Structure-Activity Studies of 1,2,4-Oxadiazoles for the Inhibition of the NAD-Dependent Lysine Deacylase Sirtuin 2.

The NAD-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from (Sirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis.

Neurodevelopmental disorders associated variants in disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migration.

The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown.

Rumen microbial degradation of bromoform from red seaweed (Asparagopsis taxiformis) and the impact on rumen fermentation and methanogenic archaea.

Background: The red macroalgae Asparagopsis is an effective methanogenesis inhibitor due to the presence of halogenated methane (CH) analogues, primarily bromoform (CHBr). This study aimed to investigate the degradation process of CHBr from A. taxiformis in the rumen and whether this process is diet-dependent.

Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni.

Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis.

Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2.

Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens' modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks.

The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination.

Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood.

Review: Ruminal microbiome and microbial metabolome: effects of diet and ruminant host.

The rumen contains a great diversity of prokaryotic and eukaryotic microorganisms that allow the ruminant to utilize ligno-cellulose material and to convert non-protein nitrogen into microbial protein to obtain energy and amino acids. However, rumen fermentation also has potential deleterious consequences associated with the emissions of greenhouse gases, excessive nitrogen excreted in manure and may also adversely influence the nutritional value of ruminant products. While several strategies for optimizing the energy and nitrogen use by ruminants have been suggested, a better understanding of the key microorganisms involved and their activities is essential to manipulate rumen processes successfully.

Structure-Reactivity Relationships on Substrates and Inhibitors of the Lysine Deacylase Sirtuin 2 from (Sirt2).

The only drug currently available for treatment of the neglected disease Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary and urgent. To this end, the targeting of epigenetic enzymes, which regulate the parasitic life cycle, emerged as a promising approach. Due to the strong effects of human sirtuin inhibitors on parasite survival and reproduction, sirtuins were postulated as potential therapeutic targets.

Not all saponins have a greater antiprotozoal activity than their related sapogenins.

The antiprotozoal effect of saponins varies according to both the structure of the sapogenin and the composition and linkage of the sugar moieties to the sapogenin. The effect of saponins on protozoa has been considered to be transient as it was thought that when saponins were deglycosilated to sapogenins in the rumen they became inactive; however, no studies have yet evaluated the antiprotozoal effect of sapogenins compared to their related saponins. The aims of this study were to evaluate the antiprotozoal effect of eighteen commercially available triterpenoid and steroid saponins and sapogenins in vitro, to investigate the effect of variations in the sugar moiety of related saponins and to compare different sapogenins bearing identical sugar moieties.

Slight changes in the chemical structure of haemanthamine greatly influence the effect of the derivatives on rumen fermentation in vitro.

Although the potential of plants extracts to improve feed efficiency and animal productivity and decrease methane emissions by enteric fermentation has been shown, the information available is often contradictory which has been attributed to differences in the complex mixture of bioactive compounds and their interactions. Understanding the degree to which structural features in a compound may affect the biological activity of an extract is essential. We hypothesised that relative small variations in the structure of a compound can have a significant influence on the ability of the derivatives to alter fermentation in the rumen.

Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.

Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse.

The effect of an isoflavonid-rich liquorice extract on fermentation, methanogenesis and the microbiome in the rumen simulation technique.

Due to the antimicrobial activity of flavonoids, it has been suggested that they may provide a possible alternative to antibiotics to stimulate productivity and reduce the environmental load of ruminant agriculture. We hypothesised that an extract of liquorice, rich in prenylated isoflavonoids and particularly glabridin, might potentially improve the efficiency of nitrogen utilisation and reduce methane production in the rumen. When added to a long-term rumen simulating fermentor (RUSITEC), liquorice extract at 1 g L-1 decreased ammonia production (-51%; P < 0.

Improving the antiprotozoal effect of saponins in the rumen by combination with glycosidase inhibiting iminosugars or by modification of their chemical structure.

