• Molecules and Cells
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• v.46 no.6
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• pp.387-398
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• 2023

Microtubule acetylation has been proposed as a marker of highly heterogeneous and aggressive triple-negative breast cancer (TNBC). The novel microtubule acetylation inhibitors GM-90257 and GM-90631 (GM compounds) cause TNBC cancer cell death but the underlying mechanisms are currently unknown. In this study, we demonstrated that GM compounds function as anti-TNBC agents through activation of the JNK/AP-1 pathway. RNA-seq and biochemical analyses of GM compound-treated cells revealed that c-Jun N-terminal kinase (JNK) and members of its downstream signaling pathway are potential targets for GM compounds. Mechanistically, JNK activation by GM compounds induced an increase in c-Jun phosphorylation and c-Fos protein levels, thereby activating the activator protein-1 (AP-1) transcription factor. Notably, direct suppression of JNK with a pharmacological inhibitor alleviated Bcl2 reduction and cell death caused by GM compounds. TNBC cell death and mitotic arrest were induced by GM compounds through AP-1 activation in vitro. These results were reproduced in vivo, validating the significance of microtubule acetylation/JNK/AP-1 axis activation in the anti-cancer activity of GM compounds. Moreover, GM compounds significantly attenuated tumor growth, metastasis, and cancer-related death in mice, demonstrating strong potential as therapeutic agents for TNBC.

• Biomolecules & Therapeutics
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• v.31 no.6
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• pp.682-691
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• 2023

Cell transformation induced by epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) is a critical event in cancer initiation and progression, and understanding the underlying mechanisms is essential for the development of new therapeutic strategies. Licorice extract contains various bioactive compounds, which have been reported to have anticancer and anti-inflammatory effects. This study investigated the cancer preventive efficacy of licochalcone D (LicoD), a chalcone derivative in licorice extract, in EGF and TPA-induced transformed skin keratinocyte cells. LicoD effectively suppressed EGF-induced cell proliferation and anchorage-independent colony growth. EGF and TPA promoted the S phase of cell cycle, while LicoD treatment caused G1 phase arrest and down-regulated cyclin D1 and up-regulated p21 expression associated with the G1 phase. LicoD also induced apoptosis and increased apoptosis-related proteins such as cleaved-caspase-3, cleaved-caspase-7, and Bax (Bcl2-associated X protein). We further investigated the effect of LicoD on the AKT signaling pathway involved in various cellular processes and found decreased p-AKT, p-GSK3β, and p-NFκB expression. Treatment with MK-2206, an AKT pharmacological inhibitor, suppressed EGF-induced cell proliferation and transformed colony growth. In conclusion, this study demonstrated the potential of LicoD as a preventive agent for skin carcinogenesis.

• The Journal of Internal Korean Medicine
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• v.44 no.6
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• pp.1243-1255
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• 2023

Objective: This study aims to explore the pharmacological effects and mechanisms of enzyme (Viscozyme)-treated garlic extract (EG) in an animal model of acute enteritis induced by lipopolysaccharide (LPS). Methods: The experiment included four subgroups: normal, control, EG200 (treated with 200 mg/kg EG), and EG400 (treated with 400 mg/kg EG). Drug administration lasted 3 days, followed by the induction of acute enteritis in all groups (except normal) through the intraperitoneal administration of 20 mg/kg of LPS 1 h after the last oral dose. Autopsy was conducted 24 h later to collect serum and colon tissue. Serum was analyzed for reactive oxygen species (ROS) and C-reactive protein (CRP), while Western blotting was performed on the colon tissue. Results: After analyzing the ROS and CRP levels in serum, the EG treatment group exhibited a significant decrease compared with the control group. The EG treatment group exhibited a significant decrease in the activation of the mitogen-activated protein kinases (MAPKs)/nuclear factor-kappa B p65 (NF-κB) pathway compared with the control group. EG administration significantly regulated apoptosis-related factors, including B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X, cysteine aspartyl-specific protease-3, and cytochrome C. Conclusions: EG treatment in mice with LPS-induced acute colitis reduced the ROS and CRP levels, suppressed the MAPKs/NF-κB pathway in the colon, and effectively alleviated acute enteritis by modulating apoptosis-related factors. Based on these findings, EG emerges as a promising candidate for the prevention and treatment of acute colitis, showing its potential therapeutic efficacy in this experimental model.

