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1.  N-Octanoyl Dopamine Inhibits the Expression of a Subset of κB Regulated Genes: Potential Role of p65 Ser276 Phosphorylation 
PLoS ONE  2013;8(9):e73122.
Background and Purpose
Catechol containing compounds have anti-inflammatory properties, yet for catecholamines these properties are modest. Since we have previously demonstrated that the synthetic dopamine derivative N-octanoyl dopamine (NOD) has superior anti-inflammatory properties compared to dopamine, we tested NOD in more detail and sought to elucidate the molecular entities and underlying mechanism by which NOD down-regulates inflammation.
Experimental Approach
Genome wide gene expression profiling of human umbilical vein endothelial cells (HUVECs) was performed after stimulation with TNF-α or in the combination with NOD. Confirmation of these differences, NFκB activation and the molecular entities that were required for the anti-inflammatory properties were assessed in subsequent experiments.
Key Results
Down regulation of inflammatory genes by NOD occurred predominantly for κB regulated genes, however not all κB regulated genes were affected. These findings were explained by inhibition of RelA phosphorylation at Ser276. Leukocyte adherence to TNF-α stimulated HUVECs was inhibited by NOD and was reflected by a diminished expression of adhesion molecules on HUVECs. NOD induced HO-1 expression, but this was not required for inhibition of NFκB. The anti-inflammatory effect of NOD seems to involve the redox active catechol structure, although the redox active para-dihydroxy benzene containing compounds also displayed anti-inflammatory effects, provided that they were sufficiently hydrophobic.
Conclusions and Implications
The present study highlighted important mechanisms and molecular entities by which dihydroxy benzene compounds exert their potential anti-inflammatory action. Since NOD does not have hemodynamic properties, NOD seems to be a promising candidate drug for the treatment of inflammatory diseases.
PMCID: PMC3759419  PMID: 24023820
3.  N-octanoyl-Dopamine Is an Agonist at the Capsaicin Receptor TRPV1 and Mitigates Is Chemia-Induced Acute Kidney Injury in Rat 
PLoS ONE  2012;7(8):e43525.
Since stimulation of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) mitigates acute kidney injury (AKI) and endogenous N-acyl dopamine derivatives are able to activate TRPV1, we tested if synthetic N-octanoyl-dopamine (NOD) activates TRPV1 and if it improves AKI. These properties of NOD and its intrinsic anti-inflammatory character were compared with those of dopamine (DA). TRPV1 activation and anti-inflammatory properties of NOD and DA were tested using primary cell cultures in vitro. The influence of NOD and DA on AKI was tested in a prospective, randomized, controlled animal study with 42 inbred male Lewis rats (LEW, RT1), treated intravenously with equimolar concentrations of DA or NOD one hour before the onset of warm ischemia and immediately before clamp release. NOD, but not DA, activates TRPV1 channels in isolated dorsal root ganglion neurons (DRG) that innervate several tissues including kidney. In TNFα stimulated proximal tubular epithelial cells, inhibition of NFκB and subsequent inhibition of VCAM1 expression by NOD was significantly stronger than by DA. NOD improved renal function compared to DA and saline controls. Histology revealed protective effects of NOD on tubular epithelium at day 5 and a reduced number of monocytes in renal tissue of DA and NOD treated rats. Our data demonstrate that NOD but not DA activates TRPV1 and that NOD has superior anti-inflammatory properties in vitro. Although NOD mitigates deterioration in renal function after AKI, further studies are required to assess to what extend this is causally related to TRPV1 activation and/or desensitization.
PMCID: PMC3423369  PMID: 22916273
4.  N-Glycosylation of Carnosinase Influences Protein Secretion and Enzyme Activity 
Diabetes  2010;59(8):1984-1990.
The (CTG)n polymorphism in the serum carnosinase (CN-1) gene affects CN-1 secretion. Since CN-1 is heavily glycosylated and glycosylation might influence protein secretion as well, we tested the role of N-glycosylation for CN-1 secretion and enzyme activity. We also tested whether CN-1 secretion is changed under hyperglycemic conditions.
N-glycosylation of CN-1 was either inhibited by tunicamycin in pCSII-CN-1–transfected Cos-7 cells or by stepwise deletion of its three putative N-glycosylation sites. CN-1 protein expression, N-glycosylation, and enzyme activity were assessed in cell extracts and supernatants. The influence of hyperglycemia on CN-1 enzyme activity in human serum was tested in homozygous (CTG)5 diabetic patients and healthy control subjects.
Tunicamycin completely inhibited CN-1 secretion. Deletion of all N-glycosylation sites was required to reduce CN-1 secretion efficiency. Enzyme activity was already diminished when two sites were deleted. In pCSII-CN-1–transfected Cos-7 cells cultured in medium containing 25 mmol/l d-glucose, the immature 61 kilodaltons (kDa) CN-1 immune reactive band was not detected. This was paralleled by an increased GlcNAc expression in cell lysates and CN-1 expression in the supernatants. Homozygous (CTG)5 diabetic patients had significantly higher serum CN-1 activity compared with genotype-matched, healthy control subjects.
