Cardano M; Magni M; Alfieri R; Chan SY; Sabbioneda S; Buscemi G; Zannini L Sex specific regulation of TSPY-Like 2 in the DNA damage response of cancer cells Journal Article In: Cell death and disease, vol. 14, iss. 3, pp. 197, 2023. @article{%a1.%Yb_68,
title = {Sex specific regulation of TSPY-Like 2 in the DNA damage response of cancer cells},
author = {Cardano M and Magni M and Alfieri R and Chan SY and Sabbioneda S and Buscemi G and Zannini L},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015022/},
doi = {10.1038/s41419-023-05722-2},
year = {2023},
date = {2023-03-01},
journal = {Cell death and disease},
volume = {14},
issue = {3},
pages = {197},
abstract = {Females have a lower probability to develop somatic cancers and a better response to chemotherapy than males. However, the reasons for these differences are still not well understood. The X-linked gene TSPY-Like 2 (TSPYL2) encodes for a putative tumor suppressor protein involved in cell cycle regulation and DNA damage response (DDR) pathways. Here, we demonstrate that in unstressed conditions TSPYL2 is maintained at low levels by MDM2-dependent ubiquitination and proteasome degradation. Upon genotoxic stress, E2F1 promotes TSPYL2 expression and protein accumulation in non-transformed cell lines. Conversely, in cancer cells, TSPYL2 accumulates only in females or in those male cancer cells that lost the Y-chromosome during the oncogenic process. Hence, we demonstrate that while TSPYL2 mRNA is induced in all the tested tumor cell lines after DNA damage, TSPYL2 protein stability is increased only in female cancer cells. Indeed, we found that TSPYL2 accumulation, in male cancer cells, is prevented by the Y-encoded protein SRY, which modulates MDM2 protein levels. In addition, we demonstrated that TSPYL2 accumulation is required to sustain cell growth arrest after DNA damage, possibly contributing to protect normal and female cancer cells from tumor progression. Accordingly, TSPYL2 has been found more frequently mutated in female-specific cancers. These findings demonstrate for the first time a sex-specific regulation of TSPYL2 in the DDR of cancer cells and confirm the existence of sexual dimorphism in DNA surveillance pathways.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Females have a lower probability to develop somatic cancers and a better response to chemotherapy than males. However, the reasons for these differences are still not well understood. The X-linked gene TSPY-Like 2 (TSPYL2) encodes for a putative tumor suppressor protein involved in cell cycle regulation and DNA damage response (DDR) pathways. Here, we demonstrate that in unstressed conditions TSPYL2 is maintained at low levels by MDM2-dependent ubiquitination and proteasome degradation. Upon genotoxic stress, E2F1 promotes TSPYL2 expression and protein accumulation in non-transformed cell lines. Conversely, in cancer cells, TSPYL2 accumulates only in females or in those male cancer cells that lost the Y-chromosome during the oncogenic process. Hence, we demonstrate that while TSPYL2 mRNA is induced in all the tested tumor cell lines after DNA damage, TSPYL2 protein stability is increased only in female cancer cells. Indeed, we found that TSPYL2 accumulation, in male cancer cells, is prevented by the Y-encoded protein SRY, which modulates MDM2 protein levels. In addition, we demonstrated that TSPYL2 accumulation is required to sustain cell growth arrest after DNA damage, possibly contributing to protect normal and female cancer cells from tumor progression. Accordingly, TSPYL2 has been found more frequently mutated in female-specific cancers. These findings demonstrate for the first time a sex-specific regulation of TSPYL2 in the DDR of cancer cells and confirm the existence of sexual dimorphism in DNA surveillance pathways. |
Moyano A; Croce AC; Scolari F Pathogen-Mediated Alterations of Insect Chemical Communication: From Pheromones to Behavior Journal Article In: Pathogens, vol. 12, iss. 11, pp. 1350, 2023. @article{%a1.%Y_127,
title = {Pathogen-Mediated Alterations of Insect Chemical Communication: From Pheromones to Behavior},
author = {Moyano A and Croce AC and Scolari F },
url = {https://www.mdpi.com/2076-0817/12/11/1350},
doi = {10.3390/pathogens12111350},
year = {2023},
date = {2023-02-23},
journal = {Pathogens},
volume = {12},
issue = {11},
pages = {1350},
abstract = {Pathogens can influence the physiology and behavior of both animal and plant hosts in a manner that promotes their own transmission and dispersal. Recent research focusing on insects has revealed that these manipulations can extend to the production of pheromones, which are pivotal in chemical communication. This review provides an overview of the current state of research and available data concerning the impacts of bacterial, viral, fungal, and eukaryotic pathogens on chemical communication across different insect orders. While our understanding of the influence of pathogenic bacteria on host chemical profiles is still limited, viral infections have been shown to induce behavioral changes in the host, such as altered pheromone production, olfaction, and locomotion. Entomopathogenic fungi affect host chemical communication by manipulating cuticular hydrocarbons and pheromone production, while various eukaryotic parasites have been observed to influence insect behavior by affecting the production of pheromones and other chemical cues. The effects induced by these infections are explored in the context of the evolutionary advantages they confer to the pathogen. The molecular mechanisms governing the observed pathogen-mediated behavioral changes, as well as the dynamic and mutually influential relationships between the pathogen and its host, are still poorly understood. A deeper comprehension of these mechanisms will prove invaluable in identifying novel targets in the perspective of practical applications aimed at controlling detrimental insect species.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pathogens can influence the physiology and behavior of both animal and plant hosts in a manner that promotes their own transmission and dispersal. Recent research focusing on insects has revealed that these manipulations can extend to the production of pheromones, which are pivotal in chemical communication. This review provides an overview of the current state of research and available data concerning the impacts of bacterial, viral, fungal, and eukaryotic pathogens on chemical communication across different insect orders. While our understanding of the influence of pathogenic bacteria on host chemical profiles is still limited, viral infections have been shown to induce behavioral changes in the host, such as altered pheromone production, olfaction, and locomotion. Entomopathogenic fungi affect host chemical communication by manipulating cuticular hydrocarbons and pheromone production, while various eukaryotic parasites have been observed to influence insect behavior by affecting the production of pheromones and other chemical cues. The effects induced by these infections are explored in the context of the evolutionary advantages they confer to the pathogen. The molecular mechanisms governing the observed pathogen-mediated behavioral changes, as well as the dynamic and mutually influential relationships between the pathogen and its host, are still poorly understood. A deeper comprehension of these mechanisms will prove invaluable in identifying novel targets in the perspective of practical applications aimed at controlling detrimental insect species. |
Marchionni E; D'Apice MR; Lupo V; Lattanzi G; Mattioli E; Lisignoli G; Gabusi E; Pepe G; Helmer Citterich M; Campione E; Nardone AM; Spitalieri P; Pucci N; Cocciadiferro D; Picchi E; Garaci F; Novelli A; Novelli G. Clinical and functional characterization of COL2A1 p.Gly444Ser variant: From a fetal phenotype to a previously undisclosed postnatal phenotype Journal Article In: Bone reports, vol. 19, pp. 101728, 2023. @article{%a1.%Y_126,
title = {Clinical and functional characterization of COL2A1 p.Gly444Ser variant: From a fetal phenotype to a previously undisclosed postnatal phenotype},
author = {Marchionni E and D'Apice MR and Lupo V and Lattanzi G and Mattioli E and Lisignoli G and Gabusi E and Pepe G and Helmer Citterich M and Campione E and Nardone AM and Spitalieri P and Pucci N and Cocciadiferro D and Picchi E and Garaci F and Novelli A and Novelli G.},
url = {https://www.sciencedirect.com/science/article/pii/S2352187223000748?via%3Dihub},
doi = {10.1016/j.bonr.2023.101728},
year = {2023},
date = {2023-02-23},
journal = {Bone reports},
volume = {19},
pages = {101728},
abstract = {COL2A1 gene encodes the alpha-1 chain of type-II procollagen. Heterozygous pathogenic variants are associated with the broad clinical spectrum of genetic diseases known as type-II collagenopathies. We aimed to characterize the NM_001844.5:c.1330G>A;p.Gly444Ser variant detected in the COL2A1 gene through trio-based prenatal exome sequencing in a fetus presenting a severe skeletal phenotype at 31 Gestational Weeks and in his previously undisclosed mild-affected father. Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. Extracellular matrix showed a disorganized fibronectin network. These results showed that p.Gly444Ser variant alters procollagen molecules processing and the assembly of mature type-II collagen fibrils, according to COL2A1-chain disorganization, displayed by protein modeling. Clinical assessment at 38 y.o., through a reverse-phenotyping approach, revealed limp gait, short and stocky appearance. X-Ray and MRI showed pelvis asymmetry with severe morpho-structural alterations of the femoral heads bilaterally, consistent with a mild form of type-II collagenopathy. This study shows how the fusion of genomics and clinical expertise can drive a diagnosis supported by cellular and bioinformatics studies to effectively establish variants pathogenicity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
COL2A1 gene encodes the alpha-1 chain of type-II procollagen. Heterozygous pathogenic variants are associated with the broad clinical spectrum of genetic diseases known as type-II collagenopathies. We aimed to characterize the NM_001844.5:c.1330G>A;p.Gly444Ser variant detected in the COL2A1 gene through trio-based prenatal exome sequencing in a fetus presenting a severe skeletal phenotype at 31 Gestational Weeks and in his previously undisclosed mild-affected father. Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. Extracellular matrix showed a disorganized fibronectin network. These results showed that p.Gly444Ser variant alters procollagen molecules processing and the assembly of mature type-II collagen fibrils, according to COL2A1-chain disorganization, displayed by protein modeling. Clinical assessment at 38 y.o., through a reverse-phenotyping approach, revealed limp gait, short and stocky appearance. X-Ray and MRI showed pelvis asymmetry with severe morpho-structural alterations of the femoral heads bilaterally, consistent with a mild form of type-II collagenopathy. This study shows how the fusion of genomics and clinical expertise can drive a diagnosis supported by cellular and bioinformatics studies to effectively establish variants pathogenicity. |
Beniamino Y; Cenni V; Piccioli M; Ciurli S; Zambelli B The Ni(II)-Binding Activity of the Intrinsically Disordered Region of Human NDRG1, a Protein Involved in Cancer Development Bachelor Thesis 2022. @bachelorthesis{%a1.%Yb_42,
title = {The Ni(II)-Binding Activity of the Intrinsically Disordered Region of Human NDRG1, a Protein Involved in Cancer Development},
author = {Beniamino Y and Cenni V and Piccioli M and Ciurli S and Zambelli B},
url = {https://www.mdpi.com/2218-273X/12/9/1272},
doi = {10.3390/biom12091272},
year = {2022},
date = {2022-12-07},
journal = {Biomolecules},
volume = {12},
issue = {9},
pages = {1272},
abstract = {Nickel exposure is associated with tumors of the respiratory tract such as lung and nasal cancers, acting through still-uncharacterized mechanisms. Understanding the molecular basis of nickel-induced carcinogenesis requires unraveling the mode and the effects of Ni(II) binding to its intracellular targets. A possible Ni(II)-binding protein and a potential focus for cancer treatment is hNDRG1, a protein induced by Ni(II) through the hypoxia response pathway, whose expression correlates with higher cancer aggressiveness and resistance to chemotherapy in lung tissue. The protein sequence contains a unique C-terminal sequence of 83 residues (hNDRG1*C), featuring a three-times-repeated decapeptide, involved in metal binding, lipid interaction and post-translational phosphorylation. In the present work, the biochemical and biophysical characterization of unmodified hNDRG1*C was performed. Bioinformatic analysis assigned it to the family of the intrinsically disordered regions and the absence of secondary and tertiary structure was experimentally proven by circular dichroism and NMR. Isothermal titration calorimetry revealed the occurrence of a Ni(II)-binding event with micromolar affinity. Detailed information on the Ni(II)-binding site and on the residues involved was obtained in an extensive NMR study, revealing an octahedral paramagnetic metal coordination that does not cause any major change of the protein backbone, which is coherent with CD analysis. hNDRG1*C was found in a monomeric form by light-scattering experiments, while the full-length hNDRG1 monomer was found in equilibrium between the dimer and tetramer, both in solution and in human cell lines. The results are the first essential step for understanding the cellular function of hNDRG1*C at the molecular level, with potential future applications to clarify its role and the role of Ni(II) in cancer development.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Nickel exposure is associated with tumors of the respiratory tract such as lung and nasal cancers, acting through still-uncharacterized mechanisms. Understanding the molecular basis of nickel-induced carcinogenesis requires unraveling the mode and the effects of Ni(II) binding to its intracellular targets. A possible Ni(II)-binding protein and a potential focus for cancer treatment is hNDRG1, a protein induced by Ni(II) through the hypoxia response pathway, whose expression correlates with higher cancer aggressiveness and resistance to chemotherapy in lung tissue. The protein sequence contains a unique C-terminal sequence of 83 residues (hNDRG1*C), featuring a three-times-repeated decapeptide, involved in metal binding, lipid interaction and post-translational phosphorylation. In the present work, the biochemical and biophysical characterization of unmodified hNDRG1*C was performed. Bioinformatic analysis assigned it to the family of the intrinsically disordered regions and the absence of secondary and tertiary structure was experimentally proven by circular dichroism and NMR. Isothermal titration calorimetry revealed the occurrence of a Ni(II)-binding event with micromolar affinity. Detailed information on the Ni(II)-binding site and on the residues involved was obtained in an extensive NMR study, revealing an octahedral paramagnetic metal coordination that does not cause any major change of the protein backbone, which is coherent with CD analysis. hNDRG1*C was found in a monomeric form by light-scattering experiments, while the full-length hNDRG1 monomer was found in equilibrium between the dimer and tetramer, both in solution and in human cell lines. The results are the first essential step for understanding the cellular function of hNDRG1*C at the molecular level, with potential future applications to clarify its role and the role of Ni(II) in cancer development. |
