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Introduction
The research activities are centered on unraveling the molecular mechanisms that govern energy metabolism and its dysfunctions associated with human diseases, particularly under conditions of glucose and lipid dysmetabolism. Metabolism has been explored using various cellular systems, including neurodegeneration models and through multi-omics analyses. Additionally, my studies aim to understand the impact of plant-derived bioactive compounds on protein aggregation involved in neurodegeneration.
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Publications
Publications (78)
Neurodegenerative diseases are among the major challenges in modern medicine, due to the progressive aging of the world population. Among these, Parkinson's disease (PD) affects 10 million people worldwide and is associated with the aggregation of the presynaptic protein α-synuclein (α-syn). Here we use two different PD models, yeast cells and neur...
The AMPK/SNF1 pathway governs energy balance in eukaryotic cells, notably influencing glucose de-repression. In S. cerevisiae , Snf1 is phosphorylated and hence activated upon glucose depletion. This activation is required but is not sufficient for mediating glucose de-repression, indicating further glucose-dependent regulation mechanisms. Employin...
Natural products from mushrooms, plants, microalgae, and cyanobacteria have been intensively explored and studied for their preventive or therapeutic potential. Among age-related pathologies, neurodegenerative diseases (such as Alzheimer’s and Parkinson’s diseases) represent a worldwide health and social problem. Since several pathological mechanis...
Calabrian Glycyrrhiza glabra is one of the most appreciated licorice varieties worldwide, and its leaves are emerging as a valuable source of bioactive compounds. Nevertheless, this biomass is usually discarded, and its valorization could contribute to boost the economic value of the licorice production chain. In this study, the effects of producti...
Astrocytes are essential players in development and functions, being particularly relevant as regulators of brain energy metabolism, ionic homeostasis and synaptic transmission. They are also the major source of l‐serine in the brain, which is synthesized from the glycolytic intermediate 3‐phosphoglycerate through the phosphorylated pathway. l‐Seri...
The growing use of photosynthetic microorganisms for food and food-related applications is driving related biotechnology research forward. Increasing consumer acceptance, high sustainability, demand of eco-friendly sources for food, and considerable global economic concern are among the main factors to enhance the focus on the novel foods. In the c...
Since the mid-1960s, methylotrophic yeast Komagataella phaffii (previously described as Pichia pastoris) has received increasing scientific attention. The interest for the industrial production of proteins for different applications (e.g., feed, food additives, detergent, waste treatment processes, and textile) is a well-consolidated scientific top...
The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central kinase modules of two opposing signaling pathways that control eukaryotic cell growth and metabolism in response to the availability of energy and nutrients. Accordingly, energy depletion activates AMPK to inhibit growth, while nutrients and high energ...
The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central kinase modules of two opposing signaling pathways that control eukaryotic cell growth and metabolism in response to the availability of energy and nutrients. Accordingly, energy depletion activates AMPK to inhibit growth, while nutrients and high energ...
Nutrition has relevant consequences for human health and increasing pieces of evidence indicate that medicinal mushrooms have several beneficial effects. One of the main issues in Western countries is represented by the challenges of aging and age-related diseases, such as neurodegenerative disorders. Among these, Parkinson’s disease (PD) affects 1...
Article Insulin and serine metabolism as sex-specific hallmarks of Alzheimer's disease in the human hippocampus Graphical abstract Highlights d Multi-omics analysis identified sex-specific AD hallmarks in human hippocampus d D-Ser/total Ser ratio increases in the hippocampus of women with AD d The insulin pathway decreases in women compared with me...
To achieve growth, microbial organisms must cope with stresses and adapt to the environment, exploiting the available nutrients with the highest efficiency. In Saccharomyces cerevisiae, Ras/PKA and Snf1/AMPK pathways regulate cellular metabolism according to the supply of glucose, alternatively supporting fermentation or mitochondrial respiration....
Background
food production represents one of the highest impacting activities on our planet, significantly contributing to climate change. Agriculture is one of the most important drivers of these changes since farming, forestry, and livestock, emit approximately one third of the global total CO2. Moreover, the modern agriculture systems mainly foc...
