Sanfilippo Cristina
@irccsme.it
IRCCS Centro Neurolesi Bonino Pulejo
Scopus Publications
Scopus Publications
Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Michele Vecchio, Martina Sortino, Giuseppe Musumeci, Manlio Vinciguerra, and Michelino Di Rosa
Springer Science and Business Media LLC
Paola Castrogiovanni, Cristina Sanfilippo, Rosa Imbesi, Giacomo Lazzarino, Giovanni Li Volti, Daniele Tibullo, Nunzio Vicario, Rosalba Parenti, Lazzarino Giuseppe, Ignazio Barbagallo,et al.
Springer Science and Business Media LLC
Cristina Sanfilippo, Paola Castrogiovanni, Manlio Vinciguerra, Rosa Imbesi, Martina Ulivieri, Francesco Fazio, Antonio Cantarella, Giuseppe Nunnari, and Michelino Di Rosa
Elsevier BV
Cristina Sanfilippo, Paola Castrogiovanni, Manlio Vinciguerra, Rosa Imbesi, Martina Ulivieri, Francesco Fazio, Kaj Blennow, Henrik Zetterberg, and Michelino Di Rosa
Springer Science and Business Media LLC
Michelino Di Rosa, Cristina Sanfilippo, Loretta Giuliano, Paola Castrogiovanni, Rosa Imbesi, Martina Ulivieri, Francesco Fazio, Kaj Blennow, and Henrik Zetterberg
Bentham Science Publishers Ltd.
Background: Cholinergic hypofunction and sleep disturbance are hallmarks of Alzheimer’s disease (AD), a progressive disorder leading to neuronal deterioration. Muscarinic acetylcholine receptors (M1-5 or mAChRs), expressed in hippocampus and cerebral cortex, play a pivotal role in the aberrant alterations of cognitive processing, memory, and learning, observed in AD. Recent evidence shows that two mAChRs, M1 and M3, encoded by CHRM1 and CHRM3 genes, respectively, are involved in sleep functions and, peculiarly, in rapid eye movement (REM) sleep. Methods: We used twenty microarray datasets extrapolated from post-mortem brain tissue of nondemented healthy controls (NDHC) and AD patients to examine the expression profile of CHRM1 and CHRM3 genes. Samples were from eight brain regions and stratified according to age and sex. Results: CHRM1 and CHRM3 expression levels were significantly reduced in AD compared with ageand sex-matched NDHC brains. A negative correlation with age emerged for both CHRM1 and CHRM3 in NDHC but not in AD brains. Notably, a marked positive correlation was also revealed between the neurogranin (NRGN) and both CHRM1 and CHRM3 genes. These associations were modulated by sex. Accordingly, in the temporal and occipital regions of NDHC subjects, males expressed higher levels of CHRM1 and CHRM3, respectively, than females. In AD patients, males expressed higher levels of CHRM1 and CHRM3 in the temporal and frontal regions, respectively, than females. Conclusion: Thus, substantial differences, all strictly linked to the brain region analyzed, age, and sex, exist in CHRM1 and CHRM3 brain levels both in NDHC subjects and in AD patients.
Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Giuseppe Musumeci, Michele Vecchio, Giovanni Li Volti, Daniele Tibullo, Giuseppe Broggi, Rosario Caltabiano, Martina Ulivieri,et al.
Elsevier BV
Paola Castrogiovanni, Ignazio Barbagallo, Rosa Imbesi, Giuseppe Musumeci, Cristina Sanfilippo, Giuseppe Broggi, Rosario Caltabiano, Daniele Tibullo, Cesarina Giallongo, Stefano Forte,et al.
Elsevier BV
Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Giuseppe Lazzarino, Valentina Di Pietro, Giovanni Li Volti, Daniele Tibullo, Ignazio Barbagallo, Giacomo Lazzarino, Roberto Avola,et al.
