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Medicaid reimbursements for physician services are determined by each state. However, how these reimbursements vary between states, and how these reimbursements vary in comparison to Medicare reimbursements is unknown for musculoskeletal radiology studies.To evaluate the variability in Medicaid and Medicare physician reimbursements for musculoskeletal imaging studies between states.We evaluated the Medicare and Medicaid physician reimbursements for the most commonly performed musculoskeletal radiology studies (15 radiographs and 10 MRIs) based on Medicare's 2017 National Summary Data File. Medicare and Medicaid reimbursements for these studies were compared by dollar difference (difference in reimbursement in dollars between Medicare and Medicaid). State-wide variability in these reimbursements was quantified by the coefficient of variation (COV) and by the dollar difference in reimbursement amounts. Medicaid and Medicare reimbursement rates were compared using a paired t-test, since the data was paired by state.The mean Medicaid reimbursement rates were lower for musculoskeletal radiographs (p 0.05) but higher for musculoskeletal MRI studies than the Medicare rates (p 0.05). As hypothesized, there was variation in both Medicare and Medicaid imaging reimbursements between states, however, the variation was substantially higher for Medicaid reimbursements. We found the Medicare reimbursement COV between states was 0.07 for all imaging studies, whereas the Medicaid reimbursement COV between states varied from 0.23 to 0.55 for radiographs and from 0.31 to 0.45 for MRIs.The data show that there is mild, but constant variation across imaging studies in Medicare reimbursement for musculoskeletal imaging studies between states. However, there is more variation in the Medicaid reimbursements across imaging studies and between states. More appropriate reimbursement may increase access to care for Medicaid patients.

In this work, the development of a disposable electrode (US$ 0.02) based on composite material on 3D-printed support of ABS was described for the electrochemical determination of Dopamine. The composition was optimized using different ratios of graphite and nail polish. An electrochemical surface treatment with potassium hydroxide was evaluated. The electrode surfaces were characterized by scanning electron microscopy, cyclic voltammetry, electrochemical impedance, and Raman spectroscopy, which indicate the better performances of the treated electrode with a 1.9-fold increase in the response and anticipation in the potential of 107 mV. The sensors were employed to quantification of DOP using differential pulse voltammetry in pharmaceutical formulations, tap water, synthetic urin, and saliva. Furthermore, the proposed method showed a linear working range from 10 to 175 μmol l−1 and from 0.02 to 10 μmol l−1, a limit of detection of 2.24 μmol l−1 and 5.7 nmol l−1, and relative standard deviation

Leishmania (L.) amazonensis is one of the species responsible for the development of cutaneous leishmaniasis in South America. After entering the vertebrate host, L. (L.) amazonensis invades mainly neutrophils, macrophages and dendritic cells. Studies have shown that gal-3 acts as a pattern recognition receptor. However, the role of this protein in the context of L. (L.) amazonensis infection remains unclear. Here, we investigated the impact of gal-3 expression on experimental infection by L. (L.) amazonensis. Our data showed that gal-3 plays a role in controlling parasite invasion, replication and the formation of endocytic vesicles. Moreover, mice with gal-3 deficiency showed an exacerbated inflammatory response. Taken together, our data shed light to a critical role of gal-3 in the host response to infection by L. (L.) amazonensis.

