Article
Refine
Year of publication
Document Type
- Article (46) (remove)
Language
- English (46)
Is part of the Bibliography
- no (46)
Keywords
- - (37)
- SLC22A1 (5)
- sepsis (5)
- OCT1 (4)
- organic cation transporter 1 (4)
- human (3)
- liver (3)
- single nucleotide polymorphism (3)
- species differences (3)
- sphingosine-1-phosphate (3)
- ALK5 (2)
- PAR2 (2)
- blood–brain barrier (2)
- drug transport (2)
- expression (2)
- fenoterol (2)
- gene expression (2)
- intestine (2)
- mortality (2)
- organic cation transporter (2)
- protein abundance (2)
- sulfur (2)
- transporter (2)
- transporters (2)
- 11β-HSD1 (1)
- 90-day mortality (1)
- <i>SLC16A1</i> (1)
- ATP-binding cassette transporters (1)
- Albuminuria (1)
- Ang-(1-7) (1)
- Aortic compliance (1)
- Apolipoprotein E knockout mice (1)
- BMD (1)
- Biomarker (1)
- CRISPR-Cas9 (1)
- CS molecular absorption (1)
- CTLA-4 (1)
- CYP2C19 (1)
- CYP2D6 (1)
- Child–Pugh score (1)
- DHEAS (1)
- DNA damage (1)
- EMSA (1)
- ERK (1)
- Estimated glomerular filtration rate (1)
- GWAS (1)
- Gram-positive infections (1)
- Heart rate reduction (1)
- Ivabradine (1)
- K-ras (1)
- Kidney disease (1)
- LAG-3 (1)
- NF-Y (1)
- OATP (1)
- OCT1 Effects (1)
- PIM1 kinase (1)
- ROS (1)
- S1P (1)
- S1P receptor signaling (1)
- S1P receptors (1)
- SHIP (1)
- SIRS (1)
- SLC10A1 (1)
- SLC22A1 (OCT1) (1)
- SLC22A2 (1)
- SMAD (1)
- SNP (1)
- Single nucleotide polymorphisms (1)
- Sphingosin-1-phosphate (1)
- TGF-β (1)
- TIM-3 (1)
- TREM-1 (1)
- The Study of Health in Pomerania (1)
- Thiamine Pharmacokinetics (1)
- Total testosterone (1)
- abomasum (1)
- acetaminophen (1)
- additive manufacturing (1)
- age (1)
- allelic expression imbalance (AEI) (1)
- amitriptyline (1)
- anticancer drugs (1)
- antimicrobial peptides (1)
- ascariasis (1)
- atomic absorption spectrometry (1)
- biofilm (1)
- brain (1)
- breast cancer (1)
- butylscopolamine (1)
- calves (1)
- cancer cells (1)
- cardiac surgery (1)
- cardiotoxicity (1)
- carnitine (1)
- cell migration (1)
- cirrhosis (1)
- cisplatin (1)
- combination therapy (1)
- cytotoxicity (1)
- dehydroepiandrosterone (1)
- diarrhoea (1)
- doxorubicin (1)
- drug metabolizing enzymes (1)
- drug transporter (1)
- drug-drug interaction (1)
- drug-eluting implant (1)
- ear canal stenosis (1)
- efflux (1)
- enzymes (1)
- estrone-3-sulfate (1)
- external auditory canal (1)
- gender (1)
- gene structure (1)
- genetic association study (1)
- genetic variants (1)
- glioblastoma (1)
- glioblastoma multiforme (1)
- glucocorticoids (1)
- glutathione (1)
- glutathione peroxidase (1)
- graphite furnace technique (1)
- haplotypes (1)
- helminth (1)
- heparin (1)
- hepatic pathology (1)
- hepatitis C (1)
- human NTCP (1)
- human kidneys (1)
- immune cells (1)
- inflammation (1)
- ins/del variant (1)
- intestinal nematode (1)
- ipratropium (1)
- isobutyrylcarnitine (1)
- kINPen (1)
- lectin (1)
- ligand-transporter interaction (1)
- lipid mediator (1)
- liquid chromatography-mass spectrometry (1)
- liver pathology (1)
- localization (1)
- luciferase reporter gene assay (1)
- lymphocyte-activation gene 3 (1)
- mTor (1)
- membrane transport (1)
- membrane transporters (1)
- metformin (1)
- microbiota (1)
- minigene (1)
- molecular absorption spectrometry (1)
- molecular modeling (1)
- monocarboxylate transporter 1 (1)
- mouse Ntcp (1)
- nephrotoxicity (1)
- neuroactive steroids (1)
- neurospheres (1)
- neurosteroids (1)
