Publications by authors named "Chien-Hsing Lee"

154 Publications

Rhopaloic acid A induces apoptosis, autophagy and MAPK activation through ROS-mediated signaling in bladder cancer.

Phytomedicine 2021 Aug 17;92:153720. Epub 2021 Aug 17.

Department of Pharmacology, School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan; Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. Electronic address:

Background: Bladder cancer (BC) is a very common type of malignant cancer in men and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that Rhopaloic acid A (RA), a compound isolated from marine sponges, fights cancer but its potential anti-tumor effect on BC is still unknown.

Purpose: The present study was aimed to explore the potential anti-tumor effects of RA against human BC cells and the underlying molecular mechanism.

Methods: Cell cytotoxicity was determined using the MTT and colony formation assays. Cell cycle distribution, apoptosis induction and generation of mitochondrial reactive oxygen species (ROS) were analyzed by flow cytometry. Mitochondrial membrane potential, acridine orange staining and intracellular ROS levels were observed using fluorescence microscopy. Levels of various signaling proteins were assessed using Western blotting. Furthermore, a zebrafish BC xenotransplantation model was used to confirm the anti-tumor effect of RA in vivo.

Results: Treatment with RA significantly suppressed the proliferation of BC cells that resulted from G2/M cycle arrest. Additionally, RA induced mitochondrial-mediated apoptosis and autophagy in BC cells. The death of BC cells induced by RA was rescued by treatment with inhibitors of apoptosis (Z-VAD-FMA) or autophagy (3-MA). RA activated the MAPK pathway and increased the production of cellular and mitochondrial ROS. Treatment with the ROS scavenger N-acetyl cysteine, effectively reversed the induction of apoptosis, autophagy, JNK activation and DNA damage elicited by RA. Finally, RA significantly inhibited tumor growth in a zebrafish BC xenotransplantation model.

Conclusion: Taken together, our findings indicate that RA induces apoptosis and autophagy and activates the MAPK pathway through ROS-mediated signaling in human BC cells. This RA-induced pathway offers insights into the molecular mechanism of its antitumor effect and shows that RA is a promising candidate for the treatment of BC.
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http://dx.doi.org/10.1016/j.phymed.2021.153720DOI Listing
August 2021

YAP-Dependent BiP Induction Is Involved in Nicotine-Mediated Oral Cancer Malignancy.

Cells 2021 Aug 13;10(8). Epub 2021 Aug 13.

Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan.

Cigarette smoking is a significant risk factor for the development and progression of oral cancer. Previous studies have reported an association between nicotine and malignancy in oral cancer. Recent studies have also demonstrated that nicotine can induce endoplasmic reticulum (ER) stress in tumor cells. Binding immunoglobulin protein (BiP) acts as a master regulator of ER stress and is frequently overexpressed in oral cancer cell lines and tissues. However, the effect of nicotine on BiP in oral cancer is unknown. Therefore, this study aimed to evaluate the role of BiP and its underlying regulatory mechanisms in nicotine-induced oral cancer progression. Our results showed that nicotine significantly induced the expression of BiP in time- and dose-dependent manners in oral squamous cell carcinoma (OSCC) cells. In addition, BiP was involved in nicotine-mediated OSCC malignancy, and depletion of BiP expression remarkably suppressed nicotine-induced malignant behaviors, including epithelial-mesenchymal transition (EMT) change, migration, and invasion. In vivo, BiP silencing abrogated nicotine-induced tumor growth and EMT switch in nude mice. Moreover, nicotine stimulated BiP expression through the activation of the YAP-TEAD transcriptional complex. Mechanistically, we observed that nicotine regulated YAP nuclear translocation and its interaction with TEAD through α7-nAChR-Akt signaling, subsequently resulting in increased TEAD occupancy on the HSPA5 promoter and elevated promoter activity. These observations suggest that BiP is involved in nicotine-induced oral cancer malignancy and may have therapeutic potential in tobacco-related oral cancer.
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http://dx.doi.org/10.3390/cells10082080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392082PMC
August 2021

Norcantharidin combined with paclitaxel induces endoplasmic reticulum stress mediated apoptotic effect in prostate cancer cells by targeting SIRT7 expression.

Environ Toxicol 2021 Jul 16. Epub 2021 Jul 16.

Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Prostate cancer (PCa), an extremely common malignancy in males, is the most prevalent disease in several countries. Norcantharidin (NCTD) has antiproliferation, antimetastasis, apoptosis, and autophagy effects in various tumor cells. Nevertheless, the antitumor effect of NCTD combined with paclitaxel (PTX), a chemotherapeutic drug, in PCa remains unknown. The cell growth, proliferative rate, cell cycle distribution, and cell death were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, colony formation assay, PI staining, and Annexin V/PI staining by flow cytomertry, whereas the mitochondrial membrane potential (MMP) and endoplasmic reticulum (ER) stress was evaluated using the MitoPotential assay and ER-ID red assay. We also evaluated the protein and mRNA expression of SIRTs by Western blotting and qRTPCR assay. Overexpression effectivity was measured by DNA transfection assay. Our study showed that cell viability and proliferative PC3 and DU145 rates were effectively inhibited after NCTD-PTX combination. We also found that NCTD-PTX combination treatment significantly enhance G2/M phase arrest, induction of cell death and ER stress, loss of MMP, and ER- or apoptotic-related protein expression. Furthermore, NCTD-PTX combination treatment was significantly decreasing the protein and mRNA expression of SIRT7 in PCa cells. Combination therapy effectively reduced cell viability, ER stress-mediated apoptosis and p-eIF2α/ATF4/CHOP/cleaved-PARP expression inhibition in SIRT7 overexpression of PCa cells. These results indicate that NCTD combined with PTX induces ER stress-mediated apoptosis of PCa cells by regulating the SIRT7 expression axis. Moreover, combination therapy may become a potential therapeutic strategy against human PCa.
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http://dx.doi.org/10.1002/tox.23334DOI Listing
July 2021

Growth arrest-specific 6 protein in HIV-infected patients: Determination of plasma level and different antiretroviral regimens.

J Microbiol Immunol Infect 2021 Jun 24. Epub 2021 Jun 24.

Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Background/purpose: Growth arrest-specific 6 (Gas6) protein is involved in cell proliferation, differentiation, adhesion, migration in response to inflammatory processes. Human immunodeficiency virus (HIV) infection induces a chronic inflammatory condition and combination of antiretroviral therapy improves immune function and decreases the inflammatory state. The aim of this study was to assess the implications of Gas6 in chronic inflammation status of HIV-infected patients undergoing different third regimens of antiretroviral therapy. The Gas6 may be a marker of chronic inflammation of HIV-infected patients.

Methods: A total of 356 adult males, including 258 HIV-infected patients and 98 healthy controls, were recruited. The demographic and clinical characteristics of the patients were collected. Laboratory assessment included hemogram, CD4 count, plasma HIV RNA load (PVL), hepatitis B and C viruses, and serum biochemistry. Plasma Gas6 concentrations were determined.

Results: The values of Gas6 were lower in HIV patients compared to healthy subjects (14.3 ± 6.4 vs 21.5 ± 15.2, p = 0.01). HIV patients that received antiviral regimen with abacavir had similar Gas6 level than those who received antiviral regimens with tenofovir (14.3 ± 6.5 vs 13.8 ± 5.9, p = 0.99). HIV patients that received antiviral regimen with protease inhibitors (PIs) had lower Gas6 level (13.1 ± 3.5 vs 14.2 ± 6.6 vs 14.6 ± 6.5, p = 0.03) than those who received antiviral regimens with non-nucleoside reverse transcriptase inhibitors (nNRTIs) and integrase inhibitors (INSTIs), respectively.

Conclusions: Decreased plasma Gas6 concentrations were observed in HIV patients. Gas6 levels are associated with different third regimen of highly active antiretroviral therapy. Gas6 may represent a unique marker for assessing the chronic inflammation state difference among cART regimens in HIV patients.
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http://dx.doi.org/10.1016/j.jmii.2021.05.001DOI Listing
June 2021

Gout as a risk factor for acute myocardial infarction: evidence from competing risk model analysis.

J Investig Med 2021 Aug 17;69(6):1161-1167. Epub 2021 May 17.

Department of Public Health, Fu-Jen Catholic University College of Medicine, New Taipei City, Taiwan

Chronic inflammation, a hallmark of gout, is implicated in the pathogenesis of atherosclerosis. Thus, in theory, gout can be expected to increase the risk of acute myocardial infarction (AMI). Yet, results from several epidemiological studies have been inconclusive. A retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohort comprised 3581 patients with gout (the gout cohort) and 14,324 patients without gout (the non-gout cohort). The primary outcome was the incidence of AMI. To estimate the effect of gout on the risk of AMI, the Lunn-McNeil competing risk model was fitted to estimate cause-specific hazard ratios (HRs) and their 95% confidence intervals (CIs). The cumulative incidence of AMI was significantly higher in the gout cohort than in the non-gout cohort, resulting in an adjusted HR of 1.36 (95% CI 1.04 to 2.76). Further, HRs of gout with incident AMI were higher in patients without hypertension, diabetes mellitus, or hyperlipidemia (ranging from 1.63 to 2.09) than in those with each of these comorbidities (ranging from 0.95 to 1.13). The results of this study suggest that patients with gout have an increased risk of AMI. The AMI risk associated with gout was conditional on patients' cardiovascular risk profile. Future work is needed to confirm these findings.
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http://dx.doi.org/10.1136/jim-2020-001714DOI Listing
August 2021

Chlorpromazine, an antipsychotic agent, induces G2/M phase arrest and apoptosis via regulation of the PI3K/AKT/mTOR-mediated autophagy pathways in human oral cancer.

Biochem Pharmacol 2021 02 31;184:114403. Epub 2020 Dec 31.

Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Pharmacology, School of Medicine; School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. Electronic address:

Chlorpromazine (CPZ), an FDA-approved phenothiazine derivative used to treat schizophrenia and other psychiatric disorders, has been demonstrated to have potential anti-tumor effects. However, the potential effects of CPZ on human oral cancer cells and the underlying molecular mechanisms remain unknown. In this study, treatment of human oral cancer cells with CPZ inhibited their proliferation and induced G2/M phase arrest. Treatment with CPZ induced apoptosis through the extrinsic death receptor and the intrinsic mitochondrial pathways. In addition, the induction of autophagy was observed by the formation of autophagosomes, the expression of autophagy-related proteins and activation of the PI3K/Akt/mTOR/p70S6K pathway. The CPZ-induced cell death was reversed by the pan-caspase inhibitor Z-VAD-FMK, by the autophagy inhibitor 3-MA and by the knockdown of LC3B using a shRNA (shLC3B), suggesting that autophagy promoted CPZ-induced apoptosis. Finally, CPZ significantly suppressed tumor growth in both a zebrafish oral cancer xenotransplantation model and in a murine model of 4-nitroquinoline-1-oxide (4NQO)-induced oral cancer. Overall, this evidence demonstrated that CPZ is a novel promising strategy for the treatment of oral cancer.
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http://dx.doi.org/10.1016/j.bcp.2020.114403DOI Listing
February 2021

Growth arrest-specific 6 modulates adiponectin expression and insulin resistance in adipose tissue.

J Diabetes Investig 2021 Apr 13;12(4):485-492. Epub 2020 Oct 13.

Division of Endocrinology and Metabolism, Department of Internal Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.

Aims/introduction: Obesity is characterized by disturbed adipocytokine expression and insulin resistance in adipocytes. Growth arrest-specific 6 (GAS6) is a gene encoding the Gas6 protein, which is expressed in fibroblasts, and its related signaling might be associated with adipose tissue inflammation, glucose intolerance and insulin resistance. The aim of this study was to investigate the associations among Gas6, adipocytokines and insulin resistance in adipocytes.

Materials And Methods: Mature Simpson Golabi Behmel Syndrome adipocytes were treated with high levels of insulin to mimic insulin resistance, and were examined for the expressions of Gas6, cytokines and adipocytokines from preadipocytes in differentiation. In an animal study, high-fat diet-induced obese mice were used to verify the Gas6 expression in vitro.