Princiotto S; Musso L; Manetti F; Marcellini V; Maga G; Crespan E; Perini C; Zaffaroni N; Beretta GL; Dallavalle S Synthesis and biological activity evaluation of 3-(hetero) arylideneindolin-2-ones as potential c-Src inhibitors Journal Article In: Journal of enzyme inhibition and medicinal chemistry, vol. 37, iss. 1, pp. 2382-2394, 2022. @article{%a1.%Yb_41,
title = {Synthesis and biological activity evaluation of 3-(hetero) arylideneindolin-2-ones as potential c-Src inhibitors},
author = {Princiotto S and Musso L and Manetti F and Marcellini V and Maga G and Crespan E and Perini C and Zaffaroni N and Beretta GL and Dallavalle S},
url = {https://www.tandfonline.com/doi/full/10.1080/14756366.2022.2117317},
doi = {10.1080/14756366.2022.2117317},
year = {2022},
date = {2022-09-05},
journal = {Journal of enzyme inhibition and medicinal chemistry},
volume = {37},
issue = {1},
pages = {2382-2394},
abstract = {Inhibition of c-Src is considered one of the most studied approaches to cancer treatment, with several heterocyclic compounds approved during the last 15 years as chemotherapeutic agents. Starting from the biological evaluation of an in-house collection of small molecules, indolinone was selected as the most promising scaffold. In this work, several functionalised indolinones were synthesised and their inhibitory potency and cytotoxic activity were assayed. The pharmacological profile of the most active compounds, supported by molecular modelling studies, revealed that the presence of an amino group increased the affinity towards the ATP-binding site of c-Src. At the same time, bulkier derivatizations seemed to improve the interactions within the enzymatic pocket. Overall, these data represent an early stage towards the optimisation of new, easy-to-be functionalised indolinones as potential c-Src inhibitors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Inhibition of c-Src is considered one of the most studied approaches to cancer treatment, with several heterocyclic compounds approved during the last 15 years as chemotherapeutic agents. Starting from the biological evaluation of an in-house collection of small molecules, indolinone was selected as the most promising scaffold. In this work, several functionalised indolinones were synthesised and their inhibitory potency and cytotoxic activity were assayed. The pharmacological profile of the most active compounds, supported by molecular modelling studies, revealed that the presence of an amino group increased the affinity towards the ATP-binding site of c-Src. At the same time, bulkier derivatizations seemed to improve the interactions within the enzymatic pocket. Overall, these data represent an early stage towards the optimisation of new, easy-to-be functionalised indolinones as potential c-Src inhibitors. |
Croce AC; Scolari F Autofluorescent Biomolecules in Diptera: From Structure to Metabolism and Behavior Journal Article In: Molecules, vol. 27, iss. 14, pp. 4458, 2022. @article{%a1.%Ybx,
title = {Autofluorescent Biomolecules in Diptera: From Structure to Metabolism and Behavior},
author = {Croce AC and Scolari F},
url = {https://www.mdpi.com/1420-3049/27/14/4458},
doi = {10.3390/molecules27144458},
year = {2022},
date = {2022-08-30},
journal = {Molecules},
volume = {27},
issue = {14},
pages = {4458},
abstract = {Light-based phenomena in insects have long attracted researchers' attention. Surface color distribution patterns are commonly used for taxonomical purposes, while optically-active structures from Coleoptera cuticle or Lepidoptera wings have inspired technological applications, such as biosensors and energy accumulation devices. In Diptera, besides optically-based phenomena, biomolecules able to fluoresce can act as markers of bio-metabolic, structural and behavioral features. Resilin or chitinous compounds, with their respective blue or green-to-red autofluorescence (AF), are commonly related to biomechanical and structural properties, helpful to clarify the mechanisms underlying substrate adhesion of ectoparasites' leg appendages, or the antennal abilities in tuning sound detection. Metarhodopsin, a red fluorescing photoproduct of rhodopsin, allows to investigate visual mechanisms, whereas NAD(P)H and flavins, commonly relatable to energy metabolism, favor the investigation of sperm vitality. Lipofuscins are AF biomarkers of aging, as well as pteridines, which, similarly to kynurenines, are also exploited in metabolic investigations. Beside the knowledge available in Drosophila melanogaster, a widely used model to study also human disorder and disease mechanisms, here we review optically-based studies in other dipteran species, including mosquitoes and fruit flies, discussing future perspectives for targeted studies with various practical applications, including pest and vector control.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Light-based phenomena in insects have long attracted researchers' attention. Surface color distribution patterns are commonly used for taxonomical purposes, while optically-active structures from Coleoptera cuticle or Lepidoptera wings have inspired technological applications, such as biosensors and energy accumulation devices. In Diptera, besides optically-based phenomena, biomolecules able to fluoresce can act as markers of bio-metabolic, structural and behavioral features. Resilin or chitinous compounds, with their respective blue or green-to-red autofluorescence (AF), are commonly related to biomechanical and structural properties, helpful to clarify the mechanisms underlying substrate adhesion of ectoparasites' leg appendages, or the antennal abilities in tuning sound detection. Metarhodopsin, a red fluorescing photoproduct of rhodopsin, allows to investigate visual mechanisms, whereas NAD(P)H and flavins, commonly relatable to energy metabolism, favor the investigation of sperm vitality. Lipofuscins are AF biomarkers of aging, as well as pteridines, which, similarly to kynurenines, are also exploited in metabolic investigations. Beside the knowledge available in Drosophila melanogaster, a widely used model to study also human disorder and disease mechanisms, here we review optically-based studies in other dipteran species, including mosquitoes and fruit flies, discussing future perspectives for targeted studies with various practical applications, including pest and vector control. |
Cristalli C; Manara MC; Valente S; Pellegrini E; Bavelloni A; De Feo A; Blalock WL; Di Bello E; Pineyro D; Merkel A; Esteller M; Tirado OM; Mai A; Scotlandi K Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response Journal Article In: Frontiers in endocrinology, vol. 13, pp. 876602, 2022. @article{%a1.%Ybw,
title = {Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response},
author = {Cristalli C and Manara MC and Valente S and Pellegrini E and Bavelloni A and De Feo A and Blalock WL and Di Bello E and Pineyro D and Merkel A and Esteller M and Tirado OM and Mai A and Scotlandi K},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2022.876602/full},
doi = {10.3389/fendo.2022.876602},
year = {2022},
date = {2022-08-30},
urldate = {2022-08-30},
journal = {Frontiers in endocrinology},
volume = {13},
pages = {876602},
abstract = {DNA methylation is an important component of the epigenetic machinery that regulates the malignancy of Ewing sarcoma (EWS), the second most common primary bone tumor in children and adolescents. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming and the DNMT1 enzyme has been demonstrated to have an important role in both maintaining the epigenome and controlling cell cycle. Here, we showed that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 induces a specific depletion of DNMT1 and affects EWS tumor proliferation through a mechanism that is independent on DNA methylation. Depletion of DNMT1 causes perturbation of the cell cycle, with an accumulation of cells in the G1 phase, and DNA damage, as revealed by the induction of γH2AX foci. These effects elicited activation of p53-dependent signaling and apoptosis in p53wt cells, while in p53 mutated cells, persistent micronuclei and increased DNA instability was observed. Treatment with MC3343 potentiates the efficacy of DNA damaging agents such as doxorubicin and PARP-inhibitors (PARPi). This effect correlates with increased DNA damage and synergistic tumor cytotoxicity, supporting the use of the DNMTi MC3343 as an adjuvant agent in treating EWS.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DNA methylation is an important component of the epigenetic machinery that regulates the malignancy of Ewing sarcoma (EWS), the second most common primary bone tumor in children and adolescents. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming and the DNMT1 enzyme has been demonstrated to have an important role in both maintaining the epigenome and controlling cell cycle. Here, we showed that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 induces a specific depletion of DNMT1 and affects EWS tumor proliferation through a mechanism that is independent on DNA methylation. Depletion of DNMT1 causes perturbation of the cell cycle, with an accumulation of cells in the G1 phase, and DNA damage, as revealed by the induction of γH2AX foci. These effects elicited activation of p53-dependent signaling and apoptosis in p53wt cells, while in p53 mutated cells, persistent micronuclei and increased DNA instability was observed. Treatment with MC3343 potentiates the efficacy of DNA damaging agents such as doxorubicin and PARP-inhibitors (PARPi). This effect correlates with increased DNA damage and synergistic tumor cytotoxicity, supporting the use of the DNMTi MC3343 as an adjuvant agent in treating EWS. |
Perut F; Graziani G; Roncuzzi L; Zini N; Avnet S; Baldini N FT-IR Spectral Signature of Sensitive and Multidrug-Resistant Osteosarcoma Cell-Derived Extracellular Nanovesicles Journal Article In: Cells, vol. 11, iss. 5, pp. 778, 2022. @article{%a1.%Yb_33,
title = {FT-IR Spectral Signature of Sensitive and Multidrug-Resistant Osteosarcoma Cell-Derived Extracellular Nanovesicles},
author = {Perut F and Graziani G and Roncuzzi L and Zini N and Avnet S and Baldini N},
url = {https://www.mdpi.com/2073-4409/11/5/778},
doi = {10.3390/cells11050778},
year = {2022},
date = {2022-08-26},
journal = {Cells},
volume = {11},
issue = {5},
pages = {778},
abstract = {Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, the outcome is unsatisfactory, and multidrug resistance (MDR) is a pivotal process in OS treatment failure. OS-derived extracellular vesicles (EVs) promote drug resistance to chemotherapy and target therapy through different mechanisms. The aim of this study was to identify subpopulations of osteosarcoma-EVs by Fourier transform infrared spectroscopy (FT-IR) to define a specific spectral signature for sensitive and multidrug-resistant OS-derived EVs. EVs were isolated from sensitive and MDR OS cells as well as from mesenchymal stem cells by differential centrifugation and ultracentrifugation. EVs size, morphology and protein expression were characterized. FT-IR/ATR of EVs spectra were acquired in the region of 400-4000 cm-1 (resolution 4 cm-1, 128 scans). The FT-IR spectra obtained were consistently different in the EVs compared to cells from which they originate. A specific spectral signature, characterized by a shift and a new band (1601 cm-1), permitted to clearly distinguish EVs isolated by sensitive and multidrug-resistant OS cells. Our data suggest that FT-IR spectroscopy allows to characterize and define a specific spectral signature for sensitive and MDR OS-derived EVs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, the outcome is unsatisfactory, and multidrug resistance (MDR) is a pivotal process in OS treatment failure. OS-derived extracellular vesicles (EVs) promote drug resistance to chemotherapy and target therapy through different mechanisms. The aim of this study was to identify subpopulations of osteosarcoma-EVs by Fourier transform infrared spectroscopy (FT-IR) to define a specific spectral signature for sensitive and multidrug-resistant OS-derived EVs. EVs were isolated from sensitive and MDR OS cells as well as from mesenchymal stem cells by differential centrifugation and ultracentrifugation. EVs size, morphology and protein expression were characterized. FT-IR/ATR of EVs spectra were acquired in the region of 400-4000 cm-1 (resolution 4 cm-1, 128 scans). The FT-IR spectra obtained were consistently different in the EVs compared to cells from which they originate. A specific spectral signature, characterized by a shift and a new band (1601 cm-1), permitted to clearly distinguish EVs isolated by sensitive and multidrug-resistant OS cells. Our data suggest that FT-IR spectroscopy allows to characterize and define a specific spectral signature for sensitive and MDR OS-derived EVs. |
Montano V; Mancuso M; Simoncini C; Torri F; Chico L; Ali G; Rocchi A; Baldinotti F; Caligo MA; Lattanzi G; Mattioli E; Cenacchi G; Barison A; Siciliano G; Ricci G A Single mtDNA Deletion in Association with a LMNA Gene New Frameshift Variant: A Case Report Journal Article In: Journal of neuromuscular diseases, vol. 9, iss. 3457-462, 2022. @article{%a1.%Yb_31,
title = {A Single mtDNA Deletion in Association with a LMNA Gene New Frameshift Variant: A Case Report},
author = {Montano V and Mancuso M and Simoncini C and Torri F and Chico L and Ali G and Rocchi A and Baldinotti F and Caligo MA and Lattanzi G and Mattioli E and Cenacchi G and Barison A and Siciliano G and Ricci G},
url = {https://content.iospress.com/articles/journal-of-neuromuscular-diseases/jnd220802},
