scholarly journals Protocatechuic Acid Prevents oxLDL-Induced Apoptosis by Activating JNK/Nrf2 Survival Signals in Macrophages

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Rosaria Varì ◽  
Beatrice Scazzocchio ◽  
Carmela Santangelo ◽  
Carmelina Filesi ◽  
Fabio Galvano ◽  
...  
Keyword(s):  
Target Genes ◽  
Protocatechuic Acid ◽  
Biological Activities ◽  
Redox Homeostasis ◽  
Protective Effects ◽  
Antioxidant Defences ◽  
Antioxidant Power ◽  
Induced Apoptosis ◽  
P53 Target Genes ◽  
Survival Signals

Protocatechuic acid (PCA), one of the main metabolites of complex polyphenols, exerts numerous biological activities including antiapoptotic, anti-inflammatory, and antiatherosclerotic effects. Oxidised LDL have atherogenic properties by damaging arterial wall cells and inducing p53-dependent apoptosis in macrophages. This study was aimed at defining the molecular mechanism responsible for the protective effects of PCA against oxidative and proapoptotic damage exerted by oxLDL in J774 A.1 macrophages. We found that the presence of PCA in cells treated with oxLDL completely inhibited the p53-dependent apoptosis induced by oxLDL. PCA decreased oxLDL-induced ROS overproduction and in particular prevented the early increase of ROS. This decrease seemed to be the main signal responsible for maintaining the intracellular redox homeostasis hindering the activation of p53 induced by ROS, p38MAPK, and PKCδ. Consequently the overexpression of the proapoptotic p53-target genes such as p66Shc protein did not occur. Finally, we demonstrated that PCA induced the activation of JNK, which, in turn, determined the increase of nuclear Nrf2, leading to inhibition of the early ROS overproduction. We concluded that the antiapoptotic mechanism of PCA was most likely related to the activation of the JNK-mediated survival signals that strengthen the cellular antioxidant defences rather than to the PCA antioxidant power.

Tauroursodeoxycholate protects from glycochenodeoxycholate-induced gene expression changes in perfused rat liver

2019 ◽  
Vol 400 (12) ◽  
pp. 1551-1565
Author(s):  
Martha Paluschinski ◽  
Mirco Castoldi ◽  
David Schöler ◽  
Nils Bardeck ◽  
Jessica Oenarto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rat Liver ◽  
Target Genes ◽  
Quantitative Polymerase Chain Reaction ◽  
Gene Array ◽  
Surrogate Marker ◽  
Rat Hepatocytes ◽  
Protective Effects ◽  
Induced Apoptosis ◽  
P53 Target Genes

Abstract Tauroursodeoxycholate (TUDC) is well known to protect against glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes. In the present study, we analyzed whether TUDC also exerts protective effects by modulating GCDC-induced gene expression changes. For this, gene array-based transcriptome analysis and quantitative polymerase chain reaction (qPCR) were performed on RNA isolated from rat livers perfused with GCDC, TUDC or a combination of both (each 20 μm for 2 h). GCDC led to a significant increase of lactate dehydrogenase (LDH) into the effluent perfusate, which was prevented by TUDC. GCDC, TUDC and co-perfusion induced distinct gene expression changes. While GCDC upregulated the expression of several pro-inflammatory genes, co-perfusion with TUDC increased the expression of pro-proliferative and anti-apoptotic p53 target genes. In line with this, levels of serine20-phosphorylated p53 and of its target gene p21 were elevated by GCDC in a TUDC-sensitive way. GCDC upregulated the oxidative stress surrogate marker 8OH(d)G and the pro-apoptotic microRNAs miR-15b/16 and these effects were prevented by TUDC. The upregulation of miR-15b and miR-16 in GCDC-perfused livers was accompanied by a downregulation of several potential miR-15b and miR-16 target genes. The present study identified changes in the transcriptome of the rat liver which suggest, that TUDC is hepatoprotective by counteracting GCDC-induced gene expression changes.

scholarly journals Strigolactone GR24 upregulates Nrf2 target genes and may protect against oxidative stress in skeletal muscle

