Therapeutic Effect Of KS-356, A Novel Small Compound Targeting CD147, on Mice with NAFLD through Modulating the Inflammatory Crosstalk between Liver and Visceral Adipose Tissue: An 18F-FDG PET/CT Study

( Kisoo Pahk ),( Sang Gil Lee ),( Hyun Woo Kwon ),( Sang Geon Kim ),( Sungeun Kim ),( Won-ki Kim ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Inflamed and dysregulated visceral adipose tissue (VAT) secretes pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) thereby promoting systemic inflammation and insulin resistance which further lead to exacerbate the progression of nonalcoholic fatty liver disease (NAFLD). CD147 has been known to play key roles in mediating the inflammatory activation of macrophages through the activation of matrix metalloproteinase-9 (MMP-9). We identified that a novel drug KS-356 could bind to CD147 and inhibit its subsequent MMP-9 activation. Here, we investigated the suppressive effects of a novel drug KS-356 on NAFLD and inflamed VAT using high-fat induced mouse model and ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET/CT), which is a well-known non-invasive imaging modality for measurement of inflammatory activity, especially M1 macrophage. Methods: NAFLD was induced by a high-fat diet (HFD) (60% fat) for 20 weeks using the C57BL/6 mice. KS-356 (50 mg/kg) was orally given daily for 20 weeks. Both insulin tolerance- and glucose-tolerance were performed to assess the status of insulin-resistance and glucose-intolerance. Before sacrifice, blood serum was acquired to analysis of C-reactive protein (CRP) levels and ¹⁸F-FDG PET/CT was taken. After sacrifice, histomolecular analysis was performed on harvested liver and VAT. Results: KS-356 significantly improved insulin sensitivity with glucose homeostasis and reduced the progression of NAFLD. Furthermore, KS-356 also ameliorated VAT inflammation and its related systemic inflammation. There was no significant difference of daily food intake between HFD and HFD with KS-356 group. Conclusions: Owing to its beneficial effect across the liver-VAT-metabolic continuum, KS-356 could be a potential therapeutic drug candidate for NAFLD and related metabolic disorder.

Correlation between Semi-Quantitative ¹⁸F-FDG PET/CT Parameters and Ki-67 Expression in Small Cell Lung Cancer

Park, Soyeon,Lee, Eunsub,Rhee, Seunghong,Cho, Jaehyuk,Choi, Sunju,Lee, Sinae,Eo, Jae Seon,Pahk, Kisoo,Choe, Jae Gol,Kim, Sungeun The Korea Society of Nuclear Medicine 2016 핵의학 분자영상 Vol.50 No.1

Purpose The aim of this study was to evaluate the relationship between semiquantitative parameters on $^{18}F$-FDG PET/CT including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and the expression level of Ki-67 in small-cell lung cancer (SCLC). Methods Ninety-four consecutive patients with SCLC were enrolled in this study. They underwent $^{18}F$-FDG PET/CT for initial evaluation of SCLC, and we measured SUVmax, avgSUVmean, MTVsum, and TLGtotal on $^{18}F$-FDG PET/CT images. The protein expression of Ki-67 was examined by immunohistochemical staining. Results Significant correlations were found between the MTVsum and Ki-67 labeling index (r=0.254, p=0.014) and the TLGtotal and Ki-67 labeling index (r=0.239, p=0.020). No correlation was found between the SUVmax and Ki-67 labeling index (r=0.116, p=0.264) and the avgSUVmean and Ki-67 labeling index (r=0.031, p=0.770). Dividing the Ki-67 expression level into three categories, it was suggested that increasing Ki-67 expression level caused a stepwise increase in the MTVsum and TLGtotal. (p=0.028 and 0.039, respectively), but not the SUVmax and avgSUVmean (p=0.526 and 0.729, respectively). Conclusion In conclusion, the volume-based parameters of $^{18}F$-FDG PET/CT correlate with immunohistochemical staining of Ki-67 in SCLC. Measurement of the MTVsum and TLGtotal by $^{18}F$-FDG PET/CT might be a simple, noninvasive, and useful method to determine the proliferative potential of cancer cells.

Long-Term Isolation Elicits Depression and Anxiety-Related Behaviors by Reducing Oxytocin-Induced GABAergic Transmission in Central Amygdala

Han, Rafael T.,Kim, Young-Beom,Park, Eui-Ho,Kim, Jin Yong,Ryu, Changhyeon,Kim, Hye Y.,Lee, JaeHee,Pahk, Kisoo,Shanyu, Cui,Kim, Hyun,Back, Seung K.,Kim, Hee J.,Kim, Yang In,Na, Heung S. Frontiers Media S.A. 2018 Frontiers in molecular neuroscience Vol.11 No.-

