1. Introduction
A large mass of research has been accumulating to provide evidence for the health benefits of olive oil feeding and to scientifically support the widespread adoption of traditional Mediterranean diet as a model of healthy eating (Menendez et al., 2007). This evidence has been attributed to the fact that olive oil, the predominant source of fat in the Mediterranean diet (Petroni et al., 1995), contains several minor non-nutrients chemicals such as α- and γ-tocopherols and β-carotene, phytosterols, pigments, terpenic acids, flavonoids such as luteolin and quercetin, squalene, and phenolic compounds, usually and incorrectly termed polyphenols (Menendez et al., 2007; Visioli et al., 2002; Trichopoulou et al., 2003; Tripoli et al., 2005; Servili et al., 2004). The main phenolic compounds in virgin olive oil are secoiridoid derivatives of 2-(3,4-dihydroxyphenyl)ethanol (3,4-DHPEA) and 2-(4-hydroxyphenyl)-ethanol (
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image1_w.jpg)
Figure 1.
Chemical structures.
In particular, the anti-inflammatory properties of olive oil phenolic compounds seem to overlap with those attributed to non-steroidal anti-inflammatory drugs (Procopio A, et al., 2009). The majority of phenolic compounds found in olive oil or table olives are derived from the hydrolysis of oleuropein, the major phenolic constituent of the leaves and unprocessed olive drupes of
2. 3,4-DHPEA-EA and acute inflammation
2.1. Materials and methods
2.2. Results
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Figure 2.
Effect of 3,4-DHPEA-EA (Ole aglycone) on histological alterations of lung tissue 4 h after carrageenan-induced injury and on PMN infiltration in the lung. Lung sections taken from carrageenan-treated mice treated with vehicle demonstrated edema, tissue injury (B) as well as infiltration of the tissue with neutrophils (B). Carrageenan-treated animals treated with 3,4-DHPEA-EA (C) demonstrated reduced lung injury and neutrophil infiltration. Section from sham animals demonstrating the normal architecture of the lung tissue (A). The histological score (D) was made by an independent observer. MPO activity, index of PMN infiltration, was significantly elevated at 4 h after carrageenan (CAR) administration in vehicle-treated mice (E), if compared with sham mice (E). 3,4-DHPEA-EA significantly reduced MPO activity in the lung (E). The figure is representative of at least 3 experiments performed on different experimental days. Data are expressed as mean ± S.E.M. from n = 10 mice for each group. **, P < 0.01 versus sham group. ##, P < 0.01 versus carrageenan.
No significant increase of TNF-α and IL-1β exudates levels was found in the sham animal (Fig. 4A,B). NO levels were also significantly increased in the exudate obtained from mice administered carrageenan (Fig. 4C). Treatment of mice with 3,4-DHPEA-EA significantly reduced NO exudates levels (Fig. 4C). No significant increase of NO exudates levels was found in the sham animal (Fig. 4C).
Effects of 3,4-DHPEA-EA on carrageenan-induced nitrotyrosine formation, lipid peroxidation and poly-ADP-ribosyl polymerase (PARP) activation - Immunohistochemical analysis of lung sections obtained from mice treated with carrageenan revealed positive staining for nitrotyrosine (Fig. 5B). In contrast, no positive staining for nitrotyrosine was found in the lungs of carrageenan-treated mice, which had been treated with 3,4-DHPEA-EA (100 μM/kg) (Fig. 5C). In addition, at 4 hours after carrageenan-induced pleurisy, MDA levels were also measured in the lungs as an indicator of lipid peroxidation. As shown in Figure 5D, MDA levels were significantly increased in the lungs of carrageenan-treated mice. Lipid peroxidation was significantly attenuated by the intraperitoneal injection of 3,4-DHPEA-EA (Fig. 5D). At the same time point (4 h after carrageenan administration), lung tissue sections were taken in order to determine the immunehistological staining for poly ADP-ribosylated proteins (an indicator of PARP activation). A positive staining for the PAR (Fig. 5F) was found primarily localized in the inflammatory cells present in the lung tissue from carrageenan-treated mice. 3,4-DHPEA-EA treatment reduced the degree of PARP activation (Fig. 5G). Please note that there was no staining for either nitrotyrosine (Fig. 5A) or PAR (Fig. 5E) in lung tissues obtained from the sham group of mice.