Results: During the differentiation of adipocytes, the expression of Gas6 gradually decreased, and was obviously downregulated with adipocyte inflammation and insulin resistance. Gas6 levels were found to be in proportion to the expression of adiponectin, which has been regarded as closely relevant to improved insulin sensitivity after metformin treatment. Similar results were also confirmed in the animal study.

Conclusions: Our results suggest that Gas6 might modulate the expression of adiponectin, and might therefore be associated with insulin resistance in adipose tissues.
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http://dx.doi.org/10.1111/jdi.13412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015836PMC
April 2021

Metformin Attenuates Osteoporosis in Diabetic Patients with Carcinoma in Situ: A Nationwide, Retrospective, Matched-Cohort Study in Taiwan.

J Clin Med 2020 Sep 2;9(9). Epub 2020 Sep 2.

Department of Medical Research, National Defense Medical Center, Taipei 11490, Taiwan.

Patients with diabetes are at increased risk of cancer development and osteoporosis. Metformin is an effective agent for diabetes management. Epidemiological studies have identified an association between metformin use and cancer prevention. This article outlines the potential for metformin to attenuate the rate of osteoporosis in diabetic patients with carcinoma in situ (CIS). From the National Health Insurance Research Database of Taiwan, 7827 patients with diabetes with CIS who were receiving metformin therapy were selected, along with 23,481 patients as 1:3 sex-, age- and index year-matched controls, who were not receiving metformin therapy. A Cox proportional hazard analysis was used to compare the rate of osteoporosis during an average of 15-year follow-up. Of the subjects who were enrolled, 801 (2.56%) had osteoporosis, including 168 from the metformin group (2.15%) and 633 from the without metformin group (2.70%). The metformin group presented a lower rate of osteoporosis at the end of follow-up ( = 0.009). The Cox proportional hazard regression analysis revealed a lower rate of osteoporosis for the metformin group (adjusted hazard ratio of 0.820; 95% confidence interval = 0.691-0.972, = 0.022). Diabetic patients with CIS under metformin therapy presented lower osteoporosis rate than those who were not receiving metformin therapy.
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http://dx.doi.org/10.3390/jcm9092839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565460PMC
September 2020

Correction to: Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy.

Cancer Cell Int 2020 26;20:410. Epub 2020 Aug 26.

Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, No. 161, Sec. 6, Min‑Chuan East Rd., Nei‑Hu, Taipei, 114 Taiwan.

[This corrects the article DOI: 10.1186/s12935-020-01401-w.].
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http://dx.doi.org/10.1186/s12935-020-01478-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448332PMC
August 2020

Extracellular Polysaccharopeptides from Fermented Turkey Tail Medicinal Mushroom, Trametes versicolor (Agaricomycetes), Mitigate Oxidative Stress, Hyperglycemia, and Hyperlipidemia in Rats with Type 2 Diabetes Mellitus.

Int J Med Mushrooms 2020 ;22(5):417-429

School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan R.O.C.; Division of Pediatric Surgery, Department of Surgery, China Medical University Children's Hospital, Taichung, 40402, Taiwan R.O.C.

The antihyperglycemic activity of extracellular polysaccharopeptides (ePSP) obtained from Trametes versicolor (TV) strain LH-1 has been reported to increase cellular glucose uptake in HepG2 cells in an insulin-independent manner. Evidence indicates that oxidative stress plays a pivotal role in the development of diabetic complications. We aimed to use an in vivo model to investigate the effects of TV-ePSP on oxidative stress and glucose homeostasis in type 2 diabetes mellitus (T2DM). Male Wistar rats fed with a high fat diet followed by a streptozotocin injection to induce T2DM were orally administered water or 0.1, 0.5, or 1.0 g/kg of TV-ePSP per day. After a 4-week administration of TV-ePSP, T2DM rats had attenuated elevations in blood glucose levels, areas under the curve in oral glucose tolerance tests, insulin resistance indices, and serum fructosamine and triglyceride in a dose-dependent manner (P < 0.05, one-way ANOVA). In addition, TV-ePSP significantly alleviated oxidative stress in T2DM rats, as shown by the decreased lipid peroxidation and the increased activity of superoxide dismutase in the plasma, and by the elevated glutathione levels in the plasma and erythrocytes. The antihyperglycemia and antihypertriglyceridemia activities of TV-ePSP may be associated with the improved oxidative stress, suggesting the beneficial effects of TV-ePSP in preventing the development of diabetic complications in T2DM patients.
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http://dx.doi.org/10.1615/IntJMedMushrooms.2020034560DOI Listing
March 2021

Comparison of 7-site skinfold measurement and dual-energy X-ray absorptiometry for estimating body fat percentage and regional adiposity in Taiwanese diabetic patients.

PLoS One 2020 24;15(7):e0236323. Epub 2020 Jul 24.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan, ROC.

Obesity and regional adiposity are important risk factors for cardiometabolic disorders. The aim of this study is to compare 7-site skinfold (SF) measurement to dual-energy x-ray absorptiometry (DXA) as the reference method for estimating body fat percentage (BF%) and regional adiposity in diabetic outpatients. A total of 59 diabetic patients (36 females and 23 males) aged 28.5-78 years (median 67.7 years) with BMI 18.8-40.6 kg/m2 (median: 25.5 kg/m2) were enrolled. 7-site skinfold measurement and DXA were performed at the same visit day and biochemistry data were collected. Our results demonstrate the BF% calculated via Jackson & Pollock 7-site skinfold equation presents a strong correlation (r = 0.672, p < 0.001 in females; r = 0.885, p < 0.001 in males) with that measured by DXA, but the means of BF% between these two methods are significantly different in both sexes (paired t-test, p < 0.001). The Bland-Altman analysis showed the mean differences (DXA-SF) of BF% were positive for female (8.74%) and male (7.22%), suggesting Jackson & Pollock 7-site skinfold equation tends to underestimate the BF%. Besides, regional SF thicknesses of 7-site skinfold measurement were significantly correlated with the matched regional adiposity quantified by DXA. Furthermore, truncal and android SF thicknesses were notably positively correlated with several cardiometabolic risk factors in gender-specific manner. Our data indicate the 7-site skinfold measurement is not an interchangeable method for precisely measuring BF%, but might be practical for evaluating the cardiometabolic risks in Taiwanese diabetic outpatients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236323PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380604PMC
September 2020

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy.

