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1. CAPE and its synthetic derivative VP961 restore BACH1/NRF2 axis in Down Syndrome

Author

Pagnotta, S., Tramutola, A., Barone, E., Di Domenico, F., Pittala, V., Salerno, L., Folgiero, V., Caforio, M., Locatelli, Franco, Petrini, S., Butterfield, D. A., Perluigi, M., Locatelli F. (ORCID:0000-0002-7976-3654), Pagnotta, S., Tramutola, A., Barone, E., Di Domenico, F., Pittala, V., Salerno, L., Folgiero, V., Caforio, M., Locatelli, Franco, Petrini, S., Butterfield, D. A., Perluigi, M., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

The cells possess several mechanisms to counteract the over-production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), including enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Moreover, an important sensor involved in the anti-oxidant response is KEAP1-NRF2-ARE signaling complex. Under oxidative stress (OS), the transcription factor NRF2 can dissociate from the KEAP1-complex in the cytosol and translocate into the nucleus to promote the transcriptional activation of anti-oxidant genes, such as heme oxygenase 1 and NADPH quinone oxidoreductase. Within this context, the activation of NRF2 response is further regulated by BACH1, a transcription repressor, that compete with the KEAP1-NRF2-ARE complex. In this work, we focused on the role of BACH1/NRF2 ratio in the regulation of the anti-oxidant response, proposing their antithetical relation as a valuable target for a therapeutic strategy to test drugs able to exert neuroprotective effects, notably in aging and neurodegenerative diseases. Among these, Down syndrome (DS) is a complex genetic disorder characterized by BACH1 gene triplication that likely results in the impairment of NRF2 causing increased OS. Our results revealed that BACH1 overexpression alters the BACH1/NRF2 ratio in the nucleus and disturbs the induction of antioxidant response genes ultimately resulting in the accumulation of oxidative damage both in Ts2Cje mice (a mouse model of DS) and human DS lymphoblastoid cell lines (LCLs). Based on this evidence, we tested Caffeic Acid Phenethyl Ester (CAPE) and the synthetic analogue VP961, which have been proven to modulate NRF2 activity. We showed that CAPE and VP961 administration to DS LCLs was able to promote NRF2 nuclear translocation, which resulted in the amelioration of antioxidant response. Overall, our study supports the hypothesis that BACH1 triplication in DS subjects is implicated in the alteration of redox homeostasis and therapeutic strategies to

Published
2022

5. High-fat diet leads to reduced protein o-glcnacylation and mitochondrial defects promoting the development of alzheimer’s disease signatures

Author

Zuliani, I., Lanzillotta, C., Tramutola, A., Barone, E., Perluigi, M., Rinaldo, S., Paone, A., Cutruzzola, F., Bellanti, F., Spinelli, M., Natale, Francesca, Fusco, Salvatore, Grassi, Claudio, Di Domenico, F., Natale F. (ORCID:0000-0001-7856-930X), Fusco S. (ORCID:0000-0003-3294-0016), Grassi C. (ORCID:0000-0001-7253-1685), Zuliani, I., Lanzillotta, C., Tramutola, A., Barone, E., Perluigi, M., Rinaldo, S., Paone, A., Cutruzzola, F., Bellanti, F., Spinelli, M., Natale, Francesca, Fusco, Salvatore, Grassi, Claudio, Di Domenico, F., Natale F. (ORCID:0000-0001-7856-930X), Fusco S. (ORCID:0000-0003-3294-0016), and Grassi C. (ORCID:0000-0001-7253-1685)

Abstract

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.

Published
2021

7. The Anti-Diabetic Drug Metformin Rescues Aberrant Mitochondrial Activity and Restrains Oxidative Stress in a Female Mouse Model of Rett Syndrome

Author

Zuliani I, Urbinati C, Valenti D, Quattrini MC, Medici V, Cosentino L, Pietraforte D, Di Domenico F, Perluigi M, Vacca RA, and De Filippis B.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Nrf2, PGC-1?, Rett syndrome, metformin, repurposing
Abstract

Metformin is the first-line therapy for diabetes, even in children, and a promising attractive candidate for drug repurposing. Mitochondria are emerging as crucial targets of metformin action both in the periphery and in the brain. The present study evaluated whether treatment with metformin may rescue brain mitochondrial alterations and contrast the increased oxidative stress in a validated mouse model of Rett syndrome (RTT), a rare neurologic disorder of monogenic origin characterized by severe behavioral and physiological symptoms. No cure for RTT is available. In fully symptomatic RTT mice (12 months old MeCP2-308 heterozygous female mice), systemic treatment with metformin (100 mg/kg ip for 10 days) normalized the reduced mitochondrial ATP production and ATP levels in the whole-brain, reduced brain oxidative damage, and rescued the increased production of reactive oxidizing species in blood. A 10-day long treatment with metformin also boosted pathways related to mitochondrial biogenesis and antioxidant defense in the brain of metformin-treated RTT mice. This treatment regimen did not improve general health status and motor dysfunction in RTT mice at an advanced stage of the disease. Present results provide evidence that systemic treatment with metformin may represent a novel, repurposable therapeutic strategy for RTT.

