Modulation of oxidative stress in response to gamma-radiation in human glioma cell lines

Journal of Neuro-Oncology -     

Potential crosstalk between cofilin-1 and EGFR pathways in cisplatin resistance of non-small-cell lung cancer

Current challenge in oncology is to establish the concept of personalized medicine in clinical practice. In this context, non-small-cell lung cancer (NSCLC) presents clinical, histological and molecular heterogeneity, being one of the most genomically diverse of all cancers. Recent advances added Epidermal Growth Factor Receptor (EGFR) as a predictive biomarker for patients with advanced NSCLC. In tumors with activating EGFR mutations, tyrosine kinase inhibitors (TKI) are indicated as first-line treatment, although restricted to a very small target population. In this context, cofilin-1 (a cytosolic protein involved with actin dynamics) has been widely studied as a biomarker of an aggressive phenotype in tumors, and overexpression of cofilin-1 is associated with cisplatin resistance and poor prognosis in NSCLC. Here, we gather information about the predictive potential of cofilin-1 and reviewed the crosstalk between cofilin-1/EGFR pathways. We aimed to highlight new perspectives of how these interactions might affect cisplatin resistance in NSCLC. We propose that cofilin-1 quantification in clinical samples in combination with presence/absence of EGFR mutation could be used to select patients that would benefit from TKI''s treatment. This information is of paramount importance and could result in a possibility of guiding more effective treatments to NSCLC patients.     

Peripheral oxidative damage in early-stage mood disorders: a nested population-based case-control study

Systemic toxicity is a relevant dimension of pathophysiology in bipolar disorder, and oxidative damage is one potential link between central and peripheral pathology. Although there is mounting evidence that chronic bipolar disorder is associated with oxidative stress, studies in the early stages of bipolar disorder are scarce, and heavily reliant on clinical in lieu of population studies. The objective of this study was to confirm leading hypotheses about the role of oxidative damage in bipolar disorder. To that end, we nested a case-control study in a population-based study of young adults aged 18-24 yr. After an initial psychopathology screen, all people with a lifetime history of (hypo)mania and matched controls underwent a structured diagnostic interview. This yielded a sample of 231 participants, in whom we measured serum protein carbonyl content (PCC) and thiobarbituric acid reactive substances (TBARS). People with bipolar disorder had higher PCC levels than healthy subjects. Those with major depression were not different from control subjects in either PCC or TBARS levels. Both bipolar disorder and major depression were associated with higher PCC levels in the a priori regression model controlling for possible confounders. These findings indicate that protein oxidative damage is present from early stages and can be seen as a sign of early illness activity in mood disorders.     

Rational coformer or solvent selection for pharmaceutical cocrystallization or desolvation

It is demonstrated that the fluid-phase thermodynamics theory conductor-like screening model for real solvents (COSMO-RS) as implemented in the COSMOtherm software can be used for accurate and efficient screening of coformers for active pharmaceutical ingredient (API) cocrystallization. The excess enthalpy, H_ex, between an API–coformer mixture relative to the pure components reflects the tendency of those two compounds to cocrystallize. Thus, predictive calculations may be performed with decent effort on a large set of molecular data in order to identify potentially new cocrystal systems. In addition, it is demonstrated that COSMO-RS theory allows reasonable ranking of coformers for API solubility improvement. As a result, experiments may be focused on those coformers, which have an increased probability of cocrystallization, leading to the largest improvement of the API solubility. In a similar way as potential coformers are identified for cocrystallization, solvents that do not tend to form solvates may be determined based on the highest H_exs with the API. The approach was successfully tested on tyrosine kinase inhibitor axitinib, which has a propensity to form relatively stable solvated structures with the majority of common solvents, as well as on thiophanate-methyl and thiophanate-ethyl benzimidazole fungicides, which form channel solvates.     

Pain and cardiorespiratory responses of children during physiotherapy after heart surgery

Objective

The aim of the present study was to determine the occurrence of pain and changes in blood pressure, heart rate, respiratory rate, and arterial oxygen saturation associated with physiotherapy in children undergoing cardiac surgery.

Methods

Eighteen extubated children were assessed for the presence of pain using the face, legs, activity, cry, consolability scale, and blood pressure, heart rate, respiratory rate and arterial oxygen saturation were simultaneously recorded. The physiological parameters were measured at the following time periods: immediately before physiotherapy, five and 10 minutes after the beginning of physiotherapy, and five minutes after its end. Pain was assessed immediately before physiotherapy, ten minutes after the beginning of physiotherapy and five minutes after its end. Pain and physiological changes were assessed by the Friedman test and the correlation between the physiological parameters and the pain scores was assessed by the Spearman test.

Results

Pain increased during physiotherapy and decreased significantly after it compared to pre-physiotherapy scores. Systolic blood pressure and heart rate increased significantly after 10 minutes of the beginning of physiotherapy. Arterial oxygen saturation tended to decrease during physiotherapy and to increase after it, although without significance. The correlation between pain scores and the physiological variables was significant only for systolic blood pressure and heart rate ten minutes after the beginning of physiotherapy.

