Jae-Seung Kang

Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects.

Benzylidene-2,4-thiazolidinedione derivatives with substitutions on the phenyl ring at the ortho or para positions of the thiazolidinedione (TZD) group were synthesized as PTP1B inhibitors with IC50 values in a low micromolar range. Compound 3e, the lowest, bore an IC50 of 5.0 microM. In vivo efficacy of 3e as an antiobesity and hypoglycemic agent was evaluated in a mouse model system. Significant improvement of glucose tolerance was observed. This compound also significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA. Compound 3e was also found to activate peroxisome proliferator-activated receptors (PPARs) indicating multiple mechanisms of action.

Persistence of Orientia tsutsugamushi in humans.

We investigated the persistence of viable Orientia tsutsugamushi in patients who had recovered from scrub typhus. Blood specimens were available from six patients with scrub typhus who were at 1 to 18 months after the onset of the illness. The EDTA-treated blood specimens were inoculated into ECV304 cells, and cultures were maintained for 7 months. Sequencing of the 56-kDa type-specific antigen gene of O. tsutsugamushi was performed to ascertain the homology of isolates. O. tsutsugamushi was isolated from all six patients, and nucleotide sequences of isolates serially collected from each patient were identical in all five patients in whom nucleotide sequences were compared. One patient relapsed 2 days after completion of antibiotic therapy; two patients complained of weakness for 1 to 2.5 months after the illness; one patient underwent coronary angioplasty 6 months later; and one patient suffered from a transient ischemic attack 8 months later. This finding suggests that O. tsutsugamushi causes chronic latent infection, which may be associated with certain clinical illnesses, preceded by scrub typhus. Antibiotic therapy abates the symptoms of scrub typhus, but does not eradicate O. tsutsugamushi from the human body.

Japanese Spotted Fever, South Korea

We describe the first case of Japanese spotted fever and the first isolate of spotted fever group rickettsia from a patient in South Korea. The isolated rickettsia from the patient was identified as Rickettsia japonica by analysis of the nucleotide sequences of 16S rRNA, gltA, ompA, ompB, and sca4 genes.

Orientia tsutsugamushi induced endothelial cell activation via the NOD1-IL-32 pathway

Orientia tsutsugamushi (OT), the causative agent of scrub typhus, is an obligate intracellular bacterium. In order to verify the inflammatory responses involved in the pathogenesis of scrub typhus, we assessed the cytokine profile of the human endothelial cell line, ECV304, after OT infection. We noted that CCL5, CCL17, IL-1alpha, IL-6, IL-8, IL-10, IL-15, TNF-alpha and TNF-beta were strongly induced in response to OT. Additionally, IL-32, the candidate modulator for the induction of IL-6 and IL-8, was increased significantly with OT infection and these increases coincided with NOD1 pathway activation. Thus, we hypothesized that NOD1 pathway and IL-32 might act on cytokine release in endothelial cells as a modulator of the inflammation caused by OT infection. NOD1 siRNA resulted in a reduction in IL-32 levels, and also reduced IL-1beta, IL-6, IL-8, and ICAM-1 expression in OT-infected ECV304 cells. These changes in IL-1beta, IL-6, IL-8, and ICAM-1 induced by NOD1 knockdown were reversed as the result of IL-32 treatment. This indicated that OT infection activated the NOD1 pathway followed by IL-32 secretion, thus resulting in the production and expression of IL-1beta, IL-6, IL-8, and ICAM-1. Therefore, IL-32 might perform a role upstream of the inflammatory reaction in endothelial cells of OT infection.

Influence of CYP2D6*10 on the pharmacokinetics of metoprolol in healthy Korean volunteers

Background and objective:  Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates. The CYP2D6*10 allele is clinically important in Koreans because of its high frequency in Asians. We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6*10 allele in Korean subjects.

Orientia tsutsugamushi Inhibits Apoptosis of Macrophages by Retarding Intracellular Calcium Release

ABSTRACT Orientia tsutsugamushi shows both pro- and antiapoptotic activities in infected vertebrate cells. Apoptosis of THP-1 cells induced by beauvericin was inhibited by O. tsutsugamushi infection. Beauvericin-induced calcium redistribution was significantly reduced and retarded in cells infected with O. tsutsugamushi. Antiapoptotic activities of O. tsutsugamushi in infected cells are most probably due to inhibition of the increase in the cytosolic calcium concentration.

