• IMMUNE NETWORK
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• 제23권3호
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• pp.23.1-23.17
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• 2023

Inflammation is a series of host defense processes in response to microbial infection and tissue injury. Inflammatory processes frequently cause extracellular acidification in the inflamed region through increased glycolysis and lactate secretion. Therefore, the immune cells infiltrating the inflamed region encounter an acidic microenvironment. Extracellular acidosis can modulate the innate immune response of macrophages; however, its role for inflammasome signaling still remains elusive. In the present study, we demonstrated that macrophages exposed to an acidic microenvironment exhibited enhanced caspase-1 processing and IL-1β secretion compared with those under physiological pH. Moreover, exposure to an acidic pH increased the ability of macrophages to assemble the NLR family pyrin domain containing 3 (NLRP3) inflammasome in response to an NLRP3 agonist. This acidosis-mediated augmentation of NLRP3 inflammasome activation occurred in bone marrow-derived macrophages but not in bone marrow-derived neutrophils. Notably, exposure to an acidic environment caused a reduction in the intracellular pH of macrophages but not neutrophils. Concordantly, macrophages, but not neutrophils, exhibited NLRP3 agonist-mediated translocation of chloride intracellular channel protein 1 (CLIC1) into their plasma membranes under an acidic microenvironment. Collectively, our results demonstrate that extracellular acidosis during inflammation can increase the sensitivity of NLRP3 inflammasome formation and activation in a CLIC1-dependent manner. Thus, CLIC1 may be a potential therapeutic target for NLRP3 inflammasome-mediated pathological conditions.

• Journal of Applied Biological Chemistry
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• 제66권
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• pp.221-226
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• 2023

혈소판의 적절한 활성화와 응집이 필요하지만 과도하거나 비정상적인 응집은 뇌졸중, 혈전증, 동맥경화증과 같은 심혈관 질환을 유발할 수 있다. 따라서 이러한 질병을 예방하고 치료하기 위해서는 혈소판 응집을 조절하거나 억제할 수 있는 물질을 찾는 것이 중요하다. 여러 연구에서 Panax 인삼의 특정 ginsenoside 화합물이 혈소판 응집을 억제할 수 있음이 알려져 있다. 이들 화합물 중 Panax ginseng의 Rk3 (G-Rk3)는 혈소판 응집 억제의 기전이 불확실 하기에 이를 밝히기 위한 연구가 필요하다. G-Rk3는 cAMP의 양을 강하게 증가시켰고 cAMP 의존성 kinase의 기질인 VASP 및 IP3R의 인산화를 유도했다. 또한, G-Rk3의 효과는 PI3K/Akt 인산화의 억제를 일으켜 세포 내 과립의 분비를 감소시켰다. 궁극적으로 G-Rk3는 혈소판 응집을 효과적으로 억제하였다. 따라서 우리는 과도한 혈소판 응집으로 인한 심혈관 질환의 예방 또는 치료제로서의 G-Rk3의 가능성을 제안한다.

• Journal of Applied Biological Chemistry
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• 제66권
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• pp.7-14
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• 2023

SD rat에서 primary culture한 chondrocyte에서 발효우슬, 당귀, 두충 추출 복합물(FAAE)이 염증 및 세포사멸 조절에 미치는 영향을 알아보고자 하였다. FAAE는 H₂O₂에 대한 세포 생존률, Smad3, Collagen type 1의 mRNA 및 단백질 발현을 증가시켰고, 염증 및 세포사멸 관련인자(NF-κB pathway, COX-2, iNOS, JNK, c-Fos, c-Jun, caspase 3, Bax, Bcl-2)의 단백질 발현을 감소시켰다. 본 연구는 FAAE가 염증 및 세포 사멸 억제를 통해 연골세포 보호효과가 있음을 시사한다.