During COVID-19 pandemic crisis, Italian Government has approved Law Decree no. 18 of 17 March 2020, in which art. 15 allows enterprises to produce, import and commercialize surgical masks notwithstanding the current rules of product certification. It is just required that the interested enterprises send to the Italian National Institute of Health a selfcertification in which they declare the technical characteristics of the masks and that masks are produced according to the safety requirements. In this context, a technical-scientific unit was established at the University of Napoli Federico II to provide interested enterprises with state-of-the-art consultancy, testing and measurement services, adhering to rigorous scientific protocols. Characterization tests were carried out on 163 surgical masks and/or materials for their construction and they have enabled the identification of pre-screening criteria to simplify the procedure for evaluating surgical masks using methods for assessing the filtration efficiency of particles and aerosols. Based on experimental results, it has been observed that a filtration efficiency for particles with sizes larger that 650 nm (PFE>650) exceeding 35% might guarantees a bacterial filtration efficiency (BFE) higher than 95% while BFE values higher than 98% are obtained when the PFE>650 is larger than 40%. PFE measurement is extremely simpler with respect to BFE, the latter being time-consuming and requiring specific equipment and methods for its realization. Many tested materials have shown the capability to assure high filtration efficiencies but Spundonded-Meltblown-Spunbonded (SMS), that are layers of non-woven fabric with different weights of Meltblown, can simultaneously guarantee high particle filtration efficiencies with pressure drop values (breathability) in the limits to classify the surgical masks as Type II/IIR. In fact, the fabric products analyzed so far have not been able to simultaneously guarantee adequate BFE and breathability values. On the contrary, Spunbonds of adequate weights can virtually verify both requirements and accredit themselves as possible materials for the production of surgical masks, at least of Type I. Further studies are needed to verify the possibility of producing low-cost, reusable surgical masks that could meet the criteria of circular economy. © 2020 Tipografia PI-ME Editrice Srl. All rights reserved.

O objetivo desse trabalho foi avaliar a qualidade fisiológica de sementes de melão da cultivar Anton, em função dos diferentes estádios de maturação de frutos armazenados e não armazenados, por meio da visualização da morfologia interna de sementes utilizando imagens de raios x. Made available in DSpace on 2021-04-07T12:34:36Z (GMT). No. of bitstreams: 1 Rev-Agr-Acad-v4-n2-2021-p21-28-Determinacao-de-alteracoes-morfologicas-durante-a-maturacao-de-sementes-de-melao-com-uso-de-raios-X-apos-warley.pdf: 267291 bytes, checksum: 7a6db97aea5352393d97001e339e1e83 (MD5) Previous issue date: 2021

Supplemental material, sj-pdf-1-jrs-10.1177_01410768211061357 for Social inequalities and extreme vulnerability of children and adolescents affected by the COVID-19 pandemic by Alo��sio Ant��nio Gomes de Matos, Kimberly Virginin Cruz Correia da Silva, Jucier Gon��alves J��nior, Ruan Neto Pereira Alves, N��dia Nara Rolim Lima, Monique Leite Sampaio, C��cera Janielly de Matos Cassiano and Modesto Leite Rolim Neto in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-3-jrs-10.1177_01410768211061357 for Social inequalities and extreme vulnerability of children and adolescents affected by the COVID-19 pandemic by Alo��sio Ant��nio Gomes de Matos, Kimberly Virginin Cruz Correia da Silva, Jucier Gon��alves J��nior, Ruan Neto Pereira Alves, N��dia Nara Rolim Lima, Monique Leite Sampaio, C��cera Janielly de Matos Cassiano and Modesto Leite Rolim Neto in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-2-jrs-10.1177_01410768211061357 for Social inequalities and extreme vulnerability of children and adolescents affected by the COVID-19 pandemic by Alo��sio Ant��nio Gomes de Matos, Kimberly Virginin Cruz Correia da Silva, Jucier Gon��alves J��nior, Ruan Neto Pereira Alves, N��dia Nara Rolim Lima, Monique Leite Sampaio, C��cera Janielly de Matos Cassiano and Modesto Leite Rolim Neto in Journal of the Royal Society of Medicine

Trypanosoma cruzi P21 protein (P21) is a putative secreted and immunomodulatory molecule with potent bioactive properties such as induction of phagocytosis and actin cytoskeleton polymerization. Despite the bioactive properties described so far, the action of P21 on parasite replication in muscle cell lineage or T. cruzi parasitism during acute experimental infection is unclear. We observed that recombinant P21 (rP21) decreased the multiplication of T. cruzi in C2C12 myoblasts, phenomenon associated with greater actin polymerization and IFN-γ and IL-4 higher expression. During experimental infection, lower cardiac nests, inflammatory infiltrate and fibrosis were observed in mice infected and treated with rP21. These results were correlated with large expression of IFN-γ counterbalanced by high levels of IL-10, which was consistent with the lower cardiac tissue injury found in these mice. We have also observed that upon stress, such as that induced by the presence of the IFN-γ cytokine, T. cruzi produced more P21. The effect of P21 in controlling the replication of T. cruzi, may indicate an evolutionary mechanism of survival developed by the parasite. Thus, when subjected to different stress conditions, the protozoan produces more P21, which induces T. cruzi latency in the host organism, enabling the protozoan to evade the host's immune system.