doi = {10.3233/JND-220802},
year = {2022},
date = {2022-08-25},
journal = {Journal of neuromuscular diseases},
volume = {9},
issue = {3457-462},
abstract = {Background: Proximal muscle weakness may be the presenting clinical feature of different types of myopathies, including limb girdle muscular dystrophy and primary mitochondrial myopathy. LGMD1B is caused by LMNA mutation. It is characterized by progressive weakness and wasting leading to proximal weakness, cardiomyopathy, and hearth conduction block. Objective: In this article, we describe the case of a patient who presented with limb-girdle weakness and a double trouble scenario -mitochondrial DNA single deletion and a new LMNA mutation. Methods: Pathophysiological aspects were investigated with muscle biopsy, Western Blot analysis, NGS nuclear and mtDNA analysis and neuromuscular imaging (muscle and cardiac MRI). Results: Although secondary mitochondrial involvement is possible, a "double trouble" syndrome can not be excluded. Conclusion: Implication deriving from hypothetical coexistence of two different pathological conditions or the possible secondary mitochondrial involvement are discussed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Proximal muscle weakness may be the presenting clinical feature of different types of myopathies, including limb girdle muscular dystrophy and primary mitochondrial myopathy. LGMD1B is caused by LMNA mutation. It is characterized by progressive weakness and wasting leading to proximal weakness, cardiomyopathy, and hearth conduction block. Objective: In this article, we describe the case of a patient who presented with limb-girdle weakness and a double trouble scenario -mitochondrial DNA single deletion and a new LMNA mutation. Methods: Pathophysiological aspects were investigated with muscle biopsy, Western Blot analysis, NGS nuclear and mtDNA analysis and neuromuscular imaging (muscle and cardiac MRI). Results: Although secondary mitochondrial involvement is possible, a "double trouble" syndrome can not be excluded. Conclusion: Implication deriving from hypothetical coexistence of two different pathological conditions or the possible secondary mitochondrial involvement are discussed. |
Joseph CR; Dusi S; Giannattasio M; Branzei D Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase Journal Article In: Nature communications, vol. 13, iss. 1, pp. 2480, 2022. @article{%a1.%Yb_29,
title = {Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase},
author = {Joseph CR and Dusi S and Giannattasio M and Branzei D},
url = {https://www.nature.com/articles/s41467-022-30215-9},
doi = {10.1038/s41467-022-30215-9},
year = {2022},
date = {2022-08-25},
journal = {Nature communications},
volume = {13},
issue = {1},
pages = {2480},
abstract = {DNA damage tolerance (DDT), activated by replication stress during genome replication, is mediated by translesion synthesis and homologous recombination (HR). Here we uncover that DDK kinase, essential for replication initiation, is critical for replication-associated recombination-mediated DDT. DDK relies on its multi-monoSUMOylation to facilitate HR-mediated DDT and optimal retention of Rad51 recombinase at replication damage sites. Impairment of DDK kinase activity, reduced monoSUMOylation and mutations in the putative SUMO Interacting Motifs (SIMs) of Rad51 impair replication-associated recombination and cause fork uncoupling with accumulation of large single-stranded DNA regions at fork branching points. Notably, genetic activation of salvage recombination rescues the uncoupled fork phenotype but not the recombination-dependent gap-filling defect of DDK mutants, revealing that the salvage recombination pathway operates preferentially proximal to fork junctions at stalled replication forks. Overall, we uncover that monoSUMOylated DDK acts with Rad51 in an axis that prevents replication fork uncoupling and mediates recombination-dependent gap-filling.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DNA damage tolerance (DDT), activated by replication stress during genome replication, is mediated by translesion synthesis and homologous recombination (HR). Here we uncover that DDK kinase, essential for replication initiation, is critical for replication-associated recombination-mediated DDT. DDK relies on its multi-monoSUMOylation to facilitate HR-mediated DDT and optimal retention of Rad51 recombinase at replication damage sites. Impairment of DDK kinase activity, reduced monoSUMOylation and mutations in the putative SUMO Interacting Motifs (SIMs) of Rad51 impair replication-associated recombination and cause fork uncoupling with accumulation of large single-stranded DNA regions at fork branching points. Notably, genetic activation of salvage recombination rescues the uncoupled fork phenotype but not the recombination-dependent gap-filling defect of DDK mutants, revealing that the salvage recombination pathway operates preferentially proximal to fork junctions at stalled replication forks. Overall, we uncover that monoSUMOylated DDK acts with Rad51 in an axis that prevents replication fork uncoupling and mediates recombination-dependent gap-filling. |
Gorski M; Rasheed H; Teumer A; Thomas LF; Graham SE; Sveinbjornsson G; Winkler TW; Gunther F; Stark KJ; Chai JF; Tayo BO; Wuttke M; Li Y; Tin A; Ahluwalia TS; Ärnlöv J; Åsvold BO; Bakker SJL; Banas B; Bansal N; Biggs ML; Biino G; et al Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies Journal Article In: Kidney international, vol. 102, iss. 3, pp. 624-639, 2022. @article{%a1.%Yb_28,
title = {Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies},
author = {Gorski M and Rasheed H and Teumer A and Thomas LF and Graham SE and Sveinbjornsson G and Winkler TW and Gunther F and Stark KJ and Chai JF and Tayo BO and Wuttke M and Li Y and Tin A and Ahluwalia TS and Ärnlöv J and Åsvold BO and Bakker SJL and Banas B and Bansal N and Biggs ML and Biino G and {et al}},
url = {https://www.sciencedirect.com/science/article/pii/S0085253822004549?via%3Dihub},
doi = {10.1016/j.kint.2022.05.021},
year = {2022},
date = {2022-08-25},
journal = {Kidney international},
volume = {102},
issue = {3},
pages = {624-639},
abstract = {Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics. |
Scolari F; Khamis FM; Perez-Staples D Editorial: Novel Insights Into Female Post-Mating Physiology in Insects Journal Article In: Frontiers in physiology, vol. 13, pp. 877222, 2022. @article{%a1.%Yb_36,
title = {Editorial: Novel Insights Into Female Post-Mating Physiology in Insects},
author = {Scolari F and Khamis FM and Perez-Staples D},
url = {https://www.frontiersin.org/articles/10.3389/fphys.2022.877222/full},
doi = {10.3389/fphys.2022.877222},
year = {2022},
date = {2022-08-24},
journal = {Frontiers in physiology},
volume = {13},
pages = {877222},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Fontana CM; Locatello L; Sabatelli P; Facchinello N; Lidron E; Maradonna F; Carnevali O; Rasotto MB; Dalla Valle L epg5 knockout leads to the impairment of reproductive success and courtship behaviour in a zebrafish model of autophagy-related diseases Journal Article In: Biomedical journal, vol. 45, iss. 2, pp. 377-386, 2022. @article{%a1.%Ybz,
title = {epg5 knockout leads to the impairment of reproductive success and courtship behaviour in a zebrafish model of autophagy-related diseases},
author = {Fontana CM and Locatello L and Sabatelli P and Facchinello N and Lidron E and Maradonna F and Carnevali O and Rasotto MB and Dalla Valle L},
url = {https://www.sciencedirect.com/science/article/pii/S2319417021000342?via%3Dihub},
doi = {10.1016/j.bj.2021.04.002},
year = {2022},
date = {2022-08-24},
journal = {Biomedical journal},
volume = {45},
issue = {2},
pages = {377-386},
abstract = {Background: Dysregulation of the autophagic flux is linked to a wide array of human diseases, and recent findings highlighted the central role of autophagy in reproduction, as well as an association between impairment of autophagy and behavioural disorders. Here we deepened on the possible multilevel link between impairment of the autophagic processes and reproduction at both the physiological and the behavioural level in a zebrafish mutant model. Methods: Using a KO epg5 zebrafish line we analysed male breeding success, fertility rate, offspring survival, ejaculate quality, sperm and testes morphology, and courtship behaviour. To this aim physiological, histological, ultrastructural and behavioural analyses on epg5+/+ and mutant epg5-/- males coupled to WT females were applied. Results: We observed an impairment of male reproductive performance in mutant epg5-/- males that showed a lower breeding success with a reduced mean number of eggs spawned by their WT female partners. The spermatogenesis and the ability to produce fertilising ejaculates were not drastically impaired in our mutant males, whereas we observed a reduction of their courtship behaviour that might contribute to explain their lower overall reproductive success. Conclusion: Collectively our findings corroborate the hypothesis of a multilevel link between the autophagic process and reproduction. Moreover, by giving a first glimpse on behavioural disorders associated to epg5 KO in model zebrafish, our results open the way to more extensive behavioural analyses, also beyond the reproductive events, that might serve as new tools for the molecular screening of autophagy-related multisystemic and neurodegenerative diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Dysregulation of the autophagic flux is linked to a wide array of human diseases, and recent findings highlighted the central role of autophagy in reproduction, as well as an association between impairment of autophagy and behavioural disorders. Here we deepened on the possible multilevel link between impairment of the autophagic processes and reproduction at both the physiological and the behavioural level in a zebrafish mutant model. Methods: Using a KO epg5 zebrafish line we analysed male breeding success, fertility rate, offspring survival, ejaculate quality, sperm and testes morphology, and courtship behaviour. To this aim physiological, histological, ultrastructural and behavioural analyses on epg5+/+ and mutant epg5-/- males coupled to WT females were applied. Results: We observed an impairment of male reproductive performance in mutant epg5-/- males that showed a lower breeding success with a reduced mean number of eggs spawned by their WT female partners. The spermatogenesis and the ability to produce fertilising ejaculates were not drastically impaired in our mutant males, whereas we observed a reduction of their courtship behaviour that might contribute to explain their lower overall reproductive success. Conclusion: Collectively our findings corroborate the hypothesis of a multilevel link between the autophagic process and reproduction. Moreover, by giving a first glimpse on behavioural disorders associated to epg5 KO in model zebrafish, our results open the way to more extensive behavioural analyses, also beyond the reproductive events, that might serve as new tools for the molecular screening of autophagy-related multisystemic and neurodegenerative diseases. |
De Giuseppe R; Tomasinelli CE; Cena H; Braschi V; Giampieri F; Preatoni G; Centofanti D; Princis MP; Bartoletti E; Biino G Development of a Short Questionnaire for the Screening for Vitamin D Deficiency in Italian Adults: The EVIDENCe-Q Project Journal Article In: Nutrients, vol. 14, iss. 9, pp. 1772, 2022. @article{%a1.%Yby,
title = {Development of a Short Questionnaire for the Screening for Vitamin D Deficiency in Italian Adults: The EVIDENCe-Q Project},
author = {{De Giuseppe R} and Tomasinelli CE and Cena H and Braschi V and Giampieri F and Preatoni G and Centofanti D and Princis MP and Bartoletti E and Biino G},
url = {https://www.mdpi.com/2072-6643/14/9/1772},
doi = {10.3390/nu14091772},
year = {2022},
date = {2022-08-23},
journal = {Nutrients},
volume = {14},
issue = {9},
pages = {1772},
abstract = {Background: To develop and validate a questionnaire for the screening of Vitamin D in Italian adults (Evaluation Vitamin D dEficieNCy Questionnaire, EVIDENCe-Q). Methods: 150 participants, attending the 11Clinical Nutrition and Dietetics Operative Unit, Internal Medicine and Endocrinology, Istituti Clinici Scientifici Maugeri IRCCS, of Pavia were enrolled. Demographic variables and serum levels of vitamin D were recorded. The EVIDENCe-Q included information regarding factors affecting the production, intake, absorption and metabolism of Vitamin D. The EVIDENCe-Q score ranged from 0 (the best status) to 36 (the worst status). Results: Participants showed an inadequate status of Vitamin D, according to the current Italian reference values. A significant difference (p < 0.0001) in the EVIDENCe-Q score was found among the three classes of vitamin D status (severe deficiency, deficiency and adequate), being the mean score higher in severe deficiency and lower in the adequate one. A threshold value for EVIDENCe-Q score of 23 for severe deficiency, a threshold value of 21 for deficiency and a threshold value of 20 for insufficiency were identified. According to these thresholds, the prevalence of severe deficiency, deficiency and insufficiency was 22%, 35.3% and 43.3% of the study population, respectively. Finally, participants with EVIDENCe-Q scores <20 had adequate levels of vitamin D. Conclusions: EVIDENCe-Q can be a useful and easy screening tool for clinicians in their daily practice at a reasonable cost, to identify subjects potentially at risk of vitamin D deficiency and to avoid unwarranted supplementation and/or costly blood testing},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: To develop and validate a questionnaire for the screening of Vitamin D in Italian adults (Evaluation Vitamin D dEficieNCy Questionnaire, EVIDENCe-Q). Methods: 150 participants, attending the 11Clinical Nutrition and Dietetics Operative Unit, Internal Medicine and Endocrinology, Istituti Clinici Scientifici Maugeri IRCCS, of Pavia were enrolled. Demographic variables and serum levels of vitamin D were recorded. The EVIDENCe-Q included information regarding factors affecting the production, intake, absorption and metabolism of Vitamin D. The EVIDENCe-Q score ranged from 0 (the best status) to 36 (the worst status). Results: Participants showed an inadequate status of Vitamin D, according to the current Italian reference values. A significant difference (p < 0.0001) in the EVIDENCe-Q score was found among the three classes of vitamin D status (severe deficiency, deficiency and adequate), being the mean score higher in severe deficiency and lower in the adequate one. A threshold value for EVIDENCe-Q score of 23 for severe deficiency, a threshold value of 21 for deficiency and a threshold value of 20 for insufficiency were identified. According to these thresholds, the prevalence of severe deficiency, deficiency and insufficiency was 22%, 35.3% and 43.3% of the study population, respectively. Finally, participants with EVIDENCe-Q scores <20 had adequate levels of vitamin D. Conclusions: EVIDENCe-Q can be a useful and easy screening tool for clinicians in their daily practice at a reasonable cost, to identify subjects potentially at risk of vitamin D deficiency and to avoid unwarranted supplementation and/or costly blood testing |