Cancer Cell Int 2020 10;20:300. Epub 2020 Jul 10.

Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, No.161, Sec.6, Min-Chuan East Rd., Nei-Hu, Taipei, 114 Taiwan.

Background: The mechanisms of neuronal protein γ-synuclein (SNCG) in the malignancy of oral squamous cell carcinoma (OSCC) are not clear. This study tested the hypothesis that SNCG is involved in nicotine-induced malignant behaviors of OSCC. The effect of nicotine on SNCG expression and epithelial-to-mesenchymal transition (EMT) markers were examined.

Methods: Short hairpin RNA (shRNA) and an antagonist specific for α7-nicotine acetylcholine receptors (α7-nAChRs) were used to examine the role of α7-nAChRs in mediating the effects of nicotine. Knockdown of SNCG in nicotine-treated cells was performed to investigate the role of SNCG in cancer malignancy. The in vivo effect of nicotine was examined using a nude mouse xenotransplantation model.

Results: Nicotine increased SNCG expression in a time- and dose-dependent manner. Nicotine treatment also increased E-cadherin and ZO-1 and decreased fibronectin and vimentin expression. After specific knockdown of α7-nAChRs and inhibition of the PI3/AKT signal, the effect of nicotine on SNCG expression was attenuated. Silencing of SNCG abolished nicotine-induced invasion and migration of OSCC cells. The xenotransplantation model revealed that nicotine augmented tumor growth and SNCG expression.

Conclusion: Nicotine upregulated SNCG expression by activating the α7-nAChRs/PI3/AKT signaling that are participated in nicotine-induced oral cancer malignancy.
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http://dx.doi.org/10.1186/s12935-020-01401-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350738PMC
July 2020

Fruiting Bodies of Chinese Caterpillar Mushroom, Ophiocordyceps sinensis (Ascomycetes) Alleviate Diabetes-Associated Oxidative Stress.

Int J Med Mushrooms 2020 ;22(1):15-29

Department of Natural Sciences, Fu Jen Catholic University, #510, JhongZheng Rd., Xinzhuang District, New Taipei City, 24205, Taiwan, ROC.

Hyperglycemia-induced complications, the major causes of death in diabetes, are closely related to the elevated oxidative stress. Our previous study indicated that fruiting bodies of Ophiocordyceps sinensis attenuated polydipsia and hyperglycemia in diabetic rats. In this study, we further investigated whether the protective effects of O. sinensis on diabetes are associated with improved oxidative status in the circulation and target organs, the liver and kidneys. Male Wistar rats were fed with a semipurified diet supplemented with fruiting bodies (FB group, 1 g/day), carcass (CC group, 1 g/day), fruiting bodies and carcass (CF group, each 0.5 g/day), or placebo (DM and R groups) for 4 weeks (day 1 to 29). On day 15, animals were injected with nicotinamide (200 mg/kg) and streptozotocin (65 mg/kg) to induce diabetes. After the induction of diabetes, fasting blood glucose (FBG) was increased and the diabetes-increased FBG (day 15 to 26) was alleviated by the supplementation of fruiting bodies (p < 0.05, one-way ANOVA). In addition, the contents of vitamins A and C in the liver were significantly higher in the FB group, and the contents of glutathione in the liver and vitamin A and C in the kidneys were significantly higher in the FB, CC, and CF groups than in the DM group. The diabetes-increased glutathione peroxidase activity in the liver was decreased in the CF group. These results suggest that O. sinensis, especially fruiting bodies, may have antihyperglycemic activity associated with the alleviated oxidative stress in the liver and kidneys.
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http://dx.doi.org/10.1615/IntJMedMushrooms.2019033275DOI Listing
February 2021

Arecoline induces epithelial mesenchymal transition in HK2 cells by upregulating the ERK-mediated signaling pathway.

Environ Toxicol 2020 Sep 22;35(9):1007-1014. Epub 2020 May 22.

Division of Nephrology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.

Arecoline, a component of betel nuts, is a known carcinogen that causes oral cancers among those who chew betel nuts. Betel nut chewing is also associated with an increased risk of chronic kidney disease (CKD), but the role of arecoline in this association is unclear. This in vitro study investigates the effects of arecoline on cultured human kidney (HK2) cells. We observed that arecoline had no effect on cell viability but increased cell migration in a dose-dependent manner. Western blot analysis showed that arecoline treatment caused a dose-dependent decrease in E-cadherin expression and dose-dependent increases in N-cadherin, vimentin, α-SMA, and collagen expression; reverse transcriptase-polymerase chain reaction analysis revealed dose-dependent increases in α-SMA and collagen mRNA. Arecoline treatment upregulated the expression of phosphorylated extracellular signal-regulated kinase through epithelial mesenchymal transition and renal fibrosis in HK2 cells. These findings demonstrate that arecoline plays a role in inducing the epithelial mesenchymal transition and fibrogenesis in renal tubule cells and suggest that arecoline promotes the progression of CKD.
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http://dx.doi.org/10.1002/tox.22937DOI Listing
September 2020

Hispidulin Inhibits Neuroinflammation in Lipopolysaccharide-Activated BV2 Microglia and Attenuates the Activation of Akt, NF-κB, and STAT3 Pathway.

Neurotox Res 2020 Jun 28;38(1):163-174. Epub 2020 Mar 28.

Department of Pharmacology, Graduate Institute of Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.

