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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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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 worldwide.Inflammatory 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 extent.Here,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 NASH.Multiple cell types in the liver,including macrophages,neutrophils,other immune cell types and hepatocytes,are involved in fatty liver disease inflammation.In 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 system.We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections.Understanding 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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Identific tion of quantitative trait loci and associated candidate genes for pregnancy success in Angus–Brahman crossbred heifers

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Journal of Animal Science and Biotechnology 2024年第1期15卷 162-170页

作者： Quinn A.Hoorn Gabriel A.Zayas eduardo e.Rodriguez laura M.Jensen Raluca G.Mateescu Peter J.Hansen Department of Animal Sciences Donald Henry Barron Reproductive and Perinatal Biology Research Programand the Genetics InstituteUniversity of FloridaGainesvilleFLUSA School of Applied Systems Biology La Trobe UniversityBundooraVIC 3083Australia

Background In beef cattle, more than 50% of the energy input to produce a unit of beef is consumed by the female that produced the calf. Development of genomic tools to identify females with high genetic merit for reproductive function could increase the profitability and sustainability of beef production.Results Genome-wide association studies(GWAS) were performed using a single-step genomic best linear unbiased prediction approach on pregnancy outcome traits from a population of Angus–Brahman crossbred heifers. Furthermore, a validation GWAS was performed using data from another farm. Heifers were genotyped with the Bovine GGP F250 array that contains 221,077 SNPs. In the discovery population, heifers were bred in winter breeding seasons involving a single round of timed artificial insemination(AI) followed by natural mating for 3 months. Two phenotypes were analyzed: pregnancy outcome to first-service AI(PAI;n = 1,481) and pregnancy status at the end of the breeding season(PeBS;n = 1,725). The heritability was estimated as 0.149 and 0.122 for PAI and PeBS, respectively. In the PAI model, one quantitative trait locus(QTL), located between 52.3 and 52.5 Mb on BTA7, explained about 3% of the genetic variation, in a region containing a cluster of γ-protocadherin genes and SLC25A2. Other QTLs explaining between 0.5% and 1% of the genetic variation were found on BTA12 and 25. In the PeBS model, a large QTL on BTA7 was synonymous with the QTL for PAI, with minor QTLs located on BTA5, 9, 10, 11, 19, and 20. The validation population for pregnancy status at the end of the breeding season were Angus–Brahman crossbred heifers bred by natural mating. In concordance with the discovery population, the large QTL on BTA7 and QTLs on BTA10 and 12 were identified.Conclusions In summary, QTLs and candidate SNPs identified were associated with pregnancy outcomes in beef heifers, including a large QTL associated with a group of protocadherin genes. Confirmation of these associations with larger populations could lead to the develo

关键词： Beef cattle Fertility GWAS QTL

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Association between baseline levels of muscular strength and risk of stroke in later life:The Cooper Center Longitudinal Study

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Journal of Sport and Health Science 2024年第5期13卷 642-649页

作者： Stephen W.Farrell David Leonard Qing Li Carolyn e.Barlow Kerem Shuval Jarett D.Berry Andjelka Pavlovic laura F.DeFina Research Division The Cooper InstituteDallasTX 75230USA Department of Internal Medicine University of Texas at Tyler School of MedicineTylerTX 75799USA

Background:Muscular strength is an important component of physical fitness.We evaluated the relationship between baseline muscular strength and risk of stroke among adults who were aged≥65 years during follow-up.Methods:We included 7627 healthy adults(mean age=43.9 years,86.0%male)underwent a baseline physical examination between 1980 and 1989.Muscular strength was determined by 1-repetition maximum measures for bench press and leg press and categorized into age-and sex-specific tertiles for each measure.Cardiorespiratory fitness(CRF)was assessed via a maximal treadmill exercise test.Those enrolled in fee-for-service Medicare from 1999 to 2019 were included in the analyses.Associations between baseline strength and stroke outcomes were estimated using a modified Cox proportional hazards model.In a secondary analysis,we examined stroke risk by categories of CRF where Quintile 1=low,Quintiles 2-3=moderate,and Quintiles 4-5=high CRF based on age and sex.Results:After 70,072 person-years of Medicare follow-up,there were 1211 earliest indications of incident stroke.In multivariable analyses,the hazard ratio(95%confidence interval(95%CI))for stroke across bench press categories were 1.0(referent),0.96(0.83-1.11),and 0.89(0.77-1.04),respectively(p trend=0.14).The trend across categories of leg press was also non-significant(p trend=0.79).Adjusted hazard ratio(95%CI)for stroke across ordered CRF categories were 1.0(referent),0.90(0.71-1.13),and 0.72(0.57-0.92)(p trende meeting public health guidelines for muscular strengthening activities is likely to improve muscular strength as well as many health outcomes in older adults,performing such activities may not be helpful in preventing stroke.Conversely,meeting guidelines for aerobic activity is likely to improve CRF and lower stroke risk.

