• Biomolecules & Therapeutics
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• v.6 no.4
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• pp.383-388
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• 1998

The present study was aimed to investigate the preventive effects of rebamipide on the multiple organ dysfunction in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS) in comparison with that of methotrexate. Endotoxemia for 6 hours resulted in little change in the levels of hemoglobin and neutrophils. However, treatment with methotrexate decreased significantly the numbers of circulating neutrophils. Significant increases in serum alanine aminotransferase (ALT,958 $\pm$ 250 lU/L, p<0.001) and aspartate aminotransferase (AST, 1350 $\pm$ 295 lU/L, p<0.001) levels induced by endotoxemia were significantly decreased by rebamipide and methotrexate. The increased level of lactic acid dehydrogenase (LDH) by LPS (2850 $\pm$ 467 lU/L, p<0.05) was significantly inhibited by rebamipide, but not by methot.elate. The elevated serum creatinine (1.2$\pm$0.1, p.0.05) and urea levels (55.3$\pm$6.5 mg/dL, p.0.01) by LPS were also decreased by rebamipide, but not by methotrexate. In line with these results, the plasma concentration of tumor necrosis factor-$\alpha$ (TNF-7,167 $\pm$ 20 pg/mL) was significantly increased upon injection of endotoxin at 1 hour by 1570$\pm$100 pg/mL, and declined to 312$\pm$35 pg/mL at 6 hours. The TNF-$\alpha$ level at 6 hours was significantly decreased by rebamipide to 207$\pm$8 pg/mL (P<0.05). Taken together, it is summarized that rebamipide inhibits the development of multiple ogran dysfunction by inhibition of neutrophil activation in association with inhibition of TNF-$\alpha$ formation in a murine model of endotoxemia.

• Journal of Cancer Prevention
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• v.21 no.2
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• pp.95-103
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• 2016

Background: Excess energy supply induces chronic low-grade inflammation in association with oxidative stress in various tissues including intestinal epithelium. The objective of this study was to investigate the effect of high-fat diet (HFD) on intestinal cell membrane integrity and intestinal tumorigenesis in $Apc^{Min/+}$ mice. Methods: Mice were fed with either normal diet (ND) or HFD for 12 weeks. The number of intestinal tumors were counted and biomarkers of endotoxemia, oxidative stress, and inflammation were determined. Changes in intestinal integrity was measured by fluorescein isothiocyanate (FITC)-dextran penetration and membrane gap junction protein expression. Results: HFD group had significantly higher number of tumors compared to ND group (P < 0.05). Blood total antioxidant capacity was lower in HFD group, while colonic 8-hydroxy-2'-deoxyguanosine level, a marker of oxidative damage, was higher in HFD group compared to that of ND group (P < 0.05). The penetration of FITC-dextran was substantially increased in HFD group (P < 0.05) while the expressions of membrane gap junction proteins including zonula occludens-1, claudin-1, and occludin were lower in HFD group (P < 0.05) compared to those in ND group. Serum concentration of lipopolysaccharide (LPS) receptor (CD14) and colonic toll-like receptor 4 (a LPS receptor) mRNA expression were significantly higher in HFD group than in ND group (P < 0.05), suggesting that significant endotoxemia may occur in HFD group due to the increased membrane permeability. Serum interleukin-6 concentration and myeloperoxidase activity were also higher in HFD group compared to those of ND group (P < 0.05). Conclusions: HFD increases oxidative stress disrupting intestinal gap junction proteins, thereby accelerating membrane permeability endotoxemia, inflammation, and intestinal tumorigenesis.