• The Korea Journal of Herbology
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• v.39 no.3
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• pp.37-47
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• 2024

Objectives : Because predicting the potential efficacy and mechanisms of Korean medicines is challenging due to their high complexity, employing an approach based on network pharmacology could be effective. In this study, network pharmacological analysis was utilized to anticipate the effects of YunPye-Hwan (YPH) in treating Chronic obstructive pulmonary disease (COPD). Methods : Compounds and their related target genes of YPH were gathered from the TCMSP and PubChem databases. These target genes of YPH were subsequently compared with gene sets associated with COPD to assess correlation. Next, core genes were identified through a two-step screening process, and finally, functional enrichment analysis of these core genes was conducted using both Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways. Results : A total of 15 compounds and 437 target genes were gathered, resulting in a network comprising 473 nodes and 14,137 edges. Among them, 276 genes overlapped with gene sets associated with COPD, indicating a significant correlation between YPH and COPD. Functional enrichment analysis of the 18 core genes revealed biological processes and pathways such as "miRNA Transcription," "Nucleic Acid-Templated Transcription," "DNA-binding Transcription Factor Activity," "MAPK signaling pathway," and "TNF signaling pathway" were implicated. Conclusion : YPH exhibited significant relevance to COPD by modulating cell proliferation, differentiation, inflammation, and cell death pathways. This study could serve as a foundational framework for further research investigating the potential use of YPH in the treatment of COPD.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.3
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• pp.229-237
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• 2024

Cough is a common symptom of several respiratory diseases. However, frequent coughing from acute to chronic often causes great pain to patients. It may turn into cough variant asthma, which seriously affects people's quality of life. For cough treatment, it is dominated by over-the-counter antitussive drugs, such as asmeton, but most currently available antitussive drugs have serious side effects. Thus, there is a great need for the development of new drugs with potent cough suppressant. BALB/c mice were used to construct mice model with cough to investigate the pharmacological effects of pectolinarigenin (PEC). Hematoxylin-eosin and Masson staining were used to assess lung injury and airway remodeling, and ELISA was used to assess the level of inflammatory factor release. In addition, inflammatory cell counts were measured to assess airway inflammation. Airway hyperresponsiveness assay was used to assess respiratory resistance in mice. Finally, we used Western blotting to explore the potential mechanisms of PEC. We found that PEC could alleviate lung tissue injury and reduce the release of inflammatory factors, inhibit of cough frequency and airway wall collagen deposition in mice model with cough. Meanwhile, PEC inhibited the Ras/ERK/c-Fos pathway to exhibit antitussive effect. Therefore, PEC may be a potential drug for cough suppression.

• The Journal of Korean Medicine
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• v.45 no.1
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• pp.114-125
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• 2024

Objectives: Network pharmacology is an analysis method that explores drug-centered efficacy and mechanism by constructing a compound-target-disease network based on system biology, and is attracting attention as a methodology for studying herbal medicine that has the characteristics for multi-compound therapeutics. Thus, we investigated the potential functions and pathways of Myrrha on Allergic Rhinitis (AR) via network pharmacology analysis and molecular docking. Methods: Using public databases and PubChem database, compounds of Myrrha and their target genes were collected. The putative target genes of Myrrha and known target genes of AR were compared and found the correlation. Then, the network was constructed using STRING database, and functional enrichment analysis was conducted based on the Gene Ontology (GO) Biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways. Binding-Docking stimulation was performed using CB-Dock. Results: The result showed that total 3 compounds and 55 related genes were gathered from Myrrha. 33 genes were interacted with AR gene set, suggesting that the effects of Myrrha are closely related to AR. Target genes of Myrrha are considerably associated with various pathways including 'Fc epsilon RI signaling pathway' and 'JAK-STAT signaling pathway'. As a result of blinding docking, AKT1, which is involved in both mechanisms, had high binding energies for abietic acid and dehydroabietic acid, which are components of Myrrha. Conclusion: Through a network pharmacological method, Myrrha was predicted to have high relevance with AR by regulating AKT1. This study could be used as a basis for studying therapeutic effects of Myrrha on AR.

• Anatomy and Cell Biology
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• v.56 no.1
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• pp.69-85
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• 2023

Depression is one of the most common neuropsychiatric disorders and is associated with dysfunction of the neuroendocrine system and alterations in specific brain proteins. Boophone disticha (BD) is an indigenous psychoactive bulb that belongs to the Amaryllidacae family, which is widely used in Southern Africa to treat depression, with scientific evidence of potent antidepressant-like effects. The present study examined the antidepressant effects of BD and its mechanisms of action by measuring some behavioural parameters in the elevated plus maze, brain content of corticosterone, brain derived neurotropic factor (BDNF), and neuroblast differentiation in the hippocampus of Balb/c mice exposed to the five day repeated forced swim stress (5d-RFSS). Male Balb/c mice were subjected to the 5d-RFSS protocol to induce depressive-like behaviour (decreased swimming, increased floating, decreased open arm entry, decreased time spent in the open arms and decreased head dips in the elevated plus maze test) and treated with distilled water, fluoxetine and BD. BD treatment (10 mg/kg/p.o for 3 weeks) significantly attenuated the 5d-RFSS-induced behavioural abnormalities and the elevated serum corticosterone levels observed in stressed mice. Additionally, 5d-RFSS exposure significantly decreased the number of neuroblasts in the hippocampus and BDNF levels in the brain of Balb/c mice, while fluoxetine and BD treatment attenuated these changes. The antidepressant effects of BD were comparable to those of fluoxetine, but unlike fluoxetine, BD did not show any anxiogenic effects, suggesting better pharmacological functions. In conclusion, our study shows that BD exerted antidepressant-like effects in 5d-RFSS mice, mediated in part by normalizing brain corticosterone and BDNF levels.