关键词： Cardiorespiratory fitness Medicare Muscular strength Stroke

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In-situ study of the microstructure evolution during tension of a Mg-Y-Zn-Al alloy processed by rapidly solidified ribbon consolidation technique

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Journal of Magnesium and Alloys 2024年第5期12卷 2024-2040页

作者： Jen? Gubicza Kristián Máthis Péter nagy Péter Jenei Zoltán Heged?s Andrea Farkas Jozef Vesely Shin-ichi Inoue Daria Drozdenko Yoshihito Kawamura Department of Materials Physics Faculty of Science E?tv?s Loránd University Department of Physics of Materials Faculty of Mathematics and Physics Charles University Deutsches elektronen-Synchrotron DeSY Magnesium Research Center Kumamoto University

Mg-Y-Zn-Al alloys processed by rapidly solidified ribbon consolidation（RSRC） technique exhibit an exceptional mechanical performance indicating promising application potential. This material has a bimodal microstructure consisting of fine recrystallized and coarse non-recrystallized grains with solute-rich stacking faults forming cluster arranged layers（CALs） and nanoplates（CANaPs）, or complete long period stacking ordered（LPSO） phase. In order to reveal the deformation mechanisms, in-situ synchrotron X-ray diffraction line profile analysis was employed for a detailed study of the dislocation arrangement created during tension in Mg-0.9% Zn-2.05% Y-0.15%Al（at%） alloy. For uncovering the effect of the initial microstructure on the mechanical performance, additional samples were obtained by annealing of the as-consolidated specimen at 300 and 400 ℃ for 2 h. The heat treatment at 300 ℃ had no significant effect on the initial microstructure, its evolution during tension and, thus, the overall deformation behavior under tensile loading. On the other hand,annealing at 400 ℃ resulted in a significant increase of the recrystallized grains fraction and a decrease of the dislocation density, leading to only minor degradation of the mechanical strength. The maximum dislocation density at the failure of the samples corresponding to the plastic strain of 10-25% was estimated to be about 16-20 × 1014m-2. The diffraction profile analysis indicated that most dislocations formed during tension were of non-basaland pyramidaltypes, what was also in agreement with the Schmid factor values revealed independently from orientation maps. It was also shown that the dislocation-induced Taylor hardening was much lower below the plastic strain of 3% than above this value, which was explained by a model of the interaction between prismatic dislocations and CANaPs/LPSO plates.

关键词： Mg-Zn-Y-Al alloy Long period stacking ordered (LPSO) phase Cluster arranged nanoplates (CANaPs) Annealing Tension Dislocation density Hardening

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Lack of evidence for germline WWP1 pathogenic variants in gastrointestinal polyposis and other phenotypes suggestive of PTeN-hamartoma-tumor syndrome

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Genes & Diseases 2024年第2期11卷 524-527页

作者： Noemi Gonzalez-Abuin Tirso Pons Teresa Fuster Isabel Quintana Mariona Terradas Gemma Aiza Joan Brunet Gabriel Capellá Heather Hampel laura Valle Hereditary Cancer Program Catalan Institute of OncologyOncobell ProgramIDIBELLHospitalet de LlobregatBarcelona 08908Spain Department of Immunology and Oncology National Center for BiotechnologySpanish National Research Council (CNB-CSIC)Madrid 28049Spain Centro de Investigación Biomédica en Red de Cáncer (CIBeRONC) Madrid 28029Spain Catalan Institute of Oncology IDIBGiGirona 17007Spain Division of Clinical Cancer Genomics Department of Medical Oncology & Therapeutic ResearchCity of Hope National Cancer CenterDuarteCA 91010USA

Germline activating variants in WWP1,which encodes an e3 ubiquitin ligase that antagonizes PTeN tumor suppressive function,have been proposed as an alternative mechanism of PTeN inactivation in PTeN-hamartoma-tumor syndrome(PHTS)-like patients with wildtype PTeN.1 More specifically,heterozygous,potentially activating wwP1 variants were first identified by Lee et al in patients affected with gastrointestinal oligopolyposis,including adenomatous,hyperplastic/serrated,and hamartomatous polyps,and occasionally with colorectal cancer(Table 1).Subsequently,based on the PHTS phenotypic features,wWP1 mutational screening was performed in patients with thyroid nodules,2 or normocephalic autism spectrum disorder(ASD),3 where germline WWP1 variants were also identified(Table S1).

