Epigenetics and Metabolism in Health and Disease

In the next 10 years, one billion people are estimated to suffer from disabling consequences of metabolic disorders, making them the number one noncommunicable disease on a global scale by 2030. Lots of risk factors such as dietary intake, lack of exercise and other life style behaviors are considered to play a role in the development of metabolic disorders. Despite the efforts that have been undertaken to unravel their potential causes, the underlying molecular mechanisms remain elusive. Evidence suggests that the pathogenesis involves changes on chromatin and chromatin-modifying enzymes, which can contribute to a persistent dysregulated metabolic phenotype. Indeed, a rising number of studies links epigenetic alterations with the diagnosis and prognosis of metabolic disorders. A prerequisite for exploiting these findings for pharmacological intervention is a detailed understanding of how differential epigenetic modifications control cell metabolism. In this mini review, we summarize the recent advances in uncovering the interplay between epigenetics and metabolic pathways on a cellular level and highlight potential new avenues for alternative treatment strategies

Epigenetics and Metabolism in Health and Disease

In the next 10 years, one billion people are estimated to suffer from disabling consequences of metabolic disorders, making them the number one noncommunicable disease on a global scale by 2030. Lots of risk factors such as dietary intake, lack of exercise and other life style behaviors are considered to play a role in the development of metabolic disorders. Despite the efforts that have been undertaken to unravel their potential causes, the underlying molecular mechanisms remain elusive. Evidence suggests that the pathogenesis involves changes on chromatin and chromatin-modifying enzymes, which can contribute to a persistent dysregulated metabolic phenotype. Indeed, a rising number of studies links epigenetic alterations with the diagnosis and prognosis of metabolic disorders. A prerequisite for exploiting these findings for pharmacological intervention is a detailed understanding of how differential epigenetic modifications control cell metabolism. In this mini review, we summarize the recent advances in uncovering the interplay between epigenetics and metabolic pathways on a cellular level and highlight potential new avenues for alternative treatment strategies

