@misc{SteinbrechtKoenigSchmidtkeetal., author = {Steinbrecht, Susanne and K{\"o}nig, Rosalie and Schmidtke, Kai-Uwe and Herzog, Natalie and Scheibner, Katrin and Kr{\"u}ger-Genge, Anne and Jung, Friedrich and Kammerer, Sarah and K{\"u}pper, Jan-Heiner}, title = {Metabolic activity testing can underestimate acute drug cytotoxicity as revealed by HepG2 cell clones overexpressing cytochrome P450 2C19 and 3A4}, series = {Toxicology}, volume = {412}, journal = {Toxicology}, issn = {0300-483X}, doi = {10.1016/j.tox.2018.11.008}, pages = {37 -- 47}, language = {en} } @misc{KruegerGengeBrauneWalteretal., author = {Kr{\"u}ger-Genge, Anne and Braune, Steffen and Walter, Maria and Kratz, Karl and K{\"u}pper, Jan-Heiner and Krengel, M. and Lendlein, Andreas and Jung, Friedrich}, title = {Influence of surface treatments of poly(n-butyl acrylate) networks on fibroblasts adhesion, morphology and viability}, series = {Clinical Hemorheology and Microcirculation}, volume = {69}, journal = {Clinical Hemorheology and Microcirculation}, number = {1-2}, issn = {1875-8622}, doi = {10.3233/CH-189130}, pages = {305 -- 316}, language = {en} } @misc{NiesProftNehringetal., author = {Nies, A. and Proft, L. and Nehring, M. E. and Gruber, Cnristian and Sievers, H. and H{\"u}nigen, Hana and Rodruigues, A. G. and Gemeinhardt, Ole and Mrowietz, Christof and Jung, Friedrich and Hiebl, Bernhard}, title = {Growth-related micromorphological characteristics of the porcine femoral artery}, series = {Clinical Hemorheology and Microcirculation}, volume = {73}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-199219}, pages = {195 -- 201}, language = {en} } @misc{ParkMatschkeMrowietzetal., author = {Park, J. W. and Matschke, K. and Mrowietz, Christof and Kr{\"u}ger-Genge, Anne and Jung, Friedrich}, title = {HELP-(Heparin-induced Extracorporeal LDL Precipitation)-apheresis in heart recipients with cardiac allograft vasculopathy and concomitant hypercholesterolemia: Influence of long-term treatment on the microcirculation}, series = {Clinical Hemorheology and Microcirculation}, volume = {73}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-199216}, pages = {19 -- 27}, language = {en} } @misc{HailekaGeorgeSteinbrechtetal., author = {Haileka, Vanessa and George, Sandra and Steinbrecht, Susanne and Jung, Friedrich and Reinehr, R. and K{\"u}pper, Jan-Heiner}, title = {Colon cancer cells cultured under hyperosmotic conditions as in vitro model to investigate dehydration effects on cancer drug susceptibility}, series = {Clinical Hemorheology and Microcirculation}, volume = {73}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-199210}, pages = {169 -- 176}, language = {en} } @misc{KruegerGengeBlockiFrankeetal., author = {Kr{\"u}ger-Genge, Anne and Blocki, Anna and Franke, Ralf-Peter and Jung, Friedrich}, title = {Vascular Endothelial Cell Biology: An Update}, series = {International Journal of Molecular Sciences}, volume = {20}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms20184411}, pages = {22}, language = {en} } @misc{JungConnesLehmann, author = {Jung, Friedrich and Connes, Philippe and Lehmann, Christian}, title = {A.L. Copley Best Paper Prize 2018}, series = {Clinical Hemorheology and Microcirculation}, volume = {72}, journal = {Clinical Hemorheology and Microcirculation}, number = {2}, issn = {1386-0291}, doi = {10.3233/CH-199008}, pages = {117 -- 118}, language = {en} } @misc{LauRangarajanKruegerGengeetal., author = {Lau, S. and Rangarajan, R. and Kr{\"u}ger-Genge, Anne and Braune, Steffen and Kammerer, Sarah and K{\"u}pper, Jan-Heiner and Lendlein, Andreas and Jung, Friedrich}, title = {Effects of acrolein in comparison to its prodrug cyclophosphamide on human primary endothelial cells in vitro}, series = {Toxicology in Vitro}, volume = {62}, journal = {Toxicology in Vitro}, issn = {0887-2333}, doi = {10.1016/j.tiv.2019.104685}, pages = {8}, abstract = {Cyclophosphamide (CPA) is one of the most successful anticancer prodrugs that becomes effective after biotransformation in the liver resulting in the toxic metabolite acrolein. Cancer is often accompanied by thromboembolic events, which might be a result of dysfunctional endothelial cells due to CPA treatment. Here, the effect of 1 mM CPA or acrolein (10/50/100/500 μM) on human umbilical vein endothelial cells (HUVECs) was analyzed after two days of treatment. The addition of CPA or 10 μM acrolein did not affect HUVECs. However, concentrations of 100 μM and 500 μM acrolein significantly reduced the number of adherent cells by 86 ± 13\% and 99 ± 1\% and cell viability by 51 ± 29\% and 93 ± 8\% compared to the control. Moreover, pronounced stress fibers as well as multiple nuclei were observed and von Willebrand factor (vWF) was completely released. Lactate dehydrogenase was 8.5 ± 7.0-fold and 252.9 ± 42.9-fold increased showing a loss of cell membrane integrity. The prostacyclin and thromboxane secretion was significantly increased by the addition of 500 μM acrolein (43.1 ± 17.6-fold and 246.4 ± 106.3-fold) indicating cell activation/pertubation. High doses of acrolein led to HUVEC death and loss of vWF production. This effect might be associated with the increased incidence of thromboembolic events in cancer patients treated with high doses of CPA.}, language = {en} } @misc{JungKruegerGengeWaldecketal., author = {Jung, Friedrich and Kr{\"u}ger-Genge, Anne and Waldeck, Peter and K{\"u}pper, Jan-Heiner}, title = {Spirulina platensis, a super food?}, series = {Journal of Cellular Biotechnology}, volume = {5}, journal = {Journal of Cellular Biotechnology}, number = {1}, issn = {2352-3689}, doi = {10.3233/JCB-189012}, pages = {43 -- 54}, abstract = {Spirulina platensis, a multicelluar, photosynthetic prokaryote (algae) contains a high amount of proteins, vitamins and minerals superior to many foods as e.g. soybeans. Thus, Spirulina platensis was recognized as nutritious food by the United Nations World Food Conference. Due to the high amount of nutritive ingredients Spirulina has a long history as dietary supplement. In addition, spirulina platensis is also efficiently used as forage with known effects on flesh, egg and plumage color, milk yield and fertility. The versatile utilization of the alga can be explained on the one hand with the nutrient levels and on the other hand with recognized effects as anti-viral, anti-bacterial, anti-oxidant, anti-diabetic, anti-cancer and anti-inflammatory substance. Therefore, this alga is named as "superfood". Beyond, these algae convert carbon dioxide into organic substances and produce oxygen during their growth in alkaline and saline water thereby not wasting fresh water allowing the production in barren areas. Despite this diverse use of Spirulina platensis due to its beneficial properties, many basic mechanisms on a molecular and cellular level are not well understood and should be explored in future studies.}, language = {en} } @misc{KruegerGengeJungKuepperetal., author = {Kr{\"u}ger-Genge, Anne and Jung, Friedrich and K{\"u}pper, Jan-Heiner and Lehmann, Christian and Franke, Ralf-Peter}, title = {Actin type and distribution in erythrocytes}, series = {Journal of Cellular Biotechnology}, volume = {3}, journal = {Journal of Cellular Biotechnology}, number = {2}, issn = {2352-3697}, doi = {10.3233/JCB-179014}, pages = {81 -- 83}, abstract = {Erythrocytes transport oxygen from the lungs to the tissues. The excess surface area together with the elasticity of the erythrocyte cell membrane provides the flexibility needed to pass through the microvasculature where the oxygen exchange occurs. Although the architecture of the red cell and its membrane-associated cytoskeletal network is known in general, the factors that control the characteristic shape change during echinocyte formation are poorly understood. In this short report we show that in echinocytes a completely reorganized membrane cytoskeleton with a box-like structure of actin filaments prevailed indicating the importance of the actin cytoskeleton during echinocyte formation.