Elsevier BV
Human behavior is influenced by both genetic and environmental factors. Monoamine oxidase A (MAOA) is among the most investigated genetic determinants of violent behaviors, while the monoamine oxidase B (MAOB) is explored in Parkinson's disease. We collected twenty-four post-mortem brain tissue datasets of 3871 and 1820 non-demented males and females, respectively, who died from causes not attributable to neurodegenerative diseases. The gene expressions of MAOA and MAOB (MAO genes) were analyzed in these subjects, who were further stratified according to age into eleven groups ranging from late Infancy (5-9 months) to centenarians (>100 years). MAO genes were differently expressed in brains during the entire life span. In particular, maximal and minimal expression levels were found in early life and around the teen years. Females tended to have higher MAO gene levels throughout their lives than those found in age-matched males, even when expressions were separately measured in different brain regions. We demonstrated the existence of age- and sex- related variations in the MAO transcript levels in defined brain regions. More in-depth protein studies are needed to confirm our preliminary results obtained only on messenger RNAs in order to establish the role played by MAO genes in human development.
Cristina Sanfilippo, Giuseppe Musumeci, Maria Kazakova, Venera Mazzone, Paola Castrogiovanni, Rosa Imbesi, and Michelino Di Rosa
Springer Science and Business Media LLC
Brain regions such as the cerebellum (CB) have been neglected for a long time in the study of Alzheimer's disease (AD) pathogenesis. In reference to a new emerging hypothesis according to which there is an altered cerebellar synaptic processing in AD, we verified the possible role played by new biomarkers in the CB of AD patients compared with not-demented healthy control subjects (NDHS). Using a bioinformatics approach, we have collected several microarray datasets and obtained 626 cerebella sample biopsies belonging to subjects who did not die from causes related to neurological diseases and 199 cerebella belonging to AD. The analysis of logical relations between the transcriptome dataset highlighted guanine nucleotide-binding protein (G protein) gamma 13 (GNG13) as a potential new biomarker for Purkinje cells (PCs). We have correlated GNG13 expression levels with already widely existing bibliography of PC marker genes, such as Purkinje cell protein 2 (PCP2), Purkinje cell protein 4 (PCP4), and cerebellin 3 (CBLN3). We showed that expression levels of GNG13 and PCP2, PCP4, and CBLN3 were significantly correlated with each other in NDHS and in AD and significantly reduced in AD patients compared with NDHS subjects. In addition, we highlighted a negative correlation between the expression levels of PC biomarkers and age. From the outcome of our investigation, it is possible to conclude that the identification of GNG13 as a potentially biomarker in PCs represents also a state of health of CB, in association with the expression of PCP2, PCP4, and CBLN3.
Paola Castrogiovanni, Cristina Sanfilippo, Rosa Imbesi, Grazia Maugeri, Debora Lo Furno, Daniele Tibullo, Alessandro Castorina, Giuseppe Musumeci, and Michelino Di Rosa
MDPI AG
Alzheimer’s disease is a progressive, devastating, and irreversible brain disorder that, day by day, destroys memory skills and social behavior. Despite this, the number of known genes suitable for discriminating between AD patients is insufficient. Among the genes potentially involved in the development of AD, there are the chitinase-like proteins (CLPs) CHI3L1, CHI3L2, and CHID1. The genes of the first two have been extensively investigated while, on the contrary, little information is available on CHID1. In this manuscript, we conducted transcriptome meta-analysis on an extensive sample of brains of healthy control subjects (n = 1849) (NDHC) and brains of AD patients (n = 1170) in order to demonstrate CHID1 involvement. Our analysis revealed an inverse correlation between the brain CHID1 expression levels and the age of NDHC subjects. Significant differences were highlighted comparing CHID1 expression of NDHC subjects and AD patients. Exclusive in AD patients, the CHID1 expression levels were correlated positively to calcium-binding adapter molecule 1 (IBA1) levels. Furthermore, both in NDHC and in AD patient’s brains, the CHID1 expression levels were directly correlated with calbindin 1 (CALB1) and neurogranin (NRGN). According to brain regions, correlation differences were shown between the expression levels of CHID1 in prefrontal, frontal, occipital, cerebellum, temporal, and limbic system. Sex-related differences were only highlighted in NDHC. CHID1 represents a new chitinase potentially involved in the principal processes underlying Alzheimer’s disease.
