Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation.

Alterations of redox homeostasis leads to a condition of resilience known as hormesis that is due to the activation of redox-sensitive pathways stimulating cell proliferation, growth, differentiation, and angiogenesis. Instead, supraphysiological production of reactive oxygen species (ROS) exceeds antioxidant defence and leads to oxidative distress. This condition induces damage to biomolecules and is responsible or co-responsible for the onset of several chronic pathologies.

PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis.

Cancer stem cells (CSCs) are a limited cell population inside a tumor bulk characterized by high levels of glutathione (GSH), the most important antioxidant thiol of which cysteine is the limiting amino acid for GSH biosynthesis. In fact, CSCs over-express xCT, a cystine transporter stabilized on cell membrane through interaction with CD44, a stemness marker whose expression is modulated by protein kinase Cα (PKCα). Since many chemotherapeutic drugs, such as Etoposide, exert their cytotoxic action by increasing reactive oxygen species (ROS) production, the presence of high antioxidant defenses confers to CSCs a crucial role in chemoresistance.

Whey proteins inhibit food intake and tend to improve oxidative balance in obese zucker rats.

Background/aims: Whey proteins (WP), obtained from milk after casein precipitation, represent a heterogeneous group of proteins. WP are reported to inhibit food intake in diet-induced experimental obesity; WP have been proposed as adjuvant therapy in oxidative stress-correlated pathologies. This work evaluates the effects of WP in comparison with casein, as a source of alimentary proteins, on food intake, weight growth and some indexes of oxidative equilibrium in Zucker Rats, genetically prone to obesity.

HO-1 downregulation favors BRAF melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition.

Heme oxygenase 1 (HO-1) plays a pivotal role in preventing cell damage. Indeed, through the antioxidant, antiapoptotic and anti-inflammatory properties of its metabolic products, it favors cell adaptation against different stressors. However, HO-1 induction has also been related to the gain of resistance to therapy in different types of cancers and its involvement in cancer immune-escape has been hypothesized.

Heme Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce Neurodegeneration?

Heme oxygenase 1 (HO-1) up-regulation is recognized as a pivotal mechanism of cell adaptation to stress. Under control of different transcription factors but with a prominent role played by Nrf2, HO-1 induction is crucial also in nervous system response to damage. However, several lines of evidence have highlighted that HO-1 expression is associated to neuronal damage and neurodegeneration especially in Alzheimer's and Parkinson's diseases.

microRNA-494 Favors HO-1 Expression in Neuroblastoma Cells Exposed to Oxidative Stress in a Bach1-Independent Way.

Heme oxygenase 1 (HO-1) is crucially involved in cell adaptation to oxidative stress and has been demonstrated to play an important role in cancer progression and resistance to therapies. We recently highlighted that undifferentiated neuroblastoma (NB) cells are prone to counteract oxidative stress through the induction of HO-1. Conversely, differentiated NB cells were more sensitive to oxidative stress since HO-1 was scarcely upregulated.

Differentiation impairs Bach1 dependent HO-1 activation and increases sensitivity to oxidative stress in SH-SY5Y neuroblastoma cells.

Neuronal adaptation to oxidative stress is crucially important in order to prevent degenerative diseases. The role played by the Nrf2/HO-1 system in favoring cell survival of neuroblastoma (NB) cells exposed to hydrogen peroxide (HO) has been investigated using undifferentiated or all-trans retinoic acid (ATRA) differentiated SH-SY5Y cells. While undifferentiated cells were basically resistant to the oxidative stimulus, ATRA treatment progressively decreased cell viability in response to HO.

HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation.

The upregulation of heme oxygenase-1 (HO-1) is one of the most important mechanisms of cell adaptation to stress. Indeed, the redox sensitive transcription factor Nrf2 is the pivotal regulator of HO-1 induction. Through the antioxidant, antiapoptotic, and antinflammatory properties of its metabolic products, HO-1 plays a key role in healthy cells in maintaining redox homeostasis and in preventing carcinogenesis.

Redox Homeostasis and Cellular Antioxidant Systems: Crucial Players in Cancer Growth and Therapy.

