Tadeusz Malinski

Harvard Medical School, Boston, Massachusetts, United States

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Publications (180)786.44 Total impact

  • Tadeusz Malinski
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    ABSTRACT: The cytotoxic peroxynitrite (ONOO(-)) is an oxidation product of the cytoprotective nitric oxide (NO). Our studies support the hypothesis that the concentration ratio of NO and ONOO(-), [NO]/[ONOO(-)] can be a marker of nitroxidative imbalance, which subsequently correlates well with endothelial dysfunction and dysfunction of the cardiovascular system. Nanosensors, described here, have been used for simultaneous monitoring and measurement of NO and ONOO(-) release from a single endothelial cell. These nanosensors, with a diameter of 200-300 nm, can be positioned accurately in close proximity of 5-10 μm from the endothelial cell membrane. The response time of the sensors is better than a millisecond and the detection limit is 10(-9) M, with a linear concentration response of up to about 2 μM. The application of these sensors for the measurement of the balance and imbalance of [NO]/[ONOO(-)] in normal and dysfunctional endothelium is demonstrated.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1208:139-55. · 1.29 Impact Factor
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    ABSTRACT: Background Previously, nitric oxide has been shown to possess antimicrobial effects. In this study, we aim to test the effect of glyceryl trinitrate (GTN) on Staphylococcus aureus growth during simulated extracorporeal circulation (SECC) and also to examine the effect of S. aureus, alone and in combination with GTN, on activation markers of the innate immune system during SECC. Methods In an in vitro system of SECC, we measured GTN-induced changes in markers of leukocyte activation in whole blood caused by S. aureus infestation, as well as the effect of GTN on S. aureus growth. Results GTN had no effect on S. aureus growth after 240 minutes SECC. Staphylococcus aureus reduced the expression of granulocyte Fcγ-receptor CD32 but stimulated the expression of monocyte CD32. Staphylococcus aureus stimulated expression of some leukocyte adhesion key proteins, activation marker CD66b, lipopolysaccharide-receptor CD14, and C3b-receptor CD35. Staphylococcus aureus and GTN addition induced significant increases in monocyte CD63 (lysosomal granule protein) levels. Conclusion GTN does not affect S. aureus growth during SECC and has no effect on SECC-induced leukocyte activation.
    The Thoracic and Cardiovascular Surgeon 12/2013; · 0.93 Impact Factor
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    ABSTRACT: Clinical trials have shown that amlodipine reduces cardiovascular events at a rate that is not predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by the pleiotropic effects of amlodipine on endothelial cell (EC) function. In this study, we elucidated the effect of amlodipine on nitric oxide (NO) bioavailability and cytotoxic peroxynitrite (ONOO(-)) and blood pressure (BP). Spontaneously hypertensive rats (SHRs) were treated with vehicle or amlodipine (5mg/kg/day) for 8 weeks and compared with untreated, baseline rats. NO and ONOO(-) release from aortic and glomerular ECs were measured ex vivo using amperometric nanosensors following maximal stimulation with calcium ionophore. BP was measured using the tail-cuff method. As compared with baseline, vehicle treatment had reduced aortic endothelial NO release from 157±11nM to 55±6nM and increased ONOO(-) from 69±7nM to 156±19nM. The NO/ONOO(-) ratio, a comprehensive measurement of eNOS function, decreased from 2.3±0.3 to 0.3±0.1. Compared with vehicle, amlodipine treatment restored NO to 101±3nM, decreased ONOO(-) to 50±4nM, and increased the NO/ONOO(-) ratio to 2.0±0.2, a level similar to baseline. Similar changes were observed for glomerular ECs. Mean arterial blood pressure increased from 149±3mm Hg (baseline) to 174±1mm Hg (vehicle). Amlodipine slightly, but significantly, decreased mean arterial blood pressure to 167±3mm Hg vs. vehicle treatment. Amlodipine increased NO bioavailability and decreased nitroxidative stress in SHRs with EC dysfunction disproportionately to BP changes. These direct, vascular effects of amlodipine on EC function may contribute to reduced risk for atherothrombotic events as observed in clinical trials.