• The Korean Journal of Pharmacology
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• v.31 no.2
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• pp.233-239
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• 1995

To verify the effect of immunosuppressants on the endotoxin-induced increase in iNOS activity, the action of immunosuppressants, dexamethasone (1.5 mg/kg), azathioprine (5 mg/kg/day) and cyclosporine (10 mg/kg), were evaluated in mice pretreated with LPS. The intraperitoneal injection of lipopolysaccharide (10 mg/kg) increased the nitric oxide synthase (NOS) activity in the brain and liver to maximum at 1 and 3 hours, respectively. The increase in NOS activity was blocked by the treatment with NOS inhibitor, LNAME(300 mg/kg) and aminoguanidine(100 mg/kg); a protein inhibitor, cycloheximide (10 mg/kg); and a transcription inhibitor of inducible NOS(iNOS), dexamethasone(1.5 mg/kg). Immunosuppressants, azathioprine (5 mg/kg) and cyclosporine (10 mg/kg), effectively blocked the increase in NOS activity. These results suggest that iNOS expression plays an important role in LPS-induced the increase in NOS activity and that immunosuppressants can be used as candidate for therapeutic agents in endotoxemia.

• YAKHAK HOEJI
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• v.45 no.1
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• pp.16-22
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• 2001

Novel yakuchinone derivatives have been designed, synthesized and evaluated their inhibitory activity of NO production in lipopolysaccharide (LPS)-activated macrophages. From this study, some enone compounds have been found to be highly active in the assay. In view of the importance of NO in septic shock and inflammation, these compounds may be useful candidates for the development of new drug to treat endotoxemia and inflammation accompanying overproduction of NO.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.125.2-125.2
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• 2003

Hepatic ischemia and reperfusion predisposes the liver to secondary stresses such as endotoxemia possibly via dysregulation of the hepatic microcirculation secondary to imbalanced regulation of vascular stress gene. In this study, we determined the effect of endotoxin on hepatic vasoregulatory gene expression in response to hepatic ischemia and reperfusion (I/R). Rats were subjected to 90 min of hepatic ischemia and 6 h of reperfusion. Lipopolysaccharide (LPS, 1 mg/kg) was injected intraperitoneally after reperfusion. (omitted)

• Asian-Australasian Journal of Animal Sciences
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• v.24 no.6
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• pp.857-866
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• 2011

This study examined the metabolism of free radicals in hepatic mitochondria of goats induced by lipopolysaccharide (LPS), and investigated the effects of melatonin (MT). Forty-eight healthy goats ($10{\pm}1.2\;kg$) were randomly selected and divided into four groups: saline control, LPS, MT+LPS and MT. The goats within each group were3 sacrificed either 3 or 6 h after treatment and the livers removed to isolate mitochondria. The respiration control ratio (RCR), the ADP:O ratio, the oxidative phosphorylation ratio (OPR), the concentration of $H_2O_2$ and the activities of Complex I-IV were determined. The mitochondrial membrane potential ($\Delta\psi_m$) was analyzed by flow cytometry. The results showed that RCR, O/P and OPR of the LPS group decreased (p<0.05), as well as activities of respiratory complexes, whereas the generation of $H_2O_2$ in Complex III increased (p<0.05) after 3 h, while Complex II and III increased after 6 h. Also, it was found that the mitochondrial membrane potential of the LPS group declined (p<0.05). However, pre-treatment with MT attenuated the injury induced by LPS, which not only presented higher (p<0.05) RCR, O/P, OPR, and respiratory complex activities, but also maintained the $\Delta\psi_m$. Interestingly, it is revealed that, in the MT+LPS group, the generation of $H_2O_2$ increased firstly in 3 h, and then significantly (p<0.05).decreased after 6 h. In the MT group, the function of mitochondria, the transmenbrane potential and the generation of $H_2O_2$ were obviously improved compared to the control group. Conclusion: melatonin prevents damage caused by LPS on hepatic mitochondria of goats.

