ApoE-deficient mice and fenritinide: a structural study of the skin

Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance and the plasma lipid profile, and to reduce body fat mass. Since these effects, together with its ability to inhibit ceramide synthesis, have suggested that fenretinide may display anti-atherosclerotic effects, the purpose of our work was to evaluate the effect of fenretinide on accumulation of lipids on the skin of a dyslipidemic mouse model that spontaneously develops atherosclerosis. To this aim, 9-weeks-old apoE-knockout (EKO) female mice were fed for 12 weeks with a Western diet, without (control) or with (0.1% w/w) fenretinide. At sacrifice, skin biopsies were excised from the thoracic region, dissected in smaller fragments and processed for structural morphology analysis on both paraffin and semithin sections. As a reference, wild-type (WT) mice were likewise treated. Morphological analysis did not show any significant difference between the skin of treated and untreated WT mice. In both the experimental groups, indeed, the epidermis appeared build-up of ordinated overlapped layers of cells and in the dermis there were no signs of alteration. The presence of foam cells was detected only in EKO mice treated and untreated. Other morphological alterations were also visible, although shared almost equally in EKO-Ctrl and EKO-Fen animals. Our data suggest that fenretinide slightly interferes with lipid accumulation in the skin of EKO mice

The presence of dominant follicles and corpora lutea does not perturb response to controlled ovarian stimulation in random start protocols

The advent of random start protocols to shorten the time needed to store oocytes in women with malignancies has represented an important improvement in the field of fertility preservation. However, Randomized Controlled Trials are difficult to implement in this area and available evidence that supports this approach remains modest. To shed more light on this issue, we compared the follicular development between the ovary carrying the dominant follicle or the corpus luteum and the contralateral resting ovary in 90 women who underwent random start controlled ovarian stimulation (COS). In fact, ovarian response did not differ between the two ovaries. Subgroup analyses according to the phase of the cycle at the initiation of COS, the type of malignancy, the use of letrozole and the magnitude of the ovarian response did not allow to identify any condition showing a difference in the follicular response between the active and the resting ovaries. In conclusion, follicular growth does not seem to be perturbed by the presence of a dominant follicle or a corpus luteum

Nutraceuticals and bioactive components from fish for dyslipidemia and cardiovascular risk reduction

Cardiovascular disease remains the most common health problem in developed countries, and residual risk after implementing all current therapies is still high. Permanent changes in lifestyle may be hard to achieve and people may not always be motivated enough to make the recommended modifications. Emerging research has explored the application of natural food-based strategies in disease management. In recent years, much focus has been placed on the beneficial effects of fish consumption. Many of the positive effects of fish consumption on dyslipidemia and heart diseases have been attributed to n-3 polyunsaturated fatty acids (n-3 PUFAs, i.e., EPA and DHA); however, fish is also an excellent source of protein and, recently, fish protein hydrolysates containing bioactive peptides have shown promising activities for the prevention/management of cardiovascular disease and associated health complications. The present review will focus on n-3 PUFAs and bioactive peptides effects on cardiovascular disease risk factors. Moreover, since considerable controversy exists regarding the association between n-3 PUFAs and major cardiovascular endpoints, we have also reviewed the main clinical trials supporting or not this association

Effects of Vegetable Proteins on Hypercholesterolemia and Gut Microbiota Modulation

Risk assessment tools, i.e., validated risk prediction algorithms, to estimate the patient\u2019s 10-year risk of developing cardiovascular disease (CVD) should be used to identify high-risk people for primary prevention. Current evidence confirms that appropriate monitoring and control of risk factors either reduces the likelihood of CVD or slows down its progression. It is thus crucial that all health professionals make appropriate use of all the available intervention strategies to control risk factors: from dietary improvement and adequate physical activity to the use of functional foods, food supplements, and drugs. The gut microbiota, which encompasses 1 7 1014 resident microorganisms, has been recently recognized as a contributing factor in the development of human disease. This review examines the effect of both some vegetable food components belong to the \u201cprotein food group\u201d and the underexploited protein-rich hempseed on cholesterolemia and gut microbiota composition

