Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention.

A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant protein production via induction of Nrf2 transcription factor.

One- and Two-Electron Oxidations of β-Amyloid by Carbonate Radical Anion (CO) and Peroxymonocarbonate (HCO): Role of Sulfur in Radical Reactions and Peptide Aggregation.

The β-amyloid (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease. The methionine (Met) residue at position 35 in Aβ C-terminal domain is critical for neurotoxicity, aggregation, and free radical formation initiated by the peptide. The role of Met in modulating toxicological properties of Aβ most likely involves an oxidative event at the sulfur atom.

Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer's disease.

Hyper-active GSK-3β favors Tau phosphorylation during the progression of Alzheimer's disease (AD). Akt is one of the main kinases inhibiting GSK-3β and its activation occurs in response to neurotoxic stimuli including, i.e.

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome.

Background: Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression.

Redox proteomic analysis of serum from aortic anerurysm patients: insights on oxidation of specific protein target.

Objectives: oxidative stress is undoubtedly one of the main players in abdominal aortic aneurysm (AAA) pathophysiology. Recent studies in AAA patients reported an increase in the indices of oxidative damage at the tissue level and in biological fluids coupled with the loss of counter-regulatory mechanisms of protection from oxidative stress. We recently reported, in a proteomic analysis of AAA patient sera, changes in the expression of several proteins exerting important modulatory activities on cellular proliferation, differentiation and response to damage.

Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype.

Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer's disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages.

Bach1 overexpression in Down syndrome correlates with the alteration of the HO-1/BVR-a system: insights for transition to Alzheimer's disease.

Bach1, among the genes encoded on chromosome 21, is a transcription repressor, which binds to antioxidant response elements of DNA thus inhibiting the transcription of specific genes involved in the cell stress response including heme oxygenase-1 (HO-1). HO-1 and its partner, biliverdin reductase-A (BVR-A), are upregulated in response to oxidative stress in order to protect cells against further damage. Since oxidative stress is an early event in Down syndrome (DS) and might contribute to the development of multiple deleterious DS phenotypes, including Alzheimer's disease (AD) pathology, we investigated the status of the Bach1/HO-1/BVR-A axis in DS and its possible implications for the development of AD.

Oxidative stress in HPV-driven viral carcinogenesis: redox proteomics analysis of HPV-16 dysplastic and neoplastic tissues.

Genital infection by high risk Human Papillomavirus (HR-HPV), although recognized as the main etio-pathogenetic factor of cervical cancer, is not per se sufficient to induce tumour development. Oxidative stress (OS) represents an interesting and under-explored candidate as a promoting factor in HPV-initiated carcinogenesis. To gain insight into the role of OS in cervical cancer, HPV-16 positive tissues were collected from patients with invasive squamous cervical carcinoma, from patients with High Grade dysplastic HPV lesions and from patients with no clinical evidence of HPV lesions.

Serum proteomics in patients with diagnosis of abdominal aortic aneurysm.

Background: Molecular mechanisms underlying abdominal aneurysm (AAA) formation and rupture are not well understood. Early detection and repair of AAA may reduce the high mortality rates associated with rupture. Serum proteomics allows the detection of alterations in the expression of proteins, guiding further studies on these target molecules as potential markers.

Formation of 3-nitrotyrosine by riboflavin photosensitized oxidation of tyrosine in the presence of nitrite.

The results of the present investigation show the susceptibility of tyrosine to undergo visible light-induced photomodification to 3-nitrotyrosine in the presence of nitrite and riboflavin, as sensitizer. By changing H2O by D2O, it could be established that singlet oxygen has a minor role in the reaction. The finding that nitration of tyrosine still occurred to a large extent under anaerobic conditions indicates that the process proceeds mainly through a type I mechanism, which involves the direct interaction of the excited state of riboflavin with tyrosine and nitrite to give tyrosyl radical and nitrogen dioxide radical, respectively.

Effects of UVB-induced oxidative stress on protein expression and specific protein oxidation in normal human epithelial keratinocytes: a proteomic approach.

Background: The UVB component of solar ultraviolet irradiation is one of the major risk factors for the development of skin cancer in humans. UVB exposure elicits an increased generation of reactive oxygen species (ROS), which are responsible for oxidative damage to proteins, DNA, RNA and lipids. In order to examine the biological impact of UVB irradiation on skin cells, we used a parallel proteomics approach to analyze the protein expression profile and to identify oxidatively modified proteins in normal human epithelial keratinocytes.

Advanced glycation end products in diabetic patients with optimized glycaemic control and their effects on endothelial reactivity: possible implications in venous graft failure.

