Publications by authors named "Yi-Jen Peng"

63 Publications

Dynamic magnetic resonance imaging features of cavernous hemangioma in the manubrium: A case report.

World J Clin Cases 2021 Jun;9(17):4262-4267

Department of Radiology, National Defense Medical Center, Tri-Service General Hospital, Taipei 114, Taiwan.

Background: Osseous hemangiomas, especially those located in the manubrium, are rare benign tumors. In a review of the literature, only three case reports of sternal hemangioma were found. A precise diagnosis is difficult because of their nonspecific findings on computed tomography (CT)/magnetic resonance imaging (MRI).

Case Summary: An 88-year-old woman was suffering from a progressively enlarging mass in the manubrium. Chest CT images showed an osteolytic and expansile lesion with cortical destruction. Vascular malformation was suspected after CT-guided biopsy. On the dynamic MRI scans, the mass showed a bright signal on the T2-weighted image, peripheral nodular enhancement on the early-phase images and progressive centripetal fill-in on the delayed-phase images. Cavernous hemangioma was suspected preoperatively based on the MRI features and finally confirmed by histopathologic analysis.

Conclusion: This uncommon case demonstrates the possible characteristic features of manubrium cavernous hemangioma on dynamic MRI scans; knowledge about these features may prevent patients from developing catastrophic complications, such as rupture or internal hemorrhage, caused by biopsy or surgery.
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http://dx.doi.org/10.12998/wjcc.v9.i17.4262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173419PMC
June 2021

Cardamonin Attenuates Inflammation and Oxidative Stress in Interleukin-1β-Stimulated Osteoarthritis Chondrocyte through the Nrf2 Pathway.

Antioxidants (Basel) 2021 May 27;10(6). Epub 2021 May 27.

Department of Orthopedics, National Defense Medical Center, Tri-Service General Hospital, Taipei 114, Taiwan.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the deterioration of articular cartilage. The progression of OA leads to an increase in inflammatory mediators in the joints, thereby promoting the destruction of the cartilage matrix. Recent studies have reported on the anti-inflammatory and antioxidant properties of cardamonin, which also appears to interact with cellular targets, such as nuclear erythroid 2-related factor 2 (Nrf2), extracellular signal-regulated kinase (ERK), and mammalian target of rapamycin (mTOR) during the progression of tumors. To date, few studies have investigated the effects of cardamonin on chondrocyte inflammation. In the current study, we determined that treating interleukin-1 beta (IL-1β-stimulated chondrocyte cells) with cardamonin significantly reduced the release of nitric oxide (NO) and prostaglandin E2 (PGE2) and significantly inhibited the expression of pro-inflammatory proteins, including inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Cardamonin was also shown to: (1) inhibit the activation and production of matrix metalloproteinases (MMPs), (2) suppress the nuclear factor-κB (NF-κB) signaling pathway, (3) suppress the expression of toll-like receptor proteins, (4) activate the Nrf2 signaling pathway, and (5) increase the levels of antioxidant proteins heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). The increase in antioxidant proteins led to corresponding antioxidant effects (which were abolished by Nrf2 siRNA). Our findings identify cardamonin as a candidate Nrf2 activator for the treatment and prevention of OA related to inflammation and oxidative stress.
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http://dx.doi.org/10.3390/antiox10060862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227809PMC
May 2021

Hypoperfusion of the infrapatellar fat pad and its relationship to MRI T2* relaxation time changes in a 5/6 nephrectomy model.

Sci Rep 2021 May 11;11(1):9924. Epub 2021 May 11.

Department and Graduate Institute of Biology and Anatomy, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei, 11490, Taiwan.

The purpose of present study was to longitudinally investigate the alterations in infrapatellar fat pad (IPFP) vascularity in 5/6 nephrectomized rats by using dynamic contrast enhanced (DCE) MRI and IPFP degeneration by using MRI T2* relaxation time. Twelve male Sprague-Dawley rats were assigned to a control group and a 5/6 nephrectomy CKD group. The right knees of all rats were longitudinally scanned by 4.7 T MRI, and serial changes in the IPFP were assessed at 0, 8, 16, 30, and 44 weeks by DCE-MRI (parameters A, k and k) and MRI T2* mapping. After MRI measurements, knee specimens were obtained and evaluated histologically. The CKD group had IPFPs with lower blood volume A and lower permeability k values from 16 weeks (p < 0.05), lower venous washout k value from 30 weeks (p < 0.001), and significantly higher T2* values reflecting adipocyte degeneration beginning at 16 weeks (p < 0.05). The histopathological results confirmed the MRI findings. Hypoperfusion and adipocytes degeneration related to CKD were demonstrated in a rodent 5/6 nephrectomy model. DCE parameters and MRI T2* can serve as imaging biomarkers of fat pad degeneration during CKD progression.
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http://dx.doi.org/10.1038/s41598-021-89336-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113578PMC
May 2021

Negative-pressure wound therapy combined with artificial dermis (Terudermis) followed by split-thickness skin graft might be an effective treatment option for wounds exposing tendon and bone: A retrospective observation study.

Medicine (Baltimore) 2021 Apr;100(14):e25395

Department of Surgery, Division of Plastic and Reconstructive Surgery.

