Rotundarpene inhibits TNF-α-induced activation of the Akt, mTOR, and NF-κB pathways, and the JNK and p38 associated with production of reactive oxygen species.

Ilex Rotunda Thunb has been shown to have anti-inflammatory and antioxidant effects. In human keratinocytes, we investigated the effect of rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the TNF-α-stimulated production of inflammatory mediators in relation to the Akt, mTOR, and NF-κB pathways, and the JNK and p38-MAPK. Rotundarpene, Akt inhibitor, Bay 11-7085, rapamycin, and N-acetylcysteine inhibited the TNF-α-stimulated production of cytokines and chemokines, increase in the levels of p-Akt and mTOR, activation of NF-κB, and production of reactive oxygen species in keratinocytes. TNF-α treatment induced phosphorylation of the JNK and p38-MAPK. Inhibitors of the c-JNK (SP600125) and p38-MAPK (SB203580) reduced the TNF-α-induced production of inflammatory mediators, binding of NF-κB to DNA, and activation of the JNK and p38-MAPK in keratinocytes. The results show that rotundarpene may reduce the TNF-α-stimulated inflammatory mediator production by suppressing the reactive oxygen species-dependent activation of the Akt, mTOR, and NF-κB pathways, and activation of the JNK and p38-MAPK in human keratinocytes. Additionally, rotundarpene appears to attenuate the Akt, mTOR, and NF-κB pathways and the JNK and p38-MAPK-mediated inflammatory skin diseases.

Lamotrigine Attenuates Proteasome Inhibition-Induced Apoptosis by Suppressing the Activation of the Mitochondrial Pathway and the Caspase-8- and Bid-Dependent Pathways.

Proteasome impairment has been shown to be involved in neuronal degeneration. Antiepileptic lamotrigine has been demonstrated to have a neuroprotective effect. However, the effect of lamotrigine on the proteasome inhibition-induced neuronal cell death has not been studied. Therefore, we assessed the effect of lamotrigine on the proteasome inhibition-induced neuronal cell apoptosis in relation to cell death process using differentiated PC12 cells and SH-SY5Y cells. The proteasome inhibitors MG132 and MG115 induced a decrease in the levels of Bid and Bcl-2 proteins, an increase in the levels of Bax and p53, loss of the mitochondrial transmembrane potential, cytochrome c release and activation of caspases (-8, -9 and -3). The addition of lamotrigine reduced the proteasome inhibitor-induced changes in the apoptosis-related protein levels, production of reactive oxygen species, depletion and oxidation of glutathione (GSH), and cell death in both cell lines. Lamotrigine and N-acetylcysteine alone did not affect the levels of 26S proteasome and activity of 20S proteasome. MG132 did not alter the levels of 26S proteasome but decreased activity of 20S proteasome. Lamotrigine and N-acetylcysteine attenuated MG132-induced decrease in the activity of 20S proteasome. The results show that lamotrigine appears to suppress the proteasome inhibitor-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The suppressive effect of lamotrigine appears to be associated with its inhibitory effect on the production of reactive oxygen species, the depletion and oxidation of GSH and the activity reduction of 20S proteasome.

Apigenin Reduces Proteasome Inhibition-Induced Neuronal Apoptosis by Suppressing the Cell Death Process.

Impairment of proteasomal function has been shown to be implicated in neuronal cell degeneration. The compounds which have antioxidant and anti-inflammatory abilities appear to provide a neuroprotective effect. Flavone apigenin is known to exhibits antioxidant and anti-inflammatory effects. Nevertheless, the effect of apigenin on the proteasome inhibition-induced neuronal apoptosis has not been studied. Therefore, we assessed the effect of apigenin on the proteasome inhibition-induced apoptotic neuronal cell death using differentiated PC12 cells and human neuroblastoma SH-SY5Y cells. Apigenin attenuated the proteasome inhibitors (MG132 and MG115)-induced decrease in the levels of Bid and Bcl-2, increase in the levels of Bax and p53, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9 and -3), cleavage of PARP-1 and cell death in both cell lines. Apigenin attenuated the production of reactive oxygen species, the depletion and oxidation of glutathione, the formations of malondialdehyde and carbonyls in cell lines treated with proteasome inhibitors. The results show that apigenin appears to attenuate the proteasome inhibitor-induced apoptosis in differentiated PC12 cells and SH-SY5Y cells by suppressing the activation of the mitochondrial pathway, and of the caspase-8- and Bid-dependent pathways. The inhibitory effect of apigenin on the proteasome inhibitor-induced apoptosis appears to be attributed to the suppressive effect on the production of reactive oxygen species, the depletion and oxidation of glutathione and the formations of malondialdehyde and carbonyls.