Published
2020

8. Proteomics study of peripheral blood mononuclear cells in down syndrome children

Author

Lanzillotta, C., Greco, Viviana, Valentini, D., Villani, A., Folgiero, V., Caforio, M., Locatelli, Franco, Pagnotta, S., Barone, E., Urbani, Andrea, Domenico, F. D., Perluigi, M., Greco V. (ORCID:0000-0003-4521-0020), Locatelli F. (ORCID:0000-0002-7976-3654), Urbani A. (ORCID:0000-0001-9168-3174), Lanzillotta, C., Greco, Viviana, Valentini, D., Villani, A., Folgiero, V., Caforio, M., Locatelli, Franco, Pagnotta, S., Barone, E., Urbani, Andrea, Domenico, F. D., Perluigi, M., Greco V. (ORCID:0000-0003-4521-0020), Locatelli F. (ORCID:0000-0002-7976-3654), and Urbani A. (ORCID:0000-0001-9168-3174)

Abstract

Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. To search for biomarkers for the early detection and exploration of the disease mechanisms, here, we investigated the protein expression signature of peripheral blood mononuclear cells (PBMCs) in DS children compared with healthy donors (HD) by using an in-depth label-free shotgun proteomics approach. Identified proteins are found associated with metabolic pathways, cellular trafficking, DNA structure, stress response, cytoskeleton network, and signaling pathways. The results showed that a well-defined number of dysregulated pathways retain a prominent role in mediating DS pathological features. Further, proteomics results are consistent with published study in DS and provide evidences that increased oxidative stress and the increased induction of stress related response, is a participant in DS pathology. In addition, the expression levels of some key proteins have been validated by Western blot analysis while protein carbonylation, as marker of protein oxidation, was investigated. The results of this study propose that PBMCs from DS children might be in an activated state where endoplasmic reticulum stress and increased production of radical species are one of the primary events contributing to multiple DS pathological features.

Published
2020

11. Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome

Author

Di Domenico, F., Tramutola, A., Barone, E., Lanzillotta, C., Defever, O., Arena, A., Zuliani, Ivana, Foppoli, C., Iavarone, Federica, Vincenzoni, F., Castagnola, Massimo, Butterfield, D. A., Perluigi, M., Zuliani I., Iavarone F. (ORCID:0000-0002-2074-5531), Castagnola M. (ORCID:0000-0002-0959-7259), Di Domenico, F., Tramutola, A., Barone, E., Lanzillotta, C., Defever, O., Arena, A., Zuliani, Ivana, Foppoli, C., Iavarone, Federica, Vincenzoni, F., Castagnola, Massimo, Butterfield, D. A., Perluigi, M., Zuliani I., Iavarone F. (ORCID:0000-0002-2074-5531), and Castagnola M. (ORCID:0000-0002-0959-7259)

Abstract

Increasing evidences support the notion that the impairment of intracellular degradative machinery is responsible for the accumulation of oxidized/misfolded proteins that ultimately results in the deposition of protein aggregates. These events are key pathological aspects of “protein misfolding diseases”, including Alzheimer disease (AD). Interestingly, Down syndrome (DS) neuropathology shares many features with AD, such as the deposition of both amyloid plaques and neurofibrillary tangles. Studies from our group and others demonstrated, in DS brain, the dysfunction of both proteasome and autophagy degradative systems, coupled with increased oxidative damage. Further, we observed the aberrant increase of mTOR signaling and of its down-stream pathways in both DS brain and in Ts65Dn mice. Based on these findings, we support the ability of intranasal rapamycin treatment (InRapa) to restore mTOR pathway but also to restrain oxidative stress resulting in the decreased accumulation of lipoxidized proteins. By proteomics approach, we were able to identify specific proteins that showed decreased levels of HNE-modification after InRapa treatment compared with vehicle group. Among MS-identified proteins, we found that reduced oxidation of arginase-1 (ARG-1) and protein phosphatase 2A (PP2A) might play a key role in reducing brain damage associated with synaptic transmission failure and tau hyperphosphorylation. InRapa treatment, by reducing ARG-1 protein-bound HNE levels, rescues its enzyme activity and conceivably contribute to the recovery of arginase-regulated functions. Further, it was shown that PP2A inhibition induces tau hyperphosphorylation and spatial memory deficits. Our data suggest that InRapa was able to rescue PP2A activity as suggested by reduced p-tau levels. In summary, considering that mTOR pathway is a central hub of multiple intracellular signaling, we propose that InRapa treatment is able to lower the lipoxidation-mediated damage to proteins, thus represe