Abstract: Skin grafts are not suitable for closing tendon- or bone-exposing wounds, which require flap surgery. Dermal regeneration templates have value for closing such wounds, but the disadvantages of the technique include implantation failures because of infection, hematoma formation, or inappropriate immobilization. Negative-pressure wound therapy was reported to increase graft acceptance in difficult wounds.This retrospective case series of 65 patients evaluated negative-pressure therapy combined with artificial dermis for the treatment of acute or chronic tendon- or bone-exposing wounds. The artificial dermis was placed after adequate wound-bed preparation, with simultaneous application of a vacuum-assisted closure system. Split-thickness skin grafting was performed after the implanted artificial dermis had become established.The overall success rate was 88.1% (59/67): 88.6% (39/44) in the chronic wounds group and 87% (20/23) in the acute-trauma group separately. The overall mean survival time of artificial dermis in success cases was 13.24 ± 7.14 days. In separately, the survival time of artificial dermis had no statistically difference in chronic wound group (13.64 ± 7.53 vs 12.60 ± 5.86. P = .943), but had significant statistical difference in acute trauma group (12.45 ± 6.44 days vs 23.33 ± 4.04 days, P = .018). Also, comorbidity of PAOD was found a strong risk factor of failure in chronic wound group (100% vs 23.1%, P < 0.001).We concluded that artificial dermis combined with negative-pressure therapy followed by split-thickness skin grafting might be a reliable and effective option for surgical reconstruction of tendon- or bone-exposing wounds, and could decreasing waiting periods of autologous skin graft.
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http://dx.doi.org/10.1097/MD.0000000000025395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036026PMC
April 2021

Astaxanthin attenuates joint inflammation induced by monosodium urate crystals.

FASEB J 2020 08 10;34(8):11215-11226. Epub 2020 Jul 10.

Department of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Gouty arthritis is the one of the most painful arthritis and is caused by an inflammatory reaction. This study investigated whether astaxanthin (AXT), which has documented anti-inflammatory and antioxidant properties, exhibits protective effects against monosodium urate (MSU) crystal-induced inflammation. Cell viability of J774A.1 murine macrophages was assessed by AXT dose-dependent incubation by MTT assays, and expression levels of iNOS and COX-2 proteins as well as secretion of IL-1β were also analyzed under MSU crystals stimulation with or without AXT treatment. The production of inflammatory mediators was found to significantly decrease with AXT treatment, and the formation of the inflammasome complex was also attenuated when cells were co-stimulated with MSU crystals and AXT. Furthermore, we found that expression of the MAPK pathway was downregulated in J774A.1 cells. AXT also inhibited the induction of COX-2 and IL-6 in human chondrocytes and synovial fibroblasts by western blots. Finally, an MSU crystal intra-articular injection rat model for gouty arthritis was utilized in which treatment groups received 5-daily intraperitoneal injections of AXT prior to MSU crystal stimulation, or once intra-articular injections of AXT following MSU crystal stimulation for 6 hours. Results of synovitis score analysis revealed that inflammation was significantly attenuated in the group which received intraperitoneal AXT injection prior to MSU crystal stimulation compared to the group which received MSU only. These results indicate that AXT attenuates the effects of MSU crystal-induced inflammation by suppressing the production of pro-inflammatory cytokines and inflammatory mediators. Our findings that the anti-inflammatory activities of AXT may be beneficial in the treatment of MSU crystal-induced arthritis.
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http://dx.doi.org/10.1096/fj.202000558RRDOI Listing
August 2020

Decoy Receptor 3 Promotes Preosteoclast Cell Death via Reactive Oxygen Species-Induced Fas Ligand Expression and the IL-1/IL-1 Receptor Antagonist Pathway.

Mediators Inflamm 2020 10;2020:1237281. Epub 2020 Jun 10.

Department and Graduate Institute of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.

Purpose: Interleukin-1 (IL-1) is a potent cytokine that plays a role in inflammatory arthritis and bone loss. Decoy receptor 3 (DCR3) is an immune modulator of monocytes and macrophages. The aim of this study was to investigate the mechanism of DCR3 in IL-1-induced osteoclastogenesis.

Methods: We treated murine macrophages with DCR3 during receptor activator of nuclear factor kappa Β ligand- (RANKL-) plus IL-1-induced osteoclastogenesis to monitor osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. Osteoclast activity was assessed using a pit formation assay. The mechanisms of inhibition were studied by biochemical analyses, including RT-PCR, immunofluorescent staining, flow cytometry, an apoptosis assay, immunoblotting, and ELISA.

Results: DCR3 suppresses IL-1-induced osteoclastogenesis in both primary murine bone marrow-derived macrophages (BMM) and RAW264.7 cells as it inhibits bone resorption. DCR3 induces RANKL-treated osteoclast precursor cells to express IL-1, secretory IL-1ra (sIL-1ra), intracellular IL-1ra (icIL-1ra), reactive oxygen species (ROS), and Fas ligand and to activate IL-1-induced interleukin-1 receptor-associated kinase 4 (IRAK4). The suppression of DCR3 during RANKL- or IL-1-induced osteoclastogenesis may be due to the abundant secretion of IL-1ra, accumulation of ROS, and expression of Fas ligand in apoptotic osteoclast precursor cells.

Conclusions: We concluded that there is an inhibitory effect of DCR3 on osteoclastogenesis via ROS accumulation and ROS-induced Fas ligand, IL-1, and IL-1ra expression. Our results suggested that the upregulation of DCR3 in preosteoclasts might be a therapeutic target in inflammatory IL-1-induced bone resorption.
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http://dx.doi.org/10.1155/2020/1237281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303756PMC
June 2021

Valproic Acid Impacts the Growth of Growth Plate Chondrocytes.

Int J Environ Res Public Health 2020 05 22;17(10). Epub 2020 May 22.

Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.

A range of bone abnormalities including short stature have been reported to be associated with the use of antiepileptic drugs (AEDs) in children. Exactly how AEDs impact skeletal growth, however, is not clear. In the present study, rat growth plate chondrocytes were cultured to study the effects of AEDs, including valproic acid (VPA), oxcarbazepine (OXA), levetiracetam (LEV), lamotrigine (LTG), and topiramate (TPM) on the skeletal growth. VPA markedly reduced the number of chondrocytes by apoptosiswhile other AEDs had no effect. The apoptosis associated noncleaved and cleaved caspase 3, and caspases were increased by exposure to VPA, which up-regulated cyclooxygenase 2 (COX-2) mRNA and protein levels likely through histone acetylation. The COX-2 inhibitor NS-398 attenuated the effects of VPA up-regulating COX-2 expression and decreased VPA-induced caspase 3 expression. The use of VPA in children should be closely monitored or replaced, where appropriate, by AEDs which do not apparently affect the growth plate chondrocytes.
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http://dx.doi.org/10.3390/ijerph17103675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277424PMC
May 2020

Interleukin 26 Skews Macrophage Polarization Towards M1 Phenotype by Activating cJUN and the NF-κB Pathway.