Magnetic Resonance Imaging Visualization of Vulnerable Atherosclerotic Plaques at the Brachiocephalic Artery of Apolipoprotein E Knockout Mice by the Blood-pool Contrast Agent B22956/1

The aim of this study was to identify, by magnetic resonance imaging (MRI), the ability of the blood-pool contrast agent B22956/1 to detect atherosclerotic plaques developing at the brachiocephalic artery of apolipoprotein E knockout (apoE-KO) mice and to possibly identify vulnerable atherosclerotic lesions. After high-fat feeding for 8 or 12 weeks, MRIs of brachiocephalic arteries were acquired before and after B22956/1 administration; then vessels were removed and analyzed by histology. B22956/1 injection caused a rapid increase in plaque signal enhancement and plaque to muscle contrast values, which remained stable up to 70 minutes. A linear correlation between signal enhancement and macrophage content was found 10 minutes after B22956/1 injection ( p < .01). Signal enhancement and plaque to muscle contrast values correlated with macrophage content 40 minutes after contrast agent administration ( p < .01). Finally, 70 minutes after B22956/1 infusion, plaque to muscle contrast significantly correlated with the percentage of stenosis ( p < .005). B22956/1 administration to high fat-fed apoE-KO mice resulted in a rapid enhancement of atherosclerotic plaques and in a great ability to rapidly visualize vulnerable plaques, characterized by a high macrophage content. These results suggest that B22956/1 could represent an interesting tool for the identification of atherosclerotic plaques potentially leading to acute cardiovascular events

Fenretinide treatment accelerates atherosclerosis development in apoE-deficient mice in spite of beneficial metabolic effects

Background and Purpose Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance, improve plasma lipid profile and reduce body fat mass. These effects, together with its ability to inhibit ceramide synthesis, suggest that fenretinide may have an anti-atherosclerotic action. Experimental Approach To this aim, nine-week-old apoE-knockout (EKO) female mice were fed for twelve weeks a Western diet, without (control) or with (0.1% w/w) fenretinide. As a reference, wild-type (WT) mice were treated similarly. Growth and metabolic parameters were monitored throughout the study. Atherosclerosis development was evaluated in the aorta and at the aortic sinus. Blood and lymphoid organs were further characterized with thorough cytological/histological and immunocytofluorimetric analyses. Key Results Fenretinide treatment significantly lowered body weight, glucose levels and plasma levels of total cholesterol, triglycerides, and phospholipids. In the liver, fenretinide remarkably reduced hepatic glycogenosis and steatosis driven by the Western diet. Treated spleens were abnormally enlarged, with severe follicular atrophy and massive extramedullary haematopoiesis. Severe renal hemosiderin deposition was observed in treated EKO mice. Treatment resulted in a threefold increase of total leukocytes (WT and EKO) and raised the activated/resting monocyte ratio in EKO mice. Finally, atherosclerosis development was markedly increased at the aortic arch, thoracic and abdominal aorta of fenretinide-treated mice. Conclusions and Implications We provide the first evidence that, despite beneficial metabolic effects, fenretinide treatment may enhance the development of atherosclerosis

Fenretinide treatment accelerates atherosclerosis development in apolipoprotein e-deficient mice in spite of beneficial metabolic effects