Requirement of MEF2D in the induced differentiation of HL60 promyeloid cells

The regulatory role of MEF2 (myocyte enhancer binding factor 2) proteins in nonmuscle tissues has not been well characterized. We examined the expression of MEF2 family members, namely, MEF2A, -B, -C, and -D, in the differentiation of HL60 promyeloid cells and observed the remarkable increase in the expressions of MEF2A and MEF2D proteins during the differentiation process into monocytes. To examine the role of MEF2, we expressed a dominant-negative form of MEF2D, without its transactivation domain, in HL60 cells. When the HL60 cell line expressing the mutant MEF2D was induced to differentiate by VitD(3) treatment, cell surface expression of CD14 and the ability to reduce NBT, which are important characteristics of differentiated monocytes, were significantly decreased compared with control HL60 cells. These results show that MEF2D is required in the differentiation process along the monocyte/macrophage lineage,

Antigenic Relationship among the Eight Prototype and New Serotype Strains of Orientia tsutsugamushi Revealed by Monoclonal Antibodies

Orientia tsutsugamushi, the etiologic agent of tsutsugamushi disease, exhibits great antigenic variation. Three classical strains (Karp, Gilliam, and Kato) and new antigenic types from Thailand (TA686, TA678, TA716, TA763, and TH1817) have been used as prototype strains of O. tsutsugamushi in many studies. In this study, monoclonal antibodies to the five Thailand strains were produced, and their reactivity against prototype strains and newly identified isolates from Korea and Japan was tested. With a panel of these monoclonal antibodies, we could analyze the antigenic relationship among various strains of O. tsutsugamushi from Thailand, Japan, and Korea. Twelve strains of the O. tsutsugamushi tested showed various reactivities to monoclonal antibodies, and no distinct pattern of reactivity was found according to their location of isolation. Although the Boryong and Kuroki strains were similar in reactivities to most monoclonal antibodies, several monoclonal antibodies could differentiate the two strains. These results indicate that the immunofluorescence antibody test using monoclonal antibodies used in this study is valuable for analyzing the antigenic relationship and classification of O. tsutsugamushi.

Isolation of a New Orientia tsutsugamushi Serotype

Orientia tsutsugamushi, the etiological agent of scrub typhus, is an antigenically diverse organism and many serologically distinct strains have been identified. The 56 kDa protein of O. tsutsugamushi, a major protein in the outer membrane, has been thought to be responsible for this antigenic variability. A strain of O. tsutsugamushi isolated in Korea cross‐reacted with both Gilliam strain‐specific and Karp strain‐specific monoclonal antibodies. When its 56 kDa protein gene was cloned and analyzed, its sequence showed variation especially between 1,200 and 1,250 bp, showing that this isolate is a new O. tsutsugamushi strain.

Diversification of Orientia tsutsugamushi genotypes by intragenic recombination and their potential expansion in endemic areas

Background Scrub typhus is a mite-borne febrile disease caused by O. tsutsugamushi infection. Recently, emergence of scrub typhus has attracted considerable attention in several endemic countries in Asia and the western Pacific. In addition, the antigenic diversity of the intracellular pathogen has been a serious obstacle for developing effective diagnostics and vaccine. Methodology/Principal findings To understand the evolutionary pathway of genotypic diversification of O. tsutsugamushi and the environmental factors associated with the epidemiological features of scrub typhus, we analyzed sequence data, including spatiotemporal information, of the tsa56 gene encoding a major outer membrane protein responsible for antigenic variation. A total of 324 tsa56 sequences covering more than 85% of its open reading frame were analyzed and classified into 17 genotypes based on phylogenetic relationship. Extensive sequence analysis of tsa56 genes using diverse informatics tools revealed multiple intragenic recombination events, as well as a substantially higher mutation rate than other house-keeping genes. This suggests that genetic diversification occurred via frequent point mutations and subsequent genetic recombination. Interestingly, more diverse bacterial genotypes and dominant vector species prevail in Taiwan compared to other endemic regions. Furthermore, the co-presence of identical and sub-identical clones of tsa56 gene in geographically distant areas implies potential spread of O. tsutsugamushi genotypes. Conclusions/Significance Fluctuation and diversification of vector species harboring O. tsutsugamushi in local endemic areas may facilitate genetic recombination among diverse genotypes. Therefore, careful monitoring of dominant vector species, as well as the prevalence of O. tsutsugamushi genotypes may be advisable to enable proper anticipation of epidemiological changes of scrub typhus.