Curcumin induces apoptosis in JAK2-mutated cells by the inhibition of JAK2/STAT and mTORC1 pathways.

Myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive and negative. The JAK2 V617F is the most common mutation in Philadelphia negative patients and results in a constitutive activation of the JAK/STAT pathway, conferring a proliferative advantage and apoptosis inhibition. Recent studies identified a functional crosstalk between the JAK/STAT and mTOR pathways. The identification of an effective therapy is often difficult, so the availability of new therapeutic approaches might be attractive. Previous studies showed that curcumin, the active principle of the Curcuma longa, can suppress JAK2/STAT pathways in different type of cancer and injuries. In this study, we investigated the anti-proliferative and pro-apoptotic effects of curcumin in JAK2 V617F-mutated cells. HEL cell line and cells from patients JAK2 V617F mutated have been incubated with increasing concentrations of curcumin for different time. Apoptosis and proliferation were evaluated. Subsequently, JAK2/STAT and AKT/mTOR pathways were investigated at both RNA and protein levels. We found that curcumin induces apoptosis and inhibition of proliferation in HEL cells. Furthermore, we showed that curcumin inhibits JAK2/STAT and mTORC1 pathways in JAK2 V617F-mutated cells. This inhibition suggests that curcumin could represent an alternative strategy to be explored for the treatment of patients with myeloproliferative neoplasms.

Reye's and Reye's-like syndromes.

The review reports various questions about Reye's syndrome and Reye's-like syndromes. Although there is a significant decrease in the classic Reye's syndrome cases, because of the reduced employment of salicylates in children (salicylate seems to be the most important inducing factor of the syndrome in paediatric subjects affected by viral infection), the problem is still of interest considering the presence of different Reye's-like forms. All these pathological situations are associated with various aetiologic or predisposing causes that are examined in the text. Particular attention is placed on metabolic disorders, especially of fatty acid metabolism, and also of one amino acid. In fact, a latent form can also be the basis of possible biochemical disturbances induced by various exogenous factors such as viral infections, particularly of the respiratory tract (more rarely of bacterial aetiology), or produced by microbial toxins, or by chemical substances, including some therapeutic drugs. A full discussion of biochemical mechanisms of salicylate-induced Reye's syndrome is reported. Finally a possible diagnostic differentiation from classic Reye's syndrome and Reye's-like syndromes plus therapeutic prospects are briefly examined.

Interleukin-18 and gestosis: correlation with Helicobacter pylori seropositivity.

The aim of this brief communication was to determine the correlation between pre-eclampsia (PE), Helicobacter pylori pathogenic strains seropositivity, and interleukin-18 (IL-18) levels. To this purpose 25 pre-eclamptic women and 25 healthy parturient women of similar age were evaluated for: IL-18 levels, by ELISAH. pylori seropositivity, by anti-IgG ELISAAnti-Cag-A antibodies using a commercial immunoblot assay.We report similar values of IL-18 in our pre-eclamptic patients and in healthy parturient women (respectively 350 +/- 150 vs. 399 +/- 132 pg ml(-1); p = 0.23). However the seropositivity for H. pylori was 84 and 32% (p < 0.001), and anti-Cag-A antibodies were present respectively in 80 and 28% of the two populations. On the basis of our data we hypothesize that H. pylori infection from Cag-A strains can be involved in some cases of PE and that the microorganism could modulate IL-18 release. In fact, differences on IL-18 production have been described by different authors between pre-eclamptic and healthy pregnant women, independently from infective pathology.

Regulation of interleukin-18 by THP-1 monocytoid cells stimulated with HIV-1 and Nef viral protein.

Interleukin (IL)-18 is a proinflammatory cytokine that plays an important role in both innate and adaptive immune responses against several infectious pathogens. Relatively little is known about its production in HIV-1 infection, and there are controversial data on the influence of IL-18 on HIV-1 replication in vitro. In this study, we investigated the effect of HIV-1 infection, and challenge with recombinant HIV-1 proteins, on IL-18 production by THP-1 cells. This is a monocytoid cell line spontaneously producing IL-18, and consequently is particularly suitable for the study of HIV-1 effects on this type of cytokine regulation. The results reported here demonstrate a significant reduction in IL-18 secretion during HIV-infection. In fact, low levels of IL-18 were released until 120 h from viral challenge (15 +/- 11 pg/mL at 24 h and 17 +/- 13 at 96 h and < 12.5 at 120 h), whereas IL-18 production by uninfected control cells was 193 +/- 104 pg/mL and 214 +/- 114 pg/mL at 24 h and 120 h respectively. At 168 h of incubation, IL-18 production by infected and uninfected cells was found to be 164 +/- 88 pg/mL and 325 +/- 101 pg/mL respectively (p = 0.001). Of the following viral proteins: gp 120, p24 and Nef, only the last one induced decreased IL-18 secretion in the supernatants of THP-1 cells. This effect is more evident with the concentrations of 5 -1.25 microg/mL of Nef protein (p < 0.0001). In conclusion, our data show that HIV-1 and its regulatory protein, Nef, are able to down-regulate the release of IL-18, in vitro. These results confirm that a variety of modulating effects on the immune response, induced by HIV-infection, may facilitate progression of HIV-1 infection.