关键词： WWP1 gastrointestinal polyposis

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Ornithine aspartate effects on bacterial composition and metabolic pathways in a rat model of steatotic liver disease

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World Journal of Hepatology 2024年第5期16卷 832-842页

作者： elisa Carolina Lange Pabulo Henrique Rampelotto Larisse Longo laura Bainy Rodrigues de Freitas Carolina Uribe-Cruz Mario Reis Alvares-da-Silva experimental Laboratory of Hepatology and Gastroenterology Hospital de Clínicas de Porto AlegrePorto Alegre 90035-007Brazil Graduate Program in Gastroenterology and Hepatology Universidade Federal do Rio Grande do SulPorto Alegre 90035-007Brazil Bioinformatics and Biostatistics Core Facility Universidade Federal do Rio Grande do SulPorto Alegre 91501-970Brazil Graduate Program in Biological Sciences:Pharmacology and Therapeutics Universidade Federal do Rio Grande do SulPorto Alegre 90035-007Brazil Facultad de Ciencias de la Salud Universidad Católica de las MisionesPosadasMisiones 3300Argentina Division of Gastroenterology Hospital de Clínicas de Porto AlegrePorto Alegre 90035-007RSBrazil Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq)researcher Brasília 71605-001Brazil

BACKGROUND Metabolic-dysfunction associated steatotic liver disease(MASLD)is a hepatic manifestation of metabolic syndrome.Studies suggest ornithine aspartate(LOLA)as drug therapy.AIM To analyze the influence of LOLA intake on gut microbiota using a nutritional model of MASLD.MeTHODS Adult male Sprague Dawley rats were randomized into three groups:Control(10 rats fed with a standard diet),MASLD(10 rats fed with a high-fat and choline-deficient diet),and LOLA(10 rats receiving 200 mg/kg/d LOLA,after the 16th week receiving high-fat and choline-deficient diet).After 28 wk of the experiment,animals were euthanized,and feces present in the intestine were collected.Following fecal DNA extraction,the V4 region of the 16S rRNA gene was amplified followed by sequencing in an Ion S5™system.ReSULTS Alpha and beta diversity metrics were comparable between MASLD and LOLA.3 OTUs were differentially abundant between MASLD and LOLA,which belong to the species Helicobacter rodentium,Parabacteroides goldsteinii,and Parabacteroides distasonis.The functional prediction provided two different metabolic profiles between MASLD and LOLA.The 9 pathways differentially abundant in MASLD are related to a change in energy source,adenosine/purine nucleotides degradation as well as guanosine and adenosine deoxyribonucleotides biosynthesis.The 14 pathways differentially abundant in LOLA are associated with four major metabolic functions primarily influenced by L-aspartate,including tricarboxylic acid cycle pathways,purine/guanosine nucleotides biosynthesis,pyrimidine ribonucleotides biosynthesis and salvage as well as lipid IVA biosynthesis.CONCLUSION Although LOLA had no influence on alpha and beta diversity in this nutritional model of MASLD,it was associated with changes in specific gut microbes and their related metabolic pathways.

关键词： Animal model Gut microbiota Metabolic-associated steatotic liver disease Metabolic prediction Ornithine aspartate

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exploring the effects of dietary inulin in rainbow trout fed a high‑starch,100%plant‑based diet

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Journal of Animal Science and Biotechnology 2024年第2期15卷 713-732页

作者： Raphaël Defaix Jep Lokesh laura Frohn Mickael Le Bechec Thierry Pigot Vincent Veron Anne Surget Sandra Biasutti Frederic Terrier Sandrine Skiba-Cassy Jerome Roy Stephane Panserat Karine Ricaud Universite de Pau et Des Pays de L’Adour E2S UPPAINRAENUMEASaint‑Pee‑Sur‑NivelleFrance Universite de Pau et Des Pays de L’Adour E2S UPPACNRSIMT Mines AlesIPREMPauFrance Universite de Pau et Des Pays de L’Adour E2S UPPAIUT des Pays de l’AdourDepartement Genie BiologiqueMont de MarsanFrance.

