Activation of c-Jun-N-terminal kinase is required for apoptosis triggered by glutathione disulfide in neuroblastoma cells

Changes in intracellular redox status are crucial events that trigger downstream proliferation or death responses through activation of specific signaling pathways. Moreover, cell responses to oxidative challenge may depend on the pattern of redox-sensitive molecular factors. The stress-activated protein kinases c-Jun-N-terminal kinase (JNK) and p38 MAP kinase (p38(MAPK)) are implicated in different forms of apoptotic neuronal cell death. Here, we investigated the effects, on neuroblastoma cells, of the prooxidant molecule GSSG, which we previously demonstrated to be an efficient proapoptotic compound able to activate the p38(MAPK) death pathway in promonocytic cells. We found that neuroblastoma cells are not prone to GSSG-induced apoptosis, although the treatment slightly induced growth arrest through the accumulation of p53 and its downstream target gene, p21. However, GSSG treatment became cytotoxic when cells were previously depleted of intracellular GSH content. Under this condition, apoptosis was triggered by an increased production of superoxide that led to a specific activation of the JNK-dependent pathway. The involvement of superoxide and JNK was demonstrated by cell death inhibition in experiments carried out in the presence of Cu,Zn superoxide dismutase or with specific inhibitors of JNK activity. Our data give support to the studies that indicate preferential requirements for the involvement of stress-activated kinases in apoptotic neuronal cells. (c) 2005 Elsevier Inc. All rights reserved

Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells

Glutathione (γ-L-glutamyl-L-cysteinyl-glycine, GSH) is the most abundant low molecular weight, thiol-containing compound within the cells and has a primary role in the antioxidant defense and intracellular signaling. Here we demonstrated that nutrient deprivation led to a significant decrease of intracellular GSH levels in three different carcinoma cell lines. This phenomenon was dependent on ABCC1-mediated GSH extrusion, along with GCL inhibition and, to a minor extent, the formation of GSH-protein mixed disulfides that synergistically contributed to the modulation of autophagy by shifting the intracellular redox state toward more oxidizing conditions. Modulation of intracellular GSH by inhibiting its de novo synthesis through incubation with buthionine sulfoximine, or by maintaining its levels through GSH ethyl ester, affected the oxidation of protein thiols, such as PRDXs and consequently the kinetics of autophagy activation. We also demonstrated that thiol-oxidizing or -alkylating agents, such as diamide and diethyl maleate activated autophagy, corroborating the evidence that changes in thiol redox state contributed to the occurrence of autophagy

Can unlisted firms benefit from market information? A data-driven approach

[EN] We employ a sample of 10,136 Italian micro-, small-, and mid-sized enterprises (MSMEs) that borrow from 113 cooperative banks to examine whether market pricing of public firms adds additional information to accounting measures in predicting default of private firms. Specifically, we first match the asset prices of listed firms following a data-driven clustering by means of Neural Networks Autoencoder so to evaluate the firm-wise probability of default (PD) of MSMEs. Then, we adopt three statistical techniques, namely linear models, multivariate adaptive regression spline, and random forest to assess the performance of the models and to explain the relevance of each predictor. Our results provide novel evidence that market information represents a crucial indicator in predicting corporate default of unlisted firms. Indeed, we show a significant improvement of the model performance, both on class-specific (F1-score for defaulted class) and overall metrics (AUC) when using market information in credit risk assessment, in addition to accounting information. Moreover, by taking advantage of global and local variable importance technique we prove that the increase in performance is effectively attributable to market information, highlighting its relevant effect in predicting corporate default.Bitetto, A.; Filomeni, S.; Modina, M. (2022). Can unlisted firms benefit from market information? A data-driven approach. En 4th International Conference on Advanced Research Methods and Analytics (CARMA 2022). Editorial Universitat Politècnica de València. 65-72. https://doi.org/10.4995/CARMA2022.2022.15045657

Redox bases underlying the anti-tumor activity of garlic-contained organo-sulfur compounds: Implication in chemoprevention and chemotherapy

The beneficial effects of phytochemicals on human health have been extensively addressed. The majority of this outcome derives from their capability to function as antioxidants, thus the consumption of foods rich in these compounds is considered an advisable preventive therapy in slowing oxidative stress-mediated degenerative processes, such as those occurring during aging. Nevertheless, high concentrations of redox-active compounds could switch the antioxidant property to a pro-oxidant action leading to cell cycle arrest and death. This aspect place phytochemicals as promising therapeutics particularly for cancer prevention or treatment. Although their beneficial properties are known from ancient times, only during the recent years the molecular mechanisms underlying the anti-proliferative effects mediated by garlic-derived organo-sulfur compounds (OSC) are going to be clarified, with particular regard to what their pro-apoptotic features concerns. This chapter discusses the main findings that have contributed to the comprehension of OSC-mediated redox-dependent events governing growth arrest and apoptosis. Particularly, we report the mechanisms through which OSC have been suggested to generate reactive oxygen species and to modulate the redox state of specific reactive cysteines. Both processes will be argued as necessary events in inducing either irreversible damage to cellular macromolecules (e.g. DNA and cytoskeleton proteins), or waves of signaling finally resulting in the activation of the apoptotic program. In this perspective, the classes of proteins which have been indicated to represent the targets of OSC-mediated oxidative modifications, and to have a role in cellular redox response will be discussed