Oxidative enzymes of olive and olive oil: interaction with antioxidants

Olive oil is one of the oldest known vegetable oils. It is a product with major importance for the diet and the economy of Greece. One of its most important quality problems is oxidative rancidity due the oxidation of compounds and formation of new compounds. In this thesis a study of oxidative enzyme, peroxidase, of virgin olive oil and mature olive fruits, from which the oil is produced, is presented. Oxidative enzyme activities be transferred in virgin olive oil during the olive extraction process and thus they could affect the quality of the oil during storage. In this respect a partial characterization of peroxidase (POD) activity in greek oil producing olives (Olea europea, koroneiki variety) has been undertaken and the presence of this enzyme activity in virgin olive oil samples was confirmed. Active POD extracts were obtained using insoluble poly(vinylpyrrolidone) in 50 mM phosphate, pH 6.0 and further purified by ammonium sulphate fractionation and Sephacryl gel permeation chromatography. Olive fruit POD showed a molecular mass of 44 ± 1.4 kDa. SDS-PAGE analysis of the gel filtration peaks showing POD activity under reducing conditions revealed that the low MW POD activity peak shows a major protein band of 43.7 kDa suggesting that POD studied in the present thesis is composed by a single polypeptide chain. POD of olives expressed catalytic activity with ABTS (2,2΄-azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid)), DMPD (N,N-dimethyl-p-phenylenediamine) and some phenolic substrates of olives and olive oils (protocatechuic, gallic and caffeic acid). However the enzyme was found ineffective with oleuropein, the major polyphenol of olives, as well as with coumaric, ferulic, ascorbic p-hydroxy benzoic acid (monophenolic substarates). pH optimum of the peroxidase-catalyzed oxidation was depended on the substrate used and it was varied from 4.0 to 6.0. The enzyme retained full activity when stored for 1-2 months at -18 oC in presence of glycerol 50% (v/v). For each substrate examined, Km and Vmax values have been determined. Accordingly, we observed that the efficiency of olives POD catalysis depends strongly on the chemical nature of the substrate oxidized. From the Arrhenius plot, the activation energy was estimated 37.9 kJ / mol. Activity assays at different temperature, 30- 60 oC, indicated a significant catalytic efficiency of the enzyme. Olive peroxidase shows significant thermal stability. The addition of SDS decreased the peroxidase activity of olives, therefore olive peroxidase is probably present in a soluble form. Moreover, we found that oleuropein, 4-methyl catechol and SDS drastically inhibited ABTS peroxidation by the olives POD preparation with an IC50 value of 47 μM 22 and 218 μM, respectively. Oleuropein is the bitter secoiridoid polyphenolic glucoside acts as free radical scavenger and inhibits free radical production. Sample of virgin olive oils have been also examined for the presence of proteins and peroxidase activity. The peroxidase activity corresponds to molecules with protein nature, as releaved by experiments of thermal inactivation and proteolysis. ........................Το ελαιόλαδο είναι ένα από τα αρχαιότερα φυτικά έλαια και αποτελεί ένα προϊόν με μέγιστη σημασία στη διατροφή και στην οικονομία της Ελλάδας. Το σημαντικότερο ίσως πρόβλημα της ποιότητας του είναι το οξειδωτικό τάγγισμα που οφείλεται στην οξείδωση κάποιων από τα συστατικά του και οδηγεί στο σχηματισμό νέων ανεπιθύμητων ενώσεων. Στην παρούσα διατριβή έγινε μελέτη του οξειδωτικού ενζύμου, υπεροξειδάση, σε ελαιοκάρπους, που αποτελούν την πρώτη ύλη παραγωγής του ελαιολάδου, και στο ίδιο το ελαιόλαδο. Οι δραστικότητες των οξειδωτικών ενζύμων, οι οποίες μπορούν να μεταφερθούν στο παρθένο ελαιόλαδο κατά την παραλαβή του από τους ελαιοκάρπους μπορούν να επηρεάσουν δραστικά την ποιότητα του παρθένου ελαιολάδου κατά την αποθήκευσή του. Γι αυτό το λόγο πραγματοποιήθηκε καθαρισμός του ενζύμου υπεροξειδάση και στη συνέχεια μερικός χαρακτηρισμός της ενζυμικής του δραστικότητας από μία ποικιλία ελαιοκάρπων (Olea europaea, ποικιλία Κορωνέικη), η οποία χρησιμοποιείται ευρύτατα στην Ελλάδα για την παραγωγή ελαιολάδου. Επιπλέον επιβεβαιώθηκε και η παρουσία της υπεροξειδάσης σε δείγματα παρθένου ελαιολάδου. Ενεργά εκχυλίσματα υπεροξειδάσης προέκυψαν αρχικά με απλή εκχύλιση τους από ελαιοκάρπους, παρουσία PVP (πολυβινυλοπυρρολιδόνη) σε 50 mM ρυθμιστικού διαλύματος φωσφορικών, pH 6.0 και στη συνέχεια με επιπλέον καθαρισμό με κατακρήμνιση με θειικό αμμώνιο. Στη συνέχεια η υπεροξειδάση διαχωρίστηκε με χρωματογραφία μοριακού ηθμού σε στήλη Sephacryl S-300 και υπολογίστηκε το μοριακό της βάρος σε 44 ± 1.4 kDa. Ηλεκτροφόρηση σε πηκτή πολυακρυλαμιδίου, παρουσία SDS, έδειξε μία κύρια πρωτεϊνική ζώνη 43.7 kDa δείχνοντας ότι η POD από ελιές αποτελείται από μια πολυπεπτιδική αλυσίδα. Η καταλυτική δραστικότητα της υπεροξειδάσης από ελαιοκάρπους εκφράστηκε χρησιμοποιώντας τα συνθετικά υποστρώματα ABTS (2,2-άζινο δις-(3-αιθυλβενζοθειαζολίνη-6-σουλφονικό οξύ), DMPD (N,N-διμεθυλο-p-φαινυλοδιαμίνη) και κάποια φαινολικά υποστρώματα που απαντώνται στις ελιές και στο ελαιόλαδο, όπως το πρωτοκατεχοϊκό, γαλλικό και καφεϊκό οξύ, αλλά και τη 4 μέθυλο κατεχόλη που απαντάται στα απόβλητα της ελαιουργίας. Ωστόσο το ένζυμο δεν ήταν ενεργό έναντι της ελευρωπαΐνης, κύριας πολυφαινόλης των ελαιοκάρπων, όπως επίσης και έναντι όλων των μονοφαινολικών ενώσεων που μελετήθηκαν, όπως κουμαρικό, φερουλικό, ασκορβικό και p-ύδροξυ βενζοϊκό οξύ. Το βέλτιστο pH της αντίδρασης που καταλύει η υπεροξειδάση εξαρτάται από το χρησιμοποιούμενο υπόστρωμα και κυμαίνεται μεταξύ των τιμών 4.0 και 6.0. Το ένζυμο διατήρησε την δραστικότητα του όταν αποθηκεύτηκε για 1-2 μήνες στους -18 oC, παρουσία 50 % (v/v) γλυκερόλης. Για το κάθε υπόστρωμα που εξετάστηκε υπολογίστηκαν εκτός από το βέλτιστο pH και οι τιμές των κινητικών χαρακτηριστικών, Km και Vmax. Σύμφωνα με τα παραπάνω, παρατηρήθηκε ότι η αποτελεσματικότητα της υπεροξειδάσης ως καταλύτης εξαρτάται σε μεγάλο βαθμό από τη χημική δομή του υποστρώματος που καταλύει. Χρησιμοποιώντας το διάγραμμα Arrhenius, υπολογίστηκε η ενέργεια ενεργοποίησης, 37.9 kJ / mol. Μελέτη της κινητικής της σε θερμοκρασίες 30- 60 oC, έδειξε ότι το ένζυμο είναι θερμοανθεκτικό. ......................

