Wonki Kim

15-Deoxy-Δ12,14-prostaglandin J2, an electrophilic lipid mediator of anti-inflammatory and pro-resolving signaling

15-deoxy-Δ(12,14)-prostagandin J(2) (15d-PGJ2) is produced in the inflamed cells and tissues as a consequence of upregulation of cyclooxygenase-2 (COX-2). 15d-PGJ2 is known to be the endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ) with multiple physiological properties. Though one of the terminal products of the COX-2-catalyzed reactions, this cyclopentenone prostaglandin exerts potent anti-inflammatory actions, in part, by antagonizing the activities of pro-inflammatory transcription factors, such as NF-κB, STAT3, and AP-1, while stimulating the anti-inflammatory transcription factor Nrf2. These effects are not necessarily dependent on its activation of PPARγ, but often involves direct interaction with the above signaling molecules and their regulators. The locally produced 15d-PGJ2 is also involved in the resolution of inflammatory responses. Thus, 15d-PGJ2, especially formed during the late phase of inflammation, might inhibit cytokine secretion and other events by antigen-presenting cells like dendritic cells or macrophages. 15d-PGJ2 can also affect the priming and effector functions of T lymphocytes and induce their apoptotic cell death. These represent a negative feedback explaining how once-initiated immunologic and inflammatory responses are switched off and terminated. In this context, 15d-PGJ2 and its synthetic derivatives have therapeutic potential for the treatment of inflammatory disorders.

Docosahexaenoic acid induces M2 macrophage polarization through peroxisome proliferator-activated receptor γ activation.

AIMS Impaired resolution of acute inflammation results in development of chronic inflammatory disorders such as atherosclerosis, asthma and arthritis. Clearance of apoptotic neutrophils by M2 macrophages, the process termed efferocytosis, is critical for complete resolution of inflammation as it prevents secondary necrosis caused by disgorgement of toxic contents from apoptotic cells in the inflamed site. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on efferocytosis. MAIN METHODS To determine the effect of DHA on efferocytosis, murine macrophage-like RAW264.7 cells were co-incubated with apoptotic Jurkat T cells, and efferocytosis was assessed by flow cytometry. The expression and production of M1 and M2 markers were determined by RT-PCR, ELISA and flow cytometry. To demonstrate the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in DHA-mediated effects, siRNA against PPARγ was utilized. The expression of PPARγ was examined by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blot analysis and immunocytochemistry. The PPARγ activation was measured by the electrophilic gel shift assay. KEY FINDINGS DHA enhanced the efferocytic ability of RAW264.7 cells, and induced their M2 polarization. Notably, knockdown of PPARγ abolished the stimulatory effect of DHA on M2 polarization as well as efferocytosis. Furthermore, lipopolysaccharide-induced production of pro-inflammatory cytokines was significantly inhibited by DHA, suggesting that DHA alters the macrophage phenotype in favor of M2 while it suppresses M1 polarization. SIGNIFICANCE These findings indicate that DHA can promote resolution of inflammation by facilitating efferocytosis through M2 macrophage polarization. Therefore, DHA may have a therapeutic potential in the management of inflammatory diseases which are related to impaired resolution of inflammation.

Influence of Propofol and Fentanyl on Deep Brain Stimulation of the Subthalamic Nucleus

We investigated the effect of propofol and fentanyl on microelectrode recording (MER) and its clinical applicability during subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. We analyzed 8 patients with Parkinsons disease, underwent bilateral STN DBS with MER. Their left sides were done under awake and then their right sides were done with a continuous infusion of propofol and fentanyl under local anesthesia. The electrode position was evaluated by preoperative MRI and postoperative CT. The clinical outcomes were assessed at six months after surgery. We isolated single unit activities from the left and the right side MERs. There was no significant difference in the mean firing rate between the left side MERs (38.7±16.8 spikes/sec, n=78) and the right side MERs (35.5±17.2 spikes/sec, n=66). The bursting pattern of spikes was more frequently observed in the right STN than in the left STN. All the electrode positions were within the STNs on both sides and the off-time Unified Parkinsons Disease Rating Scale part III scores at six months after surgery decreased by 67% of the preoperative level. In this study, a continuous infusion of propofol and fentanyl did not significantly interfere with the MER signals from the STN. The results of this study suggest that propofol and fentanyl can be used for STN DBS in patients with advanced Parkinsons disease improving the overall experience of the patients. Graphical Abstract

Heme oxygenase-1 determines the differential response of breast cancer and normal cells to piperlongumine.

Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic α,β-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine-induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2-mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine.

Helicobacter pylori induces Snail expression through ROS-mediated activation of Erk and inactivation of GSK-3β in human gastric cancer cells.

Helicobacter pylori (H. pylori) infection has been known to be implicated in human gastric carcinogenesis. Snail, the zinc‐finger transcription factor known as a key inducer of changes in the cell shape and morphogenetic movement, is aberrantly overexpressed and correlates with lymph node metastasis in gastric cancer. In the present study, we investigated whether H. pylori could induce Snail activation to provoke these changes. Using a cell scatter assay, we noticed that human gastric cancer AGS cells infected with H. pylori underwent morphological changes as well as disruption of cell–cell interaction, which was then reversed by silencing of Snail by use of small interfering RNA (siRNA). In addition, infection with H. pylori resulted in an increased intracellular level of Snail in gastric cancer cells, which was abrogated in the presence of U0126 and LY294002, inhibitors of MEK/Erk and PI3K/Akt pathways, respectively. Cycloheximide pulse‐chase experiments coupled with immunocytochemical analysis revealed that the induction of Snail by H. pylori was regulated at multiple levels, including increased transcription of Snail mRNA, inhibition of protein degradation, and enhancement of nuclear translocation of Snail. Pre‐treatment of AGS cells with N‐acetylcysteine, a well‐known reactive oxygen species (ROS) scavenger, attenuated the H. pylori‐induced activation of Erk, its binding to Snail promoter, inactivation of GSK‐3β, and accumulation of Snail. Collectively, these findings suggest that the upregulation of Snail expression induced by H. pylori and transformation to a spindle‐like shape as a consequence in gastric cancer cells are attributable to ROS‐mediated activation of Erk and the inhibition of GSK‐3β signaling.

Full Waveform Inversion Using Student’s t Distribution: a Numerical Study for Elastic Waveform Inversion and Simultaneous-Source Method

Seismic full waveform inversion (FWI) has primarily been based on a least-squares optimization problem for data residuals. However, the least-squares objective function can suffer from its weakness and sensitivity to noise. There have been numerous studies to enhance the robustness of FWI by using robust objective functions, such as l1-norm-based objective functions. However, the l1-norm can suffer from a singularity problem when the residual wavefield is very close to zero. Recently, Student’s t distribution has been applied to acoustic FWI to give reasonable results for noisy data. Student’s t distribution has an overdispersed density function compared with the normal distribution, and is thus useful for data with outliers. In this study, we investigate the feasibility of Student’s t distribution for elastic FWI by comparing its basic properties with those of the l2-norm and l1-norm objective functions and by applying the three methods to noisy data. Our experiments show that the l2-norm is sensitive to noise, whereas the l1-norm and Student’s t distribution objective functions give relatively stable and reasonable results for noisy data. When noise patterns are complicated, i.e., due to a combination of missing traces, unexpected outliers, and random noise, FWI based on Student’s t distribution gives better results than l1- and l2-norm FWI. We also examine the application of simultaneous-source methods to acoustic FWI based on Student’s t distribution. Computing the expectation of the coefficients of gradient and crosstalk noise terms and plotting the signal-to-noise ratio with iteration, we were able to confirm that crosstalk noise is suppressed as the iteration progresses, even when simultaneous-source FWI is combined with Student’s t distribution. From our experiments, we conclude that FWI based on Student’s t distribution can retrieve subsurface material properties with less distortion from noise than l1- and l2-norm FWI, and the simultaneous-source method can be adopted to improve the computational efficiency of FWI based on Student’s t distribution.

Curcumin suppresses oncogenicity of human colon cancer cells by covalently modifying the cysteine 67 residue of SIRT1

SIRT1, an NAD+-dependent histone/protein deacetylase, has diverse physiological actions. Recent studies have demonstrated that SIRT1 is overexpressed in colorectal cancer, suggesting its oncogenic potential. However, the molecular mechanisms by which overexpressed SIRT1 induces the progression of colorectal cancer and its inhibition remain largely unknown. Curcumin (diferuloymethane), a major component of the spice turmeric derived from the plant Curcuma longa L., has been reported to exert chemopreventive and anti-carcinogenic effects on colon carcinogenesis. In the present study, we found that curcumin reduced the expression of SIRT1 protein without influencing its mRNA expression in human colon cancer cells, suggesting posttranslational regulation of SIRT1 by this phytochemical. Notably, ubiquitination and subsequent proteasomal degradation of SIRT1 were induced by curcumin treatment. Results of nano-LC-ESI-MS/MS revealed the direct binding of curcumin to cysteine 67 of SIRT1. In line with this result, the protein stability and clonogenicity of a mutant SIRT1 in which cysteine 67 was substituted by alanine were unaffected by curcumin. Taken together, these observations suggest that curcumin facilitates the proteasomal degradation of oncogenic SIRT1 through covalent modification of SIRT1 at the cysteine 67 residue.

