scholarly journals Protective Effects of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, against Cisplatin-Induced Nephrotoxicity in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Seung Hee Choi ◽  
Jaechan Leem ◽  
In-Kyu Lee
Keyword(s):  
Cell Death ◽  
Plasma Levels ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Dipeptidyl Peptidase ◽  
Apoptotic Cell Death ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heme Oxygenase 1 ◽  
Nuclear Staining ◽  
Dipeptidyl Peptidase 4

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used antihyperglycemic agents for the treatment of type 2 diabetes mellitus. Recently, the pleiotropic actions of DPP-4 inhibitors have drawn much attention. In the present study, we aimed to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could protect against cisplatin-induced nephrotoxicity. We showed that pretreatment with gemigliptin attenuated cisplatin-induced renal dysfunction, as shown by analysis of plasma creatinine levels and blood urea nitrogen and histological damage. Elevated plasma levels of active glucagon-like peptide-1 were observed in gemigliptin-pretreated mice after cisplatin treatment, compared to that in cisplatin alone-treated mice. Gemigliptin attenuated cisplatin-induced apoptotic cell death, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Western blot analysis in the kidneys. Gemigliptin also decreased the plasma levels of tumor necrosis factor-αand monocyte chemoattractant protein-1 and attenuated nuclear staining of nuclear factor kappa-B p65 in the kidneys. In addition, gemigliptin increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the kidneys of cisplatin-treated mice. Taken together, these results suggest that pretreatment with gemigliptin protects against cisplatin-induced nephrotoxicity in mice, possibly via inhibition of apoptotic cell death and inflammatory responses through induction of HO-1 and NQO1 expression.

scholarly journals In Vitro Senescence and Apoptotic Cell Death of Human Megakaryocytes

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2234-2243 ◽  
Author(s):  
Giorgio Zauli ◽  
Marco Vitale ◽  
Elisabetta Falcieri ◽  
Davide Gibellini ◽  
Alessandra Bassini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Apoptotic Cell ◽  
High Surface ◽  
Suspension Cultures ◽  
Apoptotic Cell Death ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Terminal Phase ◽  
Serum Free

Abstract To investigate the fate of human megakaryocytes, CD34+ hematopoietic progenitor cells were purified from the peripheral blood or bone marrow of healthy donors and seeded in serum-free chemically defined suspension cultures. In the presence of thrombopoietin (TPO; 100 ng/mL), CD34-derived cells showed an eightfold numerical expansion and a progressive maturation along the megakaryocytic lineage. Megakaryocyte maturation was characterized ultrastructurally by the presence of a demarcation membrane system and phenotypically by a high surface expression of αIIbβ3 integrin. The number of mature megakaryocytes peaked at days 12 to 15 of culture. On the other hand, the number of platelets released in the culture supernatant by CD34-derived megakaryocytes peaked at days 18 to 21, when a high percentage of megakaryocytes showed the characteristic features of apoptosis, as evaluated by electron microscopy, terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP-biotin nick end-labeling technique (TUNEL) and uptake of propidium iodide. In other experiments, primary αIIbβ3+ megakaryocytic cells were directly purified from the bone marrow aspirates of normal donors and seeded in serum-free suspension cultures. In the absence of cytokines, αIIbβ3+ megakaryocytes progressively underwent apoptotic cell death. The addition of TPO but not interleukin-3 or erythropoietin showed some protection of αIIbβ3+ cells from apoptosis at early culture times (days 2 to 4), but it did not show any significant effect at later time points. These findings suggest that the terminal phase of the megakaryocyte life span is characterized by the onset of apoptosis, which can be modulated only to a certain extent by TPO.

Induction of heme-oxygenase 1 requires the p38MAPK and PI3K pathways and suppresses apoptotic cell death following hypericin-mediated photodynamic therapy

APOPTOSIS ◽  
2007 ◽  
Vol 12 (4) ◽  
pp. 731-741 ◽  
Author(s):  
Silvia Kocanova ◽  
Esther Buytaert ◽  
Jean-Yves Matroule ◽  
Jacques Piette ◽  
Jakub Golab ◽  
...  
Keyword(s):  
Cell Death ◽  
Photodynamic Therapy ◽  
Heme Oxygenase ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Heme Oxygenase 1

scholarly journals In Vitro Senescence and Apoptotic Cell Death of Human Megakaryocytes

