A novel Golgi mannosidase inhibitor: Molecular design,synthesis, enzyme inhibition,and inhibition of spheroid formation

Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition.     

Acute effects of Amomum villosum Lour. fruit extract on postprandial glycemia and insulin secretion: A single-blind,placebo-controlled,crossover study in healthy subjects

BackgroundAmomum villosum Lour., (Zingiberaceae) an herbaceous plant in the ginger family, has been used to treat various diseases. In a single-blind, randomized, crossover study, we assessed the postprandial blood insulin and blood glucose responses in healthy subjects (n = 40) after the Amomum villosum water extract (AVE) (5 g/person) or a placebo (5 g/person) consumption.MethodsDuring each treatment course, the healthy subject consumed a regular late afternoon meal, followed by fasting for 12 h, and arrived at the clinical study center the next morning. Blood insulin and blood glucose levels were assessed at 0, 30, 60, 90, and 120 min after AVE consumption. Between each treatment, the subjects accomplished one week of a washout period.ResultsThe AVE intake demonstrated a significant (67.26%) decline in postprandial blood glucose AUC_{0–120 min} (incremental area under the curve from 0 to 120 min) versus the placebo (P = 0.011). Furthermore, AVE reduced postprandial blood insulin AUC_{0–120 min} by 59.95% compared to the placebo group (P < 0.003), supporting the blood glucose results.ConclusionThis study revealed that AVE consumption significantly reduced postprandial insulin and glucose levels in healthy individuals, due in part to inhibition of α-glucosidase, and glucose transport.     

Demographic population structure of black howler monkeys in fragmented and continuous forest in Chiapas,Mexico: Implications for conservation

For wild primates, demography studies are increasingly recognized as necessary for assessing the viability of vulnerable populations experiencing rapid environmental change. In particular, anthropogenic changes such as habitat loss and fragmentation can cause ecological and behavioral changes in small, isolated populations, which may, over time, alter population density and demographic structure (age/sex classes and group composition) in fragment populations relative to continuous forest populations. We compared our study population of Endangered black howler monkeys (Alouatta pigra) in 34 forest fragments around Palenque National Park (PNP), Mexico (62 groups, 407 individuals), to the adjacent population in PNP, protected primary forest (21 groups, 134 individuals), and to previous research on black howlers in fragments in our study area (18 groups, 115 individuals). We used χ² and Mann–Whitney U tests to address the questions: (a) what is the current black howler demographic population structure in unprotected forest fragments around PNP? (b) How does it compare to PNP's stable, continuous population? (c) How has it changed over time? Compared to the PNP population, the fragment populations showed higher density, a significantly lower proportion of multimale groups, and significantly fewer adult males per group. The population's age/sex structure in the fragmented landscape has been stable over the last 17 years, but differed in a higher proportion of multifemale groups, higher density, and higher patch occupancy in the present. In the context of conservation, some of our results may be positive as they indicate possible population growth over time. However, long-term scarcity of adult males in fragments and associated effects on population demographic structure might be cause for concern, in that it may affect gene flow and genetic diversity. The scarcity of adult males might stem from males experiencing increased mortality while dispersing in the fragmented landscape, whereas females might be becoming more philopatric in fragments.     

Life in a fragment: Evolution of foraging strategies of translocated collared brown lemurs,Eulemur collaris,over an 18-year period

While the drivers of primate persistence in forest fragments have been often considered at the population level, the strategies to persist in these habitats have been little investigated at the individual or group level. Considering the rapid variation of fragment characteristics over time, longitudinal data on primates living in fragmented habitats are necessary to understand the key elements for their persistence. Since translocated animals have to cope with unfamiliar areas and face unknown fluctuations in food abundance, they offer the opportunity to study the factors contributing to successful migration between fragments. Here, we illustrated the evolution of the foraging strategies of translocated collared brown lemurs (Eulemur collaris) over an 18-year period in the Mandena Conservation Zone, south-east Madagascar. Our aim was to explore the ability of these frugivorous lemurs to adjust to recently colonized fragmented forests. Although the lemurs remained mainly frugivorous throughout the study period, over the years we identified a reduction in the consumption of leaves and exotic/pioneer plant species. These adjustments were expected in frugivorous primates living in a degraded area, but we hypothesize that they may also reflect the initial need to cope with an unfamiliar environment after the translocation. Since fragmentation is often associated with the loss of large trees and native vegetation, we suggest that the availability of exotic and/or pioneer plant species can provide an easy-to-access, nonseasonal food resource and be a key factor for persistence during the initial stage of the recolonization.     

