Andrographolide Induces Apoptosis in Gastric Cancer Cells through Reactivation of p53 and Inhibition of Mdm-2

Doklady Biochemistry and Biophysics - Andrographolide is a labdane diterpenoid isolated from Andrographis paniculata. The plant extract and andrographolide has long been used in traditional...     

The Effect of Ginger (Zingiber officinale) on Platelet Aggregation: A Systematic Literature Review

BackgroundThe potential effect of ginger on platelet aggregation is a widely-cited concern both within the published literature and to clinicians; however, there has been no systematic appraisal of the evidence to date.MethodsUsing the PRISMA guidelines, we systematically reviewed the results of clinical and observational trials regarding the effect of ginger on platelet aggregation in adults compared to either placebo or baseline data. Studies included in this review stipulated the independent variable was a ginger preparation or isolated ginger compound, and used measures of platelet aggregation as the primary outcome.ResultsTen studies were included, comprising eight clinical trials and two observational studies. Of the eight clinical trials, four reported that ginger reduced platelet aggregation, while the remaining four reported no effect. The two observational studies also reported mixed findings.DiscussionMany of the studies appraised for this review had moderate risks of bias. Methodology varied considerably between studies, notably the timeframe studied, dose of ginger used, and the characteristics of subjects recruited (e.g. healthy vs. patients with chronic diseases).ConclusionThe evidence that ginger affects platelet aggregation and coagulation is equivocal and further study is needed to definitively address this question.     

蔗糖和多效唑对试管生姜形成的影响

用不同浓度的蔗糖、NAA、Ca3(PO4)2、多效唑(Pac)和光照条件对江西兴国九山生姜(ZingiberofficinaleRosc.cv.Jiushan)进行试管姜的诱导,成功诱导出试管姜。结果表明,诱导试管姜的最佳培养基为:MS 6-BA0.2mgL-1 NAA0.5mgL-1 Ca3(PO4)22.5mgL-1 Pac2.5mgL-1 蔗糖8%;适宜浓度的Pac、Ca3(PO4)2、蔗糖有利于试管姜诱导;NAA和6-BA对试管姜的诱导不起促进作用;延长光照时间有利于试管姜膨大。     

Nitrogen nutrition of ginger (Zingiber officinale)

Summary Two fertilizer experiments were conducted in the field at Beerwah, South-East Queensland. In the first experiment leaf nitrogen concentrations, and the yield of ginger shoots and rhizomes at early and late harvests increased both with the total amount of nitrogen applied up to the highest level studied (336 kg N/ha as ammonium nitrate) and with the number of applications making up the total. At all levels of nitrogen application the apparent recovery of fertilizer nitrogen increased in the order 1 application <2 applications <4 applications. At 33.6 kg N/ha there appeared to be no advantage in dividing the total N applied into more than 4 applications but the data suggested higher recoveries of nitrogen with 8 applications at 112 kg N/ha and 336 kg N/ha. In the second experiment, ammonium nitrate, urea, and ammonium sulphate were found to be equally effective as nitrogen fertilizers for ginger when applied at equal rates of nitrogen per hectare. However, in terms of cost effectiveness they rated in the order urea > ammonium nitrate > ammonium sulphate.All three nitrogen sources acidified the soil, the decrease in soil pH during the growing season increasing with increasing rate of application. In Experiment 1 split applications, which increased the recovery of applied nitrogen in the crop, also increased the extent of acidification. In Experiment 2 ammonium sulphate tended to be more strongly acidifying than the other fertilizers but the difference was statistically significant only at the highest rate of nitrogen application. Because of the strong effects of nitrogen supply on both yield and soil pH, the highest yields were associated with end-of-season pH values below 5.0.     

罗平产生姜的化学成分

从生姜(Zingiber officinaleRosc.)的根茎中分离得一个骨架新颖的天然产物,经波谱鉴定为一个新的生姜内酯(1),同时分离得到7个已知化合物,分别为6-姜烯酚(2),1-去氢姜二酮(3),6-姜磺酸(4),3,5-二酮-1,7-二-{(3-甲氧基-4-羟基)-苯基}-庚烷(5),姜酮A(6),β-谷甾醇(7)和豆甾醇(8)。     

Transient Transfection of a Wild-Type p53 Gene Triggers Resveratrol-Induced Apoptosis in Cancer Cells