}, language = {en} } @misc{LeeGanesanKruegerGengeetal., author = {Lee, Seahyoung and Ganesan, Ramakrishnan and Kr{\"u}ger-Genge, Anne and Kratz, Karl and Franke, Ralf-Peter and Lendlein, Andreas and Jung, Friedrich}, title = {Substrate-enzyme affinity-based surface modification strategy for endothelial cell-specific binding under shear stress}, series = {Clinical Hemorheology and Microcirculation}, volume = {75}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-190736}, pages = {85 -- 98}, abstract = {Establishing an endothelial cell (EC) monolayer on top of the blood contacting surface of grafts is considered to be a promising approach for creating a hemocompatible surface. Here we utilized the high affinity interactions between the EC plasma membrane expressed enzyme called endothelin converting enzyme-1 (ECE-1) and its corresponding substrate big Endothelin-1 (bigET-1) to engineer an EC-specific binding surface. Since enzymatic cleavage of substrates require physical interaction between the enzyme and its corresponding substrate, it was hypothesized that a surface with chemically immobilized synthetic bigET-1 will preferentially attract ECs over other types of cells found in vascular system such as vascular smooth muscle cells (VSMCs). First, the expression of ECE-1 was significantly higher in ECs, and ECs processed synthetic bigET-1 to produce ET-1 in a cell number-dependent manner. Such interaction between ECs and synthetic bigET-1 was also detectible in blood. Next, vinyl-terminated self-assembled monolayers (SAMs) were established, oxidized and activated on a glass substrate as a model to immobilize synthetic bigET-1 via amide bonds. The ECs cultured on the synthetic bigET-1-immobilized surface processed larger amount of synthetic bigET-1 to produce ET-1 compared to VSMCs (102.9±5.13 vs. 9.75±0.74 pg/ml). The number of ECs bound to the synthetic bigET-1-immobilized surface during 1 h of shearing (5dyne/cm2) was approximately 3-fold higher than that of VSMCs (46.25±12.61 vs. 15.25±3.69 cells/100×HPF). EC-specific binding of synthetic bigET-1-immobilized surface over a surface modified with collagen, a common substance for cell adhesion, was also observed. The present study demonstrated that using the substrate-enzyme affinity (SEA) of cell type-specific enzyme and its corresponding substrate can be an effective method to engineer a surface preferentially binds specific type of cells. This novel strategy might open a new route toward rapid endothelialization under dynamic conditions supporting the long-term patency of cardiovascular implants.}, language = {en} } @misc{JungPietzsch, author = {Jung, Friedrich and Pietzsch, Jens}, title = {Regulation of bone regeneration}, series = {Clinical Hemorheology and Microcirculation}, volume = {73}, journal = {Clinical Hemorheology and Microcirculation}, number = {3}, issn = {1875-8622}, doi = {10.3233/CH-199101}, pages = {379 -- 380}, language = {en} } @misc{Jung, author = {Jung, Friedrich}, title = {COVID-19}, series = {Clinical Hemorheology and Microcirculation}, volume = {74}, journal = {Clinical Hemorheology and Microcirculation}, number = {4}, issn = {1875-8622}, doi = {10.3233/CH-209001}, pages = {347 -- 348}, abstract = {The pandemic of coronavirus disease 2019 (COVID-19), a disease caused by a novel coronavirus (CoV), SARS-CoV-2, is causing substantial morbidity and mortality. The etiology of this illness is now attributed to a novel virus belonging to the coronavirus (CoV) family. An epidemic of cases with respiratory infections detected in Wuhan, China, was first reported to the WHO Country Office in China, on December 31, 2019. This new virus seems to be very contagious and has quickly spread globally. The estimate for severe cases was approximated at 5\% based on experience from China. However, the World Health Organization's (WHO) estimate from China for severe and critical cases is near 20\% [2]. Older age seems to be the highest risk for death. Mortality data from Oxford COVID-19 Evidence Service (25/3/20) indicates a risk of mortality of 3.6\% for people in their 60 s, which increases to 8.0\% for people older than 70 and to 14.8\% for people over 80 s [3]. In addition, a very recent epidemiological study could show that already a small increase in long-term exposure to fine particular matter leads to a 20-times increase in COVID-19 death rate [4], showing that it is not only age and previous illnesses that predispose, but also the environmental conditions. In addition to respiratory disease, cardiovascular complications are reported to be a key threat in COVID-19 [5, 6]. In a second Editorial, F. Wenzel exposes this pandemic from a historical and socio-political perspective in a very interesting article [7]. In a feature about the European - Asian perspective Jung et al. present the development of COVID-19 in Germany and show a way to predict the time point at which no further new infections will occur using Normalized Case Number Curves (plateau day) [8]. Upon reaching the plateau day during a lockdown phase, a residual time-period of about 2-3 weeks can be utilized to prepare a safe unlocking period. First experiences with abdominal contrast-enhanced ultrasound (CEUS) examinations are presented by the group of E.M. Jung [6]. In the stage of an imminent organ failure with significantly reduced kidney and liver function and microcirculation, CEUS can be used to show a narrowing of the organ-supplying arteries, as well as a delayed capillary filling of vessels near the capsule, a regional reduced parenchymal perfusion or an inflammatory hyperemia with capillary hypercirculation.}, language = {en} } @misc{JungConnesLehmann, author = {Jung, Friedrich and Connes, Philippe and Lehmann, Christian}, title = {A.L. Copley Best Paper Prize 2019}, series = {Clinical Hemorheology and Microcirculation}, volume = {75}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/ch-209100}, pages = {1 -- 2}, language = {en} } @misc{MrowietzSieversPinduretal., author = {Mrowietz, Christof and Sievers, H. and Pindur, Gerhard and Hiebl, Bernhard and Jung, Friedrich}, title = {Cutaneous microcirculation in patients with peripheral arterial occlusive disease: Comparison of capillary blood circulation in the nail fold of finger and toe}, series = {Clinical Hemorheology and Microcirculation}, volume = {76}, journal = {Clinical Hemorheology and Microcirculation}, number = {2}, issn = {1875-8622}, doi = {10.3233/CH-209220}, pages = {279 -- 285}, abstract = {In patients with peripheral arterial occlusive disease (PAOD) a restricted circulation in cutaneous microvessels has been reported. In this study the velocity of erythrocytes (very) in finger nailfold capillaries - a vascular area without upstream macroangiopathy - and also in toe nailfold capillaries - a post-stenotic area -was investigated using capillary microscopy in apparently healthy subjects and patients with PAOD. Already in finger nailfold capillaries very of patients with PAOD under resting conditions was significantly lower than in capillaries of healthy subjects. This was also true for the circulation in toe capillaries. In addition, the erythrocyte velocities under resting conditions in the toe capillaries were significantly lower than in the finger capillaries. Similar results were found for the duration and the maximum velocity of postocclusive hyperemia. It is concluded that the resting blood flow in the skin microcirculation is impaired in PAOD patients, both under resting conditions and during postocclusive hyperemia in finger as well in toe nailfold capillaries.