Power transformers are central elements of power transmission systems and their deterioration can lead to system failures, causing major disruptions in service. Catastrophic failures can occur, posing major environmental hazards due to fires, explosions, or oil spillage. Early fault detection can be accomplished or estimated using electrical sensors or a chemical analysis of oil or gas samples. Conventional methods are incapable of real-time measurements with a low electrical noise due to time-consuming analyses or susceptibility to electromagnetic interference. Optical fiber sensors, passive elements that are immune to electromagnetic noise, are capable of structural monitoring by being enclosed in power transformers. In this work, optical fiber sensors embedded in 3D printed structures are studied for vibration monitoring. The fiber sensor is encapsulated between two pressboard spacers, simulating the conditions inside the power transformer, and characterized for vibrations with frequencies between 10 and 800 Hz, with a constant acceleration of 10 m/s2. Thermal aging and electrical tests are also accomplished, aiming to study the oil compatibility of the 3D printed structure. The results reported in this work suggest that structural monitoring in power transformers can be achieved using optical fiber sensors, prospecting real-time monitoring.

Power transformers have an imperative role in the future developments of the electrical grids. Treated as crucial assets for transportation and distribution of electrical energy, transformers are currently being studied regarding to the integration of technologies aiming to diagnose problems and monitoring data of electrical power grid. Furthermore, environmental noise pollution has gained importance, especially in active units of the power grid, located near consumers, such as transformers. Transformers noise can be classified according to its source: core, windings and cooling. This study addresses an experimental characterization of one of the main causes of transformers core noise - magnetostriction of electrical steel. An evaluation of magnetostriction properties of electrical steel, including resistive strain gauges and Fiber Bragg Gratings (FBGs) measurements with an Epstein frame, are presented and discussed. The magnetic flux density influence on hysteretic strain behavior of magnetostriction was evaluated, as well as the effect of a clamping load on core joints. Nowadays, optical interrogators for Bragg gratings have a high acquisition frequencies and wavelength sensitivity when compared to former optical interrogation systems, allowing to evaluate physical phenomena without electromagnetic interference and with equivalent resolution of conventional strain gauges.

B cells contribute to the immune system in many ways such as antigen presentation to CD4+ T cells, secretion of cytokines and lymphoid tissue organogenesis. Furthermore, they are the only cell type capable of producing immunoglobulins. B cells also account for critical aspects of the resistance against intracellular pathogens. Trypanosoma cruzi is an intracellular parasite that sabotages humoral response by depletion of immature B cells. Polyclonal activation and secretion of non-specific antibodies are also other mechanisms used by T cruzi to evade and subvert the mammalian host immune system, leading to increased parasitemia and susceptibility to Chagas' disease. It remained unclear whether B cell depletion occurs due to direct contact with T. cruzi or results from a global increase in inflammation. Unlike previous reports, we demonstrated in this study that T. cruzi infects human B cells, resulting in parasite-induced activation of caspase-7 followed by proteolytic cleavage of phospholipase Cγ1 and cell death. These data contribute to explain the mechanisms ruling B-cell depletion and evasion of the immune response by T. cruzi.

Power transformers are at the core of power transmission systems. The occurrence of system failure in power transformers can lead to damage of adjacent equipment and cause service disruptions. Structural and electrical integrity assessment in real time is of utter importance. Conventional techniques, typically electrical sensors or chemical analysis, present major drawbacks for real-time measurements due to high electromagnetic interference or for being time-consuming. Optical fiber sensors can be used in power transformers, as they are compact and immune to electromagnetic interferences. In this work, an optical fiber sensor composed by 2 fiber Bragg gratings, attached in a cantilever structure was explored. The prototype was developed with a 3D printer using a typical filament (ABS) that enable a fast and low-cost prototyping. The response of the sensor to vibration was tested using two different vibration axes for frequencies between 10 and 500 Hz. Oil compatibility was also studied using thermal aging and electrical tests. The studies shown that ABS is compatible with the power transformer mineral oil, but the high working temperatures may lead to material creeping, resulting in permanent structural deformation.

