Biomedical subjects

K X Liu

Publications and source records attributed to K X Liu.

At least 19 recordsLinked to original sources

PubMed2005

Formation of MTBE-DNA adducts in mice measured with accelerator mass spectrometry.

Methyl tert-butyl ether (MTBE) is a gasoline oxygenate and antiknock additive substituting for lead alkyls currently in use worldwide. Previous studies have shown that MTBE at very high doses induces tumors in rodents. The aim of the present study was to examine directly the binding ability of MTBE onto DNA, demonstrating its potential genotoxicity. MTBE-DNA adducts and their decay kinetics in mice have been measured by using doubly 14C-labeled MTBE with an advanced, ultrasensitive technique: accelerator mass spectrometry (AMS). It was found that MTBE definitely formed adducts with DNA in mouse lung, liver, and kidney in a log/log linear dose-response relationship. The distribution sequence of DNA adducts in these tissues is: lung > liver > kidney. The level of MTBE-DNA adducts peaked at 12 h postadministration in the lung and peaked at 6 h postadministration in the liver. Then the adducts declined rapidly until 5 days postadministration and thereafter declined much more slowly. To our knowledge, this is the first report on DNA adduction with MTBE in vivo. The mechanism of the formation of MTBE-DNA adducts also is discussed.

Animals↗

PubMed2003

Inhibition of nicotine-DNA adduct formation in mice by six dietary constituents.

Nicotine [3-(1-methyl-2-pyrrolidinyl)-pyridine] is a major alkaloid in tobacco products and has proven to be a potential genotoxic compound. Many natural dietary products can suppress the DNA adduction, and hence act as inhibitors of cancer. In this study, we investigated the inhibitory effects of curcumin, garlic squeeze, grapeseed extract, tea polyphenols, vitamin C, and vitamin E on nicotine-DNA adduction in vivo using an ultrasensitive method of accelerator mass spectrometry (AMS). The results demonstrated that all the dietary constituents induced marked dose-dependent decrease in nicotine-DNA adducts as compared with the control. The reduction rate reached about 50% for all agents, except garlic squeeze (40%), even at its highest dose level. Amongst the six agents, grapeseed extract exhibited the strongest inhibition to the DNA adduct formation. Therefore, we may arrive at a point that these dietary constituents are beneficial to prevent the harmful adduct formation, and thus to block the potential carcinogenesis induced by nicotine.

Animals↗

PubMed2000

Hydroxyprolylserine derivatives JBP923 and JBP485 exhibit the antihepatitis activities after gastrointestinal absorption in rats.

It has been a desire to develop orally effective therapeutic agents that restore the liver function in chronic injury. Here we demonstrated that trans-4-L-hydroxyprolyl-L-serine (JBP923) and cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485), which was previously isolated from hydrolysate of human placenta, exhibit potent antihepatitis activity after their oral administration. The increase in bilirubin concentration and activities of liver cytosolic enzymes in serum caused by alpha-naphthylisothiocyanate intoxication in rats were significantly countered both after i.v. and oral administration of these dipeptides, whereas glycyrrhizin, which has been used in the treatment of chronic hepatitis, is active only after its i.v. administration. Antihepatitis activity of dipeptides results, at least partially, from their direct effect on hepatocytes because glutamic-oxaloacetic transaminase and lactate dehydrogenase activities in the medium of hepatotoxin-exposed primary cultured hepatocytes were reduced by these compounds. When comparing the plasma concentration-time profile of JBP923 after its i.v., oral, and portal vein injection, it is suggested that JBP923 is almost completely absorbed from gastrointestinal lumen, and hepatic first-pass removal is minor. JBP923 inhibited the proton-dependent transport of glycylsarcosine in brush-border membrane vesicles, suggesting that peptide transport system(s) may recognize JBP923. Thus, these dipeptides are potent antihepatitis reagents that are still active after oral administration and may be useful for clinical applications.

1-Naphthylisothiocyanate↗

PubMed1999

Inhibitory effect of methylene blue-induced photooxidation on intimal thickening of vein graft.