<P>Isolation stress is a major risk factor for neuropsychiatric disorders such as depressive and anxiety disorders. However, the molecular mechanisms underlying isolation-induced neuropsychiatric disorders remain elusive. In the present study, we investigated the subcellular mechanisms by which long-term isolation elicits depression and anxiety-related behaviors in mice. First, we found that long-term isolation induced depression-related behaviors in the forced swimming test (FST) and the sucrose preference test, as well as anxiety-related behaviors in the elevated zero maze test (EZMT) and the open field test. Next, we showed that intracentral amygdala (CeA) injection of oxytocin (OXT), but not intracerebroventricular injection, attenuated isolation-induced depression and anxiety-related behaviors via oxytocin receptor (OXTR), not vasopressin-1a receptor (V1aR), in the FST and EZMT, respectively. Quantitative real-time polymerase chain reaction analysis revealed that after 5 weeks of isolation, mRNA transcription of OXTR in the CeA, but not that of V1aR, significantly decreased, whereas OXT and vasopressin mRNA transcription in the paraventricular nucleus of hypothalamus did not change significantly. Whole-cell patch clamping of acute brain slices demonstrated that the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in CeA neurons, but not their amplitude, was lower in isolated mice than in group-housed mice. Notably, OXT treatment increased the mIPSC frequency in the CeA neurons, but to a lesser extent in the case of isolated mice than in that of group-housed mice via OXTR. Taken together, our findings suggest that long-term isolation down-regulates OXTR mRNA transcription and diminishes OXT-induced inhibitory synaptic transmission in the CeA and may contribute to the development of depression and anxiety-related behaviors in isolated mice through the enhancement of CeA activity.</P>

Simvastatin Reduces Lipopolysaccharides-Accelerated Cerebral Ischemic Injury via Inhibition of Nuclear Factor-kappa B Activity

Jalin, Angela M.A. Anthony,Lee, Jae-Chul,Cho, Geum-Sil,Kim, Chunsook,Ju, Chung,Pahk, Kisoo,Song, Hwa Young,Kim, Won-Ki The Korean Society of Applied Pharmacology 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.6

Preceding infection or inflammation such as bacterial meningitis has been associated with poor outcomes after stroke. Previously, we reported that intracorpus callosum microinjection of lipopolysaccharides (LPS) strongly accelerated the ischemia/reperfusionevoked brain tissue damage via recruiting inflammatory cells into the ischemic lesion. Simvastatin, 3-hydroxy-3-methylgultaryl (HMG)-CoA reductase inhibitor, has been shown to reduce inflammatory responses in vascular diseases. Thus, we investigated whether simvastatin could reduce the LPS-accelerated ischemic injury. Simvastatin (20 mg/kg) was orally administered to rats prior to cerebral ischemic insults (4 times at 72, 48, 25, and 1-h pre-ischemia). LPS was microinjected into rat corpus callosum 1 day before the ischemic injury. Treatment of simvastatin reduced the LPS-accelerated infarct size by 73%, and decreased the ischemia/reperfusion-induced expressions of pro-inflammatory mediators such as iNOS, COX-2 and IL-$1{\beta}$ in LPS-injected rat brains. However, simvastatin did not reduce the infiltration of microglial/macrophageal cells into the LPS-pretreated brain lesion. In vitro migration assay also showed that simvastatin did not inhibit the monocyte chemoattractant protein-1-evoked migration of microglial/macrophageal cells. Instead, simvastatin inhibited the nuclear translocation of NF-${\kappa}B$, a key signaling event in expressions of various proinflammatory mediators, by decreasing the degradation of $I{\kappa}B$. The present results indicate that simvastatin may be beneficial particularly to the accelerated cerebral ischemic injury under inflammatory or infectious conditions.

Simvastatin Reduces Lipopolysaccharides-Accelerated Cerebral Ischemic Injury via Inhibition of Nuclear Factor-kappa B Activity

( Angela M. A. Anthony Jalin ),( Jae-chul Lee ),( Geum-sil Cho ),( Chunsook Kim ),( Chung Ju ),( Kisoo Pahk ),( Hwa Young Song ),( Won-ki Kim ) 한국응용약물학회 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.6

Preceding infection or inflammation such as bacterial meningitis has been associated with poor outcomes after stroke. Previously, we reported that intracorpus callosum microinjection of lipopolysaccharides (LPS) strongly accelerated the ischemia/reperfusion-evoked brain tissue damage via recruiting inflammatory cells into the ischemic lesion. Simvastatin, 3-hydroxy-3-methylgultaryl (HMG)-CoA reductase inhibitor, has been shown to reduce inflammatory responses in vascular diseases. Thus, we investigated whether simvastatin could reduce the LPS-accelerated ischemic injury. Simvastatin (20 mg/kg) was orally administered to rats prior to cerebral ischemic insults (4 times at 72, 48, 25, and 1-h pre-ischemia). LPS was microinjected into rat corpus callosum 1 day before the ischemic injury. Treatment of simvastatin reduced the LPS-accelerated infarct size by 73%, and decreased the ischemia/reperfusion-induced expressions of pro-inflammatory mediators such as iNOS, COX-2 and IL-1β in LPS-injected rat brains. Howeve , simvastatin did not reduce the infiltration of microglial/macrophageal cells into the LPS-pretreated brain lesion. In vitro migration assay also showed that simvastatin did not inhibit the monocyte chemoattractant protein-1-evoked migration of microglial/macrophageal cells. Instead, simvastatin inhibited the nuclear translocation of NF-κB, a key signaling event in expressions of various proinflammatory mediators, by decreasing the degradation of IκB. The present results indicate that simvastatin may be beneficial particularly to the accelerated cerebral ischemic injury under inflammatory or infectious conditions.