}, language = {en} } @misc{GehmertLehoczkyLoibletal., author = {Gehmert, Sangaa and Lehoczky, Gy{\"o}z{\"o}c and Loibl, Markus and Jung, Friedrich and Prantl, Lukas and Gehmert, Sebastian}, title = {Interaction between extracellular cancer matrix and stromal breast cells}, series = {Clinical Hemorheology and Microcirculation}, volume = {74}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-199234}, pages = {45 -- 52}, abstract = {Stromal-epithelial interactions are fundamental for normal organ development and there is a multitude of evidence that the different components of the microenvironment are also necessary for the maintenance and promotion of the "tumor organ". Deregulated tumor associated extracellular matrix (tECM) is a hallmark of cancer, causing an alteration in the amount and composition of the different components (i.e. proteins, proteoglycans, glycoproteins and polysaccharids) of the ECM. As epithelial-stromal interactions are reciprocal, it is possible that tECM itself is able to initiate tumor development. We therefore established a mouse model to examine the influence of tECM of murine breast cancer on developing breast tissue in mice.}, language = {en} } @misc{SchulzKruegerGengeJungetal., author = {Schulz, Christian and Kr{\"u}ger-Genge, Anne and Jung, Friedrich and Lendlein, Andreas}, title = {Aptamer supported in vitro endothelialization of poly(ether imide) films}, series = {Clinical Hemorheology and Microcirculation}, volume = {75}, journal = {Clinical Hemorheology and Microcirculation}, number = {2}, issn = {1875-8622}, doi = {10.3233/CH-190775}, pages = {201 -- 217}, abstract = {Implantation of synthetic small-diameter vascular bypass grafts is often associated with an increased risk of failure, due to thrombotic events or late intimal hyperplasia. As one of the causes an insufficient hemocompatibility of the artificial surface is discussed. Endothelialization of synthetic grafts is reported to be a promising strategy for creating a self-renewing and regulative anti-thrombotic graft surface. However, the establishment of a shear resistant cell monolayer is still challenging. In our study, cyto- and immuno-compatible poly(ether imide) (PEI) films were explored as potential biomaterial for cardiovascular applications. Recently, we reported that the initial adherence of primary human umbilical vein endothelial cells (HUVEC) was delayed on PEI-films and about 9 days were needed to establish a confluent and almost shear resistant HUVEC monolayer. To accelerate the initial adherence of HUVEC, the PEI-film surface was functionalized with an aptamer-cRGD peptide based endothelialization supporting system. With this functionalization the initial adherence as well as the shear resistance of HUVEC on PEI-films was considerable improved compared to the unmodified polymer surface. The in vitro results confirm the general applicability of aptamers for an efficient functionalization of substrate surfaces.}, language = {en} } @misc{HieblKruegerGengeJung, author = {Hiebl, Bernhard and Kr{\"u}ger-Genge, Anne and Jung, Friedrich}, title = {39th conference of the German society for clinical microcirculation and hemorheology (DGKMH)}, series = {Clinical Hemorheology and Microcirculation}, volume = {76}, journal = {Clinical Hemorheology and Microcirculation}, number = {2}, issn = {1875-8622}, doi = {10.3233/ch-209200}, pages = {121 -- 122}, language = {en} } @misc{JungKriegerHufertetal., author = {Jung, Friedrich and Krieger, Volker and Hufert, Frank and K{\"u}pper, Jan-Heiner}, title = {How we should respond to the Coronavirus SARS-CoV-2 outbreak: A German perspective}, series = {Clinical Hemorheology and Microcirculation}, volume = {74}, journal = {Clinical Hemorheology and Microcirculation}, number = {4}, issn = {1875-8622}, doi = {10.3233/CH-209004}, pages = {363 -- 372}, abstract = {BACKGROUND: In the early phase of the COVID-19 pandemic Germany missed to set up efficient containment measures. Consequently, the number of cases increased exponentially until a lockdown was implemented to suppress the spread of SARS-CoV-2. Fortunately, Germany has a high capability for coronavirus lab testing and more than 30,000 ICU beds. These capabilities and the lockdown turned out to be an advantage to combat the pandemic and to prevent a health-system overload. AIM: The aim was to predict the plateau day of SARS-CoV-2 infections or deaths. RESULTS: The effect on the viral spread of the German measures taken and the impact on the peak of new infection cases is shown. By normalizing daily case numbers, the plateau day of the current outbreak in Germany could be calculated to be reached at April 12, 2020 (day 103 of 2020). CONCLUSION: Normalized case number curves are helpful to predict the time point at which no further new infections will occur if the epidemic situation remains stable. Upon reaching the plateau day during a lockdown phase, a residual time-period of about 2-3 weeks can be utilized to prepare a safe unlocking period. As can be learned from Asian countries such as South Korea and Taiwan there must be strict rules to keep the risk of infection low. Those include social distancing, face mask wearing in combination with digital contact tracing and serosurveillance studies. Following those rules, a safe dance around the infection curve allows to keep the population at a reduced infection rate.}, language = {en} } @misc{KuepperJungKriegeretal., author = {K{\"u}pper, Jan-Heiner and Jung, Friedrich and Krieger, Volker and Hufert, Frank}, title = {A comparison of mortality rates between European and Asian States}, series = {Clinical Hemorheology and Microcirculation}, volume = {75}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-209008}, pages = {3 -- 5}, language = {en} } @misc{JungKruegerGengeFrankeetal., author = {Jung, Friedrich and Kr{\"u}ger-Genge, Anne and Franke, Ralf-Peter and Hufert, Frank and K{\"u}pper, Jan-Heiner}, title = {COVID-19 and the endothelium}, series = {Clinical Hemorheology and Microcirculation}, volume = {75}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-209007}, pages = {7 -- 11}, abstract = {There is growing evidence that COVID-19 not only affects the lungs but beyond that the endothelial system. Recent studies showed that this can lead to microcirculatory impairments and in consequence to functional disorders of all inner organs. The combination of endothelial dysfunction with a generalized inflammatory state and complement elements may together contribute to the overall pro-coagulative state described in COVID-19 patients leading to venular as well as to arteriolar occlusions.}, language = {en} } @misc{JungKriegerHufertetal., author = {Jung, Friedrich and Krieger, Volker and Hufert, Frank and K{\"u}pper, Jan-Heiner}, title = {Herd immunity or suppression strategy to combat COVID-19}, series = {Clinical Hemorheology and Microcirculation}, volume = {75}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-209006}, pages = {13 -- 17}, abstract = {Some months ago, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan, China, and spread rapidly around the world. Some states, such as the Netherlands, Germany, Great Britain, Sweden and the USA initially focused on keeping the restrictions for economy and society as low as possible. The responsible authorities were of the opinion - and still are e.g. in Sweden - that it is sufficient enough to protect particularly vulnerable persons such as the elderly or people with pre-existing conditions. The idea behind this is that as soon as 60 to 70 percent of the population is infected with a pathogen, a so-called "herd immunity" has developed. However, the increasing numbers of deaths and modelling studies showed the expected overload of the hospitals. Therefore, most countries decided for a temporary lockdown with the exception of Sweden. Based on the number of the total population, three times more people died from COVID-19 in Sweden (2679 deaths per 10 million inhabitants) compared to Germany (6848 deaths per 80 million inhabitants). The comparison Sweden versus Taiwan is even worse because 1072 times more people died in Sweden based on the number of the population (6 deaths per 24 million inhabitants).