Çevik, D. | Kan, Y. | Kırmızıbekmez, H.

Article | 2019 | Phytomedicine58

Background: Glycyrrhiza (licorice) species are rich in bioactive secondary metabolites and their roots are used traditionally for the treatment of several diseases. In recent years, secondary metabolites of licorice are gaining popularity, especially due to their significant cytotoxic and antitumor effects. However, Glycyrrhiza iconica, an endemic species to Turkey, was not investigated in terms of its anticancer secondary metabolites previously. Purpose: This study aimed to isolate the cytotoxic compounds from G. iconica through bioactivity-guided fractionation and to elucidate mechanisms of action of the most potent compounds. Met . . .hods: Total MeOH extract and CHCl 3 , EtOAc, n-buOH and rH 2 O subextracts were prepared from G. iconica roots. Sequential chromatographic techniques were conducted for the isolation studies. The chemical structures of the isolates were established based on NMR and HR-MS analysis. Sulforhodamine B assay was used to evaluate the cytotoxic activity of extracts, main fractions as well as isolates against hepatocellular (Huh7), breast (MCF7) and colorectal (HCT116) cancer cell lines. The mechanisms underlying the cytotoxicity of the most active compounds in Huh7 cells were elucidated by using Hoechst staining, Fluorescence-activated cell sorting and Western blot assays. Results: A new dihydrochalcone, iconichalcone (1) along with 15 known phenolic compounds were isolated from the active CHCl 3 , EtOAc and n-buOH subextracts. Compounds 2–5, 7–16 were found to be responsible for the in vitro cytotoxic activity of G. iconica against all tested cancer cell lines with IC 50 values ranging from 2.4 to 33 µM. Amongst these compounds, licoricidin (10), dehydroglyasperin C (12), iconisoflaven (13) and 1-methoxyficifolinol (15) were found to be the most active compounds according to SRB and real time bioactivity assays and submitted to further mechanistic investigations in Huh7 cells. Compounds 10, 12, 13 and 15 caused accumulation of cells in different phases of cell cycle. Moreover, 10, 12, 13 and 15 induced apoptosis through caspase activation. Besides, 12 showed activation of p53 expression and thus G 2 /M arrest as well as a condensed nuclei, established very promising results. Conclusion: The results demonstrated that the aforementioned compounds, particularly 12 could be potential lead molecules for anticancer drug development that deserve further in vivo and clinical investigations. © 2019 Elsevier Gmb Daha fazlası Daha az

Shahwar, D. | Iqbal, M.J. | Nisa, M.-U. | Todorovska, M. | Attar, Rukset | Sabitaliyevich, U.Y. | Xu, B.

Review | 2019 | International Journal of Molecular Sciences20 ( 8 )

Rapidly developing resistance against different therapeutics is a major stumbling block in the standardization of therapy. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated signaling has emerged as one of the most highly and extensively studied signal transduction cascade that induces apoptosis in cancer cells. Rapidly emerging cutting-edge research has helped us to develop a better understanding of the signaling machinery involved in inducing apoptotic cell death. However, excitingly, cancer cells develop resistance against TRAIL-induced apoptosis through different modes. Loss of cell surface expression . . . of TRAIL receptors and imbalance of stoichiometric ratios of pro- and anti-apoptotic proteins play instrumental roles in rewiring the machinery of cancer cells to develop resistance against TRAIL-based therapeutics. Natural products have shown excellent potential to restore apoptosis in TRAIL-resistant cancer cell lines and in mice xenografted with TRAIL-resistant cancer cells. Significantly refined information has previously been added and continues to enrich the existing pool of knowledge related to the natural-product-mediated upregulation of death receptors, rebalancing of pro- and anti-apoptotic proteins in different cancers. In this mini review, we will set spotlight on the most recently published high-impact research related to underlying mechanisms of TRAIL resistance and how these deregulations can be targeted by natural products to restore TRAIL-mediated apoptosis in different cancers. © 2019 by the authors. Licensee MDPI, Basel, Switzerland Daha fazlası Daha az

Farooqi, A.A. | Wang, Z. | Hasnain, S. | Attar, Rukset | Aslam, A. | Mansoor, Q. | Ismail, M.