- nortriptyline (1)
- nuclear receptors (1)
- oral cancer (1)
- oral rehydration solution (1)
- organic cation transporter 2 (1)
- ortholog comparison (1)
- osteoporosis (1)
- pancreatic carcinoma (1)
- papilloma (1)
- parotid gland (1)
- pentathiepin (1)
- peptide analysis (1)
- periodontitis (1)
- personalized implant (1)
- pesticide and drug interaction (1)
- pharmacokinetics (1)
- plasma medicine (1)
- platelets (1)
- polyspecificity (1)
- predictor (1)
- predictors (1)
- pregnenolone sulfate (1)
- preoperative workflow (1)
- promoter (1)
- protein expression (1)
- protein quantification (1)
- reactive oxygen and nitrogen species (1)
- reactive oxygen species (1)
- real-time PCR (1)
- rosuvastatin (1)
- saliva (1)
- serine proteinases (1)
- signaling (1)
- single nucleotide polymorphism (SNP) (1)
- single nucleotide polymorphisms (1)
- solute carriers (1)
- stem-like cells (1)
- structure-function (1)
- structure-to-function relationship (1)
- substrates (1)
- sumatriptan (1)
- survival (1)
- survival analysis (1)
- systemic inflammation (1)
- targeted chromosomal integration (1)
- transforming growth factor-β (1)
- transmembrane domain (1)
- trospium (1)
- tumor (1)
Institute
- Institut für Pharmakologie (46) (remove)
Publisher
- MDPI (27)
- Frontiers Media S.A. (9)
- S. Karger AG (2)
- Wiley (2)
- Dove Medical Press (1)
- Elsevier (1)
- Ferrata Storti Foundation (1)
- Nature Publishing Group (1)
- SAGE Publications (1)
- Springer Nature (1)
Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.
The multidrug resistance protein 4 (MRP4) is highly expressed in platelets and several lines of evidence point to an impact on platelet function. MRP4 represents a transporter for cyclic nucleotides as well as for certain lipid mediators. The aim of the present study was to comprehensively characterize the effect of a short-time specific pharmacological inhibition of MRP4 on signaling pathways in platelets. Transport assays in isolated membrane vesicles showed a concentrationdependent inhibition of MRP4-mediated transport of cyclic nucleotides, thromboxane (Tx)B2 and fluorescein (FITC)- labeled sphingosine-1-phosphate (S1P) by the selective MRP4 inhibitor Ceefourin-1. In ex vivo aggregometry studies in human platelets, Ceefourin-1 significantly inhibited platelet aggregation by about 30-50% when ADP or collagen was used as activating agents, respectively. Ceefourin-1 significantly lowered the ADP-induced activation of integrin aIIbb3, indicated by binding of FITC-fibrinogen (about 50% reduction at 50 mM Ceefourin-1), and reduced calcium influx. Furthermore, pre-incubation with Ceefourin-1 significantly increased PGE1- and cinaciguat-induced vasodilatorstimulated phosphoprotein (VASP) phosphorylation, indicating increased cytosolic cAMP as well as cGMP concentrations, respectively. The release of TxB2 from activated human platelets was also attenuated. Finally, selective MRP4 inhibition significantly reduced both the total area covered by thrombi and the average thrombus size by about 40% in a flow chamber model. In conclusion, selective MRP4 inhibition causes reduced platelet adhesion and thrombus formation under flow conditions. This finding is mechanistically supported by inhibition of integrin aIIbb3 activation, elevated VASP phosphorylation and reduced calcium influx, based on inhibited cyclic nucleotide and thromboxane transport as well as possible further mechanisms.
