Structure-activity relationship studies of Bz amide-containing α-GalCer derivatives as natural killer T cell modulators

Abstract

CD1d is a non-polymorphic antigen-presenting glycoprotein that recognizes glycolipids as ligands. Ligands bind to the hydrophobic grooves of CD1d, and the resulting ligand-CD1d complexes activate natural killer T (NKT) cells by means of T cell receptor recognition, leading to the secretion of various cytokines. However, details of the ligand recognition mechanism of a large hydrophobic ligand binding pocket and the relationship between cytokine induction and ligand structure are unclear. We report the synthesis of α-GalCer derivatives containing a Bz amide group having various substituting groups in the ceramide moiety, and the analysis of the structure-activity relationships. The assays reveal that the Bz amide-containing CD1d ligands function as NKT cell modulators displaying Th2 cytokine biasing responses. Furthermore, molecular dynamics simulation studies suggest that the phenyl groups can interact with the aromatic amino acid residues in the lipid binding pocket of CD1d.     

Development of hydroxamate-based histone deacetylase inhibitors containing 1,2,4-oxadiazole moiety core with antitumor activities

Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1,2,4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies.     

Cross-correlation analysis of invasive mango mealybug and its associated natural enemies in relation to meteorological factors: implications for biological control

Damage caused by invasive downey snow line mealybug, Rastrococcus iceryoides Green (Hemiptera: Pseudococcidae) has been reported to vary between 30% to complete crop loss where no control measure is applied. The current studies seek to determine factors influencing R. iceryoides population outbreaks, parasitoid – host and predator–prey relationships as well as predict optimal management strategies through weather modelling over a period of 28 months from 2008 to 2010 in Tanzania. The highest incidence of R. iceryoides was recorded during the dry season coinciding with the major mango fruiting season. The relationship between R. iceryoides and the parasitoid was positive but not significant, which implies the influence on outbreaks was negligible probably due to low percent parasitism (<12%). However, the predator abundance was directly and significantly related to that of R. iceryoides. Average temperature, average relative humidity, rainfall, and R. iceryoides abundance were autocorrelated to each other. Cross-correlation coef?cients vary significantly from ?0.286 to 0.589 for the pair-variable between R. iceryoides, temperature, relative humidity, rainfall, parasitism and predators. Our findings showed that temperature was the key climatic variable that significantly influenced R. iceryoides outbreaks while rainfall was significantly negatively associated with the pest. Time series analyses show R. iceryoides population increased 4 months after an increase in average temperature in all the sites, 11 months after rainfall and 11 months after relative humidity in Kibaha and Dar es Salaam, respectively. Our findings revealed that R. iceryoides is an excellent target for classical biological control. Thus, the importation of promising co-evolved parasitoid specific to R. iceryoides from the aboriginal home is crucial in formulating an efficient and sustainable management approaches against the invasive mealybug pest in mango agro-ecosystems.     

Soil microbiome mediates positive plant diversity‐productivity relationships in late successional grassland species

Which processes drive the productivity benefits of biodiversity remain a critical, but unanswered question in ecology. We tested whether the soil microbiome mediates the diversity‐productivity relationships among late successional plant species. We found that productivity increased with plant richness in diverse soil communities, but not with low‐diversity mixtures of arbuscular mycorrhizal fungi or in pasteurised soils. Diversity‐interaction modelling revealed that pairwise interactions among species best explained the positive diversity‐productivity relationships, and that transgressive overyielding resulting from positive complementarity was only observed with the late successional soil microbiome, which was both the most diverse and exhibited the strongest community differentiation among plant species. We found evidence that both dilution/suppression from host‐specific pathogens and microbiome‐mediated resource partitioning contributed to positive diversity‐productivity relationships and overyielding. Our results suggest that re‐establishment of a diverse, late successional soil microbiome may be critical to the restoration of the functional benefits of plant diversity following anthropogenic disturbance.     

2,2',4-trihydroxybenzophenone: crystal structure, and anti-inflammatory and antioxidant activities

The crystal structure of '2,2',4-trihydroxybenzophenone' (=(2,4-dihydroxyphenyl)(2-hydroxyphenyl)methanone; 1) was determined, and its molecular structure, along with intra- and intermolecular H-bonds, was analyzed. The anti-inflammatory potential of 1, evaluated by means of the rat-paw-edema assay, with carrageenan as inflammation stimulus, was found to be similar high as that of indomethacin. In contrast, benzophenone proper (2) was hardly active in this assay. Our results indicate that these anti-inflammatory effects are related to the action of kinins and prostaglandins. The radical-scavenging properties of 1 towards DPPH were found to be similar as those of typical phenolics, but somewhat lower than that of ascorbic acid. The structure-activity relationship (SAR) of 1 is discussed.     