• Journal of Pharmacopuncture
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• v.27 no.2
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• pp.131-141
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• 2024

Objectives: Polycystic ovary syndrome (PCOS) is one of the most common disorders and it shows up to 20% prevalence in reproductive-aged women populations, but no cures are available to date. We aimed to investigate the protective effects of Changbudodam-tang (CBD) on cell death signaling pathways, inflammation, and oxidative stress observed in Bone-Marrow derived human mesenchymal stem cell (BM-hMSC) by means of PCOS therapeutics in the future. Methods: BM-hMSCs were applied with cell deaths and injuries. Apoptosis and pyroptosis signals were quenched with their related signaling pathways using quantitative PCR, Western blot, and fluorescence image analysis. Results: Our data clearly displayed hydrogen peroxide- and nigericin-treated cell death signaling pathways via regulations of mitochondrial integrity and interleukin (IL)-1β at the cellular levels (p < 0.01 or 0.001). We further observed that pre-treatment with CBD showed protective effects against oxidative stress by enhancement of antioxidant components at the cellular level, with respect to both protein and mRNA expression levels (p < 0.05, 0.01 or 0.001). The mechanisms of CBD were examined by Western blot analysis, and it showed anti-cell death, anti-inflammatory, and antioxidant effects via normalizations of the Jun N-terminal kinase/mitogen-activated protein kinase kinase 7/c-Jun signaling pathways. Conclusion: This study confirmed the pharmacological properties of CBD by regulation of cellular oxidation and the inflammation-provoked cell death condition of BM-hMSCs, which is mediated by the MKK7/JNK/c-Jun signaling pathway.

• Journal of Life Science
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• v.24 no.10
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• pp.1132-1136
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• 2014

A yellow-colored pigment is found in turmeric, or Curcuma longa L. (Zingiberaceae), a perennial herb distributed mainly throughout tropical and subtropical regions. C. longa has potent antiviral, antimutagenic, anti-inflammatory, anticancer, and antioxidant properties. However, pharmacological mechanisms of ethanol extract derived from C. longa remain poorly understood. The aim of this study was to investigate the potential acute toxicity of C. longa (Curcuma longa L.) extract in BALB/c mice administered a single oral dose of 0, 20, 200, and 2,000 mg/kg by gavage. After the administration of the agent, signs of toxicity were observed every hour for the first 6 hr and every day for 14 days. No mortality, abnormal clinical signs, or pathological changes were observed compared to a control group, and there were no differences in the body weights of the control and treatment groups. Biological serum activities were not significantly changed in the treatment group compared to the control group. These results indicate that a single oral administration of C. longa extract does not exert any toxic effects at a dose of 2,000 mg/kg body weight and that the $LD_{50}$ of C. longa extract is greater than 2,000 mg/kg body weight. Accordingly, C. longa appears to have potential in various functional agents or foods, without toxicity.

• Journal of Pharmaceutical Investigation
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• v.33 no.3
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• pp.171-178
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• 2003

Drug interactions with food, on occasion, lead to serious nutritional and functional changes in the body as well as alterations of pharmacological effect. It, therefore, should be necessary to take drug interactions with food into consideration for effective and safe therapeutics. Diabetes mellitus is a heterogeneous group of disorders characterzed by abnormal glucose homeostasis, resulting in hyperglycemia, and is associated with increased risk of microvascular, macrovascular, and neuropathic complications. However, the precise mechanism of diabetes mellitus remains unclear. Three basic objectives in the care of diabetic patients are maintaining optimal nutrition, avoiding hypo- or hyperglycemia and preventing complications. Laminaria japonica is a brown macroalgae which can be used as a functional diet due to high content of diatery fiber. The purpose of this study was to investigate the effect of Laminaria japonica diet on the pharmacokinetics of metformin which are frequently used in the treatment of diabetes. Diabetic rats induced by streptozotocin were employed in this study. Blood concentrations of oral hypoglycemic agent, metformin, were measured by HPLC and resultant pharmacokinetic parameters were calculated by RSTRIP. The mechanisms of drug interaction with food were evaluated on the basis of pharmacokinetic parameters such as $k_{a},\;t_{1/2},\;C_{max},\;t_{max}$, and AUC. Administration of metformin in normal and diabetic rats treated with Laminaria japonica diet showed significant decrease in AUC, $C_{max},\;and\;k_a$, and increase in $t_{max}$, compared to those with normal diet. This might result from adsortion of metformin on components of Laminaria japonica, causing delayed absorption. The oral glucose test showed that Laminaria japonica diet could lower blood glucose level probably through either inhibiting the activity of disaccharidases, intestinal digestive enzymes, or delaying the absorption of glucose. More studies should be followed to fully understand pharmacokinetic changes of metformin caused by long-term Laminaria japonica diet.