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Lung cancer (LC) is the leading cause of cancer death worldwide. LC can be classified into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), with the last subtype accounting for approximately 85% of all diagnosed lung cancer cases. Despite the existence of different types of treatment for this disease, the development of resistance to therapies and tumor recurrence in patients have maintained the need to find new therapeutic options to combat this pathology, where natural products stand out as an attractive source for this search. Nordihydroguaiaretic acid (NDGA) is the main metabolite extracted from the Larrea tridentata plant and has been shown to have different biological activities, including anticancer activity. In this study, H1975, H1299, and A549 cell lines were treated with NDGA, and its effect on cell viability, proliferation, and metabolism was evaluated using a resazurin reduction assay, incorporation of BrdU, and ki-67 gene expression and glucose uptake measurement, respectively. In addition, the combination of NDGA with clinical chemotherapeutics was investigated using an MTT assay and Combenefit software (version 2.02). The results showed that NDGA decreases the viability and proliferation of NSCLC cells and differentially modulates the expression of genes associated with different metabolic pathways. For example, the LDH gene expression decreased in all cell lines analyzed. However, GLUT3 gene expression increased after 24 h of treatment. The expression of the HIF-1 gene decreased early in the H1299 and A549 cell lines. In addition, the combination of NDGA with three chemotherapeutics (carboplatin, gemcitabine, and taxol) shows a synergic pattern in the decrease of cell viability on the H1299 cell line. In summary, this research provides new evidence about the role of NDGA in lung cancer. Interestingly, using NDGA to enhance the anticancer activity of antitumoral drugs could be an improved therapeutic resource against lung cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Interleukin-3 (IL-3) is an important glycoprotein involved in regulating biological responses such as cell proliferation, survival and differentiation. Its effects are mediated via interaction with cell surface receptors. Several studies have demonstrated the expression of IL-3 in neurons and astrocytes of the hippocampus and cortices in normal mouse brain, suggesting a physiological role of IL-3 in the central nervous system. Although there is evidence indicating that IL-3 is expressed in some neuronal populations, its physiological role in these cells is poorly known. Results In this study, we demonstrated the expression of IL-3 receptor in cortical neurons, and analyzed its influence on amyloid β (Aβ)-treated cells. In these cells, IL-3 can activate at least three classical signalling pathways, Jak/STAT, Ras/MAP kinase and the PI 3-kinase. Viability assays indicated that IL-3 might play a neuroprotective role in cells treated with Aβ fibrils. It is of interest to note that our results suggest that cell survival induced by IL-3 required PI 3-kinase and Jak/STAT pathway activation, but not MAP kinase. In addition, IL-3 induced an increase of the anti-apoptotic protein Bcl-2. Conclusion Altogether these data strongly suggest that IL-3 neuroprotects neuronal cells against neurodegenerative agents like Aβ.

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Resveratrol is a polyphenolic natural compound produced by a variety of crops. Currently, resveratrol is considered a multi-target anti-cancer agent with pleiotropic activity, including the ability to prevent the proliferation of malignant cells by inhibiting angiogenesis and curtailing invasive and metastatic factors in many cancer models. However, the molecular mechanisms mediating resveratrol-specific effects on lymphoma cells remain unknown. To begin tackling this question, we treated the Burkitt's lymphoma cell line Ramos with resveratrol and assessed cell survival and gene expression. Our results suggest that resveratrol shows a significant anti-proliferative and pro-apoptotic activity on Ramos cells, inducing the DNA damage response, DNA repairing, and modulating the expression of several genes that regulate the apoptotic process and their proliferative activity. [ABSTRACT FROM AUTHOR]