Soil multitrophic network complexity enhances the link between biodiversity and multifunctionality in agricultural systems

Belowground biodiversity supports multiple ecosystem functions and services that humans rely on. However, there is a dearth of studies exploring the determinants of the biodiversity–ecosystem function (BEF) relationships, particularly in intensely managed agricultural ecosystems. Here, we reported significant and positive relationships between soil biodiversity of multiple organism groups and multiple ecosystem functions in 228 agricultural fields, relating to crop yield, nutrient provisioning, element cycling, and pathogen control. The relationships were influenced by the types of organisms that soil phylotypes with larger sizes or at higher trophic levels, for example, invertebrates or protist predators, appeared to exhibit weaker or no BEF relationships when compared to those with smaller sizes or at lower trophic levels, for example, archaea, bacteria, fungi, and protist phototrophs. Particularly, we highlighted the role of soil network complexity, reflected by co-occurrence patterns among multitrophic-level organisms, in enhancing the link between soil biodiversity and ecosystem functions. Our results represent a significant advance in forecasting the impacts of belowground multitrophic organisms on ecosystem functions in agricultural systems, and suggest that soil multitrophic network complexity should be considered a key factor in enhancing ecosystem productivity and sustainability under land-use intensification.     

Exploring the antimalarial potential of the methoxy-thiazinoquinone scaffold: Identification of a new lead candidate

A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action.     

Food sharing and affiliation: An experimental and longitudinal study in cockatiels (Nymphicus hollandicus)

Food sharing has attracted much attention because of its apparently altruistic nature and its link to prosociality. However, food sharing has been mostly studied in a reproductive context, during courtship and parental care, where the fitness benefits are obvious. We still lack a clear understanding of the functions of food sharing outside any reproductive context and within social groups of same‐aged peers. Previous studies suggest that cofeeding, the action to let another animal feed from the same monopolizable food source, may be used to build and strengthen bonds between individuals. This may be particularly crucial in social birds forming long‐term associations between mates or siblings such as psittacids and corvids. Here, we investigated food sharing and affiliative behaviors such as allopreening in a psittacine species, namely in a group of captive juvenile cockatiels (Nymphicus hollandicus) consisting of five siblings and five unrelated birds. Our main objective was to study the developmental pattern of food sharing over time and its implication in social bonding depending on kinship, affiliation, and sex. Studying cockatiels in this context is providing many new information since most of the studies on food sharing in birds focused on corvids. We found that, contrary to jackdaws, cockatiels continued to share food with multiple individuals, although the frequency of cofeeding as well as the number of cofeeding partners decreased over time. Cockatiels shared more food with their siblings than with other conspecifics but they were not more likely to do cofeeding with birds of the opposite sex. We also found evidence that young cockatiels exchanged more food with those from whom they received food (reciprocity) and, to a lesser extent, allopreening (interchange), than from other cockatiels. Our findings suggest that in cockatiels, food sharing within social groups serves the formation (and maintenance) of affiliative bonds, especially between siblings, rather than pair bonds, but might additionally be explained by reciprocity, interchange, and harassment avoidance.     

Solution structure of P01, a natural scorpion peptide structurally analogous to scorpion toxins specific for apamin-sensitive potassium channel

The venom of the North African scorpion Androctonus mauretanicus mauretanicus possesses numerous highly active neurotoxins that specifically bind to various ion channels. One of these, P05, has been found to bind specifically to calcium-activated potassium channels and also to compete with apamin, a toxin extracted from bee venom. Besides the highly potent ones, several of these peptides (including that of P01) have been purified and been found to possess only a very weak, although significant, activity in competition with apamin. The amino acid sequence of P01 shows that it is shorter than P05 by two residues. This deletion occurs within an α-helix stretch (residues 5–12). This α-helix has been shown to be involved in the interaction of P05 with its receptor via two arginine residues. These two arginines are absent in the P01 sequence. Furthermore, a proline residue in position 7 of the P01 sequence may act as an α-helix breaker. We have determined the solution structure of P01 by conventional two-dimensional ¹H nuclear magnetic resonance and show that 1) the proline residue does not disturb the α-helix running from residues 5 to 12; 2) the two arginines are topologically replaced by two acidic residues, which explains the drop in activity; 3) the residual binding activity may be due to the histidine residue in position 9; and 4) the overall secondary structure is conserved, i.e., an α-helix running from residues 5 to 12, two antiparallel stretches of β-sheet (residues 15–20 and 23–27) connected by a type I′ β-turn, and three disulfide bridges connecting the α-helix to the β-sheet.     

Male-female affiliative relationships in naturally occurring ringtailed lemurs (Lemur catta) at the Beza-Mahafaly Reserve,Madagascar

Affiliative behavior between adult male and female ringtailed lemurs was examined as part of a project concerning male affiliation with conspecifics of all age/sex classes. Males in three social groups were studied over a 12 month period. Male-female preferred partnerships existed, and were variable according to reproductive season. Dominance rank, age, or tenure of the male did not appear to affect either the number of partnerships or frequency of affiliative behaviors that males had with females. However, males residing in groups with fewer males exhibited both higher frequencies of affiliative interactions with females and were nearest neighbors to females more often than males living in a group containing more males. Females were found to be responsible for proximity maintenance of male-female dyads in the majority of cases. Neither reproductive season nor seasonal availability of food resources strongly affected the frequency of affiliative interactions between males and females, it is proposed that an important aspect of successful group membership for male ringtailed lemurs relates to the development of social relationships with adult females. Males can benefit from such relationships in terms of greater centrality to the spatial core of the group, which can result in enhanced predator protection, greater opportunities for social contact, and potentially greater access to estrous females. © 1996 Wiley-Liss, Inc.