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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

Small intestine bleeding due to multifocal angiosarcoma

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World Journal of Gastroenterology 2012年第44期18卷 6494-6500页

作者： Luisa Zacarias Fhrding Arne Macher Stefan Braunstein Wolfram Trudo Knoefel Stefan Andreas Topp Department of General Visceral and Pediatric SurgeryHeinrich-Heine-UniversityDüsseldorfMoorenstrasse 540225 DüsseldorfGermany Institute of Pathology Heinrich-Heine-UniversityDüsseldorfMoorenstrasse 540225 DüsseldorfGermany

We report a case of an 84-year-old male patient with primary small intestinal *** patient initially presented with anemia and *** endoscopy revealed no signs of upper or lower active gastrointestinal *** patient had been diagnosed 3 years previously with an aortic dilation,which was treated with a *** tomography suggested an aorto-intestinal fistula as the cause of the intestinal bleeding,leading to operative stent explantation and aortic ***,an aorto-intestinal fistula was not found,and the intestinal bleeding did not arrest *** constant need for blood transfusions made an exploratory laparotomy imperative,which showed multiple bleeding sites,predominately in the jejunal wall.A distal loop jejunostomy was conducted to contain the small intestinal bleeding and a segmental resection for histological evaluation was *** histological analysis revealed a lessdifferentiated tumor with characteristic CD31,cytokeratin,and vimentin expression,which led to the diagnosis of small intestinal ***,the infiltrated part of the jejunum was successfully resected in a subsequent operation,and adjuvant chemotherapy with paclitaxel was *** of the small intestine is an extremely rare malignant neoplasm that presents with bleeding and high *** diagnosis and treatment are essential to improve outcome.A small intestinal angiosarcoma is a challenging diagnosis to make because of its rarity,nonspecific symptoms of altered intestinal function,nonspecific abdominal pain,severe melena,and acute abdominal ***,a quick clinical and histological diagnosis and decisive measures including surgery and adjuvant chemotherapy should be the aim.

关键词： Gastrointestinal bleeding Small intestine Angiosarcoma Small intestinal neoplasm

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

Voxel-based analyses of magnetization transfer imaging of the brain in hepatic encephalopathy

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World Journal of Gastroenterology 2009年第41期15卷 5157-5164页

作者： Falk R Miese Hans-Jrg Wittsack Gerald Kircheis Arne Holstein Christian Mathys Ulrich Mdder Mathias Cohnen Institute of Radiology University Hospital Düsseldorf MNR Clinic Moorenstrasse 5 Düsseldorf 40225 Germany Department of Internal Medicine Division of Gastroenterology Hepatology and Infectious Diseases University Hospital Düsseldorf Moorenstrasse 5 Düsseldorf 40225 Germany

AIM: To evaluate the spatial distribution of cerebral abnormalities in cirrhotic subjects with and without hepatic encephalopathy (HE) found with magnetization transfer imaging (MTI).METHODS: Nineteen cirrhotic patients graded from neurologically normal to HE grade 2 and 18 healthy control subjects underwent magnetic resonance imaging. They gave institutional-review-board-approved written consent. Magnetization transfer ratio (MTR) maps were generated from MTI. We tested for significant differences compared to the control group using statistical non-parametric mapping (SnPM) for a voxelbased ***: The MTR of grey and white matter was lower in subjects with more severe HE. Changes were found in patients with cirrhosis without neurological defi cits in the basal ganglia and bilateral white matter. The loss in magnetization transfer increased in severity and spatial extent in patients with overt HE. Patients with HE grade 2 showed an MTR decrease in white and grey matter: the maximum loss of magnetization transfer effect was located in the basal ganglia [SnPM (pseudo-)t = 17.98, P = 0.0001].CONCLUSION: The distribution of MTR changes in HE points to an early involvement of basal ganglia and white matter in HE.