Microglia, resident innate immune cells in central nervous system, regulates neuroinflammation and is associated with a variety of neuropathologies. The present study investigated the antineuroinflammatory effects of hispidulin (HPD), a naturally flavone compound, in lipopolysaccharide- (LPS-) stimulated BV2 microglia cells. The expression levels of nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory factors were determined by the Griess method, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). Western blotting was used to measure various transcription factors such as Akt, nuclear factor-kappa B (NF-κB), and signal transducer and activator of transcription 3 (STAT3) activities. Our experimental results demonstrated that HPD increased cell viability and reduced apoptosis in LPS-treated BV2 microglia cells. Moreover, HPD significantly reduced the levels of NO, ROS, inducible nitric oxide synthase (iNOS), cyclooxygenase- (COX-) 2, tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and prostaglandin E2 (PGE2) in a dose-dependent manner. Phosphorylation of NF-κB/IκB, Akt, and STAT3 proteins expression by HPD was suppressed in LPS-induced BV2 microglial cells. We concluded that HPD may inhibit neuroinflammatory responses by inhibiting NF-κB pathway activation and ROS formation. These results propose that HPD has potential as anti-inflammatory agents against microglia-mediated neuroinflammatory disorders.
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http://dx.doi.org/10.1007/s12640-020-00197-xDOI Listing
June 2020

Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan.

J Clin Med 2020 Feb 29;9(3). Epub 2020 Feb 29.

School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan.

Study Objectives: Diabetes mellitus per se and its related therapy have been frequently associated with an increased risk of developing dementia. However, studies that explored the risk of dementia from the use of the novel oral antidiabetic medication dipeptidyl peptidase 4 inhibitor (DPP-4i) have been limited, especially in Asian populations. The present study aimed to determine the effect of DPP-4i on the subsequent risk of dementia among patients with type 2 diabetes (T2D) in Taiwan.

Methods: This study utilized data from the Longitudinal Health Insurance Database between 2008 and 2015. We enrolled 2903 patients aged ≥50 years, who were on DPP-4i for a diagnosis of T2D and had no dementia. A total of 11,612 subjects were included and compared with a propensity score-matched control group who did not use DPP-4i (non-DPP-4i group). Survival analysis was performed to estimate and compare the risk of dementia-including Alzheimer's disease, vascular dementia, and other dementia types-between the two groups. Both groups had a mean age of 68 years, had a preponderance of women (61.8%), and were followed up for a mean duration of 7 years. The risk of all-cause dementia was significantly lower in the DPP-4i group than in the non-DPP-4i group (hazard ratio (HR) 0.798; 95% confidence interval (CI) 0.681-0.883; < 0.001), with a class effect. This trend was particularly observed for vascular dementia (HR 0.575; 95% CI 0.404-0.681; < 0.001), but not in Alzheimer's disease (HR 0.891; 95% CI 0.712-1.265; = 0.297). The Kaplan-Meier analysis showed that the preventive effect on dementia was positively correlated with the cumulative dose of DPP-4i. DPP-4i decreased the risk of dementia with a class effect, especially vascular dementia, but not in Alzheimer's disease. Our results provide important information on the drug choice when managing patients with T2D in clinical practice.
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http://dx.doi.org/10.3390/jcm9030660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141309PMC
February 2020

ZnO Nanoparticles Induced Caspase-Dependent Apoptosis in Gingival Squamous Cell Carcinoma through Mitochondrial Dysfunction and p70S6K Signaling Pathway.

Int J Mol Sci 2020 Feb 26;21(5). Epub 2020 Feb 26.

Institute of Geriatric Welfare Technology and Science, MacKay Medical College, New Taipei City 252, Taiwan.

Zinc oxide nanoparticles (ZnO-NPs) are increasingly used in sunscreens, food additives, pigments, rubber manufacture, and electronic materials. Several studies have shown that ZnO-NPs inhibit cell growth and induce apoptosis by the production of oxidative stress in a variety of human cancer cells. However, the anti-cancer property and molecular mechanism of ZnO-NPs in human gingival squamous cell carcinoma (GSCC) are not fully understood. In this study, we found that ZnO-NPs induced growth inhibition of GSCC (Ca9-22 and OECM-1 cells), but no damage in human normal keratinocytes (HaCaT cells) and gingival fibroblasts (HGF-1 cells). ZnO-NPs caused apoptotic cell death of GSCC in a concentration-dependent manner by the quantitative assessment of oligonucleosomal DNA fragmentation. Flow cytometric analysis of cell cycle progression revealed that sub-G1 phase accumulation was dramatically induced by ZnO-NPs. In addition, ZnO-NPs increased the intracellular reactive oxygen species and specifically superoxide levels, and also decreased the mitochondrial membrane potential. ZnO-NPs further activated apoptotic cell death via the caspase cascades. Importantly, anti-oxidant and caspase inhibitor clearly prevented ZnO-NP-induced cell death, indicating the fact that superoxide-induced mitochondrial dysfunction is associated with the ZnO-NP-mediated caspase-dependent apoptosis in human GSCC. Moreover, ZnO-NPs significantly inhibited the phosphorylation of ribosomal protein S6 kinase (p70S6K kinase). In a corollary in vivo study, our results demonstrated that ZnO-NPs possessed an anti-cancer effect in a zebrafish xenograft model. Collectively, these results suggest that ZnO-NPs induce apoptosis through the mitochondrial oxidative damage and p70S6K signaling pathway in human GSCC. The present study may provide an experimental basis for ZnO-NPs to be considered as a promising novel anti‑tumor agent for the treatment of gingival cancer.
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http://dx.doi.org/10.3390/ijms21051612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084801PMC
February 2020

Static Magnetic Field Induced Neural Stem/Progenitor Cell Early Differentiation and Promotes Maturation.

Stem Cells Int 2019 16;2019:8790176. Epub 2019 Oct 16.

Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.

The potential impacts of magnetic field exposures on brain development have raised public concern. In the present study, we aimed to investigate the biophysical effects of moderate-intensity (0.5 T, Tesla) static magnetic field (SMF) on mice neural progenitor cells (mNPCs). Our results showed that the SMF exposure increased the number of neurosphere formation and enhanced proliferative activity in mNPCs. In addition, our flow cytometry data demonstrated that the proportions of S phase and G2/M phase mNPCs were remarkably increased following 5 days of SMF exposure. Moreover, the level of a mitotic regulatory protein, cyclin B, was upregulated after SMF exposure. Furthermore, the mNPCs exposed to SMF exhibited a significant increase in Sox2 expression. When mNPCs were induced to differentiation, our immunofluorescence assay revealed that the percentage of neurons (Tuj-1-positive cells) but not astrocyte (s100-positive cells) was significantly higher and displayed morphological complexity in the SMF group. Finally, our electrophysiological results demonstrated the mNPC-derived neurons from the SMF group showing a significantly increased in input resistance, which indicated more functional maturation. Based on these findings, it appears reasonable to suggest that SMF exposure could affect normal neurogenesis and promote neural lineage differentiation as well as neuronal maturation.
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http://dx.doi.org/10.1155/2019/8790176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816009PMC
October 2019

Combination of COX-2 inhibitor and metformin attenuates rate of admission in patients with rheumatoid arthritis and diabetes in Taiwan.