Ticli G; Cazzalini O; Stivala LA; Prosperi E Revisiting the Function of p21CDKN1A in DNA Repair: The Influence of Protein Interactions and Stability Journal Article In: International journal of molecular sciences, vol. 23, iss. 13, pp. 7058, 2022. @article{%a1.%Yb_38,
title = {Revisiting the Function of p21CDKN1A in DNA Repair: The Influence of Protein Interactions and Stability},
author = {Ticli G and Cazzalini O and Stivala LA and Prosperi E},
url = {https://www.mdpi.com/resolver?pii=ijms23137058},
doi = {10.3390/ijms23137058},
year = {2022},
date = {2022-08-19},
journal = {International journal of molecular sciences},
volume = {23},
issue = {13},
pages = {7058},
abstract = {The p21 protein is an important player in the maintenance of genome stability through its function as a cyclin-dependent kinase inhibitor, leading to cell-cycle arrest after genotoxic damage. In the DNA damage response, p21 interacts with specific proteins to integrate cell-cycle arrest with processes such as transcription, apoptosis, DNA repair, and cell motility. By associating with Proliferating Cell Nuclear Antigen (PCNA), the master of DNA replication, p21 is able to inhibit DNA synthesis. However, to avoid conflicts with this process, p21 protein levels are finely regulated by pathways of proteasomal degradation during the S phase, and in all the phases of the cell cycle, after DNA damage. Several lines of evidence have indicated that p21 is required for the efficient repair of different types of genotoxic lesions and, more recently, that p21 regulates DNA replication fork speed. Therefore, whether p21 is an inhibitor, or rather a regulator, of DNA replication and repair needs to be re-evaluated in light of these findings. In this review, we will discuss the lines of evidence describing how p21 is involved in DNA repair and will focus on the influence of protein interactions and p21 stability on the efficiency of DNA repair mechanisms.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The p21 protein is an important player in the maintenance of genome stability through its function as a cyclin-dependent kinase inhibitor, leading to cell-cycle arrest after genotoxic damage. In the DNA damage response, p21 interacts with specific proteins to integrate cell-cycle arrest with processes such as transcription, apoptosis, DNA repair, and cell motility. By associating with Proliferating Cell Nuclear Antigen (PCNA), the master of DNA replication, p21 is able to inhibit DNA synthesis. However, to avoid conflicts with this process, p21 protein levels are finely regulated by pathways of proteasomal degradation during the S phase, and in all the phases of the cell cycle, after DNA damage. Several lines of evidence have indicated that p21 is required for the efficient repair of different types of genotoxic lesions and, more recently, that p21 regulates DNA replication fork speed. Therefore, whether p21 is an inhibitor, or rather a regulator, of DNA replication and repair needs to be re-evaluated in light of these findings. In this review, we will discuss the lines of evidence describing how p21 is involved in DNA repair and will focus on the influence of protein interactions and p21 stability on the efficiency of DNA repair mechanisms. |
Mazzeschi M; Sgarzi M; Romaniello D; Gelfo V; Cavallo C; Ambrosi F; Morselli A; Miano C; Laprovitera N; Girone C; Ferracin M; Santi S; Rihawi K; Ardizzoni A; Fiorentino M; D'Uva G; Győrffy B; Palmer R; Lauriola M The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer Journal Article In: Journal of experimental & clinical cancer research, vol. 41, iss. 1, pp. 113, 2022. @article{%a1.%Yb_30,
title = {The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer},
author = {Mazzeschi M and Sgarzi M and Romaniello D and Gelfo V and Cavallo C and Ambrosi F and Morselli A and Miano C and Laprovitera N and Girone C and Ferracin M and Santi S and Rihawi K and Ardizzoni A and Fiorentino M and D'Uva G and Győrffy B and Palmer R and Lauriola M},
url = {https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02309-1},
doi = {10.1186/s13046-022-02309-1},
year = {2022},
date = {2022-08-19},
journal = {Journal of experimental & clinical cancer research},
volume = {41},
issue = {1},
pages = {113},
abstract = {Background: In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). Methods: In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use. Results: ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo. Conclusions: Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). Methods: In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use. Results: ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo. Conclusions: Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC. |
Valenti AC; Albini A; Imberti JF; Vitolo M; Bonini N; Lattanzi G; Schnabel RB; Boriani G Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature Journal Article In: Biology (Basel), vol. 11, iss. 4, 2022. @article{%a1.%Yb_40,
title = {Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature},
author = {Valenti AC and Albini A and Imberti JF and Vitolo M and Bonini N and Lattanzi G and Schnabel RB and Boriani G},
url = {https://www.mdpi.com/2079-7737/11/4/530},
doi = { doi: 10.3390/biology11040530},
year = {2022},
date = {2022-08-18},
journal = {Biology (Basel)},
volume = {11},
issue = {4},
abstract = {Cardiolaminopathies are a heterogeneous group of disorders which are due to mutations in the genes encoding for nuclear lamins or their binding proteins. The whole spectrum of cardiac manifestations encompasses atrial arrhythmias, conduction disturbances, progressive systolic dysfunction, and malignant ventricular arrhythmias. Despite the prognostic significance of cardiac involvement in this setting, the current recommendations lack strong evidence. The aim of our work was to systematically review the current data on the main cardiovascular outcomes in cardiolaminopathies. We searched PubMed/Embase for studies focusing on cardiovascular outcomes in LMNA mutation carriers (atrial arrhythmias, ventricular arrhythmias, sudden cardiac death, conduction disturbances, thromboembolic events, systolic dysfunction, heart transplantation, and all-cause and cardiovascular mortality). In total, 11 studies were included (1070 patients, mean age between 26-45 years, with follow-up periods ranging from 2.5 years up to 45 ± 12). When available, data on the EMD-mutated population were separately reported (40 patients). The incidence rates (IR) were individually assessed for the outcomes of interest. The IR for atrial fibrillation/atrial flutter/atrial tachycardia ranged between 6.1 and 13.9 events/100 pts-year. The IR of atrial standstill ranged between 0 and 2 events/100 pts-year. The IR for malignant ventricular arrhythmias reached 10.2 events/100 pts-year and 15.6 events/100 pts-year for appropriate implantable cardioverter-defibrillator (ICD) interventions. The IR for advanced conduction disturbances ranged between 3.2 and 7.7 events/100 pts-year. The IR of thromboembolic events reached up to 8.9 events/100 pts-year. Our results strengthen the need for periodic cardiological evaluation focusing on the early recognition of atrial arrhythmias, and possibly for the choice of preventive strategies for thromboembolic events. The frequent need for cardiac pacing due to advanced conduction disturbances should be counterbalanced with the high risk of malignant ventricular arrhythmias that would justify ICD over pacemaker implantation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cardiolaminopathies are a heterogeneous group of disorders which are due to mutations in the genes encoding for nuclear lamins or their binding proteins. The whole spectrum of cardiac manifestations encompasses atrial arrhythmias, conduction disturbances, progressive systolic dysfunction, and malignant ventricular arrhythmias. Despite the prognostic significance of cardiac involvement in this setting, the current recommendations lack strong evidence. The aim of our work was to systematically review the current data on the main cardiovascular outcomes in cardiolaminopathies. We searched PubMed/Embase for studies focusing on cardiovascular outcomes in LMNA mutation carriers (atrial arrhythmias, ventricular arrhythmias, sudden cardiac death, conduction disturbances, thromboembolic events, systolic dysfunction, heart transplantation, and all-cause and cardiovascular mortality). In total, 11 studies were included (1070 patients, mean age between 26-45 years, with follow-up periods ranging from 2.5 years up to 45 ± 12). When available, data on the EMD-mutated population were separately reported (40 patients). The incidence rates (IR) were individually assessed for the outcomes of interest. The IR for atrial fibrillation/atrial flutter/atrial tachycardia ranged between 6.1 and 13.9 events/100 pts-year. The IR of atrial standstill ranged between 0 and 2 events/100 pts-year. The IR for malignant ventricular arrhythmias reached 10.2 events/100 pts-year and 15.6 events/100 pts-year for appropriate implantable cardioverter-defibrillator (ICD) interventions. The IR for advanced conduction disturbances ranged between 3.2 and 7.7 events/100 pts-year. The IR of thromboembolic events reached up to 8.9 events/100 pts-year. Our results strengthen the need for periodic cardiological evaluation focusing on the early recognition of atrial arrhythmias, and possibly for the choice of preventive strategies for thromboembolic events. The frequent need for cardiac pacing due to advanced conduction disturbances should be counterbalanced with the high risk of malignant ventricular arrhythmias that would justify ICD over pacemaker implantation. |
Secchi M; Lodola C; Garbelli A; Bione S; Maga G DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective Journal Article In: Cancers (Basel), vol. 14, iss. 15, pp. 3820, 2022. @article{%a1.%Yb_37,
title = {DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective},
author = {Secchi M and Lodola C and Garbelli A and Bione S and Maga G},
url = {https://www.mdpi.com/2072-6694/14/15/3820},
doi = {10.3390/cancers14153820},
year = {2022},
date = {2022-08-18},
journal = {Cancers (Basel)},
volume = {14},
issue = {15},
pages = {3820},
abstract = {RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors. |
Ramdas S; Judd J; ………; Biino G; ……..; et al. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids Journal Article In: American journal of human genetics, vol. 109, iss. 8, pp. 1366-1387, 2022. @article{%a1.%Yb_35,
title = {A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids},
author = {Ramdas S and Judd J and {………} and Biino G and {……..} and {et al.}},
url = {https://www.sciencedirect.com/science/article/pii/S0002929722002658?via%3Dihub},
doi = {10.1016/j.ajhg.2022.06.012},
year = {2022},
date = {2022-08-18},
journal = {American journal of human genetics},
volume = {109},
issue = {8},
pages = {1366-1387},
abstract = {A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology. |
Piazzi M; Bavelloni A; Cenni V; Salucci S; Bartoletti Stella A; Tomassini E; Scotlandi K; Blalock WL; Faenza I Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells Journal Article In: Molecules, vol. 27, iss. 9, pp. 2742, 2022. @article{%a1.%Yb_34,
title = {Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells},
author = {Piazzi M and Bavelloni A and Cenni V and Salucci S and Bartoletti Stella A and Tomassini E and Scotlandi K and Blalock WL and Faenza I},
url = {https://www.mdpi.com/1420-3049/27/9/2742},
doi = {10.3390/molecules27092742},
year = {2022},
date = {2022-08-18},
journal = {Molecules},
volume = {27},
issue = {9},
pages = {2742},
abstract = {Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway. |
Palladini G; Di Pasqua LG; Cagna M; Croce AC; Perlini S; Mannucci B; Profumo A; Ferrigno A; Vairetti M MCD Diet Rat Model Induces Alterations in Zinc and Iron during NAFLD Progression from Steatosis to Steatohepatitis Journal Article In: International journal of molecular sciences, vol. 23, iss. 12, pp. 6817, 2022. @article{%a1.%Yb_32,
title = {MCD Diet Rat Model Induces Alterations in Zinc and Iron during NAFLD Progression from Steatosis to Steatohepatitis},
author = {Palladini G and Di Pasqua LG and Cagna M and Croce AC and Perlini S and Mannucci B and Profumo A and Ferrigno A and Vairetti M},
url = {https://www.mdpi.com/1422-0067/23/12/6817},
doi = {10.3390/ijms23126817},
year = {2022},
date = {2022-08-18},
journal = {International journal of molecular sciences},
volume = {23},
issue = {12},
pages = {6817},
abstract = {We evaluate the effects of the methionine-choline-deficient (MCD) diet on serum and hepatic zinc (Zn) and iron (Fe) and their relationships with matrix metalloproteinases (MMPs) and their modulators (TIMPs and RECK) as well as hepatic fatty acids using male Wistar rats fed 2-, 4- and 8-week MCD diets. Serum and hepatic Zn decrease after an 8-week MCD diet. Serum Fe increases after an 8-week MCD diet and the same occurs for hepatic Fe. An increase in hepatic MMP activity, associated with a decrease in RECK and TIMPs, is found in the MCD 8-week group. Liver Fe shows a positive correlation versus MMPs and RECK, and an inverse correlation versus TIMPs. A positive correlation is found comparing liver Zn with stearic, vaccenic and arachidonic acids, and an inverse correlation is found with linolenic and docosatetraenoic acids. An opposite trend is found between liver Fe versus these fatty acids. During NAFLD progression from steatosis to steatohepatitis, MCD rats exhibit an increase in Zn and a decrease in Fe levels both in serum and tissue associated with alterations in hepatic MMPs and their inhibitors, and fatty acids. The correlations detected between Zn and Fe versus extracellular matrix modulators and fatty acids support their potential role as therapeutic targets.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We evaluate the effects of the methionine-choline-deficient (MCD) diet on serum and hepatic zinc (Zn) and iron (Fe) and their relationships with matrix metalloproteinases (MMPs) and their modulators (TIMPs and RECK) as well as hepatic fatty acids using male Wistar rats fed 2-, 4- and 8-week MCD diets. Serum and hepatic Zn decrease after an 8-week MCD diet. Serum Fe increases after an 8-week MCD diet and the same occurs for hepatic Fe. An increase in hepatic MMP activity, associated with a decrease in RECK and TIMPs, is found in the MCD 8-week group. Liver Fe shows a positive correlation versus MMPs and RECK, and an inverse correlation versus TIMPs. A positive correlation is found comparing liver Zn with stearic, vaccenic and arachidonic acids, and an inverse correlation is found with linolenic and docosatetraenoic acids. An opposite trend is found between liver Fe versus these fatty acids. During NAFLD progression from steatosis to steatohepatitis, MCD rats exhibit an increase in Zn and a decrease in Fe levels both in serum and tissue associated with alterations in hepatic MMPs and their inhibitors, and fatty acids. The correlations detected between Zn and Fe versus extracellular matrix modulators and fatty acids support their potential role as therapeutic targets. |
