Min Sung Lee

Quercetin-3-O-(2″-galloyl)-α-l-rhamnopyranoside inhibits TNF-α-activated NF-κB-induced inflammatory mediator production by suppressing ERK activation.

Quercetin and its derivatives have anti-inflammatory and anti-oxidant effects. However, the effect of quercetin-3-O-(2″-galloyl)-α-l-rhamnopyranoside (QGR), a new quercetin derivative, on the tumor necrosis factor (TNF)-α-stimulated production of inflammatory mediators in keratinocytes is unclear. In addition, the effect of QGR on the ERK and NF-κB-mediated inflammatory process has not been studied. In human keratinocyte HaCat cells, we investigated the effect of QGR on the TNF-α-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-κB, which regulates the transcription genes involved in immune and inflammatory responses. QGR inhibited the TNF-α-stimulated production of cytokines and chemokines in HaCaT cells. QGR, dexamethasone, cyclosporine A, Bay 11-7085 (an inhibitor of NF-κB activation) and cell signaling ERK inhibitor attenuated the TNF-α-induced formation of inflammatory mediators and activation of the NF-κB and ERK. Unlike other compounds, dexamethasone and cyclosporine A did not reduce formation of reactive oxygen species. The results show that QGR may attenuate TNF-α-stimulated inflammatory mediator production in HaCaT cells by suppressing the activation of the ERK-mediated NF-κB pathway that is mediated by reactive oxygen species. Additionally, QGR may exhibit a preventive effect against the proinflammatory mediator-induced skin diseases by inhibiting the activation of the ERK and NF-κB pathways.

Rotundarpene inhibits Toll-like receptor 2 activation-induced production of inflammatory mediators in keratinocytes by suppressing the Akt and NF-κB pathways

Microbial components have been shown to be involved in the pathogenesis of inflammatory skin diseases. The extract of from the barks of Ilex rotunda Thunb has demonstrated anti-inflammatory and anti-oxidant effects. However, the effect of hemiterpene rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the Toll-like receptor (TLR)-2 activation-induced production of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we investigated the effect of rotundarpene on the inflammatory mediator production in relation to the TLR-2-mediated-Akt and NF-κB pathways, which regulates the transcription genes involved in immune and inflammatory responses. Rotundarpene, Akt inhibitor, Bay 11-7085 and N-acetylcysteine each attenuated the lipoteichoic acid- or peptidoglycan-induced production of cytokines and chemokines, expression of TLR-2, activation of NF-κB and Akt, and formation of reactive oxygen species in keratinocytes. Cyclosporine A attenuated the bacterial component-induced production of inflammatory mediators but did not reduce the formation of reactive oxygen species. The results show that rotundarpene may attenuate the bacterial component-stimulated production of inflammatory mediators in keratinocytes by suppressing the TLR-2-mediated activation of the Akt and NF-κB pathways. The effect of rotundarpene may be attributed to its inhibitory effect on the formation of reactive oxygen species. Rotundarpene may exert a preventive effect against the bacterial component-mediated inflammatory skin diseases.

Sesquiterpene lactone parthenolide attenuates production of inflammatory mediators by suppressing the Toll-like receptor-4-mediated activation of the Akt, mTOR, and NF-κB pathways

Microbial product lipopolysaccharide has been shown to be involved in the pathogenesis of inflammatory skin diseases. Parthenolide present in extracts of the herb feverfew has demonstrated an anti-inflammatory effect. However, the effect of parthenolide on the Akt/mTOR and NF-κB pathway activation-induced productions of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we investigated the effect of parthenolide on the inflammatory mediator production in relation to the Toll-like receptor-4-mediated-Akt/mTOR and NF-κB pathways, which regulate the transcription genes involved in immune and inflammatory responses. Parthenolide, Akt inhibitor, Bay 11–7085, and N-acetylcysteine each attenuated the lipopolysaccharide-induced production of IL-1β and PGE2, increase in the levels of cyclooxygenase, formation of reactive oxygen species, increase in the levels of Toll-like receptor-4, and activation of the Akt/mTOR and NF-κB in keratinocytes. The results show that parthenolide 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 activation of signaling transduction pathways appear to be regulated by reactive oxygen species. Parthenolide appears to attenuate the microbial product-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.

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.

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.

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.

KATP channel block prevents proteasome inhibitor-induced apoptosis in differentiated PC12 cells

Dysfunction of the proteasome system has been suggested to be implicated in neuronal degeneration. Modulation of KATP channels appears to affect the viability of neuronal cells exposed to toxic insults. However, the effect of KATP channel blockers on the neuronal cell death mediated by proteasome inhibition has not been studied. The present study investigated the effect of KATP channel blockers on proteasome inhibitor-induced apoptosis in differentiated PC12 cells and SH-SY5Y cells. 5-Hydroxydecanoate (a selective KATP channel blocker) and glibenclamide (a cell surface and mitochondrial KATP channel inhibitor) reduced the proteasome inhibitor-induced apoptosis. Addition of the KATP channel blockers attenuated the proteasome inhibitor-induced changes in the levels of apoptosis-related proteins, the loss of the mitochondrial transmembrane potential, the increase in the formation of reactive oxygen species and the depletion of glutathione in both cell lines. The results show that KATP channel blockers may attenuate proteasome inhibitor-induced apoptosis in PC12 cells by suppressing activation of the mitochondrial pathway and of the caspase-8- and Bid-dependent pathways. The preventive effect appears to be associated with the inhibition of the formation of reactive oxygen species and the depletion of glutathione. KATP channel blockade appears to prevent proteasome inhibition-induced neuronal cell death.

KATP channel block inhibits the Toll-like receptor 2-mediated stimulation of NF-κB by suppressing the activation of Akt, mTOR, JNK and p38-MAPK

Abstract Changes in the KATP channel activity have been shown to regulate inflammation and immune responses. Using human keratinocytes, we investigated the effect of KATP channel inhibition on inflammatory mediator production in relation to the Toll like receptor‐2‐mediated‐Akt, mTOR and NF‐&kgr;B pathways, as well as JNK and p38‐MAPK, which regulate the transcription genes involved in immune and inflammatory responses. 5‐Hydroxydecanoate (a selective KATP channel blocker), glibenclamide (a cell surface and mitochondrial KATP channel inhibitor), the Akt inhibitor, rapamycin, Bay 11‐7085 and N‐acetylcysteine reduced the lipoteichoic acid‐ or peptidoglycan‐induced production of cytokines and chemokines, and production of reactive oxygen species and increased the levels and activities of Kir 6.2, NF‐&kgr;B, phosphorylated‐Akt and mTOR, and the activation of JNK and p38‐MAPK in keratinocytes. Inhibitors of c‐JNK (SP600125) and p38‐MAPK (SB203580) attenuated the lipoteichoic acid‐ or peptidoglycan‐induced production of inflammatory mediators, the activation of the JNK and p38‐MAPK, and the production of reactive oxygen species in keratinocytes. The results show that KATP channel blockers may reduce the bacterial component‐stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll‐like receptor‐2‐mediated activation of the Akt, mTOR and NF‐&kgr;B pathways, as well as JNK and p38‐MAPK. The suppressive effect of KATP channel blockers appears to be achieved by the inhibition of reactive oxygen species production.

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. Copyright