1,721,039 research outputs found
Studio delle vie di trasduzione del sgnale regolate dalla proteina Nef di HIV-1 in popolazioni cellulari di origine monocito-macrofagica
No full textAngela Santoni,Paolini Rossella, Velotti Francesc
Astrocytes contacting HIV-1-infected macrophages increase the release of CCL2 in response to the HIV-1-dependent enhancement of membrane-associated TNFα in macrophages
No full textThe presence of human immunodeficiency virus (HIV)-infected macrophages in the parenchyma of central nervous system is an hallmark of acquired immunodeficiency syndrome-related neuroinflammation. Once penetrated the blood-brain barrier (BBB), macrophages closely interact with astrocytes, beginning with those lying beneath the BBB endothelium. By investigating the consequences of the cell-cell interaction between HIV-infected macrophages and astrocytes, we observed that the HIV-1 expression in macrophagic cells correlated with increased chemotactic activity in supernatants of astroglial cells. Gene array analysis revealed an impressive increase in the transcription of the gene for the CCL2/MCP-1 chemokine in astroglial cells isolated from HIV-1-infected co-cultures compared with cells from uninfected co-cultures. This phenomenon coupled with the increase in CCL2 release and depended on the cell-cell contact. In addition, it was a consequence of the HIV-1-induced enhancement of membrane-associated tumor necrosis factor-a in macrophagic cells, and correlated with increased levels of nuclear factor kappaB activation in astroglial cells. These observations could mirror a mechanism of recruitment of leukocytes through the BBB, likely contributing to the increase in both viral load and inflammation in central nervous system of HIV-infected patients. © 2010 Wiley-Liss, Inc
MicroRNAs in virus-induced tumorigenesis and IFN system.
No full textNumerous microRNAs (miRNAs), small non-coding RNAs encoded in the human genome, have been shown to be involved in cancer pathogenesis and progression. There is evidence that some of these miRNAs possess proapoptotic or proliferation promoting roles in the cell by negatively regulating target mRNAs. Oncogenic viruses are able to produce persistent infection, favoring tumor development by deregulating cell proliferation and inhibiting apoptosis. It has been recently suggested that cellular miRNAs may participate in host-virus interactions, influencing viral replication. Many mammalian viruses counteract this cellular antiviral defense by using viral proteins but also by encoding viral miRNAs involved in virus-induced tumorigenesis. Interferons (IFNs) modulate a number of non-coding RNA genes, especially miRNAs, that may be used by mammalian organisms as a mechanism of IFN system to combat viral infection and related diseases. In particular, IFNs might induce specific cellular miRNAs that target viral transcripts thereby using this strategy as part of their effectiveness against invading viruses. Therefore IFNs, interferon stimulated genes and miRNAs could act synergistically as innate response to virus infection to induce a potent non-permissive cellular environment for virus replication and virus-induced cancer. The relevance of this reviewed research topic is clearly related to the observation that although virus infections are responsible of specific tumors, other unidentified genetic alterations are likely involved in the induction of malignant transformation. The identification of such genetic alterations, i.e. miRNA expression in transformed cells, would be of considerable importance for the analysis of the pathogenesis and for the treatment of cancer induced by specific viruses as well as for the advancement of the current knowledge on the molecular mechanisms underlying virus-host interaction. In this respect, we will review also the important, still little explored, roles of miRNAs acting both as IFN-stimulated anti-viral molecules and as critical regulators of IFNs and IFN-stimulated genes
Presentation of native TROP-2 tumor antigens to human cytotoxic T lymphocytes by engineered antigen-presenting cells
No full textProfessional antigen-presenting cells (APC), e.g. dendritic cells, express immuno-proteasome components and process proteins for MHC presentation differently from non-immune cells. Thus, they induce reactivities against sets of peptides that do not overlap with those generated by non-professional APC, i.e., tumor cells, and stimulate cytotoxic T lymphocytes (CTL) that may not recognize them. The goal of this work was to establish a system for antigen presentation and in vitro stimulation of human CTL using "tumor-cell-like" engineered APC. Murine fibroblasts were transfected with human HLA Class I alleles, together with the B7.1, ICAM-1 and germ-line TROP2 genes. The last encodes a cell surface glycoprotein widely expressed by human cancers. Unseparated peripheral blood mononuclear cells from HLA Class I-matched individuals were stimulated in vitro by the engineered APC. These efficiently induced the activation and proliferation of antigen-specific HLA-restricted CTL lines and clones. The Trop-2-specific CTL demonstrated high specific cytotoxicity against the appropriate transfected target cells. They also efficiently lysed MCF-7 human tumor cells expressing endogenous HLA-A2.1, Trop-2 together with ICAM-1. These results demonstrate that Trop-2 is a target molecule recognized by human CTL. Moreover, they demonstrate that non-immune engineered APC efficiently process and present native tumor-specific proteins in the context of human MHC Class I, and stimulate the growth and cytotoxicity of specific anti-tumor CTL. © 2002 Wiley-Liss, Inc
Regulatory B (BREG) lymphocytes are increased in patients Hashimoto's thyroiditis and related autoimmune disorders
No full textInflammatory microenvironment and human papillomavirus-induced carcinogenesis
No full textMore than 15% of the global cancer burden is attributable to infectious agents. Pathogens that cause persistent infections are strongly associated with cancer, inflammation being a major component of the chronic infections as revealed by basic, clinical and epidemiological studies. Persistent infection and viral oncoproteins induce specific cellular pathways modifications that promote tumorigenesis. Deregulated and continuous immune response leads to severe tissue and systemic damage, impaired tumor surveillance and consequent carcinogenesis promotion by selecting for metastatic and therapeutically resistant tumor phenotypes. In this review, the role of inflammatory microenvironment in the HPV-induced carcinogenesis is addressed, with a specific focus on the involvement of the immune molecules and microRNAs as well as their delivery through the microvesicle cargo
