Insights on the UV-Screening Potential of Marine-Inspired Thiol Compounds.

One of the major threats to skin aging and the risk of developing skin cancer is excessive exposure to the sun's ultraviolet radiation (UVR). The use of sunscreens containing different synthetic, organic, and inorganic UVR filters is one of the most widespread defensive measures. However, increasing evidence suggests that some of these compounds are potentially eco-toxic, causing subtle damage to the environment and to marine ecosystems. Resorting to natural products produced in a wide range of marine species to counteract UVR-mediated damage could be an alternative strategy. The present work investigates marine-inspired thiol compounds, derivatives of ovothiol A, isolated from marine invertebrates and known to exhibit unique antioxidant properties. However, their potential use as photoprotective molecules for biocompatible sunscreens and anti-photo aging formulations has not yet been investigated. Here, we report on the UVR absorption properties, photostability, and in vitro UVA shielding activities of two synthetic ovothiol derivatives, 5-thiohistidine and iso-ovothiol A, by spectrophotometric and fluorimetric analysis. We found that the UVA properties of these compounds increase upon exposure to UVA and that their absorption activity is able to screen UVA rays, thus reducing the oxidative damage induced to proteins and lipids. The results of this work demonstrate that these novel marine-inspired compounds could represent an alternative eco-friendly approach for UVR skin protection.

Insights on the Hypoglycemic Potential of Crocus sativus Tepal Polyphenols: An In Vitro and In Silico Study.

Post-prandial hyperglycemia typical of diabetes mellitus could be alleviated using plant-derived compounds such as polyphenols, which could influence the activities of enzymes involved in carbohydrate digestion and of intestinal glucose transporters. Here, we report on the potential anti-hyperglycemic effect of Crocus sativus tepals compared to stigmas, within the framework of valorizing these by-products of the saffron industry, since the anti-diabetic properties of saffron are well-known, but not those of its tepals. In vitro assays showed that tepal extracts (TE) had a greater inhibitory action than stigma extracts (SE) on α-amylase activity (IC50: TE = 0.60 ± 0.09 mg/mL; SE = 1.10 ± 0.08 mg/mL; acarbose = 0.051 ± 0.07) and on glucose absorption in Caco-2 differentiated cells (TE = 1.20 ± 0.02 mg/mL; SE = 2.30 ± 0.02 mg/mL; phlorizin = 0.23 ± 0.01). Virtual screening performed with principal compounds from stigma and tepals of C. sativus and human pancreatic α-amylase, glucose transporter 2 (GLUT2) and sodium glucose co-transporter-1 (SGLT1) were validated via molecular docking, e.g., for human pancreatic α-amylase, epicatechin 3-o-gallate and catechin-3-o-gallate were the best scored ligands from tepals (-9.5 kcal/mol and -9.4 kcal/mol, respectively), while sesamin and episesamin were the best scored ones from stigmas (-10.1 kcal/mol). Overall, the results point to the potential of C. sativus tepal extracts in the prevention/management of diabetes, likely due to the rich pool of phytocompounds characterized using high-resolution mass spectrometry, some of which are capable of binding and interacting with proteins involved in starch digestion and intestinal glucose transport.

Effect of Sphingomyelinase-Treated LDLs on HUVECs.

Low-density lipoproteins (LDLs) exert a key role in the transport of esterified cholesterol to tissues. Among the atherogenic modifications of LDLs, the oxidative modification has been mainly investigated as a major risk factor for accelerating atherogenesis. Since LDL sphingolipids are also emerging as important regulators of the atherogenic process, increasing attention is devoted to the effects of sphingomyelinase (SMase) on LDL structural and atherogenic properties. The aims of the study were to investigate the effect of SMase treatment on the physical-chemical properties of LDLs. Moreover, we evaluated cell viability, apoptosis, and oxidative and inflammatory status in human umbilical vein endothelial cells (HUVECs) treated with either ox-LDLs or SMase-treated LDLs (SMase-LDLs). Both treatments were associated with the accrual of the intracellular ROS and upregulation of the antioxidant Paraoxonase 2 (PON2), while only SMase-LDLs induced an increase of superoxide dismutase 2 (SOD2), suggesting the activation of a feedback loop to restrain the detrimental effects of ROS. The increased caspase-3 activity and reduced viability observed in cells treated with SMase-LDLs and ox-LDLs suggest a pro-apoptotic effect of these modified lipoproteins on endothelial cells. Moreover, a strong proinflammatory effect of SMase-LDLs compared to ox-LDLs was confirmed by an increased activation of NF-κB and consequent increased expression of its downstream cytokines IL-8 and IL-6 in HUVECs.

