Comparative antilipidemic effect of N-acetylcysteine and sesame oil administration in diet-induced hypercholesterolemic mice

<p>Abstract</p> <p>Background</p> <p>There is an increasing number of novel antilipidemic therapies under consideration. The putative hypolipidemic effect of N-acetylcysteine (NAC) and sesame oil was studied in a mouse model of dietary-induced hypercholesterolemia.</p> <p>Methods</p> <p>Male C57bl/6 mice were assigned to the following groups: (NC) control group, (HC) group receiving test diet supplemented with 2% cholesterol and 0.5% cholic acid for 8 weeks, (HCN) group receiving the test diet with NAC supplementation (230 mg/kg p.o.) and (HCS) group fed the test diet enriched with 10% sesame oil. Total serum cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were assayed at the beginning and at the end of the experiment. Total peroxides and nitric oxide (NO) levels were measured in the serum at the end of the experiment. Hepatic and aortic lesions were evaluated by haematoxylin-eosin staining.</p> <p>Results</p> <p>Higher serum levels of total and LDL-cholesterol were recorded in all groups fed the high cholesterol diet. The HCN group presented reduced lipid levels compared to HC and HCS groups. No differences were observed between HCS and HC groups. Peroxide content in serum was markedly increased in mice consuming high cholesterol diet. NAC and sesame oil administration led to a significant decrease of serum lipid peroxidation in the levels of control group, whereas only NAC restored NO bioavailability. In terms of liver histology, the lesions observed in HCN group were less severe than those seen in the other high cholesterol groups.</p> <p>Conclusion</p> <p>Co-administration of NAC, but not sesame oil, restored the disturbed lipid profile and improved hepatic steatosis in the studied diet-induced hypercholesterolemic mice. Both agents appear to ameliorate serum antioxidant defense.</p

Correlation between mesenteric fat thickness and serum apolipoproteins in patients with peripheral arterial occlusive disease

BACKGROUND: Visceral fat possesses the most detrimental potential for cardiovascular morbidity through the release of adipokines, as well as metabolic and proinflammatory mediators, which adversely affect metabolic and vascular homeostasis. Among the different types of visceral adipose tissue, mesenteric fat is considered particularly detrimental, due to its close proximity to the portal circulation, affecting directly the liver, which is the main regulator of body metabolic homeostasis. Mesenteric fat can be reliably estimated using abdominal ultrasonography, the only available imaging method able to depict individual mesenteric leaves. Aim of the present study was to investigate the correlation of mesenteric fat thickness (MFT) with serum apolipoprotein levels in patients undergoing digital subtraction angiography in a single center. METHODS: 35 male patients with peripheral arterial disease were examined. After careful examination of the periumbilical area, the mesenteric leaves were identified. The maximal distance between each pair of sequential leaves was measured, and the mean value of the three thickest leaves was determined as the mesenteric fat thickness. Six apolipoprotein fasting serum concentrations were measured using a Luminex proteomics platform (xMAP Multiplex immunoassay): apolipoprotein A-I (apoAI), apolipoprotein A-II (apoAII), apolipoprotein B (apoB), apolipoprotein C-II (apoCII), apolipoprotein C-III (apoCIII) and apolipoprotein E (apoE). RESULTS: MFT correlated with apoAII and apoB serum concentrations. The correlations with apoAII and apoB remained significant following correction for BMI. No correlations were noted between MFT and serum apoAI, apoCII, apoCIII or apoE levels before or after adjustment for BMI. CONCLUSIONS: Our study indicates that MFT is significantly correlated with the concentration of atherogenic low density lipoproteins particles, as well as with apoAII, a determinant of free fatty acids levels. No correlation was observed between mesenteric fat thickness and very low density lipoprotein or chylomicron particles concentration

Comparative study of the impact of the antioxidant N-acetylcysteine (NAC) and of sesame oil in an experimental model of hyperlipidaemia

