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Biomedical subjects

W Yun

Publications and source records attributed to W Yun.

17 recordsLinked to original sources
PubMed2000

Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation.

Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.

Animals↗
PubMed1999

Platelet-activating factor acetylhydrolase prevents myocardial ischemia-reperfusion injury.

BACKGROUND: Platelet-activating factor (PAF) is one of the most potent biological mediators of tissue injury. PAF acetylhydrolase (PAF-AH) is a recently isolated naturally occurring enzyme that hydrolyzes PAF and renders it inactive. We hypothesize that inhibition of PAF with PAF-AH will reduce myocardial ischemia-reperfusion (I/R) injury in vivo. METHODS AND RESULTS: The coronary ligation model was used in New Zealand white rabbits. The large branch of the marginal coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. Fifteen minutes before reperfusion, animals were given either 2 mg/kg of vehicle or of PAF-AH. At the completion of 120 minutes of reperfusion, percentage of necrosis, degree of neutrophil infiltration, and measurements of regional contractility were assessed. Data are expressed as the mean+/-SEM and compared by Student's t test or Mann-Whitney ANOVA. Both groups of animals showed an equivalent area at risk; however, 46.7+/-11% was necrotic in the animal treated with vehicle. In contrast, 20.9+/-7.0% was necrotic in the animals treated with PAF-AH (P<0.05). Systolic shortening and wall thickness were significantly greater in those animals treated with PAF-AH at 15, 30, 60, and 120 minutes of reperfusion (P<0.05). Quantification of neutrophil infiltration showed a 62% reduction in the PAF-AH treated animals compared with those treated with vehicle alone. CONCLUSIONS: PAF-AH is a potent cardioprotective agent in an in vivo model of I/R injury.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1999

An essential role for NF-kappaB in the cardioadaptive response to ischemia.

BACKGROUND: Ischemic preconditioning (IP) is the phenomenon whereby brief episodes of ischemia protect the heart against a subsequent ischemic stress. We hypothesize that activation of the transcription factor NF-kappaB mediates IP. METHODS: Rabbits were randomly allocated to one of three groups: (1) 45 minutes of myocardial ischemia followed by 2 hours of reperfusion (I/R); (2) three cycles of 5-minute ischemia and 5 minutes of reperfusion followed by I/R (IP + I/R); or (3) IP in the presence of ProDTC, a specific NF-kappaB inhibitor, followed by I/R (IPProDTC + I/R). Infarct size, indices of regional contractility, and NF-kappaB activation were determined. RESULTS: In preconditioned rabbits (IP + I/R), infarct size was reduced 83% compared with both I/R alone and IPProDTC + I/R groups (p < 0.05). Throughout reperfusion, preconditioned myocardium showed enhanced regional contractile function compared with I/R and IPProDTC + I/R groups (p < 0.05). Gel shift analysis showed NF-kappaB activation with IP that was blocked by ProDTC. I/R and IPProDTC + I/R groups showed NF-kappaB activation with I/R that was absent in preconditioned animals. CONCLUSIONS: The cytoprotective effects induced by IP require activation of NF-kappaB.

Animals↗
PubMed1999

Treating myocardial ischemia-reperfusion injury by targeting endothelial cell transcription.

Exacerbation of, rather than improvement in, a hypoxic injury after reperfusion of ischemic tissues is recognized as the specific clinicopathologic entity referred to as ischemia/reperfusion (I/R) injury. Arguably, one of the most common forms of I/R injury occurs during cardiac surgery, which has a mandatory period of myocardial ischemia required to allow surgery in a bloodless, motionless field, followed by coronary artery reperfusion after removal of the aortic cross-clamp. In this review, we examine the endothelial cell activation phenotype that initiates and propagates myocardial I/R injury. Emphasis is given to the biology of one transcription factor, NF-kappaB, that has the principal role in the regulation of many endothelial cell genes expressed in activated endothelium. NF-kappaB-dependent transcription of endothelial cell genes that are transcribed in response to I/R injury may be a favorable approach to preventing tissue injury in the setting of I/R. Elucidating safe and effective therapy to inhibit transcription of endothelial cell genes involved in promoting injury after I/R injury may have wide applicability to the patients with heart disease and other forms of I/R injury.

Animals↗
PubMed1998

X-ray imaging and microspectroscopy of plants and fungi.