}, language = {en} } @misc{LauRangarajanKruegerGengeetal., author = {Lau, S. and Rangarajan, R. and Kr{\"u}ger-Genge, Anne and Braune, Steffen and K{\"u}pper, Jan-Heiner and Lendlein, Andreas and Jung, Friedrich}, title = {Age-related morphology and function of human arterial endothelial cells}, series = {Clinical Hemorheology and Microcirculation}, volume = {74}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-199238}, pages = {93 -- 107}, abstract = {Endothelialization of cardiovascular implants is regarded as a promising strategy for long-term compatibility. While umbilical vein endothelial cells are typically applied in research, human arterial endothelial cells (HAEC) from elderly donors would be the obvious source for autologous cellularization strategies. In our approach, HAEC from 16 donors of varying age (16-63 years) were divided into two groups (<30 years and >30 years) and analyzed regarding morphology, viability, proliferation, function and senescence status. No age-related differences were found regarding morphology, viability, density, prostacyclin and nitrite secretion or collagen and laminin production. However, the metabolic activity was slightly decreased (p = 0.0374) and the membrane integrity marginally impaired (p = 0.0404) in cells from older donors. Two out of three senescence assays detected more senescence markers in cells from older donors. According to the assays applied here, HAEC from young and elderly donors up to the age of 63 years could be judged equally suitable for autologous cellularization strategies. However, this finding should be regarded with caution due to the extremely large variability between individual donors. Further studies comprising a larger sample size are necessary to investigate this issue more thoroughly.}, language = {en} } @misc{JungConnesLehmann, author = {Jung, Friedrich and Connes, Philippe and Lehmann, Christian}, title = {A.L. Copley Best Paper Prize 2020}, series = {Clinical Hemorheology and Microcirculation}, volume = {77}, journal = {Clinical Hemorheology and Microcirculation}, number = {3}, issn = {1875-8622}, doi = {10.3233/ch-219001}, pages = {245 -- 246}, language = {en} } @misc{SchulzKruegerGengeLendleinetal., author = {Schulz, Christian and Kr{\"u}ger-Genge, Anne and Lendlein, Andreas and K{\"u}pper, Jan-Heiner and Jung, Friedrich}, title = {Potential Effects of Nonadherent on Adherent Human Umbilical Venous Endothelial Cells in Cell Culture}, series = {International Journal of Molecular Science}, volume = {22}, journal = {International Journal of Molecular Science}, number = {3}, doi = {10.3390/ijms22031493}, pages = {15}, abstract = {The adherence and shear-resistance of human umbilical venous endothelial cells (HUVEC) on polymers is determined in vitro in order to qualify cardiovascular implant materials. In these tests, variable fractions of HUVEC do not adhere to the material but remain suspended in the culture medium. Nonadherent HUVEC usually stop growing, rapidly lose their viability and can release mediators able to influence the growth and function of the adherent HUVEC. The aim of this study was the investigation of the time dependent behaviour of HUVEC under controlled nonadherent conditions, in order to gain insights into potential influences of these cells on their surrounding environment in particular adherent HUVEC in the context of in vitro biofunctionality assessment of cardiovascular implant materials. Data from adherent or nonadherent HUVEC growing on polystyrene-based cell adhesive tissue culture plates (TCP) or nonadhesive low attachment plates (LAP) allow to calculate the number of mediators released into the culture medium either from adherent or nonadherent cells. Thus, the source of the inflammatory mediators can be identified. For nonadherent HUVEC, a time-dependent aggregation without further proliferation was observed. The rate of apoptotic/dead HUVEC progressively increased over 90\% within two days. Concomitant with distinct blebbing and loss of membrane integrity over time, augmented releases of prostacyclin (PGI2, up to 2.91 ± 0.62 fg/cell) and platelet-derived growth factor BB (PDGF-BB, up to 1.46 ± 0.42 fg/cell) were detected. The study revealed that nonadherent, dying HUVEC released mediators, which can influence the surrounding microenvironment and thereby the results of in vitro biofunctionality assessment of cardiovascular implant materials. Neglecting nonadherent HUVEC bears the risk for under- or overestimation of the materials endothelialization potential, which could lead to the loss of relevant candidates or to uncertainty with regard to their suitability for cardiac applications. One approach to minimize the influence from nonadherent endothelial cells could be their removal shortly after observing initial cell adhesion. However, this would require an individual adaptation of the study design, depending on the properties of the biomaterial used.}, language = {en} } @misc{WiggermannKruegerGengeJung, author = {Wiggermann, P. and Kr{\"u}ger-Genge, Anne and Jung, Friedrich}, title = {Editorial}, series = {Selected papers of the 38th Conference of the German Society for Clinical Microcirculation and Hemorheology, 21-23 November 2019, Braunschweig, Germany}, volume = {73}, journal = {Selected papers of the 38th Conference of the German Society for Clinical Microcirculation and Hemorheology, 21-23 November 2019, Braunschweig, Germany}, number = {1}, publisher = {IOS Press}, doi = {10.3233/CH-199200}, pages = {1}, language = {en} } @misc{BiermannSommerauerDieschetal., author = {Biermann, Niklas and Sommerauer, Laura and Diesch, Sophia and Koch, Christoph and Jung, Friedrich and Kehrer, Andreas and Prantl, Lukas and Taeger, Christian D.}, title = {The influence of pulsed electromagnetic field therapy (PEMFT) on cutaneous blood flow in healthy volunteers}, series = {Clinical Hemorheology and Microcirculation}, volume = {76}, journal = {Clinical Hemorheology and Microcirculation}, number = {4}, doi = {10.3233/CH-209224}, pages = {495 -- 501}, abstract = {BACKGROUND: The biophysical interaction induced by low energy pulsed electromagnetic field therapy (PEMFT) on the capillary microcirculation is not well understood. Several studies indicate a significant effect of PEMFT in patients with chronic medical conditions. OBJECTIVE: The aim of this study was to evaluate the influence of PEMFT on skin microcirculation in healthy volunteers. METHODS: 15 healthy participants were included. Nine PEMF treatments were applied over three weeks in an 48-hour interval. The PEMFT system (BEMER) was placed beneath one of the participants' leg with the contralateral side serving as a control. A forty-minute application period was preceded by a 10-minute resting phase. Measuring was done using two Laser Doppler probes (LEA) placed on each anterior lateral thigh. RESULTS: All outcome parameters including flow, mixed venous oxygen saturation and relative venous hemoglobin showed a significant increase during the experiment when compared to the baseline values of the resting phase in both groups (p < 0.01). Comparing both groups, the measurement values during the experiment did not differ (p > 0.05) except for higher flow values in the control group (P = 0.03). Over time, baseline values of both groups showed no significant difference (p > 0.05). CONCLUSION: We found a significant increase of all measurement parameters during the study compared to the baseline values with no difference between the PEMF and control group.