The β3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.

Background This work presents a forecast model for non-typhoidal salmonellosis outbreaks. Method This forecast model is based on fitted values of multivariate regression time series that consider diagnosis and estimation of different parameters, through a very flexible statistical treatment called generalized auto-regressive and moving average models (GSARIMA). Results The forecast model was validated by analyzing the cases of Salmonella enterica serovar Enteritidis in Sydney Australia (2014–2016), the environmental conditions and the consumption of high-risk food as predictive variables. Conclusions The prediction of cases of Salmonella enterica serovar Enteritidis infections are included in a forecast model based on fitted values of time series modeled by GSARIMA, for an early alert of future outbreaks caused by this pathogen, and associated to high-risk food. In this context, the decision makers in the epidemiology field can led to preventive actions using the proposed model.

Most studies of inventory consolidation effects assume time-independent random demand. In this article, we consider time-dependence by incorporating an autoregressive moving average structure to model the demand for products. With this modeling approach, we analyze the effect of consolidation on inventory costs compared to a system without consolidation. We formulate an inventory setting based on continuous-review using allocation rules for regular transshipment and centralization, which establishes temporal structures of demand. Numerical simulations demonstrate that, under time-dependence, the demand conditional variance, based on past data, is less than the marginal variance. This finding favors dedicated locations for inventory replenishment. Additionally, temporal structures reduce the costs of maintaining safety stocks through regular transshipments when such temporal patterns exist. The obtained results are illustrated with an example using real-world data. Our investigation provides information for managing supply chains in the presence of time-patterned demands that can be of interest to decision-makers in the supply chain.

Here we describe modified syntheses of o-acetylbenzoic acids­ and o-acetylphenylacetic acids by Heck palladium-catalysed aryl­ation of n-butyl vinyl ether with o-iodobenzoic acids or with o-iodo­phenylacetic acids, respectively. General syntheses of benzo[b]naphtho[2,3-b]furan-6,11-diones from o-acetylbenzoic acids and 2-benzyl-3-hydroxynaphthalene-1,4-diones from o-acetylphenylacetic acids are also reported.

Detecting antibiotic residues is vital to minimize their impact. Yet, existing methods are complex and costly. Biosensors offer an alternative. While many biosensors detect various antibiotics, specific ones for beta-lactams are lacking. To address this gap, a biosensor based on the AmpC beta-lactamase regulation system (ampR–ampC) from Pseudomonas sp. IB20, an Antarctic isolate, was developed in this study. The AmpR–AmpC system is well-conserved in the genus Pseudomonas and has been extensively studied for its involvement in peptidoglycan recycling and beta-lactam resistance. To create the biosensor, the ampC coding sequence was replaced with the mCherry fluorescent protein as a reporter, resulting in a transcriptional fusion. This construct was then inserted into Escherichia coli SN0301, a beta-lactam hypersensitive strain, generating a whole-cell biosensor. The biosensor demonstrated dose-dependent detection of penicillins, cephalosporins and carbapenems. However, the most interesting aspect of this work is the high sensitivity presented by the biosensor in the detection of carbapenems, as it was able to detect 8 pg/mL of meropenem and 40 pg/mL of imipenem and reach levels of 1–10 ng/mL for penicillins and cephalosporins. This makes the biosensor a powerful tool for the detection of beta-lactam antibiotics, specifically carbapenems, in different matrices.

Background: Blueberries are polyphenol-rich fruits with antioxidant and anti-inflammatory properties. Polyphenols from berries act by blocking digestive enzymes, reshaping gastrointestinal microbiota, and affecting the release of gastrointestinal hormones to regulate insulin dynamics and glucose management. However, most studies use fruit extracts instead of fresh fruit. We aimed to evaluate postprandial glucose management and antioxidant capacity of fresh blueberries consumed acutely or as a six-day supplementation in 10 sedentary subjects. Methods: To evaluate the effect of acute blueberry intake, 150 g of blueberries were consumed together with 150 g of white bread by the subject and blood samples were collected at 0, 30, 60, 90 and 120 min to measure glucose, insulin, and plasma antioxidant capacity. To evaluate supplementation, 150 g of blueberries were provided daily for six days and sample collection was performed at day 7. Results: Acute consumption of blueberries decreased postprandial glucose area under the curve (AUC) and increased insulin levels at 15 min timepoint. Supplementation did not affect glucose levels but decreased insulin levels at 120 min. No changes in antioxidant capacity were observed. Conclusions: Consumption of fresh blueberries improves postprandial glucose management presumably due to actions on the gastrointestinal tract, while supplementation improves insulin sensitivity, probably due antioxidant and anti-inflammatory effects.

