• BMB Reports
• /
• v.38 no.1
• /
• pp.9-16
• /
• 2005

Transforming Growth Factor (TGF)-$\beta$ family, including TGF-$\beta$, bone morphorgenic protein (BMP), and activn, plays an important role in essential cellular functions such as proliferation, differentiation, apoptosis, tissue remodeling, angiognesis, immune responses, and cell adhesions. TGF-$\beta$ predominantly transmits the signals through serine/threonine receptor kinases and cytoplasmic proteins called Smads. Since the discovery of TGF-$\beta$ in the early 1980s, the dysregulation of TGF-$\beta$/Smad signaling has been implicated in the pathogenesis of human diseases. Among signal transducers in TGF-$\beta$/Smad signaling, inhibitory Smads (I-Smads), Smad6 and Smad7, act as major negative regulators forming autoinhibitory feedback loops and mediate the cross-talking with other signaling pathways. Expressions of I-Smads are mainly regulated on the transcriptional levels and post-translational protein degradations and their intracellular levels are tightly controlled to maintain the homeostatic balances. However, abnormal levels of I-Smads in the pathological conditions elicit the altered TGF-$\beta$ signaling in cells, eventually causing TGF-$\beta$-related human diseases. Thus, exploring the molecular mechanisms about the regulations of I-Smads may provide the therapeutic clues for human diseases induced by the abnormal TGF-$\beta$ signaling.

• BMB Reports
• /
• v.51 no.2
• /
• pp.59-64
• /
• 2018

The airway epithelium is the first place, where a defense mechanism is initiated against environmental stimuli. Mucociliary transport (MCT), which is the defense mechanism of the airway and the role of airway epithelium as mechanical barriers are essential in innate immunity. To maintain normal physiologic function, normal oxygenation is critical for the production of energy for optimal cellular functions. Several pathologic conditions are associated with a decrease in oxygen tension in airway epithelium and chronic sinusitis is one of the airway diseases, which is associated with the hypoxic condition, a potent inflammatory stimulant. We have observed the overexpression of the hypoxia-inducible factor 1 (HIF-1), an essential factor for oxygen homeostasis, in the epithelium of sinus mucosa in sinusitis patients. In a series of previous reports, we have found hypoxia-induced mucus hyperproduction, especially by MUC5AC hyperproduction, disruption of epithelial barrier function by the production of VEGF, and down-regulation of junctional proteins such as ZO-1 and E-cadherin. Furthermore, hypoxia-induced inflammation by HMGB1 translocation into the cytoplasm results in the release of IL-8 through a ROS-dependent mechanism in upper airway epithelium. In this mini-review, we briefly introduce and summarize current progress in the pathogenesis of sinusitis related to hypoxia. The investigation of hypoxia-related pathophysiology in airway epithelium will suggest new insights on airway inflammatory diseases, such as rhinosinusitis for clinical application and drug development.

• The Journal of the Korean dental association
• /
• v.54 no.4
• /
• pp.274-283
• /
• 2016

Bisphosphonates are widely used mainly for the treatment of osteoporosis and bone metastasis of malignancy. Since the first report of MRONJ, there have been many studies associated, however the pathogenesis of MRONJ is not yet clear. Medication-related osteonecrosis of the jaws (MRONJ) is a serious complication associated with long-term medication therapy. It is characterized by exposed necrotic bonein the jaw, which has persisted for more than 8weeks despite continuous treatment by dentist. The mechanism of development of MRONJ is still unclear and there is no definitive standard treatment for MRONJ. The purpose of this study is to investigate the jaw bone destruction mechanism of accumulated bisphosphonates, so that we can develop therapeutic method to repair the defect and stop the destruction process. The authors performed simultaneous application of PRF(Platelet rich fibrin) and BMP-2(Bone morphogenetic protein-2) to stimulate not only soft tissue healing but also osseous regeneration. Our case series demonstrate that simultaneous application of platelet rich fibrin and bone morphogenetic protein-2 can be a treatment of choice for MRONJ.

