Publications by authors named "Sun-Jae Lee"

45 Publications

NSrp70 is a lymphocyte-essential splicing factor that controls thymocyte development.

Nucleic Acids Res 2021 06;49(10):5760-5778

School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.

Alternative pre-mRNA splicing is a critical step to generate multiple transcripts, thereby dramatically enlarging the proteomic diversity. Thus, a common feature of most alternative splicing factor knockout models is lethality. However, little is known about lineage-specific alternative splicing regulators in a physiological setting. Here, we report that NSrp70 is selectively expressed in developing thymocytes, highest at the double-positive (DP) stage. Global splicing and transcriptional profiling revealed that NSrp70 regulates the cell cycle and survival of thymocytes by controlling the alternative processing of various RNA splicing factors, including the oncogenic splicing factor SRSF1. A conditional-knockout of Nsrp1 (NSrp70-cKO) using CD4Cre developed severe defects in T cell maturation to single-positive thymocytes, due to insufficient T cell receptor (TCR) signaling and uncontrolled cell growth and death. Mice displayed severe peripheral lymphopenia and could not optimally control tumor growth. This study establishes a model to address the function of lymphoid-lineage-specific alternative splicing factor NSrp70 in a thymic T cell developmental pathway.
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http://dx.doi.org/10.1093/nar/gkab389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191771PMC
June 2021

Anti-glomerular basement membrane disease associated with thin basement membrane nephropathy: A case report.

Medicine (Baltimore) 2021 May;100(20):e26095

Department of Internal Medicine.

Rationale: Simultaneous occurrence of anti-glomerular basement membrane (anti-GBM) disease and thin basement membrane nephropathy (TBMN), both of which invade the type IV collagen subunits, is very rare. Here, we present the case of a 20-year-old male patient diagnosed with both anti-GBM disease and TBMN upon presenting dyspnea and hemoptysis.

Patient Concerns: No laboratory abnormalities, except arterial hypoxemia (PaO275.4 mmHg) and microscopic hematuria, were present. Chest computed tomography revealed bilateral infiltrations in the lower lung fields; thus, administration of empirical antibiotics was initiated. Gross hemoptysis persisted nonetheless, and bronchoscopy revealed diffuse pulmonary hemorrhage with no endobronchial lesions. Broncho-alveolar lavage excluded bacterial pneumonia, tuberculosis, and fungal infection.

Diagnosis: Enzyme-linked immunosorbent assay of his serum was positive for anti-GBM antibody (95.1 U/mL). Human leukocyte antigen (HLA) test was positive for both HLA-DR15/-DR04. Other than diffuse thinning of the GBM (average thickness, 220 nm), index kidney biopsy did not demonstrate any specific abnormalities such as crescent formation.

Interventions: Methylprednisolone was administered intravenously for 7 consecutive days (500 mg/day), followed by the daily dose of oral prednisolone (80 mg). Cyclophosphamide was also orally administered every day for 3 months (250 mg/day). Following 6 sessions of plasmapheresis, the anti-GBM antibody in serum became negative.

Outcomes: There was no clinical evidence suggesting recurrence of pulmonary hemorrhage or azotemia during hospitalization and 12-month follow-up period. Twelve months after hospital discharge, oral prednisolone was discontinued.

Lessons: The patients with concurrent anti-GBM disease and TBMN will have a favorable prognosis after proper therapy. However, further research is needed to elucidate the pathogenesis and long-term outcome of the comorbidity of these 2 diseases.
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http://dx.doi.org/10.1097/MD.0000000000026095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137055PMC
May 2021

Pediatric follicular bronchiolitis with severe atelectasis: a case report.

Int J Clin Exp Pathol 2021 15;14(4):526-532. Epub 2021 Apr 15.

Department of Pathology, Daegu Catholic University Hospital, Catholic University of Daegu, College of Medicine South Korea.

Follicular bronchiolitis is a rare pulmonary disorder characterized by the presence of multiple hyperplastic lymphoid follicles with a peribronchiolar distribution. An 11-year-old girl with total atelectasis of the right middle lobe (RML) and diffuse multiple small nodules at both lung bases presented to our hospital with frequent upper respiratory infections and pneumonia. The disease progressed during a 3-month period of macrolide therapy, and thoracoscopic biopsy with lobectomy of the atelectatic RML was performed. The histopathologic diagnosis was follicular bronchiolitis. The patient's pulmonary function improved dramatically after oral steroid treatment. It can be difficult to diagnose follicular bronchiolitis based solely on clinical, laboratory, and radiologic findings; the disorder must be confirmed histopathologically. A patient with longstanding irreversible atelectasis and resulting recurrent respiratory infection may require lobectomy for the diagnosis and treatment of follicular bronchiolitis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085817PMC
April 2021

Ameliorating Fibrotic Phenotypes of Keloid Dermal Fibroblasts through an Epidermal Growth Factor-Mediated Extracellular Matrix Remodeling.

Int J Mol Sci 2021 Feb 23;22(4). Epub 2021 Feb 23.

Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Korea.

Keloid and hypertrophic scars are skin fibrosis-associated disorders that exhibit an uncontrollable proliferation of fibroblasts and their subsequent contribution to the excessive accumulation of extracellular matrix (ECM) in the dermis. In this study, to elucidate the underlying mechanisms, we investigated the pivotal roles of epidermal growth factor (EGF) in modulating fibrotic phenotypes of keloid and hypertrophic dermal fibroblasts. Our initial findings revealed the molecular signatures of keloid dermal fibroblasts and showed the highest degree of skin fibrosis markers, ECM remodeling, anabolic collagen-cross-linking enzymes, such as lysyl oxidase (LOX) and four LOX-like family enzymes, migration ability, and cell-matrix traction force, at cell-matrix interfaces. Furthermore, we observed significant EGF-mediated downregulation of anabolic collagen-cross-linking enzymes, resulting in amelioration of fibrotic phenotypes and a decrease in cell motility measured according to the cell-matrix traction force. These findings offer insight into the important roles of EGF-mediated cell-matrix interactions at the cell-matrix interface, as well as ECM remodeling. Furthermore, the results suggest their contribution to the reduction of fibrotic phenotypes in keloid dermal fibroblasts, which could lead to the development of therapeutic modalities to prevent or reduce scar tissue formation.
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http://dx.doi.org/10.3390/ijms22042198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926382PMC
February 2021

Apoptosis and fibrosis of vascular smooth muscle cells in aortic dissection: an immunohistochemical study.