Herpes Simplex Virus Type 1 (HSV-1) is ubiquitous, neurotropic, and the most common pathogenic causes of sporadic acute encephalitis in humans. Herpes simplex encephalitis is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 infects limbic system structures in the central nervous system and has been suggested as an environmental risk factor for Alzheimer's disease. However, the possible mechanisms that link HSV-1 infection with the neurodegenerative process are still largely unknown. In a previous study we demonstrated that HSV-1 triggers hyperphosphorylation of tau epitopes serine202/threonine205 and serine396/serine404 in neuronal cultures, resembling what occurs in neurodegenerative diseases. Therefore, the aim of the present study was to evaluate at the cellular level if another event associated with neurodegeneration, such as caspase-3 induced cleavage of tau, could also be triggered by HSV-1 infection in primary neuronal and astrocyte cultures. As expected, induction of caspase-3 activation and cleavage of tau protein at its specific site (aspartic acid 421) was observed by Western blot and immunofluorescence analyses in mice neuronal primary cultures infected with HSV-1. In agreement with our previous study on tau hyperphosphorylation, tau cleavage was also observed during the first 4 hours of infection, before neuronal death takes place. This tau processing has been previously demonstrated to increase the kinetics of tau aggregation in vitro and has also been observed in neurodegenerative pathologies. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) belong to the family Herpesviridae, the subfamily Alphaherpesvirinae, and the genus Simplexvirus. They are ubiquitous, neurotropic, and the most common pathogenic cause of sporadic acute encephalitis in humans. Herpes simplex encephalitis (HSE) is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 has been suggested as an environmental risk factor for Alzheimer's disease. However, the mechanisms involved in HSV-1 infection that may trigger the neurodegenerative process are still unknown. In general, HSV-1 induced cytoskeletal alterations reported to date involve the overall disruption of one or more elements of the cytoskeleton in cell lines. Axonal injury has recently attracted attention as a key predictor for the outcome of a number of brain disorders. Here we show that infection of mice neuronal cultures with HSV-1 result in marked neurite damage and neuronal death. Furthermore, in this in vitro model of infection, neurons manifested considerable alterations in microtubule dynamics and tau hyperphosphorylation. These results suggest a possible link between HSV-1 infection and neuronal cytoskeletal disruption. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 1 (HSV-1) is the most common pathogenic cause of sporadic acute encephalitis and it produces latent persistent infection lifelong in infected individuals. Brain inflammation is associated with activation of glial cells, which can detect pathogen-associated molecular patterns (PAMPs) through a variety of pattern-recognition receptors (PRR), including Toll-like receptors (TLRs). In this study, we evaluated the expression and activation of TLR2, TLR3, and TLR4 in HSV-1-infected astrocyte and neuronal primary cultures. Our results showed a clear induction in TLR2 and TLR4 expression in astrocytes as early as 1 h after HSV-1 infection, whereas no significant change was observed in neurons. In addition, infected astrocytes showed increased levels of interferon regulatory factors IRF3 and IRF7, interferon β (INFβ), interleukin 6 (IL6), and serum amyloid A (SAA3) transcripts, as well as phospho-IRF3 protein. These effects seemed to be dependent on viral replication since previous treatment of the cells with acyclovir resulted in low levels of TLRs expression and activation even after 4 h post-infection. These results suggest that reactivation of HSV-1 at the central nervous system (CNS) would likely induce and activate TLR2 and TLR4 receptors directly through interaction of astrocytes with the pathogen and also indirectly by endogenous ligands produced locally, such as serum amyloid protein, potentiating the neuroinflammatory response.

Herpes Simplex Virus Type 1 (HSV-1) is ubiquitous, neurotropic, and the most common pathogenic causes of sporadic acute encephalitis in humans. Herpes simplex encephalitis is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 infects limbic system structures in the central nervous system and has been suggested as an environmental risk factor for Alzheimer's disease. However, the possible mechanisms that link HSV-1 infection with the neurodegenerative process are still largely unknown. In a previous study we demonstrated that HSV-1 triggers hyperphosphorylation of tau epitopes serine202/threonine205 and serine396/serine404 in neuronal cultures, resembling what occurs in neurodegenerative diseases. Therefore, the aim of the present study was to evaluate at the cellular level if another event associated with neurodegeneration, such as caspase-3 induced cleavage of tau, could also be triggered by HSV-1 infection in primary neuronal and astrocyte cultures. As expected, induction of caspase-3 activation and cleavage of tau protein at its specific site (aspartic acid 421) was observed by Western blot and immunofluorescence analyses in mice neuronal primary cultures infected with HSV-1. In agreement with our previous study on tau hyperphosphorylation, tau cleavage was also observed during the first 4 hours of infection, before neuronal death takes place. This tau processing has been previously demonstrated to increase the kinetics of tau aggregation in vitro and has also been observed in neurodegenerative pathologies. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer's disease.