Individualistic responses of forest herb traits to environmental change

• Intraspecific trait variation (ITV; i.e. variability in mean and/or distribution of plant attribute values within species) can occur in response to multiple drivers. Environmental change and land‐use legacies could directly alter trait values within species but could also affect them indirectly through changes in vegetation cover. Increasing variability in environmental conditions could lead to more ITV, but responses might differ among species. Disentangling these drivers on ITV is necessary to accurately predict plant community responses to global change.
• We planted herb communities into forest soils with and without a recent history of agriculture. Soils were collected across temperate European regions, while the 15 selected herb species had different colonizing abilities and affinities to forest habitat. These mesocosms (384) were exposed to two‐level full‐factorial treatments of warming, nitrogen addition and illumination. We measured plant height and specific leaf area (SLA).
• For the majority of species, mean plant height increased as vegetation cover increased in response to light addition, warming and agricultural legacy. The coefficient of variation (CV) for height was larger in fast‐colonizing species. Mean SLA for vernal species increased with warming, while light addition generally decreased mean SLA for shade‐tolerant species. Interactions between treatments were not important predictors.
• Environmental change treatments influenced ITV, either via increasing vegetation cover or by affecting trait values directly. Species’ ITV was individualistic, i.e. species responded to different single resource and condition manipulations that benefited their growth in the short term. These individual responses could be important for altered community organization after a prolonged period.

     

A scaffold replacement approach towards new sirtuin 2 inhibitors

Sirtuins (SIRT1–SIRT7) are an evolutionary conserved family of NAD⁺-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.     

Biological control of pedological and hydro-geomorphological processes in a deciduous forest ecosystem

This study describes the effect of soil fauna and vegetation on the development of landscapes and how these actually control soil formation, geomorphological development and hydrological response. The study area is located in a semi-natural deciduous forest on marl in Luxembourg, with a strong texture contrast in the soil at 15–25 cm depth (luvic planosols). The methodology applied is both based on hydrological and geomorphological field measurements on runoff, sediment yield, perched water table dynamics, geomorphological survey, pedological survey and measurements related to in situ ectorganic horizon dynamics and litter decay, soil animal activity, as well as measurements of dynamic soil properties such as soil moisture and swelling and shrinkage. The results show that there is a positive feedback between tree type, soil fauna activity and the development of pipes, partial areas, soils and geomorphology. The landscape can be divided into two main types: Areas where Stellario-Carpinetum vegetation and partial areas are common and areas with Milio-Fagetum vegetation on dry slopes, which are differentiating more and more over time as a result of ongoing geo-ecosystem processes, and which also reflected in their sediment yield. The hydrological response is highly different for both landscape compartments as they are dominated by matrix (Beech) and pipe flow (Hornbeam) respectively. Soil fauna and tree type drive both soil and geomorphological evolution and they both can be considered as important ecosystem engineers.     

Anthropogenic Soils and Tree Distributions in a Lowland Forest in Bolivia

The distributions of 17 tree species with seeds or fruits that are commonly eaten or otherwise used by humans were studied in reference to anthropogenic soils in a seasonally dry lowland tropical forest in Bolivia. Two types of anthropogenic dark earths (ADEs) were identified: terra preta (TP: darkened with charcoal fragments and with abundant pottery shards) and terra mulata (TM: somewhat darkened but with little or no pottery). In 216 ha, we compared the densities of trees >10 cm dbh of useful species in nine TP patches, three TM patches, and six areas with nonanthropogenic soils (N-ADE). The TP, which covers approximately 20 percent of the sample area, has higher contents of organic matter, extractable P, and extractable Ca than N-ADE soils, as well as higher pH and extractable P than TM. TM has organic matter and Ca contents similar to N-ADE soils but significantly less extractable K. In general, TP has higher nutrient content than surrounding soils, both at the surface (0–10 cm) and deeper in the profile (40–50 cm). Despite these differences in soil fertility and contrary to our expectations, none of the 17 tree species were concentrated on TP perhaps because interactions between local dispersal agents and natural disturbances have masked historical patterns. Alternatively, past inhabitants of the study area may have enriched forests with useful tree species in areas where they were not practicing the intensive soil husbandry that results in ADEs.