We conclude that apart from the (CTG)n polymorphism in the signal peptide of CN-1, N-glycosylation is essential for appropriate secretion and enzyme activity. Since hyperglycemia enhances CN-1 secretion and enzyme activity, our data suggest that poor blood glucose control in diabetic patients might result in an increased CN-1 secretion even in the presence of the (CTG)5 allele.
PMCID: PMC2911063  PMID: 20460427
5.  Open lung approach associated with high-frequency oscillatory or low tidal volume mechanical ventilation improves respiratory function and minimizes lung injury in healthy and injured rats 
Critical Care  2010;14(5):R183.
To test the hypothesis that open lung (OL) ventilatory strategies using high-frequency oscillatory ventilation (HFOV) or controlled mechanical ventilation (CMV) compared to CMV with lower positive end-expiratory pressure (PEEP) improve respiratory function while minimizing lung injury as well as systemic inflammation, a prospective randomized study was performed at a university animal laboratory using three different lung conditions.
Seventy-eight adult male Wistar rats were randomly assigned to three groups: (1) uninjured (UI), (2) saline washout (SW), and (3) intraperitoneal/intravenous Escherichia coli lipopolysaccharide (LPS)-induced lung injury. Within each group, animals were further randomized to (1) OL with HFOV, (2) OL with CMV with "best" PEEP set according to the minimal static elastance of the respiratory system (BP-CMV), and (3) CMV with low PEEP (LP-CMV). They were then ventilated for 6 hours. HFOV was set with mean airway pressure (PmeanHFOV) at 2 cm H2O above the mean airway pressure recorded at BP-CMV (PmeanBP-CMV) following a recruitment manoeuvre. Six animals served as unventilated controls (C). Gas-exchange, respiratory system mechanics, lung histology, plasma cytokines, as well as cytokines and types I and III procollagen (PCI and PCIII) mRNA expression in lung tissue were measured.
We found that (1) in both SW and LPS, HFOV and BP-CMV improved gas exchange and mechanics with lower lung injury compared to LP-CMV, (2) in SW; HFOV yielded better oxygenation than BP-CMV; (3) in SW, interleukin (IL)-6 mRNA expression was lower during BP-CMV and HFOV compared to LP-CMV, while in LPS inflammatory response was independent of the ventilatory mode; and (4) PCIII mRNA expression decreased in all groups and ventilatory modes, with the decrease being highest in LPS.
Open lung ventilatory strategies associated with HFOV or BP-CMV improved respiratory function and minimized lung injury compared to LP-CMV. Therefore, HFOV with PmeanHFOV set 2 cm H2O above the PmeanBP-CMV following a recruitment manoeuvre is as beneficial as BP-CMV.
PMCID: PMC3219289  PMID: 20946631
6.  N-Octanoyl Dopamine, a Non-Hemodyanic Dopamine Derivative, for Cell Protection during Hypothermic Organ Preservation 
PLoS ONE  2010;5(3):e9713.
Although donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects.
Methodology/Principal Findings
To this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects.
In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors.
PMCID: PMC2838791  PMID: 20300525
7.  Clinical review: Immunomodulatory effects of dopamine in general inflammation 
Critical Care  2004;8(6):485-491.
Large quantitaties of inflammatory mediators are released during the course of endotoxaemia. These mediators in turn can stimulate the sympathetic nervous system (SNS) to release catecholamines, which ultimately regulate inflammation-associated impairment in tissue perfusion, myocardial impairment and vasodilatation. Treatment of sepsis is based on surgical and/or antibiotic therapy, appropriate fluid management and application of vasoactive catecholamines. With respect to the latter, discussions on the vasopressor of choice are still ongoing. Over the past decade dopamine has been considered the 'first line' vasopressor and is frequently used to improve organ perfusion and blood pressure. However, there is a growing body of evidence that dopamine has deleterious side effects; therefore, its clinical relevance seems to be more and more questionable. Nevertheless, it has not been convincingly demonstrated that other catecholamines are superior to dopamine in this respect. Apart from its haemodynamic action, dopamine can modulate immune responses by influencing the cytokine network. This leads to inhibition of expression of adhesion molecules, inhibition of cytokine and chemokine production, inhibition of neutrophil chemotaxis and disturbed T-cell proliferation. In the present review we summarize our knowledge of the immunomodulatory effects of dopamine, with an emphasis on the mechanisms by which these effects are mediated.
PMCID: PMC1065039  PMID: 15566620
adhesion molecules; cytokines; dopamine; hemostasis; sepsis

Results 1-7 (7)