The use of the products derived from the olive tree on human health dates back centuries. In several civilizations, the olive tree had and still has a very strong cultural and religious symbolism. Notably, the official seal and emblem of the World Health Organization features the rod of Asclepius over a world map surrounded by olive tree branches, chosen as a symbol of peace and health. Recently, accumulating experimental, clinical and epidemiological data have provided support to the traditional beliefs of the beneficial effect provided by olive derivates. In particular, the polyphenols present in olive leaves, olives, virgin (unrefined) olive oil and olive mill waste are potent antioxidant and radical scavengers with anti-tumor and anti-inflammatory properties. Here, we review the positive impact on human health of oleuropein, the most prevalent polyphenol present in olives. In addition, we provide data collected in our laboratory on the role of oleuropein in counteracting lipid accumulation in a mouse model of non-alcoholic fatty liver disease.

Peroxisome-proliferator activator receptorγ(PPARγ) is a nuclear receptor of central importance in energy homeostasis and inflammation. Recent experimental pieces of evidence demonstrate that PPARγis implicated in the oxidative stress response, an imbalance between antithetic prooxidation and antioxidation forces that may lead the cell to apoptotic or necrotic death. In this delicate and intricate game of equilibrium, PPARγstands out as a central player devoted to the quenching and containment of the damage and to foster cell survival. However, PPARγdoes not act alone: indeed the nuclear receptor is at the point of interconnection of various pathways, such as the nuclear factor erythroid 2-related factor 2 (NRF2), Wnt/β-catenin, and forkhead box proteins O (FOXO) pathways. Here we reviewed the role of PPARγin response to oxidative stress and its interaction with other signaling pathways implicated in this process, an interaction that emerged as a potential new therapeutic target for several oxidative-related diseases.

Experimental evidence indicates that reactive oxygen species (ROS) are involved in the development of hepatic fibrosis; they induce hepatic stellate cells (HSC) proliferation and collagen synthesis. To address the role of matrix metalloproteinase (MMP)‐2 in promoting HSC proliferation during hepatic injury, we investigated whether oxidative stress modulates the growth and invasiveness of HSC by influencing MMP‐2 activation. Cell invasiveness and proliferation, which were studied using Boyden chambers and by counting cells under a microscope, were evaluated after treatment with a superoxide‐producing system, xanthine plus xanthine oxidase (X/XO), in the presence or absence of antioxidants and MMP inhibitors. Expression and activation of MMP‐2 were evaluated via gel zymography, immunoassay, and ribonuclease protection assay. The addition of X/XO induced proliferation and invasiveness of human HSC in a dose‐dependent manner. The addition of antioxidants as well as MMP‐2–specific inhibitors impaired these phenomena. X/XO treatment increased MMP‐2 expression and secretion appreciably and significantly induced members of its activation complex, specifically membrane‐type 1 MMP and tissue inhibitor metalloproteinase 2. To study the intracellular signaling pathways involved in X/XO‐induced MMP‐2 expression, we evaluated the effects of different kinase inhibitors. The inhibition of extracellular signal‐regulated kinase 1/2 (ERK1/2) and phosphatidyl inositol 3‐kinase (PI3K) abrogated X/XO‐elicited MMP‐2 upregulation and completely prevented X/XO‐induced growth and invasiveness of HSC. In conclusion, our findings suggest that MMP‐2 is required for the mitogenic and proinvasive effects of ROS on HSC and demonstrate that ERK1/2 and PI3K are the main signals involved in ROS‐mediated MMP‐2 expression. (HEPATOLOGY 2005;41:1074–1084.)

In a recent study, a single nucleotide polymorphism (SNP) of the Toll-like receptor 4 (TLR4) gene (c.1196C>T [rs4986791, p.T399I]) emerged as conferring protection from fibrosis progression compared to a major, wild-type (WT) CC allele (p.T399). The present study examined the functional linkage of this SNP, along with another common, highly cosegregated TLR4 SNP (c.896A>G [rs4986790, p.D299G]), to hepatic stellate cell (HSC) responses. Both HSCs from TLR4^−/− mice and a human HSC line (LX-2) reconstituted with either TLR4 D299G and/or T399I complementary DNAs were hyporesponsive to lipopolysaccharide (LPS) stimulation compared to those expressing WT TLR4, as assessed by the expression and secretion of LPS-induced inflammatory and chemotactic cytokines (i.e., monocyte chemoattractant protein-1, interleukin-6), down-regulation of bone morphogenic protein and the activin membrane-bound inhibitor expression (an inhibitory transforming growth factor β pseudoreceptor), and activation of a nuclear factor κB (NF-κB)–responsive luciferase reporter. In addition, spontaneous apoptosis, as well as apoptosis induced by pathway inhibitors of NF-κB, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase were greatly increased in HSCs from either TLR4^−/− or myeloid differentiation factor 88^−/− (a TLR adaptor protein) mice, as well as in murine HSCs expressing D299G and/or T399I SNPs; increased apoptosis in these lines was accompanied by decreased phospho-ERK and Bcl-2. Conclusion: TLR4 D299G and T399I SNPs that are associated with protection from hepatic fibrosis reduce TLR4-mediated inflammatory and fibrogenic signaling and lower the apoptotic threshold of activated HSCs. These findings provide a mechanistic link that explains how specific TLR4 SNPs may regulate the risk of fibrosis progression. (HEPATOLOGY 2009.)

Chemotherapy for hepatocellular carcinoma: The present and the future

Hepatitis B virus (HBV) infection is a global public health problem with approximately 2 billion people that have been exposed to the virus. HBV is a member of a family of small, enveloped DNA viruses called hepadnaviruses, and has a preferential tropism for hepatocytes of mammals and birds. Epidemiological studies have proved a strong correlation between chronic hepatitis B virus infection and the development of hepatocellular carcinoma (HCC). HCC is the fifth most common malignancy with about 700000 new cases each year, and more than 50% of them arise in HBV carriers. A large number of studies describe the way in which HBV can contribute to HCC development. Multiple mechanisms have been proposed, including the accumulation of genetic damage due to immune-mediated hepatic inflammation and the induction of oxidative stress. There is evidence of the direct effects of the viral proteins HBx and HBs on the cell biology. Integration of HBV-DNA into the human genome is considered an early event in the carcinogenic process and can induce, through insertional mutagenesis, the alteration of gene expression and chromosomal instability. HBV has also epigenetic effects through the modification of the genomic methylation status. Furthermore, the virus plays an important role in the regulation of microRNA expression. This review will summarize the many mechanisms involved in HBV-related liver carcinogenesis.