Reactive oxygen species (ROS) and their products are components of cell signaling pathways and play important roles in cellular physiology and pathophysiology. Under physiological conditions, cells control ROS levels by the use of scavenging systems such as superoxide dismutases, peroxiredoxins, and glutathione that balance ROS generation and elimination. Under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids, and DNA, leading to cell damage that may contribute to carcinogenesis.

RAGE Expression and ROS Generation in Neurons: Differentiation versus Damage.

RAGE is a multiligand receptor able to bind advanced glycation end-products (AGEs), amphoterin, calgranulins, and amyloid-beta peptides, identified in many tissues and cells, including neurons. RAGE stimulation induces the generation of reactive oxygen species (ROS) mainly through the activity of NADPH oxidases. In neuronal cells, RAGE-induced ROS generation is able to favor cell survival and differentiation or to induce death through the imbalance of redox state.

Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib.

The activation of Nrf2 has been demonstrated to play a crucial role in cancer cell resistance to different anticancer therapies. The inhibition of proteasome activity has been proposed as a chemosensitizing therapy but the activation of Nrf2 could reduce its efficacy. Using the highly chemoresistant neuroblastoma cells HTLA-230, here we show that the strong reduction in proteasome activity, obtained by using low concentration of bortezomib (BTZ, 2.

The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance.

The transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2), acts as a sensor of oxidative or electrophilic stresses and plays a pivotal role in redox homeostasis. Oxidative or electrophilic agents cause a conformational change in the Nrf2 inhibitory protein Keap1 inducing the nuclear translocation of the transcription factor which, through its binding to the antioxidant/electrophilic response element (ARE/EpRE), regulates the expression of antioxidant and detoxifying genes such as heme oxygenase 1 (HO-1). Nrf2 and HO-1 are frequently upregulated in different types of tumours and correlate with tumour progression, aggressiveness, resistance to therapy, and poor prognosis.

Evaluating the role of hnRNP-C and FMRP in the cAMP-induced APP metabolism.

Cyclic adenosine monophosphate (cAMP) modulates synaptic plasticity and memory and manipulation of the cAMP/protein kinase A/cAMP responsive element binding protein pathway significantly affects cognitive functions. Notably, cAMP can increase the expression of the amyloid precursor protein (APP), whose proteolytic processing gives rise to amyloid beta (Aβ) peptides. Despite playing a pathogenic role in Alzheimer's disease, physiological concentrations of Aβ are necessary for the cAMP-mediated regulation of long-term potentiation, supporting the existence of a novel cAMP/APP/Aβ cascade with a crucial role in memory formation.

A novel mechanism for cyclic adenosine monophosphate-mediated memory formation: Role of amyloid beta.

Cyclic adenosine monophosphate (cAMP) regulates long-term potentiation (LTP) and ameliorates memory in healthy and diseased brain. Increasing evidence shows that, under physiological conditions, low concentrations of amyloid β (Aβ) are necessary for LTP expression and memory formation. Here, we report that cAMP controls amyloid precursor protein (APP) translation and Aβ levels, and that the modulatory effects of cAMP on LTP occur through the stimulation of APP synthesis and Aβ production.

Monomeric Aβ1-42 and RAGE: key players in neuronal differentiation.

The aggregation of amyloid-β (Aβ) peptides plays a crucial role in the onset and progression of Alzheimer's disease. Monomeric form of Aβ, indeed, could exert a physiological role. Considering the anti-oligomerization property of all-trans retinoic acid (ATRA), the involvement of monomeric Aβ1-42 in ATRA-induced neuronal differentiation has been investigated.

HO-1 up-regulation: a key point in high-risk neuroblastoma resistance to bortezomib.

High-risk neuroblastoma (NB) is characterized by the development of chemoresistance, and bortezomib (BTZ), a selective inhibitor of proteasome, has been proposed in order to overcome drug resistance. Considering the involvement of the nuclear factor-erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in the antioxidant and detoxifying ability of cancer cells, in this study we have investigated their role in differently aggressive NB cell lines treated with BTZ, focusing on the modulation of HO-1 to improve sensitivity to therapy. We have shown that MYCN amplified HTLA-230 cells were slightly sensitive to BTZ treatment, due to the activation of Nrf2 that led to an impressive up-regulation of HO-1.

