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Biomedical subjects

D Han

Publications and source records attributed to D Han.

At least 19 recordsLinked to original sources
PubMed1999

Peroxynitrite, the breakdown product of nitric oxide, is beneficial in blood cardioplegia but injurious in crystalloid cardioplegia.

BACKGROUND: Peroxynitrite (ONOO(-)) has been implicated as a primary mediator in the deleterious effects of nitric oxide (NO) in crystalloid solutions, possibly due to a lack of detoxification mechanisms, leading to the formation of.OH. In contrast, ONOO(-) may exert cardioprotective effects in blood environments secondary to detoxification and the subsequent formation of NO-donating nitrosothiols. This dichotomy in physiological effects of ONOO(-) may exist between crystalloid and blood cardioplegia (BCP) environments. In the present study, we tested the hypothesis that ONOO(-) is cardiotoxic in crystalloid cardioplegia but cardioprotective in BCP in ischemically injured hearts. METHODS AND RESULTS: In anesthetized dogs on cardiopulmonary bypass, global 37 degrees C ischemia was imposed for 30 minutes, followed by 60 minutes of intermittent 4 degrees C hyperkalemic crystalloid (Plegisol) or BCP with (+) or without (-) 5 micromol/L authentic ONOO(-). After 2 hours of reperfusion, left ventricular (LV) function (end-systolic pressure-volume relations, in percent of baseline) was 56+/-3% in Plegisol-, which was further reduced in Plegisol+ to 40+/-4%.* In contrast, postischemic systolic function was better in BCP+ groups than in BCP- groups (96+/-2%* versus 82+/-2%, respectively). Differences in functional recovery could not be attributed to differences in hemodynamics. LV end-diastolic stiffness was significantly increased with the addition of ONOO(-) in both Plegisol (298+/-26% versus 466+/-30%*) and BCP (201+/-22% versus 267+/-13%*) groups. Consistent with increased LV chamber stiffness, myocardial edema was increased in BCP+ compared with BCP- (78.9+/-0.3% versus 76.4+/-0.3%*) and in Plegisol+ compared with Plegisol- (81.1+/-0.3% versus 79.6+/-0.4%*). Creatine kinase activity was significantly increased in Plegisol+ (48+/-6) compared with that in Plegisol- (31+/-6) but was unchanged in BCP- (14+/-2) relative to BCP+ (18+/-1). Nitrotyrosine (ng/mg protein) accumulation in LV myocardial biopsy samples confirmed myocardial exposure to ONOO(-) or its metabolites (Plegisol- 1.2+/-0.1, Plegisol+ 3.31+/-0.3*, BCP- 1.4+/-0.2, BCP+ 2.9+/-0.2*). CONCLUSIONS: We conclude that (1) the postcardioplegic cardiodynamic effects of ONOO(-) depend on its environment and (2) ONOO(-) in crystalloid solution impairs postcardioplegia systolic and diastolic functional recovery, whereas (3) ONOO(-) in BCP increases functional recovery. This environment-dependent dichotomy in the effect of ONOO(-) may affect the benefits of NO-related adjuncts to crystalloid or BCP solutions (*P<0.05 versus group without ONOO(-)). :II-384-II-391.)

Animals↗
PubMed1999

Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo.

Amyloid beta-peptide (A beta), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of A beta-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of A beta-(1-42). In the A beta-(1-42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with A beta-(40-1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with A beta-(1-42). Potent antioxidants idebenone and alpha-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in A beta-(1-42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of A beta infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of A beta-(1-42)-infused rats did not differ from those in control animals, and neither idebenone nor alpha-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and alpha-tocopherol prevents learning and memory deficits caused by A beta.

Alzheimer Disease↗
PubMed1999

Mutual regulation between the intercellular messengers nitric oxide and brain-derived neurotrophic factor in rodent neocortical neurons.

