Evidence has been accumulated showing that inflammatory and cell death pathways are altered both in brain and periphery during Parkinson disease (PD). Neuronal loss in PD is associated with chronic neuroinflammation characterized by microglia activation through the release of reactive oxygen radicals, cytokines, and Prostaglandin E2. The release of these inflammatory mediators in addition to deprivation in growth factors and increase of calcium and dopamine seem implicated in triggering apoptosis. The interaction of leucine-rich repeat kinase and Fas- Associated protein with Death Domain has been implicated in the switching-on of the extrinsic apoptotic pathway via caspase-8 activation, while deficiency in PTEN induced putative kinase 1 has been shown to cause Ca2+ accumulation in mitochondria, increased generation of reactive oxygen species and intrinsic cell death. Autophagy/mitophagy appears to be impaired in the brain during PD; this impairment could be related to defective degradation of mutant α-synuclein and consequent apoptotic cell death. Regarding the peripheral blood, reduced amounts of dopamine, reduced levels of immunoreactivity for tyrosine hydroxylase and dopamine active transporter, and alterations of dopamine receptor expression have been detected in mononuclear cells from PD patients. In addition, mononuclear cells from PD patients show mitochondrial, ubiquitin–proteasome system dysfunction and up-regulation of α-synuclein gene, associated to high expression of the Fas molecule, activation of caspase-3 and -9 and proneness to apoptosis. These and other observations reported in this mini-review suggest that a better understanding of molecular dysfunctions in inflammatory and cell death/autophagy pathways, both in the brain and peripheral blood, could provide useful targets for future investigation on drug-discovery and biomarker identification in PD.

Human T-cell leukemia virus (HTLV-1) is a lymphotropic retrovirus associated to adult T cell leukemia (ATL) and to non-neoplastic inflammatory conditions affecting the central nervous system, lung or skin. The inflammatory disorders associated to HTLV-1 are mediated by different proinflammatory cytokines as IL-1α, IL-6, TNF-α. The release and the role of IL-17 is still debated. Aims of this study were to analyze IL-17 induction by HTLV-1 infection and to determine whether resveratrol (RES) is able to down regulate the pathway of cytokines production either in HTLV-1 chronically infected MT-2 cell line or in human CD4+ cells infected in vitro with HTLV-1. MT-2 and HTLV-1 infected CD4+ cells were analyzed for proinflammatory cytokine production before or after RES treatment. The concentrations of IL-17, IL-1α, IL-6, and TNF-α were measured in cell culture supernatants by ELISA and SearchLight™ technology. The IL-17 mRNA expression was evaluated by RT-PCR. NF-kB activation was detected by non-radioactive, Electro Mobility Shift Assay (EMSA). HTLV-1 RNA expression was detected by Real-time-PCR (RQ-PCR). We found that RES is capable of inducing a dose-dependent inhibition of IL-1α, IL-6 and TNF-α production in vitro and can down regulate the expression of IL-17 at both mRNA and protein levels in HTLV-1 infected cells. This effect was associated with a dose-dependent inhibition of the of the nuclear factor kappa-B (NF-kB) activity. Conversely, RES did not apparently affect HTLV-1 proliferation. These results support the anti-inflammatory properties of RES, suggesting that it might be a useful therapeutic agent for the treatment of HTLV-1 related inflammatory diseases.

We have recently found that D(−)lentiginosine, a synthetic iminosugar exerting glucosidase inhibitory activity, but not its natural enantiomer lentiginosine, is endowed with an unexpected, pro-apoptotic activity. Here, we investigated mechanisms involved in apoptosis induced by D(−)lentiginosine in MOLT-3, HT-29 and SH-SY5Y tumour cell lines. The results showed that D(−)lentiginosine increased caspase 9 expression at 18 h in all the cell lines from 1.5–3.1 folds. Cytochrome c in the cytoplasm was found to be increased from 2.3–2.6 folds in treated cells with respect to control cells. These effects were accompanied by a remarkable collapse of the mitochondrial membrane potential and by the downregulation of anti-apoptotic genes, as well as the upregulation of pro-apoptotic genes of the Bcl-2 family. U937Bcl-2 transfectants, highly expressing Bcl-2, were reluctant to undergo apoptosis even following treatment with 500 μM D(−)lentiginosine, whereas apoptosis by D(−)lentiginosine was induced also in U937 cells, naturally deficient in P53. Thus, our study establishes that the enantiomer of a natural iminosugar is endowed with a possible anti-tumorigenic effect that might be ascribed not only to their capacity to inhibit glycosidases but also to other unknown mechanisms. These data encourage further investigation on similar compounds to make them an interesting platform for the generation of new anticancer drugs.

The UV-inactivated herpes simplex virus 1 (HSV-1) and glycoprotein D (gD) of HSV-1 have been shown to activate nuclear factor kappaB (NF-kappaB) in U937 cells, but mechanisms involved in this activation have not been elucidated. Here we report that: (i) UV-inactivated HSV-1 induced an increased NF-kappaB activation in cells expressing human HVEM (for herpesvirus entry mediator) at surface level, naturally or following stable transfection, but not in cells in which this receptor was not detected by flow cytometry analysis, (ii) treatment with soluble gD induced a dose-dependent NF-kappaB activation in THP-1 cells naturally expressing HVEM, and a monoclonal antibody that prevents binding of gD to HVEM significantly reduced NF-kappaB activation by soluble gD in the same cells, (iii) coculture with transfectants expressing wild-type gD on their surface induced an approximately twofold increase in NF-kappaB activation in cells naturally expressing HVEM, while coculture with transfectants expressing a mutated form of gD, lacking its capability to bind HVEM, did not induce a similar effect and (iv) treatment with soluble gD induced a dose-dependent NF-kappaB activation in CHO transfectants expressing HVEM, but not in control CHO transfectants lacking any functional gD receptor. Overall, these results establish that HVEM is involved in NF-kappaB activation by HSV-1 gD.