}, language = {en} } @misc{BrauneKuepperJung, author = {Braune, Steffen and K{\"u}pper, Jan-Heiner and Jung, Friedrich}, title = {Effect of Prostanoids on Human Platelet Function: An Overview}, series = {International Journal of Molecular Science}, volume = {21}, journal = {International Journal of Molecular Science}, number = {23}, doi = {10.3390/ijms21239020}, pages = {20}, abstract = {Prostanoids are bioactive lipid mediators and take part in many physiological and pathophysiological processes in practically every organ, tissue and cell, including the vascular, renal, gastrointestinal and reproductive systems. In this review, we focus on their influence on platelets, which are key elements in thrombosis and hemostasis. The function of platelets is influenced by mediators in the blood and the vascular wall. Activated platelets aggregate and release bioactive substances, thereby activating further neighbored platelets, which finally can lead to the formation of thrombi. Prostanoids regulate the function of blood platelets by both activating or inhibiting and so are involved in hemostasis. Each prostanoid has a unique activity profile and, thus, a specific profile of action. This article reviews the effects of the following prostanoids: prostaglandin-D2 (PGD2), prostaglandin-E1, -E2 and E3 (PGE1, PGE2, PGE3), prostaglandin F2α (PGF2α), prostacyclin (PGI2) and thromboxane-A2 (TXA2) on platelet activation and aggregation via their respective receptors.}, language = {en} } @misc{BrauneKruegerGengeKammereretal., author = {Braune, Steffen and Kr{\"u}ger-Genge, Anne and Kammerer, Sarah and Jung, Friedrich and K{\"u}pper, Jan-Heiner}, title = {Phycocyanin from Arthrospira platensis as Potential Anti-Cancer Drug: Review of In Vitro and In Vivo Studies}, series = {Life}, volume = {11}, journal = {Life}, number = {2}, doi = {10.3390/life11020091}, pages = {91}, language = {en} } @misc{TaghizadehMehdiBrauneetal., author = {Taghizadeh, Mahmoudreza and Mehdi, Kargarfard and Braune, Steffen and Jung, Friedrich and Mahmood, Naderi}, title = {Long-term aerobic exercise training in type two diabetic patients alters the expression of miRNA-223 and its corresponding target, the P2RY12 receptor, attenuating platelet function}, series = {Clinical Hemorheology and Microcirculation}, volume = {80}, journal = {Clinical Hemorheology and Microcirculation}, number = {2}, issn = {1875-8622}, doi = {10.3233/CH-211209}, pages = {107 -- 116}, abstract = {BACKGROUND: Type two diabetes mellitus (T2DM) patients are prone to develop atherothrombotic events due to platelet hyper-reactivity stemming from platelet miRNA-223 down-regulation and over-expression of its corresponding target, P2RY12. OBJECTIVE: The study sought to determine the effects of long-term aerobic training on the expression levels of miRNA-223 and P2RY12 mRNA, and platelet function in T2DM patients. METHODS: Twenty-four patients with T2DM (age, 60.0±2.8 yrs.) were selected and randomly divided into two groups: aerobic exercise training (AET, n = 12) and control (CON, n = 12). The AET protocol was performed with moderate intensity for 12 weeks, while patients in the CON group followed their usual routine. Weight, body mass index (BMI), peak oxygen consumption (VO2peak), lipid profile, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), insulin resistance index (HOMA-IR), platelet miRNA-223 and P2RY12 expression were measured before and after the period. RESULTS: There was a significant improvement in body weight, BMI, VO2peak, FBG, HbA1c, and HOMA-IR, after 12 weeks of AET (P <  0.01). Platelet aggregation decreased significantly after 12 weeks in the AET group compared with the CON (P <  0.001) group. Platelets' miRNA-223 and P2RY12 were significantly up- and down-regulated after AET in comparison with the CON group (P <  0.05), respectively. Moreover, the relative expression of miRNA-223 and P2RY12 significantly correlated with FBG changes following the intervention. CONCLUSIONS: It can be concluded that long-term moderate-intensity aerobic training might be effective for reducing the occurrence of atherothrombotic events leading to premature death in T2DM patients through the modulation of miRNA-223, P2RY12 receptor expression, and platelet function.}, language = {en} } @misc{GreifMrowietzWendtetal., author = {Greif, G. and Mrowietz, Christof and Wendt, M. and Jung, Friedrich and Hiebl, Bernhard and Meyer-Sievers, H.}, title = {Differences in human and minipig platelet number, volume and activation induced by borosilicate glass beads in a modified chandler loop-system}, series = {Clinical Hemorheology and Microcirculation}, volume = {79}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-219201}, pages = {149 -- 155}, abstract = {The pig is the most widely used large animal model in Europe, with cardiovascular research being one of the main areas of application. Adequate refinement of interventional studies in this field, meeting the requirements of Russel and Burchs' 3 R concept, can only be performed if blood-contacting medical devices are hemocompatible. Because most medical devices for cardiovascular interventional procedures are developed for humans they are tested mostly for compatibility with human blood. The aim of this study was therefore to determine whether there are differences in behavior of porcine and human platelets when they come into contact with glass, which was used as an exemplary thrombogenic material. For this purpose changes of platelet count, platelet volume and platelet expression of the activation markers CD61, CD62P and CD63 were measured using a modified chandler loop-system simulating the fluidic effects of the blood flow. Minipig and human platelets showed significant differences in number and volume, but not in activation after 4-8 min exposure to glass.}, language = {en} } @misc{SchulzJungKuepper, author = {Schulz, Christian and Jung, Friedrich and K{\"u}pper, Jan-Heiner}, title = {Inhibition of phase-1 biotransformation and cytostatic effects of diphenyleneiodonium on hepatoblastoma cell line HepG2 and a CYP3A4-overexpressing HepG2 cell clone}, series = {Clinical Hemorheology and Microcirculation}, volume = {79}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-219117}, pages = {231 -- 243}, abstract = {Cell-based in vitro liver models are an important tool in the development and evaluation of new drugs in pharmacological and toxicological drug assessment. Hepatic microsomal enzyme complexes, consisting of cytochrome P450 oxidoreductase (CPR) and cytochrome P450 monooxygenases (CYPs), play a decisive role in catalysing phase-1 biotransformation of pharmaceuticals and xenobiotics. For a comprehensive understanding of the phase-1 biotransformation of drugs, the availability of well-characterized substances for the targeted modulation of in vitro liver models is essential. In this study, we investigated diphenyleneiodonium (DPI) for its ability to inhibit phase-1 enzyme activity and further its toxicological profile in an in vitro HepG2 cell model with and without recombinant expression of the most important drug metabolization enzyme CYP3A4. Aim of the study was to identify effective DPI concentrations for CPR/CYP activity modulation and potentially associated dose and time dependent hepatotoxic effects. The cells were treated with DPI doses up to 5,000nM (versus vehicle control) for a maximum of 48 h and subsequently examined for CYP3A4 activity as well as various toxicological relevant parameters such as cell morphology, integrity and viability, intracellular ATP level, and proliferation. Concluding, the experiments revealed a time- and concentration-dependent DPI mediated partial and complete inhibition of CYP3A4 activity in CYP3A4 overexpressing HepG2-cells (HepG2-CYP3A4). Other cell functions, including ATP synthesis and consequently the proliferation were negatively affected in both in vitro cell models. Since neither cell integrity nor cell viability were reduced, the effect of DPI in HepG2 can be assessed as cytostatic rather than cytotoxic.