• Biomolecules & Therapeutics
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• 제32권2호
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• pp.214-223
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• 2024

Metabolic abnormalities in the liver are closely associated with diverse metabolic diseases such as non-alcoholic fatty liver disease, type 2 diabetes, and obesity. The aim of this study was to evaluate the ameliorating effect of robinetin (RBN) on the significant pathogenic features of metabolic failure in the liver and to identify the underlying molecular mechanism. RBN significantly decreased triglyceride (TG) accumulation by downregulating lipogenesis-related transcription factors in AML-12 murine hepatocyte cell line. In addition, mice fed with Western diet (WD) containing 0.025% or 0.05% RBN showed reduced liver mass and lipid droplet size, as well as improved plasma insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values. CD38 was identified as a target of RBN using the BioAssay database, and its expression was increased in OPA-treated AML-12 cells and liver tissues of WD-fed mice. Furthermore, RBN elicited these effects through its anti-histone acetyltransferase (HAT) activity. Computational simulation revealed that RBN can dock into the HAT domain pocket of p300, a histone acetyltransferase, which leads to the abrogation of its catalytic activity. Additionally, knock-down of p300 using siRNA reduced CD38 expression. The chromatin immunoprecipitation (ChIP) assay showed that p300 occupancy on the promoter region of CD38 was significantly decreased, and H3K9 acetylation levels were diminished in lipid-accumulated AML-12 cells treated with RBN. RBN improves the pathogenic features of metabolic failure by suppressing the p300-CD38 axis through its anti-HAT activity, which suggests that RBN can be used as a new phytoceutical candidate for preventing or improving this condition.

• Biomolecules & Therapeutics
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• 제32권2호
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• pp.224-230
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• 2024

Pinitol (3-O-Methyl-D-chiro-inositol) has been reported to possess insulin-like effects and is known as one of the anti-diabetic agents to improve muscle, liver, and endothelial cells. However, the beneficial effects of pinitol on the skin are not well known. Here, we investigated whether pinitol had effects on human dermal fibroblasts (HDFs), and human dermal equivalents (HDEs) irradiated with ultraviolet A (UVA), which causes various damages including photodamage in the skin. We observed that pinitol enhanced wound healing in UVA-damaged HDFs. We also found that pinitol significantly antagonized the UVA-induced up-regulation of matrix metalloproteinase 1 (MMP1), and the UVA-induced down-regulation of collagen type I and tissue inhibitor of metalloproteinases 1 (TIMP1) in HDEs. Electron microscopy analysis also revealed that pinitol remarkably increased the number of collagen fibrils with regular banding patterns in the dermis of UVA-irradiated human skin equivalents. Pinitol significantly reversed the UVA-induced phosphorylation levels of ERK and JNK but not p38, suggesting that this regulation may be the mechanism underlying the pinitol-mediated effects on UVA-irradiated HDEs. We also observed that pinitol specifically increased Smad3 phosphorylation, which is representative of the TGF-β signaling pathway for collagen synthesis. These data suggest that pinitol exerts several beneficial effects on UVA-induced damaged skin and can be used as a therapeutic agent to improve skin-related diseases.

• Korean Chemical Engineering Research
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• 제62권2호
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• pp.133-141
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• 2024

전세계적으로 발병 및 사망률이 높은 동맥경화증은 뇌졸중, 심근경색 등 심혈관질환의 주요 병증의 원인인 만성 염증성 질환이다. 동맥경화증은 지질 침착으로 인해 죽종(atheroma)이 형성되고, 혈전증이 유발되면서 관련 증상이 발생한다. 동맥경화증의 합성 치료제의 부작용 우려로 인해 생물 유래 항동맥경화 소재 개발의 필요성이 강조되고 있다. 이에 따라 동맥경화증의 개선 및 치료를 위한 바이오소재의 발굴 및 기전 규명 등 관련 연구가 활발히 수행되고 있다. 주로 동맥경화증 발병 관련 인자들을 조절하여 증상을 억제하거나 지연시키는 바이오소재들이 연구되고 있으며, 대표적으로 다당류, 폴리페놀, 코엔자임 Q10이 해당된다. 우수한 활성을 가진 바이오소재의 경우에는 생체 내(동물 모델)에서의 항동맥경화증 활성이 확인되었다. 본고에서는 동맥경화증의 발병 기전을 살펴보고, 항동맥경화증 활성이 보고된 바이오소재의 연구 동향 및 활용 전망을 제시하고자 한다.

