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Potent and selective adenosine receptor (AR) agonists are of pharmacological interest for the treatment of a wide range of diseases and conditions. Among these derivatives, nucleoside-based agonists represent the great majority of molecules developed and reported to date. However, the limited availability of compounds selective for a specific AR subtype (i.e., A2BAR) and a generally long and complex synthetic route for largely substituted nucleosides are the main drawbacks of this category of molecules. Non-nucleoside agonists represent an alternative set of compounds able to stimulate the AR function and based on simplified structures. This review provides an updated overview on the structural classes of non-nucleoside AR agonists and their biological activities, with emphasis on the main derivatives reported in the literature. A focus is also given to the synthetic routes employed to develop these derivatives and on molecular modeling studies simulating their interaction with ARs.

Chestnut tannins (CT) and saturated short medium chain fatty acids (SMCFA) are valid alternatives to contrast the growth of pathogens in poultry rearing, representing a valid alternative to antibiotics. However, the effect of their blends has never been tested. Two blends of CT extract and Sn1-monoglycerides of SMCFA (SN1) were tested in vitro against the proliferation of Clostridium perfringens, Salmonella typhymurium, Escherichia coli, Campylobacter jejuni. The tested concentrations were: 3.0 g/kg of CT; 3.0 g/kg of SN1; 2.0 g/kg of CT and 1.0 g/kg of SN1; 1.0 g/kg of CT and 2.0 g/kg of SN1. Furthermore, their effect on broiler performances and meat quality was evaluated in vivo: one-hundred Ross 308 male birds were fed a basal diet with no supplement (control group) or supplemented with CT or SN1 or their blends at the same concentration used in the in vitro trial. The in vitro assay confirmed the effectiveness of the CT and SN1 mixtures in reducing the growth of the tested bacteria while the in vivo trial showed that broiler performances, animal welfare and meat quality were not negatively affected by the blends, which could be a promising alternative in replacing antibiotics in poultry production.

The addition of polyphenol extracts in ruminant diets is an effective strategy to modulate rumen microflora. The aim of this in vitro trial was to study the effects of chestnut tannin extract (CHT), vescalagin (VES) and gallic acid (GAL) on dietary fibre degradability and on the dimethyl acetals (DMA) profile and microbial community composition of rumen liquor. Four diets (basal diet; basal diet plus CHT; basal diet plus VES; basal diet plus GAL) were fermented for 24 h using ewe rumen liquor. At the end of the fermentation, the microbial communities were characterized by sequencing the 16S rRNA gene. The DMA profile was analyzed by gas chromatography. Chestnut tannin extract did not affect fibre degradability, whereas VES and GAL showed a detrimental effect. The presence of CHT, VES and GAL influenced the concentration of several DMA (i.e., 12:0, 13:0, 14:0, 15:0, 18:0 and 18:1 trans-11), whereas the composition of the microbial community was marginally affected. The inclusion of CHT led to the enrichment of the genera Anaerovibrio, Bibersteinia, Escherichia/Shigella, Pseudobutyrivibrio and Streptococcus. The results of this study support the hypothesis that the activity of CHT is due to the synergistic effect of all components rather than the property of a single component.

Currently, the number of patients with neurodegenerative pathologies is estimated at over one million, with consequences also on the economic level. Several factors contribute to their development, including overexpression of A2A adenosine receptors (A2AAR) in microglial cells and up-regulation and post-translational alterations of some casein kinases (CK), among them, CK-1δ. The aim of the work was to study the activity of A2AAR and CK1δ in neurodegeneration using in-house synthesized A2A/CK1δ dual anta-inhibitors and to evaluate their intestinal absorption. Experiments were performed on N13 microglial cells, which were treated with a proinflammatory CK cocktail to simulate an inflammatory state typical of neurodegenerative diseases. Results showed that the dual anta-inhibitors have the ability to counteract the inflammatory state, even if compound 2 is more active than compound 1. In addition, compound 2 displayed an important antioxidant effect similar to the reference compound ZM241385. Since many known kinase inhibitors are very often unable to cross lipid bilayer membranes, the ability of A2A/CK1δ double anta-inhibitors to cross the intestinal barrier was investigated by an everted gut sac assay. HPLC analysis revealed that both compounds are able to cross the intestinal barrier, making them promising candidates for oral therapy. [ABSTRACT FROM AUTHOR]

