@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} } @misc{SchulzStegenJungetal., author = {Schulz, Christian and Stegen, Sarah and Jung, Friedrich and K{\"u}pper, Jan-Heiner}, title = {Mono-CYP CHO model : a recombinant Chinese hamster ovary cell platform for investigating CYP-specific tamoxifen metabolism}, series = {International journal of molecular sciences}, volume = {26}, journal = {International journal of molecular sciences}, number = {9}, editor = {Lamb, David and Syed, Khajamohiddin}, publisher = {MDPI}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms26093992}, pages = {1 -- 24}, abstract = {The metabolism of drugs and foreign substances in humans typically involves multiple enzymatic steps, particularly in phase-1 biotransformation in the liver, where various cytochrome P450 monooxygenases (CYPs) play crucial roles. This complexity can lead to a wide range of metabolites. Understanding the contributions of individual CYPs and their interactions within these intricate enzyme cascades can be challenging. We recently developed an in vitro biotransformation platform employing various Chinese Hamster Ovarian (CHO) cell clones. These clones express human cytochrome P450 oxidoreductase (CPR), and each is defined by a specific human CYP enzyme expression, thus exhibiting no detectable endogenous CYP enzyme activity (mono-CYP CHO platform). In this study, we investigated whether the mono-CYP CHO platform is a suitable tool for modeling complex drug metabolization reactions in vitro. Tamoxifen (TAM) was selected as a model substance due to its role as a prodrug widely used in breast cancer therapy, where its main active metabolite, endoxifen, arises from a two-step metabolism primarily involving the CYP system. Specifically, the combined activity of CYP3A4 and CYP2D6 is believed to be essential for efficient endoxifen production. However, the physiological metabolization pathway of TAM is more complex and interconnected, and the reasons for TAM's therapeutic success and variability among patients are not yet fully understood. Analogous to our recently introduced mono-CYP3A4 CHO cells, we generated a CHO cell line expressing human CPR and CYP2D6, including analysis of CYP2D6 expression and specific activity. Comparative studies on the metabolization of TAM were performed with both mono-CYP CHO models individually and in co-culture with intact cells as well as with isolated microsomes. Supernatants were analyzed by HPLC to calculate individual CYP activity for each metabolite. All the picked mono-CYP2D6 clones expressed similar CYP2D6 protein amounts but showed different enzyme activities. Mono-CYP2D6 clone 18 was selected as the most suitable for TAM metabolization based on microsomal activity assays. TAM conversion with mono-CYP2D6 and -3A4 clones, as well as the combination of both, resulted in the formation of the expected main metabolites. Mono-CYP2D6 cells and microsomes produced the highest detected amounts of 4-hydroxytamoxifen and endoxifen, along with N -desmethyltamoxifen and small amounts of N , N -didesmethyltamoxifen. N -desmethyltamoxifen was the only TAM metabolite detected in notable quantities in mono-CYP3A4, while 4-hydroxytamoxifen and endoxifen were present only in trace amounts. In CYP2D6/3A4 co-culture and equal mixtures of both CYP microsomes, all metabolites were detected at concentrations around 50\% of those in individual clones, indicating no significant synergistic effects. In conclusion, our mono-CYP CHO model confirmed the essential role of CYP2D6 in synthesizing the active TAM metabolite endoxifen and indicated that CYP2D6 is also involved in producing the by-metabolite N , N -didesmethyltamoxifen. The differences in metabolite spectra between the two mono-CYP models highlight the CYP specificity and sensitivity of our in vitro system.}, language = {en} } @misc{RamplingJungConnesetal., author = {Rampling, Mike and Jung, Friedrich and Connes, Philippe and Prantl, Lukas}, title = {In memory of Prof. Dr. Bo Sandhagen}, series = {Clinical hemorheology and microcirculation}, volume = {90}, journal = {Clinical hemorheology and microcirculation}, number = {2}, publisher = {SAGE Publications}, address = {London}, issn = {1386-0291}, doi = {10.1177/13860291251343775}, pages = {49 -- 49}, language = {en} } @misc{JungPrantlRamplingetal., author = {Jung, Friedrich and Prantl, Lukas and Rampling, Mike and Connes, Philippe}, title = {Obituary for Giles Roy Cokelet}, series = {Clinical hemorheology and microcirculation}, volume = {90}, journal = {Clinical hemorheology and microcirculation}, number = {2}, publisher = {SAGE Publications}, address = {London}, issn = {1386-0291}, doi = {10.1177/13860291251343774}, pages = {50 -- 50}, language = {en} } @misc{JungConnesLehmann, author = {Jung, Friedrich and Connes, Philippe and Lehmann, Christian}, title = {A.L. Copley Best Paper Prize 2023}, series = {Clinical hemorheology and microcirculation}, volume = {89}, journal = {Clinical hemorheology and microcirculation}, number = {4}, publisher = {SAGE Publications}, address = {London}, issn = {1386-0291}, doi = {10.1177/13860291251331151}, pages = {315 -- 315}, language = {en} }