Introduction: The hippocampus is especially susceptible to age-associated neuronal pathologies, and there is concern that the age-associated rise in cortisol secretion from the adrenal gland may contribute to their etiology. Furthermore, because 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) catalyzes the reduction of cortisone to the active hormone cortisol, it is plausible that an increase in the expression of this enzyme enhances the deleterious impact of cortisol in the hippocampus and contributes to the neuronal pathologies that underlie cognitive decline in the elderly. Methods: Rhesus macaques were used as a translational animal model of human aging, to examine age-related changes in gene and protein expressions of (HSD11B1/HSD11B1) in the hippocampus, a region of the brain that plays a crucial role in learning and memory. Results: Older animals showed significantly (p < 0.01) higher base-line cortisol levels in the circulation. In addition, they showed significantly (p < 0.05) higher hippocampal expression of HSD11B1 but not NR3C1 and NR3C2 (i.e., two receptor-encoding genes through which cortisol exerts its physiological actions). A similar age-related significant (p < 0.05) increase in the expression of the HSD11B1 was revealed at the protein level by western blot analysis. Discussion: The data suggest that an age-related increase in the expression of hippocampal HSD11B1 is likely to raise cortisol concentrations in this cognitive brain area, and thereby contribute to the etiology of neuropathologies that ultimately lead to neuronal loss and dementia. Targeting this enzyme pharmacologically may help to reduce the negative impact of elevated cortisol concentrations within glucocorticoid-sensitive brain areas and thereby afford neuronal protection.

Governments must consider different issues when deciding on the location of healthcare centers. In addition to the costs of opening such centers, three further elements should be addressed: accessibility, demand, and equity. Such locations must be chosen to meet the corresponding demand, so that they guarantee a socially equitable distribution, and to ensure that they are accessible to a sufficient degree. The location of the centers must be chosen from a set of possible facilities to guarantee certain minimum standards for the operational viability of the centers. Since the set of potential locations does not necessarily cover the demand of all geographical zones, the efficiency criterion must be maximized. However, the efficient distribution of resources does not necessarily meet the equity criterion. Thus, decision-makers must consider the trade-off between these two criteria: efficiency and equity. The described problem corresponds to the challenge that governments face in seeking to minimize the impact of the pandemic on citizens, where healthcare centers may be either public hospitals that care for COVID-19 patients or vaccination points. In this paper, we focus on the problem of a zone-divided region requiring the localization of healthcare centers. We propose a non-linear programming model to solve this problem based on a coverage formula using the Gini index to measure equity and accessibility. Then, we consider an approach using epsilon constraints that makes this problem solvable with mixed integer linear computations at each iteration. A simulation algorithm is also considered to generate problem instances, while computational experiments are carried out to show the potential use of the proposed mathematical programming model. The results show that the spatial distribution influences the coverage level of the healthcare system. Nevertheless, this distribution does not reduce inequity at accessible healthcare centers, as the distribution of the supply of health centers must be incorporated into the decision-making process.

The combination of oleic acid and keracyanin had greater effects than either compound alone, targeting the NFκB cascade reducing secretion of pro-inflammatory cytokines and increasing anti-inflammatory status in THP-1 cells.

BACKGROUND The antifeedant activity of 18 sesquiterpenoids of the drimane family (polygodial, drimenol and derivatives) was investigated. RESULTS Polygodial, drimanic and nordrimanic derivatives were found to exert antifeedant effects against two insect species, Spodoptera frugiperda and Epilachna paenulata, which are pests of agronomic interest, indicating that they have potential as biopesticide agents. Among the 18 compounds tested, the epoxynordrimane compound (11) and isonordrimenone (4) showed the highest activity [50% effective concentration (EC50) = 23.28 and 25.63 nmol cm−2, respectively, against S. frugiperda, and 50.50 and 59.00 nmol/cm2, respectively, against E. paenulata]. CONCLUSION The results suggest that drimanic compounds have potential as new agents against S. frugiperda and E. paenulata. A quantitative structure–activity relationship (QSAR) analysis of the whole series, supported by electronic studies, suggested that drimanic compounds have structural features necessary for increasing antifeedant activity, namely a C-9 carbonyl group and an epoxide at C-8 and C-9. © 2018 Society of Chemical Industry