Resveratrol is a promising chemopreventive agent that mediates many cellular targets involved in cancer signaling pathways. p53 has been suggested to play a role in the anticancer properties of resveratrol. We investigated resveratrol-induced cytotoxicity in H1299 cells, which are non-small lung cancer cells that have a partial deletion of the gene that encodes the p53 protein. The results for H1299 cells were compared with those for three cell lines that constitutively express wild-type p53: breast cancer MCF-7, adenocarcinomic alveolar basal epithelia A549 and non-small lung cancer H460. Cell viability assays revealed that resveratrol reduced the viability of all four of these cell lines in a dose- and time-dependent manner. MCF-7, A549 and H460 cells were more sensitive to resveratrol than were H1299 cells when exposed to the drug for 24 h at concentrations above 100 µM. Resveratrol also increased the p53 protein levels in MCF-7 cells without altering the p53 mRNA levels, suggesting a post-translational modulation of the protein. The resveratrol-induced cytotoxicity in these cells was partially mediated by p53 and involved the activation of caspases 9 and 7 and the cleavage of PARP. In H1299 cells, resveratrol-induced cytotoxicity was less pronounced and (in contrast to MCF-7 cells) cell death was not accompanied by caspase activation. These findings are consistent with the observation that MCF-7 cells were positively labeled by TUNEL following exposure to 100 µM resveratrol whereas H1299 cells under similar conditions were not labeled by TUNEL. The transient transfection of a wild-type p53-GFP gene caused H1299 cells to become more responsive to the pro-apoptotic properties of resveratrol, similarly to findings in the p53-positive MCF-7 cells. Our results suggest a possible therapeutic strategy based on the use of resveratrol for the treatment of tumors that are typically unresponsive to conventional therapies because of the loss of normal p53 function.     

Diarylheptanoids from the rhizomes of Zingiber officinale

Seven new diarylheptanoids, i.e., (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane, (3R,5S)-3-acetoxy-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane, (3R,5S)-3,5-dihydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane, (5S)-5-acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptan-3-one, 5-hydroxy-1-(3,4-dihydroxy-5-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptan-3-one, 5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3,4-dihydroxy-5-methoxy-phenyl)heptan-3-one and 1,5-epoxy-3-hydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane were isolated from the rhizomes of Chinese ginger (Zingiber officinale Roscoe), along with 25 known compounds, i.e., 8 diarylheptanoids, 14 gingerol analogs, a diterpene and 2 steroids. Their structures were elucidated by spectroscopic and chemical methods.     

Costunolide Induces Apoptosis through Generation of ROS and Activation of P53 in Human Esophageal Cancer Eca‐109 Cells

Costunolide is a sesquiterpene lactone, which possesses potent anti‐cancer properties. However, there is little report about its effects on esophageal cancer. In our study, we investigated the effects of costunolide on the cell viability, cell cycle, and apoptosis in human esophageal cancer Eca‐109 cells. It was found that costunolide inhibited the growth of Eca‐109 cells in a dose‐dependent manner, which was associated with the loss of mitochondrial membrane potential (Δψ_m) and the production of ROS. Costunolide induced apoptosis of Eca‐109 cells as well as cell cycle arrest in G1/S phase by upregulation of P53 and P21. Costunolide triggered apoptosis in esophageal cancer cells via the upregulation of Bax, downregulation of Bcl‐2, and significant activation of caspase‐3 and poly ADP‐ribose polymerase. These effects were markedly abrogated when cells were pretreated with N‐acetylcysteine, a specific reactive oxygen specie inhibitor. These results suggest that costunolide is a potential candidate for the treatment of esophageal cancer.     

Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression

Phloridzin (phlorizin or phloretin 2′-O-glucoside) is known for blocking intestinal glucose absorption. We have investigated the anticarcinogenic effect of phloridzin and its novel derivatives using human cancer cell lines. We have synthesised novel acylated derivatives of phloridzin with six different long chain fatty acids by regioselective enzymatic acylation using Candida Antarctica lipase B. The antiproliferative effects of the new compounds were investigated in comparison with the parent compounds, phloridzin, aglycone phloretin, the six free fatty acids and chemotherapeutic drugs (sorafenib, doxorubicin and daunorubicin) using human hepatocellular carcinoma HepG2 cells, human breast adenocarcinoma MDA-MB-231 cells and acute monocytic leukemia THP-1 cells along with normal human and rat hepatocytes. The fatty acid esters of phloridzin inhibited significantly the growth of the two carcinoma and leukemia cells while similar treatment doses were not toxic to normal human or rat hepatocytes. The antiproliferative potency of fatty esters of phloridzin was comparable to the potency of the chemotherapeutic drugs. The fatty acid esters of phloridzin inhibited DNA topoisomerases IIα activity that might induce G₀/G₁ phase arrest, induced apoptosis via activation of caspase-3, and decreased ATP level and mitochondrial membrane potential in HepG2 cells. Based on the high selectivity on cancer cells, decosahexaenoic acid (DHA) ester of phloridzin was selected for gene expression analysis using RT²PCR human cancer drug target array. Antiproliferative effect of DHA ester of phloridzin could be related to the down regulation of anti-apoptotic gene (BCL2), growth factor receptors (EBFR family, IGF1R/IGF2, PDGFR) and its downstream signalling partners (PI3k/AKT/mTOR, Ras/Raf/MAPK), cell cycle machinery (CDKs, TERT, TOP2A, TOP2B) as well as epigenetics regulators (HDACs). These results suggest that fatty esters of phloridzin have potential chemotherapeutic effects mediated through the attenuated expression of several key proteins involved in cell cycle regulation, DNA topoisomerases IIα activity and epigenetic mechanisms followed by cell cycle arrest and apoptosis.     