P21 is a protein secreted by Trypanosoma cruzi (T. cruzi). Previous studies have shown a spectrum of biological activities performed by P21 such as induction of phagocytosis, leukocyte chemotaxis and inhibition of angiogenesis. However, the activity of P21 in T. cruzi infection remains unknown. Here, we reported the role of P21 in mice harboring late T. cruzi infection. Treatment with recombinant P21 protein (rP21) reduced parasite load and angiogenesis, and induced fibrosis in the cardiac tissue of infected mice. In addition, rP21 reduced the growth of epimastigotes, inhibited intracellular replication of amastigotes and modulated the parasite cell cycle. Our data suggest that P21 controls parasite replication in the host, supporting the survival of both parasite and host.

Environmental noise pollution has gained increasing importance, over the past few years. Due to population growth along with a rapid urbanization and the increasing power supply needs, more and more electrical power transformers are set near or inside of urban agglomerations. This fact has generated several complaints regarding the noise produced by this equipment, forcing manufacturers to develop low noise solutions. As it is known, magnetostriction is one of the main sources of electrical machines noise. This research presents an experimental study in which magnetostriction properties of electrical steel are evaluated and analyzed. The magnetic flux density influence on the hysteretic strain behavior of magnetostriction was addressed, as well as the effect of a clamping load on the core joints. This study was addressed by means of an Epstein frame and a data acquisition system, where strain, current and voltage data is obtained and then processed in a data logging software. These measurements gave essential inputs for numerical models which simulate the power transformer core behavior, allowing a faster evaluation of noise mitigation solutions.

O momento ideal da colheita do melão e a maturidade fisiológica estão fortemente relacionados, propiciando a preservação da qualidade fisiológica da semente após a colheita. Sendo assim, a obtenção de lotes de sementes com elevada qualidade está relacionada com a identificação precisa do momento ideal da colheita, e isto corresponde à época em que a maturidade fisiológica é atingida, coincidindo também com o momento de máximo acúmulo de massa seca, elevado vigor e alta germinabilidade. Quase sempre, as espécies que possuem sementes contidas em frutos carnosos, o ponto máximo de germinação e vigor ocorrem quando as sementes atingem a maturidade fisiológica. Deste momento em diante a germinação e vigor usualmente decrescem. No entanto, não existe um consenso no entendimento da qualidade máxima das sementes durante seu desenvolvimento. A colheita antecipada dos frutos antes das sementes atingirem o ponto de maturidade fisiológica pode ser uma alternativa para os produtores de sementes que cultivam espécies do gênero Cucumis, família Cucurbitaceae. Na situação descrita, o armazenamento dos frutos favorece a totalização do processo de maturação das sementes. O presente trabalho pretendeu identificar a época de maturação dos frutos de melão amarelo, cultivar Anton, produzidos em sistema de cultivo protegido para definir a melhor época para a obtenção de sementes com maior qualidade fisiológica, por meio de alterações enzimáticas e análise de imagens ? por meio de raios-X e SVIS ? sementes e frutos colhidos em diferentes estádios de maturação e submetidos ou não ao armazenamento. Considerando que o desenvolvimento de sementes com alta qualidade fisiológica e sanitária ocorre com o incremento de tecnologias de produção, este trabalho avaliou diferentes tecnologias para produção de sementes de alta qualidade fisiológica e sanitária de melão em cultivo protegido, buscando um maior entendimento sobre a formação, desenvolvimento e produção das sementes. Conclui-se que as sementes extraídas dos frutos de 60 Dias Após a Antese (DAA) armazenados por 15 dias apresentaram melhores resultados quando comparadas as demais épocas, destacando-se que para a avaliação de matéria seca, peso de 100 sementes, germinação e vigor, primeira contagem, envelhecimento acelerado, emergência de plântulas, as atividades de SOD e CAT, bem como o número de sementes cheias e plântulas normais, além de uniformidade, crescimento das plantas também evidenciaram um melhor resultado aos 60 DAA armazenados por 15 dias. Made available in DSpace on 2020-06-22T19:13:34Z (GMT). No. of bitstreams: 1 2018-CristianoVasconcelosCassiano.pdf: 2308112 bytes, checksum: 47567f235e810478e7a84cadddb0a072 (MD5) Previous issue date: 2018 (Mestrado em Agronomia). Faculdade de Agronomia e Medicina Veterinária. Universidade de Brasília. Brasília, DF. Orientador: Warley Marcos Nascimento, CNPH. Participação na banca examinadora, Alexandre Augusto de Morais, CNPH.