Glucose Uptake and Oxidative Stress in Caco-2 Cells: Health Benefits from Posidonia oceanica (L.) Delile.

Posidonia oceanica (L.) Delile is an endemic Mediterranean marine plant of extreme ecological importance. Previous in vitro and in vivo studies have demonstrated the potential antidiabetic properties of P. oceanica leaf extract. Intestinal glucose transporters play a key role in glucose homeostasis and represent novel targets for the management of diabetes. In this study, the ability of a hydroalcoholic P. oceanica leaf extract (POE) to modulate intestinal glucose transporters was investigated using Caco-2 cells as a model of an intestinal barrier. The incubation of cells with POE significantly decreased glucose uptake by decreasing the GLUT2 glucose transporter levels. Moreover, POE had a positive effect on the barrier integrity by increasing the Zonulin-1 levels. A protective effect exerted by POE against oxidative stress induced by chronic exposure to high glucose concentrations or tert-butyl hydroperoxide was also demonstrated. This study highlights for the first time the effect of POE on glucose transport, intestinal barrier integrity, and its protective antioxidant effect in Caco-2 cells. These findings suggest that the P. oceanica phytocomplex may have a positive impact by preventing the intestinal cell dysfunction involved in the development of inflammation-related disease associated with oxidative stress.

C. spinosa L. subsp. rupestris Phytochemical Profile and Effect on Oxidative Stress in Normal and Cancer Cells.

Spices, widely used to improve the sensory characteristics of food, contain several bioactive compounds as well, including polyphenols, carotenoids, and glucosynolates. Acting through multiple pathways, these bioactive molecules affect a wide variety of cellular processes involved in molecular mechanisms important in the onset and progress of human diseases. Capparis spinosa L. is an aromatic plant characteristic of the Mediterranean diet. Previous studies have reported that different parts (aerial parts, roots, and seeds) of C. spinosa exert various pharmacological activities. Flower buds of C. spinosa contain several bioactive compounds, including polyphenols and glucosinolates. Two different subspecies of C. spinosa L., namely, C. spinosa L. subsp. spinosa, and C. spinosa L. subsp. rupestris, have been reported. Few studies have been carried out in C. spinosa L. subsp. rupestris. The aim of our study was to investigate the phytochemical profile of floral buds of the less investigated species C. spinosa subsp. rupestris. Moreover, we investigated the effect of the extract from buds of C. spinosa subsp. rupestris (CSE) on cell proliferation, intracellular ROS levels, and expression of the antioxidant and anti-apoptotic enzyme paraoxonase-2 (PON2) in normal and cancer cells. T24 cells and Caco-2 cells were selected as models of advanced-stage human bladder cancer and human colorectal adenocarcinoma, respectively. The immortalized human urothelial cell line (UROtsa) and human dermal fibroblast (HuDe) were chosen as normal cell models. Through an untargeted metabolomic approach based on ultra-high-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF-MS), our results demonstrate that C. spinosa subsp. rupestris flower buds contain polyphenols and glucosinolates able to exert a higher cytotoxic effect and higher intracellular reactive oxygen species (ROS) production in cancer cells compared to normal cells. Moreover, upregulation of the expression of the enzyme PON2 was observed in cancer cells. In conclusion, our data demonstrate that normal and cancer cells are differentially sensitive to CSE, which has different effects on PON2 gene expression as well. The overexpression of PON2 in T24 cells treated with CSE could represent a mechanism by which tumor cells protect themselves from the apoptotic process induced by glucosinolates and polyphenols.

HDL functionality in follicular fluid in normal-weight and obese women undergoing assisted reproductive treatment.