    American Journal of Hypertension 10/2013; · 3.67 Impact Factor
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    ABSTRACT: Nebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. However, the kinetics and mechanism of nebivolol-stimulated bioavailable NO are not fully understood. Using amperometric NO and peroxynitrite (ONOO-) nanosensors, beta3-receptor (agonist: L-755,507; antagonists: SR59230A and L-748,337), ATP efflux (the mechanosensitive ATP channel blocker, gadolinium) and P2Y-receptor (agonists: ATP and 2-MeSATP; antagonist: suramin) modulators, superoxide dismutase and a NADPH oxidase inhibitor (VAS2870), we evaluated the kinetics and balance of NO and ONOO- stimulated by nebivolol in human umbilical vein endothelial cells (HUVECs). NO and ONOO- were measured with nanosensors (diameter ~ 300 nm) placed 5 +/- 2 mum from the cell membrane and ATP levels were determined with a bioluminescent method. The kinetics and balance of nebivolol-stimulated NO and ONOO- were compared with those of ATP, 2-MeSATP, and L-755,507. Nebivolol stimulates endothelial NO release through beta3-receptor and ATP-dependent, P2Y-receptor activation with relatively slow kinetics (75 +/- 5nM/s) as compared to the kinetics of ATP (194 +/- 10nM/s), L-755,507 (108 +/- 6nM/s), and 2-MeSATP (105 +/- 5nM/s). The balance between cytoprotective NO and cytotoxic ONOO- was expressed as the ratio of [NO]/[ONOO-] concentrations. This ratio for nebivolol was 1.80 +/- 0.10 and significantly higher than that for ATP (0.80 +/- 0.08), L-755,507 (1.08 +/- 0.08), and 2-MeSATP (1.09 +/- 0.09). Nebivolol induced ATP release in a concentration-dependent manner. The two major pathways (ATP efflux/P2Y receptors and beta3 receptors) and several steps of nebivolol-induced NO and ONOO- stimulation are mainly responsible for the slow kinetics of NO release and low ONOO-. The net effect of this slow kinetics of NO is reflected by a favorable high ratio of [NO]/[ONOO-] which may explain the beneficial effects of nebivolol in the treatment of endothelial dysfunction, hypertension, heart failure, and angiogenesis.
    BMC pharmacology & toxicology. 09/2013; 14(1):48.
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    ABSTRACT: BACKGROUND: Reactive oxygen species (ROS) are major determinants of vascular aging. JunD, a member of the activated protein 1 (AP-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to ROS homeostasis in the vasculature remains unknown. METHODS AND RESULTS: Endothelium-dependent vasorelaxation was impaired in young and old JunD-/- mice (6 and 22 month old) as compared with age-matched wild-type (WT). JunD-/- mice displayed an age-independent decline of endothelial NO release and eNOS activity as well as increased mitochondrial superoxide formation and peroxynitrite levels. Furthermore, vascular expression and activity of free radical scavengers manganese and extracellular superoxide dismutase as well as aldehyde dehydrogenase 2 were reduced while NADPH oxidase subunits p47phox, Nox2 and Nox4 were upregulated. These redox changes were associated with premature vascular aging as shown by reduced teIomerase activity, increased β-gal positive cells, upregulation of senescence markers p16(INK4a ) and p53 as well as mitochondrial disruption. Interestingly, old WT mice showed a reduction of JunD expression and transcriptional activity due to promoter hypermethylation and binding with tumor suppressor menin, respectively. By contrast, JunD overexpression blunted age-induced endothelial dysfunction. In human endothelial cells, JunD knockdown exerted a similar impairment of O(2)(-)/NO balance which was prevented by concomitant NADPH inhibition. In parallel, JunD expression was reduced in monocytes from old vs. young healthy subjects and correlated with mRNA levels of scavenging and oxidant enzymes. CONCLUSIONS: JunD provides protection in aging-induced endothelial dysfunction and may represent a novel target to prevent ROS-driven vascular aging.