Int J Clin Exp Pathol 2020 1;13(8):1962-1969. Epub 2020 Aug 1.

Department of Pathology, College of Medicine, Catholic University of Daegu Daegu, Republic of Korea.

Aortic dissection (AD) is a fatal disease characterized by a ruptured intima that leads to the complete rupture of the aorta. The aim of this study is to examine the immunohistochemical expression of inflammation/fibrosis-associated chemical mediators in AD patients. Surgical specimens of aortic tissues were obtained from 37 patients who underwent an open thoracic aortic repair. AD was detected with histological staining. Local congestion and hemorrhage as well as chronic inflammatory cells infiltrations were observed at the dissection. Moreover, extensive disarrangement and disruption of elastic fibers were observed in the medial layer of the aorta with dissection. In summary, our study revealed that the apoptotic rate of vascular SMCs (VSMCs) in the vascular middle layer is higher in the dissected aortas than in the control aortas, suggesting that abnormally elevated apoptosis is correlated with AD pathogenesis. Functional studies of key genes identified in the apoptotic pathways as well as in extracellular matrix would be critical in thoroughly understanding the underlying mechanisms of AD development. Targeting the mediators related to TGF-β1, the Smad family proteins, and caspase 3 or anti-apoptotic agents may provide diagnostic markers and therapeutic targets that could be used to prevent AD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476953PMC
August 2020

Metachronous extranodal natural killer/T-cell lymphoma of nasal type and primary testicular lymphoma.

Yeungnam Univ J Med 2021 Jul 11;38(3):231-234. Epub 2020 Sep 11.

Department of Pathology, Daegu Catholic University School of Medicine, Daegu, Korea.

We report a rare case of metachronous lymphoma with two distinct cell lineages in a 75-year-old man. The patient complained about having nasal obstruction for 2 years and extranodal natural killer (NK)/T-cell lymphoma of the nasal type was diagnosed from a biopsy. The immunohistochemical staining for CD56 and in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNA (EBER-ISH) were positive and the tumor cells were negative for CD20. After 13 months of concurrent chemoradiotherapy, the patient presented with swelling of the left testis. Positron emission tomography scan detected an abnormal uptake in the testis. A diffuse large B-cell lymphoma, not otherwise specified, was diagnosed from subsequent radical orchiectomy. The immunohistochemical staining revealed to be positive for CD20, BCL2, BCL6, and MYC and negative for CD10 and EBER-ISH.
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http://dx.doi.org/10.12701/yujm.2020.00675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225494PMC
July 2021

Protective Effects of Bee Venom against Endotoxemia-Related Acute Kidney Injury in Mice.

Biology (Basel) 2020 Jul 6;9(7). Epub 2020 Jul 6.

Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea.

Sepsis-associated acute kidney injury (AKI) is a leading cause of death in hospitalized patients worldwide. Despite decades of effort, there is no effective treatment for preventing the serious medical condition. Bee venom has long been used to treat a variety of inflammatory diseases. However, whether bee venom has protective effects against lipopolysaccharide (LPS)-induced AKI has not been explored. The aim of this study was to evaluate the effects of bee venom on LPS-induced AKI. The administration of bee venom alleviated renal dysfunction and structural injury in LPS-treated mice. Increased renal levels of tubular injury markers after LPS treatment were also suppressed by bee venom. Mechanistically, bee venom significantly reduced plasma and tissue levels of inflammatory cytokines and immune cell infiltration into damaged kidneys. In addition, mice treated with bee venom exhibited reduced renal expression of lipid peroxidation markers after LPS injection. Moreover, bee venom attenuated tubular cell apoptosis in the kidneys of LPS-treated mice. In conclusion, these results suggest that bee venom attenuates LPS-induced renal dysfunction and structural injury via the suppression of inflammation, oxidative stress, and tubular cell apoptosis, and might be a useful therapeutic option for preventing endotoxemia-related AKI.
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http://dx.doi.org/10.3390/biology9070154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408099PMC
July 2020

Cytological, histological, and molecular characteristics of pure invasive micropapillary carcinoma of pancreas: A case report.

Medicine (Baltimore) 2020 Jun;99(24):e20668

Department of Pathology.

Introduction: Pure invasive micropapillary carcinoma (IMPC) is a rare histologic subtype of pancreatic cancer which has a high propensity for lymph node metastasis and poor prognosis.

Patient Concerns: An 81-year-old woman was admitted to our institution with a 3-month history of back pain. Computed tomography of the abdomen and pelvis confirmed the presence of a low-density mass in the tail of the pancreas.

Diagnosis: Endoscopic ultrasound-guided fine needle aspiration cytology (FNAC) from the pancreatic mass showed small tumor cell clusters with three-dimensional aggregates and morula-like structures. The tumor was diagnosed as adenocarcinoma with micropapillary features.

Interventions: The patient underwent radical antegrade modular pancreatosplenectomy and regional lymph node dissection. Histological examination showed small clusters of tumor cells that were closely adhered to one another. The cells were located in empty stromal spaces mimicking lymphovascular channels. All tumor cells showed reverse polarity, resulting in an "inside-out" pattern. An extensive search was performed, and no typical ductal adenocarcinoma component was found. The tumor measured 1.5 × 1.3 cm and invaded into the peripancreatic fat tissue without adjacent organ invasion. One of the 12 regional lymph nodes showed metastasis. Ion Torrent next-generation sequencing identified missense mutations in KRAS, TP53, and SMAD4 using the Oncomine Comprehensive Panel version 1.