High blood cholesterol is considered to be one of the major risk factors for coronary heart disease. Clinical and experimental studies strongly correlate hypercholesterolemia to increased oxidative stress. Cardiovascular aberrations are significantly impacted by stressful situations. The activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in response to disruptions of homeostasis, or stressors, resulting in an increase of circulating glucocorticoids. Glucocorticoid receptors (GR) mediate the effects of adrenal steroids both in the peripheral organs and the brain. High fat diets are referred to increase basal HPA axis activity and influence the central stress response. Apart from regulating stress response, glucocorticoids control metabolic resources and are causatively linked to the metabolic syndrome. Much attention has been paid recently in the use of more natural and costeffective treatments which could efficiently replace the common hypolipidemic pharmaceutical agents without side effects. Nutraceuticals and functional foods have attracted great scientific interest mainly during the last decades. Although the epidemiological relationship between hypercholesterolemia and cardiovascular disease is less prominent in elderly than in younger, it is essential to achieve risk reduction both in elderly and old patients. This study investigated the action of N-acetylcysteine (NAC) and sesame oil in the lipidemic status and liver architecture of diet-induced hypercholesterolemic young and middle-aged mice. Since cardiovascular health is also endangered by stress, the impact of cholesterol enriched diet and the potential influence of NAC and sesame oil on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in the middle-aged mice. Young (3 months) and middle-aged (8 months) mice C57/bl6 were assigned to the following groups; control group, group receiving test diet supplemented with 2% cholesterol and 0.5% cholic acid, group receiving the test diet with N-acetylcysteine supplementation (230 mg/kg p.o.), group receiving test diet enriched with 10% sesame oil. Concerning midlle-aged mice two additional groups were studied; group receiving control diet with N-acetylcysteine supplementation and group fed control diet enriched with sesame oil. After 8 weeks of treatment, serum lipids, hepatic enzymes, lipid peroxidation and nitric oxide levels were determined. Plasma corticosterone levels and hypothalamic glucocorticoid receptor (GR) levels were measured in middle-aged mice. Hepatic, heart and aortic lesions of all animals were evaluated by hematoxylin-eosin staining. N-acetylcysteine co-administration improved the diet induced disturbed lipid profile, led to a significant decrease of lipid peroxidation and restored nitric oxide bioavailability in both young and middle-aged mice. Sesame oil presented antioxidant properties and restored nitric oxide levels only in young mice. N-acetylcysteine had beneficial activity concerning alkaline phosphatase (ALP) levels only in middle-aged mice. Concerning liver steatosis, the young N-acetylcysteine treated mice, receiving cholesterol diet, maintained the normal liver histology, whereas as far as the middle-aged mice, the histological lesions observed in the N-acetylcysteine treated group were less severe than those seen in the other cholesterol-fed groups. High cholesterol feeding in middle-aged