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1459
Author(s):  
Shalem Raju Modi ◽  
Tarja Kokkola
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Skeletal Muscle ◽  
Transcription Factor ◽  
Stress Responses ◽  
Mycorrhizal Fungi ◽  
Target Genes ◽  
Redox Homeostasis ◽  
Antioxidant Defences ◽  
Microarray Gene Expression

GR24 is a synthetic strigolactone analog, demonstrated to regulate the development of plants and arbuscular mycorrhizal fungi. GR24 possesses anti-cancer and anti-apoptotic properties, enhances insulin sensitivity and mitochondrial biogenesis in skeletal myotubes, inhibits adipogenesis, decreases inflammation in adipocytes and macrophages and downregulates the expression of hepatic gluconeogenic enzymes. Transcription factor Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) is a master regulator of antioxidant response, regulating a multitude of genes involved in cellular stress responses and anti-inflammatory pathways, thus maintaining cellular redox homeostasis. Nrf2 activation reduces the deleterious effects of mitochondrial toxins and has multiple roles in promoting mitochondrial function and dynamics. We studied the role of GR24 on gene expression in rat L6 skeletal muscle cells which were differentiated into myotubes. The myotubes were treated with GR24 and analyzed by microarray gene expression profiling. GR24 upregulated the cytoprotective transcription factor Nrf2 and its target genes, activating antioxidant defences, suggesting that GR24 may protect skeletal muscle from the toxic effects of oxidative stress.

scholarly journals Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

Oncogene ◽  
2005 ◽  
Vol 24 (28) ◽  
pp. 4559-4571 ◽  
Author(s):  
Eva Ceballos ◽  
Maria J Muñoz-Alonso ◽  
Bernd Berwanger ◽  
Juan C Acosta ◽  
Rafael Hernández ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Target Genes ◽  
Inhibitory Effect ◽  
Leukemia Cells ◽  
Induced Apoptosis ◽  
P53 Target Genes

scholarly journals Malus baccata var. gracilis and Malus toringoides Bark Polyphenol Studies and Antioxidant, Antimicrobial and Anticancer Activities

Processes ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 283 ◽  
Author(s):  
Hosam O. Elansary ◽  
Agnieszka Szopa ◽  
Paweł Kubica ◽  
Diaa O. El-Ansary ◽  
Halina Ekiert ◽  
...  
Keyword(s):  
High Performance ◽  
Protocatechuic Acid ◽  
Antioxidant Activities ◽  
Biological Activities ◽  
Dry Weight ◽  
Jurkat Cells ◽  
Aspergillus Ochraceus ◽  
Array Detector ◽  
Anticancer Activities ◽  
Antioxidant Power

Exploring new sources of polyphenols with biological activities that work against human diseases is the target of natural product studies. This study determined the polyphenol composition of the bark of Malus species M. baccata var. gracilis (Rehder) T.C.Ku and M. toringoides (Rehder) Hughes, using high-performance liquid chromatography with a diode-array detector (HPLC-DAD) analysis. The antiproliferative, cytotoxic, antioxidant and antimicrobial applications of these extracts, as well as the identified phenol, were studied. The HPLC-DAD analysis confirmed three polyphenols in the extracts out of the 21 screened compounds: protocatechuic acid, gallic acid, and catechin. The major constituents in M. baccata and M. toringoides were protocatechuic acid, at 3.16 and 7.15 mg 100 g−1 dry weight (DW), respectively, and catechin, at 5.55 and 6.80 mg 100 g−1 DW, respectively. M. baccata and M. toringoides bark extracts showed antioxidant activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH), β-carotene bleaching, and ferric-reducing antioxidant power (FRAP) assays, which were attributed to the dominance of protocatechuic acid. The highest antiproliferative and cytotoxic effects were against Jurkat cells. Against MCF-7 and Hela cells, there was necrotic cell accumulation in the early apoptotic as well as the late apoptotic phase. The bark extracts showed noticeable antibacterial effects against Listeria monocytogenes, Bacillus cereus, and Escherichia coli. Protocatechuic acid showed comparable results to bark extracts. There were antifungal effects against Aspergillus ochraceus, A. niger, and Candida albicans, and the activities were higher than the commercial reagent. M. baccata and M. toringoides could be considered as a new source of phenolic acids, including protocatechuic acid with anticancer, antibacterial antifungal, and antioxidant-promising effects.