Outcomes: Twelve months following surgical resection the patient remained healthy with no evidence of recurrence at clinical follow-up.

Lessons: This report highlights the diagnostic features and molecular characteristics of pure pancreatic IMPC and the challenges with diagnosis by FNAC. A centralized and collaborative accumulation of additional cases of pure IMPC could further elucidate its pathogenesis.
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http://dx.doi.org/10.1097/MD.0000000000020668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302577PMC
June 2020

LncRNAs Act as a Link between Chronic Liver Disease and Hepatocellular Carcinoma.

Int J Mol Sci 2020 Apr 20;21(8). Epub 2020 Apr 20.

Department of Pathology, Catholic University of Daegu School of Medicine, Daegu 42472, Korea.

Long non-coding RNAs (lncRNAs) are emerging as important contributors to the biological processes underlying the pathophysiology of various human diseases, including hepatocellular carcinoma (HCC). However, the involvement of these molecules in chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and viral hepatitis, has only recently been considered in scientific research. While extensive studies on the pathogenesis of the development of HCC from hepatic fibrosis have been conducted, their regulatory molecular mechanisms are still only partially understood. The underlying mechanisms related to lncRNAs leading to HCC from chronic liver diseases and cirrhosis have not yet been entirely elucidated. Therefore, elucidating the functional roles of lncRNAs in chronic liver disease and HCC can contribute to a better understanding of the molecular mechanisms, and may help in developing novel diagnostic biomarkers and therapeutic targets for HCC, as well as in preventing the progression of chronic liver disease to HCC. Here, we comprehensively review and briefly summarize some lncRNAs that participate in both hepatic fibrosis and HCC.
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http://dx.doi.org/10.3390/ijms21082883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216144PMC
April 2020

Renal hemosiderosis secondary to intravascular hemolysis after mitral valve repair: A case report.

Medicine (Baltimore) 2020 Jan;99(3):e18798

Department of Internal Medicine, Hansung Union Internal Medicine Clinic and Dialysis Center, Daegu, Republic of Korea.

Rationale: Renal hemosiderosis is a disease in which hemosiderin deposits in the renal cortex as a form of iron overload. However, cases of renal hemosiderosis due to intravascular hemolysis following mitral valve repair have been rarely reported.

Patient Concerns: We present the case of a 62-year-old woman who developed asymptomatic urinary abnormalities including microscopic hematuria and proteinuria due to renal hemosiderosis following a mitral valve repair surgery performed two years earlier.

Diagnoses: A percutaneous renal biopsy showed no specific glomerular abnormality, tubular atrophy, or interstitial fibrosis but extensive deposition of hemosiderin in the proximal tubule. The patient was diagnosed with renal hemosiderosis and chronic intravascular hemolysis following mitral valve repair.

Interventions: Our patient refused a mitral valve repeat surgery and hence was treated with oral iron preparations, N-acetylcysteine, and a β-receptor blocker.

Outcomes: Moderate mitral regurgitation with the regurgitant blood striking against the annuloplasty ring was confirmed on follow-up echocardiography. After the 24-month follow-up period, hemolytic anemia persisted, but there was no significant decline of renal function.

Lessons: For cases of chronic intravascular hemolysis accompanied with asymptomatic urinary abnormalities, a renal biopsy is required to exclude underlying kidney pathology and predict potential renal insufficiency.
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http://dx.doi.org/10.1097/MD.0000000000018798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220361PMC
January 2020

Surgical Treatment of Mandible Fracture Using Unsintered Hydroxyapatite/Poly L-Lactide Composite Fixation System.

J Craniofac Surg 2019 Nov-Dec;30(8):2573-2575

Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Bucheon, Korea.

Recently, absorbable plates have been used for various types of facial fractures. However, in the case of mandibular fractures, a large amount of force is applied after fixation. Thus, a firm fixation is necessary. In particular, unfavorable fractures are more frequent in mandibular fractures. Therefore, plates should be strong enough to withstand forces at the time of surgery. The purpose of this study was to determine clinical efficacy and usefulness of unsintered hydroxyapatite (u-HA)/poly (L-lactide) (PLLA) composite system by clinical application and follow-up of fixation in patients with mandible fracture. A total of 13 patients with mandible fractures were assessed for compliance with the selection criteria. Fracture site was confirmed with radiographic findings including X-ray and facial computed tomography images. Subjects who fulfilled all criteria underwent operation using HA/PLLA composite fixation system (OSTEOTRANS; Takiron Co Ltd, Osaka, Japan). After reduction of fracture site through oral or skin incision, we placed OSTEOTRANS plates on fracture line and performed rigid fixation with OSTEOTRANS-MX screws. Follow-up was performed at 1 week, 1, 3, and 6 months after surgery. Occlusion and mouth opening were checked by physical examination and radiographic finding. We also confirmed bone approximation status, bony gap change, and bone union status. All patients finished every follow-up. They were satisfied with outcomes without complications such as malocclusion, foreign body sensation, or tenderness. This study confirms that OSTEOTRANS can be used appropriately for mandibular fractures.
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http://dx.doi.org/10.1097/SCS.0000000000006030DOI Listing
January 2020

A comparative study of intraoral versus retromandibular approach in the management of subcondylar fracture.

BMC Surg 2019 Mar 5;19(1):28. Epub 2019 Mar 5.

Department of Plastic and Reconstructive Surgery, Hanyang University, College of Medicine, 153, Gyeongchun-ro, Guri, 11923, Republic of Korea.