    Circulation 02/2013; · 15.20 Impact Factor
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    ABSTRACT: Most patients with diabetes also have hypertension, a risk factor associated with atherothrombotic disease and characterized by endothelial cell (EC) dysfunction and loss of nitric oxide (NO) bioavailability. Recent studies suggest a possible antihypertensive effect with dipeptidyl peptidase-4 (DPP4) inhibition; however, the underlying mechanism is not understood. In this study, we tested the effects of the DPP4 inhibitor, saxagliptin, on EC function, blood pressure, and sICAM-1 levels in hypertensive rats. Spontaneously hypertensive (SH) rats were treated with vehicle or saxagliptin (10 mg/kg/day) for 8 weeks. NO and peroxynitrite (ONOO) release from aortic and glomerular ECs was stimulated with calcium ionophore and measured using electrochemical nanosensor technology. Changes in EC function were correlated with fasting glucose levels. Saxagliptin treatment was observed to increase aortic and glomerular NO release by 22% (p<0.001) and 23% (p<0.001), respectively, with comparable reductions in ONOO levels; the NO/ONOO ratio increased by >50% in both EC types (p<0.001) as compared to vehicle. Saxagliptin also reduced mean arterial pressure from 170 ± 10 to 158 ± 10 mmHg (p<0.001) and decreased sICAM-1 levels by 37% (p<0.01). The results of this study suggest that DPP4 inhibition reduces blood pressure and inflammation in hypertensive rats while increasing NO bioavailability.
    Journal of cardiovascular pharmacology 08/2012; · 2.83 Impact Factor
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    ABSTRACT: • Angiotensin II receptor blockers improve endothelial cell-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide synthase (eNOS) function. • The key finding from this study is that angiotensin II receptor blockers (ARBs) differentially enhanced nitric oxide (NO) release in a manner influenced by certain genetic variants of eNOS. This finding provides new insights into the effects of ARBs on endothelial cell-dependent vasodilation and eNOS function that are of high importance in vascular medicine and clinical pharmacology. AIM Angiotensin II receptor blockers (ARBs) improve endothelial cell (EC)-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide (NO) synthase (eNOS) function. To investigate this question, we tested the effects of various ARBs on NO release in ECs from multiple donors, including those with eNOS genetic variants linked to higher cardiovascular risk. The effects of ARBs (losartan, olmesartan, telmisartan, valsartan), at 1 µm, on NO release were measured with nanosensors in human umbilical vein ECs obtained from 18 donors. NO release was stimulated with calcium ionophore (1 µm) and its maximal concentration was correlated with eNOS variants. The eNOS variants were determined by a single nucleotide polymorphism in the promoter region (T-786C) and in the exon 7 (G894T), linked to changes in NO metabolism. RESULTS All of the ARBs caused an increase in NO release as compared with untreated samples (P < 0.01, n= 4-5 in all eNOS variants). However, maximal NO production was differentially influenced by eNOS genotype. Olmesartan increased maximal NO release by 30%, which was significantly greater (P < 0.01, n= 4-5 in all eNOS variants) than increases observed with other ARBs. The ARBs differentially enhanced NO release in ECs in a manner influenced by eNOS single nucleotide polymorphisms. These findings provide new insights into the effects of ARBs on EC-dependent vasodilation and eNOS function.
    British Journal of Clinical Pharmacology 01/2012; 74(1):141-6. · 3.69 Impact Factor
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    ABSTRACT: Amorphous silica nanoparticles (SiNP) can be used in medical technologies and other industries leading to human exposure. However, an increased number of studies indicate that this exposure may result in cardiovascular inflammation and damage. A high ratio of nitric oxide to peroxynitrite concentrations ([NO]/[ONOO(-)]) is crucial for cardiovascular homeostasis and platelet hemostasis. Therefore, we studied the influence of SiNP on the platelet [NO]/[ONOO(-)] balance and platelet aggregation. Nanoparticle-platelet interaction was examined using transmission electron microscopy. Electrochemical nanosensors were used to measure the levels of NO and ONOO(-) released by platelets upon nanoparticle stimulation. Platelet aggregation was studied using light aggregometry, flow cytometry, and phase contrast microscopy. Amorphous SiNP induced NO release from platelets followed by a massive stimulation of ONOO(-) leading to an unfavorably low [NO]/[ONOO(-)] ratio. In addition, SiNP induced an upregulation of selectin P expression and glycoprotein IIb/IIIa activation on the platelet surface membrane, and led to platelet aggregation via adenosine diphosphate and matrix metalloproteinase 2-dependent mechanisms. Importantly, all the effects on platelet aggregation were inversely proportional to nanoparticle size. The exposure of platelets to amorphous SiNP induces a critically low [NO]/[ONOO(-)] ratio leading to platelet aggregation. These findings provide new insights into the pharmacological profile of SiNP in platelets.
