Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterase 4D (PDE4D) is one of 16 PDEs expressed in cerebral microvessels, and may be involved in regulating blood-brain barrier (BBB) permeability. To assess the possible role of PDE4D in stroke-related injury in young versus aged rats, we measured microvascular PDE4D expression, parenchymal albumin immunoreactivity, and changes in the inside bore of the brain microvasculature. Ischemia caused severe hippocampal CA1 damage, associated with significant increases in vascular PDE4D and parenchymal albumin immunoreactivities. This effect was greater in the younger animals, which also had a greater increase in PDE4D expression. Ischemia significantly decreased tissue density in the perimicrovascular space in both young and aged animals. In addition, internal bore circumference and cross-sectional area of the hippocampal microvessels increased dramatically following ischemia. Increased PDE4D expression following cerebral ischemia may play a role in changing BBB permeability, which could secondarily affect ischemic outcome.
ACS Chem Neurosci 2012 Jun 20
PMID:Ischemia-induced increase in microvascular phosphodiesterase 4D expression in rat hippocampus associated with blood brain barrier permeability: effect of age. 2286 Feb 12

Intracellular delivery of nanocarriers (NC) is controlled by their design and target cell phenotype, microenvironment, and functional status. Endothelial cells (EC) lining the vascular lumen represent an important target for drug delivery. Endothelium in vivo is constantly or intermittently (as, for example, during ischemia-reperfusion) exposed to blood flow, which influences NC-EC interactions by changing NC transport properties, and by direct mechanical effects upon EC mechanisms involved in NC binding and uptake. EC do not internalize antibodies to marker glycoprotein PECAM(CD31), yet internalize multivalent NC coated with PECAM antibodies (anti-PECAM/NC) via a noncanonical endocytic pathway distantly related to macropinocytosis. Here we studied the effects of flow on EC uptake of anti-PECAM/NC spheres (~180 nm diameter). EC adaptation to chronic flow, manifested by cellular alignment with flow direction and formation of actin stress fibers, inhibited anti-PECAM/NC endocytosis consistent with lower rates of anti-PECAM/NC endocytosis in vivo in arterial compared to capillary vessels. Acute induction of actin stress fibers by thrombin also inhibited anti-PECAM/NC endocytosis, demonstrating that formation of actin stress fibers impedes EC endocytic machinery. In contrast, acute flow without stress fiber formation, stimulated anti-PECAM/NC endocytosis. Anti-PECAM/NC endocytosis did not correlate with the number of cell-bound particles under flow or static conditions. PECAM cytosolic tail deletion and disruption of cholesterol-rich plasmalemma domains abrogated anti-PECAM/NC endocytosis stimulation by acute flow, suggesting complex regulation of a flow-sensitive endocytic pathway in EC. The studies demonstrate the importance of the local flow microenvironment for NC uptake by the endothelium and suggest that cell culture models of nanoparticle uptake should reflect the microenvironment and phenotype of the target cells.
ACS Nano 2012 Oct 23
PMID:Acute and chronic shear stress differently regulate endothelial internalization of nanocarriers targeted to platelet-endothelial cell adhesion molecule-1. 2295 67

Early identification of patients with acute myocardial infarction is of prime importance due to the associated very high mortality. Only 22% of the patients presenting at emergency cardiology care with chest pain have coronary disease. A number of biochemical tests like CKMB and Troponin-T/I have been introduced for early detection of the coronary syndrome (ACS). Ischemia modified albumin (IMA) has been recently introduced as a marker of myocardial ischemia. We estimated serum IMA in four sequential samples from 25 patients admitted to ICCU. Twenty five healthy volunteers formed the control group from which the normal range was derived. IMA was significantly raised in ischemia patients than in controls as well as compared to the patients who did not have cardiac ischemia. IMA demonstrated good discrimination between the ischemic and the non-ischemic patients with an Odds Ratio of 16.9 (6.29-46.87) than CKMB which showed an Odds Ratio of 2.07 (1.18-6.08). Sensitivity and specificity of IMA for the detection of ACS was 78.0% and 82.7% compared to 58.0% and 60.0%, respectively for the CK-MB assay. The area under the ROC curve of IMA for ischemic v/s non-ischemic patients was 0.834. IMA appears to be developing into a new and very potent marker, of cardiac ischemia.
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PMID:Ischemia modified albumin: A novel marker for acute coronary syndrome. 2310 73

