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Dino Rotondo

Publications and source records attributed to Dino Rotondo.

14 recordsLinked to original sources
PubMed2004

Conjugated linoleic acids: are they beneficial or detrimental to health?

Conjugated linoleic acids (CLAs) comprise a family of positional and geometric isomers of linoleic acid (18:2n-6; LA) that are formed by biohydrogenation and oxidation processes in nature. The major dietary sources of these unusual fatty acids are foods derived from ruminant animals, in particular dairy products. The main form of CLA, cis-9, trans-11-18:2, can be produced directly by bacterial hydrogenation in the rumen or by delta-9 desaturation of the co-product vaccenic acid (trans-11-18:1) in most mammalian tissues including man. The second most abundant isomer of CLA is the trans-10, cis-12-18:2 form. Initially identified in grilled beef as a potential anti-carcinogen a surprising number of health benefits have subsequently been attributed to CLA mixtures and more recently to the main individual isoforms. It is also clear from recent studies that the two main isoforms can have different effects on metabolism and cell functions and can act through different cell signalling pathways. The majority of studies on body compositional effects (i.e. fat loss, lean gain), on cancer and cardiovascular disease attenuation, on insulin sensitivity and diabetes and on immune function have been conducted with a variety of animal models. Observations clearly emphasise that differences exist between mammalian species in their response to CLAs with mice being the most sensitive. Recent studies indicate that some but not all of the effects observed in animals also pertain to human volunteers. Reports of detrimental effects of CLA intake appear to be largely in mice and due mainly to the trans-10, cis-12 isomer. Suggestions of possible deleterious effects in man due to an increase in oxidative lipid products (isoprostanes) with trans-10, cis-12 CLA ingestion require substantiation. Unresponsiveness to antioxidants of these non-enzymatic oxidation products casts some doubt on their physiological relevance. Recent reports, albeit in the minority, that CLAs, particularly the trans-10, cis-12 isomer, can elicit pro-carcinogenic effects in animal models of colon and prostate cancer and can increase prostaglandin production in cells also warrant further investigation and critical evaluation in relation to the many published anti-cancer and anti-prostaglandin effects of CLAs.

Animals↗
PubMed2004

Prostaglandin E2 is a potent regulator of interleukin-12- and interleukin-18-induced natural killer cell interferon-gamma synthesis.

Synthesis of interferon (IFN)-gamma by natural killer (NK) cells is an important pro-inflammatory event with interleukin (IL)-12 and IL-18 playing major inductive roles. However, other temporal events are likely to regulate such processes and as prostaglandin E2 (PGE2) is ubiquitous during inflammation this study tested the hypothesis that PGE2 was capable of directly modulating cytokine-induced NK cell IFN-gamma synthesis in the absence of other immune cells. Using homogeneous NK cell lines to establish direct effects, PGE2 (0.1-1 micro m) was found to suppress NK cell IFN-gamma synthesis and antagonized the potent synergistic IFN-gamma-inducing effects of IL-12 and IL-18. The actions of PGE2 were mimicked by synthetic PGE2 analogues including misoprostol and butaprost. The selective EP2 receptor agonist butaprost, but not the EP1/EP3 agonist sulprostone, suppressed IFN-gamma synthesis and exclusively competed with PGE2 for receptor binding on NK cells. Further analysis showed that PGE2 did not modulate IL-12 receptor mRNA expression and the effects of PGE2 could be mimicked by the phosphodiesterase inhibitor 3-iosobutyl-1-methylxanthine. The absence of demonstrable receptor modulation coupled with the observed suppression of IFN-gamma synthesis by both EP2 receptor-selective agonists and IBMX suggest that PGE2 acts directly on NK cells via EP2 receptors with its downstream effects on cAMP metabolism. This conclusion is further supported by findings that PGE2 and its analogues consistently elevated levels of cAMP in NK cells. The ability of PGE2 to antagonize the potent inductive signal provided by the combination of IL-12 and IL-18 supports the concept that PGE2 may play an important role in limiting innate inflammatory processes in vivo through direct suppression of NK cell IFN-gamma synthesis.

1-Methyl-3-isobutylxanthine↗
PubMed2004

Conjugated linoleic acid inhibits proliferation and modulates protein kinase C isoforms in human prostate cancer cells.

Prostate cancer is the second most common cancer in men. The disease etiology is poorly understood, but diet and lifestyle are contributory factors. Conjugated linoleic acids (CLAs), naturally occurring fatty acids in ruminant food products, have antitumor properties in animal models of cancer and antiproliferative effects on cancer cells in vitro. The cellular mechanisms by which CLAs elicit these effects are unclear, particularly for prostate cancer cells. We have previously identified protein kinase C (PKC) isoforms, alpha, delta, iota, mu, and zeta in LNCaP prostate cancer cells. The objective of this study was to determine the effects of CLAs (individual cis-9, trans-11 and trans-10, cis-12 isoforms and a 50:50 mixture) on PKC isoform abundance in LNCaP cells. Confluent cells were treated with 6, 25, and 50 microM CLA for 0.5, 6, and 24 h. Cytosol and membrane protein fractions were assayed for PKC isoforms (mainly alpha and delta but also iota, mu, and zeta) by Western blot analysis using specific antibodies. CLAs clearly modulated the abundance of these PKC isoforms, both positively and negatively, depending on the isoform, concentration of CLAs, and period of treatment. Increased PKC-delta and decreased PKC-iota membrane abundance was consistent with CLAs eliciting increased apoptosis and, in part, with their antitumor effects.

