• Journal of Pharmacopuncture
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• v.27 no.1
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• pp.38-46
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• 2024

Objectives: Genotoxicity is evaluated through a chromosomal aberration test using cultured mammalian cells to determine the toxicity of no-pain pharmacopuncture (NPP), which has recently been used to treat musculoskeletal pain disorders in Korean medical clinical practice. Methods: An initial test was performed to determine the dosage range of the NPP, followed by the main test. In this study, NPP doses of 10.0, 5.0, and 2.5%, and negative and positive controls were tested. An in vitro chromosome aberration test was performed using Chinese hamster lung cells under short-term treatment with or without metabolic activation and under continuous treatment without metabolic activation. Results: Compared with the saline negative control group, NPP did not significantly increase the frequency of chromosomal abnormalities in Chinese hamster lung cells, regardless of the presence or absence of metabolic activation. Additionally, the number of cells with structural chromosomal abnormalities was significantly higher in the positive control group than that in the negative control group that received saline. Conclusion: Based on the above results, the chromosomal abnormality-producing effect of NPP was determined to be negative under these test conditions.

• 한국생물공학회:학술대회논문집
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• 2005.10a
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• pp.864-864
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• 2005

• Molecules and Cells
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• v.43 no.11
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• pp.964-973
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• 2020

Recent studies have highlighted that early enhancement of the glycolytic pathway is a mode of maintaining the proinflammatory status of immune cells. Thiamine, a wellknown co-activator of pyruvate dehydrogenase complex, a gatekeeping enzyme, shifts energy utilization of glucose from glycolysis to oxidative phosphorylation. Thus, we hypothesized that thiamine may modulate inflammation by alleviating metabolic shifts during immune cell activation. First, using allithiamine, which showed the most potent anti-inflammatory capacity among thiamine derivatives, we confirmed the inhibitory effects of allithiamine on the lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production and maturation process in dendritic cells. We applied the LPS-induced sepsis model to examine whether allithiamine has a protective role in hyper-inflammatory status. We observed that allithiamine attenuated tissue damage and organ dysfunction during endotoxemia, even when the treatment was given after the early cytokine release. We assessed the changes in glucose metabolites during LPS-induced dendritic cell activation and found that allithiamine significantly inhibited glucose-driven citrate accumulation. We then examined the clinical implication of regulating metabolites during sepsis by performing a tail bleeding assay upon allithiamine treatment, which expands its capacity to hamper the coagulation process. Finally, we confirmed that the role of allithiamine in metabolic regulation is critical in exerting anti-inflammatory action by demonstrating its inhibitory effect upon mitochondrial citrate transporter activity. In conclusion, thiamine could be used as an alternative approach for controlling the immune response in patients with sepsis.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.4
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• pp.187-193
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• 2005

Several signal transduction pathways have been implicated in ischemic preconditioning induced by the activation of ATP-sensitive $K^+$ $(K_{ATP})$ channels. We examined whether protein kinase C (PKC) modulated the activity of $K_{ATP}$ channels by recording $K_{ATP}$ channel currents in rabbit ventricular myocytes using patch-clamp technique and found that phorbol 12,13-didecanoate (PDD) enhanced pinacidil-induced $K_{ATP}$ channel activity in the cell-attached configuration; and this effect was prevented by bisindolylmaleimide (BIM). $K_{ATP}$ channel activity was not increased by $4{\alpha}-PDD$. In excised insideout patches, PKC stimulated $K_{ATP}$ channels in the presence of 1 mM ATP, and this effect was abolished in the presence of BIM. Heat-inactivated PKC had no effect on channel activity. PKC-induced activation of $K_{ATP}$ channels was reversed by PP2A, and this effect was not detected in the presence of okadaic acid. These results suggest that PKC activates $K_{ATP}$ channels in rabbit ventricular myocytes.

• Natural Product Sciences
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• v.19 no.1
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• pp.1-7
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• 2013

AMP-activated protein kinase (AMPK) is a major cellular energy sensor and master regulator of metabolic homeostasis. On activation, this cellular fuel sensing enzyme induces a series of metabolic changes to balance energy consumption via multiple downstream signaling pathways controlling nutrient uptake and energy metabolism. This pivotal role of AMPK has led to the development of numerous AMPK activators which might be used as novel drug candidates in the treatment of AMPK related disorders, diabetes, obesity, and other metabolic diseases. Consequently, a number of patents have been published on AMPK activators from natural products and other sources. This review covers the patented AMPK activators from natural products and their therapeutic potential in treatment or prevention of metabolic diseases including diabetes and obesity.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.2
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• pp.213-220
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• 2016

Mast cells are primary mediators of allergic inflammation. Beta-1,3-glucan (BG) protects against infection and shock by activating immune cells. Activation of the BG receptor induces an increase in intracellular $Ca^{2+}$, which may induce exocytosis. However, little is known about the precise mechanisms underlying BG activation of immune cells and the possible role of mitochondria in this process. The present study examined whether BG induced mast cell degranulation, and evaluated the role of calcium transients during mast cell activation. Our investigation focused on the role of the mitochondrial calcium uniporter (MCU) in BG-induced degranulation. Black mouse (C57) bone marrow-derived mast cells were stimulated with $0.5{\mu}g/ml$ BG, $100{\mu}g/ml$ peptidoglycan (PGN), or $10{\mu}M$ A23187 (calcium ionophore), and dynamic changes in cytosolic and mitochondrial calcium and membrane potential were monitored. BG-induced mast cell degranulation occurred in a time-dependent manner, and was significantly reduced under calcium-free conditions. Ruthenium red, a mitochondrial $Ca^{2+}$ uniporter blocker, significantly reduced mast cell degranulation induced by BG, PGN, and A23187. These results suggest that the mitochondrial $Ca^{2+}$ uniporter has an important regulatory role in BG-induced mast cell degranulation.