Cristina Sanfilippo, Giuseppe Musumeci, Paola Castrogiovanni, Francesco Fazio, Giovanni Li Volti, Ignazio Barbagallo, Grazia Maugeri, Silvia Ravalli, Rosa Imbesi, and Michelino Di Rosa
Elsevier BV
Recent findings demonstrated that physical exercise has a powerful role in improving cognitive function and delaying age-associated neurological decline. However, to date, there is a lack of information regarding the effect of physical activity (PA) on brain cells architecture. In this paper, we hypothesized that PA could play a role in the transcriptional changes of genes that enrich the main cells of central nervous system (CNS). From NCBI, we selected a microarray dataset composed of the human hippocampi (GSE110298) from 23 cognitively intact clinical cases (NDHSs) (aged 87.4 ± 6.3 years) selected to from the Rush Memory and Aging Project (MAP). The significantly expressed genes, obtained comparing hippocampi from subjects who underwent Low Physical Activity (LPA) vs those who performed High Physical Activity (HPA), were overlapped with the main genes enriching the CNS cells, obtained from the public human brain single-cell RNA-sequencing dataset (GSE67835), in order to determine the respective weighted percentages of significantly expression genes modulation (WPSEG). In NDHSs underwent HPA, the WPSEG was higher for Neurons, Dendritic Development, Synaptic transmission genes and Axon Development. In addition, in NDHSs underwent LPA we observed high expression of genes enriching Oligodendrocytes, Microglia, and Endothelial cells. Furthermore, neurogenesis and the decreasing of the T cell-mediated inflammatory process were the two main molecular mechanisms activated in the brains of NDHSs underwent HPA. From our results, it is possible to conclude that, in elderly subjects, the transcriptional profile of CNS cells changes as a function of the PA conducted during life. Performing PA periodically supports the maintenance of the physiological balance of neuronal cells and, consequently, improves the quality of life of the elderly.
Cristina Sanfilippo and Michelino Di Rosa
Elsevier
Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Giuseppe Nunnari, and Michelino Di Rosa
Elsevier BV
Alzheimer's disease (AD) is one of the most common forms of dementia with still unknown pathogenesis. Several cytokines and chemokines are involved in the pathogenesis of AD. Among the chemokines, the CXCR4/CXCL12 complex has been shown to play an important role in the pathogenetic development of AD. We investigated the expression levels of CXCR4 / CXCL12 in fifteen brain regions of healthy non-demented subjects (NDHC) (2139 sample) and AD patients (1170 sample) stratified according to sex and age. Furthermore, we correlated their expressions with the Neurogranin (NRGN) and CHI3L1 levels, two inflamm-aging markers. We highlighted that CXCR4 gene expression levels were age-correlated in the brain of NDHC subjects and that AD nullified this correlation. A similar trend, but diametrically opposite was observed for CXCL12. Its expression was decreased during the aging in both sexes, and in the brains of AD patients, it underwent an inversion of the trend, only and exclusively in females. Brains of AD patients expressed high CXCR4 and CHI3L1, and low CXCL12 and Neurogranin levels compared to NDHC subjects. Both CXCR4 and CXCL12 correlated significantly with CHI3L1 and Neurogranin expression levels, regardless of disease. Furthermore, we showed a selective modulation of CXCL12 and CXCR4 only in specific brain regions. Taken together our results demonstrate that CXCL12 and CXCR4 are linked to Neurogranin and CHI3L1 expression levels and the relationship between postsynaptic damage and microglial activation in AD could be shown using all these genes. Further confirmations are needed to demonstrate the close link between these genes.
Giuseppe Nunnari, Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Giovanni Li Volti, Ignazio Barbagallo, Giuseppe Musumeci, and Michelino Di Rosa
Elsevier BV
Abstract
Background
SARS-CoV2, the agent responsible for the current pandemic, is also causing respiratory distress syndrome (RDS), hyperinflammation and high mortality. It is critical to dissect the pathogenetic mechanisms in order to reach a targeted therapeutic approach.
