Therapeutic doses of nonsteroidal anti-inflammatory drugs inhibit osteosarcoma MG-63 osteoblast-like celss maturation, viability, and biomineralization potential

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to reduce pain and inflammation. However, their effect on bone metabolisms is not well known, and results in the literature are contradictory. The present study focusses on the effect of dexketoprofen, ketorolac, metamizole, and acetylsalicylic acid, at therapeutic doses, on different biochemical and phenotypic pathways in human osteoblast-like cells. Osteoblasts (MG-63 cell line) were incubated in culture medium with 1–10  M of dexketoprofen, ketorolac, metamizole, and acetylsalicylic acid. Flow cytometry was used to study antigenic profile and phagocytic activity. The osteoblastic differentiation was evaluated by mineralization and synthesis of collagen fibers by microscopy and alkaline phosphatase activity (ALP) by spectrophotometric assay. Short-term treatment with therapeutic doses of NSAIDs modulated differentiation, antigenic profile, and phagocyte activity of osteoblast-like cells. The treatment reduced ALP synthesis and matrix mineralization. However, nonsignificant differences were observed on collagen syntheses after treatments. The percentage of CD54 expression was increased with all treatments. CD80, CD86, and HLA-DR showed a decreased expression, which depended on NSAID and the dose applied. The treatments also decreased phagocyte activity in this cellular population. The results of this paper provide evidences that NSAIDs inhibit the osteoblast differentiation process thus reducing their ability to produce new bone mineralized extracellular matrix.This study was supported by the BIO277 research group (Junta de Andalucía), by the Department of Nursing, Faculty of Health Sciences, University of Granada and by the research group Brighton Studies in Tissue-mimicry and Aided Regeneration (BrightSTAR), School of Pharmacy & Biomolecular Sciences, University of Brighton

Anti-angiogenic potential of VEGF blocker dendron-laden gellan gum hydrogels for tissue engineering applications

Damage of non-vascularised tissues such as cartilage and cornea can result in healing processes accompanied by a non-physiological angiogenesis. Peptidic aptamers have recently been reported to block the vascular endothelial growth factor (VEGF). However, the therapeutic applications of these aptamers is limited due to their short half-life in vivo. In this work, an enhanced stability and bioavailability of a known VEGF blocker aptamer sequence (WHLPFKC) was pursued through its tethering of molecular scaffolds based on hyperbranched peptides, the poly(É -lysine) dendrons, bearing three branching generations. The proposed design allowed simultaneous and orderly-spaced exposure of sixteen aptamers per dendrimer to the surrounding biological microenvironent, as well as a relatively hydrophobic core based on di-phenylalanine aiming to promote an hydrophobic interaction with the hydrophobic moieties of ionically-crosslinked metacrylated gellan gum (iGG-MA) hydrogels. The VEGF blocker dendrons were entrapped in iGG-MA hydrogels and their capacity to prevent endothelial cell sprouting was assessed qualitatively and quantitatively using 3D in vitro models and the in vivo chick chorioallantoic membrane (CAM) assay. The data demonstrate that at nanoscale concentrations, the dendronised structures were able to enhance control of the biological actvity of WHLPFKC at the material/tissue interface and hence the anti-angiogenic capacity of iGG-MA hydrogels not only preventing blood vessel invasion, but also inducing their regression at the tissue/iGG-MA interface. The in ovo study confirmed that iGG-MA functionalised with the dendron VEGF blockers do inhibit angiogenesis by controlling both size and ramifications of blood vessels in proximity of the implanted gel surface.This work was mainly supported by the EC FP7 project Disc Regeneration (Contract No NMP3-LA-2008-213904). This study was also funded by the EC FP7 Programme contract agreement no REGPOT-CT2012-316331-POLARIS

Functionalisation of methacrylated gellan gum hydrogels by anti-angiogenic dendrons

The regeneration of cartilage in the intervertebral disc nucleus pulposus and joints is impaired by the formation of fibrocartilage that is caused by the invasion of the tissue by blood vessels. Peptides have been identified by phage display technique which are able to bind VEGF thus inhibiting angiogenesis. The present works focusses on the synthesis of poly(epsilon-lysine) dendrons of three branching generations in which the molecular root of the dendron bears a di-phenylalanine sequence to promote hydrophobic interactions with material surfaces and the uppermost molecular branches are functionalised with the amino acid sequenceWHLPFKC that is known to block VEGF. These biofunctionalised dendrons were entrapped in methacrylated Gellan Gum (GG-MA) hydrogels and tested for their ability to inhibit endothelial cell sprouting by both a 3D in vitro cell models and an in ovo model. The results show that when GG-MA is functionalised with the dendronised VEGF blockers, a regression of angiogenesis takes place around the hydrogel boundary. The in ovo study supports these findings as the GG-MA functionalised with the dendronised VEGF blockers did not elicit any acute inflammatory response, and decrease the number of converging macroscopic blood vessels as compared to positive controls. Moreover, the hydrogels prevented the infiltration of blood vessels, after 4 days of implantation.Fundação para a Ciência e TecnologiaEU 7th Framework ProgrammeMICINNJunta de Castilla y LeónCIBER-BBNFundo Social EuropeuPrograma Operacional Potencial Human

Feasibility randomized-controlled trial of online acceptance and commitment therapy for painful peripheral neuropathy in people living with HIV: The OPEN study

