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Lee T.-M.,China Medical University An Nan Hospital | Lee T.-M.,China Medical University at Taichung | Lee T.-M.,Taipei Medical University | Chen W.-T.,China Medical University An Nan Hospital | And 2 more authors.
Circulation Journal | Year: 2015

Background: The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on arrhythmias remains unknown. The aim of this study was to investigate whether sitagliptin attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression, focusing on cyclic adenosine monophosphate (cAMP) downstream signaling such as protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). Methods and Results: Male Wistar rats were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after ligating the coronary artery. Post-infarction was associated with increased oxidative stress. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham. Compared with the vehicle, infarcted rats treated with sitagliptin had significantly increased cAMP levels, decreased DPP-4 activity, oxidative stress, NGF levels and immunofluorescence-stained sympathetic hyperinnervation. Arrhythmic scores were significantly lower in the sitagliptin-treated infarcted rats than in vehicle. Ex vivo studies showed that sitagliptin increased the phosphorylated cAMP response element-binding protein (CREB), which can be reversed by H-89 (a PKA inhibitor), not brefeldin A (an Epac inhibitor). Heme oxygenase-1 (HO-1) expression was increased by a PKA agonist but not by an Epac agonist. HO-1 expression was attenuated in KG-501 (a CREB inhibitor)-treated infarcted rats in the presence of a PKA agonist. Conclusions: Sitagliptin protects ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via upregulation of HO-1 expression in a cAMP/PKA/CREB-dependent antioxidant pathway in non-diabetic infarcted rats. © 2015, Japanese Circulation Society. All rights reserved.

Chiu H.-W.,National Cheng Kung University | Chiu H.-W.,Taipei Medical University | Tseng Y.-C.,National Cheng Kung University | Hsu Y.-H.,Taipei Medical University | And 8 more authors.
Cancer Letters | Year: 2015

Sarcoma is a rare form of cancer that differs from the much more common carcinomas because it occurs in a distinct type of tissue. Many patients of sarcoma have poor response to chemotherapy and an increased risk for local recurrence. Arsenic trioxide (ATO) is used to treat certain types of leukemia. Recently, data have revealed that ATO induces sarcoma cell death in several types of solid tumor cell lines. In the present study, we investigated whether ATO induces cancer cell death and elucidated the underlying anti-cancer mechanisms. Our results showed that ATO caused concentration- and time-dependent cell death in human osteosarcoma and fibrosarcoma cells. The types of cell death that were induced by ATO were primarily autophagy and apoptosis. Furthermore, ATO activated p38, JNK and AMPK and inhibited the Akt/mTOR signaling pathways. Specifically, we found that ATO induced endoplasmic reticulum (ER) stress and suppressed proteasome activation in two types of sarcoma cell lines. However, the level of proteasome inhibition in osteosarcoma cells was lower than in fibrosarcoma cells. Thus, we used combined treatment with ATO and a proteasome inhibitor to examine the antitumor activity in fibrosarcoma cells. The data indicated showed that the combination treatment of ATO and MG132 (a proteasome inhibitor) resulted in synergistic cytotoxicity. In a fibrosarcoma xenograft mouse model, the combined treatment significantly reduced tumor progression. Immunohistochemical studies revealed that combined treatment induced autophagy and apoptosis. In summary, our results suggest a potential clinical application of ATO in sarcoma therapy and that combined treatment with a proteasome inhibitor can increase the therapeutic efficacy. © 2014 Elsevier Ireland Ltd.

Yeh D.-C.,China Medical University Beigan Hospital | Chan T.-M.,China Medical University Beigan Hospital | Chan T.-M.,China Medical University An Nan Hospital | Harn H.-J.,China Medical University at Taichung | And 7 more authors.
Cell Transplantation | Year: 2015

Adipose tissue-derived stem cells (ADSCs) have two essential characteristics with regard to regenerative medicine: the convenient and efficient generation of large numbers of multipotent cells and in vitro proliferation without a loss of stemness. The implementation of clinical trials has prompted widespread concern regarding safety issues and has shifted research toward the therapeutic efficacy of stem cells in dealing with neural degeneration in cases such as stroke, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, cavernous nerve injury, and traumatic brain injury. Most existing studies have reported that cell therapies may be able to replenish lost cells and promote neuronal regeneration, protect neuronal survival, and play a role in overcoming permanent paralysis and loss of sensation and the recovery of neurological function. The mechanisms involved in determining therapeutic capacity remain largely unknown; however, this concept can still be classified in a methodical manner by citing current evidence. Possible mechanisms include the following: 1) the promotion of angiogenesis, 2) the induction of neuronal differentiation and neurogenesis, 3) reductions in reactive gliosis, 4) the inhibition of apoptosis, 5) the expression of neurotrophic factors, 6) immunomodulatory function, and 7) facilitating neuronal integration. In this study, several human clinical trials using ADSCs for neuronal disorders were investigated. It is suggested that ADSCs are one of the choices among various stem cells for translating into clinical application in the near future. © 2015 Cognizant Comm. Corp.

