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Diabetes mellitus is a complex metabolic disease characterized by high blood sugar levels. Different pathogenic processes are involved in the etiology of the disease. Indeed, chronic diabetes hyperglycemia is often associated with severe long-term complications including cardiovascular symptoms, retinopathy, nephropathy, and neuropathy. Although the precise molecular mechanisms underlying diabetes are not yet clear, it is widely accepted that increased levels of oxidative stress are involved in the onset, development and progression of diabetes and its related complications. In this regard, the use of natural antioxidant polyphenols, able to control free radical production, to increase intracellular antioxidant defense and to prevent the onset of oxidative stress, can be of high interest. Caffeic acid phenethyl ester (CAPE), a natural polyphenolic substance, is one of the main components of propolis. Due to its multifaceted biological activities, including antioxidant, antimicrobial, anti-inflammatory, antitumor, and immunomodulatory effects, CAPE has received great attention during the last few decades. In the present paper the therapeutic potential of CAPE in diabetes is extensively reviewed.

Background:Heme Oxygenase-1 (HO-1) is a metabolic enzyme strongly involved in processes including cytoprotection, modulation of inflammatory response, anti-oxidative functions, regulation of cellular proliferation, angiogenesis, cardiovascular homeostasis, and immuno-modulation. HO-1 induction and/or activation is able to counterbalance, at least in part, oxidative stress and inflammation. For this reason, HO-1 can be regarded as an attractive target to ameliorate different stress-related pathologies. Caffeic acid phenethyl ester, a natural polyphenolic compound, behaves as HO-1 inducer and possesses a plethora of beneficial effects under oxidative stress conditions. Objectives: A small focused series of caffeic acid phenethyl ester (Cape) analogues was designed and synthesized with the aim of obtaining more potent HO-1 inducers. Method: The capacity of these new compounds to modify the levels of HO-1 was evaluated in human mesenchymal stem cells (hMSCs) derived from bone marrow. Results and conclusion: Some of tested compounds were found to be good HO-1 inducers and 3-(3,4- dihydroxyphenyl)-(2E)-2-propenoic acid 2-(3,4-dimethoxyphenyl) ethyl ester (VP961) was the most potent. VP961 tested to measure HO-1 protein expression and HO activity in in vitro system resulted more potent than the parent compound Cape both as inducer and as direct activator of the enzyme. VP961, selected as lead compound for further characterization, showed antioxidant properties in a model of H2O2-mediated ROS production and cytoprotective effects in a model of H2O2 cells viability impairment. To the best of our knowledge, VP961 is the first known compound able to activate directly HO-1 enzyme and to induce at the same time its protein expression.

Background: Obesity alters endocrine and metabolic function of the adipose tissue leading to an increased release of fatty acids, adipokynes and pro-inflammatory molecules which in turn lead to complications related to the onset of metabolic syndrome. Methods: To this regard, natural antioxidants have been found to have anti-inflammatory and protective action in cardiovascular diseases, diabetes mellitus and obesity. Caffeic acid phenethyl ester (CAPE) is synthesized in a variety of plants and is one of the main components of propolis. CAPE inhibits oxidative stress and showed beneficial effects under various experimental conditions. Aims: The aim of the study was to evaluate the effect of CAPE on adipocyte function after an inflammatory stimulus with lipopolysaccharide (LPS) (1 ng/ml for 6h). Results: Our data showed that LPS caused an increased expression of proinflammatory interleukin IL-6 and a lipolytic effect on the adipocytes. CAPE treatment inhibited LPS effects through a significant decrease of IL-6 and a concomitant increase of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/Enhancer Binding Protein alpha (CEBPα), fatty acid synthase (FAS), fatty acid binding protein 4 (FABP4), diacylglycerol O-acyltransferase 1 (DGAT1) and transcription factor sterol regulatory element binding protein-1c (SREBP-1c). Moreover, the increased levels of adiponectin, heme oxygenase-1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), peroxisome proliferator- activated receptor alpha (PPARα) and Sirtuin-1 suggest that CAPE administration restores adipocyte function following inflammation. Conclusion: In conclusion, the use of this metabolite such as a food supplement may represent a possible strategy for the treatment of conditions related to metabolic syndrome.

