• Journal of Life Science
• /
• v.22 no.6
• /
• pp.760-771
• /
• 2012

Marine triterpene glycosides are physiologically active natural compounds isolated from sea cucumbers(holothurians). It was demonstrated that they have a wide range of biological activities, including antifungal, cytotoxic, and antitumor effects. A previous study showed that stichoposide C (STC) isolated from Thelenota anax induces apoptosis through generation of ceramide by activation of acid sphingomyelinase (SMase) and neutral SMase in human leukemia cells. In this study, we investigated whether STD, a structural analog of STC, can induce apoptosis and examined the molecular mechanisms for its activity. It was found that STC and STD induce apoptosis in a dose- and time-dependent manner and lead to the activation of caspase-8, mitochondrial damage, activation of caspase-9, and activation of caspase-3 in K562 and HL-60 cells. STC activates acid SMase and neutral SMase, which results in the generation of ceramide. Specific inhibition of acid SMase or neutral SMase partially blocked STC-induced apoptosis, but not STD-induced apoptosis. In contrast, STD generates ceramide through the activation of ceramide synthase. Specific inhibition of ceramide synthase partially blocked STD-induced apoptosis, but not STC-induced apoptosis. Moreover, STC and STD markedly reduced tumor growth of HL-60 xenograft tumors and increased ceramide generation in vivo. These results indicate that STC and STD can induce apoptosis and have antitumor activity through the different molecular mechanisms, because they have a different sugar residue attached to aglycones. Thus, these results suggest that their actions are affected by a sugar residue attached to aglycones and they can be used as anticancer agents in the treatment of leukemia.

• Biomedical Science Letters
• /
• v.15 no.1
• /
• pp.61-66
• /
• 2009

Leflunomide is an immunomodulatory agent used for the treatment of rheumatoid arthritis (RA). Leflunomide known as a regulator of iNOS synthesis which largely decreases NO production in diverse cell type. However, the effect of leflunomide on chondrocyte is still poorly understood. In our previous studies, we have shown that direct production of Nitric oxide (NO) by treating chondrocytes with NO donor, sodium nitroprusside (SNP), causes apoptosis via p38 mitogen-activated protein kinase in association with elevation of p53 protein level, caspase-3 activation. In this study, we characterized the molecular mechanism by which A77 1726 inhibit apoptosis. We found that A77 1726 inhibit NO-induced apoptosis as determined by MTT (Thiazolyl Blue Tetrazolium Bromide) assay and DNA fragmentation. The inhibition of apoptosis by A77 1726 was accompanied by increased PI-3 kinase and AKT activities. So, inhibition of phosphatidylinositol (PI)-3kinase with LY294002 rescued apoptosis. Triciribine, the specific inhibitor of AKT, also abolished anti-apoptotic effect. Our results indicate that A77 1726, the active metabolite of leflunomide, mediates NO-induced apoptosis in chondrocytes by modulating up-regulation of PI-3 kinase and AKT.

• Journal of Ginseng Research
• /
• v.47 no.1
• /
• pp.23-32
• /
• 2023

Coronavirus disease 2019 (COVID-19) is a highly infectious respiratory disease caused by a severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). SARS-CoV-2 infection may cause clinical manifestations of multiple organ damage, including various neurological syndromes. There are currently two oral antiviral drugs-Paxlovid and molnupiravir-that are recognized to treat COVID-19, but there are still no drugs that can specifically fight the challenges of SARS-CoV-2 variants. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is a multimolecular complex that can sense heterogeneous pathogen-associated molecular patterns associated with neurological disorders. The NLRP3 activation stimulates the production of caspase-1-mediated interleukin (IL)-1β, IL-18, and other cytokines in immune cells. Panax (P.) ginseng is a medicinal plant that has traditionally been widely used to boost immunity and treat various pathological conditions in the nervous system due to its safety and anti-inflammatory/oxidant/viral activities. Several recent reports have indicated that P. ginseng and its active ingredients may regulate NLRP3 inflammasome activation in the nervous system. Therefore, this review article discusses the current knowledge regarding the pathogenesis of neurological disorders related to COVID-19 and NLRP3 inflammasome activation and the possibility of using P. ginseng in a strategy targeting this pathway to treat neurological disorders.