Gambarotto L; Metti S; Chrisam M; Cerqua C; Sabatelli P; Armani A; Zanon C; Spizzotin M; Castagnaro S; Strappazzon F; Grumati P; Cescon M; Braghetta P; Trevisson E; Cecconi F; Bonaldo P. Ambra1 deficiency impairs mitophagy in skeletal muscle Journal Article In: Journal of cachexia, sarcopenia and muscle, vol. 13, iss. 4, pp. 2211-2224, 2022. @article{%a1.%Yb_27,
title = {Ambra1 deficiency impairs mitophagy in skeletal muscle},
author = {Gambarotto L and Metti S and Chrisam M and Cerqua C and Sabatelli P and Armani A and Zanon C and Spizzotin M and Castagnaro S and Strappazzon F and Grumati P and Cescon M and Braghetta P and Trevisson E and Cecconi F and Bonaldo P.},
url = {https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13010},
doi = {10.1002/jcsm.13010},
year = {2022},
date = {2022-08-18},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {13},
issue = {4},
pages = {2211-2224},
abstract = {Background: Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well-known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full-body Ambra1 deficiency. Methods: To establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria-targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle-specific Ambra1 knockout (Ambra1fl/fl :Mlc1f-Cre) mice. Mitochondria-enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux. Results: Our data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild-type muscles is sufficient to enhance mitochondria clearance through the autophagy-lysosome system. Consistently with this, Ambra1-deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6-7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6-7 mice; P < 0.01) and Parkin (n = 6-7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1-deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild-type muscles (n = 4; P < 0.05). Histologically, Ambra1-deficient muscles of both 3- and 6-month-old animals display a significant decrease of myofibre cross-sectional area and a 52% reduction in oxidative fibres (n = 6-7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle. Conclusions: Our study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well-known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full-body Ambra1 deficiency. Methods: To establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria-targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle-specific Ambra1 knockout (Ambra1fl/fl :Mlc1f-Cre) mice. Mitochondria-enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux. Results: Our data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild-type muscles is sufficient to enhance mitochondria clearance through the autophagy-lysosome system. Consistently with this, Ambra1-deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6-7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6-7 mice; P < 0.01) and Parkin (n = 6-7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1-deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild-type muscles (n = 4; P < 0.05). Histologically, Ambra1-deficient muscles of both 3- and 6-month-old animals display a significant decrease of myofibre cross-sectional area and a 52% reduction in oxidative fibres (n = 6-7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle. Conclusions: Our study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria. |
Ben Khalifa R; Cacciatore I; Dimmito MP; Ciulla M; Grande R; Puca V; Robuffo I; De Laurenzi V; Chekir-Ghedira L; Di Stefano A; Marinelli L Multiple lipid nanoparticles as antimicrobial drug delivery systems Journal Article In: Journal of drug delivery science and technology, vol. 67, pp. 102887, 2022. @article{%a1.%Ybu,
title = {Multiple lipid nanoparticles as antimicrobial drug delivery systems},
author = {{Ben Khalifa R} and Cacciatore I and Dimmito MP and Ciulla M and Grande R and Puca V and Robuffo I and De Laurenzi V and Chekir-Ghedira L and Di Stefano A and Marinelli L},
url = {https://www.sciencedirect.com/science/article/pii/S1773224721005670?via%3Dihub},
doi = {10.1016/j.jddst.2021.102887},
year = {2022},
date = {2022-08-17},
journal = {Journal of drug delivery science and technology},
volume = {67},
pages = {102887},
abstract = {The present work aimed at investigating formulations based on multiple lipid nanoparticles (MLNs) containing carvacrol (CAR) and vancomycin hydrochloride (VAN) co-loaded (CAR-VAN-MLNs) as therapeutical strategy useful to improve the antibiotic activity of VAN. Drug-loaded MLNs were prepared by the ultra-sonication technique and investigated for both physico-chemical and antimicrobial properties. Results revealed that all the formulations possessed particle size lower than 150 nm and negatively charged surfaces, as suggested by the ?-potential values. The encapsulation efficiencies were higher than 70% and 21% for CAR and VAN, respectively. Moreover, differential scanning calorimetry analysis confirmed the effective drug loading, while stability studies indicated that the prepared formulations remained stable for about one month when stored at 4 oC. Finally, in vitro studies revealed a sustained drug release during the time. The morphological MLNs characterization, performed by transmission electron microscopy analysis, showed a spherical shape of the produced nanoparticles. Antimicrobial studies suggested that the co-encapsulation improved VAN antibiotic activity against Staphylococcus aureus with a possible greater advantage during systemic therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The present work aimed at investigating formulations based on multiple lipid nanoparticles (MLNs) containing carvacrol (CAR) and vancomycin hydrochloride (VAN) co-loaded (CAR-VAN-MLNs) as therapeutical strategy useful to improve the antibiotic activity of VAN. Drug-loaded MLNs were prepared by the ultra-sonication technique and investigated for both physico-chemical and antimicrobial properties. Results revealed that all the formulations possessed particle size lower than 150 nm and negatively charged surfaces, as suggested by the ?-potential values. The encapsulation efficiencies were higher than 70% and 21% for CAR and VAN, respectively. Moreover, differential scanning calorimetry analysis confirmed the effective drug loading, while stability studies indicated that the prepared formulations remained stable for about one month when stored at 4 oC. Finally, in vitro studies revealed a sustained drug release during the time. The morphological MLNs characterization, performed by transmission electron microscopy analysis, showed a spherical shape of the produced nanoparticles. Antimicrobial studies suggested that the co-encapsulation improved VAN antibiotic activity against Staphylococcus aureus with a possible greater advantage during systemic therapies. |
Cavallo C; Merli G; Zini N; D'Adamo S; Cattini L; Guescini M; Grigolo B; Di Martino A; Santi S; Borzì RM; Filardo G Small Extracellular Vesicles from Inflamed Adipose Derived Stromal Cells Enhance the NF-κB-Dependent Inflammatory/Catabolic Environment of Osteoarthritis. Journal Article In: Stem cells international, vol. 2022, pp. 9376338, 2022. @article{%a1.%Ybv,
title = {Small Extracellular Vesicles from Inflamed Adipose Derived Stromal Cells Enhance the NF-κB-Dependent Inflammatory/Catabolic Environment of Osteoarthritis. },
author = {Cavallo C and Merli G and Zini N and {D'Adamo} S and Cattini L and Guescini M and Grigolo B and Di Martino A and Santi S and Borzì RM and Filardo G},
url = {https://www.hindawi.com/journals/sci/2022/9376338/},
doi = {10.1155/2022/9376338},
year = {2022},
date = {2022-08-11},
urldate = {2022-08-11},
journal = {Stem cells international},
volume = {2022},
pages = {9376338},
abstract = {The last decade has seen exponentially growing efforts to exploit the effects of adipose derived stromal cells (ADSC) in the treatment of a wide range of chronic degenerative diseases, including osteoarthritis (OA), the most prevalent joint disorder. In the perspective of developing a cell-free advanced therapy medicinal product, a focus has been recently addressed to the ADSC secretome that lends itself to an allogeneic use and can be further dissected for the selective purification of small extracellular vesicles (sEVs). sEVs can act as "biological drug carriers" to transfer information that mirror the pathophysiology of the providing cells. This is important in the clinical perspective where many OA patients are also affected by the metabolic syndrome (MetS). ADSC from MetS OA patients are dysfunctional and "inflammatory" primed within the adipose tissue. To mimic this condition, we exposed ADSC to IL-1β, and then we investigated the effects of the isolated sEVs on chondrocytes and synoviocytes, either cultured separately or in co-culture, to tease out the effects of these "IL-1β primed sEVs" on gene and protein expression of major inflammatory and catabolic OA markers. In comparison with sEVs isolated from unstimulated ADSC, the IL-1β primed sEVs were able to propagate NF-κB activation in bystander joint cells. The effects were more prominent on synoviocytes, possibly because of a higher expression of binding molecules such as CD44. These findings call upon a careful characterization of the "inflammatory fingerprint" of ADSC to avoid the transfer of an unwanted message as well as the development of in vitro "preconditioning" strategies able to rescue the antiinflammatory/anticatabolic potential of ADSC-derived sEVs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The last decade has seen exponentially growing efforts to exploit the effects of adipose derived stromal cells (ADSC) in the treatment of a wide range of chronic degenerative diseases, including osteoarthritis (OA), the most prevalent joint disorder. In the perspective of developing a cell-free advanced therapy medicinal product, a focus has been recently addressed to the ADSC secretome that lends itself to an allogeneic use and can be further dissected for the selective purification of small extracellular vesicles (sEVs). sEVs can act as "biological drug carriers" to transfer information that mirror the pathophysiology of the providing cells. This is important in the clinical perspective where many OA patients are also affected by the metabolic syndrome (MetS). ADSC from MetS OA patients are dysfunctional and "inflammatory" primed within the adipose tissue. To mimic this condition, we exposed ADSC to IL-1β, and then we investigated the effects of the isolated sEVs on chondrocytes and synoviocytes, either cultured separately or in co-culture, to tease out the effects of these "IL-1β primed sEVs" on gene and protein expression of major inflammatory and catabolic OA markers. In comparison with sEVs isolated from unstimulated ADSC, the IL-1β primed sEVs were able to propagate NF-κB activation in bystander joint cells. The effects were more prominent on synoviocytes, possibly because of a higher expression of binding molecules such as CD44. These findings call upon a careful characterization of the "inflammatory fingerprint" of ADSC to avoid the transfer of an unwanted message as well as the development of in vitro "preconditioning" strategies able to rescue the antiinflammatory/anticatabolic potential of ADSC-derived sEVs. |
Barrios-Arpi L; Arias Y; Lopez-Torres B; Ramos-Gonzalez M; Ticli G; Prosperi E; Rodríguez J-L In Vitro Neurotoxicity of Flumethrin Pyrethroid on SH-SY5Y Neuroblastoma Cells: Apoptosis Associated with Oxidative Stress Journal Article In: Toxics, vol. 10, iss. 3, pp. 131, 2022. @article{%a1.%Ybt,
title = {In Vitro Neurotoxicity of Flumethrin Pyrethroid on SH-SY5Y Neuroblastoma Cells: Apoptosis Associated with Oxidative Stress},
author = {Barrios-Arpi L and Arias Y and Lopez-Torres B and Ramos-Gonzalez M and Ticli G and Prosperi E and Rodríguez J-L},
url = {https://www.mdpi.com/2305-6304/10/3/131#cite},
doi = {10.3390/toxics10030131},
year = {2022},
date = {2022-07-20},
journal = {Toxics},
volume = {10},
issue = {3},
pages = {131},
abstract = {Pyrethroids are neurotoxicants for animals, showing a pattern of toxic action on the nervous system. Flumethrin, a synthetic pyrethroid, is used against ectoparasites in domestic animals, plants, and for public health. This compound has been shown to be highly toxic to bees, while its effects on other animals have been less investigated. However, in vitro studies to evaluate cytotoxicity are scarce, and the mechanisms associated with this effect at the molecular level are still unknown. This study aimed to investigate the oxidative stress and cell death induction in SH-SY5Y neuroblastoma cells in response to flumethrin exposure (1–1000 µM). Flumethrin induced a significant cytotoxic effect, as evaluated by MTT and LDH leakage assays, and produced an increase in the biomarkers of oxidative stress as reactive oxygen species and nitric oxide (ROS and NO) generation, malondialdehyde (MDA) concentration, and caspase-3 activity. In addition, flumethrin significantly increased apoptosis-related gene expressions (Bax, Casp-3, BNIP3, APAF1, and AKT1) and oxidative stress and antioxidative (NFκB and SOD2) mediators. The results demonstrated, by biochemical and gene expression assays, that flumethrin induces oxidative stress and apoptosis, which could cause DNA damage. Detailed knowledge obtained about these molecular changes could provide the basis for elucidating the molecular mechanisms of flumethrin-induced neurotoxicity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pyrethroids are neurotoxicants for animals, showing a pattern of toxic action on the nervous system. Flumethrin, a synthetic pyrethroid, is used against ectoparasites in domestic animals, plants, and for public health. This compound has been shown to be highly toxic to bees, while its effects on other animals have been less investigated. However, in vitro studies to evaluate cytotoxicity are scarce, and the mechanisms associated with this effect at the molecular level are still unknown. This study aimed to investigate the oxidative stress and cell death induction in SH-SY5Y neuroblastoma cells in response to flumethrin exposure (1–1000 µM). Flumethrin induced a significant cytotoxic effect, as evaluated by MTT and LDH leakage assays, and produced an increase in the biomarkers of oxidative stress as reactive oxygen species and nitric oxide (ROS and NO) generation, malondialdehyde (MDA) concentration, and caspase-3 activity. In addition, flumethrin significantly increased apoptosis-related gene expressions (Bax, Casp-3, BNIP3, APAF1, and AKT1) and oxidative stress and antioxidative (NFκB and SOD2) mediators. The results demonstrated, by biochemical and gene expression assays, that flumethrin induces oxidative stress and apoptosis, which could cause DNA damage. Detailed knowledge obtained about these molecular changes could provide the basis for elucidating the molecular mechanisms of flumethrin-induced neurotoxicity. |
