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Targeting copper to combat macrophage-driven inflammation: a potential advanced therapeutic strategy

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4426-4427页

作者： Ralf weiskirchen Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical Chemistry(IFMPEGKC)RWTH University Hospital AachenPauwelsstr.30D-52074AachenGermany

In a recent paper published in Nature,Solier and coworkers showed that a rationally designed dimer of metformin targeting mitochondrial copper content can effectively oppose macrophage activation and plasticity.1 Since macrophages play critical roles in the initiation and maintenance of inflammation,this drug termed supformin holds promise to be a therapeutic effective in suppressing inflammation-related diseases related to macrophages.

关键词： inflammation therapeutic macrophage

Real-time condition monitoring and fault diagnosis in switched reluctance motors with Kohonen neural network

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Journal of Zhejiang University-Science C(Computers and Electronics) 2013年第12期14卷 941-952页

作者： Ali UYSAL raif BAYIR Department of Mechatronics Engineering Faculty of TechnologyKarabuk University

The faults in switched reluctance motors(SRMs) were detected and diagnosed in real time with the Kohonen neural network. When a fault happens, both financial losses and undesired situations may occur. For these reasons, it is important to detect the incipient faults of SRMs and to diagnose which faults have occurred. In this study, a test rig was realized to determine the healthy and faulty conditions of SRMs. A data set for the Kohonen neural network was created with implemented measurements. A graphical user interface(GUI) was created in Matlab to test the performance of the Kohonen artificial neural network in real time. The data of the SRM was transferred to this software with a data acquisition card. The condition of the motor was monitored by marking the data measured in real time on the weight position graph of the Kohonen neural network. This test rig is capable of real-time monitoring of the condition of SRMs, which are used with intermittent or continuous operation, and is capable of detecting and diagnosing the faults that may occur in the motor. The Kohonen neural network used for detection and diagnosis of faults of the SRM in real time with Matlab GUI was embedded in an STM32 processor. A prototype with the STM32 processor was developed to detect and diagnose the faults of SRMs independent of computers.

关键词： Switched reluctance motor Kohonen neural network Real-time condition monitoring Fault detection and diagnosis

Wilson disease-the impact of hyperimmunity on disease activity:A case report

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World Journal of Clinical Cases 2021年第6期9卷 1386-1393页

作者： Wolfgang Stremmel Thomas Longerich RenéLiere Vladimir Vacata Josef van Helden Ralf weiskirchen Pracice for Gastroenterology Medical Center Baden-BadenBaden-Baden D-76530Germany Department of General Pathology University Heidelberg HospitalInstitute of PathologyUniversity of HeidelbergHeidelberg D-69115Germany MVZ Dr.Stein+Kollegen Labor MönchengladbachMönchengladbach D-41069Germany Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical ChemistryRheinisch-Westfaelische Technische Hochschule University Hospital AachenAachen D-52074Germany

BACKGROUND In Wilson disease lack of biliary copper excretion causes hepatocellular injury by accumulation of free toxic *** overspill to serum accounts for neuronal damage as second common *** with copper chelators or zinc targets the removal of this free ***,in some patients liver disease persists for unknown reason despite normalized free *** discovery of a hyperimmunity as a contributing pathogenetic factor was discovered in this case report with implication also for other liver *** SUMMARY A 9-year-old girl was diagnosed in August 2009 by family screening of having asymptomatic Wilson disease with elevated *** at time of diagnosis antinuclear antibodies(ANA)were elevated without hyperimmunoglobulinemia(immunoglobulin G,IgG).After one year of therapy with Dpenicillamine transaminases normalized together with free serum *** continuous therapy with copper chelators free copper remained normal until today,whereas transaminases raised to alanine aminotransferase values of 571 U/L in December *** hyperimmunity a tentative steroid course on top of Dpenicillamine improved ***,hyperimmunity may have impact on liver inflammation after control of the metabolic disturbance.A retrospective cohort study confirmed the common association of elevated transaminases with ANA,but no IgG *** This hyperimmune-triggered condition may represent a new entity which per se or on top of other liver diseases induces liver inflammation responsive to steroids.

关键词： Wilson disease Copper metabolism Antinuclear antibodies Diagnosis Steroid therapy Case report

Interleukin-33 in the pathogenesis of liver fibrosis： alarming ILC2 and hepatic stellate cells

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Cellular & Molecular Immunology 2017年第2期14卷 143-145页

作者： Ralf weiskirchen Frank Tacke Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC) University Hospital RWTH Aachen Aachen D-52074 Germany Department of Medicine III University Hospital RWTH Aachen Aachen D-52074 Germany

Interleukin-33 （IL-33）, a cytokine of the IL-1 family, has been implicated inthe pathogenesis of liver fibrosis for quite some time. Indeed, IL-33 expression is upregulated in both human and murine hepatic fibrosis.1,2 To date, it is believed that IL-33 serves as an ‘alarmi’ released by stressed hepatocytes. IL-33 then attracts type 2 innate lymphoid cells （ILC）, which trigger the profibrogenic activation of hepatic stellate cells via mediators such as IL-13.