Background: Unwanted drug-drug interactions (DDIs), as caused by the upregulation of clinically relevant drug metabolizing enzymes and transporter proteins in intestine and liver, have the potential to threaten the therapeutic efficacy and safety of drugs. The molecular mechanism of this undesired but frequently occurring scenario of polypharmacy is based on the activation of nuclear receptors such as the pregnane X receptor (PXR) or the constitutive androstane receptor (CAR) by perpetrator agents such as rifampin, phenytoin or St. John’s wort. However, the expression pattern of nuclear receptors in human intestine and liver remains uncertain, which makes it difficult to predict the extent of potential DDIs. Thus, it was the aim of this study to characterize the gene expression and protein abundance of clinically relevant nuclear receptors, i.e., the aryl hydrocarbon receptor (AhR), CAR, farnesoid X receptor (FXR), glucocorticoid receptor (GR), hepatocyte nuclear factor 4 alpha (HNF4α), PXR and small heterodimer partner (SHP), in the aforementioned organs. Methods: Gene expression analysis was performed by quantitative real-time PCR of jejunal, ileal, colonic and liver samples from eight human subjects. In parallel, a targeted proteomic method was developed and validated in order to determine the respective protein amounts of nuclear receptors in human intestinal and liver samples. The LC-MS/MS method was validated according to the current bioanalytical guidelines and met the criteria regarding linearity (0.1–50 nmol/L), within-day and between-day accuracy and precision, as well as the stability criteria. Results: The developed method was successfully validated and applied to determine the abundance of nuclear receptors in human intestinal and liver samples. Gene expression and protein abundance data demonstrated marked differences in human intestine and liver. On the protein level, only AhR and HNF4α could be detected in gut and liver, which corresponds to their highest gene expression. In transfected cell lines, PXR and CAR could be quantified. Conclusions: The substantially different expression pattern of nuclear receptors in human intestinal and liver tissue may explain the different extent of unwanted DDIs in the dependence on the administration route of drugs.
Intestinal transporter proteins are known to affect the pharmacokinetics and in turn the efficacy and safety of many orally administered drugs in a clinically relevant manner. This knowledge is especially well-established for intestinal ATP-binding cassette transporters such as P-gp and BCRP. In contrast to this, information about intestinal uptake carriers is much more limited although many hydrophilic or ionic drugs are not expected to undergo passive diffusion but probably require specific uptake transporters. A transporter which is controversially discussed with respect to its expression, localization and function in the human intestine is the organic cation transporter 1 (OCT1). This review article provides an up-to-date summary on the available data from expression analysis as well as functional studies in vitro, animal findings and clinical observations. The current evidence suggests that OCT1 is expressed in the human intestine in small amounts (on gene and protein levels), while its cellular localization in the apical or basolateral membrane of the enterocytes remains to be finally defined, but functional data point to a secretory function of the transporter at the basolateral membrane. Thus, OCT1 should not be considered as a classical uptake transporter in the intestine but rather as an intestinal elimination pathway for cationic compounds from the systemic circulation.
The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated
in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer,
it usually acts as a driver of cancer progression in various tumor types by promoting invasion and
metastasis in response to activation by serine proteinases. Recently, we discovered another mode
through which PAR2 may enhance tumorigenesis: crosstalk with transforming growth factor-β
(TGF-β) signaling to promote TGF-β1-induced cell migration/invasion and invasion-associated gene
expression in ductal pancreatic adenocarcinoma (PDAC) cells. In this chapter, we review what is
known about the cellular TGF-β responses and signaling pathways affected by PAR2 expression,
the signaling activities of PAR2 required for promoting TGF-β signaling, and the potential molecular
mechanism(s) that underlie(s) the TGF-β signaling–promoting effect. Since PAR2 is activated through
various serine proteinases and biased agonists, it may couple TGF-β signaling to a diverse range of
other physiological processes that may or may not predispose cells to cancer development such as
local inflammation, systemic coagulation and pathogen infection.
Background: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been
shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell
migration by transforming growth factor (TGF)-β1. However, it is not known whether activation
of non-SMAD TGF-β signaling (e.g., RAS–RAF–MEK–extracellular signal-regulated kinase (ERK)
signaling) is required for cell migration and whether it is also dependent on PAR2. Methods: RNA
interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure
cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation
to detect a PAR2–ALK5 physical interaction. Results: Inhibition of ERK signaling with the MEK
inhibitor U0126 blunted the ability of TGF-β1 to induce migration in pancreatic cancer Panc1 cells.