Emerging and re-emerging viral infections in Europe.

Emerging viral infections are becoming a serious problem in Europe in the recent years. This is particularly true for severe acute respiratory syndrome (SARS), West Nile virus (WNV) disease, Toscana virus (TOSV) disease, and potentially for avian influenza virus (H5N1). In contrast, emergence or re-emergence of severe viral infections, including tick borne encephalitis virus, and viral haemorrhagic fever caused by Hantavirus and dengue virus have been frequently reported in several European countries. Laboratory diagnosis of these viral infections based on viral isolation or detection by immune electron microscopy, immunoassay and polymerase chain reaction (PCR) has dramatically improved in the recent years, and SARS represents a good example of a diagnostic approach to emerging viral infections. Finally, old and new promising agents are in the pipeline of pharmaceutical companies to treat emerging viral infections. However only prevention based on large epidemiological studies, and research and development of new vaccines may be able to control and eventually eradicate these deadly viral infections.

Seroprevalence study of Tick-borne encephalitis, Borrelia burgdorferi, Dengue and Toscana virus in Turin Province.

Tick borne encephalitis virus (TBEV) is present in some European countries and it is transmitted by a tick bite. Ixodes ricinus is the main vector of the infection in Italy, where fortunately clinical neurological manifestations, typical of the more serious phase of the disease, are very rarely observed. This behaviour is different from other endemic Euroasiatic areas where numerous cases of encephalitis are described. However TBE transmission has not been widely investigated in Italy and available epidemiological data have been obtained only by studies performed in Central and Northern Regions of the country. In addition seroepidemiological researches were made prevalently on subjects at high risk of tick bite, such as hunters or forest guards from Trentin and Central Italy. No precise information about TBE virus diffusion was available in the Piedmont before our investigations. We found that hunters and wild boar breeders seem to be particularly exposed to the risk of TBE virus infection in Turin Province and in particular in the Susa valley, although no neurological involvement was observed in our population. In particular a seroprevalence of about 5% was detected by the use of purified antigens ELISA test, amongst the subjects at high risk of tick bite. Moreover low risk individuals showed a seroprevalence of below 2%. In addition a parallel seroepidemiological study was performed in Turin Province for Borrelia burgdorferi, the aetiological agent of Lyme disease, also transmitted by tick bite (e.g. Ixodes ricinus), for Dengue and Toscana (TOS) arboviruses, respectively transmitted by Aedes mosquitoes and phlebotomes. Data reported here demonstrate only a sporadic presence in our population of antibodies against Borrelia and Dengue infection. Moreover using an ELISA test performed with viral purified nucleoprotein, we reported a total percentage of about 3% of subjects positive for TOSV.

Parvovirus B19 and immune disorders.

Parvovirus B19 (PVB19) is the causative agent of erythema infectiosum and sometimes the infection is correlated with severe haematological complications, or in pregnancy to fetalis hydrops. Moreover some authors suggest an infection involvement in some autoimmune diseases. To this purpose we evaluated seroprevalence for PVB19 in following the autoimmune or dysreactive pathologies: systemic lupus erythematosus (SLE), cryoglobulinemia, idiopathic systemic--ANCA associated vasculitis, rheumatoid arthritis (RA). In the case of LES, 31/42 patients were positive for PVB19 versus 21/42 of blood donors, as controls subjects (73.8% vs. 50%; significant difference for p < 0.05), moreover a significant difference for p < 0.001 was detected comparing mean titre values of IgGs against PVB19 of two groups (UI 1.94 +/- 0.90 vs. 1.24 +/- 0.80). In contrast no significant differences were found in the case of percent seropositivity of cryoglobulinemic subjects (37/57 = 64.9%, the majority of whom were HCV+) in comparison with the control group (50%). However mean units index (UI) was 1.63 +/- 0.81; p = 0.019 versus the control group. Similar result, with regard to the percentage of seropositivity, was found for vasculitis (9/17 = 52.9%). The data reported here can confirm a possible correlation between PVB19 prior infection and LES and also suggest possible implications in the case of cryoglobulinemia. In fact, most of our patients were affected by a nephropathic or systemic form of HCV+ cryoglobulinemia and the presence of other infective cofactors could be suggestive in the evolution of this clinical situation.