Dong Seok Cha

Post-transcriptional regulation of the Ras-ERK/MAPK signaling pathway.

The Ras‐ERK/MAP (Mitogen‐Activated Protein) kinase signaling pathway governs many cellular processes such as proliferation, differentiation, cell fate, homeostasis, and survival in all eukaryotes. Constitutive activation of the Ras‐ERK/MAPK signaling pathway often leads to promotion of abnormal cell growth and tumorigenesis. Although the regulation of the Ras‐ERK/MAPK signaling pathway by post‐translational modification has been well elucidated, post‐transcriptional regulations of this pathway are beginning to emerge in invertebrates and this work is extended to humans. In this review, we describe the conserved regulation of Ras‐ERK/MAPK signaling by RNA‐binding proteins (PUF, KH‐domain, HuR, and LARP) and microRNAs (let‐7 family miRNAs) and important implications for human diseases including cancers. J. Cell. Physiol. 227: 1235–1241, 2012.

Anti-inflammatory and antinociceptive properties of the leaves of Eriobotrya japonica.

AIM OF THE STUDY The leaves of Eriobotrya japonica Lindl. have been widely used as a traditional medicine for the treatment of many diseases including coughs and asthma. The present study was designed to validate the anti-inflammatory and antinociceptive properties of the n-BuOH fraction of E. japonica (LEJ) leaves. MATERIALS AND METHODS The anti-inflammatory properties of LEJ were studied using IFN-γ/LPS activated murine peritoneal macrophage model. The antinociceptive effects of LEJ were assessed using experimental models of pain, including thermal nociception methods, such as the tail immersion test and the hotplate test, and chemical nociception induced by intraperitoneal acetic acid and subplantar formalin in mice. To examine the possible connection of the opioid receptor to the antinociceptive activity of LEJ, we performed a combination test with naloxone, a nonselective opioid receptor antagonist. RESULTS In the IFN-γ and LPS-activated murine peritoneal macrophage model, LEJ suppressed NO production and iNOS expression via down-regulation of NF-κB activation. It also attenuated the expression of COX-2 and the secretion of pro-inflammatory cytokines like TNF-α and IL-6. Moreover, LEJ also demonstrated strong and dose-dependent antinociceptive activity compared to tramadol and indomethacin in various experimental pain models. In a combination test using naloxone, diminished analgesic activities of LEJ were observed, indicating that the antinociceptive activity of LEJ is connected with the opioid receptor. CONCLUSIONS The results indicate that LEJ had potent inhibitory effects on the inflammatory mediators including nitric oxide, iNOS, COX-2, TNF-α and IL-6 via the attenuation of NF-κB translocation to the nucleus. LEJ also showed excellent antinociceptive activity in both central and peripheral mechanism as a weak opioid agonist. Based on these results, LEJ may possibly be used as an anti-inflammatory and an analgesic agent for the treatment of pains and inflammatory diseases.

Antinociceptive and hypnotic properties of Celastrus orbiculatus.

ETHNOPHARMACOLOGICAL RELEVANCE Celastrus orbiculatus, a woody vine of the Celastraceae family, has been widely used as a traditional medicine for the treatment of many diseases, including rheumatoid arthritis and odontalgia. In this study, we assessed the sedative and antinociceptive activities of the methanolic extract of Celastrus orbiculatus (MCO). MATERIALS AND METHODS The antinociceptive effect of MCO was evaluated using several experimental pain models, including thermal nociception methods, such as the tail immersion and the hotplate tests, as well as chemical nociception induced by intraperitoneal acetic acid and subplantar formalin administration in mice. To verify the possible connection of the opioid receptor to the antinociceptive activity of MCO, we performed a combination test with naloxone, a nonselective opioid receptor antagonist. The sedative effect of MCO was studied using the pentobarbital-induced sleeping model. RESULTS MCO demonstrated strong and dose-dependent antinociceptive activity compared to tramadol and indomethacin in various experimental pain models. The combination test using naloxone revealed that the antinociceptive activity of MCO is associated with activation of the opioid receptor. MCO also caused decreased sleep latency and increased sleeping time in the pentobarbital-induced sleeping model; however, MCO alone did not induce sleep. CONCLUSIONS In the present study, MCO showed potent antinociceptive and sedative activities. Based on these results, MCO may be considered a valuable anti-nociceptive and hypnotic agent for the treatment of various diseases.