Medicine (Baltimore) 2019 Oct;98(41):e17371

Department of Medical Research, Tri-Service General Hospital.

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease associated with increased prevalence of type 2 diabetes mellitus (T2DM). Here, we investigated the effect of the combination of cyclooxygenase (COX)-2 inhibitors and metformin on the rate of admission in patients with RA and T2DM and compared it with that of only COX-2 inhibitors.In total, 1268 subjects with RA and T2DM under COX-2 inhibitor and metformin therapy were selected from the National Health Insurance Research Database of Taiwan, along with 2536 patients as 1:2 sex-, age-, and index year-matched controls without metformin therapy. Cox proportional hazard analysis was used to compare the rate of admission during the 10 years of follow-up.At the end of the follow-up, 72 enrolled subjects (1.89%) had admission, including 9 from the combination group (0.71%) and 63 from the COX-2 inhibitor group (2.48%). The combination group was associated with a lower rate of admission at the end of follow-up (P < .001). Cox proportional hazard regression analysis revealed the lower rate of admission for subjects under combination therapy (adjusted hazard ratio of 0.275; 95% confidence interval = 0.136-0.557, P < .001).Patients with RA and T2DM receiving the combination of COX-2 inhibitors and metformin were associated with lower admission rate than those on COX-2 inhibitors alone, and this effect may be attributed to the decrease in the levels of proinflammatory factors.
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http://dx.doi.org/10.1097/MD.0000000000017371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799465PMC
October 2019

Unraveling the Molecular Mechanism of Traditional Chinese Medicine: Formulas Against Acute Airway Viral Infections as Examples.

Molecules 2019 Sep 27;24(19). Epub 2019 Sep 27.

Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

Herbal medicine, including traditional Chinese medicine (TCM), is widely used worldwide. Herbs and TCM formulas contain numerous active molecules. Basically, they are a kind of cocktail therapy. Herb-drug, herb-food, herb-herb, herb-microbiome, and herb-disease interactions are complex. There is potential for both benefit and harm, so only after understanding more of their mechanisms and clinical effects can herbal medicine and TCM be helpful to users. Many pharmacologic studies have been performed to unravel the molecular mechanisms; however, basic and clinical studies of good validity are still not enough to translate experimental results into clinical understanding and to provide tough evidence for better use of herbal medicines. There are still issues regarding the conflicting pharmacologic effects, pharmacokinetics, drug interactions, adverse and clinical effects of herbal medicine and TCM. Understanding study validation, pharmacologic effects, drug interactions, indications and clinical effects, adverse effects and limitations, can all help clinicians in providing adequate suggestions to patients. At present, it would be better to use herbs and TCM formulas according to their traditional indications matching the disease pathophysiology and their molecular mechanisms. To unravel the molecular mechanisms and understand the benefits and harms of herbal medicine and TCM, there is still much work to be done.
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http://dx.doi.org/10.3390/molecules24193505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804036PMC
September 2019

Serum E-selectin concentration is associated with risk of metabolic syndrome in females.

PLoS One 2019 24;14(9):e0222815. Epub 2019 Sep 24.

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

Objectives: Traits of metabolic syndrome (MetS) and biomarkers of inflammation and endothelial dysfunction were examined. We investigated the differences of various biomarkers among individuals with or without Mets in a gender-specific manner. The gender-specific associations between E-selectin and MetS were further evaluated.

Methods: A total of 205 patients were recruited from the outpatient clinics of Tri-Service General Hospital, Taipei, Taiwan. Inclusion criteria were age between 20-75 years and BMI < 35 kg/m2. Demographic, anthropometric and MetS index data were compared between genders. Markers of inflammation and endothelial dysfunction were compared between individuals with or without MetS by gender.

Results: Age-adjusted E-selectin values showed significant positive correlations with BMI, waist-hip ratio, fasting plasma glucose, systolic and diastolic blood pressure, triglycerides, TNF-α, hsCRP and ICAM-1, and inverse correlation with HDL cholesterol. E-selectin levels were positively correlated with numbers of MetS components in females (P < 0.001) but not in males (P = 0.125).

Conclusions: Increased E-selectin levels are significantly associated with increased MetS risk in females, but not in males.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759160PMC
April 2020

Prevalence of diabetic macrovascular complications and related factors from 2005 to 2014 in Taiwan: A nationwide survey.

J Formos Med Assoc 2019 Nov 18;118 Suppl 2:S96-S102. Epub 2019 Sep 18.

Division of Biochemistry, National Defense Medical Center, Taipei, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, Song Shan Branch, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Background/purpose: Diabetic macrovascular complications contribute to nonignorable causes of morbidity and mortality in patients with diabetes mellitus (DM). In this study, the trends of risk factors and macrovascular complications were examined in patients with DM in Taiwan.

Methods: Health care information and International Classification of Diseases, Ninth Revision diagnostic codes were retrieved from the Taiwan Bureau of National Health Insurance claims files between 2005 and 2014. Using these data, the number of cases and annual prevalence of diabetic macrovascular complications in individuals with DM were stratified by age and sex.

Results: The prevalence of DM with either stroke or cardiovascular disease (CVD) showed a decreasing trend in enrolled patients with DM (p for trend < 0.005), but that of DM with peripheral vascular diseases (PVDs) showed an increasing trend (p for trend < 0.001). Notably, the trend of changes in the prevalence of heart failure (HF) was similar to that of changes in the prevalence of stroke, although the decrease in prevalence was not statistically significant (p for trend = 0.053).