Tannins are phenolic compounds that interfere with biohydrogenation (BH) of polyunsaturated fatty acids (FAs). The aim of the present in vitro study was to investigate the effects of two different sources of tannins on FA profiles of rumen bacteria, with particular reference to rumenic and vaccenic acid. A control diet (C; composed of 300 g/kg of wheat straw, 132 g/kg of soyabean meal, 96 g/kg of barley meal, 152 g/kg of maize meal, 300 g/kg of maize gluten and 20 g/kg of mineral vitamin premix, all expressed on dry matter (DM)) and four diets, obtained by adding to C two different types of tannins from chestnut (TC) and from quebracho (TQ) at two concentration levels (49 and 82 g/kg DM), were compared. The content of the main unsaturated FAs (C18:1 cis9, C18:1 trans11, C18:2 cis9, cis12 and C18:3 cis9, cis12, cis15) from solid-associated bacteria (SAB) and liquid-associated bacteria (LAB) was affected by the presence of tannins in the diets. In particular, C18:1 trans11 content was significantly increased, especially with TC1, whereas the decreasing of C18:1 cis9 was unaffected, regardless of the presence or the kind of tannins added to feeds. SAB contained higher amounts of intermediates of polyunsaturated FA BH (as C18:1 trans11 and C18:2 cis9, trans11) than LAB that were characterized by a higher amount of C18:0. In the concentration range adopted in this study, the effect of TC and TQ on changes of bacterial FA profile was comparable. Tannins seem to be a good means to modulate the FA profile of rumen bacteria, favouring the accumulation of C18:1 trans11 during in vitro rumen fermentation.

Twelve lactating Saanen goats were randomly assigned to four experimental diets, which differed in terms of forage:concentrate ratio and soybean oil supplementation. A 4×4 Latin square design was used. On a dry matter (DM) basis, forage:concentrate ratios were 63:37 (‘high-forage’ diet) and 35:65 (‘low-forage’ diet/high beet pulp). These diets were given either with oil (100 g·d-1) or without. The inclusion of soybean oil in the diet resulted in a significant increase in milk yield (but with HF diet) and in milk fat yield and concentration (P

The increasing use in Italy of the Cornell Net Carbohydrate and Protein System (CNCPS) led researchers of five Italianuniversities to carry out a collaborative study to evaluate the precision of the CNCPS chemical analysis and derivate fractions.Each laboratory conducted in duplicate the chemical analyses according to the Weende (dry matter; crude protein;ether extract; crude fibre; ash), Van Soest (neutral and acid detergent fibre, NDF and ADF; acid detergent lignin; ADL)and CNCPS (soluble proteins, SP; non-protein nitrogen, NPN; neutral and acid detergent insoluble protein, NDIP andADIP; starch, ST) schemes on the same five feeds (barley meal, wheat straw, maize silage, dried lucerne and fieldbeans). Anomalous analytical data were identified and corrected by the “box-plot” graphic tool before the calculation ofthe CNCPS protein (B1, B2 and B3) and carbohydrate (A, B2 and C) fractions. Finally, repeatability (chemical analysis) andreproducibility (chemical analysis and fractions) were calculated and expressed as relative values (repeatability andreproducibility standard deviation as percentage of the corresponding mean, RSDr and RSDR, respectively). Chemicalanalyses of the Weende scheme, together with NDF, ADF and ST analyses, have satisfactory repeatability (0.3-6.2%) andreproducibility (0.3-11.2%) values. On the contrary the ADL, NPN, NDIP and ADIP analyses showed high variability, bothwithin and between laboratories (RSDr and RSDR between 20 and 45%). The SP analysis had an intermediate value ofprecision (RSDr=10.6%; RSDR=16.4%).Finally, since different combinations of several chemical analyses with scarce (ADL, NPN, NDIP, ADIP, SP) or average precision(e.g. NDF and starch) are used to calculate CNCPS fractions (excluding B2 protein fraction), also the reproducibilitiesof these fractions are poor and range from 10 to 20%.