We report the rational design, synthesis, and in vitro preliminary evaluation of a new small library of non-peptide ligands of Gastrin Releasing Peptide Receptor (GRP-R), able to antagonize its natural ligand bombesin (BN) in the nanomolar range of concentration.
GRP-R is a transmembrane G-protein coupled receptor promoting the stimulation of canc...
Liver cancer is one of the most common cancer worldwide with a high mortality. Methionine is an essential amino acid required for normal development and cell growth, is mainly metabolized in the liver, and its role as an anti-cancer supplement is still controversial. Here, we evaluate the effects of methionine supplementation in liver cancer cells....
Aging and age-related neurodegeneration are among the major challenges in modern medicine because of the progressive increase in the number of elderly in the world population. Nutrition, which has important longterm consequences for health, is an important way to prevent diseases and achieve healthy aging. The beneficial effects of Vigna unguiculat...
Robust biological systems are able to adapt to internal and environmental perturbations. This is ensured by a thick crosstalk between metabolism and signal transduction pathways, through which cell cycle progression, cell metabolism and growth are coordinated. Although several reports describe the control of cell signaling on metabolism (mainly thr...
In the context of the nutrition transition, women in sub-Sahara Africa are a critical target group from a nutrition standpoint, and they experience significant discrimination in food production. Food-based, women-centered strategies are recommended to address nutrient gaps, and to educate and empower women. In this context, local natural resources,...
All proliferating cells need to match metabolism, growth and cell cycle progression with nutrient availability to guarantee cell viability in spite of a changing environment. In yeast, a signaling pathway centered on the effector kinase Snf1 is required to adapt to nutrient limitation and to utilize alternative carbon sources, such as sucrose and e...
Mitochondria play essential metabolic functions in eukaryotes. Although their major role is the generation of energy in the form of ATP, they are also involved in maintenance of cellular redox state, conversion and biosynthesis of metabolites and signal transduction. Most mitochondrial functions are conserved in eukaryotic systems and mitochondrial...
Before anaphase onset, budding yeast cells must align the mitotic spindle parallel to the mother-bud axis to ensure proper chromosome segregation. The protein kinase Snf1/AMPK is a highly conserved energy sensor, essential for adaptation to glucose limitation and in response to cellular stresses. However, recent findings indicate that it plays impo...
Several synthetic Combretastatin A4 (CA-4) derivatives were recently prepared to increase drug efficacy and stability of the natural product isolated from South African tree Combretum caffrum. A group of ten 3-amino-2-azetidinone derivatives, as Combretastatin A4 analogues, were selected through docking experiments, synthesized and tested for their...
ATP-binding cassette (ABC) transporters help export various substrates across the cell membrane and significantly contribute to drug resistance. However, a recent study reported an unusual case in which the loss of an ABC transporter in Candida albicans, orf19.4531 (previously named ROA1), increases resistance against antifungal azoles, which was a...
There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug re...
Calcium homeostasis is crucial to eukaryotic cell survival. By acting as an enzyme cofactor and a second messenger in several signal transduction pathways, the calcium ion controls many essential biological processes. Inside the endoplasmic reticulum (ER) calcium concentration is carefully regulated to safeguard the correct folding and processing o...
In eukaryotes, nutrient availability and metabolism are coordinated by sensing mechanisms and signaling pathways, which influence a broad set of cellular functions such as transcription and metabolic pathways to match environmental conditions. In yeast, Protein Kinase A (PKA) is activated in the presence of high glucose concentrations, favoring fas...
The metabolism of proliferating cells shows common features even in evolutionary distant organisms such as mammals and yeasts, for example the requirement for anabolic processes under tight control of signaling pathways. Analysis of the rewiring of metabolism, which occurs following the dysregulation of signaling pathways, provides new knowledge ab...
Here we propose the optimization of a rapid and reproducible protocol for intracellular metabolite extraction from yeast cells and their metabolic profiling by 1H-NMR spectroscopy. The protocol reliability has been validated through the comparison between the metabolome of cells in different phases of growth or with different genetic backgrounds.