Curcumin interacts directly with the Cysteine 259 residue of STAT3 and induces apoptosis in H- Ras transformed human mammary epithelial cells

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is latent but constitutively activated in many types of cancers. It is well known that STAT3 plays a key role in inflammation-associated tumorigenesis. Curcumin is an anti-inflammatory natural compound isolated from the turmeric (Curcuma longa L., Zingiberaceae) that has been extensively used in a traditional medicine over the centuries. In the present study, we have found that curcumin inhibits STAT3 signaling that is persistently overactivated in H-Ras transformed breast epithelial cells (H-Ras MCF10A). Specific cysteine residues present in STAT3 appear to be critical for the activity as well as conformation of this transcription factor. We identified the cysteine residue 259 of STAT3 as a putative site for curcumin binding. Site-directed mutation of this cysteine residue abolished curcumin-induced inactivation of STAT3 and apoptosis in H-Ras MCF10A cells. The α,β-unsaturated carbonyl moiety of curcumin appears to be essential in its binding to STAT3 in H-Ras MCF10A cells. Tetrahydrocurcumin that lacks such electrophilic moiety failed to interact with STAT3 and to induce apoptosis in the same cell line. Taken together, our findings suggest that curcumin can abrogate aberrant activation of STAT3 through direct interaction, thereby inhibiting STAT3-mediated mammary carcinogenesis.

Feasibility of the P- and S-beam methods for stability estimation of the Daegok dam in Korea

We investigate the feasibility of using the P- and Sbeam seismic methods to evaluate the stability of dams, employing these methods to analyze the Daegok dam in Korea (a concrete faced rockfill dam; CFRD). In the beam method, adjacent shot gathers are stacked to generate super shot gathers, which can be similar to those obtained using a group of shots or groups of geophones. In the super shot gathers, surface waves and unwanted noises may be suppressed due to phase shifts that occur at adjacent shot gathers, whereas deep reflection events with slight phase differences may be enhanced. For this reason, deep reflection events can be better imaged than shallow ones. By applying the P- and Sbeam methods to the Daegok dam, we were able to image the interior structures of the dam and determine physical properties such as velocities and the Poisson’s ratio. Compared with the velocities obtained from borehole P-S logging for other rockfill dams, the velocities and Poisson’s ratio obtained for the Daegok dam are reasonable. Given that a strong source generator cannot be used with dams because it might damage them, we feel that the P- and S-beam methods can be effective means of evaluating dam safety.

AVO analysis using crossplot and amplitude polynomial methods for characterisation of hydrocarbon reservoirs

AVO analysis was conducted on hydrocarbon-bearing structures by applying the crossplot and offset-coordinate amplitude polynomial techniques. To evaluate the applicability of the AVO analysis, it was conducted on synthetic data that were generated with an anticline model, and field data from the hydrocarbon-bearing Colony Sand bed in Canada. Analysis of synthetic data from the anticline model demonstrates that the crossplot method yields zero-offset reflection amplitude and amplitude variation with negative values for the upper interface of the hydrocarbon-bearing layer. The crossplot values are clustered in the third quadrant. The results of AVO analysis based on the coefficients of the amplitude polynomial are similar to those from the crossplots. These well correlated results of AVO analysis on field and synthetic data suggest that both methods successfully investigate the characteristics of the reflections from the upper interface of a hydrocarbon-bearing layer. Analysis based on the incident-angle equation facilitates the application of various interpretation methods. However, it requires the conversion of seismic data to an incident angle gather. By contrast, analysis using coefficients of the amplitude polynomial is cost-effective because it allows examining amplitude variation with offset without involving the conversion process. However, it warrants further investigation into versatile application. The two different techniques can be complement each other effectively as AVO-analysis tools for the detection of hydrocarbon reservoirs.