on Food chemistry
by Servillo L, D'Onofrio N, Giovane A, Casale R, Cautela D, Castaldo D, Iannaccone F, Neglia G, Campanile G, Balestrieri ML
Quaternary ammonium compounds containing N-trimethylamino moiety, such as choline derivatives and carnitine, abundant in meat and dairy products, are metabolic precursors of trimethylamine (TMA). A similar fate is reported for N-trimethyllysine and γ-butyrobetaine. With the aim at investigating the metabolic profile of such metabolites in most employed animal dietary sources, HPLC-ESI-MS/MS analyses on ruminant and non-ruminant milk and meat were performed. Results demonstrate, for the first time, the presence of δ-valerobetaine, occurring at levels higher than γ-butyrobetaine in all ruminant samples compared to non-ruminants. Demonstration of δ-valerobetaine metabolic origin, surprisingly, showed that it originates from rumen through the transformation of dietary N-trimethyllysine. These results highlight our previous findings showing the ubiquity of free N-trimethyllysine in vegetable kingdom. Furthermore, δ-valerobetaine, similarly to γ-butyrobetaine, can be degraded by host gut microbiota producing TMA, precursor of the proatherogenic trimethylamine N-oxide (TMAO), unveiling its possible role in the biosynthetic route of TMAO.
on Journal of agricultural and food chemistry
by Servillo L, D'Onofrio N, Neglia G, Casale R, Cautela D, Marrelli M, Limone A, Campanile G, Balestrieri ML
Ruminants' milk contains δ-valerobetaine originating from rumen through the transformation of dietary N-trimethyllysine. Among ruminant's milk, the occurrence of δ-valerobetaine, along with carnitine precursors and metabolites, has not been investigated in buffalo milk, the second most worldwide consumed milk, well-known for its nutritional value. HPLC-ESI-MS/MS analyses of bulk milk revealed that the Italian Mediterranean buffalo milk contains δ-valerobetaine at levels higher than those in bovine milk. Importantly, we detected also γ-butyrobetaine, the l-carnitine precursor, never described so far in any milk. Of interest, buffalo milk shows higher levels of acetylcarnitine, propionylcarnitine, butyrylcarnitine, isobutyrylcarnitine, and 3-methylbutyrylcarnitine (isovalerylcarnitine) than cow milk. Moreover, buffalo milk shows isobutyrylcarnitine and butyrylcarnitine at a 1-to-1 molar ratio, while in cow's milk this ratio is 5 to 1. Results indicate a peculiar short-chain acylcarnitine profile characterizing buffalo milk, widening the current knowledge about its composition and nutritional value.
on Biochimica et biophysica acta
by Servillo L, Castaldo D, Giovane A, Casale R, D'Onofrio N, Cautela D, Balestrieri ML
Ophthalmic acid (OPH), γ-glutamyl-L-2-aminobutyryl-glycine, a tripeptide analogue of glutathione (GSH), has recently captured considerable attention as a biomarker of oxidative stress in animals. The OPH and GSH biosynthesis, as well as some biochemical behaviors, are very similar. Here, we sought to investigate the presence of OPH in plants and its possible relationship with GSH, known to possess multiple functions in the plant development, growth and response to environmental changes.
on Food chemistry
by Servillo L, D'Onofrio N, Giovane A, Casale R, Cautela D, Ferrari G, Castaldo D, Balestrieri ML
We report the LC-ESI-MS/MS determination of betaines in commercial flours of cereals and pseudocereals most utilized in human nutrition. Results showed that glycine betaine, trigonelline, proline betaine, Nε-trimethyllysine were metabolites common to all examined flours, whereas an uncommon betaine, valine betaine, and glutamine betaine were present only in flours of barley, rye, oat, durum wheat, winter wheat, Triticum dicoccum and Triticum monococcum. Valine betaine and glutamine betaine, the latter never reported before in plants and animals, are not evenly distributed in the Poaceae family, but their presence or absence in flours depends on the subfamily to which the plant belongs. Interestingly, we also report for the first time the occurrence of pipecolic acid betaine (homostachydrine) and its precursor 1,2-N-methylpipecolic acid in rye flour. These two metabolites were not detected in any other cereal or pseudocereal flour, suggesting their potential role as markers of rye flour occurrence in cereal-based foods.
on Diabetology & metabolic syndrome
by Marfella R, Sardu C, Balestrieri ML, Siniscalchi M, Minicucci F, Signoriello G, Calabrò P, Mauro C, Pieretti G, Coppola A, Nicoletti G, Rizzo MR, Paolisso G, Barbieri M
No proper data on prognosis and management of type-2 diabetic ST elevation myocardial infarction (STEMI) patients with culprit obstructive lesion and multivessel non obstructive coronary stenosis (Mv-NOCS) exist. We evaluated the 12-months prognosis of Mv-NOCS-diabetics with first STEMI vs.to non-diabetics, and then Mv-NOCS-diabetics previously treated with incretin based therapy vs. a matched cohort of STEMI-Mv-NOCS never treated with such therapy.