Defatted rapeseed meal (DRM) is a sub-valorized agro-industrial by-product, with a high protein content whose peptides could have potential anticancer activity against cancer cell lines. The objective of the present study is to obtain an enzymatic hydrolysate of rapeseed protein that inhibits proliferation on a breast cancer cell line (MCF-7), but not healthy human fibroblast cells. The DRM was solubilized in an alkaline medium to obtain an alkaline rapeseed extract (RAE). Acid precipitation of the proteins contained in RAE recovered a rapeseed protein isolate (RPI). To produce protein hydrolysates, two alkaline protease and different enzyme/substrate ratios were used. All the protein hydrolysates showed antiproliferative activity on MCF-7 cells. However, only the hydrolysate recovered from the enzymatic hydrolysis of RPI (Degree of hydrolysis (DH ) between 8.5 and 9% (DH1)) did not affect human fibroblast cells, inhibiting 83.9% of MCF-7 cells’ proliferation and showing a mass yield of 22.9% (based on the initial DRM). The SDS-PAGE gel revealed that DH1 was composed mainly of 10 kDa peptides and, to a lesser extent, 5 and 2 kDa. It is concluded that DH1 is a promising peptide extract for future research as a putative anti-breast cancer agent.

Conjugated linoleic acid (CLA) isomers have been shown to possess anti-atherosclerotic properties, which may be related to the downregulation of inflammatory pathways. Whether low concentrations of CLAs are able to affect basal, unstimulated endothelial cell (EC) responses is not clear. The aim of this study was to evaluate the effects of two CLAs (cis-9, trans-11 and trans-10, cis-12) on basal inflammatory responses by ECs. EA.hy926 cells (HUVEC lineage) were cultured under standard conditions and exposed to CLAs (1 and 10 μM) for 48 hours. MTT assay was performed to determine cell viability; incorporation of FA was confirmed by gas chromatography; inflammatory mediators were assessed by multiplex immunoassay; the relative expression of genes encoding transcription factors and inflammatory cytokines was assessed through real-time PCR and static adhesion assay was used to evaluate monocyte attachment to the EC monolayer. CLAs were incorporated into ECs in a dose-dependent manner. Pre-treatment with CLA9,11 (1 uM) significantly reduced unstimulated, basal concentrations of MCP-1 (p < 0.05), and CLA10,12 at 10 uM had the same effect (p < 0.05). Both CLAs at 10 uM increased the relative expression of NFκβ (p < 0.01 and p < 0.05, respectively), while decreasing the relative expression of PPARα (p < 0.0001), COX-2 (p < 0.0001) and IL-6 (p < 0.0001). In contrast, no effect was observed in the adhesion assay for either CLA. These results suggest that both CLAs at a low concentration have a neutral or modest anti-inflammatory effect in basal conditions, which may influence endothelial function and risk of vascular disease. Interestingly, at these low CLA concentrations some pro-inflammatory genes are upregulated while others are down regulated. This suggests complex effects of CLAs on inflammatory pathways.

In recent years, the design, development, and evaluation of several inhibitors of the BACE1 enzyme, as part of Alzheimer's treatment, have gathered the scientific community's interest. Here, a linear regression model was built using binding free energy calculations through the Bennett acceptance ratio method for 20 known inhibitors of the BACE1 enzyme, with a Pearson coefficient of R = 0.88 and R2 = 0.78. The validation of this model was verified employing eight additional random inhibitors, which also gave a linear correlation with R = 0.97 and R2 = 0.93. Furthermore, this linear regression model was also used for proposing the structure of four potential BACE1 inhibitors, and the most active of them gave a theoretical Kd = 10 nM. However, these molecules have not been synthesized yet. Our team used a total time of more than 800 ns for the Molecular Dynamics to carry out this study, and all the software used were freely available.

Tomato crops can be affected by several infectious diseases produced by bacteria, fungi, and oomycetes. Four phytopathogens are of special concern because of the major economic losses they generate worldwide in tomato production; Clavibacter michiganensis subsp. michiganensis and Pseudomonas syringae pv. tomato, causative agents behind two highly destructive diseases, bacterial canker and bacterial speck, respectively; fungus Fusarium oxysporum f. sp. lycopersici that causes Fusarium Wilt, which strongly affects tomato crops; and finally, Phytophthora spp., which affect both potato and tomato crops. Polygodial (1), drimenol (2), isonordrimenone (3), and nordrimenone (4) were studied against these four phytopathogenic microorganisms. Among them, compound 1, obtained from Drimys winteri Forst, and synthetic compound 4 are shown here to have potent activity. Most promisingly, the results showed that compounds 1 and 4 affect Clavibacter michiganensis growth at minimal inhibitory concentrations (MIC) values of 16 and 32 µg/mL, respectively, and high antimycotic activity against Fusarium oxysporum and Phytophthora spp. with MIC of 64 µg/mL. The results of the present study suggest novel treatment alternatives with drimane compounds against bacterial and fungal plant pathogens.