X-ray fluorescence microscopy and microspectroscopy with micrometre spatial resolution and unprecedented capabilities for the study of biological and environmental samples are reported. These new capabilities are a result of both the combination of high-brilliance synchrotron radiation and high-performance X-ray microfocusing optics and the intrinsic advantages of X-rays for elemental mapping and chemical-state imaging. In this paper, these capabilities are illustrated by experimental results on hard X-ray phase-contrast imaging, X-ray fluorescence (XRF) imaging and microspectroscopy of mycorrhizal plant roots and fungi in their natural hydrated state. The XRF microprobe is demonstrated by the simultaneous mapping of the elemental distributions of P, S, K, Ca, Mn, Fe, Ni, Cu and Zn with a spatial resolution of approximately 1 x 3 micron and with an elemental sensitivity of approximately 500 p.p.b. Microspectroscopy with the same spatial resolution is demonstrated by recording near-edge X-ray absorption (XANES) spectra of Mn at a concentration of approximately 3 p.p.m.

Journal Article↗
PubMed1997

Measurements of emittance and absolute spectral flux of the PETRA undulator at DESY Hamburg.

The first synchrotron radiation beamline using a 4 m-long undulator at the 12 GeV storage ring PETRA delivers hard X-ray photons usable up to 300 keV. The photon intensity is measured on an absolute scale in the energy range between 16 and 60 keV and compared with calculated intensities. The experimental set-up described is also used to measure the horizontal and vertical emittance of the source.

Journal Article↗
PubMed1995

CC-1065 CBI analogs: an example of enhancement of DNA alkylation efficiency through introduction of stabilizing electrostatic interactions.

The three trimethylammonium salts 3-5 proved to be 100 times more efficient at alkylating DNA than 2 and exhibited DNA alkylation efficiencies identical to that of (+)-CC-1065 (1). In addition, the agents 3 and 4 exhibited DNA alkylation selectivities identical to that of 2. This may be attributed to spatially well-defined stabilizing electrostatic interactions between the positively charged trimethylammonium salt lying on the peripheral face of the agents and the bracketing, negatively charged phosphates located in the DNA backbone that enhance the DNA noncovalent binding affinity without affecting DNA binding or alkylation selectivity. The agent 5 exhibited an altered and more discriminating AT-rich adenine N3 alkylation selectivity than 2-4 that may be attributed to the groove placement of the large trimethylammonium salt.

Alkylation↗
PubMed1995

CBI-CDPBO1 and CBI-CDPBI1: CC-1065 analogs containing deep-seated modifications in the DNA binding subunit.

The synthesis and preliminary examination of CBI-CDPBO1 (2) and CBI-CDPBI1 (3), CBI analogs of CC-1065 (1) and the duocarmycins incorporating the 3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]benzoxazole-7-carboxylate (CDPBO) and 3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]benzimidazole-7-carboxylate (CDPBI) DNA binding subunits, are detailed. The agents contain deep-seated modifications in the DNA binding subunits of the natural products with incorporation of a nitrogen capable of functioning as a hydrogen bond acceptor (CDPBO, CDPBI) or hydrogen bond donor (CDPBI) on their inside concave face which is in intimate contact with the minor groove floor. The CDPBO subunit was prepared through use of a novel and effective MnO2-mediated oxidative coupling of 2-(benzyloxy)ethylamine with 5-hydroxyindole (4) to directly provide 2-[(benzyloxy)methyl]pyrrolo[3,2-e]benzoxazole (6, 48%) in a reaction cascade that initially proceeds with amine regioselective C4 nucleophilic addition to the in situ generated p-quinone monoimine 13. Subsequent conversion of 6 to 8 (debenzylation; MnO2-NaCN, CH3OH) and selective reduction of the fused pyrrole (Et3SiH-CF3CO2H) completed the synthesis of the 1,2-dihydro-3H-pyrrolo[3,2-e]benzoxazole-7-carboxylate ring system. The CDPBI subunit was prepared through selective C4 nitration of 22 followed by reduction of the nitro group and acid-catalyzed closure to the corresponding 2-[(benzyloxy)methyl]pyrrolo[3,2-e]benzimidazole 25. The final conversion of 25 to the 1,2-dihydro-3H-pyrrolo[3,2-e]benzimidazole-7-carboxylate ring system (CDPBI) followed the same protocols introduced for CDPBO. The DNA alkylation efficiencies of 2 and 3 were identical and both were substantially diminished relative to that of CBI-CDPI1 (40). Thus, the introduction of a single nitrogen atom in the DNA binding subunit of 40 has a pronounced and detrimental effect on the relative efficiency (100 x) of DNA alkylation. Consistent with these observations, the in vitro cytotoxic activity of (+)-2 and (+)-3 were comparable (IC50 = 200 pM, L1210) and 40 x less potent than (+)-40 (IC50 = 5 pM, L1210). In contrast to the large impact these small structural changes had on the efficiency of DNA alkylation, the selectivity of DNA alkylation by 2 and 3 was unperturbed and both agents were found to alkylate the same major sites as CBI-CDPI1 (40). The potential origin of these effects is discussed.