• Journal of Life Science
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• v.33 no.3
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• pp.295-303
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• 2023

Immune and metabolic systems are important factors in maintaining homeostasis. Immune response and metabolic regulation are highly associated, so, when the normal metabolism is disturbed, the immune response changed followed the metabolic diseases occur. Likewise, obesity is highly related to immune response. Obesity, which is caused by an imbalance in energy metabolism, is associated with metabolic diseases, such as insulin resistance, type 2 diabetes, fatty liver diseases, atherosclerosis and hypertension. As known, obesity is characterized in chronic low-grade inflammation. In obesity, the microenvironment of immune cells became inflammatory by the unique activation phenotypes of immune cells such as macrophage, natural killer cell, T cell. Also, the immune cells interact each other in cellular or cytokine mechanisms, which intensify the obesity-induced inflammatory response. This phenomenon suggests the possibility of regulating the activation of immune cells as a pharmacological therapeutic strategy for obesity in addition to the common pharmacological treatment of obesity which is aimed at inhibiting enzymes such as pancreatic lipase and α-amylase or inhibiting differentiation of preadipocytes. In this review, we summarize the activation phenotypes of macrophage, natural killer cell and T cell, and their aspects in obesity. We also summarize the pharmacological substances that alleviates obesity by regulating the activation of immune cells.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.5
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• pp.299-304
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• 2005

Cardiac hypertrophy contributes an increased risk to major cerebrovascular events. However, the molecular mechanisms underlying cerebrovascular dysfunction during cardiac hypertrophy have not yet been characterized. In the present study, we examined the molecular mechanism of isoproterenol (ISO)-evoked activation of Ras/Raf/MAPK pathways as well as PKA activity in cerebral artery of rabbits, and we also studied whether the activations of these signaling pathways were altered in cerebral artery, during ISO-induced cardiac hypertrophy compared to heart itself. The results show that the mRNA level of c-fos (not c-jun and c-myc) in heart and these genes in cerebral artery were considerably increased during cardiac hypertrophy. These results that the PKA activity and activations of Ras/Raf/ERK cascade as well as c-fos expression in rabbit heart during cardiac hypertrophy were consistent with previous reports. Interestingly, however, we also showed a novel finding that the decreased PKA activity might have differential effects on Ras and Raf expression in cerebral artery during cardiac hypertrophy. In conclusion, there are differences in molecular mechanisms between heart and cerebral artery during cardiac hypertrophy when stimulated with β2 adrenoreceptor (AR), suggesting a possible mechanism underlying cerebrovascular dysfunction during cardiac hypertrophy.

• Journal of Oral Medicine and Pain
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• v.43 no.3
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• pp.61-69
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• 2018

Obstructive sleep apnea (OSA) is a relatively common, but greatly underdiagnosed sleep-related breathing disorder, characterized by recurrent collapse of the upper airway during sleep. OSA has been associated with a variety of cardiometabolic disease, such as hypertension, coronary artery disease, cardiac arrhythmia, cerebrovascular disease and metabolic dysfunction. Neurocognitive impairment, including excessive daytime sleepiness, increased risk of motor vehicle accidents, is also related to OSA. Sleep fragmentation and related arousals during sleep lead to intermittent hypoxia, sympathetic activation, oxidative stress, systemic inflammation and metabolic dysregulation which provide biological plausibility to this pathologic mechanism. Extensive studies demonstrated that OSA is a modifiable risk factor for the above mentioned diseases and oral appliances (OAs), although continuous positive air pressure (CPAP) is a first-line therapy of OSA, are not inferior to CPAP at least in mild OSA, and may be an alternative to CPAP in CPAP-intolerant subjects with OSA. The goal of this article is to provide a current knowledge of pathologic link between OSA and cardiovascular disease, focusing on intermittent hypoxia, sympathetic activation, oxidative stress and metabolic dysregulation. Then, previous epidemiologic studies will be reviewed to understand the causal relationship between OSA and cardiovascular disease. Finally, the effects of OAs will be updated via recent metaanalyses compared to CPAP.

• Archives of Pharmacal Research
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• v.25 no.2
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• pp.111-136
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• 2002

The prodrug and antedrug concepts, which were developed to overcome the physical and pharmacological shortcomings of various therapeutic classes of agents, employ diametrically different metabolic transformations. The prodrug undergoes a predictable metabolic activation prior to exhibiting its pharmacological effects in a target tissue while the antedrug undergoes metabolic deactivation in the systemic circulation upon leaving a target tissue. An increased therapeutic index is the aspiration for both approaches in designing as well as evaluation criteria. The recent research endeavors of prodrugs include the gene-directed and antibody-directed enzymatic activation of a molecule in a targeted tissue, organ specific delivery, improved bioavailabilities and cellular penetration of nucleotides. As for antedrugs, emphasis in research has been based upon the design and synthesis of systemically inactive molecule by incorporating a metabolically labile functional group into an active molecule.