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1.
Effect of dietary supplementation with a highly pure and concentrated docosahexaenoic acid (DHA) supplement on human sperm function.
González-Ravina, C, Aguirre-Lipperheide, M, Pinto, F, Martín-Lozano, D, Fernández-Sánchez, M, Blasco, V, Santamaría-López, E, Candenas, L
Reproductive biology. 2018;(3):282-288
Abstract
The aim of this study was to evaluate the possible beneficial effects of diet supplementation with a highly concentrated and purified docosahexaenoic acid (DHA) formula on human sperm function. We performed a prospective, randomized, double blind, placebo-controlled intervention study. One-hundred eighty human semen samples from sixty infertile patients recruited in a private assisted reproduction center were included. All samples were examined according to World Health Organization guidelines. We analyzed macroscopic and microscopic sperm parameters, oxidative stress, apoptosis, lipid peroxidation, mitochondrial membrane potential and DNA fragmentation before and after supplementation with different DHA daily doses (0.5, 1 and 2 g) or placebo for 1 and 3 months. No differences were found in traditional sperm parameters except for progressive sperm motility, with a significant increase after DHA ingestion after the first month with 1 or 2 g doses and after 3 months with 0.5 g of DHA. This effect was more evident in asthenozoospermic patients. No differences were found in any molecular semen parameter except oxidative stress, in which a slight benefit was observed after DHA treatment. In conclusion, this study support previous indications that highlight the importance of DHA supplementation as a means of improving sperm quality in asthenozoospermic men.
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2.
Butyrate and docosahexaenoic acid interact in alterations of specific lipid classes in differentiating colon cancer cells.
Tylichová, Z, Slavík, J, Ciganek, M, Ovesná, P, Krčmář, P, Straková, N, Machala, M, Kozubík, A, Hofmanová, J, Vondráček, J
Journal of cellular biochemistry. 2018;(6):4664-4679
Abstract
Docosahexaenoic acid (DHA) and sodium butyrate (NaBt) exhibit a number of interactive effects on colon cancer cell growth, differentiation, or apoptosis; however, the molecular mechanisms responsible for these interactions and their impact on cellular lipidome are still not fully clear. Here, we show that both dietary agents together induce dynamic alterations of lipid metabolism, specific cellular lipid classes, and fatty acid composition. In HT-29 cell line, a model of differentiating colon carcinoma cells, NaBt supported incorporation of free DHA into non-polar lipids and their accumulation in cytoplasmic lipid droplets. DHA itself was not incorporated into sphingolipids; however, it significantly altered representation of individual ceramide (Cer) classes, in particular in combination with NaBt (DHA/NaBt). We observed altered expression of enzymes involved in Cer metabolism in cells treated with NaBt or DHA/NaBt, and exogenous Cer 16:0 was found to promote induction of apoptosis in differentiating HT-29 cells. NaBt, together with DHA, increased n-3 fatty acid synthesis and attenuated metabolism of monounsaturated fatty acids. Finally, DHA and/or NaBt altered expression of proteins involved in synthesis of fatty acids, including elongase 5, stearoyl CoA desaturase 1, or fatty acid synthase, with NaBt increasing expression of caveolin-1 and CD36 transporter, which may further promote DHA incorporation and its impact on cellular lipidome. In conclusion, our results indicate that interactions of DHA and NaBt exert complex changes in cellular lipidome, which may contribute to the alterations of colon cancer cell differentiation/apoptotic responses. The present data extend our knowledge about the nature of interactive effects of dietary fatty acids.
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3.
Ferroptosis-Induced Endoplasmic Reticulum Stress: Cross-talk between Ferroptosis and Apoptosis.