• Journal of Ginseng Research
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• 제47권5호
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• pp.672-680
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• 2023

Background: Korean Red Ginseng (KRG), the steamed root of Panax ginseng, has pharmacological activities for immunological and neurodegenerative disorders. But, the role of KRGE in multiple sclerosis (MS) remains unclear. Purpose: To determine whether KRG extract (KRGE) could inhibit demyelination in corpus callosum (CC) of cuprizone (CPZ)-induced murine model of MS Methods: Male adult mice were fed with a standard chow diet or a chow diet supplemented with 0.2% (w/w) CPZ ad libitum for six weeks to induce demyelination while were simultaneously administered with distilled water (DW) alone or KRGE-DW (0.004%, 0.02 and 0.1% of KRGE) by drinking. Results: Administration with KRGE-DW alleviated demyelination and oligodendrocyte degeneration associated with inhibition of infiltration and activation of resident microglia and monocyte-derived macrophages as well as downregulation of proinflammatory mediators in the CC of CPZ-fed mice. KRGE-DW also attenuated the level of infiltration of Th1 and Th17) cells, in line with inhibited Mrna expression of IFN-γ and IL-17, respectively, in the CC. These positive effects of KRGE-DW mitigated behavioral dysfunction based on elevated plus maze and the rotarod tests. Conclusion: The results strongly suggest that KRGE-DW may inhibit CPZ-induced demyelination due to its oligodendroglial protective and anti-inflammatory activities by inhibiting infiltration/activation of immune cells. Thus, KRGE might have potential in therapeutic intervention for MS.

• Journal of Korean Neurosurgical Society
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• 제67권3호
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• pp.364-375
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• 2024

Objective : Kinesin family member C1 (KIFC1), a non-essential kinesin-like motor protein, has been found to serve a crucial role in supernumerary centrosome clustering and the progression of several human cancer types. However, the role of KIFC1 in glioma has been rarely reported. Thus, the present study aimed to investigate the role of KIFC1 in glioma progression. Methods : Online bioinformatics analysis was performed to determine the association between KIFC1 expression and clinical outcomes in glioma. Immunohistochemical staining was conducted to analyze the expression levels of KIFC1 in glioma and normal brain tissues. Furthermore, KIFC1 expression was knocked in the glioma cell lines, U251 and U87MG, and the functional roles of KIFC1 in cell proliferation, invasion and migration were analyzed using cell multiplication, wound healing and Transwell invasion assays, respectively. The autophagic flux and expression levels matrix metalloproteinase-2 (MMP2) were also determined using imaging flow cytometry, western blotting and a gelation zymography assay. Results : The results revealed that KIFC1 expression levels were significantly upregulated in glioma tissues compared with normal brain tissues, and the expression levels were positively associated with tumor grade. Patients with glioma with low KIFC1 expression levels had a more favorable prognosis compared with patients with high KIFC1 expression levels. In vitro, KIFC1 knockdown not only inhibited the proliferation, migration and invasion of glioma cells, but also increased the autophagic flux and downregulated the expression levels of MMP2. Conclusion : Upregulation of KIFC1 expression may promote glioma progression and KIFC1 may serve as a potential prognostic biomarker and possible therapeutic target for glioma.

• BMB Reports
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• 제57권4호
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• pp.200-205
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• 2024

We conducted a comprehensive series of molecular biological studies aimed at unraveling the intricate mechanisms underlying the anti-fibrotic effects of triamcinolone acetonide (TA) when used in conjunction with fully covered self-expandable metal stents (FCSEMS) for the management of benign biliary strictures (BBS). To decipher the molecular mechanisms responsible for the anti-fibrotic effects of corticosteroids on gallbladder mucosa, we conducted a comprehensive analysis. This analysis included various methodologies such as immunohisto-chemistry, ELISA, real-time PCR, and transcriptome analysis, enabling us to examine alterations in factors related to fibrosis and inflammation at both the protein and RNA levels. Overall, our findings revealed a dose-dependent decrease in fibrosis-related signaling with higher TA concentrations. The 15 mg of steroid treatment (1X) exhibited anti-fibrosis and anti-inflammatory effects after 4 weeks, whereas the 30 mg of steroid treatment (2X) rapidly reduced fibrosis and inflammation within 2 weeks in BBS. Transcriptomic analysis results consistently demonstrated significant downregulation of fibrosis- and inflammation-related pathways and genes in steroid-treated fibroblasts. Use of corticosteroids, specifically TA, together with FCSEMS was effective for the treatment of BBS, ameliorating fibrosis and inflammation. Our molecular biological analysis supports the potential development of steroid-eluted FCSEMS as a therapeutic option for BBS in humans resulting from various surgical procedures.