Repeated Oral Administration of a Squeezed Ginger (Zingiber officinale) Extract Augmented the Serum Corticosterone Level and Had Anti-Inflammatory Properties

We investigated the ability of a ginger extract to induce an immune response in RAW 264 cells and after a repeated oral administration to mice. The squeezed ginger extract augmented the production of tumor necrosis factor-α, interleukin-6, and monocyte chemotactic protein-1 when added to RAW 264 cells. This extract was collected as its ethanol-insoluble fraction. The oral administration of the squeezed ginger extract or its ethanol-insoluble fraction once or twice to mice also augmented the tumor necrosis factor-α production in peritoneal cells; however, its long-term administration had the opposite effect. The serum corticosterone level had increased after orally administering the squeezed ginger extract and was maintained during the administration period. Oral administration of the squeezed ginger extract also inhibited arachidonic acid-induced ear edema, but its repeated administration was needed to achieve an anti-inflammatory effect. These results suggest that the repeated administration of the aqueous constituents of ginger augmented the serum corticosterone level and that this may have gradually induced anti-inflammatory activity.     

固相萃取-HPLC法测定生姜不同品种和器官中姜黄素含量

用固定萃取-HPLC法研究了生姜不同品种、同一品种不同产地及不同器官中姜黄素含量.生姜干粉用4倍量75%乙醇提取2次,提取液过C18固相萃取柱,80%的乙醇洗脱,HPLC测定姜黄素含量.13个不同品种或产地的生姜中,山东、潮州和湖北产的山东大肉姜姜黄素含量分别为0.76、1.11和0.75 mg/100 g干重,广西白肉姜、云南黄姜、潮州南姜、安徽菜姜、四川姜、四川小黄姜、梅县水姜、清远火姜、广州疏轮大肉姜和有机栽培的广州大肉姜的姜黄素含量分别为1.5450、1.08、0.84、0.92、1.16、1.00、2.63、2.86、2.20和5.01 mg/100 g干重.有机栽培的广州大肉姜的姜肉、姜皮和地上部茎叶中姜黄素含量分别为4.49、1.2和0.41 mg/100 g干重.但生姜中姜黄素含量远低于贵州产姜黄的含量(2857 mg/100 g干重).结果表明,生姜中姜黄素含量主要取决于品种,栽培地理位置对其有较少的影响.有机栽培可大大提高姜黄素含量.     

Quercetin Suppresses Twist to Induce Apoptosis in MCF-7 Breast Cancer Cells

Quercetin is a dietary flavonoid which exerts anti-oxidant, anti-inflammatory and anti-cancer properties. In this study, we investigated the anti-proliferative effect of quercetin in two breast cancer cell lines (MCF-7 and MDA-MB-231), which differed in hormone receptor. IC₅₀ value (37μM) of quercetin showed significant cytotoxicity in MCF-7 cells, which was not observed in MDA-MB-231 cells even at 100μM of quercetin treatment. To study the response of cancer cells to quercetin, with respect to different hormone receptors, both the cell lines were treated with a fixed concentration (40μM) of quercetin. MCF-7 cells on quercetin treatment showed more apoptotic cells with G1 phase arrest. In addition, quercetin effectively suppressed the expression of CyclinD1, p21, Twist and phospho p38MAPK, which was not observed in MDA-MB-231 cells. To analyse the molecular mechanism of quercetin in exerting an apoptotic effect in MCF-7 cells, Twist was over-expressed and the molecular changes were observed after quercetin administration. Quercetin effectively regulated the expression of Twist, in turn p16 and p21 which induced apoptosis in MCF-7 cells. In conclusion, quercetin induces apoptosis in breast cancer cells through suppression of Twist via p38MAPK pathway.     