Background: The purpose of this study was to compare the outcomes and effectiveness between intraoral approach and retromandibular approach for treatment of subcondylar fracture of mandible.

Methods: Between March 2011 and October 2013, 24 patients with subcondylar fractures of the mandible were treated by a single surgeon with an intraoral approach using an angulated screwdriver (n = 14) or by another surgeon using a retromandibular approach (n = 10). The interincisal distance was measured 1 week (T0), 6 weeks (T1), 3 months (T2), and 6 months (T3) postoperatively. We also compare the average operation time and the cost of operation between the two groups.

Results: At 6 months postoperatively, all 24 patients achieved satisfactory ranges of temporomandibular joint movement, with an interincisal distance > 40 mm without deviation and with stable centric occlusion. The intraoral group had the median interincisal distance of 14 mm at T0, 38 mm at T1, 42.5 mm at T2, and 43 mm at T3, while the retromandibular group had that of 15, 29, 35, and 42.5 mm respectively. There was no statistically significant difference between the intraoral and the retromandibular group at T0 and T4. However, significant differences were noted T1 and T2 (p < 0.01). The differences of average operation time between the intraoral (81 min) and retromandibular group (45 min) were statistically significant (p < 0.01). The cost of an operation was 369.96 ± 8.14 (United States dollar [USD]) in intraoral group and was 345.48 ± 0.0 (USD) in retromandibular group. The differences between the two groups were statistically significant (p < 0.01).

Conclusion: In open reduction of a subcondylar fracture of the mandible, a intraoral approach using an angulated screwdriver is superior to the retromandibular approach in terms of interincisal distance, although the operation time is longer.
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http://dx.doi.org/10.1186/s12893-019-0487-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399831PMC
March 2019

Cytopathologic Features of Secretory Carcinoma of Salivary Gland: Report of Two Cases.

J Pathol Transl Med 2019 Jan 28;53(1):70-74. Epub 2018 Dec 28.

Department of Pathology, Catholic University of Daegu School of Medicine, Daegu, Korea.

Secretory carcinoma of the salivary gland (SC) is a newly introduced rare salivary gland tumor that shares histological, immunohistochemical, and genetic characteristics with secretory carcinoma of the breast. Here, we report the cytologic features of two cases of SC confirmed by surgical resection. In these two cases, SC was incidentally detected in a 64-year-old female and a 56-yearold male. Fine needle aspiration cytology revealed nests of tumor cells with a papillary or glandular structure floating in mucinous secretions. The tumor cells demonstrated uniform, round, smooth nuclear contours and distinct nucleoli. Multiple characteristic cytoplasmic vacuoles were revealed. Singly scattered tumor cells frequently showed variable sized cytoplasmic vacuoles. The cytopathologic diagnosis of SC should be considered when characteristic cytological findings are revealed. Further immunohistochemistry and gene analyses are helpful to diagnose SC.
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http://dx.doi.org/10.4132/jptm.2018.11.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344800PMC
January 2019

Significance of Intratumoral Fibrosis in Clear Cell Renal Cell Carcinoma.

J Pathol Transl Med 2018 Sep 19;52(5):323-330. Epub 2018 Aug 19.

Department of Urology, Catholic University of Daegu School of Medicine, Daegu, Korea.

Background: Intratumoral fibrosis (ITF) is a frequent histologic finding in solid organ tumors. Renal cell carcinoma (RCC) is a highly vascularized tumor with different shapes and degrees of ITF and inflammation. ITF is a poor prognostic factor, especially in breast cancer, and is related to intratumoral necrosis (ITN) and intratumoral inflammation (ITI). However, the significance of ITF in RCC has not been fully studied. In this study, we evaluate the relationships between ITF and other clinicopathologic parameters associated with RCC prognosis.

Methods: ITF was evaluated in 204 clear cell renal cell carcinoma (CCRCC) specimens according to presence and grade of fibrosis, degree of ITI, and presence of ITN. Lysyl oxidase (LOX) expression in tumor cells was also evaluated with clinicopathologic parameters.

Results: Among 204 CCRCC cases, 167 (81.7%) showed ITF, 71 (34.8%) showed ITI, 35 (17.2%) showed ITN, and 111 (54.4%) showed LOX expression. ITF correlated with Fuhrman nuclear grade (p = .046), lymphovascular invasion (LVI) (p = .027), and ITN (p = .036). Patients with ITF had a poor five-year overall survival rate (p = .104).

Conclusions: ITF is related to other poor prognostic factors in CCRCC, such as Fuhrman nuclear grade, ITN, and LVI, but ITF itself had no significant correlation with prognosis of CCRCC.
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http://dx.doi.org/10.4132/jptm.2018.07.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166018PMC
September 2018

Association between lysyl oxidase and fibrotic focus in relation with inflammation in breast cancer.

Oncol Lett 2018 Feb 14;15(2):2431-2440. Epub 2017 Dec 14.

Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu 705-718, Repulic of South Korea.

We hypothesized that lysyl oxidase (LOX) contributes to the formation of fibrotic focus (FF) in association with inflammation and serves a significant role in breast carcinogenesis. In the present study, the association between the expression of LOX family members and FF with regards to with inflammation was analyzed, and the prognostic significance of LOX and FF in breast cancer was investigated. Immunohistochemical staining for LOX, LOX-like protein (LOXL) 1, LOXL2 and LOXL3 was performed in primary breast cancer tissues. The status of FF within the tumor was assessed, including size and grade. Levels of inflammatory markers, intratumoral and peritumoral lymphocyte infiltration were also evaluated. The clinicopathological characteristics were evaluated from the medical records of patients. In the present study, the expression of LOX family members was not associated with the presence of FF. FF was identified to be associated with intratumoral and peritumoral inflammation, tumor stage, larger tumor size, lymph node metastasis, high histologic grade, and p53 expression. LOX and LOXL3 were associated with intratumoral, and peritumoral inflammation. Furthermore, LOXL1 was associated with intratumoral inflammation and interleukin-4. In addition, LOX was associated with cluster of differentiation 8 T cells. LOXL3 was associated with expression of ER and PR, and molecular subtype. In the survival analysis, overall survival time was statistically significantly longer in the FF-negative compared with that in the FF-positive group. In conclusion, it was demonstrated that FF and the expression of LOX family members were associated with inflammation in breast cancer. FF was associated with poor prognostic markers of breast cancer. Further studies are required to clarify the mechanisms underlying the association between the LOX family, FF and inflammation in breast cancer.
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http://dx.doi.org/10.3892/ol.2017.7617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777281PMC
February 2018