The diffusible factors, nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) are both suggested to be intercellular messengers that have similar synaptic activities and developmental influences in the brain. In the present study, we have analysed their mutual regulation with respect to their production in rodent neocortical neurons. Some of the cultured rat neocortical neurons exhibited immunoreactivity for both neuronal NO synthase (NOS) and the BDNF receptor trkB. Neuronal NOS appeared to be activated autonomously and produced NO in culture as monitored by nitrite accumulation. Inhibition of the endogenous NO production in culture by a NOS inhibitor, NG-monomethyl-L-arginine (NMMA), enhanced basal expression of BDNF mRNA and protein. Similarly, cerebroventricular administration of another NOS inhibitor, N-omega-nitro-L-arginine methylester (L-NAME), but not D-NAME or saline, increased BDNF content in the neocortex. In the opposite direction, however, BDNF appeared to function as a positive regulator for NO synthesis. Addition of BDNF upregulated the neuronal NOS expression as well as NO production in neocortical culture. In agreement, BDNF knock-out mice exhibited significant impairment of neuronal NOS expression in the neocortex. Taken together, these observations suggest that the trans-synaptic signalling molecules, NO and BDNF, influence the production of each other and mutually regulate the strength of their intercellular communications.

Animals↗
PubMed1999

Regulation of nerve growth factor release by nitric oxide through cyclic GMP pathway in cortical glial cells.

In the present study, we found that S-nitroso-N-acetyl-DL-penicillamine, a spontaneous nitric oxide (NO) generator, dose-dependently inhibited basal nerve growth factor (NGF) release from mixed glial cells. To elucidate the function of endogenous NO in the regulation of NGF release, the mixed glial cells were stimulated with lipopolysaccharide (LPS) or LPS plus interferon-gamma (IFNgamma). The results showed that LPS alone induced NGF release and moderate NO production. However, costimulation with LPS plus IFNgamma greatly enhanced NO production but significantly suppressed LPS-induced NGF release. When N(G)-monomethyl-L-arginine, an NOS inhibitor, was added to the culture, the suppression of NGF release by IFNgamma was significantly reduced. Quantitative reverse transcription-polymerase chain reaction demonstrated S-nitroso-N-acetyl-DL-penicillamine was also able to inhibit the LPS-induced NGF mRNA expression. To understand the different contributions of astroglia and microglia to this phenomenon, both cell types were purified. We found purified astroglia produced high amounts of NGF but low amounts of NO. However, purified microglia produced a large amount of NO but very low amounts of NGF after stimulation with LPS or LPS plus IFNgamma. Our data also indicated the second messenger cyclic GMP, but not cyclic AMP, was able to inhibit basal NGF release. In vivo experiments confirmed that NGF protein level was significantly enhanced in rats treated with L-N(omega)-nitro-arginine methyl ester and in endothelial NO synthase mutant mice. Taken together, we conclude NO derived mainly from microglia down-regulates NGF release from astroglia at the transcriptional level by stimulating cyclic GMP pathway.

Animals↗
PubMed1999

Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154.

Clinical islet cell transplantation has resulted in insulin independence in a limited number of cases. Rejection, recurrence of autoimmunity, and impairment of normal islet function by conventional immunosuppressive drugs, e.g., steroids, tacrolimus, and cyclosporin A, may all contribute to islet allograft loss. Furthermore, intraportal infusion of allogeneic islets results in the activation of intrahepatic macrophages and endothelial cells, followed by production of proinflammatory mediators that can contribute to islet primary nonfunction. We reasoned that the beneficial effects of anti-CD154 treatment on autoimmunity, alloreactivity, and proinflammatory events mediated by macrophages and endothelial cells made it an ideal agent for the prevention of islet allograft failure. In this study, a nonhuman primate model (Papio hamadryas) was used to assess the effect of humanized anti-CD154 (hu5c8) on allogeneic islet engraftment and function. Nonimmunosuppressed and tacrolimus-treated recipients were insulin independent posttransplant, but rejected their islet allografts in 8 days. Engraftment and insulin independence were achieved in seven of seven baboon recipients of anti-CD154 induction therapy administered on days -1, 3, and 10 relative to the islet transplant. Three of three baboons treated with 20 mg/kg anti-CD154 induction therapy experienced delayed rejection episodes, first detected by elevations in postprandial blood glucose levels, on postoperative day (POD) 31 for one and on POD 58 for the other two. Re-treatment with three doses of anti-CD154 resulted in reversal of rejection in all three animals and in a return to normoglycemia and insulin independence in two of three baboons. It was possible to reverse multiple episodes of rejection with this approach. A loss of functional islet mass, as detected by reduced first-phase insulin release in response to intravenous glucose tolerance testing, was observed after each episode of rejection. One of two baboons treated with 10 mg/kg induction therapy became insulin independent post-transplant but rejected the islet graft on POD 10; the other animal experienced a reversible rejection episode on POD 58 and remained insulin independent and normoglycemic until POD 264. Two additional baboon recipients of allogeneic islets and donor bone marrow (infused on PODs 5 and 11) were treated with induction therapy (PODs -1, 3, 10), followed by initiation of monthly maintenance therapy (for a period of 6 months) on POD 28. Rejection-free graft survival and insulin independence was maintained for 114 and 238 days, with preservation of functional islet mass observed in the absence of rejection. Prevention and reversal of rejection, in the absence of the deleterious effects associated with the use of conventional immunosuppressive drugs, make anti-CD154 a unique agent for further study in islet cell transplantation.

