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)
Background: Chronic kidney disease (CKD) and low serum total testosterone (TT) concentrations are independent predictors of mortality risk in the general population, but their combined potential for improved mortality risk stratification is unknown. Methods: We used data of 1,822 men from the population-based Study of Health in Pomerania followed- up for 9.9 years (median). The direct effects of kidney dysfunction (estimated glomerular filtration rate <60 ml/min/ 1.73 m<sup>2</sup>), albuminuria (urinary albumin-creatinine ratio ≧2.5 mg/mmol) and their combination (CKD) on all-cause and cardiovascular mortality were analyzed using multivariable Cox regression models. Serum TT concentrations below the age-specific 10th percentile (by decades) were considered low and were used for further risk stratification. Results: Kidney dysfunction (hazard ratio, HR, 1.40; 95% confidence interval, CI, 1.02–1.92), albuminuria (HR, 1.38; 95% CI, 1.06–1.79), and CKD (HR, 1.42; 95% CI, 1.09–1.84) were associated with increased all-cause mortality risk, while only kidney dysfunction (HR, 2.01; 95% CI, 1.21–3.34) was associated with increased cardiovascular mortality risk after multivariable adjustment. Men with kidney dysfunction and low TT concentrations were identified as high-risk individuals showing a more than 2-fold increased all-cause mortality risk (HR, 2.52; 95% CI, 1.08–5.85). Added to multivariable models, nonsignificant interaction terms suggest that kidney dysfunction and low TT are primarily additive rather than synergistic mortality risk factors. Conclusion: In the case of early loss of kidney function, measured TT concentrations might help to detect high-risk individuals for potential therapeutic interventions and to improve mortality risk assessment and outcome.
Heart Rate Reduction by Ivabradine Improves Aortic Compliance in Apolipoprotein E-Deficient Mice
(2012)
Background: Impaired vascular compliance is associated with cardiovascular mortality. The effects of heart rate on vascular compliance are unclear. Therefore, we characterized effects of heart rate reduction (HRR) by I(f) current inhibition on aortic compliance and underlying molecular mechanisms in apolipoprotein E-deficient (ApoE<sup>–</sup>/<sup>–</sup>) mice. Methods: ApoE<sup>–</sup>/<sup>–</sup> mice fed a high-cholesterol diet and wild-type (WT) mice were treated with ivabradine (20 mg/kg/d) or vehicle for 6 weeks. Compliance of the ascending aorta was evaluated by MRI. Results: Ivabradine reduced heart rate by 113 ± 31 bpm (∼19%) in WT mice and by 133 ± 6 bpm (∼23%) in ApoE<sup>–</sup>/<sup>–</sup> mice. Compared to WT controls, ApoE<sup>–</sup>/<sup>–</sup> mice exhibited reduced distensibility and circumferential strain. HRR by ivabradine increased distensibility and circumferential strain in ApoE<sup>–</sup>/<sup>–</sup> mice but did not affect both parameters in WT mice. Ivabradine reduced aortic protein and mRNA expression of the angiotensin II type 1 (AT1) receptor and reduced rac1-GTPase activity in ApoE<sup>–</sup>/<sup>–</sup> mice. Moreover, membrane translocation of p47<sup>phox</sup> was inhibited. In ApoE<sup>–</sup>/<sup>–</sup> mice, HRR induced anti-inflammatory effects by reduction of aortic mRNA expression of IL-6, TNF-alpha and TGF-beta. Conclusion: HRR by ivabradine improves vascular compliance in ApoE<sup>–</sup>/<sup>–</sup> mice. Contributing mechanisms include downregulation of the AT1 receptor, attenuation of oxidative stress and modulation of inflammatory cytokine expression.
The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central
regulator in the development of several cancer types. In recent years, intriguing information has
become available regarding the role of S1P in the progression of Glioblastoma multiforme (GBM),
the most aggressive and common brain tumor in adults. S1P modulates numerous cellular processes
in GBM, such as oncogenesis, proliferation and survival, invasion, migration, metastasis and stem cell
behavior. These processes are regulated via a family of five G-protein-coupled S1P receptors (S1PR1-5)
and may involve mainly unknown intracellular targets. Distinct expression patterns and multiple
intracellular signaling pathways of each S1PR subtype enable S1P to exert its pleiotropic cellular
actions. Several studies have demonstrated alterations in S1P levels, the involvement of S1PRs
and S1P metabolizing enzymes in GBM pathophysiology. While the tumorigenic actions of S1P
involve the activation of several kinases and transcription factors, the specific G-protein (Gi, Gq,
and G12/13)-coupled signaling pathways and downstream mediated effects in GBM remain to be
elucidated in detail. This review summarizes the recent findings concerning the role of S1P and its
receptors in GBM. We further highlight the current insights into the signaling pathways considered
fundamental for regulating the cellular processes in GMB and ultimately patient prognosis.
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
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.
Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood–brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes. In this review, we discuss the involvement of ATP-binding cassette (ABC)- and solute carrier (SLC)-type membrane proteins in the transport of these compounds at the BBB and in the choroid plexus (CP), but also in the secretion from neurons and glial cells. Among the ABC transporters, especially BCRP (ABCG2) and several MRP/ABCC subfamily members (MRP1, MRP4, MRP8) are expressed in the brain and known to efflux conjugated steroids. Furthermore, several SLC transporters have been shown to mediate cellular uptake of steroid sulfates. These include members of the OATP/SLCO subfamily, namely OATP1A2 and OATP2B1, as well as OAT3 (SLC22A3), which have been reported to be expressed at the BBB, in the CP and in part in neurons. Furthermore, a role of the organic solute transporter OSTα-OSTβ (SLC51A/B) in brain DHEAS/PregS homeostasis has been proposed. This transporter was reported to be localized especially in steroidogenic cells of the cerebellum and hippocampus. To date, the impact of transporters on neurosteroid homeostasis is still poorly understood. Further insights are desirable also with regard to the therapeutic potential of these compounds.