}, language = {en} } @misc{GreifMrowietzMeyerSieversetal., author = {Greif, G. and Mrowietz, Christof and Meyer-Sievers, H. and Ganter, M. and Jung, Friedrich and Hiebl, Bernhard}, title = {Differences in human and sheep platelet adherence, aggregation and activation induced by glass beads in a modified chandler loop-system}, series = {Clinical Hemorheology and Microcirculation}, volume = {79}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/CH-219104}, pages = {129 -- 136}, abstract = {In human cardiovascular research, sheep in particular are used as a large animal model in addition to pigs. In these animals, medical products, developed and tested for human medical purposes, are almost exclusively used in interventional studies. Therefore, the extent to which platelets from human and ovine blood differ in terms of adherence, aggregation and activation after a 4- or 8-minutes exposure to glass was investigated. Testing was performed with platelet-rich plasma (PRP) and a modified chandler loop-system, with 4- and 8-minute blood-material exposure times corresponding to 20 and 40 test cycles, respectively, through the entire silicone tube loop of the test system. In sheep and human PRP, contact with the silicone tubing resulted in a decrease in platelet count after 4 minutes and 20 test cycles, respectively. Four more minutes (20 additional test cycles) caused a further decrease of the platelet count only in sheep PRP. When the silicon tube was partly filled with glass beads, these effects were more pronounced and stronger in sheep then in human PRP. The mean platelet volume, which was used as parameter for platelet aggregation, did not change over time in human PRP without glass exposure. With glass exposure in human and sheep PRP the mean platelet volume increased within 40 test cycles, but this increase was stronger in sheep than in human PRP. Regarding activation behavior, the activation markers CD62P and CD63 were detectable only in < 30\% (sheep) and < 45\% (human) of platelets, whereas after 8 min of glass exposure, the proportion of CD62P+ and CD63+ cells was more increased than before only in sheep. These results indicate that ovine platelets adhere more strongly to glass and show stronger aggregation behavior after glass contact than human platelets, but that ovine and human platelets differ only slightly in activability by glass.}, language = {en} } @misc{KuepperKruegerGengeJung, author = {K{\"u}pper, Jan-Heiner and Kr{\"u}ger-Genge, Anne and Jung, Friedrich}, title = {40th conference of the German society for clinical microcirculation and hemorheology (DGKMH)}, series = {Clinical Hemorheology and Microcirculation}, volume = {79}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1875-8622}, doi = {10.3233/ch-219100}, pages = {1 -- 2}, language = {en} } @misc{KuepperJung, author = {K{\"u}pper, Jan-Heiner and Jung, Friedrich}, title = {Arthrospira for use in the treatment of diseases}, pages = {13}, language = {en} } @misc{ScheibnerKuepperJung, author = {Scheibner, Katrin and K{\"u}pper, Jan-Heiner and Jung, Friedrich}, title = {In vitro Arzneimittel aus Prodrugs und deren Verwendung}, language = {de} } @misc{TartivelBlockiBrauneetal., author = {Tartivel, Lucile and Blocki, Anna M. and Braune, Steffen and Jung, Friedrich and Behl, Marc and Lendlein, Andreas}, title = {An Inverse Shape-Memory Hydrogel Scaffold Switching Upon Cooling in a Tissue-Tolerated Temperature Range}, series = {Advanced materials interfaces}, volume = {9}, journal = {Advanced materials interfaces}, number = {6}, issn = {2196-7350}, doi = {10.1002/admi.202101588}, language = {en} } @misc{LauGossenLendleinetal., author = {Lau, S. and Gossen, Maike and Lendlein, Andreas and Jung, Friedrich}, title = {Differential sensitivity of assays for determining vein endothelial cell senescence}, series = {Clinical Hemorheology and Microcirculation}, volume = {81}, journal = {Clinical Hemorheology and Microcirculation}, number = {3}, issn = {1875-8622}, doi = {10.3233/CH-211294}, pages = {191 -- 203}, language = {en} } @misc{LemmKoehlerWodtkeetal., author = {Lemm, Sandy and K{\"o}hler, Susanne and Wodtke, Robert and Jung, Friedrich and K{\"u}pper, Jan-Heiner and Pietzsch, Jens and Laube, Markus}, title = {Investigation of radiotracer metabolic stability in vitro with CYP-overexpressing hepatoma cell lines}, series = {Cells}, volume = {11}, journal = {Cells}, number = {15}, issn = {2073-4409}, doi = {10.3390/cells11152447}, language = {en} } @misc{JungConnesLehmann, author = {Jung, Friedrich and Connes, Philippe and Lehmann, Christian}, title = {A.L. Copley Best Paper Prize 2021}, series = {Clinical Hemorheology and Microcirculation}, volume = {82}, journal = {Clinical Hemorheology and Microcirculation}, number = {3}, issn = {1875-8622}, doi = {10.3233/CH-229901}, pages = {199 -- 200}, language = {en} } @misc{BrauneKruegerGengeKoehleretal., author = {Braune, Steffen and Kr{\"u}ger-Genge, Anne and K{\"o}hler, S. and K{\"u}pper, Jan-Heiner and Jung, Friedrich}, title = {Effects of Arthrospira platensis-derived substances on blood cells}, series = {Clinical Hemorheology and Microcirculation}, volume = {85(2023)}, journal = {Clinical Hemorheology and Microcirculation}, number = {3}, issn = {1875-8622}, doi = {10.3233/CH-229103}, pages = {315 -- 321}, language = {en} } @misc{LemmKoehlerWodtkeetal., author = {Lemm, Sandy and K{\"o}hler, Susanne and Wodtke, Robert and Jung, Friedrich and K{\"u}pper, Jan-Heiner and Pietzsch, Jens and Laube, Markus}, title = {Enabling insights into the cytochrome P450 isoform specific metabolism of radiotracers by CYP overexpressing hepatoblastoma cell lines}, series = {Nuclear Medicine and Biology}, journal = {Nuclear Medicine and Biology}, number = {108-109, Supplement }, issn = {1872-9614}, pages = {S66 -- S67}, language = {en} } @misc{JungConnes, author = {Jung, Friedrich and Connes, Philippe}, title = {Morphology and Function of Red Blood Cells in COVID-19 Patients: Current Overview 2023}, series = {Life}, volume = {14}, journal = {Life}, number = {4}, issn = {2075-1729}, doi = {10.3390/life14040460}, abstract = {In severe cases, SARS-CoV-2 infection leads to severe respiratory failure. Although angiotensin-converting enzyme 2 (ACE2) receptors are not expressed in red blood cells, SARS-CoV-2 can interact with red blood cells (RBCs) via several receptors or auxiliary membrane proteins. Recent data show that viral infection causes significant damage to the RBCs, altering their morphology, deformability, and aggregability. Loss of RBC deformability and/or increased aggregability favors the development of thrombotic processes in the microcirculation, as has been described to occur in COVID-19 patients. In addition, many patients also develop systemic endotheliitis associated with generalized coagulopathy. This manifests itself clinically as obstructive microthrombi in the area of the medium and smallest vessels, which can affect all internal organs. It is thought that such changes in the RBCs may contribute to the microangiopathy/microthrombosis associated with COVID-19 and may result in impaired capillary blood flow and tissue oxygenation.}, language = {en} } @misc{KordiSaydiKaramietal., author = {Kordi, Negin and Saydi, Ali and Karami, Sajad and Bagherzadeh-Rahmani, Behnam and Marzetti, Emanuele and Jung, Friedrich and Stockwell, Brent R.}, title = {Ferroptosis and aerobic training in ageing}, series = {Clinical Hemorheology and Microcirculation}, volume = {87 (2024)}, journal = {Clinical Hemorheology and Microcirculation}, number = {3}, doi = {10.3233/CH-232076}, pages = {347 -- 366}, abstract = {Ferroptosis is a form of programmed cell death that plays a significant role in causing several diseases such as heart attack and heart failure, through alterations in fat, amino acid, and iron metabolism. Comprehending the regulatory mechanisms of ferroptosis signaling is critical because it has a considerable effect on the elderly's mortality. Conversely, age-related changes in substrate metabolism and metabolite levels are recognized to give rise to obesity. Furthermore, research has proposed that aging and obesity-related changes in substrate metabolism may aggravate ferroptosis. The suppression of ferroptosis holds potential as a successful therapeutic approach for managing different diseases, including sarcopenia, cardiovascular diseases, and central nervous system diseases. However, the pathologic and biological mechanisms behind the function of ferroptosis are not fully comprehended yet. Physical activity could affect lipid, amino acid, and iron metabolism to modulate ferroptosis. The aim of this study is to showcase the current understanding of the molecular mechanisms leading to ferroptosis and discuss the role of aging and physical activity in this phenomenon.