Rajamani K.,National Dong Hwa University | Lin Y.-C.,Applied Cell Technology | Wen T.-C.,National Dong Hwa University | Hsieh J.,National Taiwan University | And 7 more authors.
Cell Transplantation | Year: 2015

As assuring cell quality is an essential parameter for the success of stem cell therapy, the impact of various senescence-inducing stress signals, and strategies to circumvent them, has been an important area of focus in stem cell research. The aim of this study was to demonstrate the capacity of trans-cinnamaldehyde (TC) in reversing stress-induced senescence and maintaining the quality of stem cells in a chemically (H2O2)- induced cell senescence model. Because of the availability and the promising application potential in regenerative medicine, adipose-derived stem cells (ADSCs) were chosen for the study. We found that H2O2 treatment resulted in the expression of senescence characteristics in the ADSCs, including decreased proliferation rate, increased senescence-associated -galactosidase (SA--gal) activity, decreased silent mating type information regulation 2 homolog (SIRT1) expression, and decreased telomerase activity. However, TC treatment was sufficient to rescue or reduce the effects of H2O2 induction, ultimately leading to an increased proliferation rate, a decrease in the percentage of SA--gal-positive cells, upregulation of SIRT1 expression, and increased telomerase activity of the senescent ADSCs at the cellular level. Moreover, a chemically induced liver fibrosis animal model was used to evaluate the functionality of these rescued cells in vivo. Liver dysfunction was established by injecting 200 mg/kg thioacetamide (TAA) intraperitoneally into Wistar rats every third day for 60 days. The experimental rats were separated into groups: normal group (rats without TAA induction), sham group (without ADSC transplantation), positive control group (transplanted with normal ADSCs), H2O2 group (transplanted with H2O2-induced senescent ADSCs), and H2O2 + TC group (transplanted with ADSCs pretreated with H2O2 and then further treated with TC). In the transplantation group, 1 × 106 human ADSCs were introduced into each rat via direct liver injection. Based on the biochemical analysis and immunohistochemical staining results, it was determined that the therapeutic effects on liver fibrosis by the induced senescent ADSCs (H2O2 group) were not as significant as those exerted by the normal ADSCs (the positive control group). However, the H2O2 + TC group showed significant reversal of liver damage when compared to the H2O2 group 1 week posttransplantation. These data confirmed that the TC treatment had the potential to reduce the effects of H2O2-induced senescence and to restore in vivo functionality of the induced senescent ADSCs. It is therefore suggested that TC has potential applications in maintaining the quality of stem cells and could aid in treating senescence-related disorders. © 2015 Cognizant Comm. Corp.

Lin H.-P.,National Health Research Institute | Lin C.-Y.,National Health Research Institute | Huo C.,National Health Research Institute | Huo C.,National Central University | And 14 more authors.
Oncotarget | Year: 2015

Prostate cancer (PCa) patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer (CRPC) within 1-3 years. Treatment with caffeic acid phenethyl ester (CAPE) suppressed cell survival and proliferation via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU-145, 22Rv1, and C4-2 CRPC cells. CAPE treatment also inhibited soft agar colony formation and retarded nude mice xenograft growth of LNCaP 104-R1 cells. We identified that CAPE treatment significantly reduced protein abundance of Skp2, Cdk2, Cdk4, Cdk7, Rb, phospho-Rb S807/811, cyclin A, cyclin D1, cyclin H, E2F1, c-Myc, SGK, phospho-p70S6kinase T421/S424, phospho-mTOR Ser2481, phospho-GSK3a Ser21, but induced p21Cip1, p27Kip1, ATF4, cyclin E, p53, TRIB3, phospho-p53 (Ser6, Ser33, Ser46, Ser392), phospho-p38 MAPK Thr180/Tyr182, Chk1, Chk2, phospho-ATM S1981, phospho-ATR S428, and phospho-p90RSK Ser380. CAPE treatment decreased Skp2 and Akt1 protein expression in LNCaP 104-R1 tumors as compared to control group. Overexpression of Skp2, or siRNA knockdown of p21Cip1, p27Kip1, or p53 blocked suppressive effect of CAPE treatment. Co-treatment of CAPE with PI3K inhibitor LY294002 or Bcl-2 inhibitor ABT737 showed synergistic suppressive effects. Our finding suggested that CAPE treatment induced cell cycle arrest and growth inhibition in CRPC cells via regulation of Skp2, p53, p21Cip1, and p27Kip1.

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