Methods
In the present investigation, we evaluated the effects of SARS-CoV2 on human bronchial epithelial cells (HBEC). We used RNA-seq datasets available online for identifying SARS-CoV2 potential genes target on human bronchial epithelial cells. RNA expression levels and potential cellular gene pathways have been analysed. In order to identify possible common strategies among the main pandemic viruses, such as SARS-CoV2, SARS-CoV1, MERS-CoV, and H1N1, we carried out a hypergeometric test of the main genes transcribed in the cells of the respiratory tract exposed to these viruses.
Results
The analysis showed that two mechanisms are highly regulated in HBEC: the innate immunity recruitment and the disassembly of cilia and cytoskeletal structure. The granulocyte colony-stimulating factor (CSF3) and dynein heavy chain 7, axonemal (DNAH7) represented respectively the most upregulated and downregulated genes belonging to the two mechanisms highlighted above. Furthermore, the carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7) that codifies for a surface protein is highly specific of SARS-CoV2 and not for SARS-CoV1, MERS-CoV, and H1N1, suggesting a potential role in viral entry. In order to identify potential new drugs, using a machine learning approach, we highlighted Flunisolide, Thalidomide, Lenalidomide, Desoximetasone, xylazine, and salmeterol as potential drugs against SARS-CoV2 infection.
Conclusions
Overall, lung involvement and RDS could be generated by the activation and down regulation of diverse gene pathway involving respiratory cilia and muscle contraction, apoptotic phenomena, matrix destructuration, collagen deposition, neutrophil and macrophages recruitment.
Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, and Michelino Di Rosa
Springer Science and Business Media LLC
Alzheimer’s disease (AD) represents one of the main forms of dementia that afflicts our society. The expression of several genes has been associated with disease development. Despite this, the number of genes known to be capable of discriminating between AD patients according to sex remains deficient. In our study, we performed a transcriptomes meta-analysis on a large court of brains of healthy control subjects (n = 2139) (NDHC) and brains of AD patients (n = 1170). Our aim was to verify the brain expression levels of CHI3L2 and its correlation with genes associated with microglia-mediated neuroinflammation (IBA1), alteration of the blood–brain barrier (PECAM1), and neuronal damage (CALB1). We showed that the CHI3L2, IBA1, PECAM1, and CALB1 expression levels were modulated in the brains of patients with AD compared to NDHC subjects. Furthermore, both in NDHC and in AD patient’s brains, the CHI3L2 expression levels were directly correlated with IBA1 and PECAM1 and inversely with CALB1. Additionally, the expression levels of CHI3L2, PECAM1, and CALB1 but not of IBA1 were sex-depended. By stratifying the samples according to age and sex, correlation differences emerged between the expression levels of CHI3L2, IBA1, PECAM1, and CALB1 and the age of NDHC subjects and AD patients. CHI3L2 represents a promising gene potentially involved in the key processes underlying Alzheimer’s disease. Its expression in the brains of sex-conditioned AD patients opens up new possible sex therapeutic strategies aimed at controlling imbalance in disease progression.
Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Maria Kazakowa, Giuseppe Musumeci, Kaj Blennow, Henrik Zetterberg, and Michelino Di Rosa
Elsevier BV
Several genetic sexual dimorphisms have been identified in animal and human brains, which may form a neural basis for sex-specific predisposition to neurological diseases. In the last years, clinical studies have observed that Alzheimer's disease (AD) disproportionately affects women compared with men. Chitinase-3-Like 1 protein (CHI3L1) has been frequently investigated in body fluids as a surrogate marker of neuroinflammation in AD and other neurological disorders. Nevertheless, the sex-related differences in CHI3L1 expression in the human brain has not yet been investigated. Here we aimed to evaluate the specificity of increase of CHI3L1 in five brain regions (cerebellum, dorsolateral prefrontal cortex, prefrontal cortex, hippocampus, and visual cortex) of male and female controls during normal aging, as well as in AD patients. We selected ten microarray datasets from NCBI, representing normal aging (n=1290) and AD (n=992), and stratified the brain specimens according to age, gender and brain region. The expression levels of CHI3L1 were correlated with age and gender. Female control brain specimens showed higher CHI3L1 expression than male brains. The expression differences between men and women were most obvious in older subjects. The expression analysis of CHI3L1 in the different brain regions of AD subjects also showed sex differences; females with AD had greater expression in the cerebellum than males. Notably, sex-associated CHI3L1 expression differences in hippocampus disappeared in AD. These findings demonstrate that the expression of CHI3L1 in the brains of cognitively unimpaired subjects and AD patients is closely linked to age and sex, which was most obvious in the cerebellum. Further studies are needed to confirm our results.
Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Daniele Tibullo, Giovanni Li Volti, Ignazio Barbagallo, Nunzio Vicario, Giuseppe Musumeci, and Michelino Di Rosa
Elsevier BV
Exploring sexual dimorphisms in the brain morphology is important for their impact and therapeutic implications for several neurological diseases. The hypothesis that sex could influence the transcriptome of brain cells could be the basis regarding the different response to cognitive decline identified in men and women. In this paper, we analyzed several prefrontal cortices (PFC) microarrays datasets of young/middle-aged healthy subjects and then Alzheimer's disease (AD) patients, according to the sex. The significant transcriptomes were overlapped with the main genes characterizing cells of the central nervous system (CNS) in order to determine the respective weighted percentages of significantly expression gene modulation (WPSEG). We identified differences in brain transcriptional activity between young and middle-aged. In middle-aged women, the WPSEG were higher for the Astrocytes, the Endotheliocytes, and the Microglia. In addition, the sex-matched analysis of transcriptome identified a convergent molecular signature in men and women AD patients. Furthermore, the WPSEG belonging to CNS cells in PFC of healthy middle-aged subjects was correlated to AD profiles according to the sex. Since our results, it is possible to conclude that during the aging the PFC' cells adopt transcriptional strategies sex-dependent that could potentially control the development of neurodegenerative diseases.
Giuseppe Musumeci, Paola Castrogiovanni, Ignazio Barbagallo, Daniele Tibullo, Cristina Sanfilippo, Giuseppe Nunnari, Giovanni Pellicanò, Piero Pavone, Rosario Caltabiano, Roberto Di Marco,et al.
MDPI AG
Background: Juvenile dermatomyositis (JDM) is a systemic, autoimmune, interferon (IFN)-mediated inflammatory muscle disorder that affects children younger than 18 years of age. JDM primarily affects the skin and the skeletal muscles. Interestingly, the role of viral infections has been hypothesized. Mammalian 2′-5′-oligoadenylate synthetase (OAS) genes have been thoroughly characterized as components of the IFN-induced antiviral system, and they are connected to several innate immune-activated diseases. The main purpose of the paper is to define the potential interrelationship between the OAS gene family network and the molecular events that characterize JDM along with double-stranded RNA (dsRNA) molecular pathways. Methods: We analyzed three microarray datasets obtained from the NCBI in order to verify the expression levels of the OAS gene family network in muscle biopsies (MBx) of JDM patients compared to healthy controls. Furthermore, From GSE51392, we decided to select significant gene expression profiles of primary nasal and bronchial epithelial cells isolated from healthy subjects and treated with polyinosinic-polycytidylic acid (poly(I:C)), a synthetic analog of double-stranded RNA (dsRNA), a molecular pattern associated with viral infection. Results: The analysis showed that all OAS genes were modulated in JDM muscle biopsies. Furthermore, 99% of OASs gene family networks were significantly upregulated. Of importance, 39.9% of modulated genes in JDM overlapped with those of primary epithelial cells treated with poly(I:C). Moreover, the microarray analysis showed that the double-stranded dsRNA virus gene network was highly expressed. In addition, we showed that the innate/adaptive immunity markers were significantly expressed in JDM muscles biopsies. and that their levels were positively correlated to OAS gene family expression. Conclusion: OAS gene expression is extremely modulated in JDM as well as in the dsRNA viral gene network. These data lead us to speculate on the potential involvement of a viral infection as a trigger moment for this systemic autoimmune disease. Further in vitro and translational studies are needed to verify this hypothesis in order to strategically plan treatment interventions.