}, language = {en} } @misc{Jung, author = {Jung, Friedrich}, title = {History of the cutaneous microcirculation from antiquity to modern times}, series = {Clinical Hemorheology and Microcirculation}, volume = {86 (2024)}, journal = {Clinical Hemorheology and Microcirculation}, number = {1-2}, doi = {10.3233/CH-248001}, pages = {29 -- 50}, abstract = {This review spans a wide arc from the first observations of the early anatomists to the present day. William Harvey was the first to describe the heart as the centre of the large and small circulatory system. He thus replaced the previously valid system of Galenos, It was Marcello Malpighi who first described that the capillary system connects the arteries with the veins. In 1688 Antoni van Leeuwenhoek (1632-1686) confirmed these results with a paper on capillary perfusion in the caudal fin of the glass eel. It was then Hermann Boerhave (1668-1738, Leiden) who was the first to carry out microcirculation tests on patients. He studied the microcirculation in the human bulbar conjunctiva. Even today, microcirculation studies in the conjunctiva bulbi of patients are carried out today. Until 1831, it was never quite clear whether the observations reported belonged mainly to the field of microcirculation, which had not yet been defined. This was done in Great Britain by Marshall Hall (1790-1857). Technical Improvements allowed increasingly sophisticated studies of the morphological structure of the terminal vasculature. According to Gustav Ricker (1870-1948, Vienna), the terminal vasculature comprises the functional unit of the smallest arteries, arterioles, capillaries and venules. In 1921 it was still thought that the blood circulation was the sole response to the pumping action of the heart. Even the classic work by Bayliss on the myogenic hypothesis (later referred to as "blood flow autoregulation") initially received little attention. More strikingly, even the findings of August Krogh, for which he received the Nobel Prize in Medicine in 1920 (for his discovery of the mechanisms of capillary motor regulation), were ignored. During an outstanding autoregulation symposium held in 1963 a broad consensus was reached on active and passive mechanisms, which is more or less valid till today. The mechanisms of regulation of capillary blood flow are now largely understood, although not completely resolved. The development of video systems with recording capability and automated off-line recording of capillary erythrocyte velocities allowed the application of morphological and dynamic studies of cutaneous capillaries in humans. These reopened the field of physiological or pathophysiological questions again for many groups worldwide. Since 1955, many publications on "microcirculation (5423)" and "capillary microscopy (2195)" have been listed in pubmed.}, language = {en} } @misc{SchulzHerzogKubicketal., author = {Schulz, Christian and Herzog, Natalie and Kubick, Stefan and Jung, Friedrich and K{\"u}pper, Jan-Heiner}, title = {Stable Chinese Hamster Ovary Suspension Cell Lines Harboring Recombinant Human Cytochrome P450 Oxidoreductase and Human Cytochrome P450 Monooxygenases as Platform for In Vitro Biotransformation Studies}, series = {Cells}, volume = {12}, journal = {Cells}, number = {17}, issn = {2073-4409}, doi = {10.3390/cells12172140}, abstract = {In the liver, phase-1 biotransformation of drugs and other xenobiotics is largely facilitated by enzyme complexes consisting of cytochrome P450 oxidoreductase (CPR) and cytochrome P450 monooxygenases (CYPs). Generated from human liver-derived cell lines, recombinant in vitro cell systems with overexpression of defined phase-1 enzymes are widely used for pharmacological and toxicological drug assessment and laboratory-scale production of drug-specific reference metabolites. Most, if not all, of these cell lines, however, display some background activity of several CYPs, making it difficult to attribute effects to defined CYPs. The aim of this study was to generate cell lines with stable overexpression of human phase-1 enzymes based on Chinese hamster ovary (CHO) suspension cells. Cells were sequentially modified with cDNAs for human CPR in combination with CYP1A2, CYP2B6, or CYP3A4, using lentiviral gene transfer. In parallel, CYP-overexpressing cell lines without recombinant CPR were generated. Successful recombinant expression was demonstrated by mRNA and protein analyses. Using prototypical CYP-substrates, generated cell lines proved to display specific enzyme activities of each overexpressed CYP while we did not find any endogenous activity of those CYPs in parental CHO cells. Interestingly, cell lines revealed some evidence that the dependence of CYP activity on CPR could vary between CYPs. This needs to be confirmed in further studies. Recombinant expression of CPR was also shown to enhance CYP3A4-independent metabolisation of testosterone to androstenedione in CHO cells. We propose the novel serum-free CHO suspension cell lines with enhanced CPR and/or defined CYP activity as a promising "humanised" in vitro model to study the specific effects of those human CYPs. This could be relevant for toxicology and/or pharmacology studies in the pharmaceutical industry or medicine.}, language = {en} } @misc{KruegerGengeKoehlerLaubeetal., author = {Kr{\"u}ger-Genge, Anne and K{\"o}hler, Susanne and Laube, Markus and Haileka, Vanessa and Lemm, Sandy and Majchrzak, Karolina and Kammerer, Sarah and Schulz, Christian and Storsberg, Joachim and Pietzsch, Jens and K{\"u}pper, Jan-Heiner and Jung, Friedrich}, title = {Anti-Cancer Prodrug Cyclophosphamide Exerts Thrombogenic Effects on Human Venous Endothelial Cells Independent of CYP450 Activation—Relevance to Thrombosis}, series = {Cells}, volume = {12}, journal = {Cells}, number = {15}, issn = {2073-4409}, doi = {10.3390/cells12151965}, abstract = {Cancer patients are at a very high risk of serious thrombotic events, often fatal. The causes discussed include the detachment of thrombogenic particles from tumor cells or the adverse effects of chemotherapeutic agents. Cytostatic agents can either act directly on their targets or, in the case of a prodrug approach, require metabolization for their action. Cyclophosphamide (CPA) is a widely used cytostatic drug that requires prodrug activation by cytochrome P450 enzymes (CYP) in the liver. We hypothesize that CPA could induce thrombosis in one of the following ways: (1) damage to endothelial cells (EC) after intra-endothelial metabolization; or (2) direct damage to EC without prior metabolization. In order to investigate this hypothesis, endothelial cells (HUVEC) were treated with CPA in clinically relevant concentrations for up to 8 days. HUVECs were chosen as a model representing the first place of action after intravenous CPA administration. No expression of CYP2B6, CYP3A4, CYP2C9 and CYP2C19 was found in HUVEC, but a weak expression of CYP2C18 was observed. CPA treatment of HUVEC induced DNA damage and a reduced formation of an EC monolayer and caused an increased release of prostacyclin (PGI2) and thromboxane (TXA) associated with a shift of the PGI2/TXA balance to a prothrombotic state. In an in vivo scenario, such processes would promote the risk of thrombus formation.