Flavanonol taxifolin attenuates proteasome inhibition-induced apoptosis in differentiated PC12 cells by suppressing cell death process.

The proteasomal dysfunction and mitochondrial impairment has been implicated in neuronal degeneration. Taxifolin has antioxidant and anti-inflammatory effects. However, the effect of taxifolin on the neuronal cell death induced by proteasome inhibition has not been studied. Therefore, in the respect of cell death process, we assessed the effect of taxifolin on the proteasome inhibition-induced apoptosis in neuronal cell injury using differentiated PC12 cells. The proteasome inhibitors MG132 and MG115 induced a decrease in Bid, Bcl-2, and survivin protein levels, an increase in Bax, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases(-8, -9 and -3), an increase in the tumor suppressor p53 levels and cleavage of PARP-1. The addition of taxifolin attenuated the proteasome inhibitor-induced changes in the apoptosis-related protein levels, formation of reactive oxygen species, depletion and oxidation of GSH, formations of malondialdehyde and carbonyls, and cell death. The results show that taxifolin may attenuate the proteasome inhibitor-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect of taxifolin appears to be attributed to its inhibitory effect on the formation of reactive oxygen species, and depletion and oxidation of GSH.

3,4,5-Tricaffeoylquinic Acid Attenuates TRAIL-induced Apoptosis in Human Keratinocytes by Suppressing Apoptosis-related Protein Activation.

Caffeoyl derivatives exhibit antiinflammatory and antioxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in keratinocytes that may be involved in skin diseases has not been studied. In this respect, we investigated the effect of 3,4,5-tricaffeoylquinic acid on TRAIL-induced apoptosis in human keratinocytes. 3,4,5-Tricaffeoylquinic acid and oxidant scavengers attenuated the decrease in the cytosolic levels of Bid, Bcl-2, and survivin proteins; the increase in the levels of cytosolic Bax, p53, and phosphorylated p53; the increase in the levels of phosphorylated p38; the increase in the mitochondrial levels of the voltage-dependent anion channel; loss of the mitochondrial transmembrane potential; the release of cytochrome c; activation of caspases (8, 9, and 3); cleavage of poly [ADP-ribose] polymerase-1; production of reactive oxygen species; the depletion of glutathione (GSH); nuclear damage; and cell death in keratinocytes treated with TRAIL. These results suggest that 3,4,5-tricaffeoylquinic acid may reduce TRAIL-induced apoptosis in human keratinocytes by suppressing the activation of the caspase-8 and Bid pathways and the mitochondria-mediated cell death pathway. The effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH. 3,4,5-Tricaffeoylquinic acid appears to be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases.

3,4,5-tricaffeoylquinic acid attenuates proteasome inhibition-mediated programmed cell death in differentiated PC12 cells.

The dysfunction of the proteasome system is suggested to be implicated in neuronal degeneration. Caffeoylquinic acid derivatives have demonstrated anti-oxidant and anti-inflammatory effects. However, the effect of 3,4,5-tricaffeoylquinic acid on the neuronal cell death induced by proteasome inhibition has not been studied. Therefore, in the respect of cell death process, we assessed the effect of 3,4,5-tricaffeoylquinic acid on the proteasome inhibition-induced programmed cell death using differentiated PC12 cells. The proteasome inhibitors MG132 and MG115 induced a decrease in Bid, Bcl-2, and survivin protein levels, an increase in Bax, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3), and an increase in the tumor suppressor p53 levels. Treatment with 3,4,5-tricaffeoylquinic acid attenuated the proteasome inhibitor-induced changes in the programmed cell death-related protein levels, formation of reactive oxygen species, GSH depletion and cell death. The results show that 3,4,5-tricaffeoylquinic acid may attenuate the proteasome inhibitor-induced programmed cell death in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect of 3,4,5-tricaffeoylquinic acid appears to be attributed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH.

Hemolytic anemia case caused by an inverted inner felt after bentall operation.

A 26-yr-old male patient reported worsened dyspnea, dizziness one year after an emergency Bentall operation for type A aortic dissection. There was evidence of hemolytic anemia and aortogram revealed a significant stenosis at the distal anastomosis site. During the reoperation, we found the inner felt at the distal anastomosis was inverted causing a significant stenosis. The reoperation successfully resolved this problem. Here, we report a rare case of hemolytic anemia caused by an inverted inner felt after Bentall operation.