Paola Castrogiovanni, Giovanni Li Volti, Cristina Sanfilippo, Daniele Tibullo, Fabio Galvano, Michele Vecchio, Roberto Avola, Ignazio Barbagallo, Lucia Malaguarnera, Sergio Castorina,et al.
Springer Science and Business Media LLC
Fasting may be exploited as a possible strategy for prevention and treatment of several diseases such as diabetes, obesity, and aging. On the other hand, high-fat diet (HFD) represents a risk factor for several diseases and increased mortality. The aim of the present study was to evaluate the impact of fasting on mouse brain aging transcriptome and how HFD regulates such pathways. We used the NCBI Gene Expression Omnibus (GEO) database, in order to identify suitable microarray datasets comparing mouse brain transcriptome under fasting or HFD vs aged mouse brain transcriptome. Three microarray datasets were selected for this study, GSE24504, GSE6285, and GSE8150, and the principal molecular mechanisms involved in this process were evaluated. This analysis showed that, regardless of fasting duration, mouse brain significantly expressed 21 and 30 upregulated and downregulated genes, respectively. The involved biological processes were related to cell cycle arrest, cell death inhibition, and regulation of cellular metabolism. Comparing mouse brain transcriptome under fasting and aged conditions, we found out that the number of genes in common increased with the duration of fasting (222 genes), peaking at 72 h. In addition, mouse brain transcriptome under HFD resembles for the 30% the one of the aged mice. Furthermore, several molecular processes were found to be shared between HFD and aging. In conclusion, we suggest that fasting and HFD play an opposite role in brain transcriptome of aged mice. Therefore, an intermittent diet could represent a possible clinical strategy to counteract aging, loss of memory, and neuroinflammation. Furthermore, low-fat diet leads to the inactivation of brain degenerative processes triggered by aging.
C. Sanfilippo, M.R. Pinzone, D. Cambria, A. Longo, M. Palumbo, R. Di Marco, F. Condorelli, G. Nunnari, L. Malaguarnera, and M. Di Rosa
Springer Science and Business Media LLC
HIV-associated neurocognitive disorders are common in HIV-infected individuals, even in the combination antiretroviral therapy (c-ART) era. Several mechanisms are involved in neuronal damage, including chronic inflammation immune activation. Mammalian 2′-5′-oligoadenylate synthetase (OAS) genes are produced in response to interferon (IFN), mainly by monocytes, and exert their antiviral functions by activation of RNase L that degrades viral and cellular RNAs. In this study, we aimed at exploring OAS gene family RNA expression in simian immunodeficiency virus encephalitis (SIVE), in HIV-associated neurocognitive disorders (HAND), and in HIV-associate dementia (HAD). We analyzed three microarray datasets obtained from the NCBI in order to assess the expression levels of OAS gene family network in brain biopsies of macaques with SIVE vs uninfected animals, as well as post-mortem brain of individuals with HAND (on or off ART) vs uninfected controls and three brain regions of HIV-infected individuals with both neurocognitive impairment (HAD) and encephalitis (HIVE). All OAS genes were upregulated both in SIVE and in HAND. OAS expression was significantly higher in high-viremic individuals; increased expression levels persisted in cART subjects when compared to healthy controls. OAS gene network analysis showed that several genes belonging to the type I IFN pathway, especially CXCL10 and IFIT3, were similarly upregulated in SIVE/HAND. Furthermore, we identified a significant upregulation of OAS gene family RNA expression in basal ganglia, white matter, and frontal cortex of HIV-1, HAD, and HAD/HIVE patients compared to healthy subjects. OAS gene family expression is increased in brain sections from individuals with HAND, HAD, and HIVE as well as macaques with SIVE. OAS family expression is likely to be induced by IFN as a consequence of viral replication in the CNS. Its long-term upregulation may contribute to the chronic inflammatory status and neurocognitive impairment we still observe in virologically suppressed individuals on c-ART.