Note | 2015 | Asian Pacific Journal of Cancer Prevention16 ( 6 ) , pp.2575 - 2580

Cancer is a multifaceted and genomically complex disease and rapidly accumulating high impact research is deepening our understanding related to the mechanisms underlying cancer development, progression and resistance to therapeutics. Increasingly it is being realized that genetic/epigenetic mutations, inactivation of tumor suppressor genes, overexpression of oncogenes, deregulation of intracellular signaling cascades and loss of apoptosis are some of the extensively studied aspects. Confluence of information suggested that rapidly developing resistance to therapeutics is adding another layer of complexity and overwhelmingly increas . . .ing preclinical studies are identifying different natural agents with efficacy and minimal off-target effects. We partition this multi-component review into citrus fruits and their bioactive ingredients mediating rebalancing of pro- and anti-apoptotic proteins to induce apoptosis in resistant cancer cells. We also discuss how oncogenic protein networks are targeted in cancer cells and how these findings may be verified in preclinical studies Daha fazlası Daha az

Tanriverdi, O. | Telci, D. | Aydin, M. | Ekici, I.D. | Miroglu, C. | Sarica, K.

Article | 2012 | Urological Research40 ( 1 ) , pp.17 - 25

An experimental study in rats was performed to evaluate the presence and the degree of both tubular apoptotic changes and crystallization at cortical, medullar and papillary regions of the kidney during hyperoxaluric phase and assess the possible protective effects of vitamin E and verapamil on these pathologic changes (particularly in papillary part of the affected kidneys). A total of 32 rats have been included into the study program. Hyperoxaluria was induced by continuous administration of ethylene glycol (0.75%). In addition to hyperoxaluria induction, animals in Groups 2 and 3 did receive a calcium channelblocking agent (verap . . .amil) and vitamin E, respectively. Histologic alterations of the kidneys including crystal formation together with apoptotic changes were evaluated on days 1, 14 and 28, respectively. Both apoptotic changes and the presence and degree of crystallization were assessed separately in renal cortical region, medulla and particularly papillary parts of the removed kidneys. Although verapamil did well limit the degree of crystal formation and apoptosis and brought it to the same levels observed in control group animals in all parts of the kidneys during intermediate phase, addition of vitamin E was failed to show the same protective effect during both intermediate and late phase evaluations. As demonstrated in our study, the limitation of both crystal deposition and apoptotic changes might be instituted by calcium channel-blocking agents. Clinical application of such agents in the prophylaxis of stone disease might limit the formation of urinary calculi, especially in recurrent stone formers. © Springer-Verlag 2011 Daha fazlası Daha az

Yenigun, V.B. | Ozpolat, B. | Torun Kose, G.

Article | 2013 | International Journal of Molecular Medicine31 ( 6 ) , pp.1477 - 1483

The cancer stem cell hypothesis emphasizes that cancers are driven by cells having stem cell properties, and it is believed that cancer stem cells (CSCs) may be responsible for resistance against therapeutic approaches and for recurrent tumors. Since the biology of the normal breast requires large numbers of stem cells, it has been thought that breast stem cells play an important role in initiating breast cancer. A better characterization of breast CSCs appears to be an essential step to improve the understanding of the biology of breast cancer and its management. The scope of this study was to isolate breast CSCs from a breast canc . . .er cell line (MCF-7) using cell surface markers, and to test whether these cells have any resistance to autophagic cell death mechanisms mediated by commonly used chemotherapies and hormonal therapies such as doxorubicin (adriamycin) and tamoxifen (anti-estrogen), respectively. For this purpose, the CD44+/CD24-/lowMCF-7 breast cancer stem/progenitor cell population was isolated and treated with doxorubicin or tamoxifen and evaluated for their response to growth, autophagy and apoptosis. Our findings suggest that CD44+/CD24-/lowcells were less sensitive to doxorubicin, but did not demonstrate a significant difference towards tamoxifen in regards to the induction of autophagy Daha fazlası Daha az

Göker, B. | Özsavci, D. | Şener, A. | Aksoy, H. | Bagişgil, V. | Yanikkaya-Demirel, G. | Uras, F.