mice resulted in increased hypothalamic GR levels. N-acetylcysteine reversed this effect. In conclusion, N-acetylcysteine co-administration enhances antioxidant capacity ameliorating serum lipid status and hepatic histopathology in young and middle-aged mice being more beneficial especially for the younger experimental animals. In addition, this antioxidant agent presents vasoprotective action by means of increased nitric oxide bio-availability. Although sesame oil exhibits antioxidant and antiatherogenic activities depending on the age of mice, its potential beneficial hypolipidemic activity is inhibited when this oil is added in a hypercholesterolemic diet without other fat substitution. However, its administration in normolipidemic mice at a level of 10% does not disturbe their lipidemic status. Finally, a diet enriched in cholesterol and cholic acid can alterate the HPA axis homeostasis of middle-aged mice. N-acetylcysteine reverses this effect and this action is probably correlated to its hypolipidemic properties.Τα υψηλά επίπεδα χοληστερόλης στο αίμα αποτελούν έναν από τους σημαντικότερους παράγοντες κινδύνου για την εμφάνιση της στεφανιαίας νόσου. Ποικίλες πειραματικές και κλινικές μελέτες συσχετίζουν την υπερχοληστερολαιμία με το αυξημένο οξειδωτικό stress. Η μη φυσιολογική λειτουργία του καρδιαγγειακού συστήματος σχετίζεται άλλωστε σημαντικά με τις καταστάσεις stress. Η ενεργοποίηση του άξονα Υποθαλάμου-Υπόφυσης-Επινεφριδίων (ΥΥΕ) απαντάται σε διαταραχές της ομοιόστασης ή κατα την επίδραση στρεσσικών παραγόντων, με συνέπεια την αύξηση των επιπέδων γλυκοκορτικοειδών στην κυκλοφορία. Οι υποδοχείς γλυκοκορτικοειδών (glucocorticoid receptors - GR) αναφέρεται ότι αποτελούν μεσολαβητές για τα αποτελέσματα των στεροειδών των επινεφρίδιων, στα περιφερικά όργανα και στον εγκέφαλο. Η πλούσια σε λιπαρά διατροφή επηρεάζει την βασική δραστηριότητα του άξονα ΥΥΕ και επιδρά στην κεντρική απάντηση στο stress. Tα γλυκοκορτικοειδή, πέρα από τη ρύθμιση της απάντησης στο stress, εμπλέκονται στην ρύθμιση των ενεργειακών αποθεμάτων και συνδέονται με το μεταβολικό σύνδρομο. Ιδιαίτερη προσοχή δίνεται τελευταία, στη χρήση περισσότερο φυσικών και πιο οικονομικών παραγόντων, που θα μπορούσαν να αντικαταστήσουν αποτελεσματικά τους κοινούς υπολιπιδαιμικούς φαρμακευτικούς παράγοντες, χωρίς να εμφανίζουν παρενέργειες. Η «διατροφοφαρμακευτική» και τα «λειτουργικά τρόφιμα» έχουν προσελκύσει μεγάλο επιστημονικό ενδιαφέρον, κυρίως κατά τις τελευταίες δεκαετίες. Αν και η επιδημιολογική σχέση μεταξύ της υπερχοληστερολαιμίας και των παθήσεων στο καρδιαγγειακό είναι λιγότερο έντονη στα ηλικιωμένα άτομα σε σχέση με τους νέους, είναι ουσιαστικό να επιτευχθεί μείωση κινδύνου εμφάνισης της νόσου πέρα από τους νέους, στα μέσης αλλά και μεγάλης ηλικίας άτομα. Η παρούσα μελέτη ερευνά τη δράση της ουσίας N-acetylcysteine (NAC) και του σησαμέλαιου στο λιπιδαιμικό προφίλ, την αντιοξειδωτική ικανότητα και την αρχιτεκτονική δομή του ήπατος υπερχοληστερολαιμικών, λόγω διατροφής, νέων και μέσης ηλικίας μυών. Δεδομένου ότι η καρδιαγγειακή λειτουργία συνδέεται άμεσα με καταστάσεις stress, μελετήθηκε επιπλέον η επίδραση της εμπλουτισμένης με χοληστερόλη διατροφής στον ΥΥΕ άξονα, σε μέσης ηλικίας μύες και ο πιθανός ρόλος που μπορεί να έχουν η ουσία N-acetylcysteine και το σησαμέλαιο στον άξονα αυτό. Αρσενικοί μύες C57bl/6, ηλικίας 3 και 8 μηνών, χωρίστηκαν στις ακόλουθες ομάδες