Background High dietary carbohydrates can spare protein in rainbow trout(Oncorhynchus mykiss)but may affect growth and health.Inulin,a prebiotic,could have nutritional and metabolic effects,along with anti-inflammatory properties in teleosts,improving growth and welfare.We tested this hypothesis in rainbow trout by feeding them a 100%plant-based diet,which is a viable alternative to fishmeal and fish oil in aquaculture feeds.In a two-factor design,we examined the impact of inulin(2%)as well as the variation in the carbohydrates(CHO)/plant protein ratio on rainbow trout.We assessed the influence of these factors on zootechnical parameters,plasma metabolites,gut microbiota,production of short-chain fatty acids and lactic acid,as well as the expression of free-fatty acid receptor genes in the mid-intestine,intermediary liver metabolism,and immune markers in a 12-week feeding trial.Results The use of 2%inulin did not significantly change the fish intestinal microbiota,but interestingly,the high CHO/protein ratio group showed a change in intestinal microbiota and in particular the beta diversity,with 21 bacterial genera affected,including Ralstonia,Bacillus,and 11 lactic-acid producing bacteria.There were higher levels of butyric,and valeric acid in groups fed with high CHO/protein diet but not with inulin.The high CHO/protein group showed a decrease in the expression of pro-inflammatory cytokines(il1b,il8,and tnfa)in liver and a lower expression of the genes coding for tight-junction proteins in mid-intestine(tjp1a and tjp3).However,the 2%inulin did not modify the expression of plasma immune markers.Finally,inulin induced a negative effect on rainbow trout growth performance irrespective of the dietary carbohydrates.Conclusions With a 100%plant-based diet,inclusion of high levels of carbohydrates could be a promising way for fish nutrition in aquaculture through a protein sparing effect whereas the supplementation of 2%inulin does not appear to improve the use of CHO when combined with a 100%plant-based diet.

关键词： Aquaculture Fish nutrition Gut microbiota Immune markers Intermediary metabolism Inulin Prebiotic Rainbow trout Short-chain fatty acids

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Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

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Bone Research 2024年第1期12卷 199-214页

作者： laura J.Brylka Assil-Ramin Alimy Miriam e.A.Tschaffon-Müller Shan Jiang Tobias Malte Ballhause Anke Baranowsky Simon von Kroge Julian Delsmann eva Pawlus Kian eghbalian Klaus Püschel Astrid Schoppa Melanie Haffner-Luntzer David J.Beech Frank Timo Beil Michael Amling Johannes Keller Anita Ignatius Timur A.Yorgan Tim Rolvien Thorsten Schinke Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf20246 HamburgGermany Department of Trauma and Orthopedic Surgery University Medical Center Hamburg-Eppendorf20246 HamburgGermany Institute of Orthopedic Research and Biomechanics University Medical Center UlmBadenWürttemberg89081 UlmGermany Department Legal Medicine University Medical Center Hamburg-Eppendorf20246 HamburgGermany Leeds Institute of Cardiovascular and Metabolic Medicine School of MedicineUniversity of LeedsLS29JT LeedsUK

Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage.Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)development.Mice with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate postnatally.Moreover,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth plates.While skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age.Likewise,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage degeneration.Importantly,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) mice.We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes.Finally,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes.Collectively,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

关键词： Piezo1 markedly ossification

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Synergistic interaction between C5a and NOD2 signaling in the regulation of chemokine expression in RAW 264.7 macrophages

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Advances in Bioscience and Biotechnology 2013年第8期4卷 30-37页

作者： Hui Tang Umme Amara Dora Tang Mark A. Barnes Christine McDonald laura e. nagy Departments of Pathobiology Cleveland Clinic Cleveland USA

The innate immune response is a complex process involving multiple pathogen-recognition receptors, including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors. Complement is also a critical component of innate immunity. While complement is known to interact with TLR-mediated signals, the interactions between NOD-like receptors and complement are not well understood. Here we report a synergistic interaction between C5a and Nod2 signaling in RAW 264.7 marophages. Long-term treatment with muramyl dipeptide (MDP), a NOD2 ligand, enhanced C5a-mediated expression of chemokine mRNAs in RAW 264.7 cells. This response was dependent on NOD2 expression and was associated with a decrease in expression of C5L2, a receptor for C5a which acts as a negative modulator of C5a receptor (C5aR) activity. MDP amplified C5a-mediated phosphorylation of p38 MAPK. Treatment of RAW264.7 cells with an inhibitor of p38 attenuated the synergistic effects of C5aon MDP-primed cells on MIP-2, but not MCP-1, mRNA. In contrast, inhibition of AKT prevented C5a stimulation of MCP-1, but not MIP-2, mRNA, in MDP-primed cells. Taken together, these data demonstrated a synergistic interaction between C5a and NOD2 in the regulation of chemokine expression in macrophages, associated with a down-regulation of C5L2, a negative regulator of C5a receptor activity.

关键词： Anaphylatoxin C5L2 C5a Receptor Complement NOD2

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