In this study, the essential oil (EO) from Laurelia sempervirens was analyzed by GC/MS and safrole (1) was identified as the major metabolite 1, was subjected to direct reactions on the oxygenated groups in the aromatic ring and in the side chain, and eight compounds (4 to 12) were obtained by the process. EO and compounds 4–12 were subjected to biological assays on 24 strains of the genus Saprolegnia, specifically of the species 12 S. parasitica and 12 S. australis. EO showed a significant effect against Saprolegnia strains. Compound 6 presents the highest activity against two resistant strains, with minimum inhibitory concentration (MIC) and minimum oomyceticidal concentration (MOC) values of 25 to 100 and 75 to 125 µg/mL, respectively. The results show that compound 6 exhibited superior activities compared to the commercial controls bronopol and azoxystrobin used to combat these pathogens.

Plant-microbiota interactions have significant effects on plant growth, health, and productivity. Rhizosphere microorganisms are involved in processes that promote physiological responses to biotic and abiotic stresses in plants. In recent years, the interest in microorganisms to improve plant productivity has increased, mainly aiming to find promising strains to overcome the impact of climate change on crops. In this work, we hypothesize that given the desertic environment of the Antarctic and the Atacama Desert, different plant species inhabiting these areas might share microbial taxa with functions associated with desiccation and drought stress tolerance. Therefore, in this study, we described and compared the composition of the rhizobacterial community associated with Deschampsia antarctica (Da), Colobanthus quitensis (Cq) from Antarctic territories, and Croton chilensis (Cc), Eulychnia iquiquensis (Ei) and Nicotiana solanifolia (Ns) from coastal Atacama Desert environments by using 16S rRNA amplicon sequencing. In addition, we evaluated the putative functions of that rhizobacterial community that are likely involved in nutrient acquisition and stress tolerance of these plants. Even though each plant microbial rhizosphere presents a unique taxonomic pattern of 3,019 different sequences, the distribution at the genus level showed a core microbiome with a higher abundance of Haliangium, Bryobacter, Bacillus, MND1 from the Nitrosomonadaceae family, and unclassified taxa from Gemmatiamonadaceae and Chitinophagaceae families in the rhizosphere of all samples analyzed (781 unique sequences). In addition, species Gemmatirosa kalamazoonesis and Solibacter usitatus were shared by the core microbiome of both Antarctic and Desert plants. All the taxa mentioned above had been previously associated with beneficial effects in plants. Also, this microbial core composition converged with the functional prediction related to survival under harsh conditions, including chemoheterotrophy, ureolysis, phototrophy, nitrogen fixation, and chitinolysis. Therefore, this study provides relevant information for the exploration of rhizospheric microorganisms from plants in extreme conditions of the Atacama Desert and Antarctic as promising plant growth-promoting rhizobacteria.

Conjugated linoleic acid (CLA) isomers may have a role in preventing atherosclerosis through the modulation of inflammation, particularly of the endothelium. However, whether low concentrations of CLAs are able to affect basal unstimulated endothelial cell (EC) responses is not clear. The aim of this study was to evaluate the effects of two CLAs (cis-9, trans-11 (CLA9,11) and trans-10, cis-12 (CLA10,12)) on the basal inflammatory responses by ECs. EA.hy926 cells (HUVEC lineage) were cultured under standard conditions and exposed to individual CLAs for 48 h. Both CLAs were incorporated into ECs in a dose-dependent manner. CLA9,11 (1 μM) significantly decreased concentrations of MCP-1 (p < 0.05), IL-6 (p < 0.05), IL-8 (p < 0.01) and RANTES (p < 0.05) in the culture medium. CLA10,12 (10 μM) decreased the concentrations of MCP-1 (p < 0.05) and RANTES (p < 0.05) but increased the concentration of IL-6 (p < 0.001). At 10 μM both CLAs increased the relative expression of the NFκβ subunit 1 gene (p < 0.01 and p < 0.05, respectively), while decreasing the relative expression of PPARα (p < 0.0001), COX-2 (p < 0.0001) and IL-6 (p < 0.0001) genes. CLA10,12 increased the relative expression of the gene encoding IκK-β at 10 μM compared with CLA9,11 (p < 0.05) and increased the relative expression of the gene encoding IκBα at 1 and 10 μM compared with linoleic acid (both p < 0.05). Neither CLA affected the adhesion of monocytes to ECs. These results suggest that low concentrations of both CLA9,11 and CLA10,12 have modest anti-inflammatory effects in ECs. Thus, CLAs may influence endothelial function and the risk of vascular disease. Nevertheless, at these low CLA concentrations some pro-inflammatory genes are upregulated while others are downregulated, suggesting complex effects of CLAs on inflammatory pathways.

