• Molecules and Cells
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• v.45 no.3
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• pp.134-147
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• 2022

The anti-oxidant enzyme heme oxygenase-1 (HO-1) is known to exert anti-inflammatory effects. From a library of pyrazolo[3,4-d]pyrimidines, we identified a novel compound KKC080096 that upregulated HO-1 at the mRNA and protein levels in microglial BV-2 cells. KKC080096 exhibited anti-inflammatory effects via suppressing nitric oxide, interleukin1β (IL-1β), and iNOS production in lipopolysaccharide (LPS)-challenged cells. It inhibited the phosphorylation of IKK and MAP kinases (p38, JNK, ERK), which trigger inflammatory signaling, and whose activities are inhibited by HO-1. Further, KKC080096 upregulated anti-inflammatory marker (Arg1, YM1, CD206, IL-10, transforming growth factor-β [TGF-β]) expression. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinetreated mice, KKC080096 lowered microglial activation, protected the nigral dopaminergic neurons, and nigral damage-associated motor deficits. Next, we elucidated the mechanisms by which KKC080096 upregulated HO-1. KKC080096 induced the phosphorylation of AMPK and its known upstream kinases LKB1 and CaMKKbeta, and pharmacological inhibition of AMPK activity reduced the effects of KKC080096 on HO-1 expression and LPS-induced NO generation, suggesting that KKC080096-induced HO-1 upregulation involves LKB1/AMPK and CaMKKbeta/AMPK pathway activation. Further, KKC080096 caused an increase in cellular Nrf2 level, bound to Keap1 (Nrf2 inhibitor protein) with high affinity, and blocked Keap1-Nrf2 interaction. This Nrf2 activation resulted in concurrent induction of HO-1 and other Nrf2-targeted antioxidant enzymes in BV-2 and in dopaminergic CATH.a cells. These results indicate that KKC080096 is a potential therapeutic for oxidative stress-and inflammation-related neurodegenerative disorders such as Parkinson's disease.

• Journal of Physiology & Pathology in Korean Medicine
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• v.38 no.1
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• pp.1-9
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• 2024

Cognitive reserve (CR) is a concept that can explain the discrepancies between the pathologic burden of the disease and clinical manifestations. It refers to the individual susceptibility to age-related brain changes and pathologies related to Alzheimer's disease, thus recognized as a factor affecting the trajectories of the disease. The purpose of this study was to explore the current states of clinical studies on neural substrates of CR in Alzheimer's disease using functional magnetic resonance imaging. We searched for clinical studies on CR using fMRI in the Pubmed, Cochrane library, RISS, KISS and ScienceON on August 14, 2023. Once the online search was finished, studies were selected manually by the inclusion criteria. Finally, we analyzed the characteristics of selected articles and reviewed the neural substrates of CR. Total thirty-four studies were included in this study. As surrogate markers of CR, not only education and occupational complexity, but also composite score and questionnaire-based method, which cover various areas of life, were mainly used. The most utilized methods in resting-state fMRI were independent component analysis, seed-based analysis, and graph theory analysis. Through the analysis, we demonstrated that neuroimaging techniques could capture the neural substrates associated with cognitive reserve. Moreover, functional connectivity of brain regions centered on prefrontal and parietal cortex and network areas such as default mode network showed a significant correlation with CR, which indicated a significant association with cognitive performance. CR may induce differential effects according to the disease status. We hope that this perspective on cognitive reserve would be helpful when conducting clinical researches on the mechanisms of traditional Korean medicine for Alzheimer's disease in the future.

• Nuclear Medicine and Molecular Imaging
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• v.40 no.6
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• pp.302-308
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• 2006