Background Neuropathic pain negatively affects quality of life among people living with HIV (PLWH). This study examined the feasibility of conducting a full‐scale randomized‐controlled trial of online acceptance and commitment therapy (“ACT OPEN”) for neuropathic pain in PLWH. Methods Using a parallel‐groups design, thirty‐eight participants were randomized to ACT OPEN or a waitlist control (2:1). Participants completed standard self‐report outcome measures at baseline, and two‐ and five‐months post‐randomization. Participants were aware of their allocation, but assessment was blinded. Results Twenty‐five participants were randomized to ACT OPEN and 13 to the control (of 133 referrals). ACT OPEN completion was 69% and two‐month trial retention was 82%. Treatment credibility and satisfaction scores for ACT OPEN were comparable to scores reported in previous trials of cognitive‐behavioural treatments for pain. Four adverse events were reported during the study, including one serious adverse event; all of these were unrelated to the research procedures. Small to moderate effects and 95% confidence intervals suggest that the true effect may favour ACT OPEN for improvements in pain intensity/interference and depression. Conclusions A full‐scale RCT of online ACT for pain management in PLWH may be feasible with refinements to trial design to facilitate recruitment. Significance Research on pain management in people living with HIV has primarily focused on pharmacological treatments with limited success. This is the first study to show the potential feasibility of a psychological treatment based on acceptance and commitment therapy delivered online and tailored for pain management in people with HIV (“ACT OPEN”). ACT OPEN may be a promising treatment in this population and further evaluation in a full‐scale randomized‐controlled trial appears warranted. Trial Registration: The trial was registered (clinicaltrials.gov; NCT03584412)

Basin-Scale Control on the Phytoplankton Biomass in Lake Victoria, Africa

The relative bio-optical variability within Lake Victoria was analyzed through the spatio-temporal decomposition of a 1997–2004 dataset of remotely-sensed reflectance ratios in the visible spectral range. Results show a regular seasonal pattern with a phase shift (around 2 months) between the south and north parts of the lake. Interannual trends suggested a teleconnection between the lake dynamics and El-Niño phenomena. Both seasonal and interannual patterns were associated to conditions of light limitation for phytoplankton growth and basin-scale hydrodynamics on phytoplankton access to light. Phytoplankton blooms developed during the periods of lake surface warming and water column stability. The temporal shift apparent in the bio-optical seasonal cycles was related to the differential cooling of the lake surface by southeastern monsoon winds. North-south differences in the exposure to trade winds are supported by the orography of the Eastern Great Rift Valley. The result is that surface layer warming begins in the northern part of the lake while the formation of cool and dense water continues in the southern part. The resulting buoyancy field is sufficient to induce a lake-wide convective circulation and the tilting of the isotherms along the north-south axis. Once surface warming spreads over the whole lake, the phytoplankton bloom dynamics are subjected to the internal seiche derived from the relaxation of thermocline tilting. In 1997–98, El-Niño phenomenon weakened the monsoon wind flow which led to an increase in water column stability and a higher phytoplankton optical signal throughout the lake. This suggests that phytoplankton response to expected climate scenarios will be opposite to that proposed for nutrient-limited great lakes. The present analysis of remotely-sensed bio-optical properties in combination with environmental data provides a novel basin-scale framework for research and management strategies in Lake Victoria

Effects of Total Resources, Resource Ratios, and Species Richness on Algal Productivity and Evenness at Both Metacommunity and Local Scales

The study of the interrelationship between productivity and biodiversity is a major research field in ecology. Theory predicts that if essential resources are heterogeneously distributed across a metacommunity, single species may dominate productivity in individual metacommunity patches, but a mixture of species will maximize productivity across the whole metacommunity. It also predicts that a balanced supply of resources within local patches should favor species coexistence, whereas resource imbalance would favor the dominance of one species. We performed an experiment with five freshwater algal species to study the effects of total supply of resources, their ratios, and species richness on biovolume production and evenness at the scale of both local patches and metacommunities. Generally, algal biovolume increased, whereas algal resource use efficiency (RUE) and evenness decreased with increasing total supply of resources in mixed communities containing all five species. In contrast to predictions for biovolume production, the species mixtures did not outperform all monocultures at the scale of metacommunities. In other words, we observed no general transgressive overyielding. However, RUE was always higher in mixtures than predicted from monocultures, and analyses indicate that resource partitioning or facilitation in mixtures resulted in higher-than-expected productivity at high resource supply. Contrasting our predictions for the local scale, balanced supply of resources did not generally favor higher local evenness, however lowest evenness was confined to patches with the most imbalanced supply. Thus, our study provides mixed support for recent theoretical advancements to understand biodiversity-productivity relationships

Connecting the Dots: Responses of Coastal Ecosystems to Changing Nutrient Concentrations

Empirical relationships between phytoplankton biomass and nutrient concentrations established across a wide range of different ecosystems constitute fundamental quantitative tools for predicting effects of nutrient management plans. Nutrient management plans based on such relationships, mostly established over trends of increasing rather than decreasing nutrient concentrations, assume full reversibility of coastal eutrophication. Monitoring data from 28 ecosystems located in four well-studied regions were analyzed to study the generality of chlorophyll a versus nutrient relationships and their applicability for ecosystem management. We demonstrate significant differences across regions as well as between specific coastal ecosystems within regions in the response of chlorophyll a to changing nitrogen concentrations. We also show that the chlorophyll a versus nitrogen relationships over time constitute convoluted trajectories rather than simple unique relationships. The ratio of chlorophyll a to total nitrogen almost doubled over the last 30-40 years across all regions. The uniformity of these trends, or shifting baselines, suggest they may result from large-scale changes, possibly associated with global climate change and increasing human stress on coastal ecosystems. Ecosystem management must, therefore, develop adaptation strategies to face shifting baselines and maintain ecosystem services at a sustainable level rather than striving to restore an ecosystem state of the past. © 2011 American Chemical Society.This research is a contribution to the Thresholds Integrated Project (contract FP6-003933-2) and WISER (contract FP7-226273), funded by the European Commission.Peer Reviewe