Cell Division↗
PubMed2003

Verotoxin activates mitogen-activated protein kinase in human peripheral blood monocytes: role in apoptosis and proinflammatory cytokine release.

. In this study, we examined the role of mitogen-activated protein (MAP) kinases in the effects of verotoxins (VTs), from Escherichia coli O157:H7, upon both apoptosis and the release of tumour necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulated factor (GM-CSF) from human monocytes. 2. Both VT1 and VT2 stimulated a weak, transient increase in c-Jun-N-terminal kinase (JNK) activity and a strong activation of both p38 mitogen-activated protein kinase (MAP kinase) and extracellular-regulated kinase (ERK) activity in human monocytes, which was sustained in the case of p38 MAP kinase. 3. Stimulation of human monocytes with VT2 (100 ng ml-1) did not result in an increase in apoptosis; however, the toxin stimulated the release of both TNF-alpha and GM-CSF. 4. Pretreatment of human monocytes with the p38 MAP kinase inhibitor SB203580, at concentrations from 100 nM to 10 microM, significantly decreased the VT1- and VT2-induced TNF-alpha and GM-CSF release from monocytes. In contrast, inhibition of MEK1 with PD98059 only significantly decreased GM-CSF release. 5. Pretreatment of monocytes with SP600125 inhibited both GM-CSF and TNF-alpha production; however, significant effects upon p38 MAP kinase and ERK activation were observed. 6. Taken together, these results suggest a role for p38 MAP kinase and ERK in cytokine generation in response to the verotoxins. A role for JNK remains undetermined.

Anthracenes↗
PubMed2003

Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants.

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is the only antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with alpha-tocopherol to inhibit lipid peroxidation. Peroxidation of lipids has been implicated in a number of pathophysiological processes, including inflammation and atherogenesis. We investigated the relative positive and negative effects of specific polyunsaturated fatty acids (PUFAs) and inflammatory cytokines on the activity and gene expression of the selenium-dependant redox enzyme GPx4. In human umbilical vein endothelial cells (HUVEC), GPx4 mRNA levels and activity were increased optimally by 114 nM selenium (as sodium selenite). Docosahexaenoic acid (DHA) and conjugated linoleic acid (CLA) further increased mRNA levels whereas arachidonic acid (ARA) had no effect; enzyme activity was decreased by DHA, was unaffected by CLA or was increased by ARA. GPx4 protein levels increased with selenium, ARA and DHA addition but not with CLA. Interleukin-1beta (IL-1beta) increased GPx4 mRNA, protein and activity whereas TNFalpha at 1 ng/ml increased activity while at 3 ng/ml it reduced activity and mRNA. Conversely, alpha-tocopherol reduced mRNA levels without affecting activity. These results indicate that lipids, cytokines and antioxidants modulate GPx4 in a complex manner that in the presence of adequate selenium, may favour protection against potentially proatherogenic processes.

Antioxidants↗
PubMed2003

Polyunsaturated fatty acids and gene expression in mammalian systems.

Over the last 30 years it has become apparent that specific dietary fatty acids are capable of regulating, either directly or indirectly through various signal pathways, the expression of numerous genes, either positively or negatively. Such nutrient-gene interactions have important effects on cell metabolism, differentiation and growth, and ultimately on disease processes. The present review describes some of the more important fatty acid-gene interactions in relation to health and disease in mammalian species, and focuses on the underlying cell signal mechanisms, including various transcription factors, affected by fatty acids and some of their oxygenated derivatives, e.g. the eicosanoids. The review also attempts to clarify some of the complexities of the effects of fatty acids by suggesting a possible overriding regulation by the redox status of the cell. The latter will at least stimulate controversy in this exciting area of lipid research.

Eicosanoids↗
PubMed2002

Lipid metabolism.

Explore the source record for details and available documents.

Angiotensin II↗
PubMed2002

Essential role for verotoxin in sustained stress-activated protein kinase and nuclear factor kappa B signaling, stimulated by Escherichia coli O157:H7 in Vero cells.

The effects of Escherichia coli O157:H7 (strains E30480 and PM601) and the associated verotoxins (VTs), VT1 and VT2, on stress-activated protein kinase and nuclear factor kappa B (NF-kappaB) signaling were investigated with Vero cells, which are extremely sensitive to the cytotoxic effects of E. coli O157:H7 in vitro. Cell-free supernatants prepared from E30480 and PM601 cultures and purified VT1 and VT2 stimulated a strong and prolonged (>4-h) activation of both c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. However, JNK activity stimulated in response to E30480 supernatants was substantially reduced following pretreatment with anti-VT1 and anti-VT2 antibodies, while a VT1 and VT2 gene knockout mutant of PM601 was unable to stimulate JNK activity. E30480 supernatants also caused a sustained activation of NF-kappaB DNA binding, degradation of inhibitory kappa B alpha (IkappaBalpha), and an increase in inhibitory kappa B kinase alpha activity, although PM601 supernatants and VT1 and VT2 had no effect. However, preincubation with VTs prolonged the transient activation of NF-kappaB and IkappaBalpha degradation stimulated by either tumor necrosis factor alpha or interleukin 1beta, while preincubation with anti-VT antibodies prevented the prolonged loss of IkappaBalpha and partially reduced DNA binding in response to E30480 supernatants. These results strongly suggest that in Vero cells, VT plays an essential role in sustained JNK and NF-kappaB signaling in response to E. coli O157:H7 and that this action may underpin their cell-selective cytotoxic effects. These studies also suggest that another component released by strain E30480 contributes to the early activation of JNK and NF-kappaB.

Animals↗