on Diabetes, obesity & metabolism
by Marfella R, Sardu C, Calabrò P, Siniscalchi M, Minicucci F, Signoriello G, Balestrieri ML, Mauro C, Rizzo MR, Paolisso G, Barbieri M
There are insufficient data on the prognosis and management of people with type 2 diabetes who experience a non-obstructive coronary artery stenosis (NOCS)-non-ST-elevation myocardial infarction (NSTEMI) event. We evaluated the 12-month prognosis of patients with diabetes and NOCS (20%-49% luminal stenosis) who experience a first NSTEMI as compared with patients without diabetes. In addition, we investigated the 12-month prognosis in patients with diabetes and NSTEMI-NOCS previously treated with incretin-based therapy compared with a matched cohort of patients with NSTEMI-NOCS never treated with such therapy. We categorized the patients with diabetes as current incretin users (6 months' treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors) and non-users of incretins. The endpoint was all-cause mortality, cardiac death, recurrent acute coronary syndrome (ACS), and heart failure. The unadjusted Kaplan-Meier analysis, and a risk-adjusted hazard analysis showed that, all-cause mortality, cardiac death, readmission for ACS and heart failure rates during the 12-month follow-up were higher in patients with diabetes and NOCS-NSTEMI than in those with NOCS-NSTEMI without diabetes. Among the patients with diabetes, the current incretin users had a significantly lower rate of all-cause mortality, cardiac death and readmission for ACS at 12 months. In patients with type 2 diabetes and NOCS-NSTEMI, we observed a higher incidence of 1-year mortality and adverse cardiovascular outcomes, as compared with patients without diabetes with NOCS-NSTEMI. In people with diabetes, non-users of incretins had a worse prognosis than current incretin users.
on Cancer letters
by Bencivenga D, Caldarelli I, Stampone E, Mancini FP, Balestrieri ML, Della Ragione F, Borriello A
p27Kip1 is a cell cycle regulator firstly identified as a cyclin-dependent kinase inhibitor. For a long time, its function has been associated to cell cycle progression inhibition at G1/S boundary in response to antiproliferative stimuli. The picture resulted complicated by the discovery that p27Kip1 is an intrinsically unstructured protein, with numerous CDK-dependent and -independent functions and involvement in many cellular processes, such as cytoskeleton dynamics and cell motility control, apoptosis and autophagy activation. Depending on the cell context, these activities might turn to be oncogenic and stimulate cancer progression and metastatization. Nevertheless, p27Kip1 role in cancer biology suppression was underscored by myriad data reporting its down-regulation and/or cytoplasmic relocalization in different tumors, while usually no genetic alterations were found in human cancers, making the protein a non-canonical oncosuppressor. Recently, mostly due to advances in genomic analyses, CDKN1B, p27Kip1 encoding gene, has been found mutated in several cancers, thus leading to a profound reappraisal of CDKN1B role in tumorigenesis. This review summarizes the main p27Kip1 features, with major emphasis to its role in cancer biology and to the importance of CDKN1B mutations in tumor development.
on Free radical biology & medicine
by Servillo L, D'Onofrio N, Casale R, Cautela D, Giovane A, Castaldo D, Balestrieri ML
Ergothioneine (Egt), 2-mercapto-L-histidine betaine (ESH), is a dietary component acting as antioxidant and cytoprotectant. In vitro studies demonstrated that Egt, a powerful scavenger of hydroxyl radicals, superoxide anion, hypochlorous acid and peroxynitrite, protects vascular function against oxidative damages, thus preventing endothelial dysfunction. In order to delve the peculiar oxidative behavior of Egt, firstly identified in cell free-systems, experiments were designed to identify the Egt oxidation products when endothelial cells (EC) benefit of its protection against high-glucose (hGluc). HPLC-ESI-MS/MS analyses revealed a decrease in the intracellular GSH levels and an increase in the ophthalmic acid (OPH) levels during hGluc treatment. Interestingly, in the presence of Egt, the decrease of the GSH levels was lower than in cells treated with hGluc alone, and this effect was paralleled by lower OPH levels. Egt was also effective in reducing the cytotoxicity of H2O2 and paraquat (PQT), an inducer of superoxide anion production, showing a similar time-dependent pattern of GSH and OPH levels, although with peaks occurring at different times. Importantly, Egt oxidation generated not only hercynine (EH) but also the sulfonic acid derivative (ESO3H) whose amounts were dependent on the oxidative stress employed. Furthermore, cell-free experiments confirmed the formation of both EH and ESO3H when Egt was reacted with superoxide anion. In summary, these data, by identifying the EH and ESO3H formation in EC exposed to hGluc, highlight the cellular antioxidant properties of Egt, whose peculiar redox behavior makes it an attractive candidate for the prevention of oxidative stress-associated endothelial dysfunction during hyperglycemia.
on Antioxidants & redox signaling
by D'Onofrio N, Servillo L, Balestrieri ML
Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD+)-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged.
on Osteoarthritis and cartilage
by Longobardi L, Temple JD, Tagliafierro L, Willcockson H, Esposito A, D'Onofrio N, Stein E, Li T, Myers TJ, Ozkan H, Balestrieri ML, Ulici V, Loeser RF, Spagnoli A
We previously found in our embryonic studies that proper regulation of the chemokine CCL12 through its sole receptor CCR2, is critical for joint and growth plate development. In the present study, we examined the role of CCR2 in injury-induced-osteoarthritis (OA).