Os dados apresentados são resultados do levantamento geoquímico regional executado pela CPRM (Residência de Porto Velho) dentro do Projeto Metalogenia das províncias Minerais do Brasil l: Área Sudeste de Rondônia. O levantamento geoquímico foi realizado nas Folhas Igarapé Xipingal (SD.20-X-A-VI), Ilha do Porto (SD.20-X-D-III), Porto Triunfo (SD.20-X-B-V), Rio Escondido (SD.20-X-D-II) e Rio Tanaru (SD.20-X-B-IV), todas na escala de 1:100.000, localizadas na região sudeste do Estado de Rondônia. Neste trabalho, foram realizadas 586 análises químicas de sedimento de corrente e 598 análises de minerais pesados de concentrado de bateia. Os resultados permitiram delinear três zonas geoquímicas anômalas: (I) Cu±Ni±Fe±V, (II) Co±Cr±Cu±Fe±Ni±Sc±V±Al±Ga e (III) Ce±La±P±Th±U±Y±Yb±Nb±Tb±Zr±Hf e através da análise de principais componentes, três fatores foram definidos e são responsáveis por 74,13% da variância das amostras: Fator 1(Co-Cr-Cu-Fe-V-Mn-Ni-Zn-Sc-Lu-In-Sn-Al-Ga); Fator 2 (Ce-La-Tb-Th-U-Y-Zr) e Fator 3 (Ba-Be-Ca-Cs-K-Li-Mg-Na-Rb-Sr). Dos 598 concentrados de bateia coletados, foi detectada a presença de partículas de ouro em 103 amostras.

Retinoic acid receptor-related orphan receptor γ-t (RORγt) and GPBAR1, a transmembrane G-protein-coupled receptor for bile acids, are attractive drug targets to develop clinically relevant small modulators as potent therapeutics for autoimmune diseases. Herein, we designed, synthesized, and evaluated several new bile acid-derived ligands with potent dual activity. Furthermore, we performed molecular docking and MD calculations of the best dual modulators in the two targets to identify the binding modes as well as to better understand the molecular basis of the inverse agonism of RORγt by bile acid derivatives. Among these compounds, 7 was identified as a GPBAR1 agonist (EC50 5.9 μM) and RORγt inverse agonist (IC50 0.107 μM), with excellent pharmacokinetic properties. Finally, the most promising ligand displayed robust anti-inflammatory activity in vitro and in vivo in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis.

The consumption of plant-based beverages as an alternative to cow’s milk has recently gained vast attention worldwide. The aim of this work is to monitor the intake of Bisphenol A (BPA), Bisphenol B (BPB) and Bisphenol S (BPS) in the Italian population through the consumption of these foodstuffs. Specifically, the development and validation of an analytical procedure for the quantitative determination of the analytes by liquid chromatography coupled to tandem mass spectrometry was reported. Thirty-four samples of plant-based beverages (soya, coconut, almond, oats and rice) of popular brands marketed in Italy were analyzed. BPA was found in 32% of the samples, while BPB was found in 3% of the samples. The risk assessment using the Rapid Assessment of Contaminant Exposure (RACE) tool demonstrated that there was no risk for all population groups, when using the current Tolerable Daily Intake (TDI) of 4 ng/kg body weight (bw)/day as a toxicological reference point. In contrast, using the new temporary TDI of 0.04 ng/kg bw/day, the existing risk was found to be real for all population groups. If this value were to become final, even more attention would have to be paid to the possible presence of BPA in food to protect consumer health.