Avolio F; Martinotti S; Khavinson VK; Esposito JE; Giambuzzi G; Marino A; Mironova E; Pulcini R; Robuffo I; Bologna G; Simeone P; Lanuti P; Guarnieri S; Trofimova S; Procopio AD; Toniato E Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line Journal Article In: International journal of molecular sciences, vol. 23, iss. 7, pp. 3607, 2022. @article{%a1.%Ybs,
title = {Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line},
author = {Avolio F and Martinotti S and Khavinson VK and Esposito JE and Giambuzzi G and Marino A and Mironova E and Pulcini R and Robuffo I and Bologna G and Simeone P and Lanuti P and Guarnieri S and Trofimova S and Procopio AD and Toniato E},
url = {https://www.mdpi.com/1422-0067/23/7/3607},
doi = {10.3390/ijms23073607},
year = {2022},
date = {2022-07-20},
journal = {International journal of molecular sciences},
volume = {23},
issue = {7},
pages = {3607},
abstract = {This study evaluates the effects of five different peptides, the Epitalon® tetrapeptide, the Vilon® dipeptide, the Thymogen® dipeptide, the Thymalin® peptide complex, and the Chonluten® tripeptide, as regulators of inflammatory and proliferative processes in the human monocytic THP-1, which is a human leukemia monocytic cell line capable of differentiating into macrophages by PMA in vitro. These peptides (Khavinson Peptides®), characterized by Prof. Khavinson from 1973 onwards, were initially isolated from animal tissues and found to be organ specific. We tested the capacity of the five peptides to influence cell cultures in vitro by incubating THP-1 cells with peptides at certain concentrations known for being effective on recipient cells in culture. We found that all five peptides can modulate key proliferative patterns, increasing tyrosine phosphorylation of mitogen-activated cytoplasmic kinases. In addition, the Chonluten tripeptide, derived from bronchial epithelial cells, inhibited in vitro tumor necrosis factor (TNF) production of monocytes exposed to pro-inflammatory bacterial lipopolysaccharide (LPS). The low TNF release by monocytes is linked to a documented mechanism of TNF tolerance, promoting attenuation of inflammatory action. Therefore, all peptides inhibited the expression of TNF and pro-inflammatory IL-6 cytokine stimulated by LPS on terminally differentiated THP-1 cells. Lastly, by incubating the THP1 cells, treated with the peptides, on a layer of activated endothelial cells (HUVECs activated by LPS), we observed a reduction in cell adhesion, a typical pro-inflammatory mechanism. Overall, the results suggest that the Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocyte, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
This study evaluates the effects of five different peptides, the Epitalon® tetrapeptide, the Vilon® dipeptide, the Thymogen® dipeptide, the Thymalin® peptide complex, and the Chonluten® tripeptide, as regulators of inflammatory and proliferative processes in the human monocytic THP-1, which is a human leukemia monocytic cell line capable of differentiating into macrophages by PMA in vitro. These peptides (Khavinson Peptides®), characterized by Prof. Khavinson from 1973 onwards, were initially isolated from animal tissues and found to be organ specific. We tested the capacity of the five peptides to influence cell cultures in vitro by incubating THP-1 cells with peptides at certain concentrations known for being effective on recipient cells in culture. We found that all five peptides can modulate key proliferative patterns, increasing tyrosine phosphorylation of mitogen-activated cytoplasmic kinases. In addition, the Chonluten tripeptide, derived from bronchial epithelial cells, inhibited in vitro tumor necrosis factor (TNF) production of monocytes exposed to pro-inflammatory bacterial lipopolysaccharide (LPS). The low TNF release by monocytes is linked to a documented mechanism of TNF tolerance, promoting attenuation of inflammatory action. Therefore, all peptides inhibited the expression of TNF and pro-inflammatory IL-6 cytokine stimulated by LPS on terminally differentiated THP-1 cells. Lastly, by incubating the THP1 cells, treated with the peptides, on a layer of activated endothelial cells (HUVECs activated by LPS), we observed a reduction in cell adhesion, a typical pro-inflammatory mechanism. Overall, the results suggest that the Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocyte, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity. |
Corradi G; Bassani B; Simonetti G; Sangaletti S; Vadakekolathu J; Fontana MC; Pazzaglia M; Gulino A; Tripodo C; Cristiano G; Bandini L; Ottaviani E; Ocadlikova D; Piccioli M; Martinelli G; Colombo MP; Rutella S; Cavo M; Ciciarello M; Curti A Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells Journal Article In: Clinical cancer research, vol. Clincanres.359, pp. 2021, 2022. @article{%a1.%Yb,
title = {Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells},
author = {Corradi G and Bassani B and Simonetti G and Sangaletti S and Vadakekolathu J and Fontana MC and Pazzaglia M and Gulino A and Tripodo C and Cristiano G and Bandini L and Ottaviani E and Ocadlikova D and Piccioli M and Martinelli G and Colombo MP and Rutella S and Cavo M and Ciciarello M and Curti A},
url = {https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-21-3594/694419/Release-of-IFN-by-Acute-Myeloid-Leukemia-Cells?redirectedFrom=fulltext},
doi = {10.1158/1078-0432.CCR-21-3594},
year = {2022},
date = {2022-05-30},
urldate = {2022-05-30},
journal = {Clinical cancer research},
volume = {Clincanres.359},
pages = {2021},
abstract = {Purpose: The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Tregs) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFN-γ released by AML cells in BM Tregs induction and its impact on AML prognosis. Experimental design: BM aspirates from AML patients were subdivided according to IFNG expression. Gene expression profiles in INFGhigh and IFNGlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFN-g release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell co-cultures. In mice, AML cells silenced for IFN-γ expression were injected intrabone. Results: IFNGhigh AMLsamples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. By contrast, in AML patients, high IFNG expression associated with poor overall survival. Notably, IFN-g release by AML cells positively correlated with a higher BM suppressive Tregs' frequency. In co-culture experiments, IFNGhigh AML cells modified MSC transcriptome by up-regulating IFN-γ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFN-γ release by AML cells on MSC-derived Treg induction. Invivo, the genetic ablation of IFN-γ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment. Conclusions: IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose: The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Tregs) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFN-γ released by AML cells in BM Tregs induction and its impact on AML prognosis. Experimental design: BM aspirates from AML patients were subdivided according to IFNG expression. Gene expression profiles in INFGhigh and IFNGlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFN-g release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell co-cultures. In mice, AML cells silenced for IFN-γ expression were injected intrabone. Results: IFNGhigh AMLsamples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. By contrast, in AML patients, high IFNG expression associated with poor overall survival. Notably, IFN-g release by AML cells positively correlated with a higher BM suppressive Tregs' frequency. In co-culture experiments, IFNGhigh AML cells modified MSC transcriptome by up-regulating IFN-γ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFN-γ release by AML cells on MSC-derived Treg induction. Invivo, the genetic ablation of IFN-γ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment. Conclusions: IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment. |
Chiarini F; Paganelli F; Balestra T; Capanni C; Fazio A; Manara MC; Landuzzi L; Petrini S; Evangelisti C; Lollini PL; Martelli AM; Lattanzi G; Scotlandi K Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma Journal Article In: Cell death & disease, vol. 13, iss. 4, pp. 346, 2022. @article{%a1.%Ybr,
title = {Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma},
author = {Chiarini F and Paganelli F and Balestra T and Capanni C and Fazio A and Manara MC and Landuzzi L and Petrini S and Evangelisti C and Lollini PL and Martelli AM and Lattanzi G and Scotlandi K},
url = {https://www.nature.com/articles/s41419-022-04729-5},
doi = {10.1038/s41419-022-04729-5},
year = {2022},
date = {2022-05-30},
urldate = {2022-05-30},
journal = {Cell death & disease},
volume = {13},
issue = {4},
pages = {346},
abstract = {Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS. |
Cardano M; Buscemi G; Zannini L Sex disparities in DNA damage response pathways: Novel determinants in cancer formation and therapy Journal Article In: iScience, vol. 25, iss. 3, pp. 103875, 2022. @article{%a1.%Ybq,
title = {Sex disparities in DNA damage response pathways: Novel determinants in cancer formation and therapy},
author = {Cardano M and Buscemi G and Zannini L},
url = {https://www.sciencedirect.com/science/article/pii/S2589004222001456?via%3Dihub},
doi = {10.1016/j.isci.2022.103875},
year = {2022},
date = {2022-05-30},
journal = {iScience},
volume = {25},
issue = {3},
pages = {103875},
abstract = {Cancer incidence and survival are different between men and women. Indeed, females have a lesser risk and a better prognosis than males in many tumors unrelated to reproductive functions. Although the reasons for these disparities are still unknown, they constitute an important starting point for the development of personalized cancer therapies. One of the mechanisms that fuels carcinogenesis is the accumulation of defects in DNA damage response (DDR) pathways, a complex signaling cascade that senses DNA lesions and, depending on the severity, coordinates transient cell-cycle arrest, DNA replication, repair, apoptosis, and senescence, preventing genomic instability and cancer. Recently, evidence of sexual dimorphisms is emerging in these pathways, therefore providing new opportunities for precision medicine. Here, we will discuss current knowledge about sexual disparities in the DDR, their role in tumorigenesis and cancer progression, and the importance of considering sex contribution in both research and cancer therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cancer incidence and survival are different between men and women. Indeed, females have a lesser risk and a better prognosis than males in many tumors unrelated to reproductive functions. Although the reasons for these disparities are still unknown, they constitute an important starting point for the development of personalized cancer therapies. One of the mechanisms that fuels carcinogenesis is the accumulation of defects in DNA damage response (DDR) pathways, a complex signaling cascade that senses DNA lesions and, depending on the severity, coordinates transient cell-cycle arrest, DNA replication, repair, apoptosis, and senescence, preventing genomic instability and cancer. Recently, evidence of sexual dimorphisms is emerging in these pathways, therefore providing new opportunities for precision medicine. Here, we will discuss current knowledge about sexual disparities in the DDR, their role in tumorigenesis and cancer progression, and the importance of considering sex contribution in both research and cancer therapies. |
Avolio F; Martinotti S; Khavinson VK; Esposito JE; Giambuzzi G; Marino A; Mironova E; Pulcini R; Robuffo I; Bologna G; Simeone P; Lanuti P; Guarnieri S; Trofimova S; Procopio AD; Toniato E. Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line Journal Article In: International journal of molecular sciences, vol. 23, iss. 7, pp. 3607, 2022. @article{%a1.%Ybo,
title = {Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line},
author = {Avolio F and Martinotti S and Khavinson VK and Esposito JE and Giambuzzi G and Marino A and Mironova E and Pulcini R and Robuffo I and Bologna G and Simeone P and Lanuti P and Guarnieri S and Trofimova S and Procopio AD and Toniato E.},
url = {https://www.mdpi.com/1422-0067/23/7/3607
},
doi = {10.3390/ijms23073607},
year = {2022},
date = {2022-05-30},
journal = {International journal of molecular sciences},
volume = {23},
issue = {7},
pages = {3607},