The effects of barrier materials on reduction of pericardial adhesion formation in rabbits: a comparative study of a hyaluronan-based solution and a temperature sensitive poloxamer solution/gel material.

OBJECTIVE: This study was performed to examine the efficacy and safety of a hyaluronan solution (Guardix-SL) and a temperature sensitive poloxamer solution/gel material (Guardix-SG) on the prevention of pericardial adhesion in rabbits. METHODS: A total of 60 rabbits were divided into three groups according to material applied after epicardial abrasion: the control group (group CO), the Guardix SL group (group SL), and the Guardix SG group (group SG). The ejection fraction and the presence of pericardial effusion were evaluated by echocardiograms at the immediate postoperative period and 2 wk after the surgery. The adhesion was evaluated macroscopically and microscopically 2 wk after the surgery. RESULTS: In the group SG, mild pericardial effusions were observed only at the immediate postoperative period in 10 out of 20 rabbits with an insignificant reduction of the ejection fraction. Group CO had a significantly higher macroscopic adhesion and fibrosis score than did groups SL and SG (P < 0.001), and group SL had a significantly higher adhesion score than did group SG (P = 0.045). Inflammation score and the expression of anti-macrophage antibody in group CO were higher than those in groups SL and SG, although the differences were not significant. CONCLUSIONS: Guardix-SL and Guardix-SG effectively reduced the adhesion formation, and Guardix-SG is more effective than Guardix-SL for preventing adhesion. However, Guardix-SG showed a potential disadvantage of decreasing the ejection fraction, although this was statistically insignificant. Further study to verify the appropriate dosage to maximize the therapeutic effect without decreasing the heart function is needed.

Is Stopping Heparin Safe in Patients on Extracorporeal Membrane Oxygenation Treatment?

Anticoagulation treatment during extracorporeal membrane oxygenation (ECMO) treatment is unavoidable. However, discontinuation of heparin infusion is necessary when challenges associated with the use of heparin, such as bleeding and thrombocytopenia, are encountered. The medical records of 94 adult (age ≥ 18 years) patients treated with ECMO from January 2011 to March 2015, at Chung-Ang University Hospital, Seoul, Korea, were reviewed. Among the 94 patients, 55 patients underwent ECMO treatment for three or more days. In 52.7% of these patients (n = 29, group A), heparin was stopped for three or more days because of thrombocytopenic events (< 50,000 cells/mm), higher than target range (> 230 seconds) activated clotting time (ACT), bleeding complications, or the need for other surgical procedures. In 43.6% of patients (n = 24, group B), heparin was continuously infused during the entire ECMO process. The mean length of ECMO support after the initiation of heparin discontinuation in patients in group A was 10.2 ± 14.7 days. There were no intracardiac, intravascular, or intracircuit thrombotic complications in group A. There was no difference in the ECMO weaning success rate between the two groups (41.4% in group A vs. 54.2% in group B, p = 0.353). Heparin discontinuation can be considered in a select group of patients with coagulation abnormalities or bleeding.

Apocynin inhibits Toll-like receptor-4-mediated activation of NF-κB by suppressing the Akt and mTOR pathways.

Microbial product lipopolysaccharide has been shown to be involved in the pathogenesis of inflammatory skin diseases. Apocynin has demonstrated to have an anti-inflammatory effect. However, the effect of apocynin on the Toll-like receptor-4-dependent activation of Akt, mammalian target of rapamycin (mTOR), and nuclear factor (NF)-κB pathway, which is involved in productions of inflammatory mediators in keratinocytes, has not been studied. Using human keratinocytes, we investigated the effect of apocynin on the inflammatory mediator production in relation to the Toll-like receptor-4-mediated-Akt/mTOR and NF-κB pathways, which regulates the transcription genes involved in immune and inflammatory responses. Apocynin, Akt inhibitor SH-5, Bay 11-7085 and N-acetylcysteine each attenuated the lipopolysaccharide-induced production of cytokines, PGE2, and chemokines, changes in the levels of Toll-like receptor-4, p-Akt, mTOR, and NF-κB, and production of reactive oxygen species in keratinocytes. The results show that apocynin appears to attenuate the lipopolysaccharide-stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll-like receptor-4-mediated activation of the Akt, mTOR, and NF-κB pathways. The effect of apocynin appears to be attributed to its inhibitory effect on the production of reactive oxygen species. Apocynin appears to attenuate the microbial product-mediated inflammatory skin diseases.

Immunohistochemical study on the distribution of neuronal nitric oxide synthase-immunoreactive neurons in the spinal cord of aged rat.