![Fig. 5 Imaging PET acquisition. Representative transaxial [ 18 F] FDG...](profile/Paola-Coccetti/publication/264867641/figure/fig2/AS:601231064068117@1520356064935/maging-PET-acquisition-Representative-transaxial-18-F-FDG-PET-images-of-a-control_Q320.jpg)
The anticancer activity of a novel pure 1,4-Diaryl-2-azetidinone (1), endowed with a higher solubility than the well known Combretastatin A4, is tested in mice. We previously reported that Compound (1) showed specific antiproliferative activity against duodenal and colon cancer cells, inducing activation of AMP-activated protein kinase and apoptosi...
Snf1, the yeast AMP-activated kinase homolog, regulates the expression of several genes involved in adaptation to glucose limitation and in response to cellular stresses. We previously demonstrated that Snf1 interacts with Swi6, the regulatory subunit of SBF and MBF complexes, and activates CLB5 transcription. Here we report that, in α-factor synch...
In Saccharomyces cerevisiae, the entrance into S phase requires the activation of a specific burst of transcription, which depends on SBF (SCB binding
factor, Swi4/Swi6) and MBF (MCB binding factor, Mbp1/Swi6) complexes. CK2 is a pleiotropic kinase involved in several cellular
processes, including the regulation of the cell cycle. CK2 is composed o...
The ubiquitin (Ub) system controls almost every aspect of eukaryotic cell biology. Protein ubiquitination depends on the sequential action of three classes of enzymes (E1, E2 and E3). E2 Ub-conjugating enzymes have a central role in the ubiquitination pathway, interacting with both E1 and E3, and influencing the ultimate fate of the substrates. Sev...
Multiple sequence alignment of family 3 E2 representative members used for the phylogenetic investigation. Identical residues (red-filled boxes) and similar residues (red boxes) are indicated.
(PDF)
Sequences of E2 enzymes belonging to family 3 and their division in sub-families R, R1, R2, G1, G2 and #, along with the corresponding entries in the UNIPROT and NCBI databases.
(XLS)
This file contains the following supporting figures for this article: Figure 2. B-factor profiles obtained for the E2 representative members of family 3 by NMA, BD and DMD. Figure 3. Rmsf profiles from MD simulations. The 3D structure of each E2 family 3 enzyme is used as a reference and each residue colored with different shade of colors according...
Consensus of chained correlations derived by NMA, BD and DMD methods, as implemented in FlexServ, using as root residues the hydrophobic residues of L7.
(PDF)
Quantitative phosphoproteomics represents a front line for functional proteomics and hence for systems biology. Here we present a new application of the surface-activated chemical ionization (SACI) technology for quantitative phosphoproteomics analysis. The main advantages of SACI-MS technology are high sensitivity, quantitative accuracy and matrix...
A series of novel 1,4-diaryl-2-azetidinones were synthesized and evaluated for antiproliferative activity, cell cycle effects, and apoptosis induction. Strong cytotoxicity was observed with the best compounds (±)-trans-20, (±)-trans-21, and enantiomers (+)-trans-20 and (+)-trans-21, which exhibited IC(50) values of 3-13 nM against duodenal adenocar...
In this review we summarize the major connections between cell growth and cell cycle in the model eukaryote Saccharomyces cerevisiae. In S. cerevisiae regulation of cell cycle progression is achieved predominantly during a narrow interval in the late G1 phase known as START (Pringle and Hartwell, 1981). At START a yeast cell integrates environmenta...
CK2 is a highly conserved protein kinase involved in different cellular processes, which shows a higher activity in actively proliferating mammalian cells and in various types of cancer and cancer cell lines. We recently demonstrated that CK2 activity is strongly influenced by growth rate in yeast cells as well. Here, we extend our previous finding...
This file contains the following supporting figures for this article: Figure 1. Intra-family multiple sequence alignment. In each alignment the families are indicated by ‘_x’. Figure 2. Conformational landscape explored in Cdc34UBC simulations. The free energy landscape is represented using projection of the Cdc34UBC macro-trajectory along the prin...
Homology modeling of Cdc34UBC to generate starting structures for molecular dynamics simulations and molecular dynamics simulations setup and analysis.
