Microwave Gaseous Discharges

Contains reports on three research projects

Microwave Gaseous Discharges

Contains reports on three research projects

Microwave Gaseous Discharges

Contains reports on three research projects.United States Atomic Energy Commission (Contract AT (30-1) 1842

Microwave Gaseous Discharges

Contains reports on five research projects

p53-R273H Sustains ROS, Pro-Inflammatory Cytokine Release and mTOR Activation While Reducing Autophagy, Mitophagy and UCP2 Expression, Effects Prevented by wtp53

p53 is the most frequently mutated or inactivated gene in cancer, as its activity is not reconcilable with tumor onset and progression. Moreover, mutations in the p53 gene give rise to mutant proteins such as p53‐R273H that, besides losing the wild type p53 (wtp53) capacity to safeguard genome integrity, may promote carcinogenesis, mainly due to its crosstalk with pro-oncogenic pathways. Interestingly, the activation of oncogenic pathways is interconnected with reactive oxygen species (ROS) and the release of pro‐inflammatory cytokines that contribute to create an inflammatory/pro‐tumorigenic milieu. In this study, based on experiments involving p53‐ R273H silencing and transfection, we showed that this mutant p53 (mutp53) promoted cancer cell survival by increasing intracellular ROS level and pro‐inflammatory/immune suppressive cytokine release, activating mTOR, reducing autophagy and mitophagy and downregulating uncoupling protein 2 (UCP2). Interestingly, p53‐R273H transfection into cancer cells carrying wtp53 induced none of these effects and resulted in p21 upregulation. This suggests that wtp53 may counteract several pro‐tumorigenic activities of p53‐R273H and this could explain the lower aggressiveness of cancers carrying heterozygous mutp53 in comparison to those harboring homozygous mutp53

P62/sqstm1/keap1/nrf2 axis reduces cancer cells death-sensitivity in response to zn(Ii)–curcumin complex

The hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according to tumor stage. The present study aimed at investigating whether the zinc–curcumin Zn(II)–curc compound, which we previously showed to display anticancer effects through multiple mechanisms, could induce NRF2 activation and to explore the underlying molecular mechanisms. Biochemical studies showed that Zn(II)–curc treatment increased the NRF2 protein levels along with its targets, heme oxygenase-1 (HO-1) and p62/SQSTM1, while markedly reduced the levels of Keap1 (Kelch-like ECH-associated protein 1), the NRF2 inhibitor, in the cancer cell lines analyzed. The silencing of either NRF2 or p62/SQSTM1 with specific siRNA demonstrated the crosstalk between the two molecules and that the knockdown of either molecule increased the cancer cell sensitivity to Zn(II)–curc-induced cell death. This suggests that the crosstalk between p62/SQSTM1 and NRF2 could be therapeutically exploited to increase cancer patient response to therapies

Viral Infection and Autophagy Dysregulation. The Case of HHV-6, EBV and KSHV

Human Herpes Virus-6 (HHV-6), Epstein-Barr Virus (EBV) and Kaposi Sarcoma Herpes Virus (KSHV) are viruses that share with other member of the Herpesvirus family the capacity to interfere with the autophagic process. In this paper, mainly based on the findings of our laboratory, we describe how, through different mechanisms, these viruses converge in reducing autophagy to impair DC immune function and how, by infecting and dysregulating autophagy in different cell types, they promote the pathologies associated with their infection, from the neurodegenerative diseases such Alzheimer's disease to cancer

Ire1 alpha/xbp1 axis sustains primary effusion lymphoma cell survival by promoting cytokine release and stat3 activation

Primary Effusion Lymphoma (PEL) is a highly aggressive B cell lymphoma associated with Kaposi’s Sarcoma-associated Herpesvirus (KSHV). It is characterized by a high level of basal Endoplasmic Reticulum (ER) stress, Unfolded Protein Response (UPR) activation and constitutive phosphorylation of oncogenic pathways such as the Signal Transducer and activator of Transcription (STAT3). In this study, we found that the inositol requiring kinase (IRE) 1alpha/X-box binding protein (XBP1) axis of UPR plays a key role in the survival of PEL cells, while double stranded RNA-activated protein kinase-like ER kinase (PERK) and activating transcription factor (ATF) 6 slightly influence it, in correlation with the capacity of the IRE1alpha/XBP1 axis to induce the release of interleukin (IL)-6, IL-10 and Vascular-Endothelial Growth Factor (VEGF). Moreover, we found that IRE1alpha/XBP1 inhibition reduced STAT3 Tyr705 phosphorylation and induced a pro-survival autophagy in PEL cells. In conclusion, this study suggests that targeting the IRE1alpha/XBP1 axis represents a promising strategy against PEL cells and that the cytotoxic effect of this treatment may be potentiated by autophagy inhibition

STAT3 and mutp53 Engage a Positive Feedback Loop Involving HSP90 and the Mevalonate Pathway

Oncosuppressor TP53 and oncogene STAT3 have been shown to engage an interplay in which they negatively influence each other. Conversely, mutant (mut) p53 may sustain STAT3 phosphorylation by displacing SH2 phosphatase while whether STAT3 could influence mutp53 has not been clarified yet. In this study we found that pharmacologic or genetic inhibition of STAT3 in both glioblastoma and pancreatic cancer cells, carrying mutp53 protein, reduced mutp53 expression level by down-regulating chaperone HSP90 as well as molecules belonging to the mevalonate pathway. On the other hand, HSP90 and the mevalonate pathway were involved in sustaining STAT3 phosphorylation mediated by mutp53. In conclusion, this study unveils for the first time that mutp53 can establish with STAT3, similarly to what observed with other oncogenic pathways, a criminal alliance with a crucial role in promoting cancerogenesis

Microwave Gaseous Discharges

Contains research objectives and reports on five research projects