BACKGROUND: We have previously speculated that methylene blue-induced photooxidation of adventitial surface for 5 minutes can completely inhibit the intimal and medial growth of surgically prepared saphenous vein in vitro. In this study, inhibitory effect of methylene blue-induced photooxidation on intimal thickening of vein graft in vivo was investigated. METHODS: Jugular vein grafts were photooxidized in 0.01% methylene blue solution for 5 minutes, and interposed into arterial circulation for 4 weeks in rabbits. Vein grafts were studied by morphometry and immunohistochemistry. RESULTS: The intimal thickening of photooxidized vein grafts were suppressed significantly compared with those in the nonphotooxidized group. Proliferated cell nuclear antigen (PCNA) index (total PCNA-positive cells/total cell count x 100%) of vein graft was significantly higher in the nonphotooxidized group than those in the photooxidized group. CONCLUSIONS: Methylene blue-induced photooxidation is effective in the inhibition of intimal thickening of vein graft interposed in the arterial circulation for 4 weeks in vivo.

Animals↗

PubMed1998

An effective method for improving hemostasis in aortic root replacement with a composite graft.

Hemostasis during aortic root replacement with a composite graft, consisting of a separate Dacron graft and a valve, was markedly improved by using a supra-annular aortic wall reinforcing suture (SAWR). Between February 1994 and January 1998, 14 consecutive patients (10 men and 4 women) underwent replacement of the aortic valve and ascending aorta with the SAWR technique. No intraoperative bleeding of the aortic proximal suture line or early death occurred in this group. No patient required reoperation for bleeding of anastomoses. Three of 10 patients who underwent elective operations were operated on successfully without blood transfusion. In addition, no clinical complications related to the SAWR technique were observed in the follow-up period. We conclude that the SAWR technique can be performed easily and may be an effective method for improving proximal hemostasis.

Aortic Dissection↗

PubMed1998

Inhibitory effect of photooxidation on intimal and medial thickening of saphenous vein.

BACKGROUND: The inhibitory effect of short-term photooxidation on medial and neointimal proliferation of human saphenous vein was investigated. METHODS: Culture medium-filled surgically prepared saphenous vein segments were photooxidized in 0.01% methylene blue solution for 5 minutes. Photooxidized and nonphotooxidized saphenous veins were checked for viability of endothelial cells by culturing vein segments for 21 days followed by histologic and immunohistochemical studies. RESULTS: Endothelial cells of saphenous vein segments remained unaffected after photooxidation. Both the intima and media of nonphotooxidized veins became highly cellular and thickened because of the proliferation and migration of smooth muscle cells. Like precultured fresh saphenous vein, intimal (0.031+/-0.017 mm; p=0.0067) and medial thicknesses (0.702+/-0.123 mm; p < 0.0001) and proliferating cell nuclear antigen-positive cell count (14+/-8/mm2; p=0.0005) of cultured photooxidized veins were significantly less than those of cultured nonphotooxidized veins (intimal thickness, 0.059+/-0.041 mm; medial thickness, 0.997+/-0.228 mm; proliferating cell nuclear antigen positive cell count, 34+/-16/mm2. CONCLUSIONS: Methylene blue-induced short-term photooxidation is effective in inhibition of intimal and medial thickening of saphenous vein.

Aged↗

PubMed1998

Ligand-induced downregulation of receptor-mediated clearance of hepatocyte growth factor in rats.

The change in tissue uptake clearance of 125I-labeled hepatocyte growth factor (HGF) after an intravenous injection of an excess (120 micrograms/kg) of unlabeled HGF was examined in rats. The heparin-washable component of the hepatic uptake clearance of 125I-HGF was only slightly changed, whereas the heparin-resistant component was significantly reduced 30 min after injection of excess HGF, followed by gradual recovery with a half-life of 3.2 h. Because the former clearance mainly represents 125I-HGF association with heparan sulfate proteoglycan on the cell surface and/or extracellular matrix, whereas the latter includes relatively specific clearance, such as receptor-mediated endocytosis, this result suggests that injection of excess HGF selectively causes downregulation of receptor-mediated HGF clearance in the liver. Downregulation could also be observed for HGF receptor density in isolated liver plasma membrane, assessed by Western blot analysis by means of anti-receptor antibody, 30 min after injection of excess unlabeled HGF, supporting the hypothesis that the overall elimination of HGF from the systemic circulation can be affected by a change in HGF receptor density on the liver cell surface.