• Tuberculosis and Respiratory Diseases
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• v.70 no.5
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• pp.390-396
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• 2011

Background: Hyaluronan (HA) is an unbranched glycosaminoglycan. It has been proposed that HA acts as a vehicle for cytokines due to the strong negative charge on its surface. We hypothesized that HA would function like a cytokine scavenger and reduce the inflammatory signaling cascade and this would lead to improved survival in rats suffering with endotoxemia. Methods: Endotoxin (Salmonella, 10 mg/kg) or an equal amount of 0.9% NaCl (NS) was injected into the jugular vein of rats. HA (1,600 kDa, 0.35%) or NS was given at 0.1 mL/kg/h for 3 hours. HA or NS infusion was started at 4 hour after endotoxin injection. The rats were divided into the control and HA groups (n=16 for each group). The mean arterial pressure (MAP) was monitored during HA or normal saline infusion. Survival was assessed every 12 hours for 3 days throughout the experiment. Results: The survival rate (%) of the rats treated with HA was higher (60%) than that of the controls (20%) when HA was infused 4 hours after lipopolysaccharide (LPS) injection. The bronchoalveolar lavage (BAL) fluid of the animals surviving HA or NS infusion 4 hours after LPS showed that the total cell counts and number of neutrophils were significantly (p < 0.01) reduced in the HA treated groups compared with that of the controls (total cell count, $9.2{\times}10^4$/mL vs. $61{\times}10^4$/mL; neutrophils, $21{\times}10^4$/mL vs. $0.2{\times}10^4$/mL, respectively). There was no significant MAP difference between the HA or control groups either with or without endotoxin. Conclusion: Infusion of hyaluronan (1,600 kDa) reduced the BAL total cell count and the number of neutrophils and it improved the survival rate of the endotoxemic rats.

• Applied Microscopy
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• v.35 no.4
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• pp.84-90
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• 2005

Neutrophils that influx into the alveolar spaces from circulatory bloods play a important role in pathogenesis of acute lung injury. During the acute inflammatory phase, in order to investigate the acceleration of macrophage phagocytosis to the neutrophils is able to reduce the neutrophil-derived acute lung injury, endotoxemia was induced by insufflation of lipopolysaccharide intratracheally and organic germanium was injected intraperitoneally after endotoxin treatment. At 5 h after endotoxin treatment, lung weight and BAL protein concentration are significantly increased (p<0.001) compared to sham, and that was remarkedly decreased (p<0.001, p<0.01) by injection of germanium. In addition germanium treatment resulted to decreased the number of alveolar PMNs and to increase the percentage of engulfed neutrophils by alveolar macrophages. These observations indicate that organic germanium may have a role of reduction to neutrophil-derived acute lung injury in endotoxemia.

• Journal of Ginseng Research
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• v.22 no.3
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• pp.181-187
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• 1998

Nitric Oxide (NO), derived from L-arginine, is produced by two types (constitutive and inducible) of nitric oxide synthase (NOS). The NO produced in large amounts by the inducible NOS is known to be responsible for the vasodilation and hypotension observed in septic shock. We have found three polyacetylene compounds which inhibited the production of NO in LPS-activated RAW 264.7 cells. Their structures were identified as panauynol, ginsenoyne A and PQ-6 by the spec- troscopic analysis (IC50 values were 32.3 $\mu$M, 2.3 $\mu$M, 1.5 $\mu$M, respectively). These polyacetylenes may be useful candidates for the development of new drug to treat endotoxemia and inflammation accompanied by the overproduction of NO.

• Archives of Pharmacal Research
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• v.21 no.4
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• pp.481-484
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• 1998

In activated macrophages the inducible form of nitric oxide synthase (i-NOS) generates high amounts of toxic mediator, nitric oxide (NO) which contributes to the circulatory failure associated with septic shock. A sesquiterpene lactone compound (yomogin) isolated from medicinal plant Artemisia princeps Pampan inhibited the production of NO in LPS-activated RAW 264.7 cells by suppressing i-NOS enzyme expression. Thus, yomogin may be a useful candidate for the development of new drugs to treat endotoxemia and inflammation accompanied by the overproduction of NO.