abstract = {This study evaluates the effects of five different peptides, the Epitalon® tetrapeptide, the Vilon® dipeptide, the Thymogen® dipeptide, the Thymalin® peptide complex, and the Chonluten® tripeptide, as regulators of inflammatory and proliferative processes in the human monocytic THP-1, which is a human leukemia monocytic cell line capable of differentiating into macrophages by PMA in vitro. These peptides (Khavinson Peptides®), characterized by Prof. Khavinson from 1973 onwards, were initially isolated from animal tissues and found to be organ specific. We tested the capacity of the five peptides to influence cell cultures in vitro by incubating THP-1 cells with peptides at certain concentrations known for being effective on recipient cells in culture. We found that all five peptides can modulate key proliferative patterns, increasing tyrosine phosphorylation of mitogen-activated cytoplasmic kinases. In addition, the Chonluten tripeptide, derived from bronchial epithelial cells, inhibited in vitro tumor necrosis factor (TNF) production of monocytes exposed to pro-inflammatory bacterial lipopolysaccharide (LPS). The low TNF release by monocytes is linked to a documented mechanism of TNF tolerance, promoting attenuation of inflammatory action. Therefore, all peptides inhibited the expression of TNF and pro-inflammatory IL-6 cytokine stimulated by LPS on terminally differentiated THP-1 cells. Lastly, by incubating the THP1 cells, treated with the peptides, on a layer of activated endothelial cells (HUVECs activated by LPS), we observed a reduction in cell adhesion, a typical pro-inflammatory mechanism. Overall, the results suggest that the Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocyte, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
This study evaluates the effects of five different peptides, the Epitalon® tetrapeptide, the Vilon® dipeptide, the Thymogen® dipeptide, the Thymalin® peptide complex, and the Chonluten® tripeptide, as regulators of inflammatory and proliferative processes in the human monocytic THP-1, which is a human leukemia monocytic cell line capable of differentiating into macrophages by PMA in vitro. These peptides (Khavinson Peptides®), characterized by Prof. Khavinson from 1973 onwards, were initially isolated from animal tissues and found to be organ specific. We tested the capacity of the five peptides to influence cell cultures in vitro by incubating THP-1 cells with peptides at certain concentrations known for being effective on recipient cells in culture. We found that all five peptides can modulate key proliferative patterns, increasing tyrosine phosphorylation of mitogen-activated cytoplasmic kinases. In addition, the Chonluten tripeptide, derived from bronchial epithelial cells, inhibited in vitro tumor necrosis factor (TNF) production of monocytes exposed to pro-inflammatory bacterial lipopolysaccharide (LPS). The low TNF release by monocytes is linked to a documented mechanism of TNF tolerance, promoting attenuation of inflammatory action. Therefore, all peptides inhibited the expression of TNF and pro-inflammatory IL-6 cytokine stimulated by LPS on terminally differentiated THP-1 cells. Lastly, by incubating the THP1 cells, treated with the peptides, on a layer of activated endothelial cells (HUVECs activated by LPS), we observed a reduction in cell adhesion, a typical pro-inflammatory mechanism. Overall, the results suggest that the Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocyte, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity. |
Bicciato S; Ferrari F Hi-C Data Analysis Methods and Protocols Book SpringerLink, 2022, ISBN: 978-1-0716-1390-0. @book{%a1.%Ybn,
title = {Hi-C Data Analysis Methods and Protocols},
author = { Bicciato S and Ferrari F},
url = {https://link.springer.com/book/10.1007/978-1-0716-1390-0},
doi = {10.1007/978-1-0716-1390-0},
isbn = {978-1-0716-1390-0},
year = {2022},
date = {2022-05-30},
volume = {2301},
publisher = {SpringerLink},
series = {Methods in Molecular Biology },
keywords = {},
pubstate = {published},
tppubtype = {book}
}
|
Bacalini MG; Palombo F; Garagnani P; Giuliani C; Fiorini C; Caporali L; Stanzani Maserati M; Capellari S; Romagnoli M; De Fanti S; Benussi L; Binetti G; Ghidoni R; Galimberti D; Scarpini E; Arcaro M; Bonanni E; Siciliano G; Maestri M; Guarnieri B; Italian Multicentric Group on clock genes; actigraphy in AD; Martucci M; Monti D; Carelli V; Franceschi C; La Morgia C; Santoro A Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population Journal Article In: Geroscience, vol. 44, iss. 2, no 881, pp. 896, 2022. @article{%a1:%Yb_63,
title = {Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population},
author = {Bacalini MG and Palombo F and Garagnani P and Giuliani C and Fiorini C and Caporali L and Stanzani Maserati M and Capellari S and Romagnoli M and De Fanti S and Benussi L and Binetti G and Ghidoni R and Galimberti D and Scarpini E and Arcaro M and Bonanni E and Siciliano G and Maestri M and Guarnieri B and {Italian Multicentric Group on clock genes and actigraphy in AD} and Martucci M and Monti D and Carelli V and Franceschi C and La Morgia C and Santoro A},
url = {https://link.springer.com/article/10.1007%2Fs11357-021-00477-0},
doi = {10.1007/s11357-021-00477-0},
year = {2022},
date = {2022-04-29},
urldate = {2022-04-29},
journal = {Geroscience},
volume = {44},
number = {881},
issue = {2},
pages = {896},
abstract = {Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity. |
Panara V; Chiacchiaretta P; Rapino M; Maruotti V; Parenti M; Piccirilli E; Pizzi AD; Caulo M Dynamic susceptibility MR perfusion imaging of the brain: not a question of contrast agent molarity Journal Article In: Neuroradiology, vol. 64, iss. 4, pp. 685-692, 2022. @article{%a1.%Yb,
title = {Dynamic susceptibility MR perfusion imaging of the brain: not a question of contrast agent molarity},
author = {Panara V and Chiacchiaretta P and Rapino M and Maruotti V and Parenti M and Piccirilli E and Pizzi AD and Caulo M},
url = {https://link.springer.com/article/10.1007%2Fs00234-021-02807-7},
doi = {10.1007/s00234-021-02807-7},
year = {2022},
date = {2022-04-13},
urldate = {2022-04-13},
journal = {Neuroradiology},
volume = {64},
issue = {4},
pages = {685-692},
abstract = {Purpose: Dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI) is increasingly used in clinical neuroimaging for a range of conditions. More highly concentrated GBCAs (e.g., gadobutrol) are often preferred for DSC imaging because it is thought that more Gd is present in the volume of interest during first pass for a given equivalent injection rate. However, faster injection of a less viscous GBCA (e.g., gadoteridol) might generate a more compact and narrower contrast bolus thus obviating any perceived benefit of higher Gd concentration. This preliminary study aimed to analyze and compare DSC examinations in the healthy brain hemisphere of patients with brain tumors using gadobutrol and gadoteridol administered at injection rates of 4 and 6 mL/s. Methods: Thirty-nine brain tumor patients studied with DSC-PWI were evaluated. A simplified gamma-variate model function was applied to calculate the mean peak, area under the curve (AUC), and full-width at half-maximum (FHWM) of concentration-time curves derived from ΔR2* signals at four different regions-of-interest (ROIs). Qualitative assessment of the derived CBV maps was also performed independently by 2 neuroradiologists. Results: No qualitative or quantitative differences between the two GBCAs were observed when administered at a flow rate of 4 mL/s. At a flow rate of 6 mL/s, gadoteridol showed lower FWHM values. Conclusion: Gadobutrol and gadoteridol are equivalent for clinical assessment of qualitative CBV maps and quantitative perfusion parameters (FHWM) at a flow rate of 4 mL/s. At 6 mL/s, gadoteridol produces a narrower bolus shape and potentially improves quantitative assessment of perfusion parameters.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose: Dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI) is increasingly used in clinical neuroimaging for a range of conditions. More highly concentrated GBCAs (e.g., gadobutrol) are often preferred for DSC imaging because it is thought that more Gd is present in the volume of interest during first pass for a given equivalent injection rate. However, faster injection of a less viscous GBCA (e.g., gadoteridol) might generate a more compact and narrower contrast bolus thus obviating any perceived benefit of higher Gd concentration. This preliminary study aimed to analyze and compare DSC examinations in the healthy brain hemisphere of patients with brain tumors using gadobutrol and gadoteridol administered at injection rates of 4 and 6 mL/s. Methods: Thirty-nine brain tumor patients studied with DSC-PWI were evaluated. A simplified gamma-variate model function was applied to calculate the mean peak, area under the curve (AUC), and full-width at half-maximum (FHWM) of concentration-time curves derived from ΔR2* signals at four different regions-of-interest (ROIs). Qualitative assessment of the derived CBV maps was also performed independently by 2 neuroradiologists. Results: No qualitative or quantitative differences between the two GBCAs were observed when administered at a flow rate of 4 mL/s. At a flow rate of 6 mL/s, gadoteridol showed lower FWHM values. Conclusion: Gadobutrol and gadoteridol are equivalent for clinical assessment of qualitative CBV maps and quantitative perfusion parameters (FHWM) at a flow rate of 4 mL/s. At 6 mL/s, gadoteridol produces a narrower bolus shape and potentially improves quantitative assessment of perfusion parameters. |
Vismara M; Negri S; Scolari F; Brunetti V; Trivigno SMG; Faris P; Galgano L; Soda T; Berra-Romani R; Canobbio I; Torti M; Guidetti GF; Moccia F Platelet-Derived Extracellular Vesicles Stimulate Migration through Partial Remodelling of the Ca2+ Handling Machinery in MDA-MB-231 Breast Cancer Cells Journal Article In: Cells, vol. 11, iss. 19, pp. 3120, 2022. @article{%a1.%Yb_65,
title = {Platelet-Derived Extracellular Vesicles Stimulate Migration through Partial Remodelling of the Ca2+ Handling Machinery in MDA-MB-231 Breast Cancer Cells},
author = {Vismara M and Negri S and Scolari F and Brunetti V and Trivigno SMG and Faris P and Galgano L and Soda T and Berra-Romani R and Canobbio I and Torti M and Guidetti GF and Moccia F},
url = {https://www.mdpi.com/2073-4409/11/19/3120},
doi = {10.3390/cells11193120},
year = {2022},
date = {2022-03-31},
journal = {Cells},
volume = {11},
issue = {19},
pages = {3120},
abstract = {Background: Platelets can support cancer progression via the release of microparticles and microvesicles that enhance the migratory behaviour of recipient cancer cells. We recently showed that platelet-derived extracellular vesicles (PEVs) stimulate migration and invasiveness in highly metastatic MDA-MB-231 cells by stimulating the phosphorylation of p38 MAPK and the myosin light chain 2 (MLC2). Herein, we assessed whether the pro-migratory effect of PEVs involves the remodelling of the Ca2+ handling machinery, which drives MDA-MB-231 cell motility. Methods: PEVs were isolated from human blood platelets, and Fura-2/AM Ca2+ imaging, RT-qPCR, and immunoblotting were exploited to assess their effect on intracellular Ca2+ dynamics and Ca2+-dependent migratory processes in MDA-MB-231 cells. Results: Pretreating MDA-MB-231 cells with PEVs for 24 h caused an increase in Ca2+ release from the endoplasmic reticulum (ER) due to the up-regulation of SERCA2B and InsP3R1/InsP3R2 mRNAs and proteins. The consequent enhancement of ER Ca2+ depletion led to a significant increase in store-operated Ca2+ entry. The larger Ca2+ mobilization from the ER was required to potentiate serum-induced migration by recruiting p38 MAPK and MLC2. Conclusions: PEVs stimulate migration in the highly metastatic MDA-MB-231 breast cancer cell line by inducing a partial remodelling of the Ca2+ handling machinery.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Platelets can support cancer progression via the release of microparticles and microvesicles that enhance the migratory behaviour of recipient cancer cells. We recently showed that platelet-derived extracellular vesicles (PEVs) stimulate migration and invasiveness in highly metastatic MDA-MB-231 cells by stimulating the phosphorylation of p38 MAPK and the myosin light chain 2 (MLC2). Herein, we assessed whether the pro-migratory effect of PEVs involves the remodelling of the Ca2+ handling machinery, which drives MDA-MB-231 cell motility. Methods: PEVs were isolated from human blood platelets, and Fura-2/AM Ca2+ imaging, RT-qPCR, and immunoblotting were exploited to assess their effect on intracellular Ca2+ dynamics and Ca2+-dependent migratory processes in MDA-MB-231 cells. Results: Pretreating MDA-MB-231 cells with PEVs for 24 h caused an increase in Ca2+ release from the endoplasmic reticulum (ER) due to the up-regulation of SERCA2B and InsP3R1/InsP3R2 mRNAs and proteins. The consequent enhancement of ER Ca2+ depletion led to a significant increase in store-operated Ca2+ entry. The larger Ca2+ mobilization from the ER was required to potentiate serum-induced migration by recruiting p38 MAPK and MLC2. Conclusions: PEVs stimulate migration in the highly metastatic MDA-MB-231 breast cancer cell line by inducing a partial remodelling of the Ca2+ handling machinery. |
Salucci S; Bartoletti-Stella A; Bavelloni A; Aramini B; Blalock WL; Fabbri F; Vannini I; Sambri V; Stella F; Faenza I Extra Virgin Olive Oil (EVOO), a Mediterranean Diet Component, in the Management of Muscle Mass and Function Preservation Journal Article In: Nutrients, vol. 14, iss. 17, pp. 3567, 2022. @article{%a1.%Yb_63,
title = {Extra Virgin Olive Oil (EVOO), a Mediterranean Diet Component, in the Management of Muscle Mass and Function Preservation},
author = {Salucci S and Bartoletti-Stella A and Bavelloni A and Aramini B and Blalock WL and Fabbri F and Vannini I and Sambri V and Stella F and Faenza I},
url = {https://www.mdpi.com/2072-6643/14/17/3567},
doi = {10.3390/nu14173567},
year = {2022},
date = {2022-03-31},
journal = {Nutrients},
volume = {14},
issue = {17},
pages = {3567},