Conclusion: From this nationwide study, we observed a decrease in the prevalence of diabetic macrovascular complications, such as stroke, CVD, and HF, but an increase in the prevalence of PVDs in the past decade in Taiwan.
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http://dx.doi.org/10.1016/j.jfma.2019.08.035DOI Listing
November 2019

Cilostazol inhibits hyperglucose-induced vascular smooth muscle cell dysfunction by modulating the RAGE/ERK/NF-κB signaling pathways.

J Biomed Sci 2019 Sep 6;26(1):68. Epub 2019 Sep 6.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background: Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction.

Objectives: In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism.

Method: We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected.

Results: Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture.

Conclusions: Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.
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http://dx.doi.org/10.1186/s12929-019-0550-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731603PMC
September 2019

Repression of metastasis-associated protein 2 for inhibiting metastasis of human oral cancer cells by promoting the p-cofilin-1/ LC3-II expression.

J Oral Pathol Med 2019 Nov 18;48(10):959-966. Epub 2019 Aug 18.

Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.

Background: The overexpression of metastasis-associated protein 2 (MTA2) contributes to human tumor progression and metastasis in various tumor cells. However, the role of MTA2 in human oral cancer progression remains unknown.

Materials And Methods: MTA2 expression in human oral tumor tissues and cell lines was measured by immunohistochemistry and Western blotting. Cell proliferation and cell cycle were analyzed using MTT assay and flow cytometry. The effects of MTA2 on oral cell migration and invasion were investigated using migration and invasion assays. The expression of MTA2, p-cofilin-1, and MTA2-induced LC3-II levels were measured using Western blotting and an immunofluorescence assay.

Results: Based on the human oral cancer tissue array and TCGA database, we found that MTA2 was increased in oral cancer tissues than in non-tumor oral tissues (P < .01). Moreover, MTA2 is significantly associated with tumor grade (P < .01) and the overall survival rate of patients with grade III tumor (P < .05). MTA2 expression in oral cancer cells was markedly higher than that in normal oral cells. Cell proliferation and cell cycle were not significantly changed in the cells inhibited by MTA2. MTA2 knockdown can inhibit cell migration and invasion of human oral cancer cells. Furthermore, we suggest that MTA2 inhibition enhances p-cofilin and LC3-II expression, and the knockdown of LC3-II expression in cells inhibited by MTA2 had the opposite effect.

Conclusion: These results indicate that MTA2 may serve as a candidate prognostic biomarker and that targeting autophagy is a potential therapeutic strategy for treating human oral cancer.
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http://dx.doi.org/10.1111/jop.12941DOI Listing
November 2019

Gas6/Axl signaling attenuates alveolar inflammation in ischemia-reperfusion-induced acute lung injury by up-regulating SOCS3-mediated pathway.

PLoS One 2019 18;14(7):e0219788. Epub 2019 Jul 18.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background: Axl is a cell surface receptor tyrosine kinase, and activation of the Axl attenuates inflammation induced by various stimuli. Growth arrest-specific 6 (Gas6) has high affinity for Axl receptor. The role of Gas6/Axl signaling in ischemia-reperfusion-induced acute lung injury (IR-ALI) has not been explored previously. We hypothesized that Gas6/Axl signaling regulates IR-induced alveolar inflammation via a pathway mediated by suppressor of cytokine signaling 3 (SOCS3).

Methods: IR-ALI was induced by producing 30 min of ischemia followed by 90 min of reperfusion in situ in an isolated and perfused rat lung model. The rats were randomly allotted to a control group and IR groups, which were treated with three different doses of Gas6. Mouse alveolar epithelium MLE-12 cells were cultured in control and hypoxia-reoxygenation (HR) conditions with or without Gas6 and Axl inhibitor R428 pretreatment.

Results: We found that Gas6 attenuated IR-induced lung edema, the production of proinflammatory cytokines in perfusates, and the severity of ALI ex vivo. IR down-regulated SOCS3 expression and up-regulated NF-κB, and Gas6 restored this process. In the model of MLE-12 cells with HR, Gas6 suppressed the activation of TRAF6 and NF-κB by up-regulating SOCS3. Axl expression of alveolar epithelium was suppressed in IR-ALI but Gas6 restored phosphorylation of Axl. The anti-inflammatory effect of Gas6 was antagonized by R428, which highlighted that phosphorylation of Axl mediated the protective role of Gas6 in IR-ALI.

Conclusions: Gas6 up-regulates phosphorylation of Axl on alveolar epithelium in IR-ALI. The Gas6/Axl signaling activates the SOCS3-mediated pathway and attenuates IR-related inflammation and injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219788PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638944PMC
March 2020

Low-Dose Aspirin for the Primary Prevention of Cardiovascular Disease in Diabetic Individuals: A Meta-Analysis of Randomized Control Trials and Trial Sequential Analysis.

J Clin Med 2019 May 5;8(5). Epub 2019 May 5.

Division of Hematology and Oncology Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.

Background: Evidence of low-dose aspirin as the primary prevention strategy for cardiovascular disease (CVD) in diabetes are unclear. This study was designed to evaluate the effect of low-dose aspirin use for the primary prevention of CVD in diabetes.

Methods: We collected randomized controlled trials of low-dose aspirin for the primary prevention of CVD in adults with diabetes lasting at least 12 months from Medline, Embase, and the Cochrane Library up to 10 November 2018. Two reviewers extracted data and appraised the reporting quality according to a predetermined protocol (CRD4201811830). This review was conducted using Cochrane standards, trial sequential analysis, and the Grading of Recommendation. The primary outcomes were major adverse cardiovascular events (MACE, including non-fatal myocardial infarction, ischemia stroke, and cardiovascular death) and an incidence of major hemorrhage (major intracranial hemorrhage and major gastrointestinal bleeding).

Results: In this primary prevention (number = 29,814 participants) meta-analysis, low-dose aspirin use reduced the risk of MACE by 9% and increased the risk of major hemorrhage by 24%. The benefits were only observed in subjects of age ≥ 60 years while reducing the same risk of MACE. In efficacy, it reduced the risk of stroke but not myocardial infarction. No increase in all-cause mortality or cardiovascular death was observed.