Purpose: Although several neuroanatomical models of panic disorder have been proposed, little is known regarding the neurological mechanisms underlying cognitive-behavioral therapy (CBT) in patients with panic disorder. This study was performed to identify the brain structures that show changes of regnioal cerebral blood flow (rCBF) after CBT in patients with panic disorder. Materials and Methods: Seven patients who were diagnosed as panic disorder by DSM-IV were treated with CBT for 8 weeks and twelve healthy volunteers joined in this study. Serial $^{99m}Tc-ECD$ brain perfusion SPECT images were acquisited and PDSS-SR (Self-Report version of Panic Disorder Severity Scale) and ACQ (Agoraphobic Cognitive Question) scores were measured just before and after CBT in all patients. Data were analyzed using SPM2. Results: Subjective symptoms were improved, and PDSS-SR and ACQ scores were significantly reduced ($14.9{\pm}3.9\;vs.\;7.0{\pm}1.8$, p<0.05; $30.3{\pm}8.5\;vs.\;21.6{\pm}3.4$, p<0.05, respectively) after CBT in panic patients. Before CBT, a significant increase of rCBF was found in the cingulate gylus, thalamus, midbrain, both medial frontal and temporal lobes of the panic patients compared to the normal volunteers. After CBT, we observed a significant rCBF decrease in the left parahippocamus, right insula and cingulate gyrus, both frontal and temporal lobes, and a significant rCBF increase in both the occipital lobes, left insula, both frontal and left parietal lobes. Conclusion: These data suggested that CBT is effective for panic disorder and diminish the activity of the brain areas associated with fear in panic disorder.

• BMB Reports
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• v.53 no.2
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• pp.100-105
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• 2020

While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague-Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorie-restricted (18R group), and 11 were both calorie- and protein-restricted with the low-protein diet (6R group). Overnight-fasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3β inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3β activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3β activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3β activity and mitochondrial function in insulin-deficient state.

• Korean Journal of Biological Psychiatry
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• v.8 no.1
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• pp.85-95
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• 2001

This study was designed to examine the effects of two antidepressant drugs on the expression of c-fos mRNA in cultured embryonic rat hippocampal neurons. The drugs used were imipramine and amitriptyline. On the fourth day of culture, hippocampal neurons were treated with variable concentrations of each drug. Competitive RT-PCR(Reverse Transcriptase-PCR) analysis was used to quantify the c-fos mRNA expression induced by each drug. Experimental results showed that acute and direct treatment with imipramine and amitriptyline with relatively low concentrations(imipramine ${\leq}10{\mu}M$, amitriptylne ${\leq}10{\mu}M$) had no inductive effect on the expression of c-fos mRNA in the rat hippocampal neurons. However, after treatment with relatively high concentrations(imipramine ${\geq}100{\mu}M$, amitriptyline ${\geq}100{\mu}M$) c-fos mRNA was not detected. These findings suggest the followings. Firstly, the action mechanisms of these drugs on the hippocampal neurons might not be mediated by c-fos but by other immediate-early genes(IEGs). Secondly, their actions may be mediated indirectly via other areas of the brain. Thirdly, the expression of c-fos might be inhibited by high concentrations of these drugs, or the high concentrations could induce cell death. Finally, though cell death remains to be confirmed, the inhibition of c-fos induction or cell death could play a role in the cognitive impairments known to be adverse effects of some antidepressants. This study is believed to be a first step toward understanding the mechanisms of learning and memory. Further studies are needed to investigate the expression of various IEGs and changes in the hippocampal neurons of rat resulting from chronic treatment with antidepressant drugs.

• Toxicological Research
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• v.17
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• pp.47-57
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• 2001

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, and its pathology is characterized by the presence of numerous numbers of senile plaques and neurofibrillary tangles. Several genetic and transgenic studies have indicated that excess amount of $\beta$-amyloid protein (A$\beta$) is produced by mutations of $\beta$TEX>$\beta$-amyloid precursor protein and causes learning impairment. Moreover, $A\beta$ has a toxic effect on cultured nerve cells. To prepare AD model animals, we have examined continuous (2 weeks) infusion of $A\beta$ into the cerebral ventricle of rats. Continuous infusion of $A\beta$ induces learning impairment in water maze and passive avoidance tasks, and decreases choline acetyltransferase activity in the frontal cortex and hippocampus. Immunohistochemical analysis revealed diffuse depositions of $A\beta$ in the cerebral cortex and hippocampus around the ventricle. Furthermore, the nicotine-evoked release of acetylcholine and dopamine in the frontal cortex/hippocampus and striatum, respectively, is decreased in the $A\beta$-infused group. Perfusion of nicotine (50 $\mu\textrm{M}$) reduced the amplitude of electrically evoked population spikes in the CA1 pyramidal cells of the control group, but not in those of the $A\beta$-infused group, suggesting the impairment of nicotinic signaling in the $A\beta$-infused group. In fact, Kd, but not Bmax, values for ［$^3H$］ cytisine binding in the hippocampus significantly increased in the $A\beta$-infused rats. suggesting the decrease in affinity of nicotinic acetylcholine receptors. Long-term potentiation (LTP) induced by tetanic stimulations in CA1 pyramidal cells, which is thought to be an essential mechanism underlying learning and memory, was readily observed in the control group, whereas it was impaired in the $A\beta$-infused group. Taken together, these results suggest that $A\beta$ infusion impairs the signal transduction mechanisms via nicotinic acetylcholine receptors. This dysfunction may be responsible, at least in part, for the impairment of LTP induction and may lead to learning and memory impairment. We also found the reduction of glutathione- and Mn-superoxide dismutase-like immunoreactivity in the brains of $A\beta$-infused rats. Administration of antioxidants or nootropics alleviated learning and memory impairment induced by $A\beta$ infusion. We believe that investigation of currently available transgenic and non-transgenic animal models for AD will help to clarify the pathogenic mechanisms and allow assessment of new therapeutic strategies.