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2234-2243 ◽  
Author(s):  
Giorgio Zauli ◽  
Marco Vitale ◽  
Elisabetta Falcieri ◽  
Davide Gibellini ◽  
Alessandra Bassini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Apoptotic Cell ◽  
High Surface ◽  
Suspension Cultures ◽  
Apoptotic Cell Death ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Terminal Phase ◽  
Serum Free

To investigate the fate of human megakaryocytes, CD34+ hematopoietic progenitor cells were purified from the peripheral blood or bone marrow of healthy donors and seeded in serum-free chemically defined suspension cultures. In the presence of thrombopoietin (TPO; 100 ng/mL), CD34-derived cells showed an eightfold numerical expansion and a progressive maturation along the megakaryocytic lineage. Megakaryocyte maturation was characterized ultrastructurally by the presence of a demarcation membrane system and phenotypically by a high surface expression of αIIbβ3 integrin. The number of mature megakaryocytes peaked at days 12 to 15 of culture. On the other hand, the number of platelets released in the culture supernatant by CD34-derived megakaryocytes peaked at days 18 to 21, when a high percentage of megakaryocytes showed the characteristic features of apoptosis, as evaluated by electron microscopy, terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP-biotin nick end-labeling technique (TUNEL) and uptake of propidium iodide. In other experiments, primary αIIbβ3+ megakaryocytic cells were directly purified from the bone marrow aspirates of normal donors and seeded in serum-free suspension cultures. In the absence of cytokines, αIIbβ3+ megakaryocytes progressively underwent apoptotic cell death. The addition of TPO but not interleukin-3 or erythropoietin showed some protection of αIIbβ3+ cells from apoptosis at early culture times (days 2 to 4), but it did not show any significant effect at later time points. These findings suggest that the terminal phase of the megakaryocyte life span is characterized by the onset of apoptosis, which can be modulated only to a certain extent by TPO.

scholarly journals Induction of apoptosis by overexpression of the DNA-binding and DNA-PK-activating protein C1D

1999 ◽  
Vol 112 (13) ◽  
pp. 2223-2232
Author(s):  
K. Rothbarth ◽  
E. Spiess ◽  
B. Juodka ◽  
U. Yavuzer ◽  
P. Nehls ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Binding ◽  
Bystander Effect ◽  
Fluorescent Protein ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Apoptotic Cell Death ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Suspension Cells ◽  
Transfected Cells

Apoptosis is induced in various tumor cell lines by vector-dependent overexpression of the conserved gene C1D that encodes a DNA-binding and DNA-PK-activating protein. C1D is physiologically expressed in 50 human tissues tested, which points to its basic cellular function. The expression of this gene must be tightly regulated because elevated levels of C1D protein, e.g. those induced by transient vector-dependent expression, result in apoptotic cell death. Cells transfected with C1D-expressing constructs show terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling of DNA ends. Transfections with constructs in which C1D is expressed in fusion with the (enhanced) green fluorescent protein from A. victoria (EGFP) allow the transfected cells to be identified and the morphological changes induced to be traced. Starting from intense nuclear spots, green fluorescence reflecting C1D expression increases dramatically at 12–24 hours post-transfection. Expression of C1D-EGFP protein is accompanied by morphological changes typical of apoptotic cell death, e.g. cytoplasmic vacuolation, membrane blebbing and nuclear disintegration. Cell shrinkage and detachment from extracellular matrix are observed in monolayer cultures while suspension cells become progressively flattened. The facility to differentiate between transfected and non-transfected cells reveals that non-transfected cells co-cultured with transfected cells also show the morphological changes of apoptosis, which points to a bystander effect. C1D-dependent apoptosis is not induced in cells with non-functional p53. Accordingly, C1D-induced apoptosis is discussed in relation to its potential to activate DNA-PK, which has been considered to act as an upstream activator of p53.

scholarly journals Ischemic Brain Injury is Mediated by the Activation of Poly(ADP-Ribose)Polymerase

1997 ◽  
Vol 17 (11) ◽  
pp. 1143-1151 ◽  
Author(s):  
Matthias Endres ◽  
Zhao-Qi Wang ◽  
Shobu Namura ◽  
Christian Waeber ◽  
Michael A. Moskowitz
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Tissue Injury ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Ischemic Brain Injury ◽  
Cell Nuclei ◽  
Ischemic Brain ◽  
Nad Depletion