OBJECTIVE: High-density lipoproteins (HDL) exert pleiotropic roles in follicular fluid (FF). Previous studies have reported a relationship between obesity, infertility, and systemic oxidative stress. The aim of our study was to investigate for the first time the HDL functional properties in FF in obesity. METHODS: In this observational study, overweight/obese (n = 20) and normal-weight women (n = 38) undergoing assisted reproductive technology were included. Compositional properties and biochemical marker of functionality (HDL oxidation rate), HDL-associated antioxidants (paraoxonase-1 activities and CoQ10 content), and lipid hydroperoxide levels were evaluated in FF from normal-weight and overweight/obese women. Correlations between biochemical parameters and indices for oocyte and embryo quality were studied. RESULTS: FF-HDL obtained from overweight/obese women are characterized by high intrinsic ability to be oxidized compared with FF-HDL from normal-weight women. These alterations are associated with lower activities of paraoxonase-1 (PON1), higher levels of lipid peroxidation, and a lower total antioxidant capacity in FF. Moreover, an association between PON1 activity and FF-HDL oxidation and clinical parameter of oocyte quality was observed. CONCLUSION: Our data suggest that the quality of FF-HDL is important determinant for oocyte quality. Therefore, targeting FF-HDL functionality, in addition to FF-HDL-C levels, may represent a promising and interesting biomarker for reproductive outcomes.

Crocus sativus tepals extract suppresses subcutaneous adipose tissue hypertrophy and improves systemic insulin sensitivity in mice on high-fat diet.

Obesity is a pressing problem worldwide for which standard therapeutic strategies have limited effectiveness. The use of natural products seems to be a promising approach to alleviate obesity and its associated complications. The tepals of Crocus sativus (Cr) plant, usually wasted in saffron production, are an unexplored source of bioactive compounds. Our aim was to elucidate the mechanisms of Cr tepals extract in obesity by investigating its effects on adipocyte differentiation, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) hypertrophy, and lipid metabolism in an animal model of diet-induced obesity. To this end, mouse 3T3-F442A preadipocytes were treated with Cr tepals extract and the expression of adipocyte differentiation genes was determined. Caloric intake, body mass, triglycerides, systemic insulin sensitivity, histology, insulin signaling, and lipid metabolism in VAT and SAT were analyzed in mice fed a 60% fat diet for 14 weeks and treated orally with Cr tepals extract during the last 5 weeks of the diet. We demonstrated for the first time that Cr tepals extract inhibits adipocyte differentiation in vitro. The animal model confirmed that oral treatment with Cr tepals extract results in weight loss, improved systemic insulin sensitivity, lower triglycerides, and improved lipid peroxidation. The suppressive effect of Cr tepals extract on adipocyte hypertrophy and inflammation was observed only in SAT, which, together with preserved SAT insulin signaling, most likely contributed to improved systemic insulin sensitivity. Our results suggest the functionality of SAT as a possible target for the treatment of obesity and its complications.

Modulation of paraoxonase-2 in human dermal fibroblasts by UVA-induced oxidative stress: A new potential marker of skin photodamage.

Paraoxonase-2 (PON2) is an intracellular protein, that exerts a protective role against cell oxidative stress and apoptosis. Genetic and environmental factors (i.e. dietary factors, cigarette smoke, drugs) are able to modulate cellular PON2 levels. The effect of ultraviolet A radiation (UVA), the oxidizing component of sunlight, on PON2 in human dermal fibroblasts (HuDe) has not been previously explored. Excessive UVA radiation is known to cause direct and indirect skin damage by influencing intracellular signalling pathways through oxidative stress mediated by reactive oxygen species (ROS) that modulate the expression of downstream genes involved in different processes, e.g. skin photoaging and cancer. The aim of this study was, therefore, to investigate the modulation of PON2 in terms of protein expression and enzyme activity in HuDe exposed to UVA (270 kJ/m2). Our results show that PON2 is up-regulated immediately after UVA exposure and that its levels and activity decrease in the post-exposure phase, in a time-dependent manner (2-24 h). The trend in PON2 levels mirror the time-course study of UVA-induced ROS. To confirm this, experiments were also performed in the presence of a SPF30 sunscreen used as shielding agent to revert modulation of PON2 at 0 and 2 h post-UVA exposure where other markers of photo-oxidative stress were also examined (NF-KB, γH2AX, advanced glycation end products). Overall, our results show that the upregulation of PON2 might be related to the increase in intracellular ROS and may play an important role in mitigation of UVA-mediated damage and in the prevention of the consequences of UV exposure, thus representing a new marker of early-response to UVA-induced damage in skin fibroblasts.

Effects of Seven Weeks of Combined Physical Training on High-Density Lipoprotein Functionality in Overweight/Obese Subjects.