scholarly journals Induction of p53-Dependent Apoptosis by Prostaglandin A2

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 492 ◽  
Author(s):  
Su-Been Lee ◽  
Sangsun Lee ◽  
Ji-Young Park ◽  
Sun-Young Lee ◽  
Ho-Shik Kim
Keyword(s):  
Target Genes ◽  
P53 Gene ◽  
Histone H2a ◽  
Molecule Inhibitor ◽  
Induction Of Apoptosis ◽  
Prostaglandin A2 ◽  
Induced Apoptosis ◽  
Inhibitor Of Protein Synthesis ◽  
P53 Target Genes ◽  
Hct116 Cells

Prostaglandin (PG) A2, one of cyclopentenone PGs, is known to induce activation of apoptosis in various cancer cells. Although PGA2 has been reported to cause activation of apoptosis by altering the expression of apoptosis-related genes, the role of p53, one of the most critical pro-apoptotic genes, on PGA2-induced apoptosis has not been clarified yet. To address this issue, we compared the apoptosis in HCT116 p53 null cells (HCT116 p53-/-) to that in HCT116 cells containing the wild type p53 gene. Cell death induced by PGA2 was associated with phosphorylation of histone H2A variant H2AX (H2AX), activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase 1 in HCT116 cells. Induction of apoptosis in PGA2-treated cells was almost completely prevented by pretreatment with a pan-caspase inhibitor, z-VAD-Fmk, or an inhibitor of protein synthesis, cycloheximide. While PGA2 induced apoptosis in HCT116 cells, phosphorylation of p53 and transcriptional induction of p53-target genes such as p21WAF1, PUMA, BAX, NOXA, and DR5 occurred. Besides, pretreatment of pifithrin-α (PFT-α), a chemical inhibitor of p53’s transcriptional activity, interfered with the induction of apoptosis in PGA2-treated HCT116 cells. Pretreatment of NU7441, a small molecule inhibitor of DNA-activated protein kinase (DNA-PK) suppressed PGA2-induced phosphorylation of p53 and apoptosis as well. Moreover, among target genes of p53, knockdown of DR5 expression by RNA interference, suppressed PGA2-induced apoptosis. In the meanwhile, in HCT116 p53-/- cells, PGA2 induced apoptosis in delayed time points and with less potency. Delayed apoptosis by PGA2 in HCT116 p53-/- cells was also associated with phosphorylation of H2AX but was not inhibited by either PFT-α or NU7441. Collectively, these results suggest the following. PGA2 may induce p53-dependent apoptosis in which DNA-PK activates p53, and DR5, a transcriptional target of p53, plays a pivotal role in HCT116 cells. In contrast to apoptosis in HCT116 cells, PGA2 may induce apoptosis in a fashion of less potency, which is independent of p53 and DNA-PK in HCT116 p53-/- cells

scholarly journals Strigolactone GR24 upregulates target genes of the cytoprotective transcription factor Nrf2 in skeletal muscle

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1459
Author(s):  
Shalem Raju Modi ◽  
Tarja Kokkola
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Transcription Factor ◽  
Stress Responses ◽  
Mycorrhizal Fungi ◽  
Target Genes ◽  
Redox Homeostasis ◽  
Arbuscular Mycorrhizal ◽  
Antioxidant Defences ◽  
Microarray Gene Expression

GR24 is a synthetic strigolactone analog, demonstrated to regulate the development of plants and arbuscular mycorrhizal fungi. GR24 possesses anti-cancer and anti-apoptotic properties, enhances insulin sensitivity and mitochondrial biogenesis in skeletal myotubes, inhibits adipogenesis, decreases inflammation in adipocytes and macrophages and downregulates the expression of hepatic gluconeogenic enzymes. Transcription factor Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) is a master regulator of antioxidant response, regulating a multitude of genes involved in cellular stress responses and anti-inflammatory pathways, thus maintaining cellular redox homeostasis. Nrf2 activation reduces the deleterious effects of mitochondrial toxins and has multiple roles in promoting mitochondrial function and dynamics. We studied the role of GR24 on gene expression in rat L6 skeletal muscle cells which were differentiated into myotubes. The myotubes were treated with GR24 and analyzed by microarray gene expression profiling. GR24 upregulated the cytoprotective transcription factor Nrf2 and its target genes, activating antioxidant defences, suggesting that GR24 may protect skeletal muscle from the toxic effects of oxidative stress.