Article | 2011 | Marmara Pharmaceutical Journal15 ( 1 ) , pp.38 - 42

During storage of platelet obtained by apheresis several changes occur. The aim of this study was to investigate the effect of storage on activation, apoptosis, protein pattern, lipid peroxidation, and the levels of nitric oxide (NO) and glutathione (GSH) of platelets. In this study, platelets obtained from healty donors (n=7) by apheresis were kept in an agitator for nine days at 20-24°C. The samples were taken on the 1st, 3 rd, 5 th and 9 th days and platelets were precipitated. Platelet activation with PAC-1 and CD62-P antibodies and platelet apoptosis were measured with Annexin-V using flow cytometer. Platelets were frozen and t . . .hawed four times and then NO, GSH and malondialdehyte (MDA) levels were assayed by spectrophotometry. Platelets protein pattern was investigated via sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) procedure. When compared to the 1st day, platelet CD62-P, PAC- 1 expressions and Annexin-V levels significantly increased on the 3rd, 5th and 9th days, while platelet NO and GSH levels significantly decreased on the 3rd, 5th and 9th days. Furthermore MDA levels significantly increased on only the 5th and 9th days. Mild changes occurred in the density of platelet protein bands. In conclusion, our results show that alterations of platelet activity during storage period may enhance platelet procoagulant activity which increases trombogenic risk. Therefore, for transfusion using fresh platelets or adjusting platelet preservation are strongly important for platelet behavior in vivo conditions Daha fazlası Daha az

Aydemir, EA | Simsek, E | Imir, N | Gokturk, RS | Yesilada, E | Fiskin, K

Article | 2015 | PHARMACOGNOSY MAGAZINE11 ( 42 ) , pp.38 - 42

Background: Fabaceae family members are known to possess preventive and therapeutic potentials against various types of cancers. Objective: The aim of this study was to investigate the cytotoxic and apoptotic effects of hydroalcoholic extracts from the aerial parts and roots of an endemic Ebenus species; Ebenus boissieri Barbey in human lung cancer cell line. Materials and Methods: After treatment with hydroalcoholic extracts cytotoxic activities of both extracts were measured by 3-(4, 5-dimethylthiazolyl-2) -2,5-diphenyltetrazolium bromide assay, whereas caspase-3 activity, tumor necrosis factor-alpha (TNF-alpha) and interferon gam . . .ma (IFN-gamma) release were measured by enzyme linked immunosorbent assay. Results: According to in vitro assay results, the increase in all caspases activity suggested that extracts induce cells to undergo apoptosis. Especially, induction in caspase-3 activity was the most remarkable result of this study. Both aerial part and root extracts induced apoptosis by increasing caspase-3 activity, TNF-alpha and IFN-gamma release. When compared to their relative controls, the concentrations of both TNF-alpha and IFN-gamma in extract-treated groups were signi.cantly and dose dependently exalted. Conclusion: Taken together, our results indicate that the hydroalcoholic extracts of E. boissieri can be considered as a source of new anti-apoptotic and therefore anti-carcinogenic agent Daha fazlası Daha az

Butt, G. | Attar, Rukset | Tabassum, S. | Aras, A. | Qadir, M.I. | Ozbey, U. | Farooqi, A.A.

