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Article: Induced pluripotent stem cell-based models: Are we ready for that heart in a dish?

Bissoli, Irene / D'Adamo, Stefania / Pignatti, Carla / Agnetti, Giulio / Flamigni, Flavio / Cetrullo, Silvia

Frontiers in cell and developmental biology

2023 Volume 11, Page(s) 1129263

Language	English
Publishing date	2023-01-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2023.1129263
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Article ; Online: NOTCH1: A Novel Player in the Molecular Crosstalk Underlying Articular Chondrocyte Protection by Oleuropein and Hydroxytyrosol.

Panichi, Veronica / Bissoli, Irene / D'Adamo, Stefania / Flamigni, Flavio / Cetrullo, Silvia / Borzì, Rosa Maria

International journal of molecular sciences

2023 Volume 24, Issue 6

Abstract: Osteoarthritis (OA) is the most common joint disease, but no effective and safe disease-modifying treatment is available. Risk factors such as age, sex, genetics, injuries and obesity can concur to the onset of the disease, variably triggering the loss ... ...

Abstract	Osteoarthritis (OA) is the most common joint disease, but no effective and safe disease-modifying treatment is available. Risk factors such as age, sex, genetics, injuries and obesity can concur to the onset of the disease, variably triggering the loss of maturational arrest of chondrocytes further sustained by oxidative stress, inflammation and catabolism. Different types of nutraceuticals have been studied for their anti-oxidative and anti-inflammatory properties. Olive-derived polyphenols draw particular interest due to their ability to dampen the activation of pivotal signaling pathways in OA. Our study aims to investigate the effects of oleuropein (OE) and hydroxytyrosol (HT) in in vitro OA models and elucidate their possible effects on NOTCH1, a novel therapeutic target for OA. Chondrocytes were cultured and exposed to lipopolysaccharide (LPS). Detailed analysis was carried out about the OE/HT mitigating effects on the release of ROS (DCHF-DA), the increased gene expression of catabolic and inflammatory markers (real time RT-PCR), the release of MMP-13 (ELISA and Western blot) and the activation of underlying signaling pathways (Western blot). Our findings show that HT/OE efficiently attenuates LPS-induced effects by firstly reducing the activation of JNK and of the NOTCH1 pathway downstream. In conclusion, our study provides molecular bases supporting the dietary supplementation of olive-derived polyphenols to revert/delay the progression of OA.
MeSH term(s)	Humans ; Chondrocytes/metabolism ; Lipopolysaccharides/pharmacology ; Osteoarthritis/metabolism ; Cells, Cultured ; Cartilage, Articular/metabolism ; Receptor, Notch1/genetics ; Receptor, Notch1/metabolism
Chemical Substances	oleuropein (2O4553545L) ; 3,4-dihydroxyphenylethanol (10597-60-1) ; Lipopolysaccharides ; NOTCH1 protein, human ; Receptor, Notch1
Language	English
Publishing date	2023-03-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24065830
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Article: Molecular Mechanisms Linking Nutrition to Metabolic Homeostasis: An Overview Picture of Current Understanding.

Pignatti, Carla / D'Adamo, Stefania / Flamigni, Flavio / Cetrulllo, Silvia

Critical reviews in eukaryotic gene expression

2021 Volume 30, Issue 6, Page(s) 543–564

Abstract: Increasing evidence supports the notion that in humans many pathological conditions including obesity, metabolic syndrome, and type 2 diabetes are closely related to the amount and quality of each nutritional component and to an impairment of the ... ...