Traitement des kératoses actiniques : l’embarras du choix

Actinic keratoses are the most frequent precancerous lesions on Caucasian skin, often giving rise to squamous cell carcinomas. Appropriate prophylaxis, screening, and early intervention can substantially reduce the incidence of the latter. While isolated actinic keratoses can easily be treated by means of cryotherapy or curettage, multiple lesions often occurring on chronically sun-damaged skin demand more potent therapeutic strategies, such as topical cytostatic or immunomodulatory drugs, or photodynamic therapy. In this review, we give a practice-oriented overview on clinical manifestations, prevention, and treatment of actinic keratoses, and we emphasise the role of general practitioners in the management of this important pathology

Ingenol Mebutate for Recalcitrant Chronic Actinic Cheilitis

We present the case of a healthy 76-year-old man with a whitish, hyperkeratotic lesion of the lower lip diagnosed as actinic cheilitis (AC) previously treated with classic red light photodynamic therapy 5 years ago. Initial treatment with 5% imiquimod cream - also with intensified application - failed. After 2 cycles thrice daily, consecutive applications of 150 μg/g ingenol mebutate gel at 3 weeks' interval, the lesions cleared completely. Surprisingly, no pustular or crusting reaction or other side effect occurred contrary to expectation. Remission was stable for 10 months, when recurrence occurred. Ingenol mebutate proved to be a feasible and safe treatment in this otherwise refractory case of AC

Survival outcomes and epidemiology of Merkel cell carcinoma of the lower limb and hip: A Surveillance, Epidemiology, and End Results analysis 2000-2018

Background: Merkel cell carcinoma of lower limb and hip skin is a rare skin tumor that has a high recurrence rate. Objective: To assess epidemiology and survival outcomes of the lower limb and hip Merkel cell carcinoma, which are less addressed in the literature. Methods: The Surveillance, Epidemiology, and End Results database was searched for all cases of skin Merkel cell carcinoma between 2000 and 2018. Demographic and clinicopathologic features were compared between lower limb and other skin localizations using the t test or χ2 test. The overall survival (OS) of lower limb Merkel cell carcinoma was calculated using the Kaplan-Meier method. Subgroups were compared using the log rank test. Multivariate cox regression was used to identify independent prognostic factors. Results: In total, 976 patients were identified. The mean age was 72.7 years. The median OS was 68 months, better than that of other localizations. Older age, regional lymph node, and distant metastasis were associated with low OS. Surgery with &gt;1-cm margins, when associated with radiotherapy, had the best OS. Age, tumor size, lymph node status, presence of metastasis, and treatment sequence were identified as independent prognostic factors. Conclusion: Lower limb and hip Merkel cell carcinomas have better OS than tumors in other skin localizations. In this dataset, the best OS was ensured using surgery with &gt;1-cm margins and adjuvant radiotherapy.</p

Surinfection de plaie chronique par Pseudomonas aeruginosa

Pseudomonas aeruginosa (PA) is a Gram-negative germ, responsible for severe infections. PA infected chronic wounds are a clinically highly relevant topic. PA has a natural resistance to many antibiotics, and there is no consensus on a first-line antibiotic to be used. In the context of chronic ulcers with an unfavorable evolution, we suggest intravenous antibiotic therapy, ideally on an in-patient basis. Given the sparse evidence from clinical trials, we heavily rely on clinical experience when it comes to managing chronic ulcers infected with PA

Rintala Flap and Posterior Perichondrial Cutaneous Graft: A Combined Approach for Nasal Tip Reconstruction

Nasal tip reconstruction requires a meticulous approach due to the complexity of the nasal anatomy and its aesthetic importance. Many procedures have been described to restore this aesthetic unit, including the paramedian forehead flap, which is one of the workhorse flaps. However, despite excellent final outcomes, this procedure may be refused by patients, due to its temporary conspicuous appearance possibly associated with serious psychological implications, and the need of multiple interventions. We aimed to present an approach combining the Rintala flap and the posterior perichondrial cutaneous graft as a valuable alternative to treat large nasal tip defects