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- Biopterin Metabolism and eNOS Expression during Hypoxic Pulmonary Hypertension in Mice. [Journal Article]
- PLoS One 2013; 8(11):e82594.
Tetrahydrobiopterin (BH4), which fosters the formation of and stabilizes endothelial NO synthase (eNOS) as an active dimer, tightly regulates eNOS coupling / uncoupling. Moreover, studies conducted in genetically-modified models demonstrate that BH4 pulmonary deficiency is a key determinant in the pathogenesis of pulmonary hypertension. The present study thus investigates biopterin metabolism and eNOS expression, as well as the effect of sepiapterin (a precursor of BH4) and eNOS gene deletion, in a mice model of hypoxic pulmonary hypertension. In lungs, chronic hypoxia increased BH4 levels and eNOS expression, without modifying dihydrobiopterin (BH2, the oxidation product of BH4) levels, GTP cyclohydrolase-1 or dihydrofolate reductase expression (two key enzymes regulating BH4 availability). In intrapulmonary arteries, chronic hypoxia also increased expression of eNOS, but did not induce destabilisation of eNOS dimers into monomers. In hypoxic mice, sepiapterin prevented increase in right ventricular systolic pressure and right ventricular hypertrophy, whereas it modified neither remodelling nor alteration in vasomotor responses (hyper-responsiveness to phenylephrine, decrease in endothelium-dependent relaxation to acetylcholine) in intrapulmonary arteries. Finally, deletion of eNOS gene partially prevented hypoxia-induced increase in right ventricular systolic pressure, right ventricular hypertrophy and remodelling of intrapulmonary arteries. Collectively, these data demonstrate the absence of BH4/BH2 changes and eNOS dimer destabilisation, which may induce eNOS uncoupling during hypoxia-induced pulmonary hypertension. Thus, even though eNOS gene deletion and sepiapterin treatment exert protective effects on hypoxia-induced pulmonary vascular remodelling, increase on right ventricular pressure and / or right ventricular hypertrophy, these effects appear unrelated to biopterin-dependent eNOS uncoupling within pulmonary vasculature of hypoxic wild-type mice.
- A dexamethasone prodrug reduces the renal macrophage response and provides enhanced resolution of established murine lupus nephritis. [Journal Article]
- PLoS One 2013; 8(11):e81483.
We evaluated the ability of a macromolecular prodrug of dexamethasone (P-Dex) to treat lupus nephritis in (NZB × NZW)F1 mice. We also explored the mechanism underlying the anti-inflammatory effects of this prodrug. P-Dex eliminated albuminuria in most (NZB × NZW)F1 mice. Furthermore, P-Dex reduced the incidence of severe nephritis and extended lifespan in these mice. P-Dex treatment also prevented the development of lupus-associated hypertension and vasculitis. Although P-Dex did not reduce serum levels of anti-dsDNA antibodies or glomerular immune complexes, P-Dex reduced macrophage recruitment to the kidney and attenuated tubulointerstitial injury. In contrast to what was observed with free dexamethasone, P-Dex did not induce any deterioration of bone quality. However, P-Dex did lead to reduced peripheral white blood cell counts and adrenal gland atrophy. These results suggest that P-Dex is more effective and less toxic than free dexamethasone for the treatment of lupus nephritis in (NZB × NZW)F1 mice. Furthermore, the data suggest that P-Dex may treat nephritis by attenuating the renal inflammatory response to immune complexes, leading to decreased immune cell infiltration and diminished renal inflammation and injury.
- A cell permeable Peptide targeting the intracellular loop 2 of endothelin B receptor reduces pulmonary hypertension in a hypoxic rat model. [Journal Article]
- PLoS One 2013; 8(11):e81309.