Background: Diabetic patients exhibit an increased risk of saphenous graft occlusion after coronary bypass. Advanced glycation end products (AGEs) are ubiquitous signalling proteins that are associated with vascular and neurological complication of diabetes. The aim of this study is to verify whether AGE levels may promote endothelial cell alterations responsible for vein graft failure.

Proteomics analysis of protein expression and specific protein oxidation in human papillomavirus transformed keratinocytes upon UVB irradiation.

Increasing evidence supports the role of oxidative stress in cancer development. Ultraviolet (UV) irradiation is one of the major sources of oxidative stress through the generation of reactive oxygen species (ROS). Besides the physiological function of ROS in cellular homeostasis, accumulating reports suggest that ROS are involved in all stages of multistep cancer development.

Expression of human papilloma virus type 16 E5 protein in amelanotic melanoma cells regulates endo-cellular pH and restores tyrosinase activity.

Background: Melanin synthesis, the elective trait of melanocytes, is regulated by tyrosinase activity. In tyrosinase-positive amelanotic melanomas this rate limiting enzyme is inactive because of acidic endo-melanosomal pH. The E5 oncogene of the Human Papillomavirus Type 16 is a small transmembrane protein with a weak transforming activity and a role during the early steps of viral infections.

UVB irradiation down-regulates HPV-16 RNA expression: implications for malignant progression of transformed cells.

A new cell line obtained from normal human epithelial keratinocytes transfected with the whole HPV-16 genome has been extensively characterised. This cell line, named HK-168, has a basal/para-basal keratinocyte phenotype, requires the use of serum-free chemically defined media and maintains the ability to differentiate toward pluri-stratified epithelia. Although immortalised it is not capable of anchorage independent growth and is not tumorigenic.

Biological response of human diploid keratinocytes to quinone-producing compounds: role of NAD(P)H:quinone oxidoreductase 1.

Reactive oxygen species (ROS) and quinones are known to determine redox balance alteration, oxidative stress and carcinogenicity. Keratinocytes of the human epidermis, a tissue particularly exposed to oxidant stimuli, possess a wide range of antioxidant and detoxifying mechanisms aimed to avoid oxidative damage of the tissue. In the present study, we evaluate the response of diploid and transformed human keratinocytes to exposure to L-dopa and tetrahydropapaveroline (THP), catechol compounds susceptible to undergo oxidation to form quinones with concomitant production of reactive oxygen species.

Ectopic deposition of melanin pigments as detoxifying mechanism: a paradigm for basal nuclei pigmentation.

Melanins are UV shielding pigments found in skin and other light exposed tissues. However, a kind of melanin, named neuromelanin (NM), is found in those deep brain loci that degenerate in Parkinson's disease (PD), where no such a function may be imagined. The NM synthetic pathway, different from the one of eumelanin based on tyrosinase, is still obscure as well as its physiological function.

Tyrosinase protects human melanocytes from ROS-generating compounds.

The effects of two tetrahydroisoquinolines (TIQs), tetrahydropapaveroline (THP) and salsolinol (SAL), on human primary melanocytes were studied. These compounds are naturally occurring alkaloids deriving from the condensation of dopamine with aldehydes. The effects on the viability were studied by treating the cells with variable concentration of THP or SAL; both TIQs were well tolerated up to roughly 30 micro M.

Cytotoxicity of dopamine-derived tetrahydroisoquinolines on melanoma cells.

Tetrahydroisoquinolines (TIQs) are endogenous alkaloid compounds detected in urine, central nervous system and some peripheral tissues in Mammalia. No data are at present available on TIQ levels in skin, although in vitro biochemical evidences indicate that they may undergo auto-oxidation with production of reactive oxygen species or may be enzymatically converted into melanin pigments. The effect of two catechol-bearing TIQs, salsolinol (SAL) and tetrahydropapaveroline (THP), on the viability of melanotic or amelanotic melanoma cell lines was investigated.

Tetrahydroisoquinoline derivatives of enkephalins: synthesis and properties.

Tetrahydroisoquinolines (TIQs) are endogenous alkaloid compounds deriving from the non-enzymatic Pictet-Spengler condensation of catecholamines with aldehydes. These compounds are able to unsettle catecholamines uptake and release from synaptosomes and have been detected in urine and in post-mortem Parkinsonian brains. We have obtained in vitro, by the reaction of dopa-enkephalin (dopa-Gly-Gly-Phe-Leu) with acetaldehyde in the presence of rameic ions, a TIQ derivative of Leu-enkephalin.