Cells 2020 04 10;9(4). Epub 2020 Apr 10.

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.

Interleukin 26 (IL-26) is a new member of the IL-10 family that is highly expressed in rheumatoid arthritis (RA). However, the functions of IL-26 produced by macrophages in RA have not been elucidated. In the present work, we evaluated the effects and the mechanisms of IL-26 on M1 and M2 macrophage differentiation. Human or mouse macrophage cells were treated with lipopolysaccharides (LPS), interferon gamma (IFNγ), or IL-4 alone or concurrently treated with IL-26 to monitor M1 or M2 macrophage subtypes. The expression level of M1 or M2 macrophage genes was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The molecular mechanisms of downstream signaling activation during differentiation were investigated by immunoblotting assay. Our results found that IL-26 promoted macrophage cells from CD80 M1 macrophage differentiation, not from the CD206 M2 phenotype. The messenger RNA of M1-type macrophage markers tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) was up-regulated in the IL-26-treated group. Also, the M1-related proinflammatory cytokines TNFα and IL-6 were induced after IL-26 stimulation. Interestingly, IL-10, a cytokine marker of M2 macrophage, was also elevated after IL-26 stimulation. Moreover, the M1-like macrophage stimulated by IL-26 underwent cJUN, nuclear factor kappa B (NF-κB), and signal transducer and activator of transcription 1 (STAT1) activation. Our findings suggested the role of IL-26 in synovial macrophages of active rheumatoid arthritis and provided a new insight into IL-26 as a candidate therapeutic target in rheumatoid arthritis.
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http://dx.doi.org/10.3390/cells9040938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227026PMC
April 2020

H-Phosphonate Synthesis and Biological Evaluation of an Immunomodulatory Phosphoglycolipid from Thermophilic Bacteria.

Org Lett 2020 04 23;22(7):2569-2573. Epub 2020 Mar 23.

Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.

The synthesis of a library of bacterial phosphoglycolipid, PGL-1, is described. Key features of the synthesis include regioselective esterification of the primary alcohol of the diacylglycerol moiety and an H-phosphonate method to install the phosphate in PGL-1 in comparison with earlier reported procedures. A representative set of PGL-1 analogues was prepared and evaluated for their biological activities. Results showed that the immunological activity of PGL-1 is dependent on the chain lengths of the fatty acids.
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http://dx.doi.org/10.1021/acs.orglett.0c00487DOI Listing
April 2020

Three-dimensional image simulation of primary diaphragmatic hemangioma: A case report.

World J Clin Cases 2019 Dec;7(24):4307-4313

Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.

Background: Fewer than 200 cases of diaphragmatic tumors have been reported in the past century. Diaphragmatic hemangiomas are extremely rare. Only nine cases have been reported in English literature to date. We report a case of cavernous hemangioma arising from the diaphragm. Pre-operative three-dimensional (3D) simulation and minimal invasive thoracoscopic excision were performed successfully, and we describe the radiologic findings and the surgical procedure in the following article.

Case Summary: A 40-year-old man was referred for further examination of a mass over the right basal lung without specific symptoms. Contrast-enhanced computed tomography revealed a poorly-enhanced lesion in the right basal lung, abutting to the diaphragm, measuring 3.1 cm × 1.5 cm in size. The mediastinum showed a clear appearance without evidence of abnormal mass or lymphadenopathy. A preoperative 3D image was reconstructed, which revealed a diaphragmatic lesion. Video-assisted thoracic surgery was performed, and a red papillary tumor was found, originating from the right diaphragm. The tumor was resected, and the pathological diagnosis was cavernous hemangioma.

Conclusion: In this rare case of diaphragmatic hemangioma, 3D image simulation was helpful for the preoperative evaluation and surgical decision making.
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http://dx.doi.org/10.12998/wjcc.v7.i24.4307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940345PMC
December 2019

Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor.

Mol Cell 2020 01 14;77(2):213-227.e5. Epub 2019 Nov 14.

Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan; Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
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http://dx.doi.org/10.1016/j.molcel.2019.10.023DOI Listing
January 2020

fMRI indicates cortical activation through TRPV1 modulation during acute gouty attacks.

Sci Rep 2019 08 26;9(1):12348. Epub 2019 Aug 26.

Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Gout is one of the most painful disease conditions. The central mechanism of pain processing in this condition remains elusive. Cerebral blood volume (CBV) responses are faithful correlates of brain activity changes; the application of CBV-weighted functional magnetic resonance imaging (fMRI) may shed light on the issue of interest. Transient receptor potential vanilloid 1 (TRPV1) is a critical ion channel expressed both peripherally in nociceptors and centrally in the brain. Whether TRPV1 plays a critical role in gout pain was also explored. Results showed that, in rats with gouty arthritis, noxious stimulation induced CBV increases in the primary somatosensory cortex and thalamus. These increases were correlated with up-regulated TRPV1 protein expression and pain behavior. Selective blockage of central TRPV1 channel activity by intrathecal administration of AMG9810 reversed the induced pain, and abolished the induced CBV increase in thalamocortical regions. The findings support that TRPV1 activation in the central pain pathway is crucial to the augmentation of pain in gouty conditions. This new information supports the development of TRPV1-based drugs for treating gout pain, while fMRI can be useful for repeated evaluation of brain activity changes induced by gout.
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http://dx.doi.org/10.1038/s41598-019-48656-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710282PMC
August 2019

Upregulation of amphiregulin by retinoic acid and Wnt signalling promotes liver cancer cell proliferation.

J Cell Physiol 2020 02 12;235(2):1689-1699. Epub 2019 Jul 12.

Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan.