• BMB Reports
• /
• v.53 no.8
• /
• pp.419-424
• /
• 2020

Bee venom (BV), secreted from the venom gland of the honey bee, contains several biological active compounds. BV has been widely used as a traditional medicine for treating human disease, including cancer. In this study, we have shown the molecular mechanism underlying the therapeutic effect of BV on cancer. Treatment with BV reduced the proliferation of cervical-cancer cells in a dose- and time-dependent manner. Interestingly, the killing effect of BV was specific to HPV-positive cervical-cancer cell lines, such as Caski and HeLa cells, and not to HPV-negative cervical-cancer cells (C33A). BV reduced the expression of HPV E6 and E7 at RNA and protein levels, leading to an increase in the expression of p53 and Rb in Caski and HeLa cells. Further, BV decreased the levels of cell-cycle proteins, such as cyclin A and B, and increased the levels of cell-cycle inhibitors, such as p21 and p27. BV significantly induced apoptosis and inhibited wound healing and migration of cervical-cancer cells. It also upregulated the expression of pro-apoptotic BAX and downregulated the expression of anti-apoptotic Bcl-2 and Bcl-XL. Cleavage of caspase-3, caspase-9, and PARP were also induced by BV treatment, whereas the phosphorylation of mitogenic signaling-related proteins, such as AKT, JNK, p38, and ERK, were downregulated. Our results indicate that BV has a therapeutic selectivity for HPV-positive malignant cells, so further clinical studies are needed to assess its clinical application.

• Molecules and Cells
• /
• v.38 no.5
• /
• pp.416-425
• /
• 2015

NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor, has recently received a great deal of attention as an important molecule that enhances antioxidative defenses and induces resistance to chemotherapy or radiotherapy. In this study, we investigated the apoptosis-inducing and Nrf2- upregulating effects of quercetin on malignant mesothelioma (MM) MSTO-211H and H2452 cells. Quercetin treatment inhibited cell growth and led to upregulation of Nrf2 at both the mRNA and protein levels without altering the ubiquitination and extending the half-life of the Nrf2 protein. Following treatment with quercetin, analyses of the nuclear level of Nrf2, Nrf2 antioxidant response element-binding assay, Nrf2 promoter-luc assay, and RT-PCR toward the Nrf2-regulated gene, heme oxygenase-1, demonstrated that the induced Nrf2 is transcriptionally active. Knockdown of Nrf2 expression with siRNA enhanced cytotoxicity due to the induction of apoptosis, as evidenced by an increase in the level of proapoptotic Bax, a decrease in the level of antiapoptotic Bcl-2 with enhanced cleavage of caspase-3 and PARP proteins, the appearance of a sub-$G_0/G_1$ peak in the flow cytometric assay, and increased percentage of apoptotic propensities in the annexin V binding assay. Effective reversal of apoptosis was observed following pretreatment with the pan-caspase inhibitor Z-VAD. Moreover, Nrf2 knockdown exhibited increased sensitivity to the anticancer drug, cisplatin, presumably by potentiating the oxidative stress induced by cisplatin. Collectively, our data demonstrate the importance of Nrf2 in cytoprotection, survival, and drug resistance with implications for the potential significance of targeting Nrf2 as a promising strategy for overcoming resistance to chemotherapeutics in MM.

• Korean Journal of Pharmacognosy
• /
• v.40 no.1
• /
• pp.65-69
• /
• 2009

The present study investigated the antiproliferative effect of Litsea japonica in HL-60/ADR, adriamycin resistant human promyelocytic leukemia cells. The 80% ethanol extract of L. japonica markedly inhibited the growth of HL-60/ADR cells. When HL-60/ADR cells were treated with the extract, several apoptosis events like as DNA fragmentation, chromatin condensation and the increase of the population of sub-G1 hypodiploid cells were observed. In the mechanism of apoptosis induction by L. japonica, we examined the changes of Bcl-2 and Bax protein expression levels, and activation of caspases. After the HL-60/ADR cells were treated with the extract, the Bcl-2 expression was decreased, whereas the expression of Bax was increased in a time-dependent manner compared to the control. In addition, the active forms of caspase-9 and -3 were increased and the cleavage of poly (ADP-ribose) polymerase, a vital substrate of effector caspase, was observed. The results suggest that the inhibitory effect of L. japonica on the growth of the HL-60/ADR appears to arise from the induction of apoptosis via the down-regulation of Bcl-2 and the activation of caspases.

• Journal of Life Science
• /
• v.25 no.4
• /
• pp.441-449
• /
• 2015

Endlicheria anomala, a neotropical plant, is found in northern South America and the Amazon region. It is traditionally used to remove poisons and cure gangrene. According to recent data, this plant has diverse biological properties such as anti-oxidative, anti-inflammatory and anti-melanogenic properties. However, the anti-cancer effect of E. anomala and its molecular mechanisms remain unclear. In this study, we examined the anti-cancer effect and the active mechanism of methanol extract of E. anomala (MEEA) in human lung adenocarcinoma cells (A549) and human liver cancer cells (HepG2). Our data revealed that MEEA showed cytotoxic activity in a dose-dependent manner and induced apoptosis both in A549 and HepG2 cells. We verified evidences of apoptosis via formation of chromatin condensation, apoptotic body and accumulation of cells in the subG1 phase. Following observed apoptosis-related phenomena, we found that the induction of apoptosis by MEEA was associated with the increase of tumor suppressor p53 and cyclin-dependent kinase inhibitor p21 (WAF1/CIP1) expression. Furthermore, MEEA-induced apoptosis was characterized with proteolytic activation of caspase-3, degradation of poly ADP ribose polymerase (PARP), and up-regulation of pro-apoptotic Bax expression. Taken together, these findings indicate that MEEA may have potential cancer therapeutic utility in A549 and HepG2 cells.