关键词： Brain Hepatic encephalopathy Magnetic resonance imaging Uver cirrhosis Magnetization transfer imaging

Molecular and epigenetic pathogenesis of germ cell tumors

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Asian Journal of Urology 2021年第2期8卷 144-154页

作者： Melanie R.Müller Margaretha A.Skowron Peter Albers Daniel Nettersheim Department of Urology Urological Research LabTranslational UroOncologyUniversity Hospital DüsseldorfDüsseldorfGermany Department of Urology University Hospital DüsseldorfDüsseldorfGermany

The development of germ cell tumors(GCTs)is a unique pathogenesis occurring at an early developmental stage during specification,migration or colonization of primordial germ cells(PGCs)in the genital *** driver mutations could not be identified so far,the involvement of the epigenetic machinery during the pathogenesis seems to play a crucial ***,it is investigated whether epigenetic modifications occurring between the omnipotent two-cell stage and the pluripotent implanting PGCs might result in disturbances eventually leading to *** progress in understanding epigenetic mechanisms during PGC development is ongoing,little is known about the complete picture of its involvement during GCT development and eventual classification into clinical *** review will shed light into the current knowledge of the complex epigenetic and molecular contribution during pathogenesis of GCTs by emphasizing on early developmental stages until arrival of late PGCs in the *** questioned how misguided migrating and/or colonizing PGCs develop to either type Ⅰ or type Ⅱ ***,we asked how pluripotency can be regulated during PGC development and which epigenetic changes contribute to GCT *** propose that SOX2 and SOX17 determine either embryonic stem cell-like(embryonal carcinoma)or PGC-like cell fate(seminoma).Finally,we suggest that factors secreted by the microenvironment,*** and BMP inhibiting molecules,dictate the fate decision of germ cell neoplasia in situ(into seminoma and embryonal carcinoma)and seminomas(into embryonal carcinoma or extraembryonic lineage),indicating an important role of the microenvironment on GCT plasticity.

关键词： Germ cell tumor Primordial germ cell Epigenetic reprogramming Plasticity Microenvironment BMP signaling SOX2 SOX17

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

SEN virus does not affect treatment response in hepatitis C virus coinfected patients but SEN virus response depends on SEN virus DNA concentration

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World Journal of Gastroenterology 2004年第13期10卷 1893-1897页

作者： Abdurrahman Sagin Ortwin Adams OliverKirschberg AndreasErhardt TobiasHeintges Dieter Hussinger Klinik fr Gastroenterologie Hepatologie und InfektiologieUniversittsklinikum DsseldorfMoorenstr 540225 DsseldorfGermany Institut fr Virologie der Heinrich-Heine-Universitt Dsseldorf Moorenstr 540225 DsseldorfGermany

AIM: To clarify the effect of SEN virus (SENV) infection on a combination therapy including interferon alfa (IFN-α) or pegylated-IFN with ribavirin in patients with chronic hepatitis and the effect of a combination therapy on ***: SENV DNA was determined by polymerase chain reaction in serum samples from 95 patients with chronic hepatitis C. Quantitative analysis was done for SENV H ***: Twenty-one (22%) of 95 patients were positive for SENV DNA. There was no difference in clinical and biochemical parameters between patients with HCV infection alone and coinfected patients. The sustained response rate for HCV clearance after combination therapy did not differ between patients with SENV (52%) and without SENV(50%, n.s.). SENV DNA was undetectable in 76% of the initially SENV positive patients at the end of follow-up. SENV H response to combination therapy was significantly correlated with SENV DNA level (P=-0.05).CONCLUSION: SENV infection had no influence on the HCV sustained response rate to the combination *** rate of SENV to the combination therapy depends on SENV DNA level.