Cell permeable peptides (CPP) aid cellular uptake of targeted cargo across the hydrophobic plasma membrane. CPP-mediated cargo delivery of receptor signaling motifs provides an opportunity to regulate specific receptor initiated signaling cascades. Both endothelin-1 receptors, ETA and ETB, have been targets of antagonist therapies for individuals with pulmonary arterial hypertension (PAH). These therapies have had success but have been accompanied by adverse reactions. Also, unlike the CPP which target specific signaling cascades, the antagonists target the entire function of the receptor. Using the CPP strategy of biased antagonism of the ETB receptor's intracellular loop 2 (ICB2), we demonstrate blunting of hypoxic pulmonary hypertension (HPH) in the rat, including indices of pulmonary arterial pressure, right ventricular hypertrophy and pulmonary vascular remodeling. Further, ex vivo analysis of the pulmonary artery treated with the IC2B peptide upon injection manifests marked reductions in Akt and ERK activation. Both kinases have been intimately related to cell proliferation and vascular contraction, the hallmarks of PAH. These observations in sum illustrate an involvement of the ETB receptor in HPH and furthermore provide a basis for a novel, CPP-based, strategy in the treatment of PAH, ultimately able to target not only ET-1, but also other factors involved in the development of PAH.
- Nanodroplet-Mediated Histotripsy for Image-guided Targeted Ultrasound Cell Ablation. [Journal Article]
- Theranostics 2013; 3(11):851-64.
This paper is an initial work towards developing an image-guided, targeted ultrasound ablation technique by combining histotripsy with nanodroplets that can be selectively delivered to tumor cells. Using extremely short, high-pressure pulses, histotripsy generates a dense cloud of cavitating microbubbles that fractionates tissue. We hypothesize that synthetic nanodroplets that encapsulate a perfluoropentane (PFP) core will transition upon exposure to ultrasound pulses into gas microbubbles, which will rapidly expand and collapse resulting in disruption of cells similar to the histotripsy process but at a significantly lower acoustic pressure. The significantly reduced cavitation threshold will allow histotripsy to be selectively delivered to the tumor tissue and greatly enhance the treatment efficiency while sparing neighboring healthy tissue. To test our hypothesis, we prepared nanodroplets with an average diameter of 204±4.7 nm at 37°C by self-assembly of an amphiphilic triblock copolymer around a PFP core followed by cross-linkage of the polymer shell forming stable nanodroplets. The nanodroplets were embedded in agarose tissue phantoms containing a sheet of red blood cells (RBCs), which were exposed to 2-cycle pulses applied by a 500 kHz focused transducer. Using a high speed camera to monitor microbubble generation, the peak negative pressure threshold needed to generate bubbles >50 μm in agarose phantoms containing nanodroplets was measured to be 10.8 MPa, which is significantly lower than the 28.8 MPa observed using ultrasound pulses alone. High speed images also showed cavitation microbubbles produced from the nanodroplets displayed expansion and collapse similar to histotripsy alone at higher pressures. Nanodroplet-mediated histotripsy created consistent, well-defined fractionation of the RBCs in agarose tissue phantoms at 10 Hz pulse repetition frequency similar to the lesions generated by histotripsy alone but at a significantly lower pressure. These results support our hypothesis and demonstrate the potential of using nanodroplet-mediated histotripsy for targeted cell ablation.
- Direct Mass Spectrometry Analysis of Untreated Samples of Ultralow Amounts Using Extraction Nano-Electrospray. [JOURNAL ARTICLE]
- Anal Methods 2013 Dec 7; 5(23)
Direct mass spectrometry analysis of untreated samples of volumes as low as 0.2 µL were achieved using fast extraction and nanoESI (electrospray ionization) in a combined fashion. The analytes in dried samples on paper substrates were extracted by organic solvent in a nanoESI tube and ionized with a high voltage applied for generating a spray. The ionization source produced stable signals for different atmospheric pressure interfaces of triple quadrupole instruments. Analysis time more than 20 minutes were available with 10 µL solvent consumed for the entire analysis process. The performance in qualitative and quantitative analysis was characterized with a wide variety of samples. Limits of detection as low as 0.1 ng/mL (corresponding to an absolute amount of 0.05 pg) were obtained for analysis of atrazine in river water, thiabendazole in orange homogenate, and methamphetamine in blood.