Apamin inhibits TNF-α- and IFN-γ-induced inflammatory cytokines and chemokines via suppressions of NF-κB signaling pathway and STAT in human keratinocytes.

Pharmacol Rep 2017 Oct 18;69(5):1030-1035. Epub 2017 Apr 18.

Department of Pathology, College of Medicine, Catholic University of Daegu, 33, Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472, Republic of Korea. Electronic address:

Background: Atopic dermatitis (AD) is identified by an increase in infiltrations of several inflammatory cells including type 2 helper (Th2) lymphocytes. Th2-related chemokines such as thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), and pro-inflammatory cytokines including interleukin (IL)-1β and IL-6 are considered to play a crucial role in AD. Tumor necrosis factor (TNF)-α- and interferon (IFN)-γ induce the inflammatory condition through production of TARC, MDC, IL-1β and IL-6, and activations of related transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT) in keratinocytes. Apamin, a peptide component of bee venom, has been reported its beneficial activities in various diseases. However, anti-inflammatory effects of apamin on inflammatory condition in keratinocytes have not been explored. Therefore, the present study aimed to demonstrate the anti-inflammatory effect of apamin on TNF-α- and IFN-γ-induced inflammatory condition in keratinocytes.

Methods: HaCaT was used as human keratinocytes cell line. Cell Counting Kit-8 was performed to measure a cytotoxicity of apamin. The effects of apamin on TNF-α-/IFN-γ-induced inflammatory condition were determined by real-time PCR and Western blot analysis. Further, NF-κB signaling pathways, STAT1, and STAT3 were analyzed by Western blot and immunofluorescence.

Results: Apamin ameliorated the inflammatory condition through suppression of Th2-related chemokines and pro-inflammatory cytokines. Further, apamin down-regulated the activations of NF-κB signaling pathways and STATs in HaCaT cells.

Conclusions: These results suggest that apamin has therapeutic effect on AD through improvement of inflammatory condition.
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http://dx.doi.org/10.1016/j.pharep.2017.04.006DOI Listing
October 2017

A Rare Case of Intramural Müllerian Adenosarcoma Arising from Adenomyosis of the Uterus.

J Pathol Transl Med 2017 Jul 29;51(4):433-440. Epub 2017 Jun 29.

Department of Pathology, Catholic University of Daegu School of Medicine, Daegu, Korea.

Müllerian adenosarcomas usually arise as polypoid masses in the endometrium of post-menopausal women. Occasionally, these tumors arise in the cervix, vagina, broad and round ligaments, ovaries and rarely in extragenital sites; these cases are generally associated with endometriosis. We experienced a rare case of extraendometrial, intramural adenosarcoma arising in a patient with adenomyosis. A 40-year-old woman presented with sudden-onset suprapubic pain. The imaging findings suggested leiomyoma with cystic degeneration in the uterine fundus. An ill-defined ovoid tumor with hemorrhagic degeneration, measuring 7.5 cm in diameter, was detected. The microscopic findings showed glandular cells without atypia and a sarcomatous component with pleomorphism and high mitotic rates. There was no evidence of endometrial origin. To recognize that adenosarcoma can, although rarely, arise from adenomyosis is important to avoid overstaging and inappropriate treatment.
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http://dx.doi.org/10.4132/jptm.2017.06.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525044PMC
July 2017

The pathogenesis of drug-induced liver injury.

Expert Rev Gastroenterol Hepatol 2016 Oct 13;10(10):1175-1185. Epub 2016 Jun 13.

a Department of Pathology, School of Medicine , Catholic University of Daegu , Daegu , Republic of Korea.

Introduction: Drugs can induce liver injury when taken as an over-dose, or even at therapeutic doses in susceptible individuals. Although severe drug-induced liver injury (DILI) is a relatively uncommon clinical event, it is a potentially life threatening adverse drug reaction and is the most common indication for the drug withdrawal. Areas covered: However, the diagnosis of DILI remains a significant challenge, because the establishment of causality is very difficult, and the histopathologic findings of DILI may be indistinguishable from those of other hepatic disorders, such as viral and alcoholic hepatitis. In this review, we provide an overview of recent advances in identification of serologic markers of diagnosis and prognosis, etiologic factors for susceptibility and diagnostic evaluation of DILI, with a focus on its pathogenic mechanisms and the role of liver biopsy. Expert commentary: Further studies of divergent research platforms, using a systems biology approach such as genomics and transcriptomics, may provide a deeper understanding of human drug metabolism and the causes, risk factors, and pathogenesis of DILI.
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http://dx.doi.org/10.1080/17474124.2016.1196133DOI Listing
October 2016

Microenvironmental interactions and expression of molecular markers associated with epithelial-to-mesenchymal transition in colorectal carcinoma.

Int J Clin Exp Pathol 2015 1;8(11):14270-82. Epub 2015 Nov 1.

Department of Pathology, College of Medicine, Catholic University of Daegu Republic of Korea.