    International Journal of Nanomedicine 01/2012; 7:631-9. · 4.20 Impact Factor
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    ABSTRACT: Generation of reactive oxygen species (ROS) is a key feature of vascular disease. Activation of the nuclear enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1) is a downstream effector of oxidative stress. PARP-1(-/-) and PARP-1(+/+) mice were injected with paraquat (PQ; 10 mg/kg i.p.) to induce intracellular oxidative stress. Aortic rings were suspended in organ chambers for isometric tension recording to analyze vascular function. PQ treatment markedly impaired endothelium-dependent relaxations to acetylcholine in PARP-1(-/-), but not PARP-1(+/+) mice (p<0.0001). Maximal relaxation was 45% in PQ treated PARP-1(-/-) mice compared to 79% in PARP-1(+/+) mice. In contrast, endothelium-independent relaxations to sodium nitroprusside (SNP) were not altered. After PQ treatment, l-NAME enhanced contractions to norepinephrine by 2.0-fold in PARP-1(-/-) mice, and those to acetylcholine by 3.3-fold, respectively, as compared to PARP-1(+/+) mice. PEG-superoxide dismutase (SOD) and PEG-catalase prevented the effect of PQ on endothelium-dependent relaxations to acetylcholine in PARP-1(-/-) mice (p<0.001 vs. PQ treated PARP-1(+/+) mice. Indomethacin restored endothelium-dependent relaxations to acetylcholine in PQ treated PARP-1(-/-) mice (p<0.05 vs. PQ treated PARP-1(+/+). PARP-1 protects from acute intracellular oxidative stress induced endothelial dysfunction by inhibiting ROS induced production of vasoconstrictor prostanoids.
    Biochemical and Biophysical Research Communications 11/2011; 414(4):641-6. · 2.28 Impact Factor
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    ABSTRACT: Endothelial cell (EC) dysfunction contributes to insulin resistance in diabetes and is characterized by reduced nitric oxide (NO) release, increased nitroxidative stress and enhanced inflammation. The purpose of this study was to test the effect of improved postprandial glucose control on EC function in insulin-resistant rats as compared to fasting glucose (FG) changes. Obese Zucker rats were treated with 10 mg/kg/day saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, for 4 or 8 weeks and compared to lean rats. NO and peroxynitrite (ONOO(-)) release from aortic and glomerular ECs was measured ex vivo using amperometric approaches and correlated with FG, postprandial glucose, insulin, soluble CD40 (sCD40) and L-citrulline levels. Saxagliptin treatment improved NO production and reduced ONOO(-) release prior to any observed changes in FG levels. In untreated obese animals, NO release from aortic and glomerular ECs decreased by 22% and 31%, respectively, while ONOO(-) release increased by 26% and 40%. Saxagliptin increased aortic and glomerular NO release by 18% and 31%, respectively, with comparable reductions in ONOO(-) levels; the NO/ONOO(-) ratio, an indicator of NO synthase coupling, increased by >40%. Improved glycemic control was further associated with a reduction in sCD40 levels by more than ten-fold (from 300 ± 206 to 22 ± 22 pg/mL, p < 0.001). These findings indicate that enhanced glycemic control with DPP4 inhibition improved NO release and reduced inflammation in a manner not predicted by FG changes alone.
    Journal of atherosclerosis and thrombosis 06/2011; 18(9):774-83. · 2.93 Impact Factor
  • Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2011; 57(14).
  • Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2011; 57(14).