- Comparison between Glaucomatous and Non-glaucomatous Eyes with Unilateral Retinal Vein Occlusion in the Fellow Eye. [Journal Article]
- Korean J Ophthalmol 2013 Dec; 27(6):440-5.
To evaluate and compare the clinical and angiographic characteristics of retinal vein occlusion (RVO) in glaucomatous and non-glaucomatous eyes with unilateral RVO in the fellow eye.Twenty-one glaucomatous eyes (GL group) and 25 age-matched non-glaucomatous eyes (non-GL group) with unilateral RVO in the fellow eye were included in this study. Fluorescein angiographic images were assessed in both groups by 3 retina specialists in order to determine the RVO occlusion site. The occlusion site was divided into 2 types: arteriovenous (AV)-crossing and non-AV-crossing (optic cup or optic nerve sited). The clinical characteristics and prevalence of AV-crossing and non-AV-crossing RVO were compared between the 2 groups.The mean baseline intraocular pressures of the RVO eye and the fellow eye did not differ between the 2 groups (RVO eye: 14.3 ± 2.5 mmHg [non-GL group], 15.5 ± 3.9 mmHg [GL group], p = 0.217; fellow eye: 14.4 ± 2.5 mmHg [non-GL group], 15.7 ± 3.7 mmHg [GL group], p = 0.148). The prevalence of systemic disease did not differ between the 2 groups (e.g., diabetes mellitus and hypertension, p = 0.802 and 0.873, respectively). AV-crossing RVO was significantly more frequent in the non-GL group (19 eyes; 76%) than in the GL group (4 eyes, 19%, p < 0.001).Non-AV-crossing RVO, i.e., optic cup- or optic nerve-sited RVO, is more frequently associated with glaucomatous changes in the fellow eye. Therefore, this type of RVO should be monitored more carefully for indications of glaucoma in the fellow eye.
- Treating Cardiovascular Atherosclerotic Plaques with Tongmaijiangzhi (TMJZ) Capsule. [Journal Article]
- Afr J Tradit Complement Altern Med 2013; 10(6):449-51.
Atherosclerotic plaques can cause serious syndromes and mortality. Cholesterol accumulation in the plaques can disrupt the arterial flow, with lumen narrowing and stenosis, which contributes to heart attack and sudden cardiac death. The pharmacological treatment to atherosclerotic plaques can be anti-hypertensives, anti-cholesterol, and cleaning of the existed plaques. This work examined the effects of pharmacological Tongmaijiangzhi (TMJZ) capsule on atherosclerotic plaques. The radiological findings of the atherosclerotic plaques of 107 patients receiving TMJZ treatment were analyzed. We found that the TMJZ administration decreases plaque volume and alters the composition in a relatively short period, showing highly promising effects. TMJZ treatment is able to remove the existed atherosclerotic plaques with no side effects observed.
- Association between AKI and Long-Term Renal and Cardiovascular Outcomes in United States Veterans. [JOURNAL ARTICLE]
- Clin J Am Soc Nephrol 2013 Dec 5.
AKI is associated with major adverse kidney events (MAKE): death, new dialysis, and worsened renal function. CKD (arising from worsened renal function) is associated with a higher risk of major adverse cardiac events (MACE): myocardial infarction (MI), stroke, and heart failure. Therefore, the study hypothesis was that veterans who develop AKI during hospitalization for an MI would be at higher risk of subsequent MACE and MAKE.Patients in the Veterans Affairs (VA) database who had a discharge diagnosis with International Classification of Diseases, Ninth Revision, code of 584.xx (AKI) or 410.xx (MI) and were admitted to a VA facility from October 1999 through December 2005 were selected for analysis. Three groups of patients were created on the basis of the index admission diagnosis and serum creatinine values: AKI, MI, or MI with AKI. Patients with mean baseline estimated GFR<45 ml/min per 1.73 m(2) were excluded. The primary outcomes assessed were mortality, MAKE, and MACE during the study period (maximum of 6 years). The combination of MAKE and MACE-major adverse renocardiovascular events (MARCE)-was also assessed.A total of 36,980 patients were available for analysis. Mean age±SD was 66.8±11.4 years. The most deaths occurred in the MI+AKI group (57.5%), and the fewest (32.3%) occurred in patients with an uncomplicated MI admission. In both the unadjusted and adjusted time-to-event analyses, patients with AKI and AKI+MI had worse MARCE outcomes than those who had MI alone (adjusted hazard ratios, 1.37 [95% confidence interval, 1.32 to 1.42] and 1.92 [1.86 to 1.99], respectively).Veterans who develop AKI in the setting of MI have worse long-term outcomes than those with AKI or MI alone. Veterans with AKI alone have worse outcomes than those diagnosed with an MI in the absence of AKI.
