PSNCBAM-1 analogs: Structural evolutions and allosteric properties at cannabinoid CB1 receptor

Allosteric modulation of the CB1Rs could represent an alternative strategy for the treatment of diseases in which these receptors are involved, without the undesirable effects associated with their orthosteric stimulation. PSNCBAM-1 is a reference diaryl urea derivative that positively affects the binding affinity of orthosteric ligands (PAM) and negatively affects the functional activity of orthosteric ligands (NAM) at CB1Rs. In this work we reported the design, synthesis and biological evaluation of three different series of compounds, derived from structural modifications of PSNCBAM-1 and its analogs reported in the recent literature. Almost all the new compounds increased the percentage of binding affinity of CP55940 at CB1Rs, showing a PAM profile. When tested alone in the [35S]GTPγS functional assay, only a few derivatives lacked detectable activity, so were tested in the same functional assay in the presence of CP55940. Among these, compounds 11 and 18 proved to be functional NAMs at CB1Rs, dampening the orthosteric agonist-induced receptor functionality by approximately 30%. The structural features presented in this work provide new CB1R-allosteric modulators (with a profile similar to the reference compound PSNCBAM-1) and an extension of the structure-activity relationships for this type of molecule at CB1Rs

Effects of Goji berries supplementation on the productive performance of rabbit

Abstract Recognized by the traditional medicine and recent scientific research studies, Lycium barbarum berries (Goji berries) have beneficial effects on human and animal health. The aim of our study was to evaluate the effects of Goji berries on the productive performance of rabbits. One month before insemination, 60 New Zealand White does were randomly assigned to one of the following 3 dietary treatments: commercial standard diet (C); C supplemented with 1% Goji berries (LG); and C supplemented with 3% Goji berries (HG). After weaning up to 91 days of age, 15 randomly selected rabbits/group were fed the same diet as the mothers (C, LG, and HG). Non-pregnant and lactating does of C group showed the highest feed intake (P < 0.01), although no significant differences in body weight (BW) were observed between groups. Nutritional treatment did not affect the offspring's feed intake. However, the rabbits fed with Goji supplementation showed not only higher mean BW both during growth (P < 0.001) and at slaughter (P < 0.01), but also better feed conversion ratio (FCR; P < 0.01) than the control group. Rabbits of LG group showed the best performances in the pre-weaning period which was probably related to the highest milk production of the LG does (P < 0.001). Indeed, LG group showed lower pre-weaning mortality (P < 0.05), higher litter size (P < 0.05), and higher litter weight (P < 0.05) at day 18 as well as higher litter size at weaning (P = 0.05) compared to C group. In conclusion, the present study demonstrates that a low percentage of dietary supplementation with Goji berry improves both reproductive and productive traits of rabbits. Although further studies are needed, our study paves the way for the use of Goji berries in the rabbit nutrition

Effect of 1\u3b1,25(OH)2 vitamin D3 in mutant P53 glioblastoma cells: Involvement of neutral sphingomyelinase1

Glioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting complementary treatments that can be helpful in improving the classic therapeutic approaches. It is known that 1\u3b1,25(OH)2 vitamin D3, a molecule involved in bone metabolism, has many serendipidy effects in cells. It targets normal and cancer cells via genomic pathway by vitamin D3 receptor or via non-genomic pathways. To interrogate possible functions of 1\u3b1,25(OH)2 vitamin D3 in multiforme glioblastoma, we used three cell lines, wild-type p53 GL15 and mutant p53 U251 and LN18 cells. We demonstrated that 1\u3b1,25(OH)2 vitamin D3 acts via vitamin D receptor in GL15 cells and via neutral sphingomyelinase1, with an enrichment of ceramide pool, in U251 and LN18 cells. Changes in sphingomyelin/ceramide content were considered to be possibly responsible for the differentiating and antiproliferative effect of 1\u3b1,25(OH)2 vitamin D in U251 and LN18 cells, as shown, respectively, in vitro by immunofluorescence and in vivo by experiments of xenotransplantation in eggs. This is the first time 1\u3b1,25(OH)2 vitamin D3 is interrogated for the response of multiforme glioblastoma cells in dependence on the p53 mutation, and the results define neutral sphingomyelinase1 as a signaling effector

Relationship between fatty acids composition/antioxidant potential of breast milk and maternal diet: Comparison with infant formulas

The fatty acid composition of human breast milk is relevant for the energy, immunity and eicosanoid production in infants. Additionally, the antioxidant properties of foods are essential for human health. Therefore, in the present study we aimed to investigate the relationship between maternal diet and fatty acids composition as well as the antioxidant potential of breast milk from donors to human milk bank of Perugia\u2019s hospital, Italy. Results were compared with infant formulas. We observed increased levels of total fatty acids and, in particular, saturated and monounsaturated fatty acids in milk from mothers fed on a vegetable and fruit-rich diet compared with a Mediterranean diet. In the same milk, a reduced antioxidant potential was found. All infant formulas resulted in richer total fatty acid content than human breast milk. Only some formulas were qualitatively similar to breast milk. Of note, the antioxidant potential of the formulas was higher or lower than the human milk with the exception of one sample. The antioxidant potential of four formulas was very high. Dietary supplementation with antioxidants has been shown to have a teratogenic effect and to increase the formation of metastases in adult. There are no data on the effects of excess antioxidants in the infants, but the possibility that they can be harmful cannot be excluded