关键词： Adult Antiviral Agents DNA Virus Infections DNA Viruses purification DNA, Viral Drug Therapy, Combination Female Hepacivirus Hepatitis C, Chronic Humans Interferon Alfa-2a Interferon-alpha Male Middle Aged Polyethylene Glycols Prevalence RNA, Viral Ribavirin

Type 2 diabetes across populations of different ancestry: deconstructing the genomic landscape

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Signal Transduction and Targeted Therapy 2024年第10期9卷 4157-4159页

作者： Georgia Xourafa Christian Herder Michael Roden Institute for Clinical Diabetology German Diabetes CenterLeibniz Center for Diabetes Research at Heinrich-Heine-University DüsseldorfDüsseldorfGermany German Center for Diabetes Research Partner DüsseldorfMünchen-NeuherbergGermany Department of Endocrinology and Diabetology Medical Faculty and University Hospital DüsseldorfHeinrich-Heine-University DüsseldorfDüsseldorfGermany

In a recent study published in Nature Medicine,Smith and colleagues used data from 1.4 million individuals across 37 genome-wide association studies(GWAS)reflecting different genetic ancestral populations to identify 12 genetic clusters,mostly shared among the different populations,and associated the weighted sums of genetic variants of each cluster—termed as partitioned polygenic scores(pPSs)—with various lab-based,anthropometric and cardiometabolic *** analyses extended previous studies on biological mechanisms linking genetics to type 2 diabetes(T2D)risk and pointed to both similarities of genetic clusters across multiple populations and differences regarding their contributions to overall T2D risk among different ethnicities.

关键词： diabetes landscape constructing

Metastasized pancreatic carcinoma with neoadjuvant FOLFIRINOX therapy and R0 resection

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World Journal of Gastroenterology 2015年第20期21卷 6384-6390页

作者： Sophie Schneitler Patric Krpil Jasmin Riemer Gerald Antoch Wolfram Trudo Knoefel Dieter Hussinger Dirk Graf Department of Gastroenterology Hepatology and Infectious DiseasesMedical FacultyUniversity Düsseldorf Department of Diagnostic and Interventional Radiology Medical FacultyUniversity Düsseldorf Department of Pathology Medical FacultyUniversity Düsseldorf Department of General Surgery Medical FacultyUniversity Düsseldorf

Patients with metastasized carcinoma of the pancreas have a very poor prognosis, and long-term survival cannot be expected. This case report describes two patients with an initial diagnosis of metastatic pancreatic cancer, both with hepatic metastases and one with an additional peritoneal carcinomatosis. Initially, both patients were treated intravenously with the FOLFIRINOX chemotherapy regimen, consisting of 5-FU, folinic acid, irinotecan and oxaliplatin. Surprisingly, the FOLFIRINOX treatment resulted in complete resolution of the hepatic metastases in both patients, with no lesions detectable by computed tomography scan. Furthermore, treatment response included decreased diameter of the primary tumor in the tail of the pancreas and disappearance of the additional peritoneal carcinomatosis. Both patients were discussed by our multidisciplinary tumor board, which recommended surgical resections of the carcinoma. The R0 resection of the primary tumor was successful in both cases and, interestingly, the resected tissues showed no evidence of the hepatic metastases intraoperatively. In the first case, the patient received a postoperative 6-mo course of adjuvant chemotherapy with gemcitabine. In the second case, the patient continued to receive the FOLFIRINOX regimen for an additional 6 mo postoperatively. At 12 mo after the operation, a nonresectable retroperitoneal lymph node metastasis was detected in the first patient, whereas the second patient remained in complete remission at the time of this report(5 mo after the adjuvant therapy was discontinued). This case report is the first of its kind to describe two cases of hepatic metastatic pancreatic carcinoma that were resectable following treatment with FOLFIRINOX. Further studies are required to examine the role of FOLFIRINOX as a neoadjuvant treatment option in subgroups of patients with initially metastasized pancreatic carcinoma.

关键词： FOLFIRINOX Neoadjuvant treatment ofpancreatic neoplasms Chemotherapy Metastaticpancreatic neoplasm Curative operation