Aim. Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance and the plasma lipid profile, and to reduce body fat mass. These effects, together with its ability to inhibit ceramide synthesis, have suggested that fenretinide may display anti-atherosclerotic effects. Methods. To this aim, 9-weeks-old apoE-knockout (EKO) female mice were fed for 12 weeks a Western diet, without (EKO-Ctrl) or with (0.1% w/w) fenretinide (EKO-Fen). As a reference, wild-type (WT) mice were likewise treated. Growth and metabolic parameters were monitored throughout the study. Atherosclerosis development was evaluated in the aorta and at the aortic sinus. Blood and lymphoid organs were further characterized with thorough cytological/histological and immunocytofluorimetric analyses. Results. Fenretinide treatment significantly lowered body weight, glucose levels and plasma levels of total cholesterol, triglycerides and phospholipids. In the liver, fenretinide remarkably reduced hepatic glycogenosis and steatosis driven by the Western diet. Treated spleens were abnormally enlarged, with severe follicular atrophy and massive extramedullary hematopoiesis. Severe renal hemosiderin deposition was observed in EKO-Fen. Treatment resulted in a threefold increase of total leukocytes (WT and EKO) and raised the activated/resting monocyte ratio in EKO-Fen. Finally, atherosclerosis development was markedly increased at the aortic arch (34.4\uc5}7.3% vs 26.1\uc5}5.8%, +32%), thoracic (14.3\uc5}4.9% vs 4.9\uc5}2.1%, +191%) and abdominal aorta (7.6\uc5}3.3% vs 3.3\uc5}1.8%,+130%) of fenretinide-treated mice. Plaque extent was further quantified at the aortic sinus and provided similar results (810.000 \u3bcm2 vs. 540.000 \u3bcm2, +50% in EKO-Fen). Plaques of treated mice were characterized by an increased collagen content and a larger necrotic core, whereas the area occupied by macrophages, foam cells and neutral lipids was comparable between EKO-Fen and EKO-Ctrl. Conclusion. We provide the first evidence that, despite beneficial metabolic effects, fenretinide treatment may prove detrimental for atherosclerosis development

Per scaldare, per cuocere e per produrre. Le strutture da fuoco dell&#8217;abitato etrusco del Forcello di Bagnolo S.Vito (MN) : aspetti tipologici e funzionali

Il Forcello di Bagnolo S.Vito (MN) \ue8 il principale abitato dell\u2019area di espansione etrusca a nord del Po nel VI e V secolo a.C. Si tratta di un insediamento esteso circa 12 ettari dalla struttura pienamente urbana: un impianto ortogonale caratterizzato da assi viari principali e strade minori che si intersecano ortogonalmente e individuano quartieri, occupati da edifici sia di tipo residenziale che produttivo. Le indagini archeologiche, estese su un\u2019area di circa 900 m2 nel nucleo centrale dell\u2019insediamento, si susseguono da oltre trent\u2019anni e hanno permesso di riconoscere nove fasi insediative, definite dallo stratificarsi di attivit\ue0 domestiche, attivit\ue0 artigianali ed eventi catastrofici. L\u2019estensione e la lunga durata delle ricerche hanno permesso di riportare alla luce decine di strutture da fuoco: focolari, forni a fossa per attivit\ue0 pirotecnologiche, resti di fornaci per la cottura della ceramica. L\u2019ampia variet\ue0 tipologica delle strutture da fuoco rinvenute \ue8 cos\uec associata alla funzione degli ambienti in cui esse si trovano, interpretata a sua volta grazie allo studio parallelo dei reperti associati e delle tecniche edilizie.The Forcello site (Bagnolo S. Vito, Mantua) is the main Etruscan settlement north of the Po in the 6th and 5th centuries BC. It is approximately 12-hectare wide, with a fully urban pattern. It\u2019s characterized by an orthogonal plan, defined by main and secondary roads that intersect each other orthogonally and outline blocks, occupied by both residential and productive buildings. The archaeological investigations are carried out in the settlement\u2019s core area, over about 900 m2. After more than thirty years of excavations, nine archaeological phases have been recognized, resulting by the stratification of domestic activities, craft activities and catastrophic events. The extension and the long duration of the researches have brought to light dozens of fire structures: hearths, pit furnaces to cast bronze or to forge iron objects, remains of kilns. The wide typological variety of the fire structures can be evaluated according to the function of the buildings in which they are located, detected by study of archaeological findings and building techniques

Skin morphology in double apoA-I/apoE knock-out mice: a structural and ultrastructural study