C. Sanfilippo, A. Longo, F. Lazzara, D. Cambria, G. Distefano, M. Palumbo, A. Cantarella, L. Malaguarnera, and M. Di Rosa
Elsevier BV
Background: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the degeneration and death of upper (UMN) and lower (LMN) motor neurons. In the last decade, it has been shown that Chitinases are an important prognostic indicator of neuro‐inflammatory damage induced by microglia and astrocytes. Materials and methods: We analyzed microarray datasets obtained from the Array Express in order to verify the expression levels of CHI3L1 and CHI3L2 in motor cortex biopsies of sALS patients with different survival times. We also divided the sALS patients into smokers and non‐smokers. In order to extend our analysis, we explored two additional microarray datasets, GSE833 and GSE26927, of post‐mortem spinal cord biopsies from sALS patients. Results: The analysis showed that CHI3L1 and CHI3L2 expression levels were significantly upregulated in the motor cortex of sALS patients, compared to the healthy controls. Moreover, their expression levels were negatively correlated with survival time. Interesting results were obtained when we compared the expression levels of Chitinases among smokers. We showed that CHI3L1 and CHI3L2 were significantly upregulated in sALS smokers compared to non‐smokers. Furthermore, we found that four genes belonging to the Chitinases network (SERPINA3, C1s, RRAD, HLA‐DQA1) were significantly upregulated in the motor cortex of sALS patients and positively correlated with Chitinases expression levels. Similar results were obtained during the exploration of the two‐microarray dataset. Conclusions: This study suggests that CHI3L1 and CHI3L2 are associated with the progression of neurodegeneration in motor cortex and spinal cord of sALS patients. HighlightsCHI3L1 and CHI3L2 were significantly upregulated in motor cortex and spinal cord of sALS patients.Cigarette smoke, modulates the CHI3L1 and CHI3L2 expression levels in the CNS of ALS patients.CHI3L1 and CHI3L2 expression levels were negatively correlated to the survival time sALS patients.The Chitinases network is modulated in motor cortex and spinal cord of sALS patients.
C. Sanfilippo, D. Cambria, A. Longo, M. Palumbo, R. Avola, M. Pinzone, G. Nunnari, F. Condorelli, G. Musumeci, R. Imbesi,et al.
Springer Science and Business Media LLC
ObjectiveThe HIV-1 virus activates the complement system, an essential element of the immune system. SERPING1 is a protease inhibitor that disables C1r/C1s in the C1 complex of the classical complement pathway.MethodsIn this paper, we performed an analysis of several microarrays deposited in GEO dataset to demonstrate that SERPING1 mRNA is modulated in CD14+ monocytes from HIV-1-infected individuals. In addition, data were validated on monocytes isolated from seronegative healthy volunteers, treated with IFNs.ResultsOur analysis shows that SERPING1 mRNA is overexpressed in monocytes from HIV-1+ patients and the expression levels correlate positively with viral load and negatively with the CD4+ T-cell count. Of note, anti-retroviral therapy is able to reduce the levels of SERPING1 mRNA, ex vivo. In addition, we found that 30% of the SERPING1 genes network is upregulated in monocytes from HIV-1+ patients. Noteworthy, the expression levels of IFITM1—an antiviral molecule belonging to the genes network—correlate positively with SERPING1 expression. Interestingly, the monocytes treatment with IFN-gamma, IFN-beta and IFN-alpha significantly upregulates the SERPING1 mRNA expression levels.ConclusionsFrom the outcome of our investigation, it is possible to conclude that SERPING1 and its network serve as important components of the innate immune system to restrict HIV-1 infection.
C. Sanfilippo, G. Nunnari, A. Calcagno, L. Malaguarnera, K. Blennow, H. Zetterberg, and M. Di Rosa
Elsevier BV
OBJECTIVES
Human Immunodeficiency Virus (HIV) infection can induce neurocognitive complications classified as HIV-associated neurocognitive disorder (HAND). The chitinase family is associated with innate immunity cells and many infectious diseases.
METHODS
We analyzed microarray datasets obtained from NCBI in order to verify the expression of chitinase family genes in hippocampus of uninfected rhesus macaques versus those with histopathologic evidence of Simian Immunodeficiency Virus Encephalitis (SIVE). Moreover, we have analysed two human microarray datasets to verify the results obtained in macaques hippocampus affected by SIVE. For these studies, we have also used the open source tools Genome-scale Integrated Analysis of gene Networks in Tissues (GIANT) to identify the chitinase genes network.