Background and Aim: Drug-induced liver injury (DILI) is a common disorder that involves both direct liver cell toxicity and immune activation. The bile acid receptor, G-protein-coupled bile acid receptor 1 (GPBAR1; Takeda G-protein-coupled receptor 5 [TGR5]), and cysteinyl leukotriene receptor (CYSLTR) 1 are G-protein-coupled receptors activated by bile acids and leukotrienes, exerting opposite effects on cell-to-cell adhesion, inflammation, and immune cell activation. To investigate whether GPBAR1 and CYSLTR1 mutually interact in the development of DILI, we developed an orally active small molecule, CHIN117, that functions as a GPBAR1 agonist and CYSLTR1 antagonist. Approach and Results: RNA-sequencing analysis of liver explants showed that acetaminophen (APAP) intoxication positively modulates the leukotriene pathway, CYSLTR1, 5-lipoxygenase, and 5-lipoxygenase activating protein, whereas GPBAR1 gene expression was unchanged. In mice, acute liver injury induced by orally dosing APAP (500 mg/kg) was severely exacerbated by Gpbar1 gene ablation and attenuated by anti-Cysltr1 small interfering RNA pretreatment. Therapeutic dosing of wild-type mice with CHIN117 reversed the liver damage caused by APAP and modulated up to 1300 genes, including 38 chemokines and receptors, that were not shared by dosing mice with a selective GPBAR1 agonist or CYSLTR1 antagonist. Coexpression of the two receptors was detected in liver sinusoidal endothelial cells (LSECs), monocytes, and Kupffer cells, whereas combinatorial modulation of CYSLTR1 and GPBAR1 potently reversed LSEC/monocyte interactions. CHIN117 reversed liver damage and liver fibrosis in mice administered CCl4. Conclusions: By genetic and pharmacological approaches, we demonstrated that GPBAR1 and CYSLTR1 mutually interact in the development of DILI. A combinatorial approach designed to activate GPBAR1 while inhibiting CYSLTR1 reverses liver injury in models of DILI.

G-protein-coupled receptors (GPCRs) are the molecular target of 40% of marketed drugs and the most investigated structures to develop novel therapeutics. Different members of the GPCRs superfamily can modulate the same cellular process acting on diverse pathways, thus representing an attractive opportunity to achieve multitarget drugs with synergic pharmacological effects. Here, we present a series of compounds with dual activity toward cysteinyl leukotriene receptor 1 (CysLT1R) and G-protein-coupled bile acid receptor 1 (GPBAR1). They are derivatives of REV5901─the first reported dual compound─with therapeutic potential in the treatment of colitis and other inflammatory processes. We report the binding mode of the most active compounds in the two GPCRs, revealing unprecedented structural basis for future drug design studies, including the presence of a polar group opportunely spaced from an aromatic ring in the ligand to interact with Arg792.60 of CysLT1R and achieve dual activity.

In the context of inflammatory diseases, the Inflammatory Bowel Diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), represent the most common in the worldwide population. The current treatment of IBD includes FANS, corticosteroids, antibiotics, immunosuppressive and anti-TNF- agents.1 However, the limited efficacy of these treatments urges the identification of new therapeutic approaches, as well as the employment of GPBAR1 agonists.2,3 This receptor has an important role in intestinal homeostasis and inflammation-driven immune disfunction. Previous studies have shown that Gpbar1-/- mice have an altered intestinal morphology with increased permeability and higher susceptibility to develop colitis. In addition, in the immune system, GPBAR1 reduces phagocytic activity and the production of pro-inflammatory cytokines (TNF-, IL-1, IL-1, IL-6 and IL-8). Modification on HDCA scaffold afforded to a small library of hyodeoxycholane analogs, as selective and potent GPBAR1 agonists. Our medicinal chemistry strategy has consisted in the introduction of a nitrile group in the side chain and different alkyl, alkenyl or aromatic substituents at C-6 on HDCA. All compounds synthesized have been tested on GPBAR1 receptor through transactivation assays using the hepatic cell line HepG2. Our studies identified compound 6 as potent and selective GPBAR1 agonist (EC50 = 0.3 M), exerting minimal activating effects on the latter receptors. GPBAR1 activation, combined with the ability to revert both the expression of inflammatory genes in vitro and the inflammatory pattern in TNBS-induced colitis model, indicates compound 6 as a promising lead for the treatment of GPBAR1-related inflammatory bowel disorders.