Apolipoprotein(apo)A-I, the main protein component of high density lipoproteins (HDLs), plays a major role in cholesterol removal from peripheral tissues and increasing evidence supports its function as an important regulator of the immune response (Annema et al., 2013). The aim of the study was to evaluate the effect of apoA-I deficiency in dyslipidemic mice, when fed a low-fat/low-cholesterol diet. Three lines of male mice were considered: wild-type mice as controls, apoE-KO mice as dyslipidemic model (Zhang et al.,1992) and apoA-I/apoE double KO mice (DKO mice). Whereas in wild-type mice cholesterol circulates almost exclusively in HDLs, apoE-KO mice are hypercholesterolemic and cholesterol mostly circulates in low-density lipoproteins. In DKO mice, cholesterol levels are comparable to wild-type mice, but HDLs are almost absent and cholesterol entirely accumulates in low-density lipoproteins. In the present study, all animals were maintained on a low-fat/low-cholesterol diet up to 30 weeks of age. At sacrifice, skin biopsies from two different anatomical areas (thoracic and abdominal regions) were harvested from each animal and processed for both light (LM) and transmission electron microscopy (TEM). Whereas the skin of apoE-KO mice was comparable to that of control mice, LM analysis in DKO mice revealed an increase in dermal thickness and a massive presence of foam cells and lymphocytes. TEM analysis showed the presence of cholesterol clefts in the papillary dermis and inside foam cells in the reticular dermis. In conclusion, our results demonstrate that in DKO mice fed a low-fat/low-cholesterol diet, the lack of apoA-I is responsible for an aberrant skin morphology, with an exacerbated inflammatory response, possibly caused by a local cholesterol accumulation

Il trattamento con fenretinide peggiora l&#8217;aterosclerosi nonostante effetti metabolici favorevoli

E\u300 noto che la fenretinide, un retinoide di derivazione sintetica studiato principalmente per la prevenzione e il trattamento del cancro, contribuisca alla riduzione della massa grassa e aumenti la tolleranza al glucosio. Questi effetti, combinati alla sua abilita\u300 di inibire la sintesi dei ceramidi, hanno fatto ipotizzare che fenretinide potesse avere effetti anti-aterosclerotici. Per testare questa ipotesi, topi apoE-KO (EKO) femmina di 9 settimane di eta\u300 sono stati alimentati per 12 settimane con dieta Western, senza supplementazione (controllo), o supplementata con 0.1% w/w fenretinide (n=20 topi/gruppo). Topi C57BL/6J (WT) sono stati similmente arruolati per escludere effetti dipendenti dal genotipo (n=10). Peso e consumo di cibo e acqua sono stati monitorati lungo tutto il periodo di trattamento. Alla fine del trattamento sono stati dosati i lipidi plasmatici e il glucosio ematico (basale e curva di carico) in EKO. Al sacrificio, cuore e aorta sono stati campionati per valutare lo sviluppo di aterosclerosi. Fegato, milza, rene, cuore, polmone e tessuto adiposo bianco addominale sono stati valutati istologicamente. Nei topi EKO, la somministrazione di fenretinide ha ridotto significativamente il peso, i livelli di glucosio ematico e i livelli di colesterolo, trigliceridi e fosfolipidi plasmatici. Nel fegato, il trattamento ha ridotto significativamente il contenuto di glicogeno e lipidi normalmente osservato a dieta Western. Inaspettatamente, l\u2019assunzione di fenretinide ha causato un abnorme ingrossamento della milza, dove si e\u300 osservata una severa atrofia follicolare e un\u2019aumentata ematopoiesi extramidollare. Quest\u2019ultimo fenomeno era rilevabile anche nel fegato, dove altresi\u300 si e\u300 osservata eritrofagocitosi. Una pesante deposizione renale di emosiderina si e\u300 riscontrata nei reni degli animali trattati. Infine, lo sviluppo di aterosclerosi e\u300 risultato marcatamente aumentato in EKO trattati vs controllo a livello dell\u2019arco aortico (34.6\ub17.3% vs 26.1\ub15.8%, +33%), aorta toracica (14.2\ub14.9% vs 4.9\ub12.1%, +190%) e addominale (7.4\ub13.3% vs 3.3\ub11.8%, +124%). Calo ponderale e riduzione dell\u2019adiposita\u300 viscerale si sono osservati anche in topi WT trattati con il farmaco, assieme ad un minore, ma presente, ingrossamento della milza. In conclusione, e\u300 stato dimostrato come, nonostante i numerosi effetti metabolici positivi, il trattamento con fenretinide possa risultare in un aggravamento severo della patologia aterosclerotica