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image3_w.jpg)
Figure 3.
Effect of 3,4-DHPEA-EA (Ole aglycone) on the immunohistochemical localization of ICAM-1 and P-selectin in the lung after carrageenan injection. No positive staining for ICAM-1 was observed in lung sections taken from sham mice (A). Lung sections taken from carrageenan-treated mice showed intense positive staining for ICAM-1 along the vessels (B). The degree of positive staining for ICAM-1 was markedly reduced in lung sections obtained from mice treated with 3,4-DHPEA-EA (C). No positive staining for P-selectin was observed in lung sections taken from sham mice (D). Lung sections taken from carrageenan-treated mice treated with vehicle showed intense positive staining for P-selectin along the vessels (E). The degree of positive staining for P-selectin was markedly reduced in tissue sections obtained from mice treated with 3,4-DHPEA-EA (F). The figure is representative of at least three experiments performed on different experimental days.
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image4.png)
Figure 4.
Effect of 3,4-DHPEA-EA (Ole aglycone) on carrageenan-induced pro-inflammatory cytokine release and NO formation in the lung. TNF-α and Il-1β levels were significantly elevated at 4 h after carrageenan administration in vehicle-treated mice (A and B respectively), if compared with sham mice (A and B respectively). 3,4-DHPEA-EA significantly reduced TNF-α and Il-1β levels (A and B respectively). Moreover nitrite and nitrate levels, stable NO metabolites, were significantly increased in the pleural exudates at 4 h after carrageenan administration (C) if compared with sham mice (C). 3,4-DHPEA-EA significantly reduced the carrageenan-induced elevation of nitrite and nitrate exudates levels (C). Data are expressed as mean ± S.E.M. from n 10 mice for each group. **, P < 0.01 versus sham group. ##, P < 0.01 versus carrageenan.
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image5_w.jpg)
Figure 5.
Effect of 3,4-DHPEA-EA (Ole aglycone) on carrageenan-induced nitrotyrosine formation, lipid peroxidation and PARP activation in the lung. No staining for nitrotyrosine is present in lung section from sham mice (A). Lung sections taken from carrageenan-treated mice treated with vehicle showed positive staining for nitrotyrosine, localized mainly in inflammatory cells (B). There was a marked reduction in the immunostaining for nitrotyrosine in the lungs of carrageenan-treated mice treated with 3,4-DHPEA-EA (C). Malondialdehyde (MDA) levels, an index of lipid peroxidation, were significantly increased in lung tissues 4 h after carrageenan administration (D), if compared with lung from sham mice (D). 3,4-DHPEA-EA significantly reduced the carrageenan-induced elevation of MDA tissues levels (D). Lung sections taken from carrageenan-treated mice showed positive staining for PAR (F). There was a marked reduction in the immunostaining for PAR in the lungs of carrageenan-treated mice treated with 3,4-DHPEA-EA (G). Lung section from sham mice showed no staining for PAR (E). The figure is representative of at least 3 experiments performed on different experimental days. Data are expressed as mean ± S.E.M. from n 10 mice for each group. **, P < 0.01 versus sham group. ##, P < 0.01 versus carrageenan.
2.4. Discussion
All of the above findings are in support of the view that 3,4-DHPEA-EA attenuates the degree of acute inflammation in the mouse. What, then, is the mechanism by which ole reduces acute inflammation? One consequence of increased oxidative stress is the activation and inactivation of redox-sensitive proteins (Bowie & O’Neill, 2000). Recent studies have observed that the acute consumption of olive oil decreased the activation of NF- κB system on mononuclear cells from healthy men (Perez-Martinez et al., 2007) and that 3,4-DHPEA-EA, trans-resveratrol, and hydroxytyrosol incubated with human umbilical vein endothelial cells inhibit LPS-triggered NF- κB and AP-1 activation (Carluccio et al., 2003). Moreover, various experimental evidence have clearly suggested that NF- κB plays a central role in the regulation of many genes responsible for the generation of mediators or proteins in acute lung inflammation associated with carrageenan administration (Cuzzocrea et al., 2006) such us TNF-α, IL-1β, nitric oxide synthase inducible (iNOS) and COX-2. By inhibiting the activation of NF- κB, the production of joint destructive inflammatory mediators may be reduced as well. In this regard, Miles
3. 3,4-DHPEA-EA and chronic inflammation
3.1. Results
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Figure 6.