Animals↗

PubMed1998

Protamine enhances the proliferative activity of hepatocyte growth factor in rats.

The effect of protamine on the proliferative activity of hepatocyte growth factor (HGF) was examined in alpha-naphthyl isothiocyanate-intoxicated rats. Protamine pre-injection increased the hepatocyte labeling index induced by HGF four- to fivefold. A similar effect was also observed in partially hepatectomized rats. Because a cell surface heparin-like substance can bind to HGF and protamine has an affinity for heparin, protamine may affect HGF pharmacokinetics. In fact, protamine injection caused a transient increase in plasma HGF concentrations after administration of HGF and, in vitro, protamine eluted HGF prebound to heparin-Sepharose. Protamine also reduced the plasma clearance of HGF and increased 2.5-fold the exposure of hepatocytes to HGF in vivo. The enhancing effect of protamine on the mitogenic response of hepatocytes to HGF was also observed in vitro (approximately 2-fold after protamine pretreatment compared with HGF alone), suggesting that the enhancing effect of protamine on HGF-induced liver regeneration results from dual effects exerted by protamine 1) lowering the overall elimination of HGF and 2) directly stimulating hepatocyte mitosis induced by HGF.

1-Naphthylisothiocyanate↗

PubMed1998

Human placental extract stimulates liver regeneration in rats.

The effect of human placental extract (HPE) on liver regeneration in rats was investigated. After intravenous administration of HPE to a-naphthylisothiocyanate (ANIT)-intoxicated rats, the labeling index in hepatocytes was significantly increased to a level 16.5 times higher than that of the control. A 1/500 dilution of HPE directly stimulated DNA synthesis of the hepatocytes in primary culture. HPE heated at 121 degrees C did not stimulate the labeling index in vivo or hepatocyte DNA synthesis in primary culture, suggesting that HPE contains heat-unstable but potent mitogens for hepatocytes. HPE contains hepatocyte growth factor (HGF), but the mitogenic effect of HPE cannot be explained by the effect exerted by HGF alone, since both the labeling index in vivo and hepatocellular DNA synthesis in vitro stimulated by HPE were much higher than those stimulated by HGF alone when the applied doses of HGF were set to be almost the same level between each case. When HPE was fractionated on a heparin-sepharose column, the mitogenic effect of HPE was found to be located mainly in the heparin-bound fraction. Hepatocyte DNA synthesis induced by this fraction was enhanced cooperatively by the heparin-unbound fraction, suggesting that there are some modulators in the heparin-unbound fraction which enhance the proliferative activity of the heparin-bound fraction by a synergetic mechanism. Both HPE and heated HPE completely recovered the biochemical marker activity for liver function (glutamic-pyruvic transaminase, GPT; alkaline phosphatase, ALP; lactate dehydrogenase, LAP; gamma-glutamyltransferase, gamma-GTP activities and the bilirubin concentration) almost to the control level in the serum of ANIT-intoxicated rats, indicating that HPE also contains a heat-stable fraction which repairs liver function.

Animals↗

PubMed1998

[Long-term results of patients undergone surgical repair for acute type A dissection].

We evaluated the long-term results of 28 operative survivors who underwent surgical repair for acute type A dissection. Residual dissection of the thoracic aorta was found in 21 patients (75.0%) postoperatively, and 6 of them underwent reoperation with no operative death. There were 2 late death; one died in the third operation for thoracoabdominal aorta and the other died of cancer. Two of 4 patients with Marfan's syndrome required total aortic replacement ultimately. Since the elective reoperation can be performed safely, careful follow-up and management is essential for the improved survival of the patients with residual aortic dissection.

Acute Disease↗

PubMed1997

Existence of two nonlinear elimination mechanisms for hepatocyte growth factor in rats.