[Image: see text] GPBAR1 agonists have been identified as potential leads for the treatment of diseases related to colon inflammation such as Crohn’s and ulcerative colitis. In this paper, we report the discovery of a small library of hyodeoxycholane analogues, decorated at C-6 with different substituents, as potent and selective GPBAR1 agonists. In vitro pharmacological assays showed that compound 6 selectively activates GPBAR1 (EC(50) = 0.3 μM) and reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in THP1 cells. The binding mode of compound 6 in GPBAR1 was elucidated by docking calculations. Moreover, compound 6 protects against TNBS-induced colitis in Gpbar1(+/+) rodent model, representing an intriguing lead for the treatment of these inflammatory disorders.

The Gram-negative Pantoea eucrina D2 was isolated from the marine sponge Chondrosia reniformis. Sponges were collected in a shallow volcanic vents system in Ischia island (South Italy), influenced by CO2 emissions and lowered pH. The chemical diversity of the secondary metabolites produced by this strain, under different culture conditions, was explored by a combined approach including molecular networking, pure compound isolation and NMR spectroscopy. The metabolome of Pantoea cf. eucrina D2 yielded a very complex molecular network, allowing the annotation of several metabolites, among them two biosurfactant clusters: lipoamino acids and surfactins. The production of each class of metabolites was highly dependent on the culture conditions, in particular, the production of unusual surfactins derivatives was reported for the first time from this genus, interestingly the production of these metabolites only arises by utilizing inorganic nitrogen as a sole nitrogen source. Major components of the extract obtained under standard medium culture conditions were isolated and identified as N-lipoamino acids by a combination of 1D and 2D NMR spectroscopy and HRESI-MS analysis. Assessment of the antimicrobial activity of the pure compounds towards some human pathogens, indicated a moderate activity of leucine containing N-lipoamino acids towards Staphylococcus aureus, Staphylococcus epidermidis and a clinical isolate of the emerging food pathogen Listeria monocytogenes.

FXR is one of the most investigated targets, expressed by entero-hepatic tissues including liver, gallbladder, intestine, and by the kidney, for its involvement in several psychopathological aspect of the organism. FXR is a bile acid sensor, with primary bile acids, chenodeoxycholic acid in humans, and cholic acid (CA) in mouse, and the corresponding taurine or glycine amide conjugates, serving as natural ligands.1 FXR activation governs bile acid homeostasis by repressing bile acid synthesis and uptake while increases their urinary excretion, as protective mechanism in conditions of impaired biliary excretion (cholestasis).2 In addition, FXR plays functional roles in regulating glucose and lipid metabolism, exerting robust anti-inflammatory activity in intestine and in the liver, and it is considered a validated target for the treatment of liver diseases, such as cholestasis, liver fibrosis, steatohepatitis (NASH), diabetes, as well as obesity and metabolic syndrome. Considering the growing interest toward this receptor, several small molecules ranging from bile acid derivatives to non-steroidal ligands have been synthesized. The first in class non-steroidal FXR ligand is GW4064,3 whose use was limited by reduced bioavailability as well as a stilbene-mediated photo-instability. Thus, recent, intense medicinal chemistry protocols have been performed in order to identify new isoxazole derivatives, modified mainly on the stilbene moiety, while the trisubstituted isoxazole, the isopropyl group at C-5 and the 2,6-dicloro-substituted phenyl moiety at C-3 were conserved. In this contribution, we report the design and the synthesis of modified GW4064 derivatives, identifying novel isoxazoles endowed with FXR agonistic activity and improved ADME properties. The pharmacological characterization and molecular docking studies allowed the identification of several FXR agonists with nanomolar potency in transactivation and SRC-1 recruitment assays. This characterization resulted in the identification of a potent FXR agonist, that prevent acute liver failure in mice caused by acetaminophen overdose in an FXR-dependent manner.