Role of glutathione in cancer progression and chemoresistance.

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.

p38MAPK inhibition: a new combined approach to reduce neuroblastoma resistance under etoposide treatment.

Neuroblastoma (NB) is the second most common solid pediatric tumor and is characterized by clinical and biological heterogeneity, and stage-IV of the disease represents 50% of all cases. Considering the limited success of present chemotherapy treatment, it has become necessary to find new and effective therapies. In this context, our approach consists of identifying and targeting key molecular pathways associated with NB chemoresistance.

Cyclic adenosine monophosphate as an endogenous modulator of the amyloid-β precursor protein metabolism.

Besides playing a pathogenic role in Alzheimer disease, amyloid-beta peptides are normally produced in low amounts in the brain, and several lines of evidence suggest that they can modulate synaptic plasticity and memory. As cyclic adenosine monophosphate (cAMP) is known to be involved in the same processes and the blockade of its degradation by phosphodiesterase 4 inhibitors has consistently shown beneficial effects on cognition, we investigated the possible correlation between this second messenger and Aβ peptides in neuronal N2a cells overexpressing the amyloid-β precursor protein (APP). We herein report that the elevation of endogenous cAMP by rolipram increased APP protein expression and both its amyloidogenic and nonamyloidogenic processing.

Cholesterol and Alzheimer's disease: a still poorly understood correlation.

A large amount of evidence suggests a pathogenic link between cholesterol homeostasis dysregulation and Alzheimer's disease (AD). In cell culture systems, the production of amyloid-β (Aβ) is modulated by cholesterol, and studies on animal models have consistently demonstrated that hypercholesterolemia is associated with an increased deposition of cerebral Aβ peptides. Consequently, a number of epidemiological studies have examined the effects of cholesterol-lowering drugs (i.

Impaired synthesis contributes to diabetes-induced decrease in liver glutathione.

Diabetes-induced glutathione (GSH) decrease is usually ascribed to GSH oxidation. Here we investigate, in streptozotocin-treated rats, if impairment of GSH synthesis contributes to GSH decrease in diabetic liver, and if antioxidant treatments can provide protection. Diabetic rats were divided into 3 groups: untreated diabetic rats (UD); N-acetyl-cysteine (NAC)-treated diabetic rats; taurine (TAU)-treated diabetic rats; a group of non-streptozotocin-treated rats was used as control (CTR).

Resistance of neuroblastoma GI-ME-N cell line to glutathione depletion involves Nrf2 and heme oxygenase-1.

Cancer cell survival is known to be related to the ability to counteract oxidative stress, and glutathione (GSH) depletion has been proposed as a mechanism to sensitize cells to anticancer therapy. However, we observed that GI-ME-N cells, a neuroblastoma cell line without MYCN amplification, are able to survive even if GSH-depleted by l-buthionine-(S,R)-sulfoximine (BSO). Here, we show that in GI-ME-N cells, BSO activates Nrf2 and up-regulates heme oxygenase-1 (HO-1).

GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses.

Background And Purpose: Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3-cyclopentyloxy-4-methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity.

Cholesterol and amyloid-β: evidence for a cross-talk between astrocytes and neuronal cells.

Accumulating data supports the concept that alterations of cholesterol metabolism might influence the development of Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive accumulation of amyloid-β (Aβ) peptides in the brain. Changes in the neuronal production of Aβ have been described as a function of cholesterol levels, thus suggesting a causal link between cholesterol homeostasis dysregulation and AD pathogenesis. Under physiological conditions, cholesterol uptake in the brain is efficiently prevented by the blood-brain barrier, and mature neurons are thought to rely on glial cells for their cholesterol supply.

PKCδ sensitizes neuroblastoma cells to L-buthionine-sulfoximine and etoposide inducing reactive oxygen species overproduction and DNA damage.

Neuroblastoma is a type of pediatric cancer. The sensitivity of neuroblastoma (NB) cancer cells to chemotherapy and radiation is inhibited by the presence of antioxidants, such as glutathione (GSH), which is crucial in counteracting the endogenous production of reactive oxygen species (ROS). We have previously demonstrated that cells depleted of GSH undergo apoptosis via oxidative stress and Protein kinase C (PKC) δ activation.