(PDF)
E2 ubiquitin-conjugating enzymes are crucial mediators of protein ubiquitination, which strongly influence the ultimate fate of the target substrates. Recently, it has been shown that the activity of several enzymes of the ubiquitination pathway is finely tuned by phosphorylation, an ubiquitous mechanism for cellular regulation, which modulates pro...
CK2 is a highly conserved protein kinase controlling different cellular processes. It shows a higher activity in proliferating mammalian cells, in various types of cancer cell lines and tumors. The findings presented herein provide the first evidence of an in vivo modulation of CK2 activity, dependent on growth rate, in Saccharomyces cerevisiae. In...
The Saccharomyces cerevisiae Snf1 protein kinase has been reported to be required for adaptation to glucose limitation and for growth on non-fermentable carbon sources. Here we present novel findings indicating that Snf1, the key regulator of cellular energy, is also involved in yeast cell cycle control. The lack of Snf1 α-catalytic subunit down-re...
Besides being the favorite carbon and energy source for the budding yeast Sacchromyces cerevisiae, glucose can act as a signaling molecule to regulate multiple aspects of yeast physiology. Yeast cells have evolved several mechanisms for monitoring the level of glucose in their habitat and respond quickly to frequent changes in the sugar availabilit...
In the present work we show that murine ATXN3 (ATXN3Q6) nuclear uptake is promoted by phosphorylation on serine 29, a highly conserved residue inside the Josephin domain. Both casein kinase 2 (CK2) and glycogen synthase kinase 3 (GSK3) are able to carry out phosphorylation on this residue. S29 phosphorylation was initially assessed in vitro on puri...
A series of Z and E combretastatin A-4 analogs bearing different substituents (OH, F, NO(2), NH(2), B(OH)(2)) in the 3' position were synthesized. These derivatives and Z and E combretastatin A-1 were analysed by monitoring their ability to inhibit cell growth in Saccharomyces cerevisiae. Combretastatin A-1 (2a), A-4 (2b) and compound 2c were found...
Following a brief description of the operational procedures of systems biology (SB), the cell cycle of budding yeast is discussed as a successful example of a top-down SB analysis. After the reconstruction of the steps that have led to the identification of a sizer plus timer network in the G1 to S transition, it is shown that basic functions of th...
The ubiquitin-conjugating enzyme Cdc34 was recently shown to be phosphorylated by CK2 on the C-terminal tail. Here we present novel findings indicating that in budding yeast CK2 phosphorylates Cdc34 within the N-terminal catalytic domain. Specifically, we show, by direct mass spectrometry analysis, that Cdc34 is phosphorylated in vitro and in vivo...
Protein kinase CK2 is a heterotetramer composed of two catalytic and two regulatory subunits. In Saccharomyces cerevisiae the catalytic subunits (alpha and alpha') are encoded by the CKA1, CKA2 genes. cka1Deltacka2(ts) mutants arrest cell cycle in both G1 and G2/M at 37 degrees C. Hence, it has been proposed that CK2 plays an important role in cell...
We have previously identified Ser201 of Sic1, a yeast cyclin-dependent kinase inhibitor, as an in vitro target of protein kinase CK2. Here we present new evidence, by using specific anti-P-Ser201 antibodies and 2-D gel electrophoresis coupled to MALDI mass spectrometry analysis, that Sic1 is phosphorylated in vivo on Ser201 shortly after its de nov...
In Saccharomyces cerevisiae, Sic1, an inhibitor of Cdk (cyclin-dependent kinase), blocks the activity of S-Cdk1 (Cdk1/Clb5,6) kinase that is required for DNA replication. Deletion of Sic1 causes premature DNA replication from fewer origins, extension of the S phase and inefficient separation of sister chromatids during anaphase. Despite the well-do...
By sequence analysis we found an amino acid stretch centred on Serine201 matching a stringent CK2 consensus site within the C-terminal, inhibitory domain of Sic1. Here we show by direct mass spectrometry analysis that Sic1, but not a mutant protein whose CK2 phospho-acceptor site has been mutated to alanine, Sic1S201A, is actually phosphorylated in...