Abstract	Increasing evidence supports the notion that in humans many pathological conditions including obesity, metabolic syndrome, and type 2 diabetes are closely related to the amount and quality of each nutritional component and to an impairment of the metabolic homeostatic mechanisms of their utilization. Cell signaling pathways that sense the availability of nutrients and the energy status of the cells communicate with signaling pahways triggered by hormones and growth factors to coordinately regulate whole-body metabolic homeostasis. The aim of this review is to provide an overview picture of current knowledge about the main molecular mechanisms that connect nutritional status, hormones, and nutrient levels with gene expression, metabolic homeostasis, and nutrient sensing. We recapitulate molecular mechanisms governing fuel selection between glucose and fatty acids in different nutritional conditions, highlighting metabolic flexibility as mechanism to ensure metabolic health. Disrupted metabolic flexibility, or metabolic inflexibility, is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer. We also describe how macronutrients that can be used as energy sources may reciprocally modulate their own metabolism as well as directly interact with transcriptional factors, nutrient sensors and nutrient sensing pathways in order to achieve metabolic homeostasis.
MeSH term(s)	Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Energy Metabolism/genetics ; Glucose/genetics ; Glucose/metabolism ; Homeostasis/genetics ; Humans ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Obesity/genetics ; Obesity/metabolism ; Obesity/pathology ; Signal Transduction/genetics
Chemical Substances	Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1071345-1
ISSN	1045-4403
ISSN	1045-4403
DOI	10.1615/CritRevEukaryotGeneExpr.2020037120
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Article ; Online: Effect of oxidative stress and 3-hydroxytyrosol on DNA methylation levels of miR-9 promoters.

D'Adamo, Stefania / Cetrullo, Silvia / Borzì, Rosa Maria / Flamigni, Flavio

Journal of cellular and molecular medicine

2019 Volume 23, Issue 11, Page(s) 7885–7889

MeSH term(s)	Azacitidine/pharmacology ; Cell Line ; DNA Methylation/drug effects ; DNA Methylation/genetics ; Demethylation ; Gene Expression Regulation/drug effects ; Gene Silencing/drug effects ; Humans ; Hydrogen Peroxide/toxicity ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Oxidative Stress/drug effects ; Phenylethyl Alcohol/analogs & derivatives ; Phenylethyl Alcohol/pharmacology ; Promoter Regions, Genetic/genetics ; Sirtuin 1/metabolism
Chemical Substances	MIRN92 microRNA, human ; MicroRNAs ; 3,4-dihydroxyphenylethanol (10597-60-1) ; Hydrogen Peroxide (BBX060AN9V) ; Sirtuin 1 (EC 3.5.1.-) ; Azacitidine (M801H13NRU) ; Phenylethyl Alcohol (ML9LGA7468)
Language	English
Publishing date	2019-09-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.14657
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Article ; Online: Nutraceutical Activity in Osteoarthritis Biology: A Focus on the Nutrigenomic Role.

D'Adamo, Stefania / Cetrullo, Silvia / Panichi, Veronica / Mariani, Erminia / Flamigni, Flavio / Borzì, Rosa Maria

Cells

2020 Volume 9, Issue 5

Abstract: Osteoarthritis (OA) is a disease associated to age or conditions that precipitate aging of articular cartilage, a post-mitotic tissue that remains functional until the failure of major homeostatic mechanisms. OA severely impacts the national health ... ...

Abstract	Osteoarthritis (OA) is a disease associated to age or conditions that precipitate aging of articular cartilage, a post-mitotic tissue that remains functional until the failure of major homeostatic mechanisms. OA severely impacts the national health system costs and patients' quality of life because of pain and disability. It is a whole-joint disease sustained by inflammatory and oxidative signaling pathways and marked epigenetic changes responsible for catabolism of the cartilage extracellular matrix. OA usually progresses until its severity requires joint arthroplasty. To delay this progression and to improve symptoms, a wide range of naturally derived compounds have been proposed and are summarized in this review. Preclinical in vitro and in vivo studies have provided proof of principle that many of these nutraceuticals are able to exert pleiotropic and synergistic effects and effectively counteract OA pathogenesis by exerting both anti-inflammatory and antioxidant activities and by tuning major OA-related signaling pathways. The latter are the basis for the nutrigenomic role played by some of these compounds, given the marked changes in the transcriptome, miRNome, and methylome. Ongoing and future clinical trials will hopefully confirm the disease-modifying ability of these bioactive molecules in OA patients.
MeSH term(s)	Animals ; Dietary Supplements ; Humans ; Nutrigenomics ; Osteoarthritis/genetics ; Osteoarthritis/physiopathology ; Osteoarthritis/therapy ; Phytochemicals/therapeutic use ; Treatment Outcome
Chemical Substances	Phytochemicals
Language	English
Publishing date	2020-05-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9051232
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Article ; Online: Nutrients and Pathways that Regulate Health Span and Life Span.