Lee, YS, Lee, DH, Choudry, HA, Bartlett, DL, Lee, YJ
Molecular cancer research : MCR. 2018;(7):1073-1076
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Abstract
Since its discovery in 2012, ferroptosis has been well characterized by the accumulation of lipid peroxides due to the failure of glutathione-dependent antioxidant defenses. It is known as an iron-dependent form of programmed cell death, which is distinct from other forms of cell death such as apoptosis and necrosis. Nonetheless, little is known about the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and its role in cell death. Recent studies reveal that the ferroptotic agent-induced ER stress response plays an important role in the cross-talk between ferroptosis and other types of cell death. Ferroptotic agents induce the unfolded protein response and subsequently ER stress-mediated activation of the PERK-eIF2α-ATF4-CHOP pathway. CHOP (C/EBP homologous protein) signaling pathway-mediated p53-independent PUMA (p53 upregulated modulator of apoptosis) expression is involved in the synergistic interaction between ferroptosis and apoptosis. This review highlights the recent literature on ferroptotic and apoptotic agent interactions through the ER stress-mediated PERK-eIF2α-ATF4-CHOP-PUMA pathway and implicates combined treatment to effectively enhance tumoricidal efficacy as a novel therapeutic strategy for cancer. Mol Cancer Res; 16(7); 1073-6. ©2018 AACR.
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4.
Iron removal enhances vitamin C-induced apoptosis and growth inhibition of K-562 leukemic cells.
Tsuma-Kaneko, M, Sawanobori, M, Kawakami, S, Uno, T, Nakamura, Y, Onizuka, M, Ando, K, Kawada, H
Scientific reports. 2018;(1):17377
Abstract
Although vitamin C (VC) has recently garnered interest as an alternative cancer therapy, its clinical effects remain controversial. It was recently reported using in vitro prostate cancer cell lines that excess extracellular iron (EEI) diminishes anti-cancer effects of VC, promoting the decomposition of hydrogen peroxide (H2O2) generated by VC. Here we demonstrated that EEI diminished the inhibitory effect of VC on the survival of K562 human leukemic cells in vitro, by reducing the amount of H2O2 and abrogating the apoptosis pathways induced by VC. In vivo, in the presence of EEI, the growth inhibitory effect of VC on K562 cells was completely abrogated; in fact, VC enhanced K562 cell growth. Reduction of EEI restored the apoptosis-inducing effect of VC in vitro and enhanced the growth inhibitory effect of VC in vivo. Further studies are warranted to investigate whether the combination of VC and iron depletion has similar effects in various other leukemic or cancer cells against which VC has been effective in previous experimental studies.
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5.
Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications.
Kumar, P, Bhadauria, AS, Singh, AK, Saha, S
Life sciences. 2018;:24-33
Abstract
A natural product betulinic acid (BA) has gained a huge significance in the recent years for its strong cytotoxicity. Surprisingly, in spite of being an interesting cancer protecting agent on a variety of tumor cells, the normal cells and tissues are rarely affected by BA. Betulinic acid and analogues (BAs) generally exert through the mechanisms that provokes an event of direct cell death and bypass the resistance to normal chemotherapeutics. Although the major mechanism associated with its ability to induce direct cell death is mitochondrial apoptosis, there are several other mechanisms explored recently. Importantly, mathematical modeling of apoptosis has been an important tool to explore the precise mechanism involved in mitochondrial apoptosis. Thus, this review is an endeavor to sum up the molecular mechanisms underlying the action of BA and future directions to apply mathematical modeling technique to better understand the precise mechanism of BA-induced apoptosis. The last section of the review encompasses the plausible structural modifications and formulations to enhance the therapeutic efficacy of BA.
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6.
Amygdalin from Apricot Kernels Induces Apoptosis and Causes Cell Cycle Arrest in Cancer Cells: An Updated Review.
Saleem, M, Asif, J, Asif, M, Saleem, U
Anti-cancer agents in medicinal chemistry. 2018;(12):1650-1655
Abstract
BACKGROUND Amygdalin is a cyanogenic glycoside which is described as a naturally occurring anticancer agent. Current review highlights apoptosis-inducing attributes of amygdalin towards different cancers and its potential application as an anti-cancer agent in cancer therapy. METHOD Data about amygdalin was retrieved from all major scientific databases i.e., PubMed, ScienceDirect, Google Scholar, Scopus and Medline by using combination of keywords like amygdalin, apoptosis, laetrile, vitamin B- 17, pro-apoptotic proteins, anti-apoptotic proteins, hydrogen cyanide, mechanism of action of amygdalin and amygdalin therapy on humans. However, no specific time frame was followed for collection of data. RESULTS Data collected from already published articles revealed that apoptosis is a central process activated by amygdalin in cancer cells. It is suggested to stimulate apoptotic process by upregulating expression of Bax (proapoptotic protein) and caspase-3 and downregulating expression of Bcl-2 (anti-apoptotic protein). It also promotes arrest of cell cycle in G0/G1 phase and decrease number of cells entering S and G2/M phases. Thus, it is proposed to enhance deceleration of cell cycle by blocking cell proliferation and growth. CONCLUSION The current review epitomizes published information and provides complete interpretations about all known anti-cancer mechanisms of amygdalin, possible role of naturally occurring amygdalin in fight against cancer and mistaken belief about cyanide toxicity causing potential of amygdalin. However, well-planned clinical trials are still needed to be conducted to prove effectiveness of this substance in vivo and to get approval for human use.