ανά ηλικία: oμάδα control, ομάδα στην οποία χορηγούνταν δίαιτα ενισχυμένη με χοληστερόλη 2% και χολικό οξύ 0.5% (test diet) για διάστημα 8 εβδομάδων, ομάδα στην οποία χορηγούνταν test diet και παράλληλα στο πόσιμο νερό η ουσία N-acetylcysteine (230 mg/kg ΣΒ) για διάστημα 8 εβδομάδων, ομάδα στην οποία χορηγούνταν test diet ενισχυμένη με σησαμέλαιο σε ποσοστό 10%, για διάστημα 8 εβδομάδων. Στους μύες ηλικίας 8 μηνών υπήρχαν δύο επιπλέον ομάδες; η ομάδα που ελάμβανε φυσιολογική δίαιτα και παράλληλα στο πόσιμο νερό την ουσία N-acetylcysteine και η ομάδα που ελάμβανε φυσιολογική δίαιτα, ενισχυμένη με σησαμέλαιο. Οκτώ εβδομάδες μετά, προσδιορίστηκε η λιπιδαιμική εικόνα των ζώων, τα επίπεδα των ολικών υπεροξειδίων, των οξειδίων αζώτου και των ηπατικών ενζύμων του ορού τους. Τα επίπεδα κορτικοστερόνης πλάσματος και τα επίπεδα πρωτεϊνικών υποδοχέων των γλυκοκορτικοειδών (GR) στον υποθάλαμο, μετρήθηκαν στα μέσης ηλικίας πειραματόζωα. Η ιστολογική εικόνα του ήπατος, της καρδιάς και της αορτής των ζώων, αξιολογήθηκαν έπειτα από χρώση με αιματοξυλίνη ηωσίνη. Η χορήγηση N-acetylcysteine βελτίωσε την διαταραγμένη, λόγω διατροφής, λιπιδαιμική εικόνα των ζώων, οδήγησε σε σημαντική μείωση των ολικών υπεροξειδίων και αποκατέστησε τη βιοδιαθεσιμότητα οξειδίων αζώτου, τόσο στους νέους όσο και στους μέσης ηλικίας μύες. Το σησαμέλαιο παρουσίασε αντιοξειδωτική δράση και αύξησε την βιοδιαθεσιμότητα οξειδίων αζώτου, μόνο στους μικρής ηλικίας μύες. Η ουσία N-acetylcysteine έδειξε ευεργετική δραστηριότητα σχετικά με τα επίπεδα αλκαλικής φωσφατάσης (ALP) στον ορό, μόνο στα μέσης ηλικίας πειραματόζωα. Αναφορικά με την ιστολογική εικόνα στο ήπαρ, οι μύες μικρής ηλικίας που ελάμβαναν N-acetylcysteine παράλληλα με την υπερχοληστερολαιμική δίαιτα, διατήρησαν συνολικά φυσιολογική ιστολογική εικόνα στο ήπαρ, ενώ στους μέσης ηλικίας μύες, οι ιστολογικές αλλοιώσεις στεάτωσης που παρατηρήθηκαν στο ήπαρ στη ομάδα που χορηγούνταν Nacetylcysteine, ήταν λιγότερο σοβαρές, συγκριτικά με τις λοιπές ομάδες που ελάμβαναν υπερχοληστερολαιμική δίαιτα. Η ενισχυμένη με χοληστερόλη και χολικό οξύ δίαιτα, στα μέσης ηλικίας πειραματόζωα, οδήγησε σε αυξημένη πρωτεϊνική έκφραση GR στον υποθάλαμο. Η ουσία N-acetylcysteine αντέστρεψε αυτήν την κατάσταση. Συμπερασματικά, η χορήγηση N-acetylcysteine, μέσω ενδεχομένως της αντιοξειδωτικής της δράσης, βελτιώνει την διαταραγμένη λιπιδαιμική εικόνα, αποκαθηστώντας την ηπατική ιστοπαθολογία στους μικρής και μέσης ηλικίας μύες, και μάλιστα η δράση της είναι ευεργετικότερη ειδικά για τα νεαρά πειραματόζωα. Επιπλέον, αυτός ο αντιοξειδωτικός παράγοντας παρουσιάζει αντιαθηρογόνο δράση που σχετίζεται με την αύξηση στη βιοδιαθεσιμότητα οξειδίων του αζώτου. Παρά το ότι το σησαμέλαιο μπορεί να δράσει αντιοξειδωτικά ή αγγειοπροστατευτικά (ανάλογα με την ηλικία των μυών), η ενδεχόμενη ευεργετική υπολιπιδαιμική δραστηριότητά του, φαίνεται ότι παρεμποδίζεται όταν προστίθεται σε μια δίαιτα ενισχυμένη σε χοληστερόλη, χωρίς να έχει γίνει κάποια υποκατάσταση στα λιπαρά της, κατα την προσθήκη του ελαίου. Εντούτοις, η ενίσχυση της φυσιολογικής δίαιτας μυών με σησαμέλαιο σε επίπεδο 10% δεν μεταβάλλει τη λιπιδαιμική τους εικόνα. Τέλος η ενισχυμένη με χοληστερόλη και χολικό οξύ δίαιτα μπορεί να επηρεάσει την ομοιοστασία του ΥΥΕ άξονα στους μέσης ηλικίας μύες και η ουσία N-acetylcysteine αντιστρέφει αυτήν την επίδραση, πιθανώς μέσω της υπολιπιδαιμικής της ικανότητας