Pignatti, Carla / D'Adamo, Stefania / Stefanelli, Claudio / Flamigni, Flavio / Cetrullo, Silvia

Geriatrics (Basel, Switzerland)

2020 Volume 5, Issue 4

Abstract: Both life span and health span are influenced by genetic, environmental and lifestyle factors. With the genetic influence on human life span estimated to be about 20-25%, epigenetic changes play an important role in modulating individual health status ... ...

Abstract	Both life span and health span are influenced by genetic, environmental and lifestyle factors. With the genetic influence on human life span estimated to be about 20-25%, epigenetic changes play an important role in modulating individual health status and aging. Thus, a main part of life expectance and healthy aging is determined by dietary habits and nutritional factors. Excessive or restricted food consumption have direct effects on health status. Moreover, some dietary interventions including a reduced intake of dietary calories without malnutrition, or a restriction of specific dietary component may promote health benefits and decrease the incidence of aging-related comorbidities, thus representing intriguing potential approaches to improve healthy aging. However, the relationship between nutrition, health and aging is still not fully understood as well as the mechanisms by which nutrients and nutritional status may affect health span and longevity in model organisms. The broad effect of different nutritional conditions on health span and longevity occurs through multiple mechanisms that involve evolutionary conserved nutrient-sensing pathways in tissues and organs. These pathways interacting each other include the evolutionary conserved key regulators mammalian target of rapamycin, AMP-activated protein kinase, insulin/insulin-like growth factor 1 pathway and sirtuins. In this review we provide a summary of the main molecular mechanisms by which different nutritional conditions, i.e., specific nutrient abundance or restriction, may affect health span and life span.
Language	English
Publishing date	2020-11-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ISSN	2308-3417
ISSN (online)	2308-3417
DOI	10.3390/geriatrics5040095
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Article ; Online: Modulation of Fatty Acid-Related Genes in the Response of H9c2 Cardiac Cells to Palmitate and n-3 Polyunsaturated Fatty Acids.

Cetrullo, Silvia / D'Adamo, Stefania / Panichi, Veronica / Borzì, Rosa Maria / Pignatti, Carla / Flamigni, Flavio

Cells

2020 Volume 9, Issue 3

Abstract: While high levels of saturated fatty acids are associated with impairment of cardiovascular functions, n-3 polyunsaturated fatty acids (PUFAs) have been shown to exert protective effects. However the molecular mechanisms underlying this evidence are not ... ...

Abstract	While high levels of saturated fatty acids are associated with impairment of cardiovascular functions, n-3 polyunsaturated fatty acids (PUFAs) have been shown to exert protective effects. However the molecular mechanisms underlying this evidence are not completely understood. In the present study we have used rat H9c2 ventricular cardiomyoblasts as a cellular model of lipotoxicity to highlight the effects of palmitate, a saturated fatty acid, on genetic and epigenetic modulation of fatty acid metabolism and fate, and the ability of PUFAs, eicosapentaenoic acid, and docosahexaenoic acid, to contrast the actions that may contribute to cardiac dysfunction and remodeling. Treatment with a high dose of palmitate provoked mitochondrial depolarization, apoptosis, and hypertrophy of cardiomyoblasts. Palmitate also enhanced the mRNA levels of sterol regulatory element-binding proteins (SREBPs), a family of master transcription factors for lipogenesis, and it favored the expression of genes encoding key enzymes that metabolically activate palmitate and commit it to biosynthetic pathways. Moreover, miR-33a, a highly conserved microRNA embedded in an intronic sequence of the SREBP2 gene, was co-expressed with the SREBP2 messenger, while its target carnitine palmitoyltransferase-1b was down-regulated. Manipulation of the levels of miR-33a and SREBPs allowed us to understand their involvement in cell death and hypertrophy. The simultaneous addition of PUFAs prevented the effects of palmitate and protected H9c2 cells. These results may have implications for the control of cardiac metabolism and dysfunction, particularly in relation to dietary habits and the quality of fatty acid intake.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Cell Line ; Cell Size/drug effects ; Cell Survival/drug effects ; Docosahexaenoic Acids/pharmacology ; Eicosapentaenoic Acid/pharmacology ; Fatty Acids/metabolism ; Fatty Acids, Omega-3/pharmacology ; Gene Expression Regulation/drug effects ; Gene Silencing/drug effects ; Hypertrophy ; Membrane Potential, Mitochondrial/drug effects ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Palmitates/pharmacology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Sterol Regulatory Element Binding Proteins/genetics ; Sterol Regulatory Element Binding Proteins/metabolism
Chemical Substances	Fatty Acids ; Fatty Acids, Omega-3 ; MIRN33 microRNA, rat ; MicroRNAs ; Palmitates ; RNA, Messenger ; Sterol Regulatory Element Binding Proteins ; Docosahexaenoic Acids (25167-62-8) ; Eicosapentaenoic Acid (AAN7QOV9EA)
Language	English
Publishing date	2020-02-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9030537
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Article ; Online: Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes.