• Nutrition Research and Practice
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• v.6 no.2
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• pp.97-105
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• 2012

$Schizandra$ $chinensis$ Baillon is a traditional folk medicine plant that is used to treat and prevent several inflammatory diseases and cancer in Korea, but the underlying mechanisms involved in its anti-allergic activity are not fully understood. This study was designed to investigate mechanisms of anti-allergic activity of a $Schizandra$ $chinensis$ Baillon water extract (SCWE) in immunoglobulin E (IgE)-antigen complex-stimulated RBL2H3 cells and to assess whether gastric and intestinal digestion affects the anti-allergic properties of SCWE. Oxidative stress is an important consequence of the allergic inflammatory response. The antioxidant activities of SCWE increased in a concentration-dependent manner. RBL-2H3 cells were sensitized with monoclonal anti-dinitrophenol (DNP) specific IgE, treated with SCWE, and challenged with the antigen DNP-human serum albumin. SCWE inhibited ${\beta}$-hexosaminidase release and expression of interleukin (IL)-4, IL-13, and tumor necrosis factor-alpha (TNF-${\alpha}$) mRNA and protein in IgE-antigen complex-stimulated RBL2H3 cells. We found that digested SCWE fully maintained its antioxidant activity and anti-allergic activity against the IgE-antigen complex-induced activation of RBL-2H3 cells. SCWE may be useful for preventing allergic diseases, such as asthma. Thus, SCWE could be used as a natural functional ingredient for allergic diseases in the food and/or pharmaceutical industries.

• Journal of Trauma and Injury
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• v.25 no.4
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• pp.247-253
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• 2012

Purpose: Hemorrhage is a main cause of death in trauma patients. The goal of this study is to describe the characteristics of trauma patients with massive bleeding and to evaluate the prognostic factors concerning their survival. Methods: This study was performed retrospectively and included trauma patients with massive bleeding who had been treated from March 2007 to August 2012. The inclusion criterion was patients who received more than 10 U of packed red blood cells within the first 24 hours after visiting the emergency department. Based on their medical records, we collected data in terms of demographic findings, mechanisms of injury, initial clinical and laboratory findings, methods for hemostasis (emergency surgery and/or angioembolization), transfusion, injury severity score (ISS), revised trauma score (RTS) and trauma and injury severity score (TRISS). We used the Mann-Whitney U test and Fisher's exact test to compare the variables between the patients that survived and those that did not. We performed a logistic regression analysis with the significant variables from the univariate test. Results: Thirty-two(32) patients were enrolled. The main mechanisms of injury were falls and motor vehicle accidents. The mean transfusion amount of packed red blood cells (PRBC) was 17.4 U. The mean elapsed time for the first hemostasis (surgery or embolization) was 3.5 hours. The initial technical success rates were 83.3%(15/18) in angioembolization and 66.7%(8/12) in surgery. The overall mortality rate was 34.4%(11/32). The causes of death were bleeding, brain swelling and multiple organ failure. The ISS(25.5 vs 46.3, p=0.000), TRISS(73.6 vs 45.1, p=0.034) and base excess(<-12 mmol/L, p=0.020) were significantly different between the patients who survived and those who did not. Conclusion: The ISS was a prognostic factor for trauma patients with massive bleeding.