Redox bases underlying the anti-tumor activity of garlic-contained organo-sulfur compounds: Implication in chemoprevention and chemotherapy

The beneficial effects of phytochemicals on human health have been extensively addressed. The majority of this outcome derives from their capability to function as antioxidants, thus the consumption of foods rich in these compounds is considered an advisable preventive therapy in slowing oxidative stress-mediated degenerative processes, such as those occurring during aging. Nevertheless, high concentrations of redox-active compounds could switch the antioxidant property to a pro-oxidant action leading to cell cycle arrest and death. This aspect place phytochemicals as promising therapeutics particularly for cancer prevention or treatment. Although their beneficial properties are known from ancient times, only during the recent years the molecular mechanisms underlying the anti-proliferative effects mediated by garlic-derived organo-sulfur compounds (OSC) are going to be clarified, with particular regard to what their pro-apoptotic features concerns. This chapter discusses the main findings that have contributed to the comprehension of OSC-mediated redox-dependent events governing growth arrest and apoptosis. Particularly, we report the mechanisms through which OSC have been suggested to generate reactive oxygen species and to modulate the redox state of specific reactive cysteines. Both processes will be argued as necessary events in inducing either irreversible damage to cellular macromolecules (e.g. DNA and cytoskeleton proteins), or waves of signaling finally resulting in the activation of the apoptotic program. In this perspective, the classes of proteins which have been indicated to represent the targets of OSC-mediated oxidative modifications, and to have a role in cellular redox response will be discussed

SOMALIA 1992-1994: UNA MISSIONE, MOLTI DUBBI. Le difficoltà incontrate dalla Comunità internazionale nella c.d. "imposizione della pace".

La missione umanitaria in Somalia dei primi anni novanta viene ricordata come un insuccesso dell’ONU e, più in generale, della Comunità internazionale, in un Stato devastato dalla guerra civile. Il presente elaborato si propone di ricercare le possibili cause che potrebbero aver condotto i nobili propositi umanitari di soccorso alla popolazione, nel vicolo cieco dell’escalation dell’uso della forza militare all’interno di un c.d. “failed State”. Una missione articolata (33 Stati partecipanti) contraddistinta, appunto, dalla consistente divergenza politico-militare tra gli Stati partecipanti, per quanto concerneva le modalità d’uso della forza militare in relazione al mandato ricevuto. La ricerca si estende alla liceità della nuova prassi del Consiglio di Sicurezza negli interventi di polizia internazionali mediante delega di uso della forza, finanche all’opportunità nell’utilizzo degli strumenti di peace keeping di terza generazione nelle sempre più complesse missioni internazionali di mantenimento della pace

Reactive oxygen species-dependent c-Jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide

The pharmacological properties of garlic and its derivatives are long known, and their underling mechanisms are being extensively investigated. In this study we have addressed the effects of diallyl disulfide (DADS), an oil-soluble garlic molecule, on cell growth of neuroblastoma cell SH-SY5Y, focusing on the redox events associated with this compound. Treatment of SH-SY5Y cells with DADS resulted in arrest of cell cycle in G(2)/M phase and commitment to apoptosis through the activation of the mitochondrial pathway (Bcl-2 down-regulation, cytochrome c release into the cytosol, and activation of caspase-9 and caspase-3). The earliest oxidative event observed after DADS treatment was the increase of production of reactive oxygen species, which reached the maximum yield on 30 min of DADS treatment. The oxidative burst resulted in protein and lipid damage as demonstrated by protein carbonyl accumulation and lipid peroxidation. We demonstrated that apoptosis induction was highly dependent on the activation of the redox-sensitive c-Jun NH2-terminal kinase (JNK)/c-jun pathway. In particular, we established that DADS treatment induces JNK dissociation from glutathione S-transferase and its activation by phosphorylation. Moreover, treatment with JNK inhibitor I significantly reduced DADS-induced apoptosis and treatment with the spin trap 5,5'-dimethyl-1-pyrroline N-oxide or overexpression of the antioxidant enzyme copper, zinc superoxide dismutase, resulted in the inhibition of DADS-mediated toxicity through attenuation of JNK/c-jun pathway activation. Overall, the results suggest a pivotal role for oxidative stress in DADS-induced apoptosis and, taking into account that tumor cells are deficient in antioxidants, suggest a plausible utilization of this compound as an antiproliferative agent in cancer therapy