Published
2019

12. Proteomic identification of altered protein O-GlcNAcylation in a triple transgenic mouse model of Alzheimer's disease

Author

Tramutola, A., Sharma, N., Barone, E., Lanzillotta, C., Castellani, A., Iavarone, F., Vincenzoni, F., Castagnola, M., Butterfield, D. A., Gaetani, S., Cassano, T., Perluigi, M., Di Domenico, F., Iavarone F. (ORCID:0000-0002-2074-5531), Castagnola M. (ORCID:0000-0002-0959-7259), Tramutola, A., Sharma, N., Barone, E., Lanzillotta, C., Castellani, A., Iavarone, F., Vincenzoni, F., Castagnola, M., Butterfield, D. A., Gaetani, S., Cassano, T., Perluigi, M., Di Domenico, F., Iavarone F. (ORCID:0000-0002-2074-5531), and Castagnola M. (ORCID:0000-0002-0959-7259)

Abstract

PET scan analysis demonstrated the early reduction of cerebral glucose metabolism in Alzheimer disease (AD) patients that can make neurons vulnerable to damage via the alteration of the hexosamine biosynthetic pathway (HBP). Defective HBP leads to flawed protein O-GlcNAcylation coupled, by a mutual inverse relationship, with increased protein phosphorylation on Ser/Thr residues. Altered O-GlcNAcylation of Tau and APP have been reported in AD and is closely related with pathology onset and progression. In addition, type 2 diabetes patients show an altered O-GlcNAcylation/phosphorylation that might represent a link between metabolic defects and AD progression. Our study aimed to decipher the specific protein targets of altered O-GlcNAcylation in brain of 12-month-old 3×Tg-AD mice compared with age-matched non-Tg mice. Hence, we analysed the global O-GlcNAc levels, the levels and activity of OGT and OGA, the enzymes controlling its cycling and protein specific O-GlcNAc levels using a bi-dimensional electrophoresis (2DE) approach. Our data demonstrate the alteration of OGT and OGA activation coupled with the decrease of total O-GlcNAcylation levels. Data from proteomics analysis led to the identification of several proteins with reduced O-GlcNAcylation levels, which belong to key pathways involved in the progression of AD such as neuronal structure, protein degradation and glucose metabolism. In parallel, we analysed the O-GlcNAcylation/phosphorylation ratio of IRS1 and AKT, whose alterations may contribute to insulin resistance and reduced glucose uptake. Our findings may contribute to better understand the role of altered protein O-GlcNAcylation profile in AD, by possibly identifying novel mechanisms of disease progression related to glucose hypometabolism.

Published
2018

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

Author

Di Domenico, F, Pupo, G, Mancuso, Cesare, Barone, Eugenio, Paolini, F, Arena, A, Blarzino, C, Schmitt, Fa, Head, E, Butterfield, Da, Perluigi, M., Mancuso, Cesare (ORCID:0000-0001-6532-483X), Di Domenico, F, Pupo, G, Mancuso, Cesare, Barone, Eugenio, Paolini, F, Arena, A, Blarzino, C, Schmitt, Fa, Head, E, Butterfield, Da, Perluigi, M., and Mancuso, Cesare (ORCID:0000-0001-6532-483X)

Abstract

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. In the present study, we showed increased total Bach1 protein levels in the brain of all DS cases coupled with reduced induction of brain HO-1. Furthermore, increased oxidative stress could, on one hand, overcome the inhibitory effects of Bach1 and, on the other hand, promote BVR-A impairment. Our data show that the development of AD in DS subjects is characterized by (i) increased Bach1 total and poly-ubiquitination; (ii) increased HO-1 protein levels; and (iii) increased nitration of BVR-A followed by reduced activity. To corroborate our findings, we analyzed Bach1, HO-1, and BVR-A status in the Ts65Dn mouse model at 3 (young) and 15 (old) months of age. The above data support the hypothesis that the dysregulation of HO-1/BVR-A system contributes to the early increase of oxidative stress in DS and provide potential mechanistic paths involved in the neurodegenerative process and AD development.