Poly(ADP-ribose)polymerase (PARP, EC 2.4.2.30), an abundant nuclear protein activated by DNA nicks, mediates cell death in vitro by nicotinamide adenine dinucleotide (NAD) depletion after exposure to nitric oxide. The authors examined whether genetic deletion of PARP (PARP null mice) or its pharmacologic inhibition by 3-aminobenzamide (3-AB) attenuates tissue injury after transient cerebral ischemia. Twenty-two hours after reperfusion following 2 hours of filamentous middle cerebral artery occlusion, ischemic injury was decreased in PARP−/− and PARP+/− mice compared with PARP+/+ litter mates, and also was attenuated in 129/SV wild-type mice after 3-AB treatment compared with controls. Infarct sparing was accompanied by functional recovery in PARP−/− and 3-AB–treated mice. Increased poly(ADP-ribose) immunostaining observed in ischemic cell nuclei 5 minutes after reperfusion was reduced by 3-AB treatment. Levels of NAD—the substrate of PARP—were reduced 2 hours after reperfusion and were 35% of contralateral levels at 24 hours. The decreases were attenuated in PARP−/− mice and in 3-AB–treated animals. Poly(ADP-ribose)polymerase cleavage by caspase-3 (CPP-32) has been proposed as an important step in apoptotic cell death. Markers of apoptosis, such as oligonucleosomal DNA damage, total DNA fragmentation, and the density of terminal deoxynucleotidyl transferase dUTP nick-end–labelled (TUNEL +) cells, however, did not differ in ischemic brain tissue of PARP−/− mice or in 3-AB–treated animals versus controls, although there were differences in the number of TUNEL-stained cells reflecting the decrease in infarct size. Thus, ischemic brain injury activates PARP and contributes to cell death most likely by NAD depletion and energy failure, although the authors have not excluded a role for PARP in apoptotic cell death at earlier or later stages in ischemic cell death. Inhibitors of PARP activation could provide a potential therapy in acute stroke.

Ischemia-Induced Up-Regulation of Heme Oxygenase-1 Protects From Apoptotic Cell Death and Tissue Necrosis

2008 ◽  
Vol 150 (2) ◽  
pp. 293-303 ◽  
Author(s):  
Yves Harder ◽  
Michaela Amon ◽  
René Schramm ◽  
Martin Rücker ◽  
Claudia Scheuer ◽  
...  
Keyword(s):  
Cell Death ◽  
Heme Oxygenase ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Heme Oxygenase 1 ◽  
Tissue Necrosis

scholarly journals Dual Targeting of the p38 MAPK-HO-1 Axis and cIAP1/XIAP by Demethoxycurcumin Triggers Caspase-Mediated Apoptotic Cell Death in Oral Squamous Cell Carcinoma Cells

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 703 ◽  
Author(s):  
Ming-Hsien Chien ◽  
Wei-En Yang ◽  
Yi-Chieh Yang ◽  
Chia-Chi Ku ◽  
Wei-Jiunn Lee ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Death ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
P38 Mapk ◽  
Squamous Cell ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Heme Oxygenase 1 ◽  
Caspase 8

Demethoxycurcumin (DMC) is a curcumin analogue with better stability and higher aqueous solubility than curcumin after oral ingestion and has the potential to treat diverse cancers, including oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anticancer effects and underlying mechanisms of DMC against OSCC. We found that DMC suppressed cell proliferation via simultaneously inducing G2/M-phase arrest and cell apoptosis. Mechanistic investigations found that the downregulation of cellular IAP 1 (cIAP1)/X-chromosome-linked IAP (XIAP) and upregulation of heme oxygenase-1 (HO-1) were critical for DMC-induced caspase-8/-9/-3 activation and apoptotic cell death. Moreover, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK)1/2 were activated by DMC treatment in OSCC cells, and only the inhibition of p38 MAPK significantly abolished DMC-induced HO-1 expression and caspase-8/-9/-3 activation. The analyses of clinical datasets revealed that patients with head and neck cancers expressing high HO-1 and low cIAP1 had the most favorable prognoses. Furthermore, a combinatorial treatment of DMC with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, significantly enhanced the inhibitory effect of gefitinib on the proliferation of OSCC cells. Overall, the current study supported a role for DCM as part of a therapeutic approach for OSCC through suppressing IAPs and activating the p38-HO-1 axis.

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