- Plasma Ceruloplasmin, a Regulator of Nitric Oxide Activity, and Incident Cardiovascular Risk in Patients with CKD. [JOURNAL ARTICLE]
- Clin J Am Soc Nephrol 2013 Dec 5.
Increased serum levels of the acute-phase reactant ceruloplasmin predict adverse clinical outcomes in the setting of acute coronary syndromes and heart failure, but their role in patients with CKD is unclear. This study investigated the relationship of ceruloplasmin with clinical outcomes in CKD, especially with regard to traditional cardiac biomarkers.Serum ceruloplasmin levels in consecutive study participants with CKD (n=654; estimated GFR<60 ml/min per 1.73 m(2)) as well as a control group of non-CKD participants matched for age and sex (n=250) were measured. Study participants were enrolled during 2001-2006 from a population of patients presenting for elective diagnostic coronary angiography and prospectively followed for 3 years (median follow-up=1095 days) to determine incident major adverse cardiac events (defined as a composite of death, nonfatal myocardial infarction, and stroke).Serum ceruloplasmin levels in CKD patients were elevated versus controls (median [interquartile range]; 25.5 [21.8-29.6] versus 22.7 [19.7-26.5] mg/dl; P<0.001) and associated with increased risk of future major adverse cardiac events (hazard ratio, 1.35; 95% confidence interval, 1.0 to 1.82; P=0.04). After adjusting for traditional risk factors, higher serum ceruloplasmin was still associated with higher risk of major adverse cardiac events at 3 years (hazard ratio, 1.61; 95% confidence interval, 1.15 to 2.25; P=0.01).In CKD patients, increased serum ceruloplasmin, a regulator of nitric oxide activity, is associated with increased risk of long-term adverse cardiovascular events, even after multivariable model adjustment for traditional clinical and biologic risk factors.
- Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor Consortium study. [JOURNAL ARTICLE]
- Neuro Oncol 2013 Dec 4.
BackgroundA phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent low-grade glioma to measure sustained response and/or stable disease lasting ≥6 months and progression-free survival.MethodsThirty-five evaluable patients received 2 doses (10 mg/kg each) of single-agent BVZ intravenously 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included neuroimaging and expression of tumor angiogenic markers (vascular endothelial growth factor [VEGF], VEGF receptor 2, hypoxia-inducible factor 2α, and carbonic anhydrase 9).ResultsThirty-five evaluable patients (median age 8.4 y [range, 0.6-17.6]) received a median of 12 courses of BVZ + CPT-11 (range, 2-26). Twenty-nine of 35 patients (83%) received treatment for at least 6 months. Eight patients progressed on treatment at a median time of 5.4 months (range, 1-17.8). Six patients (17.7%) still in follow-up have had stable disease without receiving additional treatment for a median of 40.1 months (range, 30.6-49.3) from initiating therapy. The 6-month and 2-year progression-free survivals were 85.4% (SE ± 5.96%) and 47.8% (SE ± 9.27%), respectively. The commonest toxicities related to BVZ included grades 1-2 hypertension in 24, grades 1-2 fatigue in 23, grades 1-2 epistaxis in 18, and grades 1-4 proteinuria in 15. The median volume of enhancement decreased significantly between baseline and day 15 (P < .0001) and over the duration of treatment (P < .037).ConclusionThe combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.