scholarly journals The Protective Effects of Isoliquiritigenin and Glycyrrhetinic Acid against Triptolide-Induced Oxidative Stress in HepG2 Cells Involve Nrf2 Activation

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Ling-Juan Cao ◽  
Huan-De Li ◽  
Miao Yan ◽  
Zhi-Hua Li ◽  
Hui Gong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Biological Activities ◽  
Antioxidant Response ◽  
Current Data ◽  
Glycyrrhetinic Acid ◽  
Protective Effects ◽  
Nrf2 Activation ◽  
Wide Range

Triptolide (TP), an active ingredient ofTripterygium wilfordiiHook f., possesses a wide range of biological activities. Oxidative stress likely plays a role in TP-induced hepatotoxicity. Isoliquiritigenin (ISL) and glycyrrhetinic acid (GA) are potent hepatoprotection agents. The aim of the present study was to investigate whether Nrf2 pathway is associated with the protective effects of ISL and GA against TP-induced oxidative stress or not. HepG2 cells were treated with TP (50 nM) for 24 h after pretreatment with ISL and GA (5, 10, and 20 μM) for 12 h and 24 h, respectively. The results demonstrated that TP treatment significantly increased ROS levels and decreased GSH levels. Both ISL and GA pretreatment decreased ROS and meanwhile enhanced intracellular GSH content. Additionally, TP treatment obviously decreased the protein expression of Nrf2 and its target genes including HO-1 and MRP2 except NQO1. Moreover, both ISL and GA displayed activities as inducers of Nrf2 and increased the expression of HO-1, NQO1, and MRP2. Taken together the current data confirmed that ISL and GA could activate the Nrf2 antioxidant response in HepG2 cells, increasing the expression of its target genes which may be partly associated with their protective effects in TP-induced oxidative stress.

scholarly journals Increased p53 Acetylation By SIRT1 Inhibition Is Required for Optimal Activation of p53 Activity and Significantly Enhances the Ability of HDM2 Inhibitors to Target CML LSC

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4521-4521
Author(s):  
Yann Pierre Kevin Duchartre ◽  
Ling Li ◽  
Tinisha McDonald ◽  
YinWei Ho ◽  
Yao-Te Hsieh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Myelogenous Leukemia ◽  
Growth And Survival ◽  
Cycle Arrest ◽  
Cd34 Cells ◽  
Induced Apoptosis ◽  
P53 Target Genes