关键词：白细胞介素1 白细胞介素13 肝细胞肝硬化家庭淋巴细胞纤维化胰岛素人类

Evidence of active oviposition avoidance to systemically applied imidacloprid in the Colorado potato beetle

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Insect Science 2024年第5期31卷 1543-1554页

作者： Alitha Edison Anja Michelbach Dominique Sowade Hanna Kertzel Luise Schmidt Martin Schafer Maximilian Hackhausen raif Nauen Pablo Duchen Shuqing Xu Institute for Evolution and Biodiversity University of MunsterHufferstraBe 1Munster48149Germany Institute of Organismic and Molecular Evolution(iomE) University of MainzHanns-Dieter-Husch-Weg 15Mainz55128Germany Current address:Department of Cell and Tissue Dynamics MunsterGermany Crop Science Division Research and Development DepartmentBayer AGMonheimGermany

Agricultural pests can develop behavioral resistance to insecticides by choosing to feed or oviposit on insecticide-free *** young larvae have relatively low mobility,oviposition preferences from female adults may play a critical role in shaping the evolu-tionary trajectory of pest *** oviposition avoidance of insecticide-treated hosts was found in different agriculture pests,it remains unclear whether female adults actively choose to occupy insecticide-free *** address this question,we investigated feeding and oviposition preferences between imidacloprid-treated and imidacloprid-free plants in the Colorado potato beetle,Leptinotarsa decemlineata Say,a major potato *** performed behavioral choice assays on two strains that differed in both fecundity and insecticide *** found that one strain preferred to feed on the insecticide-free plants and that this preference is not ***,the other strain chose plants for feeding and oviposition *** analyses of the moving patterns of the beetles suggested that the oviposition preference in the first strain is likely due to active learning.

关键词： Colorado potato beetle host preferences imidacloprid insecticide resis-tance oviposition pesticide avoidance

Endoglin in liver fibrogenesis: Bridging basic science and clinical practice

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World Journal of Biological Chemistry 2014年第2期5卷 180-203页

作者： Steffen K Meurer Muhammad Alsamman David Scholten Ralf weiskirchen Institute of Clinical Chemistry and Pathobiochemistry RWTH University Hospital Aachen D-52074 Aachen Germany Department of Internal Medicine Ⅲ RWTH University Hospital Aachen D-52074 Aachen Germany

Endoglin, also known as cluster of differentiation CD105, was originally identified 25 years ago as a novel marker of endothelial cells. Later it was shown that endoglin is also expressed in pro-fibrogenic cells including mesangial cells, cardiac and scleroderma fibroblasts, and hepatic stellate cells. It is an integral membranebound disulfide-linked 180 kDa homodimeric receptor that acts as a transforming growth factor-β(TGF-β) auxiliary co-receptor. In humans, several hundreds of mutations of the endoglin gene are known that give rise to an autosomal dominant bleeding disorder that is characterized by localized angiodysplasia and arteriovenous malformation. This disease is termed hereditary hemorrhagic telangiectasia type Ⅰ and induces various vascular lesions, mainly on the face, lips, hands and gastrointestinal mucosa. Two variants of endoglin(i.e., S- and L-endoglin) are formed by alternative splicing that distinguishes from each other in the length of their cytoplasmic tails. Moreover, a soluble form of endoglin, i.e.,sol-Eng, is shedded by the matrix metalloprotease-14 that cleaves within the extracellular juxtamembrane region. Endoglin interacts with the TGF-β signaling receptors and influences Smad-dependent and-independent effects. Recent work has demonstrated that endoglin is a crucial mediator during liver fibrogenesis that critically controls the activity of the different Smad branches. In the present review, we summarize the present knowledge of endoglin expression and function, its involvement in fibrogenic Smad signaling, current models to investigate endoglin function, and the diagnostic value of endoglin in liver disease.

关键词： Telangiectasia Signalling Transforming growth factor-β Disease Bleeding disorders

Human intestinal acyl-CoA synthetase 5 is sensitive to the inhibitor triacsin C

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World Journal of Gastroenterology 2011年第44期17卷 4883-4889页

作者： Elke Kaemmerer Anne Peuscher Andrea Reinartz Christian Liedtke Ralf weiskirchen Jürgen Kopitz Nikolaus Gassler Department of Pediatrics RWTH Aachen UniversityAachenGermany Institute of Pathology RWTH Aachen University Department of Plant Biotechnology Fraunhofer Institute for Molecular Biology and Applied Ecology (IME) Institute of Pathology RWTH Aachen University Department of Medicine Ⅲ RWTH Aachen University Institute of Clinical Chemistry and Pathobiochemistry RWTH Aachen University Institute of Pathology University of Heidelberg

AIM:To investigate whether human acyl-CoA synthetase 5(ACSL5) is sensitive to the ACSL inhibitor triacsin ***:The ACSL isoforms ACSL1 and ACSL5 from rat as well as human ACSL5 were cloned and recombinantly expressed as 6xHis-tagged *** 2+-affinity purified recombinant enzymes were assayed at pH 7.5 or pH 9.5 in the presence or absence of triacsin *** addition,ACSL5 transfected CaCo2 cells and intestinal human mucosa were ***5 expression in cellular systems was verified using Western blot and *** ACSL assay mix included TrisHCl(pH 7.4),ATP,CoA,EDTA,DTT,MgCl 2,[9,103 H] palmitic acid,and triton *** 200 μL reaction was initiated with the addition of solubilized,purified recombinant proteins or cellular *** were terminated after 10,30 or 60 min of incubation with Doles ***:Expression of soluble recombinant ACSL proteins was found after incubation with isopropyl betaD-1-thiogalactopyranoside and after ultracentrifugation these were further purified to near homogeneity with Ni 2+-affinity *** C selectively and strongly inhibited recombinant human ACSL5 protein at pH 7.5 and pH 9.5,as well as recombinant rat ACSL1(sensitive control),but not recombinant rat ACSL5(insensitive control).The IC50 for human ACSL5 was about 10 μmol/*** inhibitory triacsin C effect was similar for different incubation times(10,30 and 60 min) and was not modified by the N-or C-terminal location of the *** order to evaluate ACSL5 sensitivity to triacsin C in a cellular environment,stable human ACSL5 CaCo2 transfectants and mechanically dissected normal human intestinal mucosa with high physiological expression of ACSL5 were *** both models,ACSL5 peak activity was found at pH 7.5 and pH 9.5,corresponding to the properties of recombinant human ACSL5 *** the presence of triacsin C(25 μmol/L),total ACSL activity was dramatically diminished in human ACSL5 transfectants as well as in AC

关键词： Acyl-CoA synthetase 5 Fatty acid metabolism Mitochondria Triacsin C

The expression and antigenicity identification of recombinant rat TGF-β1 in bacteria

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Cell Research 2001年第2期11卷 95-100页

作者： GAO CHUN FANG, XIAN TAO KONG, AXEL M GRESSNER, RALF weiskirchen Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, R 1Department of Laboratory Medicine Changzheng Hospital Second Military Medical University Shanghai 200003 China 1Department of Laboratory Medicine Changzheng Hospital Second Military Medical University Shanghai 200003 China 2Institute of Clinical Chemistry and Pathobiochemistry Central Laboratory RWTH-University Hospital Pauwelsstr 30 D-52074 Aachen Germany 2Institute of Clinical Chemistry and Pathobiochemistry Central Laboratory RWTH-University Hospital Pauwelsstr 30 D-52074 Aachen Germany

In order to study structure-function details of TGF-β1, the recombinant mature form of rat TGF-β1 was expressed in bacteria. Synthesis of the 112 amino-acid carboxyl-terminal part of TGF-β1 (amino acid 279-390) was controlled by an inducible gene expression system based on bacteriophage T7 RNA polymerase. This system allowed an active and selective synthesis of recombinant TGF-β1. The molecular weight of expressed TGF-β1 monomer determined on SDS-polyacrylamide gel under reducing conditions was about 13 kD. Serial detergent washes combined with a single gel-filtration purification step were sufficient to purify the expression product to homogeneity. Amino-terminal sequencing revealed that the N-terminal of the recombinant protein was identical to the published data. In Western blot analysis the recombinant polypeptide showed excellent antigenicity against polyclonal TGF-β1 antibody. The mature recombinant rat TGF-β1 expressed in this study provides a useful tool for future detailed structural and functional studies.

关键词： TGF-β1 recombinant expression inclusion bodies purification antigenicity.

Intestinal Wnt in the transition from physiology to oncology

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World Journal of Clinical Oncology 2022年第3期13卷 168-185页

作者： Julia Swoboda Patrick Mittelsdorf Yuan Chen Ralf weiskirchen Johannes Stallhofer Silke Schüle Nikolaus Gassler Section Pathology Institute of Forensic MedicineJena University HospitalJena 07747Germany Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical ChemistryRWTH University Hospital AachenAachen 52074Germany Department of Internal Medicine IV(Gastroenterology Hepatologyand Infectious Diseases)Jena University HospitalJena 07747Germany Department of General Visceral and Vascular SurgeryJena University HospitalJena 07747Germany

Adult stem cells are necessary for self-renewal tissues and regeneration after *** in the intestine,which self-renews every few days,they play a key role in tissue ***,complex regulatory mechanisms are needed to prevent hyperproliferation,which can lead in the worst case to carcinogenesis or under-activation of stem cells,which can result in dysfunctional *** main regulatory signaling pathway is the Wnt/β-catenin signaling *** is a highly conserved pathway,withβ-catenin,a transcription factor,as target *** ofβ-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripotency,proliferation,cell differentiation and regulation of cell *** review presents a brief overview of the Wnt/β-catenin signaling pathway,the regulatory mechanism of this pathway and its role in intestinal ***,this review highlights the molecular mechanisms and the histomorphological features of Wnt ***,the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.

关键词： Wnt signaling Beta-catenin Intestine Colorectal cancer Cell signaling Intestinal stem cells