Animals↗
PubMed1999

Parental occupational exposure to hydrocarbons and risk of acute lymphocytic leukemia in offspring.

Parental exposure to hydrocarbons at work has been suggested to increase the risk of childhood leukemia. Evidence, however, is not entirely consistent. Very few studies have evaluated the potential parental occupational hazards by exposure time windows. The Children's Cancer Group recently completed a large-scale case-control study involving 1842 acute lymphocytic leukemia (ALL) cases and 1986 matched controls. The study examined the association of self-reported occupational exposure to various hydrocarbons among parents with risk of childhood ALL by exposure time window, immunophenotype of ALL, and age at diagnosis. We found that maternal exposure to solvents [odds ratio (OR), 1.8; 95% confidence interval (CI), 1.3-2.5] and paints or thinners (OR, 1.6; 95% CI, 1.2-2.2) during the preconception period (OR, 1.6; 95% CI, 1.1-2.3) and during pregnancy (OR, 1.7; 95% CI, 1.2-2.3) and to plastic materials during the postnatal period (OR, 2.2; 95% CI, 1.0-4.7) were related to an increased risk of childhood ALL. A positive association between ALL and paternal exposure to plastic materials during the preconception period was also found (OR, 1.4; 95% CI, 1.0-1.9). The ALL risk associated with parental exposures to hydrocarbons did not vary greatly with immunophenotype of ALL. These results suggest that the effect of parental occupational exposure to hydrocarbons on offspring may depend on the type of hydrocarbon and the timing of the exposure.

Adolescent↗
PubMed1998

Promoter analysis of the Drosophila genes encoding TFIIB and TATA box-binding protein.

We have analyzed the 5'-flanking regions of the Drosophila genes encoding the TFIIB and TATA box-binding proteins (TBP) and mapped the regulatory regions required for their efficient expression. We found that the 500 bp long region (-439 to +60) and the 401 bp long region (-261 to +138) are required for the efficient expression of TFIIB and TBP genes, respectively. In the TFIIB promoter region, the upstream DNA between -439 and -280 and the downstream DNA between +8 and +60 are necessary for the stimulation of promoter activity. The upstream DNA between -439 and -280 stimulates transcription in an orientation dependent manner. In the TBP promoter region, the upstream DNA between -261 and -207, and the downstream DNA between +15 and +138 are necessary for the stimulation of promoter activity. The upstream DNA (-261 to -207) required for TBP promoter activity contains a 11 bp long palindromic sequence and a DNA replication-related element sequence. Particularly, we could find that the downstream promoter regions of TFIIB and TBP genes contain the conserved nucleotide sequences, suggesting the presence of a common regulatory mechanism for the expression of these two genes.

Animals↗
PubMed1998

A comparative molecular analysis of four rat smooth muscle cell lines.