Effect of 3,4-DHPEA-EA (Ole aglycone) on the clinical expression of CIA and on body weight. A, no clinical signs were observed in sham mice. CIA developed rapidly in mice immunized with CII and clinical signs such as periarticular erythema and edema (B) were seen with a 100% incidence of CIA at day 28 (D). E, hind paw erythema and swelling increased in frequency and severity in a time dependent mode. CIA-3,4-DHPEA-EA mice demonstrated a significant reduction in the clinical signs of CIA (C), leading to a decrease in the incidence of arthritis in a dose-dependent manner (D). Swelling of hind paws (F) over time was measured at 2-day intervals. G, beginning on day 25, the CII-challenged mice gained significantly less weight and this trend continued through day 35. CIA-3,4-DHPEA-EA mice demonstrated a significant reduced incidence of weight loss (G) as well as less paw edema in a dose dependent manner (F). The figure is representative of all the animals in each group. Values are means ± S.E.M. of 20 animals for each group. **, P < 0.01 versus sham-control; °, P < 0.01 versus CIA.
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Figure 7.
Morphological changes of CIA. Representative hematoxylin and eosin-stained section of joint was examined by light microscopy. The histological evaluation (on day 35) of joint from CIA-control mice (B and G) revealed signs of severe arthritis, with inflammatory cell infiltration and bone erosion. The histological alterations of the joint were significantly reduced in the tissues from CIA-3,4-DHPEA-EA (40 μg/kg)-treated mice (C and G). Masson’s trichrome stain reveals decreased collagen in bone and cartilage of arthritic joint due to bone erosion and cartilage degradation in CIA-control mice (E and G). The alterations of joint were significantly reduced in 3,4-DHPEA-EA (40 μg/kg)-treated mice (F and G). There was no evidence of pathology in the sham-control mice (A, D, and G). The histological score (G) was made by an independent observer. The figure is representative of at least three experiments performed on different experimental days. Values are means ± S.E.M. of 20 animals for each group. **, P < 0.01 versus sham-control; °, P < 0.01 versus CIA.
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image8.jpeg)
Figure 8.
Effect of 3,4-DHPEA-EA (Ole aglycone) treatment on cytokine and chemokine expression and neutrophil infiltration. A substantial increase in the expression of MIP-1 (A), MIP-2 (B), MPO activity (F), plasma TNF-α (C), IL-1β (D), and IL-6 levels (E) was found in CIA-control mice 35 days after CII immunization. CIA-3,4-DHPEA-EA mice demonstrated a significant reduction in the expression of MIP-1 (A), MIP-2 (B), MPO activity (F), plasma TNF-α (C), IL-1β (D), and IL-6 levels in a dose dependent manner (E). Values are means ± S.E.M. of 20 animals for each group. **, P < 0.01 versus sham control; °, P < 0.01 versus CIA-control. ND, not detectable.
mice in a dose dependent manner compared with those in CIA-control mice (Fig. 9E). The release of free radicals and oxidant molecules during chronic inflammation has been suggested to contribute significantly to the tissue injury (Cuzzocrea et al., 2001). On day 35, positive staining for nitrotyrosine, a marker of nitrosative injury, was found in the tibiotarsal joints of vehicle-treated CIA-control mice (Fig. 11, A and A1). 3,4-DHPEA-EA (40 μg/kg) treatment significantly reduced the formation of nitrotyrosine (Fig. 11B). Immunohistochemical analysis of joint sections obtained from CII-challenged mice revealed positive staining for PAR (Fig. 12, A and A1). In contrast, no positive PAR was found in the tibiotarsal joints of CII-challenged mice treated with 3,4-DHPEA-EA (40 μg/kg) (Fig. 12B). There was no staining for either nitrotyrosine or PAR in the tibiotarsal joints obtained from sham-control mice (data not shown).