Nonlinearity in the overall elimination of hepatocyte growth factor (HGF) was examined in rats. After intravenous administration, the plasma clearance (CLplasma) of HGF exhibited a dose-dependent biphasic reduction with high- and low-affinity components. If we consider our previous finding that both receptor-mediated endocytosis (RME) and a low-affinity uptake mechanism, probably mediated by heparan sulfate proteoglycan (HSPG), in the liver are major HGF clearance mechanisms, it may be that saturation of CLplasma at lower and higher doses represents saturation of RME and HSPG-mediated uptake, respectively. At an HGF dose (1.46 nmol/kg), which completely saturates the high-affinity component, CLplasma was almost completely reduced when HGF was premixed with heparin. However, CLplasma was reduced by heparin to, at most, one-fifth that after HGF alone in a dose near the linear range (3.66 pmol/kg). Saturation of CLplasma for HGF premixed with heparin was monophasic and nonlinear only at the lowest HGF doses. In vitro, high-affinity binding of [35S]heparin to HGF was found, showing that one HGF molecule binds to the penta- or hexasaccharide unit. Because mitogenic activity of HGF has been reported in the presence of heparin, these results suggest that heparin mainly inhibits low-affinity HGF uptake by complexing with HGF, whereas its effect on RME is relatively minor.

Animals↗

PubMed1995

Contribution of parenchymal and non-parenchymal liver cells to the clearance of hepatocyte growth factor from the circulation in rats.

PURPOSE: The distribution of 125I-hepatocyte growth factor (HGF) to either liver parenchymal cells (PC) or non-parenchymal cells (NPC) was investigated in rats. METHODS: After injection of a trace amount of 125I-HGF, the distribution of radioactivity determined by microautoradiography closely resembled that of 125I-epidermal growth factor which distributes mainly to PC. RESULTS: The uptake clearance of 125I-HGF estimated by determining the radioactivity of isolated liver cells was three times higher for PC than for NPC. This suggests that HGF distributes mainly to PC at relatively low doses. On the other hand, the uptake clearance by PC fell on coadministering an excess (80 micrograms/kg) of unlabeled HGF, while no change was observed for NPC, indicating that a saturable process for the hepatic handling of HGF exists only in PC where the HGF receptor is expressed. CONCLUSIONS: At such a dose the uptake clearance was comparable for both PC and NPC showing that HGF distributes to both cell types although NPC have few HGF receptors. Since the distribution to NPC was relatively non-specific and heparin-sensitive, it may be that heparin-like substances, which are believed to exist on PC and/or the extracellular matrix, also exist on NPC.

Animals↗

PubMed1995

Change in hepatic handling of hepatocyte growth factor during liver regeneration in rats.

The change in the hepatic uptake clearance of hepatocyte growth factor (HGF) during liver regeneration in rats was examined. The hepatic uptake clearance per gram liver of 125I-labeled HGF in vivo decreased to a minimum level only 15 min after partial hepatectomy (PH). In the perfused liver, in which the effect of endogenous substances can be ignored, the hepatic uptake clearance of 125I-HGF did not change until at least 3 h after PH, suggesting that the decrease in the clearance in vivo is caused by some endogenous inhibitors. Such a decrease in the clearance cannot be explained only by the elevated endogenous HGF concentration in plasma. In addition, at 48 h after PH the decrease in hepatic uptake clearance was comparable for in vivo and perfused liver (approximately 50 and 60% reduction, respectively), suggesting that the decreased hepatic clearance in vivo at that time was caused mainly by reduction in the binding and/or uptake by the liver itself. In addition, the hepatic uptake clearance of 125I-HGF at that time in the presence of an excess (135 pM) of unlabeled HGF was comparable with that of the control, indicating that only the saturable portion of hepatic uptake clearance is reduced. The internalization rate constant representing the probability of cell surface-bound 125I-HGF being internalized per unit time increased to three times that of the control at 15 min after PH, demonstrating that the internalization of HGF is enhanced immediately after the start of liver regeneration.

Animals↗

PubMed1995

[Effect of acupuncture on heart rate variability in coronary heart disease patients].