Activated hepatic stellate cells promote hepatocellular carcinoma (HCC) progression. Hepatic stellate cells play a key role in retinoid metabolism, and activation of stellate cells increases retinoic acid (RA) in the liver. However, the role of RA in HCC proliferation remains unclear. We aimed to analyse the mechanism of RA in HCC proliferation. Thirty-eight patients who had undergone hepatic resection for HCCs were recruited. Paired non-tumour tissues, adjacent and distal to HCCs, were collected, and the RA levels in the tissues were analysed. The mechanisms of RA and HCC proliferation were assessed in liver cancer cell lines by protein and gene expression analyses. Early recurrence of HCC was significantly higher in patients with a higher RA concentration than in those with a lower RA concentration in tissues adjacent to HCCs (61.1% vs. 20%, p = .010). RA promoted HCC cell proliferation and activated the expression of Amphiregulin, a growth factor in hepatocarcinogenesis. The promoter of Amphiregulin contained the binding sites of the RA receptor, RXRα. Wnt signalling also activated the expression of Amphiregulin, and the RA and Wnt pathways acted synergistically to increase the expression of Amphiregulin. Furthermore, RXRα interacted with β-catenin and then translocated to the nucleus to activate Amphiregulin. An increased RA concentration in the tissues adjacent to the tumour was associated with an early recurrence of HCC. RA activated the expression of Amphiregulin, and then promoted HCC proliferation, which might partly contribute to early recurrence of HCC after hepatic resection.
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http://dx.doi.org/10.1002/jcp.29088DOI Listing
February 2020

Chondroprotective Effects of Genistein against Osteoarthritis Induced Joint Inflammation.

Nutrients 2019 May 27;11(5). Epub 2019 May 27.

Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.

Genistein is an isoflavone extracted from soybean (Glycine max). This compound has anti-inflammatory, anti-oxidative, and anti-cancer effects; however, the mechanism underlying the effects of genistein on IL-1β-stimulated human osteoarthritis (OA) chondrocytes remains unknown. Our objectives in this study were to explore the anti-inflammatory effects of genistein on IL-1β-stimulated human OA chondrocytes and to investigate the potential mechanisms which underlie them. Our results from an in-vitro model of osteoarthritis indicate that genistein inhibits the IL-1β-induced expression of the catabolic factors nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX-2), and matrix metalloproteinases (MMPs). Genistein was shown to stimulate Ho-1 expression, which has been associated with Nrf-2 pathway activation in human chondrocytes. In a rat model, genistein was also shown to attenuate the progression of traumatic osteoarthritis. Taken together, these results demonstrate the effectiveness of genistein in mediating the inflammation associated with joint disorders. Our results also indicate that genistein could potentially serve as an alternative therapeutic treatment for OA.
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http://dx.doi.org/10.3390/nu11051180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566664PMC
May 2019

The potent anti-inflammatory effect of Guilu Erxian Glue extracts remedy joint pain and ameliorate the progression of osteoarthritis in mice.

J Orthop Surg Res 2018 Oct 19;13(1):259. Epub 2018 Oct 19.

Department of Life Science, Fu Jen Catholic University, New Taipei City, Taiwan.

Background: Osteoarthritis (OA) is a slow progressing, degenerative disorder of the synovial joints. Guilu Erxian Glue (GEG) is a multi-component Chinese herbal remedy with long-lasting favorable effects on several conditions, including articular pain and muscle strength in elderly men with knee osteoarthritis. The present study aimed to identify the effects of Guilu Erxian Paste (GE-P) and Liquid (GE-L) extracted from Guilu Erxian Glue in anterior cruciate ligament transection (ACLT)-induced osteoarthritis mice, and to compare the effectiveness of different preparations on knee cartilage degeneration during the progression of osteoarthritis.

Methods: Male C57BL/6J mice underwent anterior cruciate ligament transection to induce mechanically destabilized osteoarthritis in the right knee. 4 weeks later, the mice were orally treated with PBS, celecoxib (10 mg/kg/day), Guilu Erxian Paste (100 or 300 mg/kg/day), and Guilu Erxian Liquid (100 or 300 mg/kg/day) for 28 consecutive days. Von Frey and open-field tests (OFT) were used to evaluate pain behaviors (mechanical hypersensitivity and locomotor performance). Narrowing of the joint space and osteophyte formation were examined radiographically. Inflammatory cytokine (IL-1β, IL-6, and TNF-α) levels in the articular cartilage were determined by quantitative real-time PCR. Histopathological examinations were conducted to evaluate the severity and extent of the cartilage lesions.

Results: Guilu Erxian Paste and Guilu Erxian Liquid (300 mg/kg/day) were significantly more effective (p < 0.01) than celecoxib (10 mg/kg/day) in decreasing secondary allodynia when compared to the saline-treated group (p < 0.05). Open-field tests revealed no significant motor dysfunction between the Guilu Erxian Paste- and Guilu Erxian Liquid-treated mice compared to the saline-treated mice. Radiographic findings also confirmed that the administration of Guilu Erxian Paste and Guilu Erxian Liquid (100 and 300 mg/kg/day) significantly and dose-dependently reduced osteolytic lesions and bone spur formation in the anterior cruciate ligament transection-induced osteoarthritis mice when compared to the saline-treated group. Notably, Guilu Erxian Liquid (100 mg/kg/day) treatment significantly reduced the mRNA levels of IL-1β, IL-6, and TNF-α as well as relative the protein expression of IL-1β and TNF-α to the effect of celecoxib. Guilu Erxian Paste and Guilu Erxian Liquid (300 mg/kg/day) markedly attenuated cartilage destruction, surface unevenness, proteoglycan loss, chondrocyte degeneration, and cartilage erosion in the superficial layers (p < 0.01 and p < 0.001 respectively).

Conclusions: As expected, our findings suggest that the anti-inflammatory effects of Guilu Erxian Liquid (GE-L), following marked decrease on both IL-1β and TNF-α during the early course of post-traumatic osteoarthrosis (OA), may be of potential value in the treatment of osteoarthritis.
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http://dx.doi.org/10.1186/s13018-018-0967-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194592PMC
October 2018

Dexamethasone Down-regulates Osteocalcin in Bone Cells through Leptin Pathway.

Int J Med Sci 2018 8;15(5):507-516. Epub 2018 Mar 8.

Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC.