Memory-Enhancing Effect of a Supercritical Carbon Dioxide Fluid Extract of the Needles of Abies koreana on Scopolamine-Induced Amnesia in Mice

Abies koreana Wilson (A. koreana) is a shrub or broadly pyramidal evergreen tree endemic in the mountainous regions of South Korea. We obtained the essential oil (EO) from alpine needle leaves of A. koreana by the supercritical fluid extraction (SFE) method. EO was analyzed by gas chromatography–mass spectrometry (GC–MS), and 68 compounds were identified constituting 95.66% of the oil. The major components were elemol (11.17%), terpinen-4-ol (9.77%), sabinene (8.86%), 10(15)-cadien-4-ol (7.16%), α-terpineol (6.13%), α-pinene (6.07%) and γ-terpinene (4.71%). To investigate the memory-enhancing effects, we conducted a passive avoidance test using a scopolamine (1 mg/kg, ip)-induced amnesia mouse model. A peritoneal injection of EO from A. koreana (100 mg/kg) showed a memory enhancing effect of 72.7% compared with the control. These results suggest that EO of A. koreana may be a useful therapeutic agent against such amnesia-inducing diseases as Alzheimer and vascular dementia.

Anti-metastatic properties of the leaves of Eriobotrya japonica

The leaves of Eriobotrya japonica Lindl. have been widely used as a traditional medicine for the treatment of many diseases including gastroenteric disorders, diabetes mellitus, chronic bronchitis and asthma. In the present study, the anti-metastatic action of the EtOAc fraction of the leaves of E. japonica (LEJ) was investigated. LEJ showed potent inhibitory effects on MMP-2 and MMP-9 activities and expressions via down-regulation of NF-κB translocation to the nucleus in B16F10 cells. In addition, the cell migration and invasion were down-regulated by LEJ. LEJ also significantly suppressed lung metastasis in vivo. Moreover, we isolated the compounds ursolic acid and 2α-hydroxyursolic acid from LEJ and both compounds also significantly suppressed MMP-2 and MMP-9 activities, indicating that they are the active components of LEJ. The present results demonstrate that LEJ may be used as valuable antimetastatic agent for the treatment of cancer metastasis.

Anti-inflammatory and anti-nociceptive properties of Prunus padus.

ETHNOPHARMACOLOGICAL RELEVANCE Prunus padus Linne has been widely used as a traditional medicine, with beneficial effects in numerous diseases, including stroke, neuralgia and hepatitis. In this study, we demonstrated anti-inflammatory and anti-nociceptive activities of the methylene chloride fraction of P. padus (MPP). MATERIALS AND METHODS In vitro studies, the anti-inflammatory effects of MPP were examined using IFN-γ/LPS-activated murine peritoneal macrophage model. To confirm the anti-inflammatory effects of MPP in vivo, trypsin-induced paw edema test was also conducted. The anti-nociceptive activities of MPP were measured using various experimental pain models including thermal nociception methods such as the tail immersion test and the hot plate test as well as chemical nociception methods like acetic acid-induced writhing test and formalin test. To determine whether analgesic activity of MPP is connected with the opioid receptor, we carried out combination test with naloxone, a nonselective opioid receptor antagonist. RESULTS In the current study, MPP showed potent inhibitory effect on IFN-γ/LPS-induced NO production. MPP also suppressed not only iNOS enzyme activity but also iNOS expression. Moreover, MPP inhibited COX-2 expression dose dependently. IFN-γ/LPS stimulation induced the translocation of NF-κB to nucleus but it was attenuated in the presence of MPP. In vivo study revealed that MPP could reduce paw volume after subplantar injection of trypsin. In addition, MPP showed potent analgesic activities both thermal and chemical nociception compared to tramadol and indomethacin. Furthermore, pre-treatment of naloxone slightly suppress the analgesic activity of MPP indicating that MPP acts as a partial opioid receptor agonist. CONCLUSIONS In the present study, MPP showed potent anti-inflammatory properties through not only by suppressing various inflammatory mediators in vitro, but reducing the inflammatory edema in vivo. MPP also exhibited strong anti-nociceptive activities via both central and peripheral mechanism by acting as a partial opioid agonist. Based on these results we suggest that P. padus has the potential to provide a therapeutic approach to inflammation-mediated chronic diseases as an effective anti-inflammatory agent and painkiller.

The Ras-ERK MAPK regulatory network controls dedifferentiation in Caenorhabditis elegans germline.