Review | 2017 | Cellular and Molecular Biology63 ( 12 ) , pp.5 - 10

Interdisciplinary research has revolutionized the field of medicine and we have witnessed exponential increase in the high-impact research in past few decades. However, the road to this burgeoning research field is obstacle-ridden because of intratumor heterogeneity, loss of apoptosis and dysregulation of spatio-temporally controlled signaling pathways. Ground-breaking findings obtained through genetic, genomic and proteomic studies have considerably improved our concepts related to the complexity of protein network and excitingly, discovery of miRNAs has added another layer of intricacy to quantitatively regulated gene networks. In . . . this review, we chronicle the milestone achievements and discuss how Pterostilbenes effectively regulated different cellular pathways. We have provided detailed mechanistic insights related to regulation of JAK-STAT signaling, Notch pathway, Wnt mediated intracellular signaling by pterostilbene. Underlying mechanisms about regulation of PI3K/AKT and MAPK pathways by pterostilbene in different cancers. Regulation of Metastasis-associated protein 1 (MTA1) proteins and Human telomerase reverse transcriptase (hTERT) in cancer cells by pterostilbene. Pterostilbene has also been reported to modulate the expression of various oncogenic and tumor suppressor microRNAs in cancer cells. Better and sharper comprehension of the concepts associated with the modes of action of pterostilbene in different cancers will be useful in identification of cancers which can be efficiently targeted by pterostilbene. © 2017 by the C.M.B. Association Daha fazlası Daha az

Verim, L. | Timirci-Kahraman, O. | Akbulut, H. | Akbas, A. | Ozturk, T. | Turan, S. | İşbir, Turgay

Article | 2014 | In Vivo28 ( 3 ) , pp.397 - 402

Background: The present study aimed to evaluate the role of functional polymorphisms of apoptosis-associated Fatty acid synthase (FAS) and fatty acid synthase ligand (FASL) genes in bladder cancer susceptibility as first presentation in a Turkish population. Patients and Methods: Genotypes of 91 patients with bladder cancer and 101 healthy controls were evaluated for the polymorphism of FAS-1377 G/A and FASL-844 T/C genes by polymerase chain reaction and restriction fragment length polymorphism analysis. Results: The frequency of the FAS-1377 G allele was significantly higher in patients with bladder cancer compared to controls (p

Gasparri, M.L. | Attar, Rukset | Palaia, I. | Perniola, G. | Marchetti, C. | Di Donato, V. | Panici, P.B.

Article | 2015 | Asian Pacific Journal of Cancer Prevention16 ( 9 ) , pp.3635 - 3638

Several improvements in ovarian cancer treatment have been achieved in recent years, both in surgery and in combination chemotherapy with targeting. However, ovarian tumors remain the women's cancers with highest mortality rates. In this scenario, a pivotal role has been endorsed to the immunological environment and to the immunological mechanisms involved in ovarian cancer behavior. Recent evidence suggests a loss of the critical balance between immune-activating and immune-suppressing mechanisms when oncogenesis and cancer progression occur. Ovarian cancer generates a mechanism to escape the immune system by producing a highly sup . . .pressive environment. Immune-activated tumor infiltrating lymphocytes (TILs) in ovarian tumor tissue testify that the immune system is the trigger in this neoplasm. The TIL mileau has been demonstrated to be associated with better prognosis, more chemosensitivity, and more cases of optimal residual tumor achieved during primary cytoreduction. Nowadays, scientists are focusing attention on new immunologically effective tumor biomarkers in order to optimize selection of patients for recruitment in clinical trials and to identify relationships of these biomarkers with responses to immunotherapeutics. Assessing this point of view, TILs might be considered as a potent predictive immunotherapy biomarker Daha fazlası Daha az

Yazihan, N. | Kocak, M.K. | Akcil, E. | Billur, D. | Ermis, E. | Cesaretli, Y. | Uzunalimoglu, O.