Transcriptional regulation of smooth muscle cell (SMC) differentiation is a rapidly growing area of interest that has relevance for understanding intimal disease. Despite the wealth of data accumulating in vitro, however, no study has compared the cell-specific marker profile, transfectability, promoter activity, and growth characteristics among several SMC culture systems. Accordingly, we performed a comprehensive analysis of the marker profile, growth properties, transfectability, and SMC promoter activity in four rat SMC lines (A7r5, adult and pup aortic, and PAC1). Despite alterations in chromosomal number and structure, A7r5, adult aortic, and PAC1 cells express all SMC markers studied including SM alpha-actin, SM calponin, SM22, tropoelastin, and to a lesser extent, SM myosin heavy chain (SMMHC). In contrast, pup aortic cells express very low or undetectable levels of all the above markers except tropoelastin. Adult aortic, pup, and PAC1 cells display similar growth curves and levels of proto-oncogene transcripts, whereas those in the A7r5 line are comparatively less. All cell lines studied except pup cells show expression of SMC differentiation genes during active growth, indicating that growth and differentiation are not mutually exclusive in cultured smooth muscle. Transfection studies reveal dramatic differences in DNA uptake and SMC-restricted promoter activity between cell lines. Collectively, these results provide detailed information relating to SMC molecular biology in culture that should facilitate the selection of a cell line for studying the transcriptional regulatory mechanisms underlying SMC differentiation.

Actins↗
PubMed1998

Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat.

BACKGROUND & AIMS: Hydrophobic bile acids have been implicated in the pathogenesis of cholestatic liver injury. The hypothesis that hydrophobic bile acid toxicity is mediated by oxidant stress in an in vivo rat model was tested in this study. METHODS: A dose-response study of bolus intravenous (i.v.) taurochenodeoxycholic acid (TCDC) in rats was conducted. Rats were then pretreated with parenteral alpha-tocopherol, and its effect on i.v. TCDC toxicity was evaluated by liver blood tests and by assessing mitochondrial lipid peroxidation. RESULTS: Four hours after an i.v. bolus of TCDC (10 mumol/100 g weight), serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels peaked, hepatic mitochondria showed evidence of increased lipid peroxidation, and serum bile acid analysis was consistent with a cholestatic injury. Liver histology at 4 hours showed hepatocellular necrosis and swelling and mild portal tract inflammation. Treatment with parenteral alpha-tocopherol was associated with a 60%-70% reduction in AST and ALT levels, improved histology, and a 60% reduction in mitochondrial lipid peroxidation in rats receiving TCDC. CONCLUSIONS: These data show that hepatocyte injury and oxidant damage to mitochondria caused by i.v. TCDC can be significantly reduced by pretreatment with the antioxidant vitamin E. These in vivo findings support the role for oxidant stress in the pathogenesis of bile acid hepatic toxicity.

Animals↗
PubMed1998

Topical application of alpha-tocopherol modulates the antioxidant network and diminishes ultraviolet-induced oxidative damage in murine skin.

The aim of this study was to investigate the effects of topical alpha-tocopherol application on epidermal and dermal antioxidants and its ability to prevent ultraviolet (UV)-induced oxidative damage. Hairless mice received topical applications of alpha-tocopherol 24 h before a single, acute UV irradiation (10 x minimal erythemal dose). The four major antioxidant enzymes (catalase, superoxide dismutase, glutathione reductase and glutathione peroxidase), hydrophilic and lipophilic antioxidants, and lipid hydroperoxides, markers of oxidative damage, were assayed in both epidermis and dermis of hairless mice. Topical alpha-tocopherol treatment increased dermal superoxide dismutase activity by 30% (P < 0.01) and protected epidermal glutathione peroxidase and superoxide dismutase from depletion after UV irradiation. Total and reduced glutathione levels in the epidermis increased by 50% after the topical treatment (P < 0.05), as did dermal ascorbate levels (by 40%: P < 0.01). The topical treatment increased alpha-tocopherol levels both in the epidermis (62-fold) and the dermis (22-fold: P < 0.001 in each layer). Furthermore, alpha-tocopherol treatment significantly reduced the formation of epidermal lipid hydroperoxides after UV irradiation (P < 0.05). These results demonstrate that topical administration of alpha-tocopherol protects cutaneous tissues against oxidative damage induced by UV irradiation in vivo, and suggest that the underlying mechanism of this effect involves the up-regulation of a network of enzymatic and non-enzymatic antioxidants.