Our study aimed to investigate the effects of exercise on HDL composition and functional properties in overweight/obese subjects. Eighteen overweight/obese subjects (nine F and nine M, BMI = 30.3 ± 3 kg/m2) attended supervised training for 7 weeks. The protocol included combined resistance and conditioning training four to five times each week. The activity of the antioxidant enzyme paraoxonase-1 (PON1) associated with HDL was evaluated in all subjects before and after the training intervention. Moreover, myeloperoxidase (MPO) levels and oxidative stress markers (ox-LDLs and total antioxidant capacity) were studied in the serums of the subjects. At the end of the intervention, the activity of PON1 was increased (p < 0.0001), and MPO levels and the MPO/PON1 ratio were decreased (p < 0.0001). In addition, a significant improvement in muscle strength and maximal oxygen uptake (VO2max) (p < 0.0001) and a significant reduction in total and visceral adipose tissue mass (p < 0.001) and waist circumference (p < 0.008), without any significant decrease in body weight, were observed. A significant correlation was established between serum MPO/PON ratios, HDL redox activity and ox-LDLs. In conclusion, our results demonstrate that exercise training, without modifications of dietary habits, improved HDL functionality in overweight/obese adults, without any significant reduction in BMI or modifications of glucose and lipid biochemical parameters.

Examining the Antioxidant and Superoxide Radical Scavenging Activity of Anise, (Pimpinella anisum L. Seeds), Esculetin, and 4-Methyl-Esculetin Using X-ray Diffraction, Hydrodynamic Voltammetry and DFT Methods.

Pimpinella anisum L., or anise, is a plant that, besides its nutritional value, has been used in traditional medical practices and described in many cultures in the Mediterranean region. A possible reason for anise's therapeutic value is that it contains coumarins, which are known to have many biomedical and antioxidant properties. HPLC analysis in our laboratory of the anise extract shows the presence of the coumarin esculetin. We used a hydrodynamic voltammetry rotating ring-disk electrode (RRDE) method to measure the superoxide scavenging abilities of anise seeds and esculetin, which has marked scavenging activity. A related coumarin, 4-methyl-esculetin, also showed strong antioxidant activity as measured by RRDE. Moreover, this study includes the X-ray crystal structure of esculetin and 4-methyl-esculetin, which reveal the H-bond and the stacking intermolecular interactions of the two coumarins. Coordinates of esculetin crystal structure were used to perform a DFT study to arrive at the mechanism of superoxide scavenging. Besides performing a H(hydroxyl) abstraction in esculetin position 6 by superoxide, the scavenging also includes the presence of a second superoxide radical in a π-π approach. Both rings of esculetin were explored for this attack, but only the pyrone ring was effective. As a result, one product of esculetin scavenging is H2O2 formation, while the second superoxide remains π-π trapped within the pyrone ring to form an esculetin-η-O2 complex. Comparison with other coumarins shows that subtle structural differences in the coumarin framework can imply marked differences in scavenging. For instance, when the catechol moiety of esculetin (position 6,7) is shifted to position 7,8 in 4-methyl-7,8-dihydroxy coumarin, that coumarin shows a superoxide dismutase action, which, beside H2O2 formation, includes the formation and elimination of a molecule of O2. This is in contrast with the products formed through esculetin superoxide scavenging, where a second added superoxide remains trapped, and forms an esculetin-η-O2 complex.

Antioxidant and Pro-Oxidant Properties of Carthamus Tinctorius, Hydroxy Safflor Yellow A, and Safflor Yellow A.

(1) Carthamus Tinctorius L. (safflower) is extensively used in traditional herbal medicine. (2) The aim of this study was to investigate the bioactive properties of polyphenol extracts from flowers of Carthamus Tinctorius (CT) cultivated in Italy. We also evaluated the properties of two bioactive water-soluble flavonoid compounds, hydroxy safflor yellow A (HSYA) and safflor yellow A (SYA), contained in Carthamus Tinctorius petals. (3) The total polyphenol content was 3.5 ± 0.2 g gallic acid equivalent (GAE)/100 g, flavonoids content was 330 ± 23 mg catechin equivalent (CE)/100 g in the flowers. The extract showed a high antioxidant activity evaluated by oxygen radical absorbance capacity (ORAC) and 2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assays. In addition, flower extract, SYA, and HSYA were able to reduce the susceptibility of low-density lipoprotein to copper-induced lipid peroxidation. In order to investigate the bioactive properties of flower extract, SYA, and HSYA we also studied their modulatory effect of oxidative stress on human dermal fibroblasts (HuDe) oxidized by tert-butyl hydroperoxide (t-BOOH). The CT extract at concentrations ranging from 0.01-20 mg GAE/mL of polyphenols, exerted a protective effect against t-BOOH triggered oxidative stress. At higher concentration the extract exerted a pro-oxidant effect. Similar results have been obtained using HSYA and SYA. (4) These results demonstrate a biphasic effect exerted by HSYA, SYA, and flower extracts on oxidative stress.