The aim of this review was to contribute to the knowledge of lipid requirements in dairy ewes, by reviewing experi- mental papers about lipid supplementation in dairy ewe feeding. The number of trials in ewe feeding is lower than that in dairy cow feeding and, leaving calcium soap of palm oil out of consideration, there is a lack of knowledge regarding the effects of protected and unprotected lipid sources on milk yield and quality from dairy ewes. On the basis of data reported in the literature, the optimal dose of calcium soap of palm oil resulted to be 100-120 g/d. Also, milk fatty acid composition may be improved by adding calcium soap of fatty acids to ewe diets. The general effect of calcium salt sup- plementation is an increase in milk unsaturated fatty acids and a decrease in saturated ones. However, more research is needed in order to explain the effect of different fat sources (protected and unprotected) on milk yield and quality from dairy ewes.

Thirty-two Appenninica lambs were submitted to a growth trial from day 60 to day 110 of age (on average) and the com- position of gains was estimated by means of the comparative slaughter technique. Sixteen different diets, based on wheat straw as the forage and on field bean (Vicia faba var. minor) as the sole protein feed, were tested both by means of ANOVA and of response surface analysis, a multiple regression method designed to study additive and interaction effects. This study thus examined the combined effect of 4 levels of dietary CP (13, 15, 18, 20% DM) and 4 levels of rumen protected lysine and methionine, replacing 4 levels of field bean CP (0, 1, 2, 3 percent units), upon intakes, gains, digestibility and retentions of nutrients within gains. The animals had rather high gains (250 g/d on average) and retention efficiencies both of feed nitrogen and energy. Dietary CP levels higher than 18% and amino acid supplementation appeared of no use in improving the lambs’ performance. It is concluded that field bean may represent a valid alternative to soy bean as a pro- tein feed for growing ruminants in the so-called “organic” animal production where transgenic soy is banned.

The aim of this review was to contribute to the knowledge of neutral detergent fibre (NDF) and non structural carbo- hydrate (NSC) requirements in the nutrition of dairy ewes. NDF and NSC requirements were evaluated by analysing a dataset that involved 30 experimental trials carried out from 1985 to 2003. The dataset included chemical composition of the experimental diets, individual milk yield, body weight, milk protein and fat content. These selected papers regard 10 different dairy ewe breeds (Valle del Belice, Bergamasca, Comisana, Delle Langhe, Massese, Sarda, Chios, Manchega, Lacaune and Friesian) and lactating ewes in mid lactation, kept under non homogeneous environmental and feeding conditions. Results substantially confirmed that which was recently reported in literature: NDF requirements are higher in late lactation than during early lactation and they vary between 33-38% on DM, while NSC requirements are higher during early lactation than in late lactation when the energy from NSC promotes an increase in fat deposits.

Aim of the study was to verify the effects of butyric acid glycerides, as a supplemental ingredient in the diet, on live performance of broiler chickens and on the morphology of their small intestine, since short chain fatty acids are known as selective protection factors against intestinal microbial parasites, potent growth promoters of the gut wall tissues, also in terms of immune modulation response. An experiment was carried out on 150 Ross 308 female chickens, allotted to 5 treatments, over a 35 d ays period: the control, with soybean oil as the energy supplement, and 4 treatments with increasing amounts (0.2, 0.35, 0.5, 1% mixed feed) of a mixture of butyric acid glycerides (mono-, di- and tri- glycerides). Treated animals showed a higher live weight at slaughtering (P