Abstract BCR-ABL tyrosine kinase inhibitors (TKI) are effective in inducing remissions and prolonging survival in chronic myelogenous leukemia (CML) patients, but do not eliminate leukemia stem cells (LSCs) that are responsible for establishment, maintenance and recurrence of the disease. We have shown that the NAD-dependent SIRT1 deacetylase is overexpressed in CML LSC (Li et al., Cancer Cell, 21:266, 2013). SIRT1 participates in the maintenance, growth and treatment resistance of CML LSC by deacetylation and inhibition of the p53 pathway that regulates cell cycle and apoptosis. Inhibition of SIRT1 using RNAi and the small molecule SIRT1 inhibitor Tenovin-6 (TV-6) inhibits growth and survival of CML LSC by itself and results in enhanced targeting of LSC in combination with TKI treatment. The effects of SIRT1 inhibition are related at least in part to enhanced acetylation of the p53 protein associated with enhanced p53 transcriptional activity. Here we examined the efficacy of an alternative strategy to activate p53, using inhibition of the p53 regulatory protein HDM2, in activating p53 transcriptional activity and inhibiting CML LSC growth and survival compared to SIRT1 inhibition. Nutlin-3 (Nut-3) is a small molecule HDM2 inhibitor that disrupts the p53-HDM2 interaction which has proceeded to clinical trials. Treatment of CML CP CD34+ cells with Nut-3 (1, 2, 5µM) increased expression of the p53 target genes p21 (associated with cell cycle arrest) and NOXA and PIG3 (associated with apoptosis), inhibited proliferation and induced apoptosis to a significantly lesser extent than TV-6 (1, 2 µM) (Nut 5 µM vs TV 2 µM ; p<0.0003) . However, Nutlin-3 enhanced p53 target gene expression and inhibited proliferation and survival of normal CD34+ cells to a similar extent as CML CD34+ cells. This was in contrast to TV-6 which although inhibiting proliferation of both CML and normal CD34+ cells, selectively induced apoptosis in CML compared to normal CD34+ cells. Treatment of CML CD34+ cells with the combination of Nut-3 (2, 5µM) and TV-6 (1µM) significantly increased the expression of p53 target genes (p21, PIG3, NOXA), and enhanced apoptosis of CML CD34+ cells compared to Nut-3 or TV-6 alone. 32D-BCR-ABL cells transduced with lentivirus vectors expressing p53 shRNA demonstrated significantly reduced apoptosis following treatment with the combination of Nut-3 and TV-6 compared to cells expressing control shRNA, indicating that the effects of this treatment are p53 dependent. Our results indicate that enhancement of p53 acetylation by SIRT1 inhibition is required for optimal activation of p53 transcriptional activity and induction of apoptosis in CML LSC. These results further support SIRT1 as a valid therapeutic target in CML, and suggest that addition of SIRT1 inhibitors may significantly enhance the ability of HDM2 inhibitors to eliminate CML LSC. Table 1 : Effects of Nutlin-3, Tenovin-6 or combination on the expression of apoptosis/cell cycle arrest related-genes, apoptosis and proliferation in cord blood and CML CD34+ cells. Figure 1 Figure 1. SEM values ; significance, compared to controls: ***p<0.001. ****p<0.0001. Key words : Chronic Myelogenous Leukemia (CML), hematopoietic stem cells, p53, SIRT1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Myricetin Suppresses the Propagation of Hepatocellular Carcinoma via Down-Regulating Expression of YAP

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 358 ◽  
Author(s):  
Minjing Li ◽  
Jinliang Chen ◽  
Xiaofei Yu ◽  
Sen Xu ◽  
Defang Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Target Genes ◽  
Protective Effects ◽  
Kinase Activation ◽  
Anti Cancer ◽  
Subsequent Degradation ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Myricetin is a naturally occurring flavonoid with protective effects against a variety of cancers. However, the molecular mechanism of myricetin against hepatocellular carcinoma (HCC) has still not been fully elucidated. Previous studies have indicated that YAP is essential for cancer initiation and progression. However, whether YAP contributes to the anti-cancer effects of myricetin remains unclear. Herein, we aimed to investigate the effect of myricetin on HCC, and identify the underlying mechanisms. We report that myricetin induced apoptosis and proliferation inhibition in HepG2 and Huh-7 cells. Myricetin inhibited expression of YAP by promoting its phosphorylation and subsequent degradation. Myricetin inhibited YAP expression by stimulating kinase activation of LATS1/2. Knockdown expression of LATS1/2 by shRNA attenuated myricetin-induced phosphorylation and degradation of YAP. Furthermore, myricetin sensitized HCC cells to cisplatin treatment through inhibiting YAP and its target genes, both in vitro and in vivo. The identification of the LATS1/2-YAP pathway as a target of myricetin may help with the design of novel strategies for human HCC prevention and therapy.

381: Promoter Hypermethylation Profile of Kidney Cancer with New Pro-Apoptotic P53 Target Genes and Possible Clinical Implications

2006 ◽  
Vol 175 (4S) ◽  
pp. 125-125
Author(s):  
Frank Christoph ◽  
Steffen Weikert ◽  
Carsten Kempkensteffen ◽  
Martin Schostak ◽  
Hans Krause ◽  
...  
Keyword(s):  
Kidney Cancer ◽  
Target Genes ◽  
Promoter Hypermethylation ◽  
Clinical Implications ◽  
P53 Target Genes
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