This study aimed to determine the in vitro cytotoxicity and understand possible cytotoxic mechanisms via an in silico study of eleven chalcones synthesized from two acetophenones. Five were synthesized from a prenylacetophenone isolated from a plant that grows in the Andean region of the Atacama Desert. The cytotoxic activity of all the synthesized chalcones was tested against breast cancer cell lines using an MTT cell proliferation assay. The results suggest that the prenyl group in the A-ring of the methoxy and hydroxyl substituents of the B-ring appear to be crucial for the cytotoxicity of these compounds. The chalcones 12 and 13 showed significant inhibitory effects against growth in MCF-7 cells (IC50 4.19 ± 1.04 µM and IC50 3.30 ± 0.92 µM), ZR-75-1 cells (IC50 9.40 ± 1.74 µM and IC50 8.75 ± 2.01µM), and MDA-MB-231 cells (IC50 6.12 ± 0.84 µM and IC50 18.10 ± 1.65 µM). Moreover, these chalcones showed differential activity between MCF-10F (IC50 95.76 ± 1.52 µM and IC50 95.11 ± 1.97 µM, respectively) and the tumor lines. The in vitro results agree with molecular coupling results, whose affinity energies and binding mode agree with the most active compounds. Thus, compounds 12 and 13 can be considered for further studies and are candidates for developing new antitumor agents. In conclusion, these observations give rise to a new hypothesis for designing chalcones with potential cytotoxicity with high potential for the pharmaceutical industry.

Synthesis, MAO−B inhibitory activity and antioxidant profile of new prenylated chalcones obtained from the natural compound 5 (4-hydroxy-3-(3-methylbut-2-en-1-yl)phenylethanone), previously isolated from S. graveolens, are reported. Five compounds exhibit high inhibition and selectivity against MAO−B, with IC50 values in the low micromolar range. In addition, three compounds better antioxidants than butylated hydroxytoluene (BHT). Important features for MAO−B inhibitory activity were observed by docking analysis: H-bonding interaction between Tyr435, Tyr398 and FAD co-factor.

Endothelial dysfunction and inflammation are recognised factors in the development of atherosclerosis. Evidence suggests that intake of industrial trans fatty acids (TFAs) promotes endothelial dysfunction, while ruminant TFAs may have the opposite effect. The aim of this study was to compare the effects of elaidic acid (EA (18:1n-9t); an industrially produced TFA) and trans vaccenic acid (TVA (18:1n-7t); a natural TFA found in ruminant milk and meat) on inflammatory responses of endothelial cells (ECs). ECs (EA.hy926 cells) were cultured under standard conditions and exposed to TFAs (1 to 50 μM) for 48 h. Then, the cells were cultured for a further 6 or 24 h with tumour necrosis factor alpha (TNF-α, 1 ng/mL) as an inflammatory stimulant. ECs remained viable after treatments. TFAs were incorporated into ECs in a dose-dependent manner. Preincubation with EA (50 µM) increased production of MCP-1, RANTES, and IL-8 in response to TNF-α, while preincubation with TVA (1 µM) decreased production of ICAM-1 and RANTES in response to TNF-α. Preincubation with EA (50 µM) upregulated toll-like receptor 4 and cyclooxygenase 2 gene expression in response to TNF-α. In contrast, preincubation with TVA (1 µM) downregulated TNF-α induced nuclear factor kappa B subunit 1 gene expression. Preincubation of ECs with EA (50 µM) increased THP-1 monocyte adhesion. In contrast, preincubation of ECs with TVA (1 µM) reduced THP-1 monocyte adhesion, while preincubation of ECs with TVA (50 µM) decreased the level of surface expression of ICAM-1 seen following TNF-α stimulation. The results suggest that TVA has some anti-inflammatory properties, while EA enhances the response to an inflammatory stimulus. These findings suggest differential effects induced by the TFAs tested, fitting with the idea that industrial TFAs and ruminant TFAs can have different and perhaps opposing biological actions in an inflammatory context.