic glycolysis and inducing cel-lular senescence.

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two paths for stabilization of eRG in prostate carcinogenesis： tMPRSS2-eRG fusions and speckle-type pox virus and zinc finger protein mutations

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Asian Journal of Andrology 2016年第4期18卷 594-595页

作者： laura e Pascal Zhou Wang Department of Urology University of Pittsburgh Cancer Institute Department of Pharmacology and Chemical Biology Department of Pathology University of Pittsburgh School of Medicine Pittsburgh PA 15232 USA.

Speckle-type POZ （pox virus and zinc finger protein） protein （SPOP） is ane3 ubiquitin ligase adaptor protein that specifically promotes the ubiquitination and proteasome degradation of proteins. SPOP mutations are frequent in prostate cancer, and in a previous study, An et al. demonstrated that SPOP induced the degradation of the androgen receptor （AR） suggesting that SPOP is important in maintaining prostate homeostasis. In this current highlighted report, An and colleagues showed that eRG, which has been implicated as an oncoprotein in prostate cancer.

关键词： @@

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the role of p53 in developmental syndromes

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Journal of Molecular Cell Biology 2019年第3期11卷 200-211页

作者： Margot e.Bowen laura D.Attardi Division of Radiation and Cancer Biology in the Department of Radiation Oncology Stanford University School of MedicineStanfordCA 94305USA Department of Genetics Stanford University School of MedicineStanfordCA 94305USA

While it is well appreciated that loss of the p53 tumor suppressor protein promotes cancer,growing evidence indicates that increased p53 activity underlies the developmental defects in a wide range of genetic *** inherited or de novo mutations that cause these syndromes affect diverse cellular processes,such as ribosome biogenesis,DNA repair,and centriole duplication,and analysis of human patient samples and mouse models demonstrates that disrupting these cellular processes can activate the p53 ***,many of the developmental defects in mouse models of these syndromes can be rescued by loss of p53,indicating that inappropriate p53 activation directly contributes to their pathogenesis.A role for p53 in driving developmental defects is further supported by the observation that mouse strains with broad p53 hyperactivation,due to mutations affecting p53 pathway components,display a host of tissue-specific developmental defects,including hematopoietic,neuronal,craniofacial,cardiovascular,and pigmentation ***,germline activating mutations in tP53 were recently identified in two human patients exhibiting bone marrow failure and other developmental *** in mice suggest that p53 drives developmental defects by inducing apoptosis,restraining proliferation,or modulating other developmental programs in a cell type-dependent ***,we review the growing body of evidence from mouse models that implicates p53 as a driver of tissue-specific developmental defects in diverse genetic syndromes.

关键词： p53 Mdm2 development embryo congenital defect syndrome genetic disorder

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A Systems Biology Approach for Studying Heterotopic Ossification： Proteomic Analysis of Clinical Serum and tissue Samples

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Genomics, Proteomics & Bioinformatics 2018年第3期16卷 212-220页

作者： erin L. Crowgey Jennifer t. Wyffels Patrick M. Osborn thomas t. Wood laura e. edsberg Nemours Biomedical Research Nemours Alfred I. duPont Hospital for Children Wilmington DE 19803 USA Natural and Health Sciences Researeh Center Center for Wound Healing Research Daemen College Amherst NY 14226 USA Department of Computer and Information Sciences Center for Bioinformatics and Computational Biology University of Delaware Newark DE 19711 USA San Antonio Military Medical Center San Antonio TX 78219 USA

Heterotopic ossification （HO） refers to the abnormal formation of bone in soft tissue. Although some of the underlying processes of HO have been described, there are currently no clinical tests using validated biomarkers for predicting HO formation. As such, the diagnosis is made radiographically after HO has formed. to identify potential and novel biomarkers for HO, we used isobaric tags for relative and absolute quantitation （itRAQ） and high-throughput antibody arrays to produce a semi-quantitative proteomics survey of serum and tissue from subjects with （HO ＋） and without （HO-） heterotopic ossification. the resulting data were then analyzed using a systems biology approach. We found that serum samples from subjects experiencing traumatic injuries with resulting HO have a different proteomic expression controls. Subsequent quantitative eLISA identified profile compared to those from the matched five blood serum proteins that were differentially regulated between the HO-- and HO- groups. Compared to HO- samples, the amount of insulin-like growth factor I （IGF1） was up-regulated in HO＋ samples, whereas a lower amount of osteopontin （OPN）, myeloperoxidase （MPO）, runt-related transcription factor 2 （RUNX2）,and growth differentiation factor 2 or bone morphogenetic protein 9 （BMP-9） was found in HO ＋ samples （Welch two sample t-test; P 〈 0.05）. these proteins, in combination with potential serum biomarkers previously reported, are key candidates for a serum diagnostic panel that may enable early detection of HO prior to radiographic and clinical manifestations.

关键词： Heterotopic ossification Proteomics Runt-related transcriptionfactor 2 extracellular matrixorganization Keratinization

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Potential roles of functional bacterial amyloid proteins,bacterial biosurfactants and other putative gut microbiota products in the etiopathogeny of Parkinson’s Disease

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BIOCeLL 2021年第1期45卷 1-16页

作者： eMILIA MANOLe laura DUMItReSCU CRIStINA NICULIȚe BOGDAN OVIDIU POPeSCU laura CRIStINA CeAFALAN Victor Babeș”National Institute of Pathology Bucharest050088Romania Colentina Clinical Hospital Bucharest020125Romania Carol Davila”University of Medicine and Pharmacy Bucharest020021Romania

An increasing number of studies provide evidence for the existence of a microbiota-gut-brain axis and its potential involvement in the development of sporadic Parkinson’s disease and other neurodegenerative *** neuropathologic hallmark of Parkinson’s disease is the presence of brain intraneuronal aggregates of misfolded alpha-synuclein,known as Lewy *** gut microbiota products may trigger alpha-synuclein conformational changes in the neurons of the enteric nervous system,which can then spread to the brain in a prion-like fashion through the vagus *** may interfere with neuroinflammatory pathways and susceptibility to *** this review,we assess the potential role of putative gut microbiota products in the etiopathogeny of Parkinson’s disease,with a special emphasis on functional bacterial amyloid proteins,bacterial biosurfactants,endotoxins and short-chain fatty *** possible roles of molecular hydrogen,a common byproduct of bacterial fermentation,are also addressed.

关键词： Alpha-synuclein endotoxins Short-chain fatty acids

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