Administration, Cutaneous↗
PubMed1998

Half-dose gadolinium-enhanced MR imaging with magnetization transfer technique in brain tumors: comparison with conventional contrast-enhanced MR imaging.

OBJECTIVE: The purpose of this study was to determine whether half-dose enhanced MR imaging with magnetization transfer (MT) saturation can replace standard-dose enhanced MR imaging without MT saturation in patients who have brain tumors. SUBJECTS AND METHODS: Three sets of enhanced T1-weighted MR images were prospectively obtained for each of 25 patients with 32 brain tumors; the first conventional MR images without MT were obtained after administration of standard-dose (0.1-mmol/kg) gadopentetate dimeglumine. Within 1 week, patients underwent administration of one half-dose (0.05 mmol/kg) of the contrast medium, and then two sets of enhanced T1-weighted images were obtained with and then without MT. The degree of contrast enhancement was assessed qualitatively for all 32 tumors and quantitatively for 26 tumors. In the quantitative analysis, we compared mean values for tumor-brain contrast-to-noise ratios in three sets of images. RESULTS: The visual conspicuity of enhancing lesions in half-dose T1-weighted MR images with MT was comparable with that of standard-dose conventional T1-weighted MR images in 43% of cases including most extraaxial tumors. In approximately 75% of cases, the degree of enhancement of the lesions was similar for half-dose T1-weighted images obtained with and without MT. Overall, mean values for tumor-brain contrast-to-noise ratios were significantly lower in half-dose T1-weighted images with MT than in standard-dose T1-weighted images. Also, mean values for tumor-brain contrast-to-noise ratios were significantly higher in half-dose T1-weighted images with MT than in half-dose T1-weighted images without MT. CONCLUSION: Because half-dose enhanced MR imaging with MT yields enhancement comparable with that of standard-dose enhanced conventional MR imaging in less than 50% of cases, the former technique would replace the latter in only limited cases such as selected extraaxial tumors.

Adult↗
PubMed1998

A case of type IIa early gastric cancer developed in pernicious anemia.

Pernicious anemia is an autoimmune disease characterized by a gastric mucosal defect which results in an insufficiency of intrinsic factor to facilitate the absorption of the physiologic amount of cobalamin. Increased risk of cancers of the stomach has been reported for patients with pernicious anemia. We report here a case of a 65 year old woman who had been diagnosed as having pernicious anemia 16 months previously, was receiving monthly vitamin B12 injections, and developed early gastric cancer type IIa by routine follow-up gastroscopic examination. This patient underwent endoscopic mucosal resection for an early gastric cancer lesion with a free resection margin.

Aged↗
PubMed1998

The CVC removal distress syndrome: an unappreciated complication of central venous catheter removal.

The removal of a central venous catheter (CVC) can be complicated by rare but potentially life-threatening neurocardiopulmonary distress. The clinical courses of eight patients who had CVC removal complications are reviewed. Seven patients had catheter removal from the right internal jugular vein, and one from the right subclavian vein. The complications occurred after complete removal of the catheter (four patients), after guidewire replacement for catheter change (three patients), and after detachment of the hemostasis side port of the Swan introducer during sheath removal (one patient). Each of them had more than one complication. The major complications were: neurologic paresis or coma (four patients), respiratory failure (four patients), and shock (two patients). One patient died of pulmonary sepsis. The overall mortality rate was 12.5 per cent. Guidelines for safe removal of central venous catheters are proposed. Possible mechanisms of the complications are discussed. We refer to the observed complications as the CVC removal distress syndrome.

Adult↗
PubMed1997

Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization.

Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders associated with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic reduction of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the xc- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric analysis of freshly prepared human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.

Animals↗