Clean Synthetic Strategies to Biologically Active Molecules from Lignin:A Green Path to Drug Discovery**

Deriving active pharmaceutical agents from renewable resources is crucial to increasing the economic feasibility of modern biorefineries and promises to alleviate critical supply-chain dependencies in pharma manufacturing. Our multidisciplinary approach combines research in lignin-first biorefining, sustainable catalysis, and alternative solvents with bioactivity screening, an in vivo efficacy study, and a structural-similarity search. The resulting sustainable path to novel anti-infective, anti-inflammatory, and anticancer molecules enabled the rapid identification of frontrunners for key therapeutic indications, including an anti-infective against the priority pathogen Streptococcus pneumoniae with efficacy in vivo and promising plasma and metabolic stability. Our catalytic methods provided straightforward access, inspired by the innate structural features of lignin, to synthetically challenging biologically active molecules with the core structure of dopamine, namely, tetrahydroisoquinolines, quinazolinones, 3-arylindoles and the natural product tetrahydropapaveroline. Our diverse array of atom-economic transformations produces only harmless side products and uses benign reaction media, such as tunable deep eutectic solvents for modulating reactivity in challenging cyclization steps.</p

Clean Synthetic Strategies to Biologically Active Molecules from Lignin:A Green Path to Drug Discovery**

Deriving active pharmaceutical agents from renewable resources is crucial to increasing the economic feasibility of modern biorefineries and promises to alleviate critical supply-chain dependencies in pharma manufacturing. Our multidisciplinary approach combines research in lignin-first biorefining, sustainable catalysis, and alternative solvents with bioactivity screening, an in vivo efficacy study, and a structural-similarity search. The resulting sustainable path to novel anti-infective, anti-inflammatory, and anticancer molecules enabled the rapid identification of frontrunners for key therapeutic indications, including an anti-infective against the priority pathogen Streptococcus pneumoniae with efficacy in vivo and promising plasma and metabolic stability. Our catalytic methods provided straightforward access, inspired by the innate structural features of lignin, to synthetically challenging biologically active molecules with the core structure of dopamine, namely, tetrahydroisoquinolines, quinazolinones, 3-arylindoles and the natural product tetrahydropapaveroline. Our diverse array of atom-economic transformations produces only harmless side products and uses benign reaction media, such as tunable deep eutectic solvents for modulating reactivity in challenging cyclization steps.</p

Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes

The myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein-coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2) strongly activated MEF2. Using pharmacological and protein-based inhibitors, we demonstrated that PGE2 regulates MEF2 via the EP3 receptor, the betagamma subunit of Gi/o protein and two concomitantly activated downstream pathways. The first consists of Tiam1, Rac1, and its effector p21-activated kinase 2, the second of protein kinase D. Both pathways converge on and inactivate histone deacetylase 5 (HDAC5) and thereby de-repress MEF2. In vivo, endotoxemia in MEF2-reporter mice induced upregulation of PGE2 and MEF2 activation. Our findings provide an unexpected new link between inflammation and cardiac remodeling by de-repression of MEF2 through HDAC5 inactivation, which has potential implications for new strategies to treat inflammatory cardiomyopathies

Serum MicroRNA-21 as Marker for Necroinflammation in Hepatitis C Patients with and without Hepatocellular Carcinoma

Background: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC. Methodology/Principal Findings: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dCT of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%. Conclusions/Significance: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC

ATUAÇÃO FISIOTERAPÊUTICA NO IRONMAN BRASIL

Dentre as provas de triathlon o ironman é a que exige mais do atleta, ao seu término os atletas necessitam de cuidados especiais. A Fisioterapia, coordenada pela equipe do projeto de Fisioterapia Desportiva do CEFID UDESC, está presente no ironman Brasil desde que a prova começou a ser realizada em Florianópolis. Este trabalho objetivou descrever o atendimento fisioterapêutico realizado desde a implantação da fisioterapia no ironman Brasil. O atendimento tem o intuito de realizar uma abordagem precoce numa lesão, melhorar os fatores psicológicos através da massagem, diminuir o tempo de recuperação, reverter o quadro de câimbras e evitar a hipotermia. O atendimento fisioterapêutico ficou dividido em quatro áreas de atuação: área de transição, chegada, centro médico e o setor fisioterapêutico. Na área de transição foram utilizados o alongamento e a massagem; na chegada foi realizada a triagem, definindo quem iria para o setor de fisioterapia e quem necessitava de cuidados médicos; no centro médico foram realizados massagem, alongamento e mobilização passiva; no setor fisioterapêutico eram realizadas a massagem, o alongamento e a crioterapia. A massagem pós-evento pode reduzir a tensão muscular, estimular o relaxamento e diminuir o tempo de recuperação. O alongamento muscular pode aliviar a câimbra muscular. O uso da crioterapia visa diminuir os sinais da resposta inflamatória. Com isso a Fisioterapia favorece uma melhor recuperação do atleta, bem como a manutenção de sua integridade física. A abordagem utilizada no ironman pode ser de grande valia para outros tipos de esporte, onde o atleta é levado ao esforço extremo