Protection of Polyphenols against Glyco-Oxidative Stress: Involvement of Glyoxalase Pathway.

Chronic high glucose (HG) exposure increases methylglyoxal (MGO)-derived advanced glycation end-products (AGEs) and is involved in the onset of pathological conditions, such as diabetes, atherosclerosis and chronic-degenerative diseases. Under physiologic conditions the harmful effects of MGO are contrasted by glyoxalase system that is implicated in the detoxification of Reactive Carbonyl Species (RCS) and maintain the homeostasis of the redox environment of the cell. Polyphenols are the most abundant antioxidants in the diet and present various health benefits. Aims of the study were to investigate the effects of HG-chronic exposure on glyco-oxidation and glyoxalase system in intestinal cells, using CaCo-2 cells. Moreover, we studied the effect of apple polyphenols on glyco-oxidative stress. Our data demonstrated that HG-treatment triggers glyco-oxidation stress with a significant increase in intracellular Reactive Oxygen Species (ROS), lipid peroxidation, AGEs, and increase of Glyoxalase I (GlxI) activity. On the contrary, Glyoxalase II (GlxII) activity was lower in HG-treated cells. We demonstrate that apple polyphenols exert a protective effect against oxidative stress and dicarbonyl stress. The increase of total antioxidant capacity and glutathione (GSH) levels in HG-treated cells in the presence of apple polyphenols was associated with a decrease of GlxI activity.

Bladder Cancer Chemosensitivity is Affected by Paraoxonase-2 Expression.

The goal of the current study was to identify potential roles of paraoxonase-2 in bladder carcinogenesis. T24 bladder cancer cells were transfected with plasmids inducing paraoxonase-2 silencing or overexpression. Upon the selection of clones stably down- or upregulating paraoxonase-2, cell proliferation, migration, and the production of reactive oxygen species were evaluated, before and after treatment with cisplatin and gemcitabine, used alone or in combination. The activity levels of both caspase-3 and caspase-8 were also analyzed. shRNA-mediated gene silencing and the overexpression of paraoxonase-2 revealed that the enzyme was able to promote both the proliferation and migration of T24 cells. Moreover, the knockdown of paraoxonase-2 was significantly associated with a reduced cell viability of T24 cells treated with chemotherapeutic drugs and led to both an increase of reactive oxygen species production and caspase-3 and caspase-8 activation. Conversely, under treatment with anti-neoplastic compounds, a higher proliferative capacity was found in T24 cells overexpressing paraoxonase-2 compared with controls. In addition, upon enzyme upregulation, both the production of reactive oxygen species and activation of caspase-3 and caspase-8 were reduced. Although further analyses will be required to fully understand the involvement of paraoxonase-2 in bladder tumorigenesis and in mechanisms leading to the development of chemoresistance, the data reported in this study seem to demonstrate that the enzyme could exert a great impact on tumor progression and susceptibility to chemotherapy, thus suggesting paraoxonase-2 as a novel and interesting molecular target for effective bladder cancer treatment.

Polyphenols and the glycaemic index of legume pasta.

Legume flours contain elevated levels of healthy functional components. The aim of the present paper was to evaluate the levels of polyphenols and flavonoids and total antioxidant capacity of pasta obtained using 100% legume flours (100% pea flour, 100% red lentil flour, and 60% grass pea flour and 40% chickpea flour). Moreover, the post-prandial glycaemic responses, the glycaemic index and glycaemic load were evaluated. The levels of the bioactive compounds (total polyphenols and flavonoids) and the antioxidant properties were higher in all products obtained with legume flours compared with durum wheat semolina (DWS) pasta. After cooking by boiling, a decrease in the total content of polyphenols of about 50%-60% was observed in all pasta samples. The comparison of the post-prandial increase of glucose after intake of pasta obtained with 100% legume flours demonstrated significant differences compared with DWS pasta. Glycaemic index (GI) and glycaemic load (GL) values of DWS pasta were 52.59 ± 8.41% and 26.14 ± 3.12, respectively. The GI values and GL values were 20.07 ± 7.67% and 6.88 ± 2.63 in the product containing grass pea and chickpea flour, 22.38 ± 6.92% and 8.30 ± 2.56 in the product containing red lentil flour, and 23.39 ± 6.72% and 8.65 ± 2.50 in the product containing pea flour. The results suggest that pasta formulated with legume flours is a low glycaemic food and can be considered a suitable source of polyphenols and flavonoids in human diet.