Brefeldin A Is a Potent Inducer of Apoptosis in Human Cancer Cells Independently of p53

Brefeldin A (BFA) is a natural product that affects the structure and function of the Golgi apparatus and is in development for cancer chemotherapy. We observed that a wide range of cancer cells could undergo DNA fragmentation associated with apoptosis after BFA treatment. This DNA fragmentation was induced within 15 h in HL60 leukemia cells and after 48 h in K562 leukemia and HT-29 colon carcinoma cells with BFA concentrations as low as 0.1 μM.The DNA fragmentation had the typical internucleosomal pattern in HL60 and HT-29 cells. Apoptotic cells were also detected by microscopy. BFA-induced apoptosis is p53-independent as HL60 and K562 cells are p53 null and HT-29 are p53 mutant cells. BFA could potentiate UCN-01 and staurosporine-induced DNA fragmentation in HL60 cells. Cyclin B1/Cdc2 kinase activity decreased after BFA treatment in HL60 cells, indicating that BFA-induced DNA fragmentation was independent of a cyclin B1/Cdc2 kinase upregulation pathway. Cycloheximide could not prevent BFA-induced DNA fragmentation in HL60 cells, suggesting that protein synthesis is not needed for HL60 cells to undergo apoptosis. On the contrary, cycloheximide blocked BFA-induced DNA fragmentation in HT-29 cells, indicating that apoptosis in HT-29 cells requires macromolecular synthesis. Cell-free system experiments suggested that cytosolic proteins play an important role in triggering DNA fragmentation during apoptosis induced by BFA. Our results show that transduction signaling pathways play central roles in apoptotic regulation.     

ATR Activation Necessary But Not Sufficient for p53 Induction and Apoptosis in Hydroxyurea-Hypersensitive Myeloid Leukemia Cells

Hydroxyurea (HU) is a competitive inhibitor of ribonucleotide reductase that is used for the treatment of myeloproliferative disorders. HU inhibits DNA replication and induces apoptosis in a cell type-dependent manner, yet the relevant pathways that mediate apoptosis in response to this agent are not well characterized. In this study, we employed the human myeloid leukemia 1 (ML-1) cell line as a model to investigate the mechanisms of HU-induced apoptosis. Exposure of ML-1 cells to HU caused rapid cell death that was accompanied by hallmark features of apoptosis, including membrane blebbing, phosphatidylserine translocation, and caspase activation. HU-induced apoptosis required new protein synthesis, was induced by HU exposures as short as 15 min, and correlated with the accumulation of p53 and induction of the p53 target gene PUMA. p53 induction in ML-1 cells was ATR dependent and downregulation of p53 through RNAi delayed HU-induced apoptosis. HU did not induce p53 or induce apoptosis in Molt-3 leukemia cells, even though exposure to HU induced a comparable level of DNA damage and robustly activated the ATR pathway. The microtubule inhibitor nocodazole suppressed HU-induced p53 accumulation in ML-1 cells suggesting that a microtubule-dependent event contributes to p53 induction and apoptosis in this cell line. Our findings outline an HU-induced cell death pathway and suggest that activation of the ATR is necessary, but not sufficient, for stabilization of p53 in response to DNA replication stress.     

Advanced Glycation End Products Induce Human Corneal Epithelial Cells Apoptosis through Generation of Reactive Oxygen Species and Activation of JNK and p38 MAPK Pathways

Advanced Glycation End Products (AGEs) has been implicated in the progression of diabetic keratopathy. However, details regarding their function are not well understood. In the present study, we investigated the effects of intracellular reactive oxygen species (ROS) and JNK, p38 MAPK on AGE-modified bovine serum albumin (BSA) induced Human telomerase-immortalized corneal epithelial cells (HUCLs) apoptosis. We found that AGE-BSA induced HUCLs apoptosis and increased Bax protein expression, decreased Bcl-2 protein expression. AGE-BSA also induced the expression of receptor for advanced glycation end product (RAGE). AGE-BSA-RAGE interaction induced intracellular ROS generation through activated NADPH oxidase and increased the phosphorylation of p47phox. AGE-BSA induced HUCLs apoptosis was inhibited by pretreatment with NADPH oxidase inhibitors, ROS quencher N-acetylcysteine (NAC) or neutralizing anti-RAGE antibodies. We also found that AGE-BSA induced JNK and p38 MAPK phosphorylation. JNK and p38 MAPK inhibitor effectively blocked AGE-BSA-induced HUCLs apoptosis. In addition, NAC completely blocked phosphorylation of JNK and p38 MAPK induced by AGE-BSA. Our results indicate that AGE-BSA induced HUCLs apoptosis through generation of intracellular ROS and activation of JNK and p38 MAPK pathways.