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        Evaluation of Neo-Osteogenesis in Eosinophilic Chronic Rhinosinusitis Using a Nasal Polyp Murine Model

        Roza Khalmuratova,Mingyu Lee,Jong-Wan Park,신현우 대한천식알레르기학회 2020 Allergy, Asthma & Immunology Research Vol.12 No.2

        Purpose: Osteitis refers to the development of new bone formation and remodeling of bone in chronic rhinosinusitis (CRS) patients; it is typically associated with eosinophilia, nasal polyps (NPs), and recalcitrant CRS. However, the roles of ossification in CRS with or without NPs remain unclear due to the lack of appropriate animal models. Thus, it is necessary to have a suitable animal model for greater advances in the understanding of CRS pathogenesis. Methods: BALB/c mice were administered ovalbumin (OVA) and staphylococcal enterotoxin B (SEB). The numbers of osteoclasts and osteoblasts and bony changes were assessed. Micro computed tomography (micro-CT) scans were conducted to measure bone thickness. Immunofluorescence, immunohistochemistry, and quantitative polymerase chain reaction were performed to evaluate runt-related transcription factor 2 (RUNX2), osteonectin, interleukin (IL)-13, and RUNX2 downstream gene expression. Gene set enrichment analysis was performed in mucosal tissues from control and CRS patients. The effect of resveratrol was evaluated in terms of osteogenesis in a murine eosinophilic CRS NP model. Results: The histopathologic changes showed markedly thickened bones with significant increase in osteoblast numbers in OVA/SEB-treated mice compared to the phosphate-buffered saline-treated mice. The structural changes in bone on micro-CT were consistent with the histopathological features. The expression of RUNX2 and IL-13 was increased by the administration of OVA/SEB and showed a positive correlation. RUNX2 expression mainly co-localized with osteoblasts. Bioinformatic analysis using human CRS transcriptome revealed that IL-13-induced bony changes via RUNX2. Treatment with resveratrol, a candidate drug against osteitis, diminished the expression of IL-13 and RUNX2, and the number of osteoblasts in OVA/SEB-treated mice. Conclusions: In the present study, we found the histopathological and radiographic evidence of osteogenesis using a previously established murine eosinophilic CRS NP model. This animal model could provide new insights into the pathophysiology of neo-osteogenesis and provide a basis for developing new therapeutics.

      • KCI우수등재

        Immune Cell Responses and Mucosal Barrier Disruptions in Chronic Rhinosinusitis

        Roza Khalmuratova,박종완,신현우 대한면역학회 2017 Immune Network Vol.17 No.1

        Chronic rhinosinusitis (CRS) is one of the most common presentations of upper airway illness and severely affects patient quality of life. Its frequency is not surprising given levels of environmental exposure to microbes, pollutants, and allergens. Inflammatory cells, inflammatory cytokine and chemokine production, and airway remodeling have been detected in the sinonasal mucosae of CRS patients, although the precise pathophysiological mechanisms causing such persistent inflammation remain unclear. Given its high prevalence and considerable associated morbidity, continued research into CRS is necessary to increase our understanding of factors likely to contribute to its pathogenesis, and facilitate the development of novel therapeutic strategies to improve treatment. The purpose of this review is to summarize the current state of knowledge regarding immune cell responses and epithelial alterations in CRS.

      • Wound healing of nasal mucosa in a rat

        Khalmuratova, Roza,Jeon, Sea-Yuong,Kim, Dae Woo,Kim, Jin-Pyeong,Ahn, Seong-Ki,Park, Jung-Je,Hur, Dong-Gu SAGE Publications 2009 American journal of rhinology & allergy Vol.23 No.6

        <P>BACKGROUND: Postoperative wound healing of the nasal mucosa is a highly organized process. However, this process still has not been fully understood. The present study aimed to establish a wound healing model in a rat and describe histomorphological changes of the nasal mucosa after mechanical injury. METHODS: Unilateral wound in the nasal cavity was induced using the brushing technique in 4-week-old, Sprague-Dawley rats. Experimental rats were divided into five groups (n = 7 for each group). Animals were killed 1 hour and 2, 5, 14, and 28 days after injury. The histological sections were examined for inflammatory cell infiltration, goblet, and ciliated cell formation in hematoxylin and eosin staining. The subepithelial and epithelial thicknesses were measured and expressed as the subepithelial thickness index (STI) and epithelial thickness index (ETI). Fibrosis was evaluated by subepithelial fibrosis index (SFI) in Masson's trichrome-stained sections. RESULTS: Respiratory epithelial discontinuity and hemorrhage were observed 1 hour after injury. On day 2, edematous subepithelium and infiltration of neutrophils could be found on the injured site. Day 5 was characterized by the infiltration of monocytes and granulation tissue. SFI and ETI values increased significantly at day 14. Goblet cells and ciliated cells began to regenerate from day 14 and restored to near normal at day 28. CONCLUSION: Using mechanical injury, the wound healing model of the nasal mucosa was established in a rat. The regeneration of respiratory mucosa was completed on day 28 after injury.</P>

      • KCI등재

        Crosstalk Between Mucosal Inflammation and Bone Metabolism in Chronic Rhinosinusitis

        Roza Khalmuratova,신현우 대한이비인후과학회 2021 Clinical and Experimental Otorhinolaryngology Vol.14 No.1

        Chronic rhinosinusitis (CRS) is a multifactorial and highly heterogeneous upper airway disease that affects approximately 12% of the general population. There is increasing evidence supporting the impact of osteitis on the pathophysiology of CRS. Osteitis is frequently observed in patients with CRS, and is associated with severe sinonasal inflammation and recalcitrant cases. The overlying inflammatory sinonasal mucosa plays a critical role in the initiation of osteitis; however, the underlying molecular mechanisms and functional significance remain unclear. Increasingly many studies have suggested that immune cells play a crucial role in the bone remodeling process in CRS. The purpose of this review is to summarize the current state of knowledge regarding the specific role of sinonasal inflammation in bone remodeling in CRS patients.

      • Immune Cell Responses and Mucosal Barrier Disruptions in Chronic Rhinosinusitis

        Khalmuratova, Roza,Park, Jong-Wan,Shin, Hyun-Woo 한국조명·전기설비학회 2017 한국조명·전기설비학회 학술대회논문집 Vol. No.

        <P>Chronic rhinosinusitis (CRS) is one of the most common presentations of upper airway illness and severely affects patient quality of life. Its frequency is not surprising given levels of environmental exposure to microbes, pollutants, and allergens. Inflammatory cells, inflammatory cytokine and chemokine production, and airway remodeling have been detected in the sinonasal mucosae of CRS patients, although the precise pathophysiological mechanisms causing such persistent inflammation remain unclear. Given its high prevalence and considerable associated morbidity, continued research into CRS is necessary to increase our understanding of factors likely to contribute to its pathogenesis, and facilitate the development of novel therapeutic strategies to improve treatment. The purpose of this review is to summarize the current state of knowledge regarding immune cell responses and epithelial alterations in CRS.</P>

      • KCI등재후보

        Roles of Periostin in Symptom Manifestation and Airway Remodeling in a Murine Model of Allergic Rhinitis

        허동구,Roza Khalmuratova,안성기,하영술,민양기 대한천식알레르기학회 2012 Allergy, Asthma & Immunology Research Vol.4 No.4

        Purpose: Periostin was originally identified as a secreted factor during screening of a mouse osteoblastic library. In a recent study, periostin was found to directly regulate eosinophil accumulation in allergic mucosal inflammation. Chronic eosinophilic inflammation is related to the development of remodeling. The present study examined the expression of periostin and evaluated its role in the inflammatory process and remodeling associated with allergic rhinitis. Methods: A murine model of allergic rhinitis was established in periostin knockout mice. We analyzed the expression of periostin, manifestation of nasal symptoms, eosinophilic inflammation, and subepithelial fibrosis as well as the expression of MMP-2, TIMP-1, and type 1 collagen in nasal tissue. Results: Periostin was mainly distributed in the subepithelial tissue of the nasal mucosa. The subepithelial tissue was thinner in the knockout group than in the control group. No differences in the expression of MMP-2 or TIMP-1 were found in the knockout group. However, after a month of allergen challenge, type I collagen in the nasal tissue was lower in the knockout group than in the control group. The number of eosinophils and the symptom score were also lower in the knockout group. Conclusions: Periostin is expressed in nasal tissues of murine models of allergic rhinitis. Periostin deficiency may affect the remodeling of nasal tissue with reduced subepithelial fibrosis, and lead to less eosinophilic inflammation.

      • KCI등재후보

        Immunohistochemical Study on β1- and β2-Adrenergic Receptors in Rat Vestibular Nuclei

        안성기,Roza Khalmuratova,허동구,김호엽,박현우,주연희,강흥수 대한평형의학회 2012 Research in Vestibular Science Vol.11 No.2

        Background and Objectives: The aim of this study was to examine the localizations of β1- and β2-adrenergic receptors (ARs) in rat vestibular nuclei by immunohistochemical staining procedure. Materials and Methods: Twelve male Sprague-Dawley rats were used in this study. Primary antibodies for the β1- and β2-ARs were used. The sections were treated with a biotinylated goat anti-rabbit antibody. The sections were then incubated in avidin-biotin-peroxidase reagent and processed with immunoperoxidase using 3.3’-diaminobenzidine tetrahydrochloride. Results: β1-AR and β2-AR immunopositive neurons were found to be distributed throughout the four major vestibular nuclei. Both receptors were primarily detected in neuronal somata and their proximal dendrites. β1-AR and β2-AR were moderately expressed in the superior vestibular nucleus, lateral vestibular nucleus, medial vestibular nucleus,and spinal vestibular nucleus. Conclusion: The present study demonstrates, for the first time, that β1-AR and β2-AR receptors are localized in rat vestibular nuclei. Furthermore, this study may provide additional speculation into the role of ARs during vestibular signal processing. Further studies are needed to clarify the roles played by β1-ARs and β2-ARs through physiologic and functional studies. Background and Objectives: The aim of this study was to examine the localizations of β1- and β2-adrenergic receptors (ARs) in rat vestibular nuclei by immunohistochemical staining procedure. Materials and Methods: Twelve male Sprague-Dawley rats were used in this study. Primary antibodies for the β1- and β2-ARs were used. The sections were treated with a biotinylated goat anti-rabbit antibody. The sections were then incubated in avidin-biotin-peroxidase reagent and processed with immunoperoxidase using 3.3’-diaminobenzidine tetrahydrochloride. Results: β1-AR and β2-AR immunopositive neurons were found to be distributed throughout the four major vestibular nuclei. Both receptors were primarily detected in neuronal somata and their proximal dendrites. β1-AR and β2-AR were moderately expressed in the superior vestibular nucleus, lateral vestibular nucleus, medial vestibular nucleus,and spinal vestibular nucleus. Conclusion: The present study demonstrates, for the first time, that β1-AR and β2-AR receptors are localized in rat vestibular nuclei. Furthermore, this study may provide additional speculation into the role of ARs during vestibular signal processing. Further studies are needed to clarify the roles played by β1-ARs and β2-ARs through physiologic and functional studies.

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