Published
2015

30. Lack of p53 affects the expression of several brain mitochondrial proteins: insights from proteomics into important pathways regulated by p53

Author

Fiorini, A, Sultana, R, Barone, E, Cenini, G, Perluigi, M, Mancuso, Cesare, Cai, J, Klein, Jb, St Clair, D, Butterfield, Da, Mancuso, Cesare (ORCID:0000-0001-6532-483X), Fiorini, A, Sultana, R, Barone, E, Cenini, G, Perluigi, M, Mancuso, Cesare, Cai, J, Klein, Jb, St Clair, D, Butterfield, Da, and Mancuso, Cesare (ORCID:0000-0001-6532-483X)

Abstract

The tumor suppressor protein p53 has been described "as the guardian of the genome" for its crucial role in regulating the transcription of numerous genes responsible for cells cycle arrest, senescence, or apoptosis in response to various stress signals. Although p53 promotes longevity by decreasing the risk of cancer through activation of apoptosis or cellular senescence, several findings suggest that an increase of its activity may have deleterious effects leading to selected aspects of the aging phenotype and neurodegenerative diseases. There is the link between p53 and oxidative stress, the latter a crucial factor that contributes to neurodegenerative processes like Alzheimer disease (AD). In the present study, using a proteomics approach, we analyzed the impact of lack of p53 on the expression of several brain mitochondrial proteins involved in different pathways, and how lack of p53 may present a target to restore neuronal impairments. Our investigation on isolated brain mitochondria from p53((-/-)) mice also provides a better understanding of the p53-mitochondria relationship and its involvement in the development of many diseases.

Published
2012

31. Heme oxygenase-1 posttranslational modifications in the brain of subjects with Alzheimer disease and mild cognitive impairment

Author

Barone, Eugenio, Di Domenico, F, Sultana, R, Coccia, R, Mancuso, Cesare, Perluigi, M, Butterfield, Da, Mancuso, Cesare (ORCID:0000-0001-6532-483X), Barone, Eugenio, Di Domenico, F, Sultana, R, Coccia, R, Mancuso, Cesare, Perluigi, M, Butterfield, Da, and Mancuso, Cesare (ORCID:0000-0001-6532-483X)

Abstract

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Oxidative and nitrosative stress plays a principal role in the pathogenesis of AD. The induction of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in the brain represents one of the earliest mechanisms activated by cells to counteract the noxious effects of increased reactive oxygen species and reactive nitrogen species. Although initially proposed as a neuroprotective system in AD brain, the HO-1/BVR-A pathophysiological features are under debate. We previously reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative posttranslational modifications in the brain of subjects with AD and those with mild cognitive impairment (MCI). Furthermore, other groups proposed the observed increase in HO-1 in AD brain as a possible neurotoxic mechanism. Here we provide new insights about HO-1 in the brain of subjects with AD and MCI, the latter condition being the transitional phase between normal aging and early AD. HO-1 protein levels were significantly increased in the hippocampus of AD subjects, whereas HO-2 protein levels were significantly decreased in both AD and MCI hippocampi. In addition, significant increases in Ser-residue phosphorylation together with increased oxidative posttranslational modifications were found in the hippocampus of AD subjects. Interestingly, despite the lack of oxidative stress-induced AD neuropathology in cerebellum, HO-1 demonstrated increased Ser-residue phosphorylation and oxidative posttranslational modifications in this brain area, suggesting HO-1 as a target of oxidative damage even in the cerebellum. The significance of these findings is profound and opens new avenues into the comprehension of the role of HO-1 in the pathogenesis of AD.

Published
2012

32. Sex differences in brain proteomes of neuron-specific STAT3-null mice after cerebral ischemia/reperfusion

Author

Di Domenico, F, Casalena, G, Jia, J, Sultana, R, Barone, Eugenio, Cai, J, Pierce, Wm, Cini, C, Mancuso, Cesare, Perluigi, M, Davis, Cm, Alkayed, Nj, Butterfield, Ad, Mancuso, Cesare (ORCID:0000-0001-6532-483X), Di Domenico, F, Casalena, G, Jia, J, Sultana, R, Barone, Eugenio, Cai, J, Pierce, Wm, Cini, C, Mancuso, Cesare, Perluigi, M, Davis, Cm, Alkayed, Nj, Butterfield, Ad, and Mancuso, Cesare (ORCID:0000-0001-6532-483X)

Abstract

Signal transduction and activator of transcription-3 (STAT3) plays an important role in neuronal survival, regeneration and repair after brain injury. We previously demonstrated that STAT3 is activated in brain after cerebral ischemia specifically in neurons. The effect was sex-specific and modulated by sex steroids, with higher activation in females than males. In the current study, we used a proteomics approach to identify downstream proteins affected by ischemia in male and female wild-type (WT) and neuron-specific STAT3 knockout (KO) mice. We established four comparison groups based on the transgenic condition and the hemisphere analyzed, respectively. Moreover, the sexual variable was taken into account and male and female animals were analyzed independently. Results support a role for STAT3 in metabolic, synaptic, structural and transcriptional responses to cerebral ischemia, indeed the adaptive response to ischemia/reperfusion injury is delayed in neuronal-specific STAT3 KO mice. The differences observed between males and females emphasize the importance of sex-specific neuronal survival and repair mechanisms, especially those involving antioxidant and energy-related activities, often caused by sex hormones.

Published
2012

38. HO-1/BVR-a system analysis in plasma from probable Alzheimer's disease and mild cognitive impairment subjects: a potential biochemical marker for the prediction of the disease.