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    ABSTRACT: The purpose of this study was to investigate the mechanism of noxious effects of amorphous silica nanoparticles on human endothelial cells. Nanoparticle uptake was examined by transmission electron microscopy. Electrochemical nanosensors were used to measure the nitric oxide (NO) and peroxynitrite (ONOO(-)) released by a single cell upon nanoparticle stimulation. The downstream inflammatory effects were measured by an enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and flow cytometry, and cytotoxicity was measured by lactate dehydrogenase assay. We found that the silica nanoparticles penetrated the plasma membrane and rapidly stimulated release of cytoprotective NO and, to a greater extent, production of cytotoxic ONOO(-). The low [NO]/[ONOO(-)] ratio indicated increased nitroxidative/oxidative stress and correlated closely with endothelial inflammation and necrosis. This imbalance was associated with nuclear factor κB activation, upregulation of key inflammatory factors, and cell death. These effects were observed in a nanoparticle size-dependent and concentration-dependent manner. The [NO]/[ONOO(-)] imbalance induced by amorphous silica nanoparticles indicates a potentially deleterious effect of silica nanoparticles on vascular endothelium.
    International Journal of Nanomedicine 01/2011; 6:2821-35. · 4.20 Impact Factor
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    ABSTRACT: Cardiovascular disease remains the leading cause of morbidity and premature mortality in most industrialized countries as well as in developing nations. A pro-oxidative state appears to promote and/or exacerbate vascular disease complications. Furthermore, a state of low-grade chronic inflammation can promote increased oxidative stress and lead to endothelial cell and platelet dysfunction ultimately contributing to thrombogenesis. In this study, the effect of a proprietary astaxanthin prodrug (CDX-085) on thrombus formation was investigated using a mouse model of arterial thrombosis. The influence of free astaxanthin, the active drug of CDX-085, on human endothelial cells and rat platelets was evaluated to investigate potential mechanisms of action. Oral administration of CDX-085 (0.4% in chow, approximately 500 mg/kg/day) to 6-8 week old C57BL/6 male mice for 14 days resulted in significant levels of free astaxanthin in the plasma, liver, heart and platelets. When compared to control mice, the CDX-085 fed group exhibited significant increases in basal arterial blood flow and significant delays in occlusive thrombus formation following the onset of vascular endothelial injury. Primary human umbilical vein endothelial cells (HUVECs) and platelets isolated from Wistar-Kyoto rats treated with free astaxanthin demonstrated significantly increased levels of released nitric oxide (NO) and significantly decreased peroxynitrite (ONOO-) levels. Observations of increased NO and decreased ONOO- levels in endothelial cells and platelets support a potential mechanism of action for astaxanthin (CDX-085 active drug). These studies support the potential of CDX-085 and its metabolite astaxanthin in the treatment or prevention of thrombotic cardiovascular complications.
    Thrombosis Research 10/2010; 126(4):299-305. · 3.13 Impact Factor
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    ABSTRACT: Elevation of nitric oxide (NO*) can either promote or inhibit ultraviolet B light (UVB)-induced apoptosis. In this study, we determined real-time concentration of NO* and peroxynitrite (ONOO(-)) and their role in regulation of membrane integrity and apoptosis. Nanosensors (diameter 300-500 nm) were used for direct in situ simultaneous measurements of NO* and ONOO(-) generated by UVB in cultured keratinocytes and mice epidermis. An exposure of keratinocytes to UVB immediately generated ONOO(-) at maximal concentration of 190 nm followed by NO(*) release with a maximal concentration of 91 nm. The kinetics of UVB-induced NO*/ONOO(-) was in contrast to cNOS agonist stimulated NO*/ONOO(-) from keratinocytes. After stimulating cNOS by calcium ionophore (CaI), NO* release from keratinocytes was followed by ONOO(-) production. The [NO*] to [ONOO(-)] ratio generated by UVB decreased below 0.5 indicating a serious imbalance between cytoprotective NO* and cytotoxic ONOO(-)-a main component of nitroxidative stress. The NO*/ONOO(-) imbalance increased membrane damage and cell apoptosis was partially reversed in the presence of free radical scavenger. The results suggest that UVB-induced and cNOS-produced NO* is rapidly scavenged by photolytically and enzymatically generated superoxide (O(2) (-)) to produce high levels of ONOO(-), which enhances oxidative injury and apoptosis of the irradiated cells.
    Photochemistry and Photobiology 01/2010; 86(2):389-96. · 2.29 Impact Factor
  • Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2010; 55(10).