An explanation of the pathophysiology of adverse neurodevelopmental outcomes in iron deficiency

Iron deficiency (ID) is a major public health problem worldwide among children aged 0-12 months. Several factors seem to contribute to the iron-deficient state in infancy, including insufficient antenatal and neonatal iron supplementation, exclusive breastfeeding, and early umbilical cord clamping after birth. The most concerning complications of ID, except for anemia, are related to altered long-term neurodevelopment. Clinical studies have shown a negative impact of ID anemia on fetal and neonatal behavior including impairments of motor maturity, autonomic response, memory/learning, and mood. ID-induced defects during infancy seem to persist later in life, even after ID treatment. The underlying mechanisms involve dysfunctional myelination, neuro-transmission alterations, and altered synaptogenesis and/or dendritogenesis. The purpose of the present review is to summarize these mechanisms and to provide recommendations for future clinical research in the field

Comparative antilipidemic effect of N-acetylcysteine and sesame oil administration in diet-induced hypercholesterolemic mice

Background: There is an increasing number of novel antilipidemic therapies under consideration. The putative hypolipidemic effect of N-acetylcysteine (NAC) and sesame oil was studied in a mouse model of dietary-induced hypercholesterolemia. Methods: Male C57bl/6 mice were assigned to the following groups: (NC) control group, (HC) group receiving test diet supplemented with 2% cholesterol and 0.5% cholic acid for 8 weeks, (HCN) group receiving the test diet with NAC supplementation (230 mg/kg p.o.) and (HCS) group fed the test diet enriched with 10% sesame oil. Total serum cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were assayed at the beginning and at the end of the experiment. Total peroxides and nitric oxide (NO) levels were measured in the serum at the end of the experiment. Hepatic and aortic lesions were evaluated by haematoxylin-eosin staining. Results: Higher serum levels of total and LDL-cholesterol were recorded in all groups fed the high cholesterol diet. The HCN group presented reduced lipid levels compared to HC and HCS groups. No differences were observed between HCS and HC groups. Peroxide content in serum was markedly increased in mice consuming high cholesterol diet. NAC and sesame oil administration led to a significant decrease of serum lipid peroxidation in the levels of control group, whereas only NAC restored NO bioavailability. In terms of liver histology, the lesions observed in HCN group were less severe than those seen in the other high cholesterol groups. Conclusion: Co-administration of NAC, but not sesame oil, restored the disturbed lipid profile and improved hepatic steatosis in the studied diet-induced hypercholesterolemic mice. Both agents appear to ameliorate serum antioxidant defense

A Novel Experimental Model of Colorectal Endometriosis

Purpose: Endometriosis is a disease that affects 6–10% of the female population, mainly women of reproductive age, and causes a variety of cyclic symptoms. Deep infiltrating endometriosis and in particular bowel involvement presents a challenge for modern surgery. To date, there are no experimental animal models in this field, demonstrating experimental induction of endometriosis directly attached to surface of the colon imitating human colorectal endometriosis; hence, the implementation of novel pharmaceutical and surgical strategies for the management of colorectal endometriosis is mainly limited to clinical studies. Aim of the study: To investigate whether induction of colorectal endometriotic lesions in is feasible in rats. Materials and Methods: Twenty, female, adult, non-pregnant Sprague Dawley rats sustained uterine horn resection, which was then placed around the rectum of the rat with the endometrial surface in direct contact with the bowel serosa and approximated in the serosal surface of the colon with two sutures. Results: Two weeks following, surgery rats were euthanized and the bowel was surgically explored. The presence of a cystic lump at the site of the surgical intervention was evaluated macroscopically and microscopically. Histopathology documented the presence of cystic endometriosis. The endometriotic focus was adherent to the bowel wall by large fibrous nodules with concomitant replacement of part of the outer longitudinal muscle layer. Conclusions: The findings of our study support that the proposed experimental model of colorectal endometriosis is feasible, easily reproducible and may be implemented in future research in this field

Metabolic Response of Adult Male Offspring Rats to Prenatal Caffeine Exposure

Caffeine is the most widely consumed psychoactive substance, with recommendations from health associations and regulatory bodies for limiting caffeine consumption during pregnancy being increasingly common. Prenatal exposure to caffeine has been shown to increase the risk of developing abnormalities in lipid metabolism in adult life. We further investigated the effect of prenatal caffeine exposure (PCE) (20 mg/kg of body weight) on the metabolic “reserve” of male Sprague Dawley offspring fed on a high fructose diet in adult life. Male adult PCE offspring were assigned to four groups; Nw and Nf: offspring of control mothers (N group of mothers), having received tap water or high fructose water respectively; Cw and Cf: offspring exposed to caffeine during gestation (C group of mothers) and receiving tap water or a high fructose water solution, respectively. Cf rats presented increased scrum triglyceride level, as well as raised systolic and diastolic blood pressure levels, together with extensive renal tissue oedema in adulthood, compared to the other groups (p&lt;0.05 for all comparisons). These findings show further evidence for potential detrimental metabolic effects of prenatal caffeine exposure during adulthood in this animal model