The antiprotozoal effect of saponins is transitory, as when saponins are deglycosylated to sapogenins by rumen microorganisms they become inactive. We hypothesised that the combination of saponins with glycosidase-inhibiting iminosugars might potentially increase the effectiveness of saponins over time by preventing their deglycosylation in the rumen. Alternatively, modifying the structure of the saponins by substituting the sugar moiety with other small polar residues might maintain their activity as the sugar substitute would not be enzymatically cleaved.

Natural and artificial feeding management before weaning promote different rumen microbial colonization but not differences in gene expression levels at the rumen epithelium of newborn goats.

The aim of this work was to evaluate the effect of feeding management during the first month of life (natural with the mother, NAT, or artificial with milk replacer, ART) on the rumen microbial colonization and the host innate immune response. Thirty pregnant goats carrying two fetuses were used. At birth one kid was taken immediately away from the doe and fed milk replacer (ART) while the other remained with the mother (NAT).

Antiprotozoal Effect of Saponins in the Rumen Can Be Enhanced by Chemical Modifications in Their Structure.

The antiprotozoal effect of saponins is transitory, as when saponins are deglycosylated to the sapogenin by rumen microorganisms they become inactive. We postulated that the substitution of the sugar moiety of the saponin with small polar residues would produce sapogen-like analogs which might be resistant to degradation in the rumen as they would not be enzymatically cleaved, allowing the antiprotozoal effect to persist over time. In this study, we used an acute assay based on the ability of protozoa to break down [C] leucine-labeled and a longer term assay based on protozoal motility over 24 h to evaluate both the antiprotozoal effect and the stability of this effect with fifteen hederagenin -esters esterified with two identical groups, and five cholesterol and cholic acid based derivatives carrying one to three succinate residues.

The Role of Ciliate Protozoa in the Rumen.

First described in 1843, Rumen protozoa with their striking appearance were assumed to be important for the welfare of their host. However, despite contributing up to 50% of the bio-mass in the rumen, the role of protozoa in rumen microbial ecosystem remains unclear. Phylogenetic analysis of 18S rDNA libraries generated from the rumen of cattle, sheep, and goats has revealed an unexpected diversity of ciliated protozoa although variation in gene copy number between species makes it difficult to obtain absolute quantification.

In vitro screening of natural feed additives from crustaceans, diatoms, seaweeds and plant extracts to manipulate rumen fermentation.

Background: Eight natural products from animal, unicellular algae, brown seaweed and plant origins were chosen according to their theoretical antimicrobial activity: Diatomaceous earths (DE), insoluble chitosan (ICHI), soluble chitosan (CHI), seaweed meal (SWM), Ascophyllum nodosum (ASC), Laminaria digitata (LAM), neem oil (NOIL) and an ivy fruit extract rich in saponins (IVY). Dose-response incubations were conducted to determine their effect on rumen fermentation pattern and gas production, while their anti-protozoal activity was tested using (14) C-labelled bacteria.

Results: DE, SWM, NOIL and ICHI had very small effects on rumen function when used at inclusion rate up to 2 g L(-1) .

Response of the rumen archaeal and bacterial populations to anti-methanogenic organosulphur compounds in continuous-culture fermenters.

Study of the efficacy of methanogenesis inhibitors in the rumen has given inconsistent results, mainly due to poorly understood effects on the key microbial groups involved in pathways for methane (CH4) synthesis. The experiment described in this report was designed to assess the effect of propyl propane thiosulfinate (PTS), diallyl disulfide (DDS) and bromochloromethane (BCM) on rumen fermentation, methane production and microbial populations in continuous culture fermenters. No effects on total volatile fatty acids (VFA) were observed with PTS or DDS, but VFA were decreased with BCM.

An antimethanogenic nutritional intervention in early life of ruminants modifies ruminal colonization by Archaea.

The aim of this work was to study whether feeding a methanogen inhibitor from birth of goat kids and their does has an impact on the archaeal population colonizing the rumen and to what extent the impact persists later in life. Sixteen goats giving birth to two kids were used. Eight does were treated (D+) with bromochloromethane after giving birth and over 2 months.

