135 research outputs found
Entrada, Acolhimento e Integração de Requerentes e Beneficiários de Proteção Internacional em Portugal: Relatório Estatístico do Asilo 2020
info:eu-repo/semantics/publishedVersio
Proatherosklerotische Wechselwirkung von oxidativem Stress, Low-Density-Lipoprotein, Angiotensin II und Endothelin-1 in humanen Endothelzellen
Eine der häufigsten kardiovaskulären Erkrankungen ist die Atherosklerose. Bei der Entstehung einer Atherosklerose spielt eine Hyperlipoproteinämie eine entscheidende Rolle. Ein weiterer Faktor für die Entstehung kardiovaskulärer Erkrankungen ist ein hoher Blutdruck. In dieser Arbeit wurde eine mögliche Interaktion zwischen Lipoproteinen und den blutdruckregulierenden Endothelin- und Renin-Angiotensin-Systemen untersucht. Weiterführende Analysen erfolgten an Rezeptoren für die Aufnahme von nLDL und oxLDL. Abschließend wurden Signalwege untersucht, die durch nLDL und oxLDL aktiviert werden. Tierexperimentielle Untersuchungen in Aorten und Herzen fettreich gefütterter Wildtyp- Mäuse unterstützen die Zellkultur-Ergebnisse einer Induzierung des Endothelin-Systems durch erhöhte Lipoproteine. Zusammenfassend zeigt diese Arbeit neue Mechanismen der Interaktion von Lipoproteinen und blutdruckregulierenden Systemen in Endothelzellen. Die Rezeptoren scheinen dabei eine Schlüsselrolle zu spielen. Dies spricht für eine Potenzierung von Hyperlipoproteinämie und Hypertonie bei der Entstehung von Herz-Kreislauf-Erkrankungen
IL-17 in Peritoneal Dialysis-Associated Inflammation and Angiogenesis: Conclusions and Perspectives
Long-term peritoneal dialysis (PD) is associated with peritoneal membrane remodeling. This includes changes in peritoneal vasculature, which may ultimately lead to inadequate solute and water removal and treatment failure. The potential cause of such alterations is chronic inflammation induced by repeated episodes of infectious peritonitis and/or exposure to bioincompatible PD fluids. While these factors may jeopardize the peritoneal membrane integrity, it is not clear why adverse peritoneal remodeling develops only in some PD patients. Increasing evidence points to the differences that occur between patients in response to the same invading microorganism and/or the differences in the course of inflammatory reaction triggered by different species. Such differences may be related to the involvement of different inflammatory mediators. Here, we discuss the potential role of IL-17 in these processes with emphasis on its impact on peritoneal mesothelial cells and peritoneal vascularity
Cross-Talk of NADPH Oxidases and Inflammation in Obesity
Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies
Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
Background. Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc). Autoantibodies (Abs) against endothelial cell antigens have been implicated in SSc and SRC. However, their detailed roles remain poorly defined. Pro-inflammatory cytokine interleukin-6 (IL-6) has been found to be increased in SSc, but its role in SRC is unclear. Here, we aimed to determine how the autoantibodies from patients with SSc and SRC affect IL-6 secretion by micro-vascular endothelial cells (HMECs). Methods. Serum IgG fractions were isolated from either SSc patients with SRC (n = 4) or healthy individuals (n = 4) and then each experiment with HMECs was performed with SSc-IgG from a separate patient or separate healthy control. IL-6 expression and release by HMECs was assessed by quantitative reverse transcription and quantitative PCR (RT-qPCR) and immunoassays, respectively. The mechanisms underlying the production of IL-6 were analyzed by transient HMEC transfections with IL-6 promoter constructs, electrophoretic mobility shift assays, Western blots and flow cytometry. Results. Exposure of HMECs to IgG from SSc patients, but not from healthy controls, resulted in a time- and dose-dependent increase in IL-6 secretion, which was associated with increased AKT, p70S6K, and ERK1/2 signalling, as well as increased c-FOS/AP-1 transcriptional activity. All these effects could be reduced by the blockade of the endothelial PAR-1 receptor and/or c-FOS/AP-1silencing. Conclusions. Autoantibodies against PAR-1 found in patients with SSc and SRC induce IL-6 production by endothelial cells through signalling pathways controlled by the AP-1 transcription factor. These observations offer a greater understanding of adverse endothelial cell responses to autoantibodies present in patients with SRC
17ß-Estradiol Regulates mTORC2 Sensitivity to Rapamycin in Adaptive Cardiac Remodeling
Adaptive cardiac remodeling is characterized by enhanced signaling of mTORC2 downstream kinase Akt. In females, 17ß-estradiol (E2), as well as Akt contribute essentially to sex-related premenopausal cardioprotection. Pharmacologic mTOR targeting with rapamycin is increasingly used for various clinical indications, yet burdened with clinical heterogeneity in therapy responses. The drug inhibits mTORC1 and less-so mTORC2. In male rodents, rapamycin decreases maladaptive cardiac hypertrophy whereas it leads to detrimental dilative cardiomyopathy in females. We hypothesized that mTOR inhibition could interfere with 17β-estradiol (E2)-mediated sexual dimorphism and adaptive cell growth and tested responses in murine female hearts and cultured female cardiomyocytes. Under physiological in vivo conditions, rapamycin compromised mTORC2 function only in female, but not in male murine hearts. In cultured female cardiomyocytes, rapamycin impaired simultaneously IGF-1 induced activation of both mTOR signaling branches, mTORC1 and mTORC2 only in presence of E2. Use of specific estrogen receptor (ER)α- and ERβ-agonists indicated involvement of both estrogen receptors (ER) in rapamycin effects on mTORC1 