• Molecules and Cells
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• v.38 no.11
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• pp.941-949
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• 2015

Rheumatoid arthritis is a chronic inflammatory disease that leads to bone and cartilage erosion. The inhibition of osteoblast differentiation by the inflammatory factor TNF-${\alpha}$ is critical for the pathogenesis of rheumatoid arthritis. To modulate TNF-${\alpha}$ mediated inhibition of osteoblast differentiation is required to improve therapeutic efficacy of rheumatoid arthritis. Here, we explored the potential role of rocaglamide-A, a component of Aglaia plant, in osteoblast differentiation. Rocaglamide-A prevented TNF-${\alpha}$ mediated inhibition of osteoblast differentiation, and promoted osteoblast differentiation directly, in both C2C12 and primary mesenchymal stromal cells. Mechanistically, Rocaglamide-A inhibited the phosphorylation of NF-${\kappa}B$ component p65 protein and the accumulation of p65 in nucleus, which resulted in the diminished NF-${\kappa}B$ responsible transcriptional activity. Oppositely, overexpression of p65 reversed rocaglamide-A's protective effects on osteoblast differentiation. Collectively, rocaglamide-A protected and stimulated osteoblast differentiation via blocking NF-${\kappa}B$ pathway. It suggests that rocaglamide-A may be a good candidate to develop as therapeutic drug for rheumatoid arthritis associated bone loss diseases.

• BMB Reports
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• v.48 no.10
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• pp.571-576
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• 2015

SB743921 is a potent inhibitor of the spindle protein kinesin and is being investigated in ongoing clinical trials for the treatment of myeloma. However, little is known about the molecular events underlying the induction of cell death in multiple myeloma (MM) by SB743921, alone or in combination treatment. Here, we report that SB743921 induces mitochondria-mediated cell death via inhibition of the $NF-{\kappa}B$ signaling pathway, but does not cause cell cycle arrest in KMS20 MM cells. SB743921-mediated inhibition of the $NF-{\kappa}B$ pathway results in reduced expression of SOD2 and Mcl-1, leading to mitochondrial dysfunction. We also found that combination treatment with SB743921 and bortezomib induces death in bortezomib-resistant KMS20 cells. Altogether, these data suggest that treatment with SB743921 alone or in combination with bortezomib offers excellent translational potential and promises to be a novel MM therapy.

• Korean Journal of Clinical Pharmacy
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• v.23 no.3
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• pp.206-212
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• 2013

Purpose: The aim of this study was to investigate the effect of nimodipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Methods: Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of nimodipine (0.5 or 2 mg/kg) in rats. The effect of nimodipine on the P-glycoprotein as well as cytochrome P450 (CYP) 3A4 activity was also evaluated. Results: Nimodipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $10.2{\mu}M$. Compared to those animals in the oral control group (warfarin without nimodipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (0.5 mg/kg, P<0.05; 2 mg/kg, P<0.01) by 31.3-57.6%, and the peak plasma concentration ($C_{max}$) was significantly higher (2 mg/kg, P<0.05) by 29.4% after oral administration of warfarin with nimodipine, respectively. Consequently, the relative bioavailability of warfarin increased by 1.31- to 1.58-fold and the absolute bioavailability of warfarin with nimodipine was significantly greater by 64.1-76.9% compared to that in the control group (48.7%). In contrast, nimodipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Conclusion: Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism rather than P-glycoprotein-mediated efflux by nimodipine.

• Korean Journal of Plant Resources
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• v.31 no.6
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• pp.612-621
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• 2018

Honey used as conventional medicine has various pharmacological properties. In the honey and anti-inflammatory effect, Gelam honey and Manuka honey has been reported to exert anti-inflammatory activity. However, the anti-inflammatory effect and potential mechanisms of acacia honey (AH) are not well understood. In this study, we investigated anti-inflammatory activity and mechanism of action of AH in LPS-stimulated RAW264.7 cells. AH attenuated NO production through inhibition of iNOS expression in LPS-stimulated RAW264.7 cells. AH also decreased the expressions of $IL-1{\beta}$, IL-6 and $TNF-{\alpha}$ as pro-inflammatory cytokines, and MCP-1 expression as a pro-inflammatory chemokine. In the elucidation of the molecular mechanisms, AH decreased LPS-mediated $I{\kappa}B$-${\alpha}$ degradation and subsequent nuclear accumulation of p65, which resulted in the inhibition of $NF-{\kappa}B$ activation in RAW264.7 cells. AH dose-dependently suppressed LPS-mediated phosphorylation of ERK1/2 and p38 in RAW264.7 cells. In addition, AH significantly inhibited ATF2 phosphorylation and nuclear accumulation of ATF2 in LPS-stimulated RAW264.7 cells. These results suggest that AH has an anti-inflammatory effect, inhibiting the production of pro-inflammatory mediators such as NO, iNOS, $TNF-{\alpha}$, IL-6, $IL-1{\beta}$ and MCP-1 via interruption of the $NF-{\kappa}B$ and MAPK/ATF2 signaling pathways.