}, language = {en} } @misc{MantskavaJungSanikidzeetal., author = {Mantskava, Maia and Jung, Friedrich and Sanikidze, Tamar and Momtselidze, Nana}, title = {Parallel study of the rheological status, vascular changes and intracardiac hemodynamics in heart failure in coronary artery disease}, series = {Clinical Hemorheology and Microcirculation}, volume = {84}, journal = {Clinical Hemorheology and Microcirculation}, number = {2}, issn = {1386-0291}, doi = {10.3233/CH-231744}, pages = {185 -- 192}, abstract = {BACKGROUND: Ischemic heart disease is a pathological chronic and acute condition, which is provoked by insufficient blood supply or its complete cessation. To reduce the number of patients, all approaches and studies that can positively affect the prevention and treatment of the disease are important. This is very important in monitoring and treating diseases of all systems and organs, especially in diseases of the cardiovascular system. The aim of our work was to elucidate the relationship between the rheological status of blood, vascular changes and intracardiac hemodynamics in heart failure in coronary artery disease patients with different functional classes. OBJECTIVES: The aim of our work was to elucidate the relationship between the rheological status of blood, vascular changes and intracardiac hemodynamics in heart failure in coronary artery disease patients with different functionalclasses. METHODS: We examined 76 men and women patients with coronary artery disease - I-IV functional class (by New York Heart Association Functional Classification NYHA)), mean age - 59.2±4 years. The control group consisted of 20 apparently healthy volunteers (Woman: Man -1:1), whose average age was 52±3 years. Representatives of the control group did not take any medication during the study period and were apparently healthy. The electrocardiogram of the subjects in the control group corresponded to the norm. All subjects underwent clinical and laboratory studies in a standard way: to describe the rheological status of blood, the erythrocyte aggregability index (EAI), erythrocyte deformability index (EDI), and plasma viscosity were determined; to assess vascular changes - resistance index of resistive arteries (RIRA); to study intracardiac hemodynamics, echocardiology was performed according to the recommendations proposed by the American Association of Physicians. RESULTS: Rheological changes are present from the very beginning of the disease and progress along with the severity of the disease. Therefore, it is possible to assess the severity of the disease based on rheological disorders, which can precede the onset of ischemic heart disease. The vascular status resistance index increases in the early stages of the disease, with I functional class - RIRA increased by 46\%. The cardiac index, which determines the adequacy of the global perfusion pressure, is the main indicator of hemodynamics and is negatively related to the increase in erythrocyte aggregation, although this indicator turned out to be statistically unreliable. CONCLUSION: The interpretation of our data will allow us to better understand the pathogenesis of heart failure, as well as recommend a list of tests, and methods that were discussed in the article to assess the clinical condition of patients. Continuing research in the same direction, we believe that we will be able to make adjustments to research methods and to the algorithm for drug therapy}, language = {en} } @misc{ShafieeKordiGadrunietal., author = {Shafiee, Neda and Kordi, Negin and Gadruni, Keivan and SalehFard, Ziba and Jung, Friedrich and Heidari, Naser}, title = {Cardiac rehabilitation in coronary artery bypass grafting patients: Effect of eight weeks of moderate-intensity continuous training versus high-intensity interval training}, series = {Clinical Hemorheology and Microcirculation}, volume = {83}, journal = {Clinical Hemorheology and Microcirculation}, number = {3}, issn = {1386-0291}, doi = {10.3233/CH-221605}, pages = {305 -- 314}, abstract = {BACKGROUND: Physical training in patients with heart failure can affect hemodynamic, cardiac and angiogenesis parameters. OBJECTIVE: The aim of the present study was to investigate the effects of traditional moderate-intensity rehabilitation training and interval training on some angiogenesis factors in coronary artery bypass graft (CABG) patients. METHODS: Thirty CABG patients (mean age±SD, 55±3 years) were randomly assigned to one of three groups: high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) or the control group. After the initial assessments, eligible patients in the experimental groups (HIIT and MICT) performed exercise training for 8 weeks, while the control group did not. Angiogenesis and angiostatic indices, including pro-adrenomedullin (pro-ADM), basic fibroblast growth factor (bFGF), and endostatin, were then measured. RESULTS: The results showed no significant difference between pro-ADM in the HIIT and MICT groups (P = 0.99), but a significant difference was found between MICT and the control group and between HIIT and the control group (P = 0.001). There is also no significant difference between the bFGF levels in the HIIT and MICT training groups (P = 1.00), but the changes in this factor between the training groups and the control group were significant (P = 0.001). There was a significant difference between the levels of endostatin in all three groups. CONCLUSIONS: Two methods of cardiac rehabilitation (HIIT and MICT) may be useful for the recovery of patients with coronary artery bypass grafting. This improvement manifested itself in changes in angiogenesis and angiostatic indices in this study. However, more extensive studies are needed to investigate the effects of these two types of rehabilitation programs on other indicators of angiogenesis and angiostatic.}, language = {en} } @misc{KammererNowakMantkeetal., author = {Kammerer, Sarah and Nowak, Elisabeth and Mantke, Ren{\´e} and Jung, Friedrich and K{\"u}pper, Jan-Heiner}, title = {In vitro simulation of the liver first-pass effect with biotransformation-competent HepG2 cells to study effects of MG-132 on liver and cancer cells}, series = {Clinical Hemorheology and Microcirculation}, volume = {86}, journal = {Clinical Hemorheology and Microcirculation}, number = {1-2}, issn = {1386-0291}, doi = {10.3233/CH-238108}, pages = {159 -- 168}, abstract = {BACKGROUND: Liver biotransformation is the major route for drug metabolism in humans, often catalysed by cytochrome P450 (CYP) enzymes. This first-pass effect can lead to hepatotoxicity and influences the bioavailability of drugs. OBJECTIVE: We aimed to establish in vitro culture systems simulating the liver first-pass to study effects of the proteasome inhibitor MG-132 simultaneously on hepatocytes and cancer cells. METHODS: The first-pass effect was simulated by conditioned medium transfer (CMT) from pre-treated HepG2 CYP3A4-overexpressing cells to either pancreatic cancer cell line PANC-1 or primary colon cancer cells, and by indirect co-culture (CC) of liver and cancer cells in a shared medium compartment. Experimental proteasome inhibitor MG-132 was used as test substance as it is detoxified by CYP3A4. RESULTS: Cancer cells showed higher viabilities in the first-pass simulation by CMT and CC formats when compared to monocultures indicating effective detoxification of MG-132 by HepG2 CYP3A4-overexpressing cells. HepG2-CYP3A4 cells showed reduced viabilites after treatment with MG-132. CONCLUSIONS: We successfully established two different culture systems to simulate the liver first-pass effect in vitro. Such systems easily allow to study drug effects simultaneously on liver and on target cancer cells. They are of great value in pre-clinical cancer research, pharmaceutical research and drug development.}, language = {en} }