abstract = {Aging results in a progressive decline in skeletal muscle mass, strength and function, a condition known as sarcopenia. This pathological condition is due to multifactorial processes including physical inactivity, inflammation, oxidative stress, hormonal changes, and nutritional intake. Physical therapy remains the standard approach to treat sarcopenia, although some interventions based on dietary supplementation are in clinical development. In this context, thanks to its known anti-inflammatory and antioxidative properties, there is great interest in using extra virgin olive oil (EVOO) supplementation to promote muscle mass and health in sarcopenic patients. To date, the molecular mechanisms responsible for the pathological changes associated with sarcopenia remain undefined; however, a complete understanding of the signaling pathways that regulate skeletal muscle protein synthesis and their behavior during sarcopenia appears vital for defining how EVOO might attenuate muscle wasting during aging. This review highlights the main molecular players that control skeletal muscle mass, with particular regard to sarcopenia, and discusses, based on the more recent findings, the potential of EVOO in delaying/preventing loss of muscle mass and function, with the aim of stimulating further research to assess dietary supplementation with EVOO as an approach to prevent or delay sarcopenia in aging individuals.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Aging results in a progressive decline in skeletal muscle mass, strength and function, a condition known as sarcopenia. This pathological condition is due to multifactorial processes including physical inactivity, inflammation, oxidative stress, hormonal changes, and nutritional intake. Physical therapy remains the standard approach to treat sarcopenia, although some interventions based on dietary supplementation are in clinical development. In this context, thanks to its known anti-inflammatory and antioxidative properties, there is great interest in using extra virgin olive oil (EVOO) supplementation to promote muscle mass and health in sarcopenic patients. To date, the molecular mechanisms responsible for the pathological changes associated with sarcopenia remain undefined; however, a complete understanding of the signaling pathways that regulate skeletal muscle protein synthesis and their behavior during sarcopenia appears vital for defining how EVOO might attenuate muscle wasting during aging. This review highlights the main molecular players that control skeletal muscle mass, with particular regard to sarcopenia, and discusses, based on the more recent findings, the potential of EVOO in delaying/preventing loss of muscle mass and function, with the aim of stimulating further research to assess dietary supplementation with EVOO as an approach to prevent or delay sarcopenia in aging individuals. |
Qiu X; Boufaied N; Hallal T; Feit A; de Polo A; Luoma AM; Alahmadi W; Larocque J; Zadra G; Xie Y; Gu S; Tang Q; Zhang Y; Syamala S; Seo JH; Bell C; O'Connor E; Liu Y; Schaeffer EM; Jeffrey Karnes R; Weinmann S; Davicioni E; Morrissey C; Cejas P; Ellis L; Loda M; Wucherpfennig KW; Pomerantz MM; Spratt DE; Corey E; Freedman ML; Shirley Liu X; Brown M; Long HW; Labbé DP MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets Journal Article In: Nature communications, vol. 13, iss. 1, pp. 2559, 2022. @article{%a1.%Yb_62,
title = {MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets},
author = {Qiu X and Boufaied N and Hallal T and Feit A and de Polo A and Luoma AM and Alahmadi W and Larocque J and Zadra G and Xie Y and Gu S and Tang Q and Zhang Y and Syamala S and Seo JH and Bell C and O'Connor E and Liu Y and Schaeffer EM and Jeffrey Karnes R and Weinmann S and Davicioni E and Morrissey C and Cejas P and Ellis L and Loda M and Wucherpfennig KW and Pomerantz MM and Spratt DE and Corey E and Freedman ML and Shirley Liu X and Brown M and Long HW and Labbé DP},
url = {https://www.nature.com/articles/s41467-022-30257-z},
doi = {10.1038/s41467-022-30257-z},
year = {2022},
date = {2022-03-31},
journal = {Nature communications},
volume = {13},
issue = {1},
pages = {2559},
abstract = {c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes. |
Palladini G; Cagna M; Di Pasqua LG; Adorini L; Croce AC; Perlini S; Ferrigno A; Berardo C; Vairetti M Obeticholic Acid Reduces Kidney Matrix Metalloproteinase Activation Following Partial Hepatic Ischemia/Reperfusion Injury in Rats Journal Article In: Pharmaceuticals (Basel), vol. 15, iss. 5, pp. 524, 2022. @article{%a1.%Yb_61,
title = {Obeticholic Acid Reduces Kidney Matrix Metalloproteinase Activation Following Partial Hepatic Ischemia/Reperfusion Injury in Rats},
author = {Palladini G and Cagna M and Di Pasqua LG and Adorini L and Croce AC and Perlini S and Ferrigno A and Berardo C and Vairetti M},
url = {https://www.mdpi.com/1424-8247/15/5/524},
doi = {10.3390/ph15050524},
year = {2022},
date = {2022-03-31},
journal = {Pharmaceuticals (Basel)},
volume = {15},
issue = {5},
pages = {524},
abstract = {We have previously demonstrated that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) protects the liver via downregulation of hepatic matrix metalloproteinases (MMPs) after ischemia/reperfusion (I/R), which can lead to multiorgan dysfunction. The present study investigated the capacity of OCA to modulate MMPs in distant organs such as the kidney. Male Wistar rats were dosed orally with 10 mg/kg/day of OCA (5 days) and were subjected to 60-min partial hepatic ischemia. After 120-min reperfusion, kidney biopsies (cortex and medulla) and blood samples were collected. Serum creatinine, kidney MMP-2, and MMP-9-dimer, tissue inhibitors of MMPs (TIMP-1, TIMP-2), RECK, TNF-alpha, and IL-6 were monitored. MMP-9-dimer activity in the kidney cortex and medulla increased after hepatic I/R and a reduction was detected in OCA-treated I/R rats. Although not significantly, MMP-2 activity decreased in the cortex of OCA-treated I/R rats. TIMPs and RECK levels showed no significant differences among all groups considered. Serum creatinine increased after I/R and a reduction was detected in OCA-treated I/R rats. The same trend occurred for tissue TNF-alpha and IL-6. Although the underlying mechanisms need further investigation, this is the first study showing, in the kidney, beneficial effects of OCA by reducing TNF-alpha-mediated expression of MMPs after liver I/R.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We have previously demonstrated that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) protects the liver via downregulation of hepatic matrix metalloproteinases (MMPs) after ischemia/reperfusion (I/R), which can lead to multiorgan dysfunction. The present study investigated the capacity of OCA to modulate MMPs in distant organs such as the kidney. Male Wistar rats were dosed orally with 10 mg/kg/day of OCA (5 days) and were subjected to 60-min partial hepatic ischemia. After 120-min reperfusion, kidney biopsies (cortex and medulla) and blood samples were collected. Serum creatinine, kidney MMP-2, and MMP-9-dimer, tissue inhibitors of MMPs (TIMP-1, TIMP-2), RECK, TNF-alpha, and IL-6 were monitored. MMP-9-dimer activity in the kidney cortex and medulla increased after hepatic I/R and a reduction was detected in OCA-treated I/R rats. Although not significantly, MMP-2 activity decreased in the cortex of OCA-treated I/R rats. TIMPs and RECK levels showed no significant differences among all groups considered. Serum creatinine increased after I/R and a reduction was detected in OCA-treated I/R rats. The same trend occurred for tissue TNF-alpha and IL-6. Although the underlying mechanisms need further investigation, this is the first study showing, in the kidney, beneficial effects of OCA by reducing TNF-alpha-mediated expression of MMPs after liver I/R. |
Okbay A; Wu Y; Wang N; Jayashankar H; Bennett M; Nehzati SM; …...; Biino G; ….....; et al Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals. Journal Article In: Nature genetics, vol. 54, iss. 4, pp. 437-449, 2022. @article{%a1.%Yb_60,
title = {Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals.},
author = {Okbay A and Wu Y and Wang N and Jayashankar H and Bennett M and Nehzati SM and …... and Biino G and …..... and et al},
url = {https://www.nature.com/articles/s41588-022-01016-z},
doi = {10.1038/s41588-022-01016-z},
year = {2022},
date = {2022-03-31},
journal = {Nature genetics},
volume = {54},
issue = {4},
pages = {437-449},
abstract = {We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of about 3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of about 3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57. |
Negri S; Scolari F; Vismara M; Brunetti V; Faris P; Terribile G; Sancini G; Berra-Romani R; Moccia F GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells Journal Article In: Cells, vol. 11, iss. 23, pp. 3860, 2022. @article{%a1.%Yb_59,
title = {GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells},
author = {Negri S and Scolari F and Vismara M and Brunetti V and Faris P and Terribile G and Sancini G and Berra-Romani R and Moccia F},
url = {https://www.mdpi.com/2073-4409/11/23/3860},
doi = {10.3390/cells11233860},
year = {2022},
date = {2022-03-31},
urldate = {2022-03-31},
journal = {Cells},
volume = {11},
issue = {23},
pages = {3860},
abstract = {Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABAA receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABAB receptors is still unknown. Preliminary evidence showed that GABAA receptor stimulation can induce an increase in endothelial Ca2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca2+]i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca2+ release from neutral and acidic Ca2+ stores, respectively, and sustained by store-operated Ca2+ entry. GABAA and GABAB receptors were both required to trigger the endothelial Ca2+ response. Unexpectedly, we found that the GABAA receptors signal in a flux-independent manner via the metabotropic GABAB receptors. Likewise, the full Ca2+ response to GABAB receptors requires functional GABAA receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABAA receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABAB receptors is still unknown. Preliminary evidence showed that GABAA receptor stimulation can induce an increase in endothelial Ca2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca2+]i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca2+ release from neutral and acidic Ca2+ stores, respectively, and sustained by store-operated Ca2+ entry. GABAA and GABAB receptors were both required to trigger the endothelial Ca2+ response. Unexpectedly, we found that the GABAA receptors signal in a flux-independent manner via the metabotropic GABAB receptors. Likewise, the full Ca2+ response to GABAB receptors requires functional GABAA receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit. |
Marinelli L; Ciulla M; Ritsema JAS; van Nostrum CF; Cacciatore I; Dimmito MP; Palmerio F; Orlando G; Robuffo I; Grande R; Puca V; Di Stefano A Preparation, Characterization, and Biological Evaluation of a Hydrophilic Peptide Loaded on PEG-PLGA Nanoparticles Bachelor Thesis 2022. @bachelorthesis{nokey,
title = {Preparation, Characterization, and Biological Evaluation of a Hydrophilic Peptide Loaded on PEG-PLGA Nanoparticles},
author = {Marinelli L and Ciulla M and Ritsema JAS and van Nostrum CF and Cacciatore I and Dimmito MP and Palmerio F and Orlando G and Robuffo I and Grande R and Puca V and {Di Stefano A}},
url = {https://www.mdpi.com/1999-4923/14/9/1821},
doi = {10.3390/pharmaceutics14091821},
year = {2022},
date = {2022-03-31},
journal = {Pharmaceutics},
volume = {14},
issue = {9},
pages = {1821},
abstract = {The encapsulation of peptides and proteins in nanosystems has been extensively investigated for masking unfavorable biopharmaceutical properties, including short half-life and poor permeation through biological membranes. Therefore, the aim of this work was to encapsulate a small antimicrobial hydrophilic peptide (H-Ser-Pro-Trp-Thr-NH2, FS10) in PEG-PLGA (polyethylene glycol-poly lactic acid-co-glycolic acid) nanoparticles (Nps) and thereby overcome the common limitations of hydrophilic drugs, which because they facilitate water absorption suffer from rapid degradation. FS10 is structurally related to the well-known RNAIII inhibiting peptide (RIP) and inhibits S. aureus biofilm formation. Various parameters, including different method (double emulsion and nanoprecipitation), pH of the aqueous phase and polymeric composition, were investigated to load FS10 into PEG-PLGA nanoparticles. The combination of different strategies resulted in an encapsulation efficiency of around 25% for both the double emulsion and the nanoprecipitation method. It was found that the most influential parameters were the pH-which tailors the peptides charge-and the polymeric composition. FS10-PEG-PLGA nanoparticles, obtained under optimized parameters, showed size lower than 180 nm with zeta potential values ranging from -11 to -21 mV. In vitro release studies showed that the Nps had an initial burst release of 48-63%, followed by a continuous drug release up to 21 h, probably caused by the porous character of the Nps. Furthermore, transmission electron microscopy (TEM) analysis revealed particles with a spherical morphology and size of around 100 nm. Antimicrobial assay showed that the minimum inhibitory concentration (MIC) of the FS10-loaded Nps, against S. aureus strains, was lower (>128 µg/mL) than that of the free FS10 (>256 µg/mL). The main goal of this work was to develop polymeric drug delivery systems aiming at protecting the peptide from a fast degradation, thus improving its accumulation in the target site and increasing the drug-bacterial membrane interactions.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
The encapsulation of peptides and proteins in nanosystems has been extensively investigated for masking unfavorable biopharmaceutical properties, including short half-life and poor permeation through biological membranes. Therefore, the aim of this work was to encapsulate a small antimicrobial hydrophilic peptide (H-Ser-Pro-Trp-Thr-NH2, FS10) in PEG-PLGA (polyethylene glycol-poly lactic acid-co-glycolic acid) nanoparticles (Nps) and thereby overcome the common limitations of hydrophilic drugs, which because they facilitate water absorption suffer from rapid degradation. FS10 is structurally related to the well-known RNAIII inhibiting peptide (RIP) and inhibits S. aureus biofilm formation. Various parameters, including different method (double emulsion and nanoprecipitation), pH of the aqueous phase and polymeric composition, were investigated to load FS10 into PEG-PLGA nanoparticles. The combination of different strategies resulted in an encapsulation efficiency of around 25% for both the double emulsion and the nanoprecipitation method. It was found that the most influential parameters were the pH-which tailors the peptides charge-and the polymeric composition. FS10-PEG-PLGA nanoparticles, obtained under optimized parameters, showed size lower than 180 nm with zeta potential values ranging from -11 to -21 mV. In vitro release studies showed that the Nps had an initial burst release of 48-63%, followed by a continuous drug release up to 21 h, probably caused by the porous character of the Nps. Furthermore, transmission electron microscopy (TEM) analysis revealed particles with a spherical morphology and size of around 100 nm. Antimicrobial assay showed that the minimum inhibitory concentration (MIC) of the FS10-loaded Nps, against S. aureus strains, was lower (>128 µg/mL) than that of the free FS10 (>256 µg/mL). The main goal of this work was to develop polymeric drug delivery systems aiming at protecting the peptide from a fast degradation, thus improving its accumulation in the target site and increasing the drug-bacterial membrane interactions. |