3-Nitrocoumarin is described in the literature as a specific inhibitor of mammalian phospholipase-C and here we studied the effect of 3-nitrocoumarin on budding yeast phosphatidylinositol-specific phospholipase-C and its effect on yeast growth. 3-Nitrocoumarin is a powerful inhibitor in vitro of the yeast Plc1 protein with an IC(50) of 57 nM and it...
The CDC25 gene product is a guanine nucleotide exchange factor for Ras proteins in yeast. Recently it has been suggested that the intracellular levels of guanine nucleotides may influence the exchange reaction. To test this hypothesis we measured the levels of nucleotides in yeast cells under different growth conditions and the relative amount of R...
![Figure 3 In vivo [ 32 P]P i labelling of Cdc28 and Cdc28-S46A (A)...](profile/Gian-Luigi-Russo/publication/12325611/figure/fig2/AS:667610156892177@1536182073830/n-vivo-32-PP-i-labelling-of-Cdc28-and-Cdc28-S46A-A-Autoradiography-of-phosphorylated_Q320.jpg)
The CDK (cyclin-dependent kinase) family of enzymes is required for the G(1)-to-S-phase and G(2)-to-M-phase transitions during the cell-division cycle of eukaryotes. We have shown previously that the protein kinase CKII catalyses the phosphorylation of Ser-39 in Cdc2 during the G(1) phase of the HeLa cell-division cycle [Russo, Vandenberg, Yu, Bae,...
The CDC25 gene product is an exchange factor for Ras proteins and it activates the Ras/cAMP pathway in the yeast Saccharomyces cerevisiae. The overexpression of the CDC25 gene in S. cerevisiae cells causes a partial glucose-derepressed phenotype which is particularly evident for expression of invertase. To define domains of Cdc25 protein relevant f...
Addition of glucose to glucose-deprived cells of the yeast Saccharomyces cerevisiae triggers rapid turnover of phosphatidylinositol, phosphatidylinositol-phosphate and phosphatidylinositol 4,5-bisphosphate. Glucose stimulation of PI turnover was measured both as an increase in the specific ratio of 32P-labeling and as an increase in the level of di...
The minimal active domain (GEF domain) of the mouse Ras exchange factor CDC25Mm was purified to homogeneity from recombinant Escherichia coli culture. The 256 amino acids polypeptide shows high activity in vitro and forms a stable complex with H-ras p21 in absence of guanine nucleotides. Circular dichroism (CD) spectra in the far UV region indicate...
The minimal active domain of the mouse CDC25Mm, a GDP/GTP exchange factor (GEF) active on H-ras protein, was determined by constructing several deletion mutants of the C-terminal domain of the protein. The functional activity of these fragments was analyzed for the ability to complement the yeast temperature sensitive mutation cdc25-1 and to cataly...
Cells of the yeast Saccharomyces cerevisiae display a wide range of glucose-induced regulatory phenomena, including glucose-induced activation of the RAS-adenylate cyclase pathway and phosphatidylinositol turnover, rapid post-translational effects on the activity of different enzymes as well as long-term effects at the transcriptional level. A gene...
By using a cotransfection assay with a ras-responsive fos-luciferase reporter gene, we present evidence that the catalytic domain of CDC25Mm constitutively activates p21ras in mammalian cells in vivo. Using immunopurified CDC25Mm-specific antibodies we show that different protein species are recognized in mouse tissues.
In the yeast Saccharomyces cerevisiae genetic and biochemical evidence indicates that the product of the CDC25 gene activates the RAS/adenylyl cyclase/protein kinase A pathway by acting as a guanine nucleotide protein. Here we report the isolation of a mouse brain cDNA homologous to CDC25. The mouse cDNA, called CDC25Mm, complements specifically po...
The CDC25 gene is transcribed at a very low level in S. cerevisiae cells. We have studied the effects of an overexpression of this regulatory gene by cloning either the whole CDC25 open reading frame (pIND25-2 plasmid) or its 3' terminal portion (pIND25-1 plasmid) under the control of the inducible strong GAL promoter. The strain transformed with p...