• Advances in Traditional Medicine
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• v.5 no.3
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• pp.216-230
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• 2005

Although the field of study in immune enhancing compounds is relatively new, natural products from plants represent a rich and promising source of novel molecules with immunomodulating properties, Microglial cells, the main immune effector cells of the brain, usually display a ramified morphology and low expression levels of immunologically relevant antigens such as MHC class I and class II. Since any compound which participates in activation of phagocytic cells contributes to the production of potentially toxic factors, the search for convenient in vitro test-systems and study of mechanisms of action of these agents are of great interest. Human blood polymorphonuclear (PMN) cells and primary microglial cells isolated from Sprague-Dawley rats were used as cellular screening tests for study of phagocytosis-stimulating action of immunomodulating agents. Numbers of phagocytic activity were evaluated by the phagocyte ingestion of yeast cells and NO-synthase activity, nitrite production, and nitroblue tetrazolium test were determined after phagocyte stimulation. It was possible to demonstrate that indexes of phagocytic activity can be used as quantitative indicators for measurement immunomodulating activity. As a positive control, Zymosan A-induced phagocytosis in both PMN cells and primary microglial cells was used. $IFN-{\gamma}$ (0.1 -1 U/ml) stimulated phagocytosis in PMN cells 1.2 times after 2 - 3 h incubation, although at higher concentrations (10 - 100 U/ml) it strongly inhibited phagocytosis. In a similar way, at higher concentrations, $IFN-{\gamma}$ (100 - 500 U/ml) suppressed phagocytosis in zymosan-A stimulated microglial cells. When Polypodium leucotomus, cambricum and vulgare extracts were tested alone, increased levels of phagocytosis were observed in PMN. In addition, microglial cells showed both increased phagocytosis and MHC class-II antigen expressions. Surprisingly, when PMN and microglia were treated with a combination of Polypodium and $IFN-{\gamma}$, phagocytosis was not inhibited. We did not find changes in NO-synthase activity and nitrite production in both microglia and PMN cells activated by different immunomodulating agents. These results indicate that primary microglial cell cultures as well as human PMN cells can provide reproducible quantitative results in screening phagocytic activity of different immunoactive compounds. Furthermore, both inhibitory or activation mechanisms might be studied using these in vitro experimental approaches.

• Asian-Australasian Journal of Animal Sciences
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• v.20 no.8
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• pp.1182-1189
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• 2007

An intracerebroventricular (ICV) infusion of somatostatin 1-28 (SRIF) was used as a thirst-controlling peptide antagonist to investigate whether or not thirst-controlling peptides are involved in the significant decrease in feed intake during the initial stages of feeding large-type goats on dry forage. A continuous ICV infusion of SRIF was conducted at a small dose of $4{\mu}g$ ml/h for 27 h from day 1 to day 2. Goats (n = 5) were fed roughly crushed alfalfa hay cubes for 2 h twice daily and water was given ad libitum. Feed intake was measured during ICV infusion of artificial cerebrospinal fluid (ACSF) and SRIF. The feed intake during SRIF infusion increased significantly compared to that during ACSF infusion. In comparison to the ACSF treatment, plasma osmolality during the SRIF treatment significantly decreased during the first half of the 2 h feeding period. The factor causing the decrease in plasma osmolality during the ICV infusion of SRIF was a decrease in plasma Na, K, Cl, and Mg concentrations. In comparison to the ACSF infusion treatment, parotid saliva secretion volumes during the 2 h feeding period in the SRIF infusion treatment were significantly larger. While there was no significant difference in cumulative water intake (thirst levels) between the SRIF and the ACSF treatments upon conclusion of the 2 h feeding period, based on the plasma osmolality results it is thought that thirst level increases brought about by alfalfa hay cube feeding in the first half of the feeding period were reduced. It is thought that the somatostatin-induced increases in feed intake during the 2 h feeding period in the present experiment were caused by decreases in plasma osmolality brought about by the somatostatin infusion. As a result, it is suggested that the significant decrease in feed intake during the initial stages of feeding in large-type goats given roughly crushed alfalfa hay cubes, was due to the actions of thirst-controlling peptides.