Author

Di Domenico F, Barone E, Mancuso C, Perluigi M, Cocciolo A, Mecocci P, Butterfield DA, Coccia R, Di Domenico, Fabio, Barone, Eugenio, Mancuso, Cesare, Perluigi, Marzia, Cocciolo, Annalisa, Mecocci, Patrizia, Butterfield, D Allan, and Coccia, Raffaella

Abstract

Several studies showed increased oxidative and nitrosative stress in plasma from patients with Alzheimer's disease (AD), however, little and controversial knowledge has emerged about the antioxidant functionality of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in blood. The current study reports increased levels of both HO-1 and BVR-A in plasma from probable AD patients, as a result of the increased oxidative environment. However, the increase of oxidative stress in plasma result also in the increase of BVR-A 3-nitrotyrosine levels and the decrease of BVR-A phosphotyrosine levels and reductase activity, suggesting that nitrosative stress play the prominent oxidative role in plasma during AD. Our data on HO-1/BVR-A status in plasma closely correlate with recent reports in hippocampus of subjects with AD and arguably its early form, mild cognitive impairment. Moreover, we show that alterations on HO-1/BVR-A system are tightly connected with cognitive decline indexed by Mini-Mental Status Exam scores. We hypothesize that the HO-1/BVR-A system status in plasma might reflect the ongoing situation in the brain, offering an important biochemical tool for the potential prediction of AD at the earliest stages of the disease. [ABSTRACT FROM AUTHOR]

Published
2012
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39. Oxidative and nitrosative modifications of biliverdin reductase-A in the brain of subjects with Alzheimer's disease and amnestic mild cognitive impairment.

Author

Barone E, Di Domenico F, Cenini G, Sultana R, Coccia R, Preziosi P, Perluigi M, Mancuso C, Butterfield DA, Barone, Eugenio, Di Domenico, Fabio, Cenini, Giovanna, Sultana, Rukhsana, Coccia, Raffaella, Preziosi, Paolo, Perluigi, Marzia, Mancuso, Cesare, and Butterfield, D Allan

Subjects
BRAIN metabolism, TYROSINE metabolism, ALDEHYDES, ALZHEIMER'S disease, BRAIN, CEREBELLUM, COGNITION disorders, HIPPOCAMPUS (Brain), HOMEOSTASIS, OXIDOREDUCTASES, RESEARCH funding, TYROSINE, WESTERN immunoblotting, OXIDATIVE stress, REACTIVE nitrogen species, PRECIPITIN tests
Abstract

Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Published
2011
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41. Effects of UVB-induced oxidative stress on protein expression and specific protein oxidation in normal human epithelial keratinocytes: a proteomic approach

Author

De Marco Federico, Grillo Caterina, Giorgi Alessandra, Cini Chiara, Foppoli Cesira, Blarzino Carla, Di Domenico Fabio, Perluigi Marzia, Butterfield David A, Schininà Maria E, and Coccia Raffaella

Subjects
Cytology, QH573-671
Abstract

Abstract 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. Results The expression levels of fifteen proteins - involved in maintaining the cytoskeleton integrity, removal of damaged proteins and heat shock response - were differentially regulated in UVB-exposed cells, indicating that an appropriate response is developed in order to counteract/neutralize the toxic effects of UVB-raised ROS. On the other side, the redox proteomics approach revealed that seven proteins - involved in cellular adhesion, cell-cell interaction and protein folding - were selectively oxidized. Conclusions Despite a wide and well orchestrated cellular response, a relevant oxidation of specific proteins concomitantly occurs in UVB-irradiated human epithelial Keratinocytes. These modified (i.e. likely dysfunctional) proteins might result in cell homeostasis impairment and therefore eventually promote cellular degeneration, senescence or carcinogenesis.

Published
2010
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42. Expression of human papilloma virus type 16 E5 protein in amelanotic melanoma cells regulates endo-cellular pH and restores tyrosinase activity

Author

Coccia Raffaella, Morici Salvatrice, Paolini Francesca, Perluigi Marzia, Blarzino Carla, Foppoli Cesira, Di Domenico Fabio, Cini Chiara, and De Marco Federico