Minguzzi, Manuela / Panichi, Veronica / D'Adamo, Stefania / Cetrullo, Silvia / Cattini, Luca / Flamigni, Flavio / Mariani, Erminia / Borzì, Rosa Maria

International journal of molecular sciences

2021 Volume 22, Issue 21

Abstract: Notch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. ...

Abstract	Notch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. NOTCH1 is the most abundantly expressed NOTCH receptors in normal cartilage and its expression increases in osteoarthritis (OA), when chondrocytes exit from their healthy "maturation arrested state" and resume their natural route of proliferation, hypertrophy, and terminal differentiation. The latter are hallmarks of OA that are easily evaluated in vitro in 2-D or 3-D culture models. The aim of our study was to investigate the effect of NOTCH1 knockdown on proliferation (cell count and Picogreen mediated DNA quantification), cell cycle (flow cytometry), hypertrophy (gene and protein expression of key markers such as RUNX2 and MMP-13), and terminal differentiation (viability measured in 3-D cultures by luminescence assay) of human OA chondrocytes. NOTCH1 silencing of OA chondrocytes yielded a healthier phenotype in both 2-D (reduced proliferation) and 3-D with evidence of decreased hypertrophy (reduced expression of RUNX2 and MMP-13) and terminal differentiation (increased viability). This demonstrates that NOTCH1 is a convenient therapeutic target to attenuate OA progression.
MeSH term(s)	Aged ; Cell Culture Techniques, Three Dimensional ; Cells, Cultured ; Chondrocytes/metabolism ; Chondrocytes/pathology ; Core Binding Factor Alpha 1 Subunit/metabolism ; Female ; Humans ; Hypertrophy/etiology ; Hypertrophy/metabolism ; Hypertrophy/pathology ; Male ; Matrix Metalloproteinase 13/metabolism ; Osteoarthritis/etiology ; Osteoarthritis/metabolism ; Osteoarthritis/pathology ; Receptor, Notch1/metabolism ; Signal Transduction
Chemical Substances	Core Binding Factor Alpha 1 Subunit ; NOTCH1 protein, human ; RUNX2 protein, human ; Receptor, Notch1 ; MMP13 protein, human (EC 3.4.24.-) ; Matrix Metalloproteinase 13 (EC 3.4.24.-)
Language	English
Publishing date	2021-11-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222112012
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Article ; Online: Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases.

Olivotto, Eleonora / Minguzzi, Manuela / D'Adamo, Stefania / Astolfi, Annalisa / Santi, Spartaco / Uguccioni, Mariagrazia / Marcu, Kenneth B / Borzì, Rosa Maria

Scientific reports

2021 Volume 11, Issue 1, Page(s) 21697

Abstract: IKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and ... ...