The tumor microenvironment is known to play a critical role in tumor progression, invasion and metastasis. The epithelial-to-mesenchymal transition (EMT) is understood as a process of tumor invasion and metastasis. Therefore, we investigated the relation between the EMT and the microenvironment of colorectal carcinoma (CRC). The histological features and expression of EMT markers in tumor cells and surrounded stromal cells were obtained from the surgically resected tissues of 39 patients using microscopic review and immunohistochemistry. The loss of expression of E-cadherin was more prominent in the invasive front of tumor than the surface, where α-smooth muscle actin-positive carcinoma-associated fibroblasts (CAFs) are accumulated. The signaling molecules of the Wnt and TGF-β1-Smad pathway were expressed more frequently in the tumor cells and/or CAFs of the invasive margin than those of the tumor surface. The expressions of related transcription factors, such as SNAIL and ZEB1, were increased in the tumor cells and CAFs. The process of EMT may be activated in the tumor margin of CRC under the control of CAFs. Related signaling molecules and transcription factors might be induced by paracrine effects of the surrounding CAFs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713529PMC
October 2016

Notch signaling affects biliary fibrosis via transcriptional regulation of RBP-jκ in an animal model of chronic liver disease.

Int J Clin Exp Pathol 2015 1;8(10):12688-97. Epub 2015 Oct 1.

Department of Pathology, Catholic University of Daegu School of Medicine 3056-6 Daemyung-4 Dong, Nam-Gu, Daegu, Republic of Korea.

Liver repair in patients with a chronic liver disease requires the orchestrated action of epithelial, mesenchymal, and inflammatory cells. Notch components are expressed in both the epithelial and mesenchymal compartments of the adult liver and are differentially regulated after injury. However, the functional role of Notch signaling in regulating epithelial/mesenchymal cross-talk during fibrogenic pathologic repair remains unknown. The aim of this study was to investigate how proliferation of the bile duct influences biliary fibrosis and to recognize the effect of inhibiting Notch signaling in biliary fibrotic tissue of the injured liver. We designed a synthetic decoy oligodeoxynucleotide (ODN) for recombination signal binding protein immunoglobulin kappa J (RBP-jκ), which is a common DNA-binding partner of Notch receptors. The effect of blocking RBP-jκ on fibrogenesis was assessed in the 3,5-Diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet mouse model. We observed the reduced fibrosis and decreased expression of associated signaling molecules after the RBP-jκ decoy ODN treatment. These data demonstrate that Notch signaling may play an important role in progression of ductular reaction and fibrosis. Further studies are required to unveil how ductular cells interact with other liver cell types, such as hepatic stellate cells or Kupffer cells,in patients with cholestatic liver diseases based on Notch signaling. These results suggest that controlling the ductular reaction using a synthetic ring type decoy RBP-jκ ODN will help develop a novel therapeutic approach targeting biliary fibrosis in patients with chronic liver diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680403PMC
October 2016

Transesophageal imaging of a left main coronary artery ostium occlusion in infective endocarditis: a case report.

Korean J Anesthesiol 2015 Jun 28;68(3):292-4. Epub 2015 May 28.

Department of Anesthesia and Pain Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea.

A 43-year-old woman was admitted due to fever, chills, and headache for several days and was diagnosed as infective endocarditis. Intraoperative transesophageal echocardiography (TEE) examination confirmed severe aortic stenosis and showed relatively fresh 1.5 cm vegetation on the left coronary cusp of the aortic valve (AV) with frequent diastolic prolapse into the aortic root. This mobile vegetation partially occluded left coronary ostium, but it did not cause cardiac failure. TEE showed the vegetation to be in good position across the AV. The AV replacement with removal of vegetation and mitral valvuloplasty were performed. The patient was weaned from cardiopulmonary bypass without any hemodynamic instability or changes in ST segment on electrocardiography. She was discharged on the 28th postoperative day without any complication.
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http://dx.doi.org/10.4097/kjae.2015.68.3.292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452675PMC
June 2015

Anti-fibrotic effect of natural toxin bee venom on animal model of unilateral ureteral obstruction.

Toxins (Basel) 2015 May 29;7(6):1917-28. Epub 2015 May 29.

Department of Pathology, College of Medicine, Catholic University of Daegu, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu 705-718, Korea.

Progressive renal fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure. Bee venom (BV) has been widely used as a traditional medicine for various diseases. However, the precise mechanism of BV in ameliorating the renal fibrosis is not fully understood. To investigate the therapeutic effects of BV against unilateral ureteral obstruction (UUO)-induced renal fibrosis, BV was given intraperitoneally after ureteral ligation. At seven days after UUO surgery, the kidney tissues were collected for protein analysis and histologic examination. Histological observation revealed that UUO induced a considerable increase in the number of infiltrated inflammatory cells. However, BV treatment markedly reduced these reactions compared with untreated UUO mice. The expression levels of TNF-α and IL-1β were significantly reduced in BV treated mice compared with UUO mice. In addition, treatment with BV significantly inhibited TGF-β1 and fibronectin expression in UUO mice. Moreover, the expression of α-SMA was markedly withdrawn after treatment with BV. These findings suggest that BV attenuates renal fibrosis and reduces inflammatory responses by suppression of multiple growth factor-mediated pro-fibrotic genes. In conclusion, BV may be a useful therapeutic agent for the prevention of fibrosis that characterizes progression of chronic kidney disease.
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http://dx.doi.org/10.3390/toxins7061917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488681PMC
May 2015

Apamin inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration through suppressions of activated Akt and Erk signaling pathway.

Vascul Pharmacol 2015 Jul 28;70:8-14. Epub 2015 Feb 28.

Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu 705-718, Republic of Korea. Electronic address:

The increased proliferation and migration of vascular smooth muscle cells (VSMC) are key process in the development of atherosclerosis lesions. Platelet-derived growth factor (PDGF) initiates a multitude of biological effects that contribute to VSMC proliferation and migration. Apamin, a component of bee venom, has been known to block the Ca(2+)-activated K(+) channels. However, the effects of apamin in the regulation PDGF-BB-induced VSMC proliferation and migration has not been identified. In this study, we investigate the inhibitory effect of apamin on PDGF-BB-induced VSMC proliferation and migration. Apamin suppressed the PDGF-BB-induced VSMC proliferation and migration with no apparent cytotoxic effect. In accordance with these findings, apamin induced the arrest of cell cycle progression at G0/G1 phase. Apamin also decreased the expressions of G0/G1 specific regulatory proteins including proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin-dependent kinases (CDK) 4, cyclin E and CDK2, as well as increased the expression of p21(Cip1) in PDGF-BB-induced VSMC. Moreover, apamin inhibited PDGF-BB-induced phosphorylation of Akt and Erk1/2. These results suggest that apamin plays an important role in prevention of vascular proliferation and migration through the G0/G1 cell cycle arrest by PDGF signaling pathway. Thus, apamin may be a promising candidate for the therapy of atherosclerosis.
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http://dx.doi.org/10.1016/j.vph.2014.12.004DOI Listing
July 2015

Ovarian angioleiomyoma: a case report.

Int J Clin Exp Pathol 2014 15;7(11):8235-9. Epub 2014 Oct 15.

Department of Pathology, Catholic University of Daegu College of Medicine Daegu, Republic of Korea.

Angioleiomyoma (ALM) is a rare and painful, benign neoplasm that is referred to an uncommon type of leiomyoma originating from smooth muscle cells of arterial and venous walls. ALM is very rarely found in the female genital organs such as uterus or ovary. Herein, we present the case of a huge primary ovarian ALM in a 35 year-old woman, clinically and radiologically mimicking an ovarian fibroma, which histologically has diffuse myxoid degeneration. This is the third case of ovarian ALM and the first case of ovarian ALM with diffuse degeneration reported in English literatures, to the best of our knowledge.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270608PMC
September 2015

Retroperitoneal hemorrhage from an unrecognized puncture of the lumbar right segmental artery during lumbar chemical sympathectomy: diagnosis and management.

J Clin Anesth 2014 Dec 18;26(8):671-5. Epub 2014 Oct 18.

Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Yangsan, 626-770, Korea. Electronic address:

Lumbar chemical sympathectomy has been performed using fluoroscopic guidance for needle positioning. An 84 year old woman with atherosclerosis obliterans was referred to the pain clinic for intractable cold allodynia of her right foot. A thermogram showed decreased temperature of both feet compared with temperatures above both ankles. The patient agreed to undergo lumbar chemical sympathectomy using fluoroscopy after being informed of the associated risks of nerve injury, hemorrhage, infection, transient back pain, and transient hypotension. During the procedure and three hours afterward, no abnormal signs or symptoms were found except an increase in right leg temperature. The patient was ambulatory after the procedure. However, one day after undergoing lumbar chemical sympathectomy, she visited our emergency department for abdominal discomfort and postural dizziness. Her blood pressure was 80/50 mmHg, and flank tenderness was noted. Retroperitoneal hemorrhage from the second right lumbar segmental artery was shown on computed tomography and angiography. Vital signs were stabilized immediately after embolization into the right lumbar segmental artery.
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http://dx.doi.org/10.1016/j.jclinane.2014.06.001DOI Listing
December 2014

Inhibitory effects of bee venom on Propionibacterium acnes-induced inflammatory skin disease in an animal model.

Int J Mol Med 2014 Nov 12;34(5):1341-8. Epub 2014 Sep 12.

Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu, Republic of Korea.

Propionibacterium acnes (P. acnes) is a major contributing factor to the inflammatory component of acne. The many prescription medications for acne allow for a large number of potential combination treatments. However, several antibiotics, apart from their antibacterial effects, exert side‑effects, such as the suppression of host inflammatory responses. Purified bee venom (BV) is a natural toxin produced by honeybees (Apis mellifera L.). BV has been widely used as a traditional medicine for various diseases. In the present study, to investigate the therapeutic effects of BV against P. acnes-induced inflammatory skin disease, P. acnes was intradermally injected into the ears of mice. After the injection, BV was applied to the skin surface of the right ear. Histological observation revealed that P. acnes induced a considerable increase in the number of infiltrated inflammatory cells. However, treatment with BV markedly reduced these reactions compared with the P. acnes-injected mice not treated with BV. Moreover, the expression levels of tumor necrosis factor (TNF)-α, and interleukin (IL)-1β were significantly reduced in the BV-treated mice compared with the untreated P. acnes-injected mice. In addition, treatment with BV significantly inhibited Toll-like receptor (TLR)2 and CD14 expression in P. acnes-injected tissue. The binding activity of nuclear factor-κB (NF-κB) and activator protein (AP)-1 was markedly suppressed following treatment with BV. The results from our study, using an animal model, indicate that BV exerts an inhibitory effect on inflammatory skin diseases. In conclusion, our data indicate that BV has potential for use as an anti-acne agent and may be useful in the pharmaceutical and cosmetics industries.
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http://dx.doi.org/10.3892/ijmm.2014.1933DOI Listing
November 2014

Transcription factors related to epithelial mesenchymal transition in tumor center and margin in invasive lung adenocarcinoma.

Int J Clin Exp Pathol 2014 15;7(7):4095-103. Epub 2014 Jun 15.

Department of Pathology, School of Medicine, Catholic University of Daegu Daegu, Republic of Korea.