and mTORC2. Classical feedback mechanisms common in tumour cells with upregulation of PI3K signaling were not involved. E2 effect on Akt-pS473 downregulation by rapamycin was independent of ERK as shown by sequential mTOR and MEK-inhibition. Furthermore, regulatory mTORC2 complex defining component rictor phosphorylation at Ser1235, known to interfere with Akt-substrate binding to mTORC2, was not altered. Functionally, rapamycin significantly reduced trophic effect of E2 on cell size. In addition, cardiomyocytes with reduced Akt-pS473 under rapamycin treatment displayed decreased SERCA2A mRNA and protein expression suggesting negative functional consequences on cardiomyocyte contractility. Rictor silencing confirmed regulation of SERCA2A expression by mTORC2 in E2-cultured female cardiomyocytes. These data highlight a novel modulatory function of E2 on rapamycin effect on mTORC2 in female cardiomyocytes and regulation of SERCA2A expression by mTORC2. Conceivably, rapamycin abrogates the premenopausal “female advantage”
Multi-Parameter Analysis of Biobanked Human Bone Marrow Stromal Cells Shows Little Influence for Donor Age and Mild Comorbidities on Phenotypic and Functional Properties
Heterogeneous populations of human bone marrow-derived stromal cells (BMSC) are among the most frequently tested cellular therapeutics for treating degenerative and immune disorders, which occur predominantly in the aging population. Currently, it is unclear whether advanced donor age and commonly associated comorbidities affect the properties of ex vivo-expanded BMSCs. Thus, we stratified cells from adult and elderly donors from our biobank (n = 10 and n = 13, mean age 38 and 72 years, respectively) and compared their phenotypic and functional performance, using multiple assays typically employed as minimal criteria for defining multipotent mesenchymal stromal cells (MSCs). We found that BMSCs from both cohorts meet the standard criteria for MSC, exhibiting similar morphology, growth kinetics, gene expression profiles, and pro-angiogenic and immunosuppressive potential and the capacity to differentiate toward adipogenic, chondrogenic, and osteogenic lineages. We found no substantial differences between cells from the adult and elderly cohorts. As positive controls, we studied the impact of in vitro aging and inflammatory cytokine stimulation. Both conditions clearly affected the cellular properties, independent of donor age. We conclude that in vitro aging rather than in vivo donor aging influences BMSC characteristics
Renal Ischemia/Reperfusion Injury in Soluble Epoxide Hydrolase-Deficient Mice
Aim 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids
(EETs) are cytochrome P450 (CYP)-dependent eicosanoids that play opposite
roles in the regulation of vascular tone, inflammation, and apoptosis. 20-HETE
aggravates, whereas EETs ameliorate ischemia/reperfusion (I/R)-induced organ
damage. EETs are rapidly metabolized to dihydroxyeicosatrienoic acids (DHETs)
by the soluble epoxide hydrolase (sEH). We hypothesized that sEH gene (EPHX2)
deletion would increase endogenous EET levels and thereby protect against
I/R-induced acute kidney injury (AKI). Methods Kidney damage was evaluated in
male wildtype (WT) and sEH-knockout (KO)-mice that underwent 22-min renal
ischemia followed by two days of reperfusion. CYP-eicosanoids were analyzed by
liquid chromatography tandem mass spectrometry. Results Contrary to our
initial hypothesis, renal function declined more severely in sEH-KO mice as
indicated by higher serum creatinine and urea levels. The sEH-KO-mice also
featured stronger tubular lesion scores, tubular apoptosis, and inflammatory
cell infiltration. Plasma and renal EET/DHET-ratios were higher in sEH-KO than
WT mice, thus confirming the expected metabolic consequences of sEH
deficiency. However, CYP-eicosanoid profiling also revealed that renal, but
not plasma and hepatic, 20-HETE levels were significantly increased in sEH-KO
compared to WT mice. In line with this finding, renal expression of Cyp4a12a,
the murine 20-HETE-generating CYP-enzyme, was up-regulated both at the mRNA
and protein level, and Cyp4a12a immunostaining was more intense in the renal
arterioles of sEH-KO compared with WT mice. Conclusion These results indicate
that the potential beneficial effects of reducing EET degradation were
obliterated by a thus far unknown mechanism leading to kidney-specific up-
regulation of 20-HETE formation in sEH-KO-mice
Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation
The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood
pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with
the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are
associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic
sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated
signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to
investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation,
as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R
signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects
Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well
as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to
potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang
II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1RAbs-
induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation.
Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling
has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise
alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface,
we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This
current study thus provides extended insights into the molecular action of AT1R-Abs and associated
mechanisms of interrelated pathogenesis
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