The heart rate variability (HRV) of 20 coronary heart disease patients has been determined before and after acupuncture treatment by using frequency domain analysis of HRV. The results showed that there was significant difference between the change of low frequency (LF) components in HRV before and after manipulatory acupuncturing Neiguan group and electro-acupuncturing Neiguan group (P < 0.05), while there was no significant difference in the control group (P > 0.05), also no significant difference on the change of high frequency (HF) components in HRV before and after acupuncture in both groups. In the electro-puncturing group, the LF/HF change was marked (P < 0.05). And in manipulatory acupuncturing group, the value of LF reduced to the lowest level 10 minutes after acupuncture treatment, and then gradually restored 20 to 30 minutes later, without any rebound phenomenon. It suggested that acupuncture could regulate and improve HRV in coronary heart disease patients. Its mechanism might be relevant to the central regulation and neurotransmitter participation.

Acupuncture Therapy↗

PubMed1994

Antigen expression in normal and neoplastic canine tissues defined by a monoclonal antibody generated against canine mesothelioma cells.

Monoclonal antibody (MAb) 3B5 generated against canine mesothelioma cells was applied to canine tumors and normal tissues via immunohistochemical and immunoblotting techniques to evaluate antigen binding. By use of an avidin-biotin immunoperoxidase complex (ABC) method, immunoreactivity was noted in reactive mesothelial cells and in normal tissues was observed primarily in mesothelial cell linings, endothelial cells, and smooth muscle of blood vessels and soft tissues; the reactivity was nearly equivalent in frozen or formalin-fixed, paraffin-embedded tissue sections. Use of the ABC method on formalin-fixed, paraffin-embedded tumors yielded moderate to strong cytoplasmic immunostaining of neoplastic cells in 10/11 (91%) mesotheliomas, 18/23 (78%) hemangiosarcomas, 4/10 (40%) intestinal and lung carcinomas, and < or = 20% of hemangiomas, leiomyosarcomas, leiomyomas, mammary carcinomas, and squamous cell carcinomas. No immunostaining of tumor cells was observed in fibrosarcomas, hemangiopericytomas, perianal gland carcinomas, and melanomas. Immunoblotting was performed on samples that demonstrated strong immunoreactivity with MAb 3B5 by the ABC method: mesothelioma, hemangiosarcoma, urinary bladder (smooth muscle), and lung (alveolar capillaries). These analyses showed that MAb 3B5 bound a major antigen of 78 kilodaltons (kd) and minor antigens at 56 and 54 kd in normal and neoplastic tissues. The preliminary immunohistochemical results suggest that MAb 3B5 may possess utility in diagnosis of mesotheliomas and hemangiosarcomas, discrimination of cell types in proliferative serosal lesions, and demonstration of vascularity or angiogenesis in neoplastic and inflammatory lesions.

Animals↗

PubMed1994

Heparin-hepatocyte growth factor complex with low plasma clearance and retained hepatocyte proliferating activity.

Because hepatocyte growth factor is known to have affinity for heparin, we studied the binding isotherm and found that hepatocyte growth factor has a high-affinity binding site for 35S-heparin with an equilibrium dissociation constant of approximately 0.6 nmol/L. We then analyzed the pharmacokinetic behavior of the heparin-hepatocyte growth factor complex in rats. The area under the plasma concentration-time profiles of trichloroacetic acid-precipitable radioactivities from 0 to 30 min after the intravenous administration of the heparin-125I-hepatocyte growth factor complex was approximately three times that after the administration of 125I-hepatocyte growth factor only. Because we previously demonstrated that the liver is the major clearance organ for hepatocyte growth factor, the hepatic uptake of 125I-hepatocyte growth factor and the heparin-125I-hepatocyte growth factor complex was compared. The liver-to-plasma concentration ratio after the intravenous administration of the complex was half that after the administration of 125I-hepatocyte growth factor only. Furthermore, the steady state hepatic extraction ratio of 125I-hepatocyte growth factor in perfused rat liver decreased depending on the heparin concentration. In addition, the biological activity of the complex was examined by assessing the 125I-deoxyuridine incorporation in cultured rat hepatocytes. Although the half-effective concentration of hepatocyte growth factor increased slightly--namely, two to three times in the presence of heparin compared with that in its absence--the maximal activity was not changed. We conclude that the heparin-hepatocyte growth factor complex, which retains biological activity, exhibits much lower clearances for hepatic uptake and plasma disappearance than hepatocyte growth factor itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Decrease in the hepatic clearance of hepatocyte growth factor in carbon tetrachloride-intoxicated rats.