Despite in vivo studies suggesting an important function for nitric oxide (NO) in the spinal cord in the transmission of pain signals, sympathetic nerve activity and presumably other spinal functions, changes of neuronal NO synthase (nNOS)-containing neurons with aging in the spinal cord has not been investigated. In the present study, we demonstrated for the first time that the number of nNOS-immunoreactive neurons was significantly decreased in the central autonomic nucleus and the superficial dorsal horn of spinal cord in aged rats. Morphologically, the number and length of dendritic branches also seemed to be decreased. Combined with our previous studies, age-related decreases in the number of nNOS-immunoreactive neurons in the central autonomic nucleus and the superficial dorsal horn might be associated with the abnormality of micturition function or pain perception encountered in the elderly. However, the mechanisms underlying the decreased immunoreactivity for nNOS, and the functional implications require elucidation.

Rotundarpene attenuates cholesterol oxidation product-induced apoptosis by suppressing the mitochondrial pathway and the caspase-8- and bid-dependent pathways.

The extract of from the barks of Ilex Rotunda Thunb has demonstrated anti-inflammatory and anti-oxidant effects. Nevertheless, the effect of rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the neuronal cell death induced by cholesterol oxidation products is unclear. We assessed the preventive effect of rotundarpene on the cholesterol oxidation product-induced apoptosis in neuronal cells using differentiated PC12 cells. 7-Ketocholesterol and 25-hydroxycholesterol induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels, increase in Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3), cleavage of PARP-1 and an increase in the tumor suppressor p53 levels. Rotundarpene attenuated the cholesterol oxidation product-induced changes in the apoptosis-related protein levels, formation of reactive oxygen species, depletion of GSH, nuclear damage and cell death. The results show that rotundarpene may attenuate the cholesterol oxidation product-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect appears to be attributed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH. Rotundarpene appears to attenuate cholesterol-oxidation product-mediated neuronal degeneration.

Menadione induces the formation of reactive oxygen species and depletion of GSH-mediated apoptosis and inhibits the FAK-mediated cell invasion.

Menadione induces apoptosis in tumor cells. However, the mechanism of apoptosis in ovarian cancer cells exposed to menadione is not clear. In addition, it is unclear whether menadione-induced apoptosis is mediated by the depletion of glutathione (GSH) contents that is associated with the formation of reactive oxygen species. Furthermore, the effect of menadione on the invasion and migration of human epithelial ovarian cancer cells has not been studied. Therefore, we investigated the effects of menadione exposure on apoptosis, cell adhesion, and cell migration using the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. The results suggest that menadione may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of menadione appears to be mediated by the formation of reactive oxygen species and the depletion of GSH. Menadione inhibited fetal-bovine-serum-induced cell adhesion and migration of OVCAR-3 cells, possibly through the suppression the focal adhesion kinase (FAK)-dependent activation of cytoskeletal-associated components. Therefore, menadione might be beneficial in the treatment of epithelial ovarian adenocarcinoma and combination therapy.

Clinical manifestations and treatment outcomes of pulmonary aspergilloma.

BACKGROUND: Pulmonary aspergilloma usually results from the ingrowth of colonized Aspergillus from a damaged bronchial tree, a pulmonary cyst, or from the cavities of patients with underlying lung diseases. In the present study, we analyzed the clinical features, diagnostic methods, and managements of 36 patients with pulmonary aspergilloma. METHODS: Thirty-six patients were diagnosed as having pulmonary aspergilloma at Chung-Ang University Hospital between February 1988 and February 2000. Their medical records were reviewed retrospectively. RESULTS: The age of patients (median +/- SD) was 53.3 +/- 11.8 years, the male to female ratio was 2.36:1, and the most frequent symptom was hemoptysis, which occurred in 24 patients (65%). The most common underlying disease was pulmonary tuberculosis (81%), and the upper lobes of both lungs were the most frequently involved sites. Nine patients received a chest CT in the prone position and seven of these showed a movable fungus ball. Eleven patients were positive for the precipitin antibody to A. fumigatus. Twenty patients underwent surgical resection, and post-operative complications were reported in seven cases. The post-operative mortality was 5.6% (2/36). CONCLUSION: Pulmonary aspergilloma usually develops in the patients with underlying lung diseases. Resectional lung surgery is considered the mainstay of therapy for pulmonary aspergilloma. However, this operation is associated with significant complications and death in some cases. Therefore, it is necessary to develop reasonable criteria for selection of candidates for such surgery.