• IMMUNE NETWORK
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• 제22권6호
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• pp.48.1-48.13
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• 2022

With the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, which are randomly mutated, the dominant strains in regions are changing globally. The development of preclinical animal models is imperative to validate vaccines and therapeutics against SARS-CoV-2 variants. The objective of this study was to develop a non-human primate (NHP) model for SARS-CoV-2 Delta variant infection. Cynomolgus macaques infected with Delta variants showed infectious viruses and viral RNA in the upper (nasal and throat) and lower respiratory (lung) tracts during the acute phase of infection. After 3 days of infection, lesions consistent with diffuse alveolar damage were observed in the lungs. For cellular immune responses, all macaques displayed transient lymphopenia and neutrophilia in the early stages of infection. SARS-CoV-2 Delta variant spike protein-specific IgM, IgG, and IgA levels were significantly increased in the plasma of these animals 14 days after infection. This new NHP Delta variant infection model can be used for comparative analysis of the difference in severity between SARS-CoV-2 variants of concern and may be useful in the efficacy evaluation of vaccines and universal therapeutic drugs for mutations.

• IMMUNE NETWORK
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• 제22권6호
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• pp.51.1-51.20
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• 2022

Trypanosoma cruzi, the etiological agent of Chagas disease, is an intracellular protozoan parasite, which is now present in most industrialized countries. About 40% of T. cruzi infected individuals will develop severe, incurable cardiovascular, gastrointestinal, or neurological disorders. The molecular mechanisms by which T. cruzi induces cardiopathogenesis remain to be determined. Previous studies showed that increased IL-6 expression in T. cruzi patients was associated with disease severity. IL-6 signaling was suggested to induce pro-inflammatory and pro-fibrotic responses, however, the role of this pathway during early infection remains to be elucidated. We reported that T. cruzi can dysregulate the expression of host PIWI-interacting RNAs (piRNAs) during early infection. Here, we aim to evaluate the dysregulation of IL-6 signaling and the piRNAs computationally predicted to target IL-6 molecules during early T. cruzi infection of primary human cardiac fibroblasts (PHCF). Using in silico analysis, we predict that piR_004506, piR_001356, and piR_017716 target IL6 and SOCS3 genes, respectively. We validated the piRNAs and target gene expression in T. cruzi challenged PHCF. Secreted IL-6, soluble gp-130, and sIL-6R in condition media were measured using a cytokine array and western blot analysis was used to measure pathway activation. We created a network of piRNAs, target genes, and genes within one degree of biological interaction. Our analysis revealed an inverse relationship between piRNA expression and the target transcripts during early infection, denoting the IL-6 pathway targeting piRNAs can be developed as potential therapeutics to mitigate T. cruzi cardiomyopathies.

• 대한약침학회지
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• 제27권2호
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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.

• Korean Circulation Journal
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• 제53권6호
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• pp.351-366
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• 2023