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract 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. E5 has been shown to interact with 16 kDa subunit C of the trans-membrane Vacuolar ATPase proton pump ultimately resulting in its functional suppressions. However, the cellular effects of such an interaction are still under debate. With this work we intended to explore whether the HPV16 E5 oncoprotein does indeed interact with the vacuolar ATPase proton pump once expressed in intact human cells and whether this interaction has functional consequences on cell metabolism and phenotype. Methods The expression of the HPV16-E5 oncoproteins was induced in two Tyrosinase-positive amelanotic melanomas (the cell lines FRM and M14) by a retroviral expression construct. Modulation of the intracellular pH was measured with Acridine orange and fluorescence microscopy. Expression of tyrosinase and its activity was followed by RT-PCR, Western Blot and enzyme assay. The anchorage-independence growth and the metabolic activity of E5 expressing cells were also monitored. Results We provide evidence that in the E5 expressing cells interaction between E5 and V-ATPase determines an increase of endo-cellular pH. The cellular alkalinisation in turn leads to the post-translational activation of tyrosinase, melanin synthesis and phenotype modulation. These effects are associated with an increased activation of tyrosine analogue anti-blastic drugs. Conclusion Once expressed within intact human cells the HPV16-E5 oncoprotein does actually interact with the vacuolar V-ATPase proton pump and this interaction induces a number of functional effects. In amelanotic melanomas these effects can modulate the cell phenotype and can induce a higher sensitivity to tyrosine related anti-blastic drugs.

Published
2009
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44. Involvement of stat3 in mouse brain development and sexual dimorphism: A proteomics approach

Author

Stephanie J. Murphy, Nabil J. Alkayed, Chiara Cini, Gabriella Casalena, Jian Cai, Giancarlo Solaini, Alessandra Baracca, Suzan Dziennis, D. Allan Butterfield, Giorgio Lenaz, Jia Jia, Rukhsana Sultana, William M. Pierce, Marzia Perluigi, Fabio Di Domenico, Di Domenico F., Casalena G., Sultana R., Cai J., Pierce W.M., Perluigi M., Cini C., Baracca A., Solaini G., Lenaz G., Jia J., Dziennis S., Murphy S.J., Alkayed N.J., and Butterfield D.A.

Subjects
Male, STAT3 Transcription Factor, Transgene, Central nervous system, Mice, Transgenic, Nerve Tissue Proteins, Biology, Proteomics, Neuroprotection, Article, STAT3, Mice, DEVELOPMENT, medicine, Animals, BRAIN, Molecular Biology, Brain Chemistry, Mice, Knockout, ALZHEIMERS-DISEASE BRAIN, MITOCHONDRIAL STAT3, PARKINSONS-DISEASE, OXIDATIVE STRESS, 14-3-3 PROTEINS, Sex Characteristics, neuron-specific stat3, proteomics, sexual dimorphism, General Neuroscience, Nervous tissue, medicine.anatomical_structure, Knockout mouse, PROTEOMICS, Female, Neurology (clinical), Neuron, Neuroscience, Developmental Biology, Sex characteristics
Abstract

Although the role of STAT3 in cell physiology and tissue development has been largely investigated, its involvement in the development and maintenance of nervous tissue and in the mechanisms of neuroprotection is not yet known. The potentially wide range of STAT3 activities raises the question of tissue- and gender-specificity as putative mechanisms of regulation. To explore the function of STAT3 in the brain and the hypothesis of a gender-linked modulation of STAT3, we analyzed a neuron-specific STAT3 knockout mouse model investigating the influence of STAT3 activity in brain protein expression pattern in both males and females in the absence of neurological insult. We performed a proteomic study aimed to reveal the molecular pathways directly or indirectly controlled by STAT3 underscoring its role in brain development and maintenance. We identified several proteins, belonging to different neuronal pathways such as energy metabolism or synaptic transmission, controlled by STAT3 that confirm its crucial role in brain development and maintenance. Moreover, we investigated the different processes that could contribute to the sexual dimorphic behavior observed in the incidence of neurological and mental disease. Interestingly both STAT3 KO and gender factors influence the expression of several mitochondrial proteins conferring to mitochondrial activity high importance in the regulation of brain physiology and conceivable relevance as therapeutic target.

Published
2010

45. Redox imbalance and metabolic defects in the context of Alzheimer disease.

Author

Di Domenico F, Lanzillotta C, and Perluigi M

Subjects
Humans, Animals, Reactive Oxygen Species metabolism, Brain metabolism, Brain pathology, Oxidative Stress, Homeostasis, Mitochondria metabolism, Alzheimer Disease metabolism, Alzheimer Disease pathology, Oxidation-Reduction, Energy Metabolism
Abstract

Redox reactions play a critical role for intracellular processes, including pathways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, fundamental mechanisms for signal transduction. Disturbance of redox homeostasis is associated with many disorders. Among these, Alzheimer's disease is a neurodegenerative pathology that presents hallmarks of oxidative damage such as increased ROS production, decreased activity of antioxidant enzymes, oxidative modifications of macromolecules, and changes in mitochondrial homeostasis. Interestingly, alteration of redox homeostasis is closely associated with defects of energy metabolism, involving both carbohydrates and lipids, the major energy fuels for the cell. As the brain relies exclusively on glucose metabolism, defects of glucose utilization represent a harmful event for the brain. During aging, a progressive perturbation of energy metabolism occurs resulting in brain hypometabolism. This condition contributes to increase neuronal cell vulnerability ultimately resulting in cognitive impairment. The current review discusses the crosstalk between alteration of redox homeostasis and brain energy defects that seems to act in concert in promoting Alzheimer's neurodegeneration., (© 2024 Federation of European Biochemical Societies.)