• Journal of Veterinary Science
• /
• v.21 no.3
• /
• pp.49.1-49.14
• /
• 2020

Background: Coinfection with avian leukosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV) is common in chickens, and the molecular mechanism of the synergistic pathogenic effects of the coinfection is not clear. Exosomes have been identified as new players in the pathogenesis of retroviruses. The different functions of exosomes depend on their cargo components. Objectives: The aim of this study was to investigate the function of co-regulation differentially expressed proteins in exosomes on coinfection of ALV-J and REV. Methods: Here, viral replication in CEF cells infected with ALV-J, REV or both was detected by immunofluorescence microscopy. Then, we analyzed the exosomes isolated from supernatants of chicken embryo fibroblast (CEF) cells single infected and coinfected with ALV-J and REV by mass spectrometry. KEGG pathway enrichment analyzed the co-regulation differentially expressed proteins in exosomes. Next, we silenced and overexpressed tripartite motif containing 62 (TRIM62) to evaluate the effects of TRIM62 on viral replication and the expression levels of NCK-association proteins 1 (NCKAP1) and actin-related 2/3 complex subunit 5 (ARPC5) determined by quantitative reverse transcription polymerase chain reaction. Results: The results showed that coinfection of ALV-J and REV promoted the replication of each other. Thirty proteins, including TRIM62, NCK-association proteins 1 (NCKAP1, also known as Nap125), and Arp2/3-5, ARPC5, were identified. NCKAP1 and ARPC5 were involved in the actin cytoskeleton pathway. TRIM62 negatively regulated viral replication and that the inhibition of REV was more significant than that on ALV-J in CEF cells coinfected with TRIM62. In addition, TRIM62 decreased the expression of NCKAP1 and increased the expression of ARPC5 in coinfected CEF cells. Conclusions: Collectively, our results indicated that coinfection with ALV-J and REV competitively promoted each other's replication, the actin cytoskeleton played an important role in the coinfection mechanism, and TRIM62 regulated the actin cytoskeleton.

• The Korean Journal of Pain
• /
• v.35 no.2
• /
• pp.173-182
• /
• 2022

Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins' antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the anti-nociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.

• Tuberculosis and Respiratory Diseases
• /
• v.60 no.4
• /
• pp.426-436
• /
• 2006

Background : Particulate matters (PM) when inhaled is known to induce pulmonary diseases including asthma and chronic bronchitis when inhaled. Despite the epidemiological proofevidence, the pathogenesis of PM-related pulmonary diseases is unclearremain poorly understood. Methods : Primary alveolar macrophages were harvested from the SPF and inflammatory rats by bronchioalveolar lavage (BAL). The cultured primary alveolar macrophages were treated with the medium only, PM only ($5{\sim}40{\mu}g/cm^2$), LPS (5ng/ml) only, and PM with LPS for 24 and 48 hours. The level of secreted nitric oxide (NO) was assayed from the cultured medium by using the Griess reaction. The cultured cells were utilized for the western blotting against the inducible nitric oxide synthase (iNOS) proteins. Immunocyto- chemical staining against the iNOS and NT-proteins were performed in cells that cultured in the $Lab-Tek^{(R)}$ chamber slide after treatments. Results : The PM that utilizein this experiments induced NO formation with iNOS expression in the cultured SPF and inflammatory rats alveolar macrophages, by itself. When the cells were co-treated with PM and LPS, there was a statistically significant synergistic effect on NO formation and iNOS expression over the LPS effect. The cells from the sham control showed minimal immunoreactivity for the NT-proteins. Significantly higher quantities of NT-proteins were detected in the PM and PM with LPS co-treated cells than from the sham control. Conclusion : Increased iNOS expression and NO formation with increased NT-proteins formation might be involved in the pathogenesis of PM-induced lung injury.

• The Plant Pathology Journal
• /
• v.30 no.4
• /
• pp.355-366
• /
• 2014

In this study, resistance responses were investigated during the interaction of Botrytis fabae with two faba bean cultivars expressing different levels of resistance against this pathogen, Nubaria (resistant) and Giza 40 (susceptible). Disease severity was assessed on leaves using a rating scale from 1 to 9. Accumulation levels of reactive oxygen species (ROS), lipid peroxidation and antioxidant enzymes (superoxide dismutase, catalase and ascorbate peroxidase) were measured in leaf tissues at different times of infection. The expression profiles of two pathogenesis-related proteins (PRPs) encoded by the genes PR-1 and ${\beta}$-1,3-glucanase were also investigated using reverse transcription RT-PCR analysis. The accumulation of these defense responses was induced significantly in both cultivars upon infection with B. fabae compared with un-inoculated controls. The resistant cultivar showed weaker necrotic symptom expression, less ROS accumulation, a lower rate of lipid peroxidation and higher activity of the enzymatic ROS scavenging system compared with susceptible cultivar. Interestingly, ROS accumulated rapidly in the resistant leaf tissues and peaked during the early stages of infection, whereas accumulation was stronger and more intense in the susceptible tissues in later stages. Moreover, the response of the resistant cultivar to infection was earlier and stronger, exhibiting high transcript accumulation of the PR genes. These results indicated that the induction of oxidant/antioxidant responses and the accumulation of PRPs are part of the faba bean defense mechanism against the necrotrophic fungus B. fabae with a different intensity and timing of induction, depending on the resistance levels.