The tumor microenvironment has many roles involving tumor progression, invasion and metastasis. The tumor cells at the tumor border loose epithelial properties and acquire mesenchymal features. This, epithelial-to-mesenchymal transition (EMT) has been suggested to be an important process for tissue and lymphovascular invasion. Pulmonary tissue samples from 15 patients with primary adenocarcinoma were evaluated with using immunofluorescence multi-staining the EMT-associated markers including E-cadherin and alpha-smooth muscle actin (α-SMA), and transcription factors including E-SNAIL and SLUG, and ZEB1. The data were analyzed in specific area, such as tumor center and tumor border. In this study we show that the invasive adenocarcinoma differentially expressed SNAIL and SLUG, and Zeb1 and it was associated with the loss of epithelial marker (E-cadherin) and gaining of mesenchymal marker (α-SMA) at the invasive border of lung carcinoma. The positive rates of SNAIL and ZEB1 were 26.7% and 0% in the tumor center and 40% and 20% in tumor margin, respectively. In addition, the expression of both SNAIL and ZEB1 at the border of tumor was observed in two cases (2/10). These two cases were associated with lymph node metastasis and advanced stage. The process of EMT has been suggested to be of prime importance for tissue and lymphovascular invasion. The process of EMT may be activated in the tumor border of lung adenocarcinoma. Related transcription factors, such as SNAIL and SLUG, and ZEB1, might be induced by paracrine effects of surrounded inflammatory cells and fibroblasts.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129023PMC
May 2015

Immunohistochemical study for the origin of ductular reaction in chronic liver disease.

Int J Clin Exp Pathol 2014 15;7(7):4076-85. Epub 2014 Jun 15.

Department of Pathology, Catholic University of Daegu School of Medicine Daegu, Republic of Korea.

The appearance of proliferating bile ductular structures, which is called the "atypical ductular reaction" is frequently observed in various chronic liver diseases associated. However, the origin of these increased bile ductules has been a matter of controversy. In this study, we investigated the origin of ductular cells as an aspect of relation between epithelial to mesenchymal transition (EMT) and epithelial members of liver parenchyme, such as hepatocyte and cholangiocyte by immunohistochemical staining of human liver. Thirteen specimens of surgically resected liver with biliary cirrhosis were selected. Three sets of double immunohistochemical stains were done; Hep-Par 1 - cytokeratin 19 (CK19), Hep-Par 1 - α-sm ooth mus cle actin (α-SMA) and CK19 - α-SMA. As a result, we investigated the dual expression of the markers of hepatocyte and cholangiocyte in the same cell; in ductular cell and surrounding hepatocyte. However, there seems to be no dual expression of markers for EMT with epithelial markers. This study suggests a possibility of phenotypic change of mature hepatocyte into cholangiocyte. Future studies will be necessary to determine the role that proliferating cholangiocytes play in the pathogenesis of biliary fibrosis and how cholangiocytes interact with other cell types of the liver such as hepatic stellate cells or Kupffer cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129021PMC
May 2015

Apamin inhibits hepatic fibrosis through suppression of transforming growth factor β1-induced hepatocyte epithelial-mesenchymal transition.

Biochem Biophys Res Commun 2014 Jul 27;450(1):195-201. Epub 2014 May 27.

Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu, South Korea. Electronic address:

Apamin is an integral part of bee venom, as a peptide component. It has long been known as a highly selective block Ca(2+)-activated K(+) (SK) channels. However, the cellular mechanism and anti-fibrotic effect of apamin in TGF-β1-induced hepatocytes have not been explored. In the present study, we investigated the anti-fibrosis or anti-EMT mechanism by examining the effect of apamin on TGF-β1-induced hepatocytes. AML12 cells were seeded at ∼60% confluence in complete growth medium. Twenty-four hours later, the cells were changed to serum free medium containing the indicated concentrations of apamin. After 30 min, the cells were treated with 2 ng/ml of TGF-β1 and co-cultured for 48 h. Also, we investigated the effects of apamin on the CCl4-induced liver fibrosis animal model. Treatment of AML12 cells with 2 ng/ml of TGF-β1 resulted in loss of E-cadherin protein at the cell-cell junctions and concomitant increased expression of vimentin. In addition, phosphorylation levels of ERK1/2, Akt, Smad2/3 and Smad4 were increased by TGF-β1 stimulation. However, cells treated concurrently with TGF-β1 and apamin retained high levels of localized expression of E-cadherin and showed no increase in vimentin. Specifically, treatment with 2 μg/ml of apamin almost completely blocked the phosphorylation of ERK1/2, Akt, Smad2/3 and Smad4 in AML12 cells. In addition, apamin exhibited prevention of pathological changes in the CCl4-injected animal models. These results demonstrate the potential of apamin for the prevention of EMT progression induced by TGF-β1 in vitro and CCl4-injected in vivo.
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http://dx.doi.org/10.1016/j.bbrc.2014.05.089DOI Listing
July 2014

Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition.

World J Hepatol 2014 Apr;6(4):207-16

Sun-Jae Lee, Kyung-Hyun Kim, Kwan-Kyu Park, Department of Pathology, Catholic University of Daegu, College of Medicine, Daegu, 705-718, South Korea.

Liver injuries are repaired by fibrosis and regeneration. The cause of fibrosis and diminished regeneration, especially in liver cirrhosis, is still unknown. Epithelial-mesenchymal transition (EMT) has been found to be associated with liver fibrosis. The possibility that EMT could contribute to hepatic fibrogenesis reinforced the concept that activated hepatic stellate cells are not the only key players in the hepatic fibrogenic process and that other cell types, either hepatic or bone marrow-derived cells could contribute to this process. Following an initial enthusiasm for the discovery of this novel pathway in fibrogenesis, more recent research has started to cast serious doubts upon the real relevance of this phenomenon in human fibrogenetic disorders. The debate on the authenticity of EMT or on its contribution to the fibrogenic process has become very animated. The overall result is a general confusion on the meaning and on the definition of several key aspects. The aim of this article is to describe how EMT participates to hepatic fibrosis and discuss the evidence of supporting this possibility in order to reach reasonable and useful conclusions.
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http://dx.doi.org/10.4254/wjh.v6.i4.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009476PMC
April 2014
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