Alkylation↗
PubMed1995

1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogs of CC-1065 and the duocarmycins: synthesis and evaluation.

An extensive study of analogs of the potent antitumor antibiotics CC-1065 and the duocarmycins which incorporate the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) alkylation subunit are detailed. In contrast to early speculation, deep-seated modifications in the CC-1065 and duocarmycin alkylation subunits are well tolerated and the CBI-based analogs proved to be potent cytotoxic agents and efficacious antitumor compounds. Full details of studies defining a direct relationship between functional stability and in vitro cytotoxic potency are described. As such, the readily accessible CBI-based analogs were found to be four times more stable and four times more potent than the corresponding analogs containing the authentic CPI alkylation subunit of CC-1065 and comparable in potency to agents containing the authentic alkylation subunit of duocarmycin SA. Similarly, the CBI-based agents alkylate DNA with an unaltered sequence selectivity at an enhanced rate and with a greater efficiency than the corresponding CPI analog and were comparable to the corresponding analog incorporating the duocarmycin SA alkylation subunit. Systematic and extensive modifications and simplifications in the DNA binding subunits attached to CBI were explored with the comparisons of both enantiomers of CC-1065 and the duocarmycins 2 and 3 with enantiomers of 18-24, 25-29, 57-61, 62-65, 66-68, 72, 73, 78 and 79.

Alkylation↗
PubMed1994

Molecular basis for sequence selective DNA alkylation by (+)- and ent-(-)-CC-1065 and related agents: alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity.

A detailed evaluation of the DNA alkylation selectivity of (+)-CC-1065, ent-(-)-CC-1065 and a series of aborted and extended analogs possessing the CPI alkylation subunit is detailed and the refinement of a model that accommodates the offset AT-rich adenine N3 alkylation selectivity of the enantiomeric agents is presented. The natural enantiomers bind in the minor groove in the 3'-->5' direction starting from the adenine N3 alkylation site across a 2 base (N-BOC-CPI; i.e. 5'-AA), 3.5 base (CPI-CDPI1/CPI-PDE-I1; i.e. 5'-AAA), 5 base (CC-1065/CPI-CDPI2; i.e. 5'-AAAAA) or 6.5 base (CPI-CDPI3; i.e. 5'-AAAAAA) AT-rich site. In contrast, the unnatural enantiomers bind in the reverse 5'-->3' direction in the minor groove and the binding site necessarily starts at the first 5' base preceding the adenine N3 alkylation site and extends across the alkylation site to the adjacent 3' bases covering an AT-rich site of 2 bases (N-BOC-CPI; e.g., 5'-AA), 5 bases (CC-1065/CPI-CDPI2; eg. 5'-AAAAA), or 6.5 bases (CPI-CDPI3; e.g. 5'-AAAAAA). Notably, the model accommodates the unusual observation that both enantiomers of N-BOC-CPI alkylate the same sites within duplex DNA (5'-AA > 5'-TA) and the required reversed binding orientation of the enantiomeric agents. The reversed binding orientation is required to permit access to the electrophilic cyclopropane and the resulting offset AT-rich alkylation selectivity is the natural consequence of the diastereomeric relationship of the adducts. Three dimensional models of the natural and unnatural enantiomer alkylations are presented which clearly illustrate the offset binding sites. A fundamentally simple model for the CC-1065 DNA alkylation reaction, that accommodates the behavior of both enantiomers, is provided in which the sequence selectivity is derived from the noncovalent binding selectivity of the agents preferentially in the narrower, sterically more accessible AT-rich minor groove, the inherent steric accessibility to the adenine N3 alkylation site that accompanies deep penetration of the agent into the minor groove within an AT-rich site, and the 2 base-pair (N-BOC-CPI), 3.5 base-pair (CPI-PDE-I1/CPI-CDPI1), 5 base-pair (CC-1065/CPI-CDPI2), or 6.5 base-pair (CPI-CDPI3) site size required to permit agent binding in the minor groove at the alkylation site.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylation↗