• BMB Reports
• /
• v.51 no.10
• /
• pp.508-513
• /
• 2018

Fibronectin fragments found in the synovial fluid of patients with osteoarthritis (OA) induce the catabolic responses in cartilage. Nuclear high-mobility group protein Box 1 (HMGB1), a damage-associated molecular pattern, is responsible for the regulation of signaling pathways related to cell death and survival in response to various stimuli. In this study, we investigated whether changes induced by 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) in HMGB1 expression influences the pathogenesis of OA via an HMGB1-modulated autophagy signaling pathway. Human articular chondrocytes were enzymatically isolated from articular cartilage. The level of mRNA was measured by quantitative real-time PCR. The expression of proteins was examined by western blot analysis, immnunofluorescence assay, and enzyme-linked immunosorbent assay. Interaction of proteins was evaluated by immunoprecipitation. The HMGB1 level was significantly lower in human OA cartilage than in normal cartilage. Although 29-kDa FN-f significantly reduced the HMGB1 expression at the mRNA and protein levels 6 h after treatment, the cytoplasmic level of HMGB1 was increased in chondrocytes treated with 29-kDa FN-f, which significantly inhibited the interaction of HMGB1 with Beclin-1, increased the interaction of Bcl-2 with Beclin-1, and decreased the levels of Beclin-1 and phosphorylated Bcl-2. In addition, the level of microtubule-associated protein 1 light chain 3-II, an autophagy marker, was down-regulated in chondrocytes treated with 29-kDa FN-f, whereas the effect was antagonized by mTOR knockdown. Furthermore, prolonged treatment with 29-kDa FN-f significantly increased the release of HMGB1 into the culture medium. These results demonstrated that 29-kDa FN-f inhibits chondrocyte autophagy by modulating the HMGB1 signaling pathway.

• YAKHAK HOEJI
• /
• v.54 no.6
• /
• pp.500-506
• /
• 2010

TNF-${\alpha}$ and VCAM-1 play a pivotal role in the pathogenesis of rheumatoid arthritis, and the development of drugs targeting these molecules has extended the therapeutical approaches to rheumatoid arthritis patients. Bispecific antibodies combine the antigen-binding sites of two antibodies within a single molecule and thus they are able to bind to two different epitopes simultaneously. A specific bispecific antibody format termed "Di-diabody" was made for the efficient approach to anti-inflammation. In this study, the DNA vector construct of Di-diabody was built up against two antigens, VCAM-1 and TNF-${\alpha}$. For evaluating this Di-diabody as a bispecific antibody on the efficacy of anti-inflammation, the proteins were analyzed according to each antigen binding affinity and cell based assay related separate molecules. The 7H/Humira Di-diabody produced in this study interacted with its ligands, VCAM-1 and TNF-${\alpha}$, respectively. Also, this antibody exhibited the similar functional activities as compared to 7H-IgG in respect to inhibition of hVCAM-1-induced cell adhesion and Humira-IgG in respect to inhibition of TNF-${\alpha}$ induced cytotoxicity. Further study to elucidate the pharmacological significance of the Di-diabody is warranted using experimental animals.

• The Plant Pathology Journal
• /
• v.34 no.4
• /
• pp.257-268
• /
• 2018

Rice blast disease, caused by Magnaporthe oryzae, results in an extensive loss of rice productivity. Previously, we identified a novel M. oryzae secreted protein, termed MSP1 which causes cell death and pathogen-associated molecular pattern (PAMP)-triggered immune (PTI) responses in rice. Here, we report the transcriptome profile of MSP1-induced response in rice, which led to the identification of 21,619 genes, among which 4,386 showed significant changes (P < 0.05 and fold change > 2 or < 1/2) in response to exogenous MSP1 treatment. Functional annotation of differentially regulated genes showed that the suppressed genes were deeply associated with photosynthesis, secondary metabolism, lipid synthesis, and protein synthesis, while the induced genes were involved in lipid degradation, protein degradation, and signaling. Moreover, expression of genes encoding receptor-like kinases, MAPKs, WRKYs, hormone signaling proteins and pathogenesis-related (PR) proteins were also induced by MSP1. Mapping these differentially expressed genes onto various pathways revealed critical information about the MSP1-triggered responses, providing new insights into the molecular mechanism and components of MSP1-triggered PTI responses in rice.