• BMB Reports
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• v.52 no.3
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• pp.208-213
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• 2019

Chemoresistance is the primary obstacle in the treatment of locally advanced and metastatic nasopharyngeal carcinoma (NPC). Recent evidence suggests that the transcription factor forkhead box M1 (FoxM1) is involved in chemoresistance. Our group previously confirmed that FoxM1 is overexpressed in NPC. In this study, we investigated the role of FoxM1 in cisplatin resistance of the cell lines 5-8F and HONE-1 and explored its possible mechanism. Our results showed that FoxM1 and NBS1 were both overexpressed in NPC tissues based on data from the GSE cohort (GSE12452). Then, we measured FoxM1 levels in NPC cells and found FoxM1 was overexpressed in NPC cell lines and could be stimulated by cisplatin. MTT and clonogenic assays, flow cytometry, ${\gamma}H2AX$ immunofluorescence, qRT-PCR, and western blotting revealed that downregulation of FoxM1 sensitized NPC cells to cisplatin and reduced the repair of cisplatin-induced DNA double-strand breaks via inhibition of the MRN (MRE11-RAD50-NBS1)-ATM axis, which might be related to the ability of FoxM1 to regulate NBS1. Subsequently, we demonstrated that enhanced sensitivity of FoxM1 knockdown cells could be reduced by overexpression of NBS1. Taken together, our data demonstrate that downregulation of FoxM1 could improve the sensitivity of NPC cells to cisplatin through inhibition of MRN-ATM-mediated DNA repair, which could be related to FoxM1-dependent regulation of NBS1.

• BMB Reports
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• v.50 no.10
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• pp.510-515
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• 2017

Triglyceride (TG) accumulation causes macrophage cell death, which affects the development of atherosclerosis. Here, we examined whether caspase-2 is implicated in TG-induced macrophage cell death. We found that caspase-2 activity is increased in TG-treated THP-1 macrophages, and that inhibition of caspase-2 activity drastically inhibits TG-induced cell death. We previously reported that TG-induced macrophage cell death is triggered by caspase-1, and thus investigated the relationship between caspase-2 and caspase-1 in TG-induced macrophage cell death. Inhibition of caspase-2 activity decreased caspase-1 activity in TG-treated macrophages. However, caspase-1 inhibition did not affect caspase-2 activity, suggesting that caspase-2 is upstream of caspase-1. Furthermore, we found that TG induces activation of caspase-3, -7, -8, and -9, as well as cleavage of PARP. Inhibition of caspase-2 and -1 decreased TG-induced caspase-3, -7, -8, and -9 activation and PARP cleavage. Taken together, these results suggest that TG-induced macrophage cell death is mediated via the caspase-2/caspase-1/apoptotic caspases/PARP pathways.

• Archives of Pharmacal Research
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• v.14 no.4
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• pp.330-335
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• 1991

The effects of physostigmine and neostigmine on the parathin induced toxicity were examined in adult female rats. Physostigmine $(100\;{\mu}g/kg,\;ip)$ or neostigmine $(200\;{\mu}g/kg,\;ip)$ inhibited acetylcholinesterase (AChE) and cholinesterase (ChE) activities in blood, brain and lung when the enzyme activity was measured 30 min after the treatment. At the doses of two carbamates equipotent on brain AChE, neostigmine showed greater inhibition on peripheral AChE/ChE. The enzyme activity returned to normal in 120 min following the carbamates except in the lung of rats treated with neostigmine. Carbamates administered 30 min prior to parathion (2 mg/kg) antagonized the inhibition of AChE/ChE by parathion when the enzyme activity was measured 2 hr following parathion. Neostigmine showed greater protective effect on peripheral AChE/ChE. The effect of either carbamate on AChE/ChE was not significant 2 hr beyond the parathion treatment. Carbamates decreased the mortality of rats challenged with a lethal dose of parathion (4 mg/kg, ip) either when treated alone or in combination with atropine (10 mg/kg, ip). Lethal action of paraoxon (1.5 mg/ks ip), the active metabolite of parathion was also decreased by the carbamate treatment indicating that the protection was not mediated by competitive inhibition of metabolic conversion of parathion to paraoxon. The results suggest that carbamylation of the active sites may not be the sole underlying mechanism of protection provided by the carbamates.