Acid and neutral sphingomyelinase behavior in radiation-induced liver pyroptosis and in the protective/preventive role of rMnSOD

Sphingomyelins (SMs) are a class of relevant bioactive molecules that act as key modulators of different cellular processes, such as growth arrest, exosome formation, and the inflammatory response influenced by many environmental conditions, leading to pyroptosis, a form of programmed cell death due to Caspase-1 involvement. To study liver pyroptosis and hepatic SM metabolism via both lysosomal acid SMase (aSMase) and endoplasmic reticulum/nucleus neutral SMase (nSMase) during the exposure of mice to radiation and to ascertain if this process can be modulated by protective molecules, we used an experimental design (previously used by us) to evaluate the effects of both ionizing radiation and a specific protective molecule (rMnSOD) in the brain in collaboration with the Joint Institute for Nuclear Research, Dubna (Russia). As shown by the Caspase-1 immunostaining of the liver sections, the radiation resulted in the loss of the normal cell structure alongside a progressive and dose-dependent increase of the labelling, treatment, and pretreatment with rMnSOD, which had a significant protective effect on the livers. SM metabolic analyses, performed on aSMase and nSMase gene expression, as well as protein content and activity, proved that rMnSOD was able to significantly reduce radiation-induced damage by playing both a protective role via aSMase and a preventive role via nSMase

Does hunted wild boar meat meet modern consumer nutritional expectations?

The present study aimed to evaluate the nutritional characteristics of hunted wild boar (WB) meat and compare them with those of meat from analogous domestic animals (pigs) reared in two different rearing systems: indoor-intensive (PI) and outdoor-extensive (PO). WB meat showed a lower amount of lipid content compared to pork and a higher antioxidant activity compared to PI and PO. The comparison of the fatty acid composition of WB and domestic pig reveals significant differences in saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA), with WB having the highest PUFA level and the lowest SFA. The omega 6/omega 3 (n-6/n-3) PUFA ratio, PUFA/SFA, atherogenic and thrombogenic indices (AI and TI), as well as the hypocholesterolemic/hypercholesterolemic index (h/H), were calculated. The n-6/n-3 PUFA ratio was higher in pork independently of the rearing system. The PUFA/SFA ratio of WB meat was above the minimum ratio of 0.40 recommended to contribute to a reduction in the risk of coronary diseases in pork from both rearing systems. AI and TI were lower in meat from hunted wild boars compared to commercially reared pigs, while h/H was higher in WB in comparison with pork meat. WB meat shows good nutritional quality; therefore, the use of game meat as a food source could be appropriate and could benefit contemporary consumers looking for “green” and high-nutritional products

Ambivalent Mobilities and Survival Strategies of Moroccan and Bangladeshi Families in Italy in Times of Crisis

This article investigates the link between the economic crisis and migrant family reunification with a focus on mobility strategies of reunited families. Drawing on in-depth interviews with Moroccan and Bangladeshi families, carried out in the Metropolitan City of Venice, between 2012 and 2016, the article aims to show the complex process of further separation that reunified families endure in order to deal with the consequences of the crisis. Family unity does not represent a definitive and lasting achievement. Rather, it is a status that must be constantly protected in order to fulfil the requirements imposed by reunification policies. Migrant families must undertake various forms of mobility to maintain their housing, occupational and economic standards and sometimes may move to other countries to preserve their unity. In response to the crisis, migrants appropriate the instruments of citizenship in order to increase their mobility capital and the opportunity to stay in Europe

Citizen to Stay or Citizen to Go? Naturalization, Security, and Mobility of Migrants in Italy

https://doi.org/10.1080/15562948.2016.1208316We analyze the relation between naturalization, mobility, and security through 50 in-depth interviews with migrants of different origins living in two Italian regions. We show how migrants pursue naturalization both to protect themselves against bureaucracy and deportation and to move to a third country. The second migration is motivated by improving one's conditions, forced by the economic crisis, or completes the original migratory project once a strong passport is obtained. We argue that citizenship is not essentially linked to either stability or mobility and that mobility should be understood as neither exceptional nor always chosen

Risultati preliminari delle indagini archeologiche ed etnografiche presso il sito di Togolok 1

Modern Turkmenistan is mainly constituted by a desert landscape, yet despite its harsh climate, cultures have been able to construct networks of water channels since the Bronze Age. This has resulted in a man-made landscape that integrates towns and villages. Extensive surveys and recent archaeological excavations have highlighted that between 2400 and 2100 BC (Namazga V period), the region of the Murghab alluvial fan was characterised by the development of complex urban societies. However, starting from the Late Bronze Age, a new group of mobile pastoralists appeared in the Murghab region and settled along the edges of the sedentary sites. Although their presence is well-attested both by survey and excavation data, their degree of interaction with the sedentary farmers is still debated. In modern Turkmenistan, semi-mobile shepherds continue to drive their cattle across the Murghab, using mobile camps for different months. This paper presents the preliminary results of the excavation of the sedentary site of Togolok 1, as well as the first ethnographic study of the mobile communities of the Murghab region