Conclusion

Manipulation after the beginning of physiotherapy seems to be accompanied by significant pain and by important associated cardiovascular changes. Apparent analgesia and improved respiratory function were observed after respiratory physiotherapy.     

RA Differentiation Enhances Dopaminergic Features,Changes Redox Parameters,and Increases Dopamine Transporter Dependency in 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells

Research on Parkinson’s disease (PD) and drug development is hampered by the lack of suitable human in vitro models that simply and accurately recreate the disease conditions. To counteract this, many attempts to differentiate cell lines, such as the human SH-SY5Y neuroblastoma, into dopaminergic neurons have been undertaken since they are easier to cultivate when compared with other cellular models. Here, we characterized neuronal features discriminating undifferentiated and retinoic acid (RA)-differentiated SH-SYSY cells and described significant differences between these cell models in 6-hydroxydopamine (6-OHDA) cytotoxicity. In contrast to undifferentiated cells, RA-differentiated SH-SY5Y cells demonstrated low proliferative rate and a pronounced neuronal morphology with high expression of genes related to synapse vesicle cycle, dopamine synthesis/degradation, and of dopamine transporter (DAT). Significant differences between undifferentiated and RA-differentiated SH-SY5Y cells in the overall capacity of antioxidant defenses were found; although RA-differentiated SH-SY5Y cells presented a higher basal antioxidant capacity with high resistance against H₂O₂ insult, they were twofold more sensitive to 6-OHDA. DAT inhibition by 3α-bis-4-fluorophenyl-methoxytropane and dithiothreitol (a cell-permeable thiol-reducing agent) protected RA-differentiated, but not undifferentiated, SH-SY5Y cells from oxidative damage and cell death caused by 6-OHDA. Here, we demonstrate that undifferentiated and RA-differentiated SH-SY5Y cells are two unique phenotypes and also have dissimilar mechanisms in 6-OHDA cytotoxicity. Hence, our data support the use of RA-differentiated SH-SY5Y cells as an in vitro model of PD. This study may impact our understanding of the pathological mechanisms of PD and the development of new therapies and drugs for the management of the disease.     

The NFκB-mediated control of RS and JNK signaling in vitamin A-treated cells: Duration of JNK-AP-1 pathway activation may determine cell death or proliferation

Nuclear factor kappa B (NFκB) has emerged as a crucial regulator of cell survival, playing important functions in cellular resistance to oxidants and chemotherapeutic agents. Recent studies showed that NFκB mediates cell survival through suppression of the accumulation of reactive species (RS) and a control of sustained activation of the Jun-N-terminal kinase (JNK) cascade. This work was undertaken in order to evaluate the role of NFκB in modulating the pro-oxidant effects of supplementation with vitamin A (retinol, ROH) in Sertoli cells, a major ROH physiological target. In this work, we reported that ROH treatment increases mitochondrial RS formation leading to a redox-dependent activation of NFκB. NFκB activation played a pivotal role in counteract RS accumulation in ROH-treated cells, since NFκB inhibition with DNA decoy oligonucleotides or pharmacological inhibitors (BAY-117082) potentiated ROH-induced RS accumulation and oxidative damage. In the presence of NFκB inhibition, ROH-induced oxidative stress promoted a prolonged activation of the JNK-activator protein 1 (AP-1) pathway and induced significant decreases in cell viability. Inhibition of JNK-AP-1 with decoy oligonucleotides to AP-1 or JNK inhibitor SP600125 prevented the decreases in cell viability. Antioxidants blocked the persistent JNK-AP-1 activation, cell oxidative damage, and the decreases in cell viability induced by NFκB inhibition. Finally, our data point superoxide dismutase (SOD)2 as a potential antioxidant factor involved in NFκB protective effects against ROH-induced oxidative stress. Taken together, data presented here show that NFκB mediates cellular resistance to the pro-oxidant effects of vitamin A by inhibiting RS accumulation and the persistent and redox-dependent activation of JNK-AP-1 cascade.     

Time-related increase in mitochondrial superoxide production,biomolecule damage and antioxidant enzyme activities in cortical astrocyte cultures

According to the free radical theory of aging, biological senescence processes develop from a general failure to maintain organism's homeostasis, probably due to oxidative stress. The brain is particularly susceptible to oxidative damage, and astrocytes are chiefly responsible for its antioxidant defense. Here we evaluated and compared the enzymatic antioxidant activities, mitochondrial superoxide production, and oxidative damage in biomolecule in cortex astrocytes from newborn Wistar rats maintained for 10-13 or 40-47 days in culture. We show that, besides an increase in antioxidant enzyme activities in matured astrocyte cultures, there was an increase in lipoperoxidation and in protein oxidation, probably due to an increase in mitochondrial electron transport chain superoxide production. This could indicate that the increasing in defense mechanisms was not sufficient to avoid oxidative biomolecule damage during maturation.