Extra-virgin olive oil phenols block cell cycle progression and modulate chemotherapeutic toxicity in bladder cancer cells
Full text linkEpidemiological data indicate that the daily consumption of extra‐virgin olive oil (EVOO), a common dietary habit of the Mediterranean area, lowers the incidence of certain types of cancer, in particular bladder neoplasm. The aim of the present study was to evaluate the antiproliferative activity of polyphenols extracted from EVOO on bladder cancer (BCa), and to clarify the biological mechanisms that trigger cell death. Furthermore, we also evaluated the ability of low doses of extra‐virgin olive oil extract (EVOOE) to modulate the in vitro activity of paclitaxel or mitomycin, two antineoplastic drugs used in the management of different types of cancer. Our results showed that EVOOE significantly inhibited the proliferation and clonogenic ability of T24 and 5637 BCa cells in a dose‐dependent manner. Furthermore, cell cycle analysis after EVOOE treatment showed a marked growth arrest prior to mitosis in the G2/M phase for both cell lines, with the subsequent induction of apoptosis only in the T24 cells. Notably, simultaneous treatment of mitomycin C and EVOOE reduced the drug cytotoxicity due to inhibition of ROS production. Conversely, the co‐treatment of T24 cells with paclitaxel and the polyphenol extract strongly increased the apoptotic cell death at each tested concentration compared to paclitaxel alone. Our results support the epidemiological evidence indicating that olive oil consumption exerts health benefits and may represent a starting point for the development of new anticancer strategies
Cancer Regulator MicroRNA: Potential Relevance in Diagnosis, Prognosis and Treatment of Cancer
No full textMicroRNAs (miRNAs) are small (typically 22 nucleotides) non-coding, endogenous, single-stranded RNAs. MiRNA genes are evolutionarily conserved and are located within the introns or exons of protein-coding genes, as well as in intergenic areas. Before the discovery of miRNAs, it had been known that a large part of the genome is not translated into proteins. This so called "junk" DNA was thought to be evolution debris with no function. Recently, the explosive research in this area has established miRNAs as powerful regulators of gene expression. While only about 1,424 human miRNA sequences have been identified so far, genomic computational analysis indicates that as many as 50,000 miRNAs may exist in the human genome, and each may have multiple targets based on similar sequences in the 3'-UTR of mRNA. MiRNAs have been implicated in different areas such as the immune response, neural development, DNA repair, apoptosis, oxidative stress response and others and it is impressive the list of diseases which have recently been found to be associated with abnormal miRNA expression. Here, we focus our attention on the importance of cancer regulator miRNAs. They are divided into oncomiRs and anti-oncomiRs that negatively regulate tumor suppressor genes and oncogenes, respectively. Importantly, the association of miRNAs with cancer has prompted additional functional classification of these short RNAs and their potential relevance in cancer diagnosis, prognosis and treatment
Role of the microenvironment in tumourigenesis: focus on virus-induced tumors
No full textTumor microenvironment can differ considerably in various types of tumors in terms of cellular and cytokine networks and molecular drivers. The well known link between inflammation and cancer has recently found a number of genetic and molecular confirmations. In this respect, numerous reports have revealed that infection and chronic inflammation can contribute to cancer development, progression and control. Adhesion molecules, chemokines and proinflammatory cytokines, that enroll leukocytes, are persistently present in cancer microenvironment, thus increasing the risk for developing tumors. In this respect, cancer-derived microvescicles, in particular exosomes, exert an important role in the recruitment and reprogramming of components of tumor microenvironment. The relationship between cancer and virus infection has generated, in recent years, a great interest for studies aiming to better understand the role of the immune system in the control of these infections and of the immune cofactors in the promotion of the virus-induced neoplastic transformation. This suggests that virus-induced immune alterations may play a role to create an immunotolerogenic microenvironment during the carcinogenesis process
Characterization of Monocyte-Derived Dendritic Cells able to induce an E6/E7-specific, HLA I-restricted, cytotoxic activity
No full textThe adoptive transfer of cancer Ag-specific effector T cells in patients can result in tumor rejection, thereby illustrating the immune system potential for cancer therapy. Viruses involved in tumorigenesis are useful targets because viral proteins are not expressed in normal cells and their expression is required to maintain the malignant phenotype. Between oncoviruses, high risk human papillomavirus (HPV) has a well-characterized transforming propriety and it has been associated with squamous cell carcinoma of the ano-genital and oral tracts. Cutaneous genotypes are, instead, associated with some forms of non-melanoma skin cancer. Transforming ability of HPV is based on the function of E6 and E7 viral oncoproteins, which interact and inactivate pRB and p53 oncosuppressors, respectively. For these reasons vaccines targeting oncogenic E6 and E7 are ideal candidates to elicit strong immune responses without generating autoimmunity.
Here we report results obtained using a protocol based on human monocyte-derived dendritic cells (MDDC) and/or langerhans cells (MDLC) incubated in vitro with necrotic keratinocytes expressing both E6 and E7 oncoproteins derived from mucosal (HPV16) or cutaneous (HPV38) genotypes. We observed the capability of MDDCs i) to uptake necrotic material from transformed keratinocytes; ii) to upregulate the expression of class I HLA and CD86 co-stimulatory molecule following uptake and iii) to specifically prime in vitro cytotoxic T lymphocytes against E6/E7-expressing keratinocytes.
We also provide preliminary evidences indicating the ability of necrotic keratinocytes to alter the microRNA profile in immature MDLC compared to prototipical stimuli as bacterial lipopolisaccharyde
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