Published
2024
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46. Biliverdin Reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β.

Author

Lanzillotta C, Tramutola A, Lanzillotta S, Greco V, Pagnotta S, Sanchini C, Di Angelantonio S, Forte E, Rinaldo S, Paone A, Cutruzzolà F, Cimini FA, Barchetta I, Cavallo MG, Urbani A, Butterfield DA, Di Domenico F, Paul BD, Perluigi M, Duarte JMN, and Barone E

Subjects
Phosphorylation, Animals, Mice, Humans, Brain metabolism, Insulin Receptor Substrate Proteins metabolism, Unfolded Protein Response, Diabetes Mellitus, Type 2 metabolism, Proto-Oncogene Proteins c-akt metabolism, Alzheimer Disease metabolism, Glycogen Synthase Kinase 3 beta metabolism, Mitochondria metabolism, Oxidoreductases Acting on CH-CH Group Donors metabolism, Insulin metabolism, Signal Transduction, Insulin Resistance
Abstract

Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated with insulin resistance. Here, we demonstrate that reduced BVR-A levels alter insulin signaling and mitochondrial bioenergetics in the brain. Loss of BVR-A leads to IRS1 hyper-activation but dysregulates Akt-GSK3β complex in response to insulin, hindering the accumulation of pGSK3β S9 into the mitochondria. This event impairs oxidative phosphorylation and fosters the activation of the mitochondrial Unfolded Protein Response (UPRmt). Remarkably, we unveil that BVR-A is required to shuttle pGSK3β S9 into the mitochondria. Our data sheds light on the intricate interplay between insulin signaling and mitochondrial metabolism in the brain unraveling potential targets for mitigating the development of brain insulin resistance and neurodegeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2024
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47. Aging exacerbates oxidative stress and liver fibrosis in an animal model of Down Syndrome.

Author

Giallongo S, Ferrigno J, Caltabiano R, Broggi G, Alanazi AM, Distefano A, Tropea E, Tramutola A, Perluigi M, Volti GL, Barone E, and Barbagallo IA

Subjects
Animals, Mice, Liver metabolism, Liver pathology, Lipid Metabolism, Male, Lipid Peroxidation, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Oxidative Stress, Down Syndrome metabolism, Down Syndrome pathology, Down Syndrome genetics, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Disease Models, Animal, Aging metabolism
Abstract

Down Syndrome (DS) is a common genetic disorder characterized by an extra copy of chromosome 21, leading to dysregulation of various metabolic pathways. Oxidative stress in DS is associated with neurodevelopmental defects, neuronal dysfunction, and a dementia onset resembling Alzheimer's disease. Additionally, chronic oxidative stress contributes to cardiovascular diseases and certain cancers prevalent in DS individuals. This study investigates the impact of ageing on oxidative stress and liver fibrosis using a DS murine model (Ts2Cje mice). Our results show that DS mice show increased liver oxidative stress and impaired antioxidant defenses, as evidenced by reduced glutathione levels and increased lipid peroxidation. Therefore, DS liver exhibits an altered inflammatory response and mitochondrial fitness as we showed by assaying the expression of HMOX1, CLPP, and the heat shock proteins Hsp90 and Hsp60. DS liver also displays dysregulated lipid metabolism, indicated by altered expression of PPARα, PPARγ, FATP5, and CTP2. Consistently, these changes might contribute to non-alcoholic fatty liver disease development, a condition characterized by liver fat accumulation. Consistently, histological analysis of DS liver reveals increased fibrosis and steatosis, as showed by Col1a1 increased expression, indicative of potential progression to liver cirrhosis. Therefore, our findings suggest an increased risk of liver pathologies in DS individuals, particularly when combined with the higher prevalence of obesity and metabolic dysfunctions in DS patients. These results shed a light on the liver's role in DS-associated pathologies and suggest potential therapeutic strategies targeting oxidative stress and lipid metabolism to prevent or mitigate liver-related complications in DS individuals.

Published
2024
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48. Shaping down syndrome brain cognitive and molecular changes due to aging using adult animals from the Ts66Yah murine model.