How a committed cell can be reverted to an undifferentiated state is a central question in stem cell biology. This process, called dedifferentiation, is likely to be important for replacing stem cells as they age or get damaged. Tremendous progress has been made in understanding this fundamental process, but its mechanisms are poorly understood. Here we demonstrate that the aberrant activation of Ras-ERK MAPK signaling promotes cellular dedifferentiation in the Caenorhabditis elegans germline. To activate signaling, we removed two negative regulators, the PUF-8 RNA-binding protein and LIP-1 dual specificity phosphatase. The removal of both of these two regulators caused secondary spermatocytes to dedifferentiate and begin mitotic divisions. Interestingly, reduction of Ras-ERK MAPK signaling, either by mutation or chemical inhibition, blocked the initiation of dedifferentiation. By RNAi screening, we identified RSKN-1/P90(RSK) as a downstream effector of MPK-1/ERK that is critical for dedifferentiation: rskn-1 RNAi suppressed spermatocyte dedifferentiation and instead induced meiotic divisions. These regulators are broadly conserved, suggesting that similar molecular circuitry may control cellular dedifferentiation in other organisms, including humans.

Protocatechuic acid extends lifespan and increases stress resistance in Caenorhabditis elegans

Veronica peregrina has a wide range of types of constituents with various pharmacological properties. Here in this study, we isolated protocatechuic acid (PCA) from V. peregrina and examined PCAs effects on the lifespan and stress tolerance using Caenorhabditis elegans model system. We found that lifespan of wild-type worms was significantly lengthened in the presence of PCA in a dose dependent manner. PCA also elevated tolerance of worms against osmotic, heat shock, and oxidative stress. We also demonstrated antioxidant capacity of PCA by checking intracellular reactive oxygen species level and antioxidant enzyme activities such as catalase and superoxide dismutase. We further investigated several factors including pharyngeal pumping rate and progeny production that might influence prolonged lifespan and enhanced stress tolerance by PCA. Interestingly, both factors were significantly reduced after PCA exposure, indicating PCA exerts longevity activity by shifting food intake and reproduction at least in part. In addition, PCA-treated aged worms showed increased body movement compared to untreated controls suggesting PCA could enhance healthspan as well as lifespan.

Catalpol Modulates Lifespan via DAF-16/FOXO and SKN-1/Nrf2 Activation in Caenorhabditis elegans

Catalpol is an effective component of rehmannia root and known to possess various pharmacological properties. The present study was aimed at investigating the potential effects of catalpol on the lifespan and stress tolerance using C. elegans model system. Herein, catalpol showed potent lifespan extension of wild-type nematode under normal culture condition. In addition, survival rate of catalpol-fed nematodes was significantly elevated compared to untreated control under heat and oxidative stress but not under hyperosmolality conditions. We also found that elevated antioxidant enzyme activities and expressions of stress resistance proteins were attributed to catalpol-mediated increased stress tolerance of nematode. We further investigated whether catalpols longevity effect is related to aging-related factors including reproduction, food intake, and growth. Interestingly, catalpol exposure could attenuate pharyngeal pumping rate, indicating that catalpol may induce dietary restriction of nematode. Moreover, locomotory ability of aged nematode was significantly improved by catalpol treatment, while lipofuscin levels were attenuated, suggesting that catalpol may affect age-associated changes of nematode. Our mechanistic studies revealed that mek-1, daf-2, age-1, daf-16, and skn-1 are involved in catalpol-mediated longevity. These results indicate that catalpol extends lifespan and increases stress tolerance of C. elegans via DAF-16/FOXO and SKN-1/Nrf activation dependent on insulin/IGF signaling and JNK signaling.

Genistein from Vigna angularis Extends Lifespan in Caenorhabditis elegans.

The seed of Vigna angularis has long been cultivated as a food or a folk medicine in East Asia. Genistein (4′,5,7-trihydroxyisoflavone), a dietary phytoestrogen present in this plant, has been known to possess various biological properties. In this study, we investigated the possible lifespan-extending effects of genistein using Caenorhabditis elegans model system. We found that the lifespan of nematode was significantly prolonged in the presence of genistein under normal culture condition. In addition, genistein elevated the survival rate of nematode against stressful environment including heat and oxidative conditions. Further studies demonstrated that genistein-mediated increased stress tolerance of nematode could be attributed to enhanced expressions of stress resistance proteins such as superoxide dismutase (SOD-3) and heat shock protein (HSP-16.2). Moreover, we failed to find genistein-induced significant change in aging-related factors including reproduction, food intake, and growth, indicating genistein exerts longevity activity independent of affecting these factors. Genistein treatment also led to an up-regulation of locomotory ability of aged nematode, suggesting genistein affects healthspan as well as lifespan of nematode. Our results represent that genistein has beneficial effects on the lifespan of C. elegans under both of normal and stress condition via elevating expressions of stress resistance proteins.