Microbial and chemical composition of liquid-associated bacteria in goats' rumen and fermenters.

This study was undertaken to investigate the relationship between chemical composition and microbial profile of rumen liquid-associated bacteria (LAB) in vivo (Murciano-Granadina goats) and in a rumen simulation system (single-flow continuous-culture fermenters). To achieve this aim, analyses of purine bases along with some molecular techniques (quantitative PCR to assess abundance and DGGE to identify biodiversity and bacterial profile) were carried out. A control diet (AHC) based on alfalfa hay (AH) and concentrate (C) in a 1:1 ratio and two experimental diets (AHCBI and AHCBII), in which concentrate was partially replaced with multinutrient blocks, were used.

Oral administration of cobalt acetate alters milk fatty acid composition, consistent with an inhibition of stearoyl-coenzyme A desaturase in lactating ewes.

Previous investigations have shown that cobalt (Co) modifies milk fat composition in cattle, consistent with an inhibition of stearoyl-coenzyme A desaturase (SCD) activity, but it remains unclear whether other ruminant species are also affected. The present study examined the effects of oral administration of Co acetate on intake, rumen function, and milk production and fatty acid (FA) composition in sheep. Twenty lactating Assaf ewes were allocated into 1 of 4 groups and used in a continuous randomized block design that involved a 15-d adaptation, a 6-d treatment, and a 10-d posttreatment period.

In vitro-in vivo study on the effects of plant compounds on rumen fermentation, microbial abundances and methane emissions in goats.

Two in vitro and one in vivo experiments were conducted to investigate the effects of a selection of plant compounds on rumen fermentation, microbial concentration and methane emissions in goats. Treatments were: control (no additive), carvacrol (CAR), cinnamaldehyde (CIN), eugenol (EUG), propyl propane thiosulfinate (PTS), propyl propane thiosulfonate (PTSO), diallyl disulfide (DDS), a mixture (40 : 60) of PTS and PTSO (PTS+PTSO), and bromochloromethane (BCM) as positive control with proven antimethanogenic effectiveness. Four doses (40, 80, 160 and 320 µl/l) of the different compounds were incubated in vitro for 24 h in diluted rumen fluid from goats using two diets differing in starch and protein source within the concentrate (Experiment 1).

Nutrient utilization, ruminal fermentation, microbial abundances, and milk yield and composition in dairy goats fed diets including tomato and cucumber waste fruits.

The effects of replacing 35% of cereals-based concentrate with feed blocks (FB) containing waste fruits of tomato, cucumber, or barley grain in diets for lactating goats on nutrient utilization, ruminal fermentation, microbial N flow to the duodenum, milk yield and quality, methane emissions, and abundances of total bacteria and methanogens were studied. Eight Murciano-Granadina goats (39.4 ± 5.

Ricinoleic acid inhibits methanogenesis and fatty acid biohydrogenation in ruminal digesta from sheep and in bacterial cultures.

Ricinoleic acid (RA; 12-hydroxy-cis-9-18:1) is the main fatty acid component of castor oil. Although a precursor for CLA synthesis in lactic acid bacteria, RA was found previously not to form CLA in ruminal digesta but to have some inhibitory properties. The present study was undertaken to evaluate the potential of RA to modulate ruminal biohydrogenation and methanogenesis.

The role of microbes in rumen lipolysis and biohydrogenation and their manipulation.

Despite the fact that the ruminant diet is rich in polyunsaturated fatty acids (PUFA), ruminant products - meat, milk and dairy - contain mainly saturated fatty acids (SFA) because of bacterial lipolysis and subsequent biohydrogenation of ingested PUFA in the rumen. The link between SFA consumption by man and coronary heart disease is well established. In contrast, ruminant products also contain fatty acids that are known to be beneficial to human health, namely conjugated linoleic acids (CLAs).