Author

Lanzillotta C, Baniowska MR, Prestia F, Sette C, Nalesso V, Perluigi M, Barone E, Duchon A, Tramutola A, Herault Y, and Di Domenico F

Subjects
Animals, Mice, Male, Female, Cognition physiology, Hippocampus metabolism, Hippocampus pathology, Cognitive Dysfunction genetics, Cognitive Dysfunction metabolism, Cognitive Dysfunction pathology, Mice, Transgenic, Down Syndrome genetics, Down Syndrome pathology, Down Syndrome metabolism, Aging genetics, Aging pathology, Aging physiology, Disease Models, Animal, Brain metabolism, Brain pathology
Abstract

Down syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy of Homo sapiens chromosome 21 (HSA21). The increased dosage of genes on HSA21 is associated with early neurodevelopmental changes and subsequently at adult age with the development of Alzheimer-like cognitive decline. However, the molecular mechanisms promoting brain pathology along aging are still missing. The novel Ts66Yah model represents an evolution of the Ts65Dn, used in characterizing the progression of brain degeneration, and it manifest phenotypes closer to human DS condition. In this study we performed a longitudinal analysis (3-9 months) of adult Ts66Yah mice. Our data support the behavioural alterations occurring in Ts66Yah mice at older age with improvement in the detection of spatial memory defects and also a new anxiety-related phenotype. The evaluation of hippocampal molecular pathways in Ts66Yah mice, as effect of age, demonstrate the aberrant regulation of redox balance, proteostasis, stress response, metabolic pathways, programmed cell death and synaptic plasticity. Intriguingly, the genotype-driven changes observed in those pathways occur early promoting altered brain development and the onset of a condition of premature aging. In turn, aging may account for the subsequent hippocampal deterioration that fall in characteristic neuropathological features. Besides, the analysis of sex influence in the alteration of hippocampal mechanisms demonstrate only a mild effect. Overall, data collected in Ts66Yah provide novel and consolidated insights, concerning trisomy-driven processes that contribute to brain pathology in conjunction with aging. This, in turn, aids in bridging the existing gap in comprehending the intricate nature of DS phenotypes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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49. Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer's Disease.

Author

Staurenghi E, Testa G, Leoni V, Cecci R, Floro L, Giannelli S, Barone E, Perluigi M, Leonarduzzi G, Sottero B, and Gamba P

Abstract

Down syndrome (DS) is a complex chromosomal disorder considered as a genetically determined form of Alzheimer's disease (AD). Maintenance of brain cholesterol homeostasis is essential for brain functioning and development, and its dysregulation is associated with AD neuroinflammation and oxidative damage. Brain cholesterol imbalances also likely occur in DS, concurring with the precocious AD-like neurodegeneration. In this pilot study, we analyzed, in the brain of the Ts2Cje (Ts2) mouse model of DS, the expression of genes encoding key enzymes involved in cholesterol metabolism and of the levels of cholesterol and its main precursors and products of its metabolism (i.e., oxysterols). The results showed, in Ts2 mice compared to euploid mice, the downregulation of the transcription of the genes encoding the enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and 24-dehydrocholesterol reductase, the latter originally recognized as an indicator of AD, and the consequent reduction in total cholesterol levels. Moreover, the expression of genes encoding enzymes responsible for brain cholesterol oxidation and the amounts of the resulting oxysterols were modified in Ts2 mouse brains, and the levels of cholesterol autoxidation products were increased, suggesting an exacerbation of cerebral oxidative stress. We also observed an enhanced inflammatory response in Ts2 mice, underlined by the upregulation of the transcription of the genes encoding for α-interferon and interleukin-6, two cytokines whose synthesis is increased in the brains of AD patients. Overall, these results suggest that DS and AD brains share cholesterol cycle derangements and altered oxysterol levels, which may contribute to the oxidative and inflammatory events involved in both diseases.

Published
2024
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50. Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease.

Author

Perluigi M, Di Domenico F, and Butterfield DA

Subjects
Humans, Amyloid beta-Peptides metabolism, Quality of Life, Oxidative Stress physiology, Oxidation-Reduction, Lipids, Alzheimer Disease metabolism
Abstract

Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, and it seems to link different hypotheses and mechanisms of AD neuropathology with high fidelity. The brain is particularly vulnerable to oxidative damage, mainly because of its unique lipid composition, resulting in an amplified cascade of redox reactions that target several cellular components/functions ultimately leading to neurodegeneration. The present review highlights the "OS hypothesis of AD," including amyloid beta-peptide-associated mechanisms, the role of lipid and protein oxidation unraveled by redox proteomics, and the antioxidant strategies that have been investigated to modulate the progression of AD. Collected studies from our groups and others have contributed to unraveling the close relationships between perturbation of redox homeostasis in the brain and AD neuropathology by elucidating redox-regulated events potentially involved in both the pathogenesis and progression of AD. However, the complexity of AD pathological mechanisms requires an in-depth understanding of several major intracellular pathways affecting redox homeostasis and relevant for brain functions. This understanding is crucial to developing pharmacological strategies targeting OS-mediated toxicity that may potentially contribute to slow AD progression as well as improve the quality of life of persons with this severe dementing disorder.

Published
2024
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