Background: Recently, increasing attention has been given to neuroendocrine differentiation (NED) of Prostate Cancer and its diagnostic, prognostic and therapeutic potential. During multistep carcinogenesis, cytodifferentiation of malignant/premalignant cells into more mature or normal-like cells, has become an attractive modality of treatment and promises to be a less toxic and a more specific targeting strategy than conventional chemotherapy. In this study we investigated the capacity of a polyphenol, ellagic acid (EA), to induce differentiation of two prostate cancer cell lines: LnCap and DU145. Methods: NED markers, Chromogranin A (CgA) and p75NGFR levels were evaluated by immunocytochemistry. DNA methyltransferase- 1 (DNMT-1) and phospho-Rb (p-Rb) expression were evaluated by western blotting. Akt activation was evaluated by ELISA. Finally the ability of EA to induce DNA damage in cancer cells was examined using the COMET assay. Results: Treatment with EA significantly reduced CgA levels and increased p75NGFR expression. Moreover p-Rb, DNMT-1 levels and Akt activation/phosphorylation were decreased. EA treatment induced, in a dose-dependent manner, a marked increase in DNA damage, both in LnCap and DU145 cell lines. Conclusions: The results of this study demonstrate that EA treatment represents a new approach and highly effective strategy in reducing carcinogenesis. Therefore, EA may be considered in a promising new class of cancer therapeutic agent, with both antiproliferative and pro-differentiation properties.

Reactive oxygen species (ROS) could be important causative agents of a number of human diseases, including cancer. Thus, antioxidants, which control the oxidative stress state, represent a major line of defense regulating overall health. Human plasma contains many different nonenzymatic antioxidants. Because of their number, it is difficult to measure each of these different antioxidants separately. In addition, the antioxidant status in human plasma is dynamic and may be affected by many factors. Thus, the relationship between nonenzymatic antioxidant capacity of plasma and levels of well-known markers of oxidative stress (oxidized proteins, lipid hydroperoxides, decreases in thiol groups) better reflects health status. The present study considers antioxidant capacity and oxidative stress in human plasma of patients with colon cancer or precancerous lesions, as well as before and after surgical removal of tumors and/or chemo/radiation therapy. Healthy blood donors were used as controls. Colon cancer patients demonstrated a significant decrease in nonproteic antioxidant status and in total thiol groups with respect to healthy controls, whereas oxidized proteins and lipid hydroperoxide levels were significantly increased. In patients with precancerous lesions, the only unmodified parameter was the thiol group level. After surgery, the levels of oxidized proteins, lipid hydroperoxides, and total thiol groups were restored to those seen in healthy subjects, whereas nonproteic antioxidant capacity remained unmodified from that determined before surgery. Conversely, chemo/radiation therapy increased both nonproteic antioxidant capacity and levels of oxidized proteins and lipid hydroperoxides and significantly decreased total thiol groups. These results further support the hypothesis that oxidative stress correlates to the risk of some forms of cancer, not only in the initial stages but also during progression.

To obtain methotrexate (MTX) derivatives with a balanced hydrolipophilic character, we synthesized a series of conjugates in which the drug was linked to lipoamino acid (LAA)‐glucose residues (LAAG‐MTX). These conjugates displayed increased solubility in polar media compared with the corresponding LAA‐MTX conjugates previously described. In vitro biological testing of LAAG‐MTX indicated that the introduction of the sugar moiety decreased the biological activity of these MTX conjugates. The tetradecyl derivative 6b, however, was effective in inhibiting the dihydrofolate reductase activity in vitro and showed an inhibitory effect on human lymphoblastoid cell growth. Drug Dev. Res. 52:454–461, 2001. © 2001 Wiley‐Liss, Inc.

Considerable evidence indicates that reactive oxygen species play an etiological role in both cardiotoxicity and the skin necrosis induced by adriamycin (ADM). An increase in glutathione peroxidase activity on addition of selenium to cultured MCR-5 lung fibroblasts was observed; this increase was accompanied by enhanced cellular resistance to ADM toxicity. Moreover, the presence of exogenous antioxidant systems, such as superoxide dismutase, catalase, vitamin E, dimethylsulfoxide, and desferroxamine, an iron chelating agent, resulted in significant protection from ADM-mediated damage.