Nuclear factor-kappaB (NF-kappaB), a stress-regulated transcription factor belonging to the Rel family, has a pivotal role in the control of the inflammatory and the innate immune responses. Its activation rapidly induces the transcription of a variety of genes encoding cell adhesion molecules, inflammatory and chemotactic cytokines, cytokine receptors, and enzymes that produce inflammatory mediators. More recently, NF-kappaB activation has been connected with multiple aspects of oncogenesis, including the control of cell proliferation, migration, cell cycle progression, and apoptosis. Interestingly, NF-kappaB is constitutively activated in several types of cancer cells, including hematological and epithelial malignancies. In addition, activation of NF-kappaB in cancer cells by chemotherapy or radiation therapy has been associated with the acquisition of resistance to apoptosis, which has emerged as a significant impediment to effective cancer treatment. Selective cyclopentenone inhibitors of the IkappaB kinase, the key enzyme controlling NF-kappaB activation, were recently shown to be potent inducers of apoptosis in chemoresistant lymphoid malignancies. Increasing evidence, summarized in this review, indicates that the development of selective NF-kappaB inhibitors may represent a promising therapeutic tool to sensitize tumor cells to apoptosis and increase the efficacy of conventional anticancer drugs in a wide spectrum of malignancies.

Herpes simplex viruses (HSV) are ubiquitous pathogens causing a variety of diseases ranging from mild illness to severe life-threatening infections. HSV utilize cellular signaling pathways and transcription factors to promote their replication. Here we report that HSV type 1 (HSV-1) induces persistent activation of transcription factor NF-B, a critical regulator of genes involved in inflammation, by activating the IB kinase (IKK) in the early phase of infection. Activated NF-B enhances HSV-1 gene expression. HSV-1-induced NF-B activation is dependent on viral early protein synthesis and is not blocked by the anti-herpetic drug acyclovir. IKK inhibition by the anti-inflammatory cyclopentenone prostaglandin A 1 blocks HSV-1 gene expression and reduces virus yield by more than 3000-fold. The results identify IKK as a potential target for anti-herpetic drugs and suggest that cyclopentenone prostaglandins or their derivatives could be used in the treatment of HSV infection.One intriguing aspect of herpesviruses is their ability to influence host defense mechanisms and replication of other pathogens by inducing a stress response, via activation of cellular transcription factors, among which is nuclear factor-B (NF-B).1 NF-B is a critical regulator of the immediate-early pathogen response, playing an important role in promoting inflammation and viral gene expression (1). In most eukaryotic cells NF-B exists as an inactive cytoplasmic complex, whose predominant form is a heterodimer composed of p50 and p65 (Rel A) subunits, bound to inhibitory proteins of the IB family, usually IB␣ (1, 2). NF-B is activated in response to a variety of stress and pathogenic stimuli, including UV radiation, bacterial and viral infection, and proinflammatory cytokines (2, 3). Several stimuli activate NF-B by augmenting the activity of the IB kinase (IKK) complex, containing two catalytic subunits (IKK-␣ and IKK-␤) and the IKK-␥ or NEMO regulatory subunit (4, 5). IKK phosphorylates IBs at sites that trigger their ubiquitination and proteasome-mediated degradation (1, 4). Freed NF-B dimers translocate to the nucleus and activate a variety of genes encoding adhesion molecules, inflammatory and chemotactic cytokines, cytokine receptors, and enzymes that produce inflammatory mediators (1, 2). NF-B also activates the transcription of viral genes and is involved in several pathological events including progression of AIDS by enhancing human immunodeficiency virus type 1 (HIV-1) transcription (6, 7). Several viruses, including HIV-1 (8), cytomegalovirus (9), SV40 (10), and hepatitis B virus (11), contain functionally important NF-B-binding sites. In the case of HSV-1, NF-B-binding sites are located in the ICP0 and Vmw65 genes (12).In addition to containing NF-B-binding sites in its genome, HSV-1 can also induce NF-B nuclear translocation (13), and two immediate-early (IE) proteins, ICP4 and ICP27, were found to be required for this effect (13, 14); however, the signaling pathway utilized by the virus to activate the factor has still not been defin...

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dRotaviruses, nonenveloped viruses presenting a distinctive triple-layered particle architecture enclosing a segmented doublestranded RNA genome, exhibit a unique morphogenetic pathway requiring the formation of cytoplasmic inclusion bodies called viroplasms in a process involving the nonstructural viral proteins NSP5 and NSP2. In these structures the concerted packaging and replication of the 11 positive-polarity single-stranded RNAs take place to generate the viral double-stranded RNA (dsRNA) genomic segments. Rotavirus infection is a leading cause of gastroenteritis-associated severe morbidity and mortality in young children, but no effective antiviral therapy exists. Herein we investigate the antirotaviral activity of the thiazolide anti-infective nitazoxanide and reveal a novel mechanism by which thiazolides act against rotaviruses. Nitazoxanide and its active circulating metabolite, tizoxanide, inhibit simian A/SA11-G3P[2] and human Wa-G1P[8] rotavirus replication in different types of cells with 50% effective concentrations (EC 50 s) ranging from 0.3 to 2 g/ml and 50% cytotoxic concentrations (CC 50 s) higher than 50 g/ml. Thiazolides do not affect virus infectivity, binding, or entry into target cells and do not cause a general inhibition of viral protein expression, whereas they reduce the size and alter the architecture of viroplasms, decreasing rotavirus dsRNA formation. As revealed by protein/protein interaction analysis, confocal immunofluorescence microscopy, and viroplasm-like structure formation analysis, thiazolides act by hindering the interaction between the nonstructural proteins NSP5 and NSP2. Altogether the results indicate that thiazolides inhibit rotavirus replication by interfering with viral morphogenesis and may represent a novel class of antiviral drugs effective against rotavirus gastroenteritis. R otaviruses are complex nonenveloped viruses belonging to the Reoviridae family. The rotavirion has a distinctive triple-layered particle (TLP) architecture that surrounds a genome composed of 11 segments of double-stranded RNA (dsRNA) encoding six structural viral proteins (VPs) and six nonstructural proteins (NSPs) (1, 2). The capsid structure comprises an inner-core shell of VP2 dimers and an intermediate shell formed by trimers of the major structural protein VP6, which interacts with both the VP2 core protein and the outer shell constituted by the VP4 protein (the rotavirus spikes, which express P-serotype epitopes), and VP7 glycoprotein trimers, which express G-serotype epitopes (2). The P and G serotypes represent independently segregating neutralization epitopes imparting immunity to infection. VP7, which is the second most abundant protein in the virion, is cotranslationally glycosylated as it is inserted into the endoplasmic reticulum (ER) membrane via a cleavable signal sequence found at the N terminus of the protein (1, 2). Rotaviruses exhibit a unique morphogenetic pathway. Double-layered particles (DLPs) are assembled in the cytoplasm at special areas termed viroplasms and the...