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image9.jpeg)
Figure 9.
Effect of 3,4-DHPEA-EA (Ole aglycone) treatment on COX-2 immunostaining and on serum PGE2 levels. A marked increase in COX-2 (A and in particular A1) staining was evident in the paw 35 days after initiation of CIA. There was a marked reduction in the immunostaining for COX-2 (B) in the paw of CIA-3,4-DHPEA-EA (40 μg/kg) mice. To verify the binding specificity for COX-2, some sections were also incubated with only the secondary antibody (no primary antibody). No positive staining for COX-2 was found in the sections indicating that the immunoreaction was positive (see negative control C). In addition, a marked increase of PGE2 levels was found in the serum of CIA control mice 35 days after CII immunization (E). The treatment with 3,4-DHPEA-EA also caused a significant reduction in a dose-dependent manner of the serum levels of the metabolite of COX-2 (E). The figure is representative of at least three experiments performed on different experimental days. Densitometry analysis of immunocytochemistry photographs (n = 5) for COX-2 from paw section was assessed (D). The assay was performed by using Optilab Graftek software on a Macintosh personal computer (CPU G3-266). Data are expressed as a percentage of total tissue area. **, P < 0.01 versus sham control; °, P < 0.01 versus CIA. ND, not detectable.
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image10.jpeg)
Figure 10.
Effect of 3,4-DHPEA-EA (Ole aglycone) treatment on iNOS immunostaining. A marked increase in iNOS (A and in particular A1) staining was evident in the paw 35 days after initiation of CIA. There was a marked reduction in the immunostaining for iNOS (B) in the paw of CIA-3,4-DHPEA-EA (40 μg/kg) mice. To verify the binding specificity for iNOS, some sections were also incubated with only the secondary antibody (no primary antibody). No positive staining for iNOS was found in the sections, indicating that the immunoreaction was positive (see negative control C). The figure is representative of at least three experiments performed on different experimental days. Densitometry analysis of immunocytochemistry photographs (n = 5) for iNOS from paw section was assessed (D). The assay was performed by using Optilab Graftek software on a Macintosh personal computer (CPU G3-266). Data are expressed as a percentage of total tissue area. **, P < 0.01 versus sham-control; °, P < 0.01 versus CIA. ND, not detectable.
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image11.jpeg)
Figure 11.
Effect of 3,4-DHPEA-EA (Ole aglycone) treatment on nitrotyrosine immunostaining. A marked increase in nitrotyrosine (A and in particular A1) staining was evident in the paw 35 days after initiation of CIA. There was a marked reduction in the immunostaining for nitrotyrosine (B) in the paw of CIA-3,4-DHPEA-EA (40 μg/kg)-treated mice. To verify the binding specificity for nitrotyrosine, some sections were also incubated with only the secondary antibody (no primary antibody). No positive staining for nitrotyrosine was found in the sections, indicating that the immunoreaction was positive (see negative control C). The figure is representative of at least three experiments performed on different experimental days. Densitometry analysis of immunocytochemistry photographs (n = 5) for nitrotyrosine from paw section was assessed (D). The assay was performed by using Optilab Graftek software on a Macintosh personal computer (CPU G3-266). Data are expressed as a percentage of total tissue area. **, P < 0.01 versus sham control; °, P < 0.01 versus CIA. ND, not detectable.
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image12.jpeg)
Figure 12.
Effect of 3,4-DHPEA-EA (Ole aglycone) treatment on PARP immunostaining. A marked increase in PARP (A and in particular A1), staining was evident in the paw 35 days after initiation of CIA. There was a marked reduction in the immunostaining for PARP (B) in the paw of CIA-3,4-DHPEA-EA (40 μg/kg)-treated mice. To verify the binding specificity for PARP, some sections were also incubated with only the secondary antibody (no primary antibody). No positive staining for PARP was found in the sections, indicating that the immunoreaction was positive (see negative control C). The figure is representative of at least three experiments performed on different experimental days. Densitometry analysis of immunocytochemistry photographs (n = 5) for PARP from paw section was assessed (D). The assay was performed by using Optilab Graftek software on a Macintosh personal computer (CPU G3-266). Data are expressed as a percentage of total tissue area. **, P <0.01 versus sham-control; °, P<0.01 versus CIA. ND, not detectable.