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7.
Reactive oxygen species modulate itraconazole-induced apoptosis via mitochondrial disruption in Candida albicans.
Lee, W, Lee, DG
Free radical research. 2018;(1):39-50
Abstract
Itraconazole (ITC), a well-known fungistatic agent, has potent fungicidal activity against Candida albicans. However, its mechanism of fungicidal activity has not been elucidated yet, and we aimed to identify the mechanism of ITC against C. albicans. ITC caused cell shrinkage via potassium leakage through the ion channel. Since shrunken cells could indicate apoptosis, we investigated apoptotic features. Annexin V-FITC and TUNEL assays indicated that fungicidal activity of ITC was involved in apoptosis. Subsequently, we confirmed an intracellular factor that could cause apoptosis. ITC treatment caused reactive oxygen species (ROS) accumulation. To confirm whether ROS is related with ITC-triggered cell death, cell viability was examined using the ROS scavenger N-acetylcysteine (NAC). NAC pretreatment recovered ITC-induced cell death, indicating that antifungal activity of ITC is associated with ROS, which is also confirmed by impaired glutathione-related antioxidant system and oxidized intracellular lipids. Moreover, ITC-induced mitochondrial dysfunction, in turn, triggered cytochrome c release and metacaspase activation, leading to apoptosis. Unlike the only ITC-treatment group, cells with NAC pretreatment did not show significant damage to mitochondria, and attenuated apoptotic features. Therefore, our results suggest that ITC induces apoptosis as fungicidal mechanism, and intracellular ROS is major factor to trigger the apoptosis by ITC in C. albicans.
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Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells.
Zielke, S, Meyer, N, Mari, M, Abou-El-Ardat, K, Reggiori, F, van Wijk, SJL, Kögel, D, Fulda, S
Cell death & disease. 2018;(10):994
Abstract
Autophagy is a well-described degradation mechanism that promotes cell survival upon nutrient starvation and other forms of cellular stresses. In addition, there is growing evidence showing that autophagy can exert a lethal function via autophagic cell death (ACD). As ACD has been implicated in apoptosis-resistant glioblastoma (GBM), there is a high medical need for identifying novel ACD-inducing drugs. Therefore, we screened a library containing 70 autophagy-inducing compounds to induce ATG5-dependent cell death in human MZ-54 GBM cells. Here, we identified three compounds, i.e. loperamide, pimozide, and STF-62247 that significantly induce cell death in several GBM cell lines compared to CRISPR/Cas9-generated ATG5- or ATG7-deficient cells, pointing to a death-promoting role of autophagy. Further cell death analyses conducted using pharmacological inhibitors revealed that apoptosis, ferroptosis, and necroptosis only play minor roles in loperamide-, pimozide- or STF-62247-induced cell death. Intriguingly, these three compounds induce massive lipidation of the autophagy marker protein LC3B as well as the formation of LC3B puncta, which are characteristic of autophagy. Furthermore, loperamide, pimozide, and STF-62247 enhance the autophagic flux in parental MZ-54 cells, but not in ATG5 or ATG7 knockout (KO) MZ-54 cells. In addition, loperamide- and pimozide-treated cells display a massive formation of autophagosomes and autolysosomes at the ultrastructural level. Finally, stimulation of autophagy by all three compounds is accompanied by dephosphorylation of mammalian target of rapamycin complex 1 (mTORC1), a well-known negative regulator of autophagy. In summary, our results indicate that loperamide, pimozide, and STF-62247 induce ATG5- and ATG7-dependent cell death in GBM cells, which is preceded by a massive induction of autophagy. These findings emphasize the lethal function and potential clinical relevance of hyperactivated autophagy in GBM.