Article | 2015 | Trace Elements and Electrolytes32 ( 4 ) , pp.211 - 220

Accumulation of cadmium (Cd) which is a wide spread environmental toxin results in toxicity of tissues. Liver is one of the most affected tissues by Cd exposure. Cd exposure induces inflammation in affected tissues. Galectin-3 is an inflammation related molecule, which takes part in cell survival, apoptosis and migration. The present study focused on the role of proinflammatory levels in Cd toxicity and their relationships with galectin-3 levels. Male Wistar rats were exposed to Cd at the dose of 15 ppm for 8 weeks. Inflammatory status in liver was evaluated by measuring the tissue tumor necrosis factor-? (TNF-?), interleukin 1ß (IL . . .-1ß), and interleukin-8 (IL-8) levels. Liver tissue cytochrome c level was used to identify apoptosis. Hypoxia inducible factor (HIF)-1? and galectin-3 mRNA expression levels were evaluated by RT-PCR. Tissue galectin-3, TNF-?, IL-1ß, and IL-8 levels were evaluated by ELISA. Liver tissue was evaluated histopathologically. A significant increase in galectin-3 tissue level was observed after Cd toxicity, which was accompanied by a significant increase in liver TNF-?, IL-1ß, and IL-8 levels. Cd toxicity resulted in an increase in the cytochrome c levels. Chronic Cd toxicity induced inflammation and apoptosis in rat livers. Cd toxicity led to an increase in galectin-3 production in liver tissues whereas suppresses HIF-1? mRNA expression. The formation of TNF-? and IL-8 at the expense of Cd exposure may likely trigger apoptosis and galectin-3 expression increase. © 2015 Dustri-Verlag Dr. K. Feistle Daha fazlası Daha az

Simsek, E. | Imir, N. | Aydemir, E.A. | Gokturk, R.S. | Yeşilada, Erdem | Fiskin, K.

Article | 2017 | Pharmacognosy Magazine13 ( 50 ) , pp.254 - 259

Background: Ebenus boissieri Barbey is an Antalya, Turkey-endemic plant belonging to Fabaceae family. The aerial parts and the roots of E. boissieri Barbey were used in this study. Objective: In the present study, we have examined the apoptotic effects of hydroalcoholic extracts of E. boissieri Barbey in human cervical cancer cell line HeLa. Materials and Methods: To determine the cytotoxic effect, cells were treated with various concentrations of extracts for 24, 48, and 72 h incubation periods. Cytotoxic effects were examined by Cell Titer 96 aqueous nonradioactive cell proliferation assay and the results were corrected by live/de . . .ad viability/cytotoxicity assay and trypan blue exclusion assay. Apoptotic effects were studied with multicaspase kit. Tumor necrosis factor-Alpha (TNF-?) and interferon gamma (IFN-?) release were also measured by enzyme-linked immunosorbent assay. Results: According to the results, E. boissieri Barbey extract caused significant increase in caspase levels. Thus, we suggest that the extract induces cells to undergo apoptosis. Especially, there was a sharp induction in caspase-3 activity. Levels of both TNF-? and IFN-? in extract-Treated groups were significantly and dose dependently exalted as compared to their relative controls. Conclusion: The effects of the extract on caspase-3, TNF-?, and IFN-? levels mediate the plausible mechanism of apoptosis induction in HeLa. To the best of our knowledge, this is the first report indicating any pharmacological properties of E. Boissieri on HeLa cells. Abbreviations used: Tumor necrosis factor-Alpha (TNF-?); Interferon gamma (IFN-?); 3-(4, 5 dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-Tetrazolium (MTS); Phosphate-Buffered Saline (PBS); Fetal Bovine Serum (FBS); para-Nitroanilin pNA; Enzyme-Linked ImmunoSorbent Assay (ELISA); Sodium Dodesyl sulphate-Polyacrilamide gel electrophoresis (SDS-PAGE); Tris-Buffered Saline (TBS); Hydocloric acid (HCl); Standart Error of Mean (SEM); National Cancer Institute (NCI); half maximal inhibitory concentration (IC50) Daha fazlası Daha az