• 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.

• Clinics in Shoulder and Elbow
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• 제27권1호
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• pp.32-38
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• 2024

Background: Open reduction and internal fixation (ORIF) with a locking plate is a popular surgical treatment for proximal humeral fractures (PHF). This study aimed to assess the occurrence of complications in elderly patients with PHF treated surgically using ORIF with a locking plate and to investigate the potential differences between patients treated by shoulder surgeons and non-shoulder surgeons. Methods: A retrospective study was conducted using a single-center database to identify patients aged ≥70 years who underwent ORIF for PHF between January 1, 2011, and December 31, 2021. Data on the Neer classification, follow-up, occurrence of avascular necrosis of the humeral head, implant failure, and revision surgery were also collected. Statistical analyses were performed to calculate the overall frequency of complications according to the Neer classification. Results: The rates of implant failure, avascular osteonecrosis, and revision surgery were 15.7%, 4.8%, and 15.7%, respectively. Complications were more common in patients with Neer three- and four-part fractures. Although the difference between surgeries performed by shoulder surgeons and non-shoulder surgeons did not reach statistical significance, the rate of complications and the need for revision surgery were nearly two-fold higher in the latter group. Conclusions: PHF are highly prevalent in the elderly population. However, the ORIF surgical approach, as demonstrated in this study, is associated with a considerable rate of complications. Surgeries performed by non-shoulder surgeons had a higher rate of complications and a more frequent need for revision surgery. Future studies comparing surgical treatments and their respective complication rates are crucial to determine the optimal therapeutic options. Level of evidence: III.

• IMMUNE NETWORK
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• 제21권4호
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• pp.30.1-30.12
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• 2021

High expression of mitofusin-2 (MFN2), a mitochondrial fusion protein, has been frequently associated with poor prognosis of patients with cervical cancer. Here, we aimed to identify the function of MFN2 in cervical cancer to understand its influence on disease prognosis. To this end, from cervical adenocarcinoma, we performed an MTT assay and quantitative RT-PCR (qRT-PCR) analysis to assess the effects of MFN2 on the proliferation and of HeLa cells. Then, colony-formation ability and tumorigenesis were evaluated using a tumor xenograft mouse model. The migration ability related to MFN2 was also measured using a wound healing assay. Consequently, epithelial-mesenchymal transition (EMT) of MFN2-knockdowned HeLa cells originating from adenocarcinoma. markers related to MFN2 were assessed by qRT-PCR. Clinical data were analyzed using cBioPortal and The Cancer Genome Atlas. We found that MFN2 knockdown reduced the proliferation, colony formation ability, migration, and in vivo tumorigenesis of HeLa cells. Primarily, migration of MFN2-knockdowned HeLa cells decreased through the suppression of EMT. Thus, we concluded that MFN2 facilitates cancer progression and in vivo tumorigenesis in HeLa cells. These findings suggest that MFN2 could be a novel target to regulate the EMT program and tumorigenic potential in HeLa cells and might serve as a therapeutic target for cervical cancer. Taken together, this study is expected to contribute to the treatment of patients with cervical cancer.

• IMMUNE NETWORK
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• 제22권1호
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• pp.8.1-8.20
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• 2022

Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1β, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA.