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Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage

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Neural Regeneration Research 2025年第9期20卷 2454-2463页

作者： Victoria Jiménez Carretero IrisÁlvarez-Merz Jorge Hernández-Campano Sergei A.Kirov Jesús M.Hernández-Guijo department of Pharmacology and Therapeutic School of MedicineUniv.Autónoma de MadridMadridSpain Ramón y Cajal Institute for Health Research(IRYCIS) Neurobiology-Research ServiceHospital Ramón y CajalMadridSpain Institute of Neurobiology Faculty of Mathematics and Natural SciencesHeinrich Heine University DüsseldorfDüsseldorfGermany department of Neuroscience and Regenerative Medicine&department of Neurosurgery Medical College of Georgia at Augusta UniversityAugustaGAUSA

The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is ***,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely *** release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the *** findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma *** amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-d-aspartate *** N-methyl-d-aspartate receptors prevented neuronal damage in the presence of these amino acids during *** is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-d-aspartate receptor ***,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain *** these pathways co uld highlight new therapeutic targets to mitigate brain injury.

关键词： cell swelling N-methyl-d-aspartate receptor non-excitatory amino acids stroke synaptic transmission

Extrahepatic intraductal ectopic hepatocellular carcinoma:bile duct filling defect

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Hepatobiliary & Pancreatic diseases International 2009年第6期8卷 650-652页

作者： Moritz Schmelzle Hanno Matthaei Nadja Lehwald Andreas Raffel Roy Y.Tustas Natalia Pomjanski Petra Reinecke Marcus Schmitt Jan Schulte am Esch Wolfram T.Knoefel Claus F.Eisenberger department of General Visceral and Pediatric Surgery Heinrich-Heine-University Düsseldorf Institute of Cytopathology heinrich-heine-university düsseldorf Institute of Pathology heinrich-heine-university düsseldorf department of Gastroenterology Hepatology and Infectious Diseases Heinrich-Heine-University Düsseldorf

BACKGROUNd:Obstructive jaundice caused by an intraductal hepatocellular carcinoma is a rare initial *** report a rare case of an extrahepatic icteric type hepatocellular ***:A 75-year-old patient was admitted to our hospital because of obstructive jaundice 3 months after resection of multilocular hepatocellular carcinoma.A postoperative bile leakage was treated by placement of a decompressing stent in the common bile *** retrograde choledochoscopy showed extended blood clots filling the bile duct system and computed tomography revealed a local swelling in the common extrahepatic bile *** level of alpha-fetoprotein(AFP)was only slightly elevated but that of CA19-9 was dramatically *** showed an intraductal filling defect typical of a cholangiocellular ***:Bile duct brushing cytology showed no cholangiocellular carcinoma but hepatocellular carcinoma cells in the extrahepatic bile *** extrahepatic bile duct resection was *** examination confirmed the diagnosis of extrahepatic intraductal growth of hepatocellular ***:Ectopic hepatocellular carcinoma is a rare but important differentially diagnosed of extrahepatic bile duct filling defect.

关键词： hepatocellular carcinoma cholangiocellular carcinoma bile duct obstructive jaundice

Synthesis and electronic properties of expanded 5-(hetero)arylthien-2-yl substituted 3-ethynyl quinoxalines with AIE characteristics

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Science China Chemistry 2018年第8期61卷 909-924页

作者： Franziska K.Merkt Thomas J.J.Müller Institute of Organic Chemistry and Macromolecular Chemistry Heinrich Heine University Düsseldorf

Expanded 5-(hetero)aryl-thien-2-yl substituted 3-ethynyl quinoxaline dyes with variable substitution pattern on the peripheral thiophene ring were synthesized in moderate to very good yields by Suzuki and Buchwald-Hartwig coupling of the corresponding brominated 3-ethynyl quinoxalines. dumbbell-shaped bis(thienyl 3-ethynyl quinoxalines) are also accessible by the Suzuki protocol. The photophysical properties were investigated by UV and fluorescence spectroscopy. Most of the obtained compounds display fluorescence in solution and some of them also in the solid state. Additionally, tuning of the emission color of the quinoxaline based chromophores can be conveniently accomplished by the remote substituent group. The determined absorption and emission maximum as well as the Stokes shifts strongly correlate with Hammett σp+parameters. Besides,photophysical properties of selected derivatives in the solid state, biphasic solutions, and PMMA films, along with their relationships, are comparatively investigated. Moreover, two 5-(hetero)aryl-thien-2-yl substituted 3-ethynyl quinoxaline dyes are aggregation induced emission(AIE) chromophores indicated by restriction of molecular motions. A covalently restricted 3-ethynyl quinoxaline supports that the inhibition of molecular rotation is responsible for the significant enhancement of fluorescence in acetonitrile/water mixtures.

关键词： absorption aggregation induced emission cross-coupling fluorescence heterocycles palladium

A Third-Order Accurate Wave Propagation Algorithm for Hyperbolic Partial differential Equations

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Communications on Applied Mathematics and Computation 2020年第3期2卷 403-427页

作者： Christiane Helzel Institute of Mathematics Heinrich-Heine-University DüsseldorfDüsseldorfGermany

We extend LeVeque's wave propagation algorithm,a widely used finite volume method for hyperbolic partial differential equations,to a third-order accurate *** resulting scheme shares main properties with the original method,i.e.,it is based on a wave decomposition at grid cell interfaces,it can be used to approximate hyperbolic problems in divergence form as well as in quasilinear form and limiting is introduced in the form of a wave limiter.

关键词： Wave propagation algorithm Hyperbolic partial differential equations Third-order accuracy

Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system

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Neural Regeneration Research 2019年第8期14卷 1309-1312页

作者： Florian Simon Nicolaos Floros Wiebke Ibing Hubert Schelzig Artis Knapsis department of Vascular and Endovascular Surgery Heinrich-Heine-University of Düsseldorf

Erythropoietin (EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progerdtor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were pos-让ive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of is

关键词： erythropoietin apoptosis central nervous system cerebral ischemia animal model stroke human trials age comorbidity spinal cord ischemia

Single-cell transcriptome profiling of human HSCs during development:new insights into HSC ontogeny

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Signal Transduction and Targeted Therapy 2023年第3期8卷 877-878页

作者： Edgar Grinstein Csaba Mahotka department of Hematology Oncology and Clinical ImmunologyMedical FacultyHeinrich Heine UniversityDüsseldorfGermany Institute of Pathology Medical FacultyHeinrich Heine UniversityDüsseldorfGermany

A study recently published in Nature reported a single-cell transcriptome map of human hematopoietic stem cells(HSCs)and a gene expression signature that distinguishes nascent HSCs from non-HSCs during prenatal development.1 This transcriptome map provides an important tool for further elucidation of human HSC ontogeny and could also serve as a guide for generation of transplantable HSCs ex vivo,1 to widen the therapeutic application of HSCs.

关键词： HSCs transcriptome hematopoietic

Multiple sclerosis drug repurposing for neuroregeneration

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Neural Regeneration Research 2024年第3期19卷 507-508页

作者： Peter Göttle Michael dietrich Patrick Küry department of Neurology Medical FacultyHeinrich-Heine UniversityDüsseldorfGermany

Multiple sclerosis(MS)is an autoimmune disorder of the central nervous system(CNS)and is primarily characterized by immune cell infiltration leading to relapses followed by remission phases and a disease course turning progressive over time with neurodegenerative processes taking over(Amin and Hersh,2023).Of note,beyond relapse-associated worsening early in disease progression independent of relapse activity may arise independently of relapse activity and can occur in all ***-mediated damage of myelin sheaths and the subsequent loss of mature oligodendrocytes are resulting in impaired axonal integrity,neurodegeneration and accounts for irreversible neuronal damage(Kuhlmann et al.,2023).The current landscape of available disease-modifying therapies comprises mainly immunomodulatory drugs that effectively diminish relapses and slow down progression at the onset form of the disease,namely relapsing MS(RMS).In this regard,a number of drugs have been approved as disease-modifying therapies for MS by US Food and drug Administration and European Medicines Agencies(Box 1).

关键词： drugs impaired irreversible

Human iPSC-derived iMSCs improve bone regeneration in mini-pigs

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Bone Research 2019年第4期7卷 399-409页

作者： Pascal Jungbluth Lucas-Sebastian Spitzhorn Jan Grassmann Stephan Tanner david Latz Md Shaifur Rahman Martina Bohndorf Wasco Wruck Martin Sager Vera Grotheer Patric Kropil Mohssen Hakimi Joachim Windolf Johannes Schneppendahl James Adjaye department of Trauma and Hand Surgery Heinrich Heine University Hospital DüsseldorfMoorenstr.540225 DüsseldorfGermany Institute for Stem Cell Research and Regenerative Medicine Medical FacultyHeinrich Heine UniversityDüsseldorfMoorenstr.540225 DüsseldorfGermany Animal Research Institute Heinrich Heine UniversityDüsseldorfMoorenstr.540225 DüsseldorfGermany department of diagnostic and Interventional Radiology Medical FacultyHeinrich Heine UniversityDüsseldorfMoorenstr.540225 DüsseldorfGermany Vivantes Klinikum Am Urban Dieffenbachstraβe 110967 BerlinGermany

Autologous bone marrow concentrate(BMC)and mesenchymal stem cells(MSCs)have beneficial effects on the healing of bone *** address the shortcomings associated with the use of primary MSCs,induced pluripotent stem cell(iPSC)-derived MSCs(iMSCs)have been proposed as an *** aim of this study was to investigate the bone regeneration potential of human iMSCs combined with calcium phosphate granules(CPG)in critical-size defects in the proximal tibias of mini-pigs in the early phase of bone healing compared to that of a previously reported autograft treatment and treatment with a composite made of either a combination of autologous BMC and CPG or CPG *** were derived from iPSCs originating from human fetal foreskin fibroblasts(HFFs).They were able to differentiate into osteoblasts in vitro,express a plethora of bone morphogenic proteins(BMPs)and secrete paracrine signaling-associated cytokines such as PdGF-AA and *** and histomorphometrically,HFF-iMSC+CPG transplantation resulted in significantly better osseous consolidation than the transplantation of CPG alone and produced no significantly different outcomes compared to the transplantation of autologous BMC+CPG after 6 *** results of this translational study imply that iMSCs represent a valuable future treatment option for load-bearing bone defects in humans.

关键词： healing alone treatment

Micromechanical adaptation as a treatment for spinal cord injury

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Neural Regeneration Research 2019年第11期14卷 1909-1911页

作者： Veronica estrada Hans werner Müller Molecular Neurobiology Laboratory Department of Neurology Heinrich-Heine-University Medical Center Düsseldorf

Spinal cord injury: Thus far injury of the spinal cord is incurable and, in the majority of cases, a devastating and life-changing event. The worldwide incidence rate of spinal cord injury (SCI) ranges from 250,000 to 900,000 (***, 2013;Kumar et al., 2018) new cases per year. SCI outcome includes the damage of axons, demyelination of axons, loss of signal transduction, and consequential long-lasting motor and sensory deficits. Additionally, the non-use of muscles can lead to atrophy and joint contractures, thereby further reducing the possibility of recovery. depending on the spinal level and the severity of the injury, the extent of the damage can vary and spontaneous recovery is possible to varying degrees.

关键词： Micromechanical adaptation spinal cord injury spinal cord injury(SCI)