Glucocorticoid therapy, especially at higher doses, is associated with significant adverse side effects including osteoporosis. Leptin, secreted from adipose tissue, has diverse effects on bone tissue regulation. As glucocorticoids stimulate leptin synthesis and secretion directly in adipose tissue we hypothesised that dexamethasone (DEX) induced osteoporosis may, in part, be mediated by an osteoblast dependent leptin-leptin receptor pathway. Human bone cells expressed leptin and leptin receptors (Ob-Ra and Ob-Rb). DEX increased leptin, Ob-Ra and Ob-Rb expression in a dose-dependent manner while decreasing expression of osteocalcin. In the presence of leptin, Cbfa1 and osteonectin expression showed no significant change, whereas osteocalcin expression was decreased. Recombinant human quadruple antagonist leptin suppressed DEX-induced osteocalcin downregulation. The signaling pathway involved up-regulation of JAK2. In conclusion, upregulation of leptin and Ob-Rb in human bone cells by DEX is associated with down-regulation of osteocalcin expression. The down regulation of osteocalcin by DEX was partially through a leptin autocrine/paracrine loop. Adverse effects of DEX on the skeleton may be modified by targeting leptin signaling pathways.
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http://dx.doi.org/10.7150/ijms.21881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859774PMC
August 2018

Overexpression of CD164 in oral cavity squamous cell carcinoma predicts a favourable prognosis.

Oncol Lett 2017 Nov 15;14(5):6103-6108. Epub 2017 Sep 15.

Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Centre, Taipei 11490, Taiwan, R.O.C.

The aim of the present study was to investigate the association between cluster of differentiation (CD) 164 expression with clinicopathological parameters and prognosis among patients with oral cavity squamous cell carcinoma (OSCC). The present study retrospectively reviewed 70 patients with OSCC who underwent curative primary surgery. A number of patients subsequently received postoperative chemoradiotherapy although the specimens were not exposed to radiation or chemotherapy prior to anti-CD164 antibody immunohistochemical staining. CD164 overexpression was arbitrarily defined as exhibiting an H-score of ≥120. Univariate and multivariate analyses were performed for sex, age, American Joint Committee on Cancer stage, tumour location, histological grade, surgical margin and H-score. The 5-year overall survival rate was 54.4% and the median follow-up time was 46 months for surviving patients. Univariate analyses revealed that a low overall survival rate was associated with advanced-stage disease (P<0.001), buccogingival tumour location (P=0.038) and a CD164 H-score of <120 (P=0.016). Multivariate Cox's regression analyses revealed that poor overall survival rate was associated with advanced-stage disease (P=0.001) and a CD164 H-score of <120 (P=0.04). CD164 overexpression in OSCC was associated with favourable survival rate. Thus, CD164 expression may be a clinically useful predictor of prognosis in patients with OSCC.
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http://dx.doi.org/10.3892/ol.2017.6966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661421PMC
November 2017

Knee subchondral bone perfusion and its relationship to marrow fat and trabeculation on multi-parametric MRI and micro-CT in experimental CKD.

Sci Rep 2017 06 8;7(1):3073. Epub 2017 Jun 8.

Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

The pathogenesis of chronic kidney disease (CKD) is multifactorial. In the progression of CKD arthropathy, arteriosclerosis may alter the knee subchondral bone marrow by altering blood flow through the bone vasculature. Herein, multi-parametric MRI assessment, including dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), magnetic resonance spectroscopy (MRS), MRI T2*, contrast enhanced MR angiography (CE-MRA), and micro-CT were applied in a rodent nephrectomy model to: 1) investigate the blood perfusion of subchondral bone marrow and its relationship to fat water content and trabeculation pattern in CKD and 2) demonstrate the feasibility of using multi-parametric MRI parameters as imaging biomarkers to evaluate the disease's progression. Two groups of rats in our study underwent either 1) no intervention or 2) 5/6 nephrectomy. We found that in the CKD group, perfusion amplitude A and elimination constant k values were significantly decreased, and vascular permeability k was significantly increased. MRS showed that fat fraction (FF) was significantly lower, water fraction (WF) was significantly higher in the CKD group. Micro-CT showed a significant loss of trabecular bone. Knee subchondral bone marrow perfusion deficiency in experimental CKD may be associated with decreased fat content, increased water content, and sparse trabeculation.
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http://dx.doi.org/10.1038/s41598-017-03059-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465086PMC
June 2017

Cytoplasmic aryl hydrocarbon receptor regulates glycogen synthase kinase 3 beta, accelerates vimentin degradation, and suppresses epithelial-mesenchymal transition in non-small cell lung cancer cells.

Arch Toxicol 2017 May 17;91(5):2165-2178. Epub 2016 Oct 17.

Institute of Toxicology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei 10, Taiwan.

Aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, has been studied extensively in carcinogenesis through the genomic pathway. In recent years, AHR has also been reported to exert positive or negative effects on epithelial-mesenchymal transition (EMT), the crucial step in tumor malignant progression. However, the detailed mechanism remains controversial. Analysis of AHR-expression levels in non-small cell lung cancer cell lines and lung cancer tissues revealed an inverse correlation between AHR protein levels and tumor cell invasion and metastasis. Overexpression of wild-type AHR in H1299 cells (AHR poorly expressed, potently invasive) not only accelerated mesenchymal vimentin degradation, but also prevented cell invasion in vitro and in vivo. In the absence of AHR agonists, the overexpressed AHR protein was predominantly localized in the cytoplasm, where it interacted with vimentin and functioned as an E3 ubiquitin ligase. A 6-h incubation with the proteasome inhibitor MG-132 fully rescued vimentin from AHR-mediated proteasomal degradation. In AHR-overexpressing H1299 cells, either vimentin degradation or invasive suppression could be reversed when glycogen synthase kinase 3 beta (GSK3β) was inactivated by CHIR-99021 treatment. In contrast, silencing of AHR in A549 cells (AHR highly expressed, weakly invasive) resulted in the downregulation of epithelial biomarkers (E-cadherin and claudin-1), augmentation of mesenchymal vimentin level, and GSK3β Ser-9 hyper-phosphorylation, which led to enhanced invasiveness. This work demonstrates that cytoplasmic, resting AHR protein may act as an EMT suppressor via a non-genomic pathway. Depletion of cytoplasmic AHR content represents a potential switch for EMT, thereby leading to the scattering of tumor cells.
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http://dx.doi.org/10.1007/s00204-016-1870-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399057PMC
May 2017

Genistein suppresses leptin-induced proliferation and migration of vascular smooth muscle cells and neointima formation.