Along with the development of immunosuppressive drugs, major advances on xenotransplantation were achieved by understanding the immunobiology of xenograft rejection. Most importantly, three predominant carbohydrate antigens on porcine endothelial cells were key elements provoking hyperacute rejection: α1,3-galactose, SDa blood group antigen, and N-glycolylneuraminic acid. Preformed antibodies binding to the porcine major xenoantigen causes complement activation and endothelial cell activation, leading to xenograft injury and intravascular thrombosis. Recent advances in genetic engineering enabled knock-outs of these major xenoantigens, thus producing xenografts with less hyperacute rejection rates. Another milestone in the history of xenotransplantation was the development of co-stimulation blockaded strategy. Unlike allotransplantation, xenotransplantation requires blockade of CD40-CD40L pathway to prevent T-cell dependent B-cell activation and antibody production. In 2010s, advanced genetic engineering of xenograft by inducing the expression of multiple human transgenes became available. So-called 'multi-gene' xenografts expressing human transgenes such as thrombomodulin and endothelial protein C receptor were introduced, which resulted in the reduction of thrombotic events and improvement of xenograft survival. Still, there are many limitations to clinical translation of cardiac xenotransplantation. Along with technical challenges, zoonotic infection and physiological discordances are major obstacles. Social barriers including healthcare costs also need to be addressed. Although there are several remaining obstacles to overcome, xenotransplantation would surely become the novel option for millions of patients with end-stage heart failure who have limited options to traditional therapeutics.

• Korean Circulation Journal
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• 제53권5호
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• pp.313-327
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• 2023

Background and Objectives: Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Recent advances in PAH-specific drugs have improved its outcomes, although the healthcare burden of novel therapeutics may lead to a discrepancy in outcomes between developing and developed countries. We analyzed how the epidemiology and clinical features of PAH has changed through the rapidly advancing healthcare infrastructure in South Korea. Methods: PAH was defined according to a newly devised 3-component algorithm. Using a nationwide health insurance claims database, we delineated annual trends in the prevalence, incidence, medication prescription pattern, and 5-year survival of PAH in Korea. Cumulative survival and potential predictors of mortality were also assessed among 2,151 incident PAH cases. Results: Between 2002 or 2004 and 2018, the prevalence and incidence of PAH increased 75-fold (0.4 to 29.9 per million people) and 12-fold (0.5 to 6.3 per million person-years), respectively. The proportion of patients on combination PAH-specific drug therapy has also steadily increased up to 29.0% in 2018. Among 2,151 incident PAH cases (median [interquartile range] age, 50 [37-62] years; 67.2% female), the 5-year survival rate and median survival duration were 71.8% and 13.1 years, respectively. Independent predictors of mortality were age, sex, etiology of PAH, diabetes, dyslipidemia, and chronic kidney disease. Conclusions: This nationwide study delineated that the prevalence and incidence of PAH have grown rapidly in Korea since the early 2000s. The use of combination therapy has also increased, and the 5-year survival rate of PAH in Korea was similar to those in western countries.

• 대한한의학회지
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• 제45권1호
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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.

• IMMUNE NETWORK
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• 제22권2호
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• pp.15.1-15.16
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• 2022

Foreign molecules, including viruses and bacteria-derived toxins, can also induce airway inflammation. However, to the best of our knowledge, the roles of these molecules in the development of airway inflammation have not been fully elucidated. Herein, we investigated the precise role and synergistic effect of virus-mimicking double-stranded RNA (dsRNA) and staphylococcal enterotoxin B (SEB) in macrophages and epithelial cells. To identify cytokine expression profiles, both the THP-1-derived macrophages and BEAS-2B epithelial cells were stimulated with dsRNA or SEB. A total of 21 cytokines were evaluated in the culture supernatants. We observed that stimulation with dsRNA induced cytokine production in both cell types. However, cytokine production was not induced in SEB-stimulated epithelial cells, compared to the macrophages. The synergistic effect of dsRNA and SEB was evaluated observing cytokine level and intracellular phospho-signaling. Fifteen different types were detected in high-dose dsRNA-stimulated epithelial cells, and 12 distinct types were detected in macrophages; those found in macrophages lacked interferon production compared to the epithelial cells. Notably, a synergistic effect of cytokine induction by co-stimulation of dsRNA and SEB was observed mainly in epithelial cells, via activation of most intracellular phosphor-signaling. However, macrophages only showed an accumulative effect. This study showed that the type and severity of cytokine productions from the epithelium or macrophages could be affected by different intensities and a combination of dsRNA and SEB. Further studies with this approach may improve our understanding of the development and exacerbation of airway inflammation and asthma.