The recent literature dealing with the effect of the diet on the quality of milk and meat fat is reviewed. Some aspects ofthe rumen metabolism of lipids are dealt with: lipolysis, bio-hydrogenation, synthesis of microbial fatty acids and inhibitionmechanisms on fermentation. Firstly, the influence of forage is considered. Pasture is the best forage, better if highhill pasture, as compared to hay and silage: short chain fatty acids (SCFA) (shorter than C10) are increased, mediumchain fatty acids (MCFA) (C12 through C16) are decreased, oleic (OA), linoleic (LA) and linolenic (LNA) acids are increasedand so are the conjugated linoleic acid pool of isomers (CLA) and n-3 polyunsaturated fatty acids (n-3 PUFA). Secondly,the energy supplementation of diets with fats is looked at. Animal fats depress milk yield and SCFA, while OA is increasedbecause of the enhanced activity of mammary Δ9 desaturase. Fish oil depresses milk yield as well, but promotes CLA andn-3 PUFA. If animal fats are protected against rumen bacteria, milk yield and milk fat depression are avoided. Vegetablefats are richer in unsaturated fatty acids (UFA), thus more susceptible to the rumen bio-hydrogenation. As calcium soapsor inside whole seeds, plant fats are protected and CLA is increased. CLA is an important component of fat. In ruminantsit comes from the desaturation of vaccenic acid (VA) both in rumen and udder; and the yield of VA depends on the dietquality. In conclusion, simple directions are given on how to improve the quality of animal fat by dietary means, withoutaffecting yield.

Three equations have been elaborated and proposed to predict the requirements of net energy and protein digestible in the intestine and NDF voluntary intake of growing young Chianina bulls, starting from 400 kg live weight. The animals examined in the present study were 100 young Chianina bulls starting from about 400 kg live weight, at 10 months of age, up to the average slaughter weight of 800 kg at 20 months average age. The diet was based on hay and concentrates. The equation for the prediction of net energy fits quite perfectly to another experimental equation formerly proposed by Giorgetti and is characterised by a very high value of the correlation coefficient for the regression comparison between observed and predicted figures (R2=0.90). The statistical reliance degree of the PDIN prediction equation is lower, but still very good (R2=0.75 between observed and predicted values), but that of the estimate of NDF daily intake resulted very poor (R2=0.26 between observed and predicted values), probably due to the non homogeneity of the intake capacity of the 100 examined animals. The correlation between daily gains and the concentration of NDF in the diet DM results good (R2=0.87), showing that young Chianina bulls take advantage of the diet fibre. Further useful indications on the nutritional and dietary requirements of young Chianina bulls are added to the scarce information currently available.

Olive oil and CLA enriched olive oil were compared with each other in a growth trial with broiler chickens, as energy supplements to the diet. A commercial CLA blend was used at the level of 1 kg per 100 kg mixed integrated feed. Two hundred and forty commercial hybrid broilers (Ross 308) were randomly subdivided and allotted to 8 pens of 30 birds each. Four pens of birds were fed the olive oil diet and considered the control group; the other 4 pens were fed the olive oil supplemented with CLA and considered the treated group. The experiment lasted 47 days. The live performance of the treated birds resulted different from the performance of the control ones: the final body weight was slightly lighter (2.544 kg vs 2.639 kg; P≤0.05) with a lower feed intake (4.886 kg feed vs 4.998 kg, P≤0.05) and, of course, an almost perfectly overlapping feed/gain ratio (1.90 vs 1.91). The fatty acid composition of the breast fat of the CLA treated birds resulted enriched by the two major CLA isomers, trans 10 cis 12 and cis 9 trans 11, whereas oleic acid and the linoleic, linolenic and arachidonic polyunsaturated acids showed a decrease (P≤0.05). CLA appears a recommendable ingredient in the diets of broilers as it improves the beneficial characteristics of poultry meat.