J Cell Mol Med 2017 03 28;21(3):422-431. Epub 2016 Sep 28.

Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan.

Obesity is a strong risk factor for the development of cardiovascular diseases and is associated with a marked increase in circulating leptin concentration. Leptin is a peptide hormone mainly produced by adipose tissue and is regulated by energy level, hormones and various inflammatory mediators. Genistein is an isoflavone that exhibits diverse health-promoting effects. Here, we investigated whether genistein suppressed the atherogenic effect induced by leptin. The A10 cells were treated with leptin and/or genistein, and then the cell proliferation and migration were analysed. The reactive oxygen species (ROS) and proteins levels were also measured, such as p44/42MAPK, cell cycle-related protein (cyclin D1 and p21) and matrix metalloproteinase-2 (MMP-2). Immunohistochemistry and morphometric analysis were used for the neointima formation in a rat carotid artery injury model. Genistein (5 μM) significantly inhibited both the proliferation and migration of leptin (10 ng/ml)-stimulated A10 cells. In accordance with these finding, genistein decreased the leptin-stimulated ROS production and phosphorylation of the p44/42MAPK signal transduction pathway. Meanwhile, genistein reversed the leptin-induced expression of cyclin D1, and cyclin-dependent kinase inhibitor, p21. Genistein attenuated leptin-induced A10 cell migration by inhibiting MMP-2 activity. Furthermore, the leptin (0.25 mg/kg)-augmented neointima formation in a rat carotid artery injury model was attenuated in the genistein (5 mg/kg body weight)-treated group when compared with the balloon injury plus leptin group. Genistein was capable of suppressing the atherogenic effects of leptin in vitro and in vivo, and may be a promising candidate drug in the clinical setting.
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http://dx.doi.org/10.1111/jcmm.12986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323876PMC
March 2017

Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Susceptibility to Osteoarthritis of the Knee: A Case-Control Study and Meta-Analysis.

PLoS One 2016;11(9):e0161754. Epub 2016 Sep 22.

School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC.

Background: Studies of angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and the risks of knee osteoarthritis (OA) have yielded conflicting results.

Objective: To determine the association between ACE I/D and knee OA, we conducted a combined case-control study and meta-analysis.

Methods: For the case-control study, 447 knee OA cases and 423 healthy controls were recruited between March 2010 and July 2011. Knee OA cases were defined using the Kellgren-Lawrence grading system, and the ACE I/D genotype was determined using a standard polymerase chain reaction. The association between ACE I/D and knee OA was detected using allele, genotype, dominant, and recessive models. For the meta-analysis, PubMed and Embase databases were systematically searched for prospective observational studies published up until August 2015. Studies of ACE I/D and knee OA with sufficient data were selected. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for the D versus I allele with regard to knee OA risk.

Results: We found no significant association between the D allele and knee OA [OR: 1.09 (95% CI: 0.76-1.89)] in the present case-control study, and the results of other genetic models were also nonsignificant. Five current studies were included, and there were a total of six study populations after including our case-control study (1165 cases and 1029 controls). In the meta-analysis, the allele model also yielded nonsignificant results [OR: 1.37 (95% CI: 0.95-1.99)] and a high heterogeneity (I2: 87.2%).

Conclusions: The association between ACE I/D and knee OA tended to yield negative results. High heterogeneity suggests a complex, multifactorial mechanism, and an epistasis analysis of ACE I/D and knee OA should therefore be conducted.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033346PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161754PLOS
September 2016

Renal Protective Effects of Low Molecular Weight of Inonotus obliquus Polysaccharide (LIOP) on HFD/STZ-Induced Nephropathy in Mice.

Int J Mol Sci 2016 Sep 13;17(9). Epub 2016 Sep 13.

Institute of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in diabetes mellitus. Oxidative stress, insulin resistance and pro-inflammatory cytokines have been shown to play an important role in pathogeneses of renal damage on type 2 diabetes mellitus (DM). Inonotus obliquus (IO) is a white rot fungus that belongs to the family Hymenochaetaceae; it has been used as an edible mushroom and exhibits many biological activities including anti-tumor, anti-oxidant, anti-inflammatory and anti-hyperglycemic properties. Especially the water-soluble Inonotus obliquus polysaccharides (IOPs) have been previously reported to significantly inhibit LPS-induced inflammatory cytokines in mice and protect from streptozotocin (STZ)-induced diabetic rats. In order to identify the nephroprotective effects of low molecular weight of IOP fraction (LIOP), from the fruiting bodies of Inonotus obliquus, high-fat diet (HFD) plus STZ-induced type 2-like diabetic nephropathy C57BL/6 mice were investigated in this study. Our data showed that eight weeks of administration of 10-100 kDa, LIOP (300 mg/kg) had progressively increased their sensitivity to glucose (less insulin tolerance), reduced triglyceride levels, elevated the HDL/LDL ratio and decreased urinary albumin/creatinine ratio(ACR) compared to the control group. By pathological and immunohistochemical examinations, it was indicated that LIOP can restore the integrity of the glomerular capsules and increase the numbers of glomerular mesangial cells, associated with decreased expression of TGF-β on renal cortex in mice. Consistently, three days of LIOP (100 μg/mL) incubation also provided protection against STZ + AGEs-induced glucotoxicity in renal tubular cells (LLC-PK1), while the levels of NF-κB and TGF-β expression significantly decreased in a dose-dependent manner. Our findings demonstrate that LIOP treatment could ameliorate glucolipotoxicity-induced renal fibrosis, possibly partly via the inhibition of NF-κB/TGF-β1 signaling pathway in diabetic nephropathy mice.
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http://dx.doi.org/10.3390/ijms17091535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037810PMC
September 2016

Interleukin 26 suppresses receptor activator of nuclear factor κB ligand induced osteoclastogenesis via down-regulation of nuclear factor of activated T-cells, cytoplasmic 1 and nuclear factor κB activity.