RESULTS
CHIT1, CHI3L1 and CHI3L2 levels were significantly increased in SIVE hippocampus as compared to non-infected control specimens. Furthermore, we found a negative correlation between CHIA vs. Brain Viral Load (BVL). These data was confirmed partially in human brain section of HAD/HIVE subjects. Also, we showed that HIV-1 was able to modulate the expression of CHIT1, CHI3L1, CHI3L2 and CHID1 in human macrophages.
CONCLUSIONS
These results suggest that chitinase gene expression is altered in SIVE and in HAD/HIVE brain sections and call for more studies examining whether this is a protective immunological reaction or a destructive tissue response to encephalitis.
Cristina Sanfilippo, Orestes Forlenza, Henrik Zetterberg, and Kaj Blennow
Springer Science and Business Media LLC
Synaptic dysfunction is linked to both major depressive disorder (MDD) and Alzheimer’s disease (AD). Synapse protein concentrations in cerebrospinal fluid (CSF) may be useful biomarkers to monitor synaptic dysfunction and degeneration that lead to depressive symptoms and AD, respectively. CSF neurogranin (Ng), a post-synaptic protein, has emerged as a promising tool to measure synaptic dysfunction and/or loss in AD. The aim of this study was to test the specific hypothesis that CSF neurogranin (Ng) is able to differentiate AD from MDD and cognitively normal controls. CSF samples from 44 healthy control individuals (CTRL), 86 patients with mild cognitive impairment (MCI), 36 of whom had prodromal AD as defined by a positive CSF AD biomarker signature, 25 AD dementia and 6 patients with MDD were analysed using an in house enzyme-linked immunosorbent assay for Ng. CSF Ng levels were significantly higher in AD patients and in prodromal AD (MCI patients with an “AD-like” CSF tau and Aβ42 profile) compared with CTRL individuals (p < 0.0001 for both groups) and MDD patients (p < 0.001 and p < 0.01, respectively). Significantly higher CSF Ng concentration was also seen in prodromal AD patients as compared to MCI patients without biomarker evidence of underlying AD pathology (p < 0.0001). CSF Ng correlated positively with the classical axonal injury markers CSF T-tau and P-tau (p < 0.0001), whereas correlation to plaque pathology as reflected by CSF Aβ42 was less clear. Negative correlations of CSF Ng with cognitive evaluation scores (MMSE and CAMCOG) were observed. This study strengthens the clinical utility of CSF Ng as a CSF biomarker for AD. AD patients in both MCI and dementia stages of the disease had increased CSF Ng concentrations compared with cognitively normal control individuals, patients with non-AD MCI and patients with MDD. The lowest CSF Ng concentrations were seen in patients with MDD, a finding that warrants validation in further studies.
C. Sanfilippo, L. Malaguarnera, and M. Di Rosa
Elsevier BV
BACKGROUND
Alzheimer disease is the most typical form of dementia. The causes of AD are not yet completely understood, but they include a combination of genetic, environmental and lifestyle factors that influence ja person's risk for developing the disease. New biomarkers related to these processes could be important for the diagnosis and follow-up of AD patients.
OBJECTIVE
The intent of this study was to weigh the expression levels of chitinases genes in brain regions of late-onset AD (LOAD) patients.
MATERIALS AND METHODS
We analysed three microarray datasets obtained from the NCBI in order to verify the expression levels of chitinase genes family in brain biopsies (CR, DLPFC and VC) of LOAD patients compared to healthy subjects. We also divided the sample in function of sex difference and ages.
RESULTS
The analysis showed that all chitinases genes were modulated in LOAD brain regions compared to healthy subjects. Furthermore positively correlation was identified between chitinases gene expression and healthy age's subjects. Moreover, it has been shown that CHI3L1 and CHI3L2 were regulated differently in healthy and LOAD brain depending on the sex.
CONCLUSION
It is possible to conclude that all chitinases could be considered new potential markers for LOAD disease.