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    ABSTRACT: Endothelial cell (EC) dysfunction contributes to hypertension and mechanisms of atherosclerosis. Agents that improve EC function may provide vascular protection, especially in patients with multiple risk factors. In this study, we examined the effects of beta(1)-selective antagonists, nebivolol and metoprolol, on vascular and renal EC function in spontaneously hypertensive (SH) rats with diabetes. Male SH rats were treated with streptozotocin (STZ) to induce type 2 diabetes, followed by treatment with nebivolol or metoprolol at 2 mg/kg/day (vs. vehicle). After 4 weeks, aortic and glomerular ECs were isolated, stimulated with calcium ionophore (CaI), and assayed for nitric oxide (NO), and peroxynitrite (ONOO(-)) release using amperometric approaches. Glucose and mean blood pressure (BP) levels were significantly elevated in diabetic SH rats. In aortic ECs isolated from diabetic SH rats, NO production decreased by 20% whereas ONOO(-) increased by 16%, an effect linked to NAD(P)H oxidase and endothelial NO synthase (eNOS) uncoupling. Nebivolol treatment reduced glucose and BP levels and restored aortic EC function in diabetic SH rats, as indicated by a 30% increase and 23% decrease in NO and ONOO(-) levels, respectively. The NO/ONOO(-) ratio increased by more than twofold with nebivolol treatment in aortic and glomerular ECs. Despite similar reductions in glucose and mean BP levels, metoprolol had a smaller effect on the NO/ONOO(-) ratio in glomerular ECs but no effect in aortic ECs. Vascular and renal NO was significantly reduced in diabetic hypertensive rats and correlated with metabolic changes. Nebivolol reversed these effects in a manner consistent with enhanced endothelial function.
    American Journal of Hypertension 10/2009; 22(11):1160-6. · 3.67 Impact Factor
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    ABSTRACT: Bioactive, patterned micro- and nanoscale surfaces that can be spatially engineered for three-dimensional ligand presentation and sustained release of signaling molecules represent a critical advance for the development of next-generation diagnostic and therapeutic devices. Lithography is ideally suited to patterning such surfaces due to its precise, easily scalable, high-throughput nature; however, to date polymers patterned by these techniques have not demonstrated the capacity for sustained release of bioactive agents. We demonstrate here a class of lithographically-defined, electropolymerized polymers with monodisperse micro- and nanopatterned features capable of sustained release of bioactive drugs and proteins. We show that precise control can be achieved over the loading capacity and release rates of encapsulated agents and illustrate this aspect using a fabricated surface releasing a model antigen (ovalbumin) and a cytokine (interleukin-2) for induction of a specific immune response. We further demonstrate the ability of this technique to enable three-dimensional control over cellular encapsulation. The efficacy of the described approach is buttressed by its simplicity, versatility, and reproducibility, rendering it ideally suited for biomaterials engineering.
    Advanced Functional Materials 07/2009; 19(18):2888-2895. · 10.44 Impact Factor
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    ABSTRACT: A detailed overview of nitric oxide and nitric oxide synthases in the kidney is presented. Physiologically, constitutive and inducible nitric oxide synthases have been detected in basically all vascular segments of the kidney, including all large vessels and arterioles that are primarily involved in the regulation of renal hemodynamics. It was observed that nitric oxide increases renal blood flow, decreases renal vascular resistance, and exerts variable effects on glomerular filtration rate depending on the experimental conditions. In addition, macula densa generated nitric oxide appears to mediate tubuloglomerular feedback. Constitutive and inducible nitric oxide synthases have also been delineated in most renal tubular segments. The inner medullary collecting duct was shown to contain the highest amount of constitutive nitric oxide synthase as compared to other nephron segments. It appears that nitric oxide may directly enhance tubular reabsorption in the collecting duct and the proximal tubule. Pressure-natriuresis, which may be a combination of both hemodynamic effects and an influence on tubular transport, may also be influenced directly and/or indirectly by nitric oxide. Due to its diverse functions, nitric oxide has been implicated in the pathophysiology of several renal diseases. Cyclosporin A toxicity, renal mass reduction, glomerular thrombosis, and ureteral obstruction, have all been found to be associated with diminished nitric oxide. On the other hand, incipient diabetes mellitus, ischemic acute renal failure, renal dysfunction of septic shock, advanced liver cirrhosis, and glomerulonephritis appear to be related to overabundant nitric oxide synthesis. Much has been learned regarding nitric oxide and the kidney, however, important questions remain to be clarified. Exciting new developments in nitric oxide research, including selective nitric oxide synthase inhibitors and alterations of the nitric oxide synthase gene(s), will add to the present understanding of nitric oxide. The kidney will probably turn out to be an organ amenable to some nitric oxide related therapeutic interventions.