• Journal of Ginseng Research
• /
• v.47 no.2
• /
• pp.228-236
• /
• 2023

Background: QiShen YiQi pills (QSYQ) is a Traditional Chinese Medicine (TCM) formula, which has a significant effect on the treatment of patients with myocardial infarction (MI) in clinical practice. However, the molecular mechanism of QSYQ regulation pyroptosis after MI is still not fully known. Hence, this study was designed to reveal the mechanism of the active ingredient in QSYQ. Methods: Integrated approach of network pharmacology and molecular docking, were conducted to screen active components and corresponding common target genes of QSYQ in intervening pyroptosis after MI. Subsequently, STRING and Cytoscape were applied to construct a PPI network, and obtain candidate active compounds. Molecular docking was performed to verify the binding ability of candidate components to pyroptosis proteins and oxygen-glucose deprivation (OGD) induced cardiomyocytes injuries were applied to explore the protective effect and mechanism of the candidate drug. Results: Two drug-likeness compounds were preliminarily selected, and the binding capacity between Ginsenoside Rh2 (Rh2) and key target High Mobility Group Box 1 (HMGB1)was validated in the form of hydrogen bonding. 2 μM Rh2 prevented OGD-induced H9c2 death and reduced IL-18 and IL-1β levels, possibly by decreasing the activation of the NLRP3 inflammasome, inhibiting the expression of p12-caspase1, and attenuating the level of pyroptosis executive protein GSDMD-N. Conclusions: We propose that Rh2 of QSYQ can protect myocardial cells partially by ameliorating pyroptosis, which seems to have a new insight regarding the therapeutic potential for MI.

• The Journal of Korean Medicine
• /
• v.34 no.3
• /
• pp.126-142
• /
• 2013

Objectives: Previous reports have shown that Bogijetong-Tang (BJT) is effective in peripheral neuropathy induced by taxol and crush injury. In this study, we researched the effects of BJT on diabetic neuropathy induced by STZ in the mouse. Methods: We performed both in vitro and in vivo experiments to verify the effects of BJT on diabetic neuropathy induced by STZ in mice. Changes in axonal recovery were observed with immunofluorescence staining using NF-200, Hoechst33258, $S100{\beta}$, caspase 3 and anti-cdc2. Proliferation and degeneration of Schwann cells were investigated by immunofluorescence staining and western blot analyses. Results: BJT showed considerable effects on neurite outgrowth and axonal regeneration in diabetic neuropathy. BJT contributed to the creation of NF-200, GAP-43, Cdc2, phospho-vimentin, ${\beta}1$, active ${\beta}1$, ${\beta}3$ integrin, phospho-Erk1/2 protein. Conclusions: Through this study, we found that BJT is effective for enhanced axonal regeneration via dynamic regulation of regeneration-associated proteins. Therefore, BJT had a pharmaceutical property enhancing recovery of peripheral nerves induced by diabetic neuropathy and could be a candidate for drug development after more research.

• Journal of Life Science
• /
• v.24 no.9
• /
• pp.1001-1005
• /
• 2014

Ginsenoside Rg3 is one of the active ingredients extracted from red ginseng, and it is an effective chemical component of the human body and well known in herbal medicine as a restorative agent. Several studies have shown that Rg3 has a potent anti-tumor effect on various cancer cell lines. However, Rg3-induced apoptosis in B16F10 melanoma cancer cells is not well understood. In the present study, we tested whether ginsenoside Rg3 could induce apoptosis in B16F10 melanoma cells. We found that Rg3 could inhibit B16F10 melanoma cell viability in a dose-dependent manner, but not normal cells, such as EA.hy.926 and NIH3T3 cells. We also found that Rg3 could induce apoptosis in B16F10 melanoma cells using tunnel-staining assay in a dose-dependent manner. Rg3 treatment induces the phosphorylation of p38 and the expression of Bax, but it inhibits the expressions of the phosphorylation of focal adhesion kinase Bcl2 and pro-caspase3. Taken together, our data suggest that Rg3 could be useful as an anti-cancer agent in B16F10 melanoma cells.