Rheumatology (Oxford) 2016 Nov 21;55(11):2074-2083. Epub 2016 Aug 21.

Department and Graduate institute of Biology and Anatomy

Objective: IL-26 has been shown to have high expression in RA. However, the effects of IL-26 on bone destruction in RA have not been evaluated. The aim of this study was to investigate the effects and mechanisms of IL-26 on RANK ligand (RANKL)-induced osteoclastogenesis.

Methods: We treated cells with IL-26 in RANKL-induced oseteoclastogenesis to monitor osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. Osteoclast activity was assessed by pit formation assay and F-actin ring formation. The mechanism of the inhibition was studied by biochemical analyses such as RT-PCR, immunofluorescence staining and immunoblotting. In addition, cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

Results: IL-26 inhibited RANKL-induced TRAP-positive multinucleated cells and inhibited RANKL-induced nuclear factor κB (NF-κB) activation and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) nuclear translocation in RAW264.7 cells. Also, IL-26 significantly inhibited the bone-resorbing activity and F-actin ring formation ability of mature osteoclasts. Moreover, IL-26 suppressed RANKL-induced mitogen-activated protein kinase activation and NFATc1 downstream gene expression.

Conclusion: We suggest that the inhibitory activity of IL-26 on osteoclastogenesis is via down-regulation of RANKL-induced NF-κB and NFATc1 expression. Our results suggest IL-26 as a possible new remedy against osteolytic bone destruction.
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http://dx.doi.org/10.1093/rheumatology/kew302DOI Listing
November 2016

Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases.

Sci Rep 2016 07 1;6:28612. Epub 2016 Jul 1.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1α. The findings promoted us to test whether aneurysmal prone factors could up-regulate the expression of MMP-2 and MMP-9 through aberrantly increased HIF-1α and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1α and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1α can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1α inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1α is pivotal for the development of AAA. Our study provides a rationale for using HIF-1α inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens.
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http://dx.doi.org/10.1038/srep28612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929442PMC
July 2016

Heat shock protein 70 and AMP-activated protein kinase contribute to 17-DMAG-dependent protection against heat stroke.

J Cell Mol Med 2016 10 31;20(10):1889-97. Epub 2016 May 31.

Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan.

Heat shock protein 70 (Hsp70) preconditioning induces thermotolerance, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a role in the process of autophagy. Here, we investigated whether 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) protected against heat stroke (HS) in rats by up-regulation of Hsp70 and phosphorylated AMPK (pAMPK). To produce HS, male Sprague-Dawley rats were placed in a chamber with an ambient temperature of 42°C. Physiological function (mean arterial pressure, heart rate and core temperature), hepatic and intestinal injury, inflammatory mediators and levels of Hsp70, pAMPK and light chain 3 (LC3B) in hepatic tissue were measured in HS rats or/and rats pre-treated with 17-DMAG. 17-DMAG pre-treatment significantly attenuated hypotension and organ dysfunction induced by HS in rats. The survival time during HS was also prolonged by 17-DMAG treatment. Hsp70 expression was increased, whereas pAMPK levels in the liver were significantly decreased in HS rats. Following pre-treatment with 17-DMAG, Hsp70 protein levels increased further, and pAMPK levels were enhanced. Treatment with an AMPK activator significantly increased the LC3BII/LC3BI ratio as a marker of autophagy in HS rats. Treatment with quercetin significantly suppressed Hsp70 and pAMPK levels and reduced the protective effects of 17-DMAG in HS rats. Both of Hsp70 and AMPK are involved in the 17-DMAG-mediated protection against HS. 17-DMAG may be a promising candidate drug in the clinical setting.
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http://dx.doi.org/10.1111/jcmm.12881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020632PMC
October 2016

Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling.

Oxid Med Cell Longev 2016 21;2016:3190617. Epub 2015 Dec 21.

Graduate Institute of Medical Sciences, National Defense Medical Center and Department of Pathology, Tri-Service General Hospital, 325 Section 2, Cheng-gong Road, Neihu, Taipei 114, Taiwan; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, No. 386, Dazhong 1st Road, Zuoying District, Kaohsiung 81362, Taiwan.

In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.
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http://dx.doi.org/10.1155/2016/3190617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699022PMC
October 2016

Heterogeneous prognosis and adjuvant chemotherapy in pathological stage I non-small cell lung cancer patients.

Thorac Cancer 2015 Sep 27;6(5):620-8. Epub 2015 Feb 27.

Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center Taipei, Taiwan.

Background: Even after curative resection, the prognosis of pathological stage I non-small cell lung cancer (NSCLC) can be heterogeneous, and the use of adjuvant chemotherapy in these patients is controversial. We aimed to identify the prognostic factors and role of adjuvant chemotherapy in pathological stage I NSCLC.

Methods: We retrospectively analyzed the correlations between clinicopathological factors and survival in 179 patients with resected pathological stage I NSCLC.

Results: After a median follow-up of 93 months, overall and disease-free survival were not significantly different between pathological stage IA (n = 138) and IB (n = 41) patients. The prognosis of pathological stage I patients with poorly differentiated tumors was significantly worse than that of those with non-poorly differentiated tumors (P = 0.003). Multivariate analysis revealed that poor tumor differentiation was an independent factor for poor survival (hazard ratio = 6.889). A marginally significant survival benefit was observed in poorly differentiated pathological stage I patients who received adjuvant chemotherapy (P = 0.053). Pathological stage IA patients who received adjuvant chemotherapy had a worse prognosis than those who did not receive adjuvant chemotherapy (P < 0.001), whereas pathological stage IA patients with poorly differentiated tumors who received adjuvant chemotherapy had better survival than who did not receive adjuvant chemotherapy (P < 0.001).