    07/2009; 3(4):253-299.
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    ABSTRACT: A porphyrinic sensor was developed and used to monitor the release of nitric oxide (NO) by a fetal bovine aorta endothelial (FBAE) cell culture and a primary bovine aorta endothelial (BAE) cell culture, with populations of several thousand cells. The sensor consisted of either a platinum mesh or reticulated vitreous carbon support covered with several layers of a p-type semiconducting metalloporphyrin and a cation exchanger, Nafion. Tissue and cell cultures can be grown directly on the surface of the sensor and NO release can be measured by amperometric or differential pulse voltammetry methods. The detection limit of the sensor deposited on reticulated vitrous carbon and platinum mesh support is 10 nM and 0.1 μM respectively. The response time is about one millisecond and precision 5-6%. The peak NO concentration released from FBAE cells was 190 ± 20 nM and 70 ± 20 nM when agonized by calcium ionophore (A23187) and bradykinin respectively. The maximum NO concentration released from the primary culture BAE cells was 770 ± 50 nM and 400 ± 50 nM when agonized by angiotensin II and bradykinin respectively.
    07/2009; 4(1):63-69.

Publication Stats

6k Citations
786.44 Total Impact Points

Institutions

  • 2013
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2011–2012
    • Trinity College Dublin
      • School of Pharmacy and Pharmaceutical Sciences
      Dublin, L, Ireland
  • 2006–2012
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
    • Adam Mickiewicz University
      • Department of Biochemistry
      Poznań, Greater Poland Voivodeship, Poland
  • 2000–2012
    • Ohio University
      • Department of Chemistry and Biochemistry
      Athens, OH, United States
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 2010
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 1985–2009
    • Oakland University
      • Department of Chemistry
      Rochester, MI, United States
  • 2008
    • Medical University of Graz
      • Institut für Physiologische Chemie
      Graz, Styria, Austria
  • 2004–2008
    • Medical University of Vienna
      • Universitätsklinik für Orthopädie
      Vienna, Vienna, Austria
  • 2005
    • Elucida Research
      Beverly, Massachusetts, United States
    • University of Alberta
      • Department of Pharmacology
      Edmonton, Alberta, Canada
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
  • 2001–2004
    • Medical University of Gdansk
      • Department of Clinical Chemistry
      Danzig, Pomeranian Voivodeship, Poland
  • 1997–2004
    • University of Vienna
      • • Department of Cardio-Thoracic Surgery
      • • Department of Surgery
      Vienna, Vienna, Austria
    • New York University
      • Department of Medicine
      New York City, NY, United States
    • Duke University
      • Department of Biomedical Engineering (BME)
      Durham, NC, United States
    • Slovak University of Technology in Bratislava
      • Department of Analytical Chemistry
      Bratislava, Bratislavsky Kraj, Slovakia
  • 1998–2001
    • University of Zurich
      • Institute of Physiology
      Zürich, ZH, Switzerland
    • Jagiellonian University
      • Department of Pharmacology
      Kraków, Lesser Poland Voivodeship, Poland
  • 1997–2000
    • Universita degli studi di Ferrara
      • Section of Internal Medicine, Gerontology and Geriatrics
      Ferrara, Emilia-Romagna, Italy
  • 1993–1999
    • William Beaumont Army Medical Center
      El Paso, Texas, United States
    • University of Idaho
      • Department of Chemistry
      Moscow, Idaho, United States
  • 1996–1998
    • Slovak Academy of Sciences
      • Institute of Normal and Pathological Physiology
      Presburg, Bratislavský, Slovakia
  • 1995
    • Duke University Medical Center
      Durham, North Carolina, United States
    • Loyola University Chicago
      • Physiology
      Chicago, IL, United States
    • St. George's School
      Middletown, Rhode Island, United States
    • University of Pennsylvania
      • Department of Oral Medicine
      Philadelphia, PA, United States
    • Henry Ford Health System
      • Department of Neurology
      Detroit, MI, United States