Abstract	IKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and contribute to immune cell chemotaxis in osteoarthritis (OA). Here we employed shRNA retroviruses to stably and efficiently ablate the expression of each IKK in primary OA chondrocytes to determine their individual contributions for monocyte chemotaxis in response to chondrocyte conditioned media. Both IKKα and IKKβ KDs blunted both the monocyte chemotactic potential and the protein levels of CCL2/MCP-1, the chemokine with the highest concentration and the strongest association with monocyte chemotaxis. These findings were mirrored by gene expression analysis indicating that the lowest levels of CCL2/MCP-1 and other monocyte-active chemokines were in IKKαKD cells under both basal and IL-1β stimulated conditions. We find that in their response to IL-1β stimulation IKKαKD primary OA chondrocytes have reduced levels of phosphorylated NFkappaB p65pSer536 and H3pSer10. Confocal microscopy analysis revealed co-localized p65 and H3pSer10 nuclear signals in agreement with our findings that IKKαKD effectively blunts their basal level and IL-1β dependent increases. Our results suggest that IKKα could be a novel OA disease target.
MeSH term(s)	Cells, Cultured ; Chemokine CCL2/metabolism ; Chemokines/immunology ; Chemokines/metabolism ; Chemotaxis/physiology ; Chondrocytes/metabolism ; Female ; Humans ; I-kappa B Kinase/metabolism ; I-kappa B Kinase/physiology ; Inflammation ; Interleukin-1beta/metabolism ; Interleukin-1beta/physiology ; Male ; Middle Aged ; Monocytes/metabolism ; NF-kappa B/metabolism ; Osteoarthritis/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases ; Signal Transduction/physiology ; Transcription Factor RelA
Chemical Substances	CCL2 protein, human ; Chemokine CCL2 ; Chemokines ; IL1B protein, human ; Interleukin-1beta ; NF-kappa B ; RELA protein, human ; Transcription Factor RelA ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; TBK1 protein, human (EC 2.7.11.1) ; I-kappa B Kinase (EC 2.7.11.10)
Language	English
Publishing date	2021-11-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-01063-2
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Article: Inhibitory activity of aqueous extracts from Anabaena minutissima, Ecklonia maxima and Jania adhaerens on the cucumber powdery mildew pathogen in vitro and in vivo

Righini, Hillary / Somma, Annalisa / Cetrullo, Silvia / D’Adamo, Stefania / Flamigni, Flavio / Quintana, Antera Martel / Roberti, Roberta

Journal of applied phycology. 2020 Oct., v. 32, no. 5

2020

Abstract: Aqueous extracts from Anabaena minutissima BEA 0300B (ANA), Ecklonia maxima (ECK) and Jania adhaerens (JAN) were evaluated for their antifungal effect against powdery mildew disease caused by Podosphaera xanthii on cucumber detached cotyledons and ... ...

Abstract	Aqueous extracts from Anabaena minutissima BEA 0300B (ANA), Ecklonia maxima (ECK) and Jania adhaerens (JAN) were evaluated for their antifungal effect against powdery mildew disease caused by Podosphaera xanthii on cucumber detached cotyledons and seedlings. All the extracts were sprayed on detached cotyledons at 2.5, 5.0 and 10.0 mg dry biomass mL⁻¹ water and those of ANA and JAN at 5.0 and 10.0 mg mL⁻¹ on seedlings before pathogen challenge (10⁶ spores mL⁻¹). ANA and JAN at 5.0 and 10.0 mg mL⁻¹ reduced infected area and fungal sporulation on both detached cotyledons and seedlings. ANA and JAN at 5.0 and 10.0 mg mL⁻¹ were also evaluated for their elicitation of seedling defence responses, 1, 2 and 3 days before P. xanthii inoculation. Treatments reduced disease symptoms depending on extract, concentration and application time. Both extracts differentially induced the expression of PR genes, which may have concurred to pathogen control. At all times, ANA mainly induced AePR3 and PR1 genes, at 5.0 and 10.0 mg mL⁻¹, respectively, while JAN mainly induced AePR3 and PR4 at 5.0 mg mL⁻¹. This suggests that both ANA and JAN activated the expression of genes within the jasmonic acid and salicylic acid pathway. Proteins, phycobiliproteins, chlorophylls, carotenoids and antioxidant activities determined in the extracts could be involved in the antifungal effect or induction of plant systemic resistance. These results demonstrate that aqueous extracts from algae and cyanobacteria may be considered for further studies as a bio-based strategy for sustainable disease management.
Keywords	Anabaena ; Ecklonia ; Jania ; Podosphaera xanthii ; algology ; antifungal properties ; antioxidants ; application timing ; biomass ; carotenoids ; cucumbers ; disease control ; fungi ; jasmonic acid ; pathogens ; phycobiliprotein ; powdery mildew ; salicylic acid ; seedlings ; sporulation
Language	English
Dates of publication	2020-10
Size	p. 3363-3375.
Publishing place	Springer Netherlands
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1002324-0
ISSN	1573-5176 ; 0921-8971
ISSN (online)	1573-5176
ISSN	0921-8971
DOI	10.1007/s10811-020-02160-x
Database	NAL-Catalogue (AGRICOLA)

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