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Nicotine induces apoptosis in human osteoblasts via a novel mechanism driven by H2O2 and entailing Glyoxalase 1-dependent MG-H1 accumulation leading to TG2-mediated NF-kB desensitization: Implication for smokers-related osteoporosis.
Marinucci, L, Balloni, S, Fettucciari, K, Bodo, M, Talesa, VN, Antognelli, C
Free radical biology & medicine. 2018;:6-17
Abstract
Nicotine contained in cigarette smoke contributes to the onset of several diseases, including osteoporosis, whose emerging pathogenic mechanism is associated with osteoblasts apoptosis. Scanty information is available on the molecular mechanisms of nicotine on osteoblasts apoptosis and, consequently, on an important aspect of the pathogenesis of smokers-related osteoporosis. Glyoxalase 1 (Glo1) is the detoxification enzyme of methylglyoxal (MG), a major precursor of advanced glycation end products (AGEs), potent pro-apoptotic agents. Hydroimidazolone (MG-H1) is the major AGE derived from the spontaneous MG adduction of arginine residues. The aim of this study was to investigate whether, and by means of which mechanism, the antiglycation defence Glo1 was involved in the apoptosis induced by 0.1 and 1µM nicotine in human primary osteoblasts chronically exposed for 11 and 21 days. By using gene overexpression/silencing and scavenging/inhibitory agents, we demonstrated that nicotine induces a significant intracellular accumulation of hydrogen peroxide (H2O2) that, by inhibiting Glo1, drives MG-H1 accumulation/release. MG-H1, in turn, triggers H2O2 overproduction via receptor for AGEs (RAGE) and, in parallel, an apoptotic mitochondrial pathway by inducing Transglutaminase 2 (TG2) downregulation-dependent NF-kB desensitization. Measurements of H2O2, Glo1 and MG-H1 circulating levels in smokers compared with non-smokers or in smokers with osteoporosis compared with those without this bone-related disease supported the results obtained in vitro. Our findings newly pose the antiglycation enzymatic defense Glo1 and MG-H1 among the molecular events involved in nicotine-induced reactive oxygen species-mediated osteoblasts apoptosis, a crucial event in smoker-related osteoporosis, and suggest novel exposure markers in health surveillance programmes related to smokers-associated osteoporosis.
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10.
Oleuropein aglycone: A polyphenol with different targets against amyloid toxicity.
Leri, M, Oropesa-Nuñez, R, Canale, C, Raimondi, S, Giorgetti, S, Bruzzone, E, Bellotti, V, Stefani, M, Bucciantini, M
Biochimica et biophysica acta. General subjects. 2018;(6):1432-1442
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Abstract
BACKGROUND Many data highlight the benefits of the Mediterranean diet and its main lipid component, extra-virgin olive oil (EVOO). EVOO contains many phenolic compounds that have been found effective against several aging- and lifestyle-related diseases, including neurodegeneration. Oleuropein, a phenolic secoiroid glycoside, is the main polyphenol in the olive oil. It has been reported that the aglycone form of Oleuropein (OleA) interferes in vitro and in vivo with amyloid aggregation of a number of proteins/peptides involved in amyloid, particularly neurodegenerative, diseases avoiding the growth of toxic oligomers and displaying protection against cognitive deterioration. METHODS In this study, we carried out a cellular and biophysical study on the relationships between the effects of OleA on the aggregation and cell interactions of the D76N β2-microglobulin (D76N b2m) variant associated with a familial form of systemic amyloidosis with progressive bowel dysfunction and extensive visceral amyloid deposits. RESULTS Our results indicate that OleA protection against D76N b2m cytotoxicity results from i) a modification of the conformational and biophysical properties of its amyloid fibrils; ii) a modification of the cell bilayer surface properties of exposed cells. CONCLUSIONS This study reveals that OleA remodels not only D76N b2m aggregates but also the cell membrane interfering with the misfolded proteins-cell membrane association, in most cases an early event triggering amyloid-mediated cytotoxicity. GENERAL SIGNIFICANCE The data provided in the present article focus on OleA protection, featuring this polyphenol as a promising plant molecule useful against amyloid diseases.