![](http://cdnintech.com/media/chapter/41347/1512345123/media/image13_w.jpg)
Figure 13.
Effect of 3,4-DHPEA-EA (Ole aglycone) post-treatment on joint inflammation. Starting the treatment at day 28, we have also demonstrated that 3,4-DHPEA-EA post-treatment (40 μg/kg) caused a significantly lower arthritis score (A) and a reduction of foot increase (B) compared with the CIA-control. In addition, we have also shown a reduction in the histological damage (C) and increased body weight (D) in 3,4-DHPEA-EA -treated mice. Data are expressed as a percentage of total tissue area. **, P< 0.01 versus sham-control; °, P< 0.01 versus CIA.
3.2. Discussion
Rheumatoid arthritis is an inflammatory disease characterized by chronic inflammation of the synovial joints associated with proliferation of synovial cells and infiltration of activated immunoinflammatory cells, including memory T cells, macrophages, and plasma cells, leading to progressive destruction of cartilage and bone (Hitchon
nitration of lipids, DNA disruption, and nitration and deamination of DNA bases (Filippin et al., 2008). In this report, an intense immunostaining of nitrotyrosine formation also suggested that a structural alteration of joint had occurred, most probably due to the formation of highly reactive nitrogen derivatives ROS produce strand breaks in DNA, which triggers energy-consuming DNA repair mechanisms and activates the nuclear enzyme poly(ADP-ribosyl) polymerase (PARP). There is various evidence that the activation of PARP may also play an important role in inflammation (Genovese et al., 2005). Continuous or excessive activation of PARP produces extended chains of ADP-ribose (PAR) on nuclear proteins and results in a substantial depletion of intracellular NAD and subsequently, ATP, leading to cellular dysfunction and, ultimately, cell death (Chiarugi, 2002). We demonstrate here that 3,4-DHPEA-EA treatment reduced the activation of PARP with a decrease in PAR expression in the joint during CIA. In this regard, several studies demonstrated that hydroxytyrosol, a hydrolysis product of 3,4-DHPEA-EA, also exerts an inhibitory effect on peroxynitrite-dependent DNA base modifications and tyrosine nitration (Deiana et al., 1999). Likewise, Salvini et al. (2006) showed a 30% reduction of oxidative DNA damage in peripheral blood lymphocytes during intervention in postmenopausal women with virgin olive oil containing high amounts of phenols. Thus, 3,4-DHPEA-EA, given at the onset of the disease, reduced paw swelling, clinical score, and the histological severity of the disease when injected after the onset of clinical arthritis. Amelioration of joint disease was associated with near to full inhibition of cytokines as well as inhibition of neutrophil infiltration, which is a key player in RA. Therefore, 3,4-DHPEA-EA was also administered from day 28 after collagen immunization, targeting this early initiation phase of CIA. Then, with treatment starting at day 28, 3,4-DHPEA-EA post-treatment caused a significant reduction of inflamed joints collected at day 35. In conclusion, RA is a complex chronic inflammatory disease dependent on multiple interacting environmental and genetic factors, making it difficult to understand its pathogenesis and thereby to find effective therapies. Taken together, the results of the present study enhance our understanding of the role of ROS generation in the pathophysiology of CII-induced arthritis, implying that olive oil compounds such as 3,4-DHPEA-EA may be useful in the therapy of inflammation.
4. Overall conclusion
Oxidative stress is described as an imbalance between ROS synthesis and antioxidant system in the mammal body where the normal production of oxidants is counteracted by several antioxidative mechanisms. Food constituents are the normal substrate for energy generation but a hypercaloric diet may result in higher ROS, thus inducing oxidative stress. Epidemiological studies have shown that populations consuming a predominantly olive oil-based Mediterranean-style diet exhibit lower incidences of breast cancer and other chronic diseases than those eating a northern European or North American diet. Habitual high intakes of olive oil, especially virgin olive oil, provide a continuous supply of antioxidants, which may reduce oxidative stress via inhibition of lipid peroxidation, a factor that is currently linked to a host of diseases such as cancer, heart disease, and ageing.
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