Plants control soil gas exchanges possibly via mucilage

Background: Gaseous matter exchanges in soil are determined by the connectivity of the pore system which is easily clogged by fresh root exudates. However, it remains unclear how a hydrogel (e.g., mucilage) affects soil pore tortuosity and gas diffusion properties when drying.Aims: The aim of this viewpoint study is to extend the understanding of gas exchange processes in the rhizosphere by (a) relating it to the patterns formed by drying mucilage within pore space and (b) to give a concept of the effect of drying mucilage on soil gas diffusivity using the combination of experimental evidence and simulations.Methods: To describe the effect of mucilage on soil gas exchanges, we performed gas diffusion experiments on dry soil–mucilage samples and took images of glass beads mixed with mucilage to visualize the formation of mucilage after drying, using Environmental Scanning Electron Microscopy. Finally, we set up simulations to characterize the geometric distribution of mucilage within soil during the drying process.Results: Experiments of gas diffusion show that mucilage decreases gas diffusion coefficient in dry soil without significantly altering bulk density and porosity. Electron microscopy indicates that during drying mucilage forms filaments and interconnected structures throughout the pore space reducing gas phase connectivity. The evolution of these geometric structures is explained via pore scale modelling based on identifying the elastic strength of rhizodeposition during soil drying.Conclusion: Our results suggest that releasing mucilage may be a plant adaption strategy to actively alter gas diffusion in soil

Plants control soil gas exchanges possibly via

Background: Gaseous matter exchanges in soil are determined by the connectivity of the pore system which is easily clogged by fresh root exudates. However, it remains unclear how a hydrogel (e.g., mucilage) affects soil pore tortuosity and gas diffusion properties when drying.Aims: The aim of this viewpoint study is to extend the understanding of gas exchange processes in the rhizosphere by (a) relating it to the patterns formed by drying mucilage within pore space and (b) to give a concept of the effect of drying mucilage on soil gas diffusivity using the combination of experimental evidence and simulations.Methods: To describe the effect of mucilage on soil gas exchanges, we performed gas diffusion experiments on dry soil–mucilage samples and took images of glass beads mixed with mucilage to visualize the formation of mucilage after drying, using Environmental Scanning Electron Microscopy. Finally, we set up simulations to characterize the geometric distribution of mucilage within soil during the drying process.Results: Experiments of gas diffusion show that mucilage decreases gas diffusion coefficient in dry soil without significantly altering bulk density and porosity. Electron microscopy indicates that during drying mucilage forms filaments and interconnected structures throughout the pore space reducing gas phase connectivity. The evolution of these geometric structures is explained via pore scale modelling based on identifying the elastic strength of rhizodeposition during soil drying.Conclusion: Our results suggest that releasing mucilage may be a plant adaption strategy to actively alter gas diffusion in soil

Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters

Here, we report on a potent class of substituted ureidothiophenes targeting energy-coupling factor (ECF) transporters, an unexplored target, which is not addressed by any antibiotic on the market. Since the ECF module is crucial for the vitamin transport mechanism, prevention of substrate uptake should ultimately lead to cell death. By utilizing a combination of virtual and functional whole-cell screening of our in-house library, the membrane-bound protein mediated uptake of folate could be effectively inhibited. Structure-based optimization of our hit compound yielded low-micromolar inhibitors, whereby the most active compounds showed in addition potent antimicrobial activities against a panel of clinically relevant Gram-positive pathogens without significant cytotoxic effects

Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters

Here, we report on a potent class of substituted ureidothiophenes targeting energy-coupling factor (ECF) transporters, an unexplored target that is not addressed by any antibiotic in the market. Since the ECF module is crucial for the vitamin transport mechanism, the prevention of substrate uptake should ultimately lead to cell death. By utilizing a combination of virtual and functional whole-cell screening of our in-house library, the membrane-bound protein mediated uptake of folate could be effectively inhibited. Structure-based optimization of our hit yielded low-micromolar inhibitors, whereby the most active compounds showed in addition potent antimicrobial activities against a panel of clinically relevant Gram-positive pathogens without significant cytotoxic effects. © 2022 American Chemical Society.Horizon 2020 Framework Programme, ERC starting grant 757913, Marie Skłodowska Curie grant agreement no. 66525