Eight Massese ewes were fed 4 diets with alfalfa hay as the forage (73% on the DM basis): 1) control diet (C); 2) diet C supplemented with olive oil calcium soaps, 50 g/d (L); 3) diet C supplemented with protected methionine, 5 g/d (M) or 4) plus both soaps and methionine (ML); the experimenthal design was a 4x4 Latin square with 2 replicates per diet. During the experimental periods, lasting one week each, the ewes were milked twice daily (8:00 a.m. and 7:00 p.m.). Milk yield was not affected by diet quality, but milk fat percentage and 6.5% fat corrected milk yield were higher in diets L, M and ML with respect to diet C (P

Little information is available about the effect of different forage species on the rumen biohydrogenation process. The aim of the present work is to compare the in vitro production of CLA and C18:1 isomers after incubation of three different herbage species in rumen liquor from sheep. Pasture herbage samples of lucerne (Medicago sativa; MS), ryegrass (Lolium multiflorum; LM) and oats (Avena sativa; AS) were submitted to in vitro fermentation with sheep rumen inoculum. Samples were collected at 2, 4, 6 and 8 hours of fermentation. The fatty acid profile of MS was characterised by 11.62 (g/100 g of lipid extract) of linoleic acid (LA) and 27.08 (g/100 g of lipid extract) of α-linolenic acid (LNA), whereas LA in the other two herbages was 6.60 (g/100 g of lipid extract) and 6.95 (g/100 g of lipid extract) in AS and LM, respectively; LNA was 52.20 (g/100 g of lipid extract) and 54.49 (g/100 g of lipid extract) in AS and LM, respectively. The crude fat content of botanical species was respectively 11.90 (g/100g DM) for AS, and 15.77 (g/100g DM) for LM and 26.17 (g/100g DM) for MS. Rumenic acid (RA, cis-9, trans-11 CLA) was the predominant CLA isomer and the maximum yield was attained with AS after 6 hours of fermentation (0.81 g/100 g of lipid extract); RA concentration remained quite low with the other two herbages. The concentration of the other isomer (trans-10, cis-12 CLA) was always very low; the maximum yield (0.09 g/100 g of lipid extract) was reached after 6 hours with AS. The maximum yield of vaccenic acid (VA, trans-11 C18:1) was reached after 8 hours with MS (2.64 g/100 g of lipid extract). This herbage also produced the highest amount of trans-10 C18:1 at 6 and 8 hours (0.17 g/100 g of lipid extract). AS appeared to have induced the highest amounts of RA relative to the other two forages. The differences in conjugated dienes and C18:1 isomers content during fermentation could be due not only to different amounts of LA or LNA in the herbage, but also to different releasing times of FA from the plant substrate.

Mixtures of mono-, di- and tri-glycerides from olive oil (MDT) were added to: palm oil (PO), olive oil (OO), soybean oil (SO), free fatty acids from palm oil (PFA), free fatty acids from olive oil (OFA). The compound mixtures were used as energy supplements in the diets of broiler chickens in comparison with plain SO and plain animal fat (AF). Two hundred and ten birds were randomly allotted to 7 dietary treatments with the diverse oil sources: 6 birds per cage, 5 cages per treatment. The effects of the treatments on growth rates, feed/gain ratios and acidic composition of abdominal fat of hybrid Ross 308 female chickens were studied. The animals were slaughtered at the end of the trial, at day 35. The breast meat quality was then evaluated by a panel of 15 trained members and analysed for shelf life duration. The AF treat- ment gave the highest weight gain, but only in the first week. MDT + OO (50/50) resulted the best combination, with slight, non significant, better performances and a decidedly better quality in terms of acidic composition of abdominal fat, taste and juiciness of breast meat and shelf life.

Based on a screening of a chemical library of A2A adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called "dual anta-inhibitors", demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the A2AAR. The N6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17, IC50 = 0.59 μM and KiA2A = 0.076 μM) showed the best balance of A2AAR affinity and CK1δ inhibitory activity. Computational studies were performed to simulate, at the molecular level, the protein–ligand interactions involving the compounds of our series. Hence, the dual anta-inhibitor 17 could be considered the lead compound of new therapeutic agents endowed with synergistic effects for the treatment of chronic neurodegenerative and cancer diseases. [ABSTRACT FROM AUTHOR]