Phosphocreatine is a major cellular source of high energy phosphates, which is crucial to maintain cell viability under conditions of impaired metabolic states, such as decreased oxygen and energy availability (i.e., ischemia). Many methods exist for the bulk analysis of phosphocreatine and its dephosphorylated product creatine; however, no method exists to image the distribution of creatine or phosphocreatine at the cellular level. In this study, Fourier transform infrared (FTIR) spectroscopic imaging has revealed the ex vivo development of creatine microdeposits in situ in the brain region most affected by the disease, the cerebellum of cerebral malaria (CM) diseased mice; however, such deposits were also observed at significantly lower levels in the brains of control mice and mice with severe malaria. In addition, the number of deposits was observed to increase in a time-dependent manner during dehydration post tissue cutting. This challenges the hypotheses in recent reports of FTIR spectroscopic imaging where creatine microdeposits found in situ within thin sections from epileptic, Alzheimer's (AD), and amlyoid lateral sclerosis (ALS) diseased brains were proposed to be disease specific markers and/or postulated to contribute to the brain pathogenesis. As such, a detailed investigation was undertaken, which has established that the creatine microdeposits exist as the highly soluble HCl salt or zwitterion and are an ex-vivo tissue processing artifact and, hence, have no effect on disease pathogenesis. They occur as a result of creatine crystallization during dehydration (i.e., air-drying) of thin sections of brain tissue. As ischemia and decreased aerobic (oxidative metabolism) are common to many brain disorders, regions of elevated creatine-to-phosphocreatine ratio are likely to promote crystal formation during tissue dehydration (due to the lower water solubility of creatine relative to phosphocreatine). The results of this study have demonstrated that although the deposits do not occur in vivo, and do not directly play any role in disease pathogenesis, increased levels of creatine deposits within air-dried tissue sections serve as a highly valuable marker for the identification of tissue regions with an altered metabolic status. In this study, the location of crystalline creatine deposits were used to identify whether an altered metabolic state exists within the molecular and granular layers of the cerebellum during CM, which complements the recent discovery of decreased oxygen availability in the brain during this disease.
ACS Chem Neurosci 2012 Dec 19
PMID:FTIR imaging of brain tissue reveals crystalline creatine deposits are an ex vivo marker of localized ischemia during murine cerebral malaria: general implications for disease neurochemistry. 2325 37

Increased calcium influx through the L-type Ca(2+) channel or overexpression of the alpha subunit of the channel induces cardiac hypertrophy. Cardiac hypertrophy results from increased oxidative stress and alterations in cell calcium levels following ischemia-reperfusion injury and is an independent risk factor for increased morbidity and mortality. We find that decreasing the movement of the auxiliary beta subunit with a peptide derived against the alpha-interacting domain (AID) of the channel attenuates ischemia-reperfusion injury. We compared the efficacy of delivering the AID peptide using a trans-activator of transcription (TAT) sequence with that of the peptide complexed to multifunctional polymeric nanoparticles. The AID-tethered nanoparticles perfused through the myocardium more diffusely and associated with cardiac myocytes more rapidly than the TAT-labeled peptide but had similar effects on intracellular calcium levels. The AID-complexed nanoparticles resulted in a similar reduction in release of creatine kinase and lactate dehydrogenase after ischemia-reperfusion to the TAT-labeled peptide. Since nanoparticle delivery also holds the potential for dual drug delivery, we conclude that AID-complexed nanoparticles may provide an effective platform for peptide delivery in cardiac ischemia-reperfusion injuries.
ACS Nano 2013 Mar 26
PMID:Examining efficacy of "TAT-less" delivery of a peptide against the L-type calcium channel in cardiac ischemia-reperfusion injury. 2343 14

Coupling Fourier transform infrared spectroscopy with focal plane array detectors at synchrotron radiation sources (SR-FTIR-FPA) has provided a rapid method to simultaneously image numerous biochemical markers in situ at diffraction limited resolution. Since cells and nuclei are well resolved at this spatial resolution, a direct comparison can be made between FTIR functional group images and the histology of the same section. To allow histological analysis of the same section analyzed with infrared imaging, unfixed air-dried tissue sections are typically fixed (after infrared spectroscopic analysis is completed) via immersion fixation. This post fixation process is essential to allow histological staining of the tissue section. Although immersion fixation is a common practice in this filed, the initial rehydration of the dehydrated unfixed tissue can result in distortion of subcellular morphology and confound correlation between infrared images and histology. In this study, vapor fixation, a common choice in other research fields where postfixation of unfixed tissue sections is required, was employed in place of immersion fixation post spectroscopic analysis. This method provided more accurate histology with reduced distortions as the dehydrated tissue section is fixed in vapor rather than during rehydration in an aqueous fixation medium. With this approach, accurate correlation between infrared images and histology of the same section revealed that Purkinje neurons in the cerebellum are rich in cytosolic proteins and not depleted as once thought. In addition, we provide the first direct evidence of intracellular lactate within Purkinje neurons. This highlights the significant potential for future applications of SR-FTIR-FPA imaging to investigate cellular lactate under conditions of altered metabolic demand such as increased brain activity and hypoxia or ischemia.
ACS Chem Neurosci 2013 Jul 17
PMID:Subcellular biochemical investigation of purkinje neurons using synchrotron radiation fourier transform infrared spectroscopic imaging with a focal plane array detector. 2363 13

Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12 members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.
ACS Chem Biol 2013 Aug 16
PMID:PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3. 2374 72

Common methods of loading magnetic resonance imaging (MRI) contrast agents into nanoparticles often suffer from challenges related to particle formation, complex chemical modification/purification steps, and reduced contrast efficiency. This study presents a simple, yet advanced process to address these issues by loading gadolinium, an MRI contrast agent, exclusively on a liposome surface using a polymeric fastener. The fastener, so named for its ability to physically link the two functional components together, consisted of chitosan substituted with diethylenetriaminepentaacetic acid (DTPA) to chelate gadolinium, as well as octadecyl chains to stabilize the modified chitosan on the liposome surface. The assembly strategy, mimicking the mechanisms by which viruses and proteins naturally anchor to a cell, provided greater T1 relaxivity than liposomes loaded with gadolinium in both the interior and outer leaflet. Gadolinium-coated liposomes were ultimately evaluated in vivo using murine ischemia models to highlight the diagnostic capability of the system. Taken together, this process decouples particle assembly and functionalization and, therefore, has considerable potential to enhance imaging quality while alleviating many of the difficulties associated with multifunctional particle fabrication.
ACS Nano 2013 Nov 26
PMID:A polymeric fastener can easily functionalize liposome surfaces with gadolinium for enhanced magnetic resonance imaging. 2408 77

Targeted nanomedicine holds promise to find clinical use in many medical areas. Endothelial cells that line the luminal surface of blood vessels represent a key target for treatment of inflammation, ischemia, thrombosis, stroke, and other neurological, cardiovascular, pulmonary, and oncological conditions. In other cases, the endothelium is a barrier for tissue penetration or a victim of adverse effects. Several endothelial surface markers including peptidases (e.g., ACE, APP, and APN) and adhesion molecules (e.g., ICAM-1 and PECAM) have been identified as key targets. Binding of nanocarriers to these molecules enables drug targeting and subsequent penetration into or across the endothelium, offering therapeutic effects that are unattainable by their nontargeted counterparts. We analyze diverse aspects of endothelial nanomedicine including (i) circulation and targeting of carriers with diverse geometries, (ii) multivalent interactions of carrier with endothelium, (iii) anchoring to multiple determinants, (iv) accessibility of binding sites and cellular response to their engagement, (v) role of cell phenotype and microenvironment in targeting, (vi) optimization of targeting by lowering carrier avidity, (vii) endocytosis of multivalent carriers via molecules not implicated in internalization of their ligands, and (viii) modulation of cellular uptake and trafficking by selection of specific epitopes on the target determinant, carrier geometry, and hydrodynamic factors. Refinement of these aspects and improving our understanding of vascular biology and pathology is likely to enable the clinical translation of vascular endothelial targeting of nanocarriers.
ACS Nano 2014 May 27
PMID:Vascular targeting of nanocarriers: perplexing aspects of the seemingly straightforward paradigm. 2478 60

Rapid advances in imaging technologies have pushed novel spectroscopic modalities such as Fourier transform infrared spectroscopy (FTIR) and X-ray absorption spectroscopy (XAS) at the sulfur K-edge to the forefront of direct in situ investigation of brain biochemistry. However, few studies have examined the extent to which sample preparation artifacts confound results. Previous investigations using traditional analyses, such as tissue dissection, homogenization, and biochemical assay, conducted extensive research to identify biochemical alterations that occur ex vivo during sample preparation. In particular, altered metabolism and oxidative stress may be caused by animal death. These processes were a concern for studies using biochemical assays, and protocols were developed to minimize their occurrence. In this investigation, a similar approach was taken to identify the biochemical alterations that are detectable by two in situ spectroscopic methods (FTIR, XAS) that occur as a consequence of ischemic conditions created during humane animal killing. FTIR and XAS are well suited to study markers of altered metabolism such as lactate and creatine (FTIR) and markers of oxidative stress such as aggregated proteins (FTIR) and altered thiol redox (XAS). The results are in accordance with previous investigations using biochemical assays and demonstrate that the time between animal death and tissue dissection results in ischemic conditions that alter brain metabolism and initiate oxidative stress. Therefore, future in situ biospectroscopic investigations utilizing FTIR and XAS must take into consideration that brain tissue dissected from a healthy animal does not truly reflect the in vivo condition, but rather reflects a state of mild ischemia. If studies require the levels of metabolites (lactate, creatine) and markers of oxidative stress (thiol redox) to be preserved as close as possible to the in vivo condition, then rapid freezing of brain tissue via decapitation into liquid nitrogen, followed by chiseling the brain out at dry ice temperatures is required.
ACS Chem Neurosci 2015 Feb 18
PMID:In situ biospectroscopic investigation of rapid ischemic and postmortem induced biochemical alterations in the rat brain. 2535 Aug 66


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