Relationship of fruit and vegetable intake to dietary antioxidant capacity and markers of oxidative stress: A sex-related study.

OBJECTIVES: Oxidative stress contributes to the development of chronic diseases. Fruits and vegetables contain several phytonutrients (carotenoids, polyphenols) that exert antioxidant effects. The aim of this study was to investigate sex differences in fruit and vegetable intake, and the relationship to plasma levels of carotenoids as well as to total antioxidant capacity (pTAC). We studied also sex differences in the relationship between fruit and vegetables intake and plasma levels of lipid hydroperoxides, as well as of oxidized low-density lipoprotein (ox-LDL). METHODS: This study included 83 healthy adults (35 men and 48 women, mean age 40 ± 10 y). Dietary intake of carotenoids and total antioxidant capacity (dTAC) were evaluated on the basis of a 15-d food frequency questionnaire. Plasma levels of ß-carotene, lutein, and pTAC were studied. Moreover, levels of plasma lipid hydroperoxides and ox-LDL were evaluated using the ferrous oxidation-xylenol orange 2 (FOX2) assay and a monoclonal antibody-based enzyme-linked immunosorbent assay procedure, respectively. RESULTS: Dietary habits were sex-related with a higher intake of fruits and vegetables (P < 0.05) and ß-carotene (P < 0.001) in women than in men. Mean values of plasma lutein and ß-carotene were higher in women than in men. Mean values of ox-LDL and lipid hydroperoxides were higher in men than in women (P < 0.05). Significant negative correlations were established between the individual values of ox-LDL and the levels of lutein versus ß-carotene and versus pTAC values in plasma in both groups. Individuals belonging to the tertile with the highest daily intake of fruits and vegetables or the highest daily dTAC showed the lowest levels of plasma ox-LDL. In each category, sex-related differences were observed with men showing higher levels of ox-LDL than women. Moreover, lower levels of plasma ß-carotene were observed in men in each tertile of daily intake of fruits and vegetables compared with females. CONCLUSIONS: Based on the data obtained, we confirm that high fruit and vegetable consumption exerts a positive effect on antioxidant defenses and decreases oxidative damage of plasma lipoproteins for both sexes. The results suggest that the protective effect can be found to a higher extent in women than in men. Sex-based differences are apparent in many chronic diseases. Thus, a higher consumption of antioxidant-rich fruits and vegetables should be recommended in efforts to prevent diseases in which sex-related differences in oxidative stress play a considerable role.

Effect of High Glucose-Induced Oxidative Stress on Paraoxonase 2 Expression and Activity in Caco-2 Cells.

(1) Background: Hyperglycemia leads to several biochemical and physiological consequences, such as the generation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), which are involved in the development of several human diseases. Intestinal cells are continuously exposed to pro-oxidants and lipid peroxidation products from ingested foods, and also to glyco-oxidative damage. It has been reported that free radical generation may be linked to the development of inflammation-related gastrointestinal diseases. (2) Methods: The effects of high glucose (HG) treatment (50 mM) were assessed in terms of free radical production, lipid peroxidation, and AGEs formation. Furthermore, the expression and the antiapoptotic and antioxidant activity of the paraoxonase-2 (PON2) enzyme in intestinal cells has been investigated. (3) Results: Caco-2 cells treated with media supplied with high glucose (HG) (50 mM) showed, with respect to physiological glucose concentration (25 mM), an increase in ROS production, lipid peroxidation, and AGEs formation. Moreover, a lower PON2 expression and activity in HG-treated cells was related to activation of the apoptotic pathways. (4) Conclusions: Our results demonstrated that high glucose concentrations triggered glyco-oxidative stress in intestinal cells; the downregulation of PON2 could result in a higher oxidative stress and might contribute to intestinal dysfunction.