Conclusions: Poor differentiation is an independent prognostic factor in pathological stage I NSCLC after surgical resection. Adjuvant chemotherapy may be beneficial in poorly differentiated pathological stage IA NSCLC patients.
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http://dx.doi.org/10.1111/1759-7714.12233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567008PMC
September 2015

Growth Arrest-Specific 6 Protein in Patients with Sjögren Syndrome: Determination of the Plasma Level and Expression in the Labial Salivary Gland.

PLoS One 2015 7;10(10):e0139955. Epub 2015 Oct 7.

Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.

Aims: Growth arrest-specific protein 6 (Gas6) is a vitamin K-dependent protein expressed by endothelial cells and leukocytes that are involved in cell survival, migration, and proliferation in response to inflammatory processes. The aim of this study was to assess the implications of Gas6 in Sjögren syndrome (SS) and its expression in the labial salivary gland.

Methods And Results: A total of 254 adults, including 159 with primary Sjögren syndrome (pSS), 34 with secondary Sjögren syndrome (sSS), and 61 normal controls, were recruited. Plasma Gas6 concentrations were determined, and Gas6 expressions in labial salivary gland (LSG) tissues from controls and pSS and sSS patients were also evaluated. Plasma Gas6 concentrations were significantly lower among patients with pSS than normal controls (13.5 ± 8.6 vs. 19.9 ± 13.4 ng/ml, p < 0.001). There were, however, no significant differences in plasma Gas6 levels between pSS and sSS patients (13.5 ± 8.6 vs. 16.9 ± 11.2 ng/ml, p = 0.068). In multivariate logistic regression analysis, after adjustment for white blood cell count, hemoglobin level, platelet count, lymphocyte count, and C3 and C4 levels, lower plasma Gas6 concentrations were significantly associated with an increased risk of SS. Moreover, by using a semi-quantitative scale to evaluate Gas6 expression in LSG tissues, Gas6 expression was found to be markedly lower in LSG tissues from pSS patients than in tissues from normal controls.

Conclusions: Decreased plasma Gas6 concentration and LSG expression were associated with pSS. As such, Gas6 may represent a novel independent risk factor for pSS, with a potential role in salivary gland inflammation and dysfunction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139955PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596882PMC
June 2016

Breast Nonmass Enhancement Detected with MRI: Uility and Lesion Characterization with Second-Look Ultrasonography.

Breast J 2015 Nov-Dec;21(6):579-87. Epub 2015 Sep 22.

Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

The purpose of this study was to verify the utility of second-look ultrasonography (US) in evaluating nonmass enhancement (NME) lesions detected on breast magnetic resonance imaging (MRI) by analysing its correlation and imaging features. From July 2008 to June 2012, 102 consecutive MRI-detected NME lesions were subsequently evaluated with US. Lesions were evaluated according to the established Breast Imaging Reporting and Data System (BI-RADS) lexicon. The correlation between MRI-detected NME lesion characteristics, lesion size, histopathological findings and features at second-look US were analysed. Second-look US identified 44/102 (43%) of the NME lesions revealed by MRI. A US correlate was seen in 34/45 (76%) malignant lesions compared with 10/57 (18%) benign lesions (p < 0.0001). The likelihood of malignancy was significantly higher for NME lesions with a US correlate than lesions without: 34/44 (77%) versus 11/58 (19%) (p < 0.0001). The malignancy of the 44 (43%) MRI-detected NME lesions with a US correlate was significantly associated with US lesion margins and BI-RADS categories (p = 0.001 and 0.002 respectively). Second-look US of MRI-detected NME lesions is useful for decision-making as part of the diagnostic workup. Familiarity with the US features associated with malignancy improves the utility of US in the workup of these NME abnormalities.
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http://dx.doi.org/10.1111/tbj.12491DOI Listing
August 2016

Platelet-Rich Plasma Attenuates 30-kDa Fibronectin Fragment-Induced Chemokine and Matrix Metalloproteinase Expression by Meniscocytes and Articular Chondrocytes.

Am J Sports Med 2015 Oct 25;43(10):2481-9. Epub 2015 Aug 25.

Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

Background: Proteolytic fragments of fibronectin have catabolic effects on cartilage and menisci. Platelet-rich plasma (PRP) is increasingly being used to treat a range of joint conditions, but it is unknown whether PRP influences fibronectin fragment (FN-f) procatabolic activity.

Hypotheses: The procatabolic activity of FN-f on meniscocytes and articular chondrocytes is attenuated by cotreatment with PRP.

Study Design: Controlled laboratory study.

Methods: Human meniscocytes were treated with FN-f (30 kDa) with or without PRP coincubation, and gene expression was analyzed by complementary DNA microarray analysis. Validation of altered expression of known and novel chemokine and protease genes was undertaken by real-time polymerase chain reaction (RT-PCR) in articular chondrocytes and meniscocytes. Chemokine release was assayed by enzyme-linked immunosorbent assay, and intracellular pathway signaling was evaluated by Western immunoblotting.

Results: Microarray analysis and RT-PCR showed increased expression of matrix metalloproteinase (MMP)1, MMP2, MMP3, MMP9, MMP13, interleukin (IL)-6, IL-8 (CXCL8), CCL5, CCL20, and CXCL10 chemokines in meniscocytes after treatment with FN-f. Upregulation of these genes was significantly attenuated by PRP. Similar results were seen with articular chondrocytes, although no changes in MMP2 or MMP9 levels were identified. PRP-induced suppression of gene expression was associated with activation of Akt and p44/p42.

Conclusion: PRP treatment attenuates the 30-kDa FN-f-induced expression of a range of proinflammatory chemokines and MMPs, including IL-8, IL-6, CCL20, CCL5, CXCL10, MMP1, MMP3, and MMP13, by both meniscocytes and articular chondrocytes.

Clinical Relevance: These observations provide support for the use and further trials of PRP in management of cartilage and meniscal injuries.
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http://dx.doi.org/10.1177/0363546515597489DOI Listing
October 2015
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