To examine whether a decrease in hepatic uptake, clearance or both of hepatocyte growth factor contributes to increased plasma hepatocyte growth factor levels, we kinetically analyzed hepatic hepatocyte growth factor handling using rats with carbon tetrachloride-induced liver injury in both in vivo and perfused liver systems. After the intravenous administration of tracer 125I-hepatocyte growth factor, the time profile of trichloroacetic acid-precipitable 125I-hepatocyte growth factor was analyzed, and tissue clearance and total body plasma clearance were determined. For the tissues examined (liver, kidney, lung, spleen and adrenal), liver and adrenal clearance of 125I-hepatocyte growth factor decreased significantly. It was found that the hepatic clearance explains the bulk of the total body plasma clearance. The hepatic clearance and the total body clearance decreased to minimums (approximately 40% of control) 24 hr after carbon tetrachloride administration and recovered to near-control values over a 6-day period. At 24 hr after carbon tetrachloride administration, a single-pass liver perfusion of 125I-hepatocyte growth factor was performed, and its results were compared with the control results. After a 15-min perfusion of 125I-hepatocyte growth factor, we washed the liver sequentially with heparin and then with acid buffer to separately determine the cell-surface-bound and internalized 125I-hepatocyte growth factor. In carbon tetrachloride-intoxicated rats, both the acid-washable binding and the internalized 125I-hepatocyte growth factor dropped to almost half of the control values, but the decrease in heparin-washable binding was minimal. In contrast, when 125I-hepatocyte growth factor was perfused with excess unlabeled hepatocyte growth factor (135 pmol/L), mostly saturating the cell-surface receptors, the change in cell-surface-bound 125I-hepatocyte growth factor and internalized 125I-hepatocyte growth factor in carbon tetrachloride-intoxicated rats was minimal. This finding, along with our previous finding that the cell-surface hepatocyte growth factor receptors are greatly down-regulated in carbon tetrachloride-intoxicated rats, suggests that the hepatic clearance of hepatocyte growth factor through receptor-mediated endocytosis decreases in carbon tetrachloride-intoxicated rats. The decrease in the hepatic clearance of hepatocyte growth factor could be one of the causes of the elevated hepatocyte growth factor level in the circulating blood in liver diseases.

Animals↗

PubMed1992

Importance of the liver in plasma clearance of hepatocyte growth factors in rats.

After intravenous administration of 125I-labeled hepatocyte growth factor (HGF), trichloroacetic acid-precipitable radioactivity in the plasma disappeared rapidly with an early phase half-life of 4 min. The amounts of 125I-HGF distributed to the liver, adrenal, spleen, kidney, and lung tissues were much greater than those that could be accounted for by distribution to the extracellular space alone. The first-pass removal of 125I-HGF by the liver was approximately 26%; the liver accounted for approximately 70% of early-phase removal. The hepatic handling was also analyzed using a single-pass perfused liver system. The steady-state extraction ratio of tracer 125I-HGF was 0.48 but dropped to 0.23 in the presence of excess HGF (135 pM), demonstrating hepatic removal saturation of HGF. In the presence of excess HGF, the heparin-washable 125I-HGF, the heparin-resistant and acid-washable 125I-HGF, and the internalized 125I-HGF dropped to 54, 31, and 32% of the control values. The presence of at least two binding sites for HGF on the liver cell surfaces was made clear: the heparin-washable site and the heparin-resistant and acid-washable binding site, considered to have higher affinity for HGF. The internalization of 125I-HGF was observed to some extent even in the presence of excess HGF and phenylarsine oxide, known to be an inhibitor of polypeptides receptor-mediated endocytosis, suggesting the contribution of a relatively nonspecific internalization mechanism as well as receptor-mediated endocytosis.

Animals↗