ERK activation in response to PAR2 agonistic peptide (PAR2–AP) was strong and rapid, while it was
moderate and delayed in response to TGF-β1. Basal and TGF-β1-dependent ERK, but not SMAD
activation, was blocked by U0126 in Panc1 and other cell types indicating that ERK activation is
downstream or independent of SMAD signaling. Moreover, cellular depletion of PAR2 in HaCaT
cells strongly inhibited TGF-β1-induced ERK activation, while the biased PAR2 agonist GB88 at 10
and 100 µM potentiated TGF-β1-dependent ERK activation and cell migration. Finally, we provide
evidence for a physical interaction between PAR2 and ALK5. Our data show that both PAR2–APand TGF-β1-induced cell migration depend on ERK activation, that PAR2 expression is crucial for
TGF-β1-induced ERK activation, and that the functional cooperation of PAR2 and TGF-β1 involves a
physical interaction between PAR2 and ALK5
Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration, and apoptosis as well as the function of immune cells. S1P is generated from sphingosine (Sph), which derives from the ceramide metabolism. In particular, high concentrations of S1P are present in the blood. This originates mainly from erythrocytes, endothelial cells (ECs), and platelets. While erythrocytes function as a storage pool for circulating S1P, platelets can rapidly generate S1P de novo, store it in large quantities, and release it when the platelet is activated. Platelets can thus provide S1P in a short time when needed or in the case of an injury with subsequent platelet activation and thereby regulate local cellular responses. In addition, platelet-dependently generated and released S1P may also influence long-term immune cell functions in various disease processes, such as inflammation-driven vascular diseases. In this review, the metabolism and release of platelet S1P are presented, and the autocrine versus paracrine functions of platelet-derived S1P and its relevance in various disease processes are discussed. New pharmacological approaches that target the auto- or paracrine effects of S1P may be therapeutically helpful in the future for pathological processes involving S1P.
PIM1 Inhibition Affects Glioblastoma Stem Cell Behavior and Kills Glioblastoma Stem-like Cells
(2021)
Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become a focus in cancer research. We have previously demonstrated that PIM1 is involved in survival of GBM cells and in GBM growth in a mouse model. However, little is known about the importance of PIM1 in cancer stem cells. Here, we report on the role of PIM1 in GBM stem cell behavior and killing. PIM1 inhibition negatively regulates the protein expression of the stem cell markers CD133 and Nestin in GBM cells (LN-18, U-87 MG). In contrast, CD44 and the astrocytic differentiation marker GFAP were up-regulated. Furthermore, PIM1 expression was increased in neurospheres as a model of GBM stem-like cells. Treatment of neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, and LY294002) diminished the cell viability associated with reduced DNA synthesis rate, increased caspase 3 activity, decreased PCNA protein expression, and reduced neurosphere formation. Our results indicate that PIM1 affects the glioblastoma stem cell behavior, and its inhibition kills glioblastoma stem-like cells, pointing to PIM1 targeting as a potential anti-glioblastoma therapy.
Course of disease and risk factors for hospitalization in outpatients with a SARS-CoV-2 infection
(2022)
We analyzed symptoms and comorbidities as predictors of hospitalization in 710 outpatients in North-East Germany with PCR-confirmed SARS-CoV-2 infection. During the first 3 days of infection, commonly reported symptoms were fatigue (71.8%), arthralgia/myalgia (56.8%), headache (55.1%), and dry cough (51.8%). Loss of smell (anosmia), loss of taste (ageusia), dyspnea, and productive cough were reported with an onset of 4 days. Anosmia or ageusia were reported by only 18% of the participants at day one, but up to 49% between days 7 and 9. Not all participants who reported ageusia also reported anosmia. Individuals suffering from ageusia without anosmia were at highest risk of hospitalization (OR 6.8, 95% CI 2.5–18.1). They also experienced more commonly dyspnea and nausea (OR of 3.0, 2.9, respectively) suggesting pathophysiological connections between these symptoms. Other symptoms significantly associated with increased risk of hospitalization were dyspnea, vomiting, and fever. Among basic parameters and comorbidities, age > 60 years, COPD, prior stroke, diabetes, kidney and cardiac diseases were also associated with increased risk of hospitalization. In conclusion, due to the delayed onset, ageusia and anosmia may be of limited use in differential diagnosis of SARS-CoV-2. However, differentiation between ageusia and anosmia may be useful for evaluating risk for hospitalization.