Conclusions: We suggested the use of low-dose aspirin as the primary prevention strategy for CVD in diabetes, particularly in an older population. The absolute benefits were largely counterbalanced by the bleeding hazard.
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http://dx.doi.org/10.3390/jcm8050609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572181PMC
May 2019

Reactive oxygen species mediate the chemopreventive effects of syringin in breast cancer cells.

Phytomedicine 2019 Aug 28;61:152844. Epub 2019 Jan 28.

Department of Nutrition and Health Science, School of Medical and Health Sciences, Fooyin University, Kaohsiung 83102, Taiwan. Electronic address:

Background: Syringin (Syr), a phenylpropanoid glycoside extracted from Eleutherococcus senticosus, possesses various biological properties, including anticancer activities. However, the cytotoxicity effects of Syr on breast cancer have not yet been elucidated.

Purpose: In this study, we evaluated the anticancer potential of Syr on breast carcinoma and the mechanism involved.

Study Design/methods: Non-tumorigenic (M10), tumorigenic (MCF7) and metastatic (MDA-MB-231) breast cancer cell lines as well as xenograft model were treated with Syr. Proliferation and cell cycle distribution were evaluated using the MTT, the colony formation assay and flow cytometry. The expression levels of cytotoxicity-related proteins were detected by Western blot.

Results: Here, we found that colony formation inhibition, cell cycle arrest in the G2/M phase, down-regulation of X-linked inhibitor of apoptosis protein (XIAP), cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3/9 activation were observed in MCF7 and MDA-MB-231 cells treated with Syr. Moreover, pretreatment with a pan-caspase inhibitor (Z-DEVD-FMK) inhibited Syr-induced apoptosis. In addition, treatment with Syr also increased the production of reactive oxygen species (ROS). However, the antioxidant N-acetyl-cysteine (NAC) reversed the ROS levels and rescued the apoptotic changes. Meanwhile, Syr inhibited the growth of breast cancer xenograft models and dramatically decreased tumor volume without any obvious body weight loss in vivo.

Conclusion: Our findings suggest that Syr induces oxidative stress to suppress the proliferation of breast cancer and thus might be an effective therapeutic agent to treat breast cancer.
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http://dx.doi.org/10.1016/j.phymed.2019.152844DOI Listing
August 2019

Praeruptorin-B Inhibits 12-O-Tetradecanoylphorbol-13-Acetate-Induced Cell Invasion by Targeting AKT/NF-κB via Matrix Metalloproteinase-2/-9 Expression in Human Cervical Cancer Cells.

Cell Physiol Biochem 2019 ;52(6):1255-1266

Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Background/aims: Praeruptorins, a seselin-type coumarin, possess anti-inflammatory and antitumor promoting properties. However, molecular mechanisms through which Praeruptorin-B (Pra-B) exerts an antimetastatic effect on cervical cancer cells remain unclear.

Methods: Cell viability was examined using the MTT assay, whereas cell migration and invasion were examined using the Boyden chamber assay. Western blotting and RT-PCR were performed to investigate the inhibitory effect of Pra-B on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-2/-9 (MMP-2/-9) expression in HeLa cells. The findings of the luciferase assay confirmed the inhibitory effect of Pra-B on TPA-induced transcriptional activity of MMP2/-9 in HeLa cells.

Results: Pra-B inhibited TPA-induced metastatic ability of human cervical cancer cells without any significant toxicity. Pra-B suppressed TPA-induced mRNA and protein expression and transcriptional activity of MMP-2/-9 in HeLa cells. Furthermore, Pra-B inhibited AKT phosphorylation but did not affect the MAPK pathway. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 (a PI3K inhibitor) reduced cell invasion and MMP-2/-9 expression and transcriptional activity. In addition, Pra-B attenuated TPA-induced nuclear translocation of NF-κB-p65/-p50, which reduced Ikk-α phosphorylation in HeLa cells. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 reduced NF-κB nuclear translocation.

Conclusion: These results suggested that Pra-B-mediated inhibition of TPA-induced cell metastasis involved the suppression of p-AKT/NF-κB via MMP-2/-9 expression in HeLa cells. Pra-B can be a potential antimetastatic agent against cervical cancer.
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http://dx.doi.org/10.33594/000000088DOI Listing
May 2019

Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells.

Mar Drugs 2019 Apr 6;17(4). Epub 2019 Apr 6.

Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.

Lymphangiogenesis is an important biological process associated with cancer metastasis. The development of new drugs that block lymphangiogenesis represents a promising therapeutic strategy. Marine fungus-derived compound phomaketide A, isolated from the fermented broth of sp. NTOU4195, has been reported to exhibit anti-angiogenic and anti-inflammatory effects. However, its anti-lymphangiogenic activity has not been clarified to date. In this study, we showed that phomaketide A inhibited cell growth, migration, and tube formation of lymphatic endothelial cells (LECs) without an evidence of cytotoxicity. Mechanistic investigations revealed that phomaketide A reduced LECs-induced lymphangiogenesis via vascular endothelial growth factor receptor-3 (VEGFR-3), protein kinase Cδ (PKCδ), and endothelial nitric oxide synthase (eNOS) signalings. Furthermore, human proteome array analysis indicated that phomaketide A significantly enhanced the protein levels of various protease inhibitors, including cystatin A, serpin B6, tissue factor pathway inhibitor (TFPI), and tissue inhibitor matrix metalloproteinase 1 (TIMP-1). Importantly, phomaketide A impeded tumor growth and lymphangiogenesis by decreasing the expression of LYVE-1, a specific marker for lymphatic vessels, in tumor xenograft animal model. These results suggest that phomaketide A may impair lymphangiogenesis by suppressing VEGFR-3, PKCδ, and eNOS signaling cascades, while simultaneously activating protease inhibitors in human LECs. We document for the first time that phomaketide A inhibits lymphangiogenesis both and , which suggests that this natural product could potentially treat cancer metastasis.
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http://dx.doi.org/10.3390/md17040215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520718PMC
April 2019

Author Correction: Predictive Value of Serum Gamma-glutamyltranspeptidase for Future Cardiometabolic Dysregulation in Adolescents- a 10-year longitudinal study.

Sci Rep 2018 Nov 13;8(1):16934. Epub 2018 Nov 13.

Department of Pathology, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-34497-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233213PMC
November 2018
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