• Molecules and Cells
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• v.40 no.4
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• pp.280-290
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• 2017

Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers ($eIF2{\alpha}$ phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132-induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene in Drosophila mitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress-mediated neurodegenerative diseases.

• Korean Journal of Plant Resources
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• v.33 no.4
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• pp.271-278
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• 2020

In this study, we evaluated the anti-cancer activity and potential molecular mechanism of 70% ethanol extracts of the Berchemia floribunda (BF) which belongs to Rhamnaceae against human colorectal cancer cells. The treatment of BF decreased the cell proliferation in HCT116 cell and suppressed cellular accumulation of Cyclin D1 protein. Inhibition of proteasomal activity by MG132 attenuated BF-mediated Cyclin D1 downregulation and Cyclin D1 was decreased in the cell treated with BF. These findings indicates that BF-mediated Cyclin D1 downregulation may be result from Cyclin D1 proteasomal degradation. Additionally, BF-mediated Cyclin D1 degradation was blocked in the presence of LiCl, a GSK3β inhibitor, but not PD98059, SP600125, SB203580, Bay11-7082, LY294002 an ERK1/2 inhibitor, JNK inhibitor, p38 inhibitor, IκK inhibitor and PI3K inhibitor. Furthermore, BF phosphorylated Cyclin D1 at threonine-286 (Thr286), and LiCl-induced GSK3β inhibition reduced the BF mediated phosphorylation of Cyclin D1 at Thr286. These results suggested that BF may downregulate Cyclin D1 expression as a potential anti-cancer target through GSK3β dependent Cyclin D1 degradation. Therefore, this study provides that the extract of BF has anticancer activity against human colorectal cancer cells.

• Korean Journal of Veterinary Research
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• v.28 no.1
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• pp.29-36
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• 1988

To examine the selectivity of verapamil, used in the cardiovascular diseases, on alpha-1 and alpha-2 adrenoceptor-induced pressor rsponses, effects of verapamil on alpha-adrenoceptor agonist-induced pressor responses were investigated in urethane-anesthetized rabbits, spinal rabbits, rats and pithed rats. To evaluate the effects of verapamil on each pressor response induced by norepinephrine, phenylephrine and clonidine, these agonists were previously injected into a ear vein, and then same procedures were performed 1~2 min after treatment with intravenous verapamil. The results are summarized as follows: 1. Intravenous verapamil produced dose-dependent depressor response in rabbits and rats. 2. Pressor responses to intravenous norepinephrine($10{\mu}g/kg$) and phenylphrine($30{\mu}g/kg$) were inhibited by pretreatment with intravenous verapamil in rabbits and no difference was noted between the degree of both inhibitions of the pressor response by verapamil. 3. Pressor responses to intravenous norepinephrine($3{\mu}g/kg$), phenylephrine($20{\mu}g/kg$) and clonidine ($300{\mu}g/kg$) were inhibited by pretreatment with intravenous verapamil in spinal rabbits. No difference was noted between the inhibition of norepinephrine-induced pressor response and that of phenylephrine-induced pressor response by verapamil. The inhibition of clonidine-induced pressor response by verapamil was more prominent than that of norepinephrine- or phenylephrine-induced pressor response. 4. Pressor responses to intravenous norepinephrine($3{\mu}g/kg$) and phenylephrine($10{\mu}g/kg$) were inhibited by pretreatment with intravenous verapairlil in rats and no difference was noted between the degree of both inhibitions of the pressor response by verapamil. 5. Pressor responses to intravenous norepinephrine ($3{\mu}g/kg$), phenylephrine($30{\mu}g/kg$) and clonidine($100{\mu}g/kg$) were inhibited by pretreatment with intravenous verapamil in pithed rats. No difference was noted between the inhibition of norepinephrine-induced pressor response and that of phenylephrine-induced pressor response by verapamil. The inhibition of clonidine-induced pressor response by verapamil was more prominent than that of norepinephrine- or phenylephrine-induced pressor response. These results suggest that verapamil significantly inhibits both pressor responses mediated by alpha-1 and alpha-2 adrenoceptors and the inhibition is greater in alpha-2 adrenoceptor-induced response than in alpha-1 adrenoceptor-induced one, and calcium channel takes part in the process of the pressor response mediated by alpha-1 adrenoceptors as well as alpha-2 adrenoceptors.