Discovery of Oxidized p-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 µM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-ß1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 µM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors.

Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC50 of 4.78 ± 0.08 µM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC50 of 0.48 ± 0.02 µM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.

Constructing functional metal-organic frameworks by ligand design for environmental applications.

Metal-organic frameworks (MOFs) with unique physical and chemical properties are composed of metal ions/clusters and organic ligands, including high porosity, large specific surface area, tunable structure and functionality, which have been widely used in chemical sensing, environmental remediation, and other fields. Organic ligands have a significant impact on the performance of MOFs. Selecting appropriate types, quantities and properties of ligands can well improve the overall performance of MOFs, which is one of the critical issues in the synthesis of MOFs. This article provides a comprehensive review of ligand design strategies for functional MOFs from the number of different types of organic ligands. Single-, dual- and multi-ligand design strategies are systematically presented. The latest advances of these functional MOFs in environmental applications, including pollutant sensing, pollutant separation, and pollutant degradation are further expounded. Furthermore, an outlook section of providing some insights on the future research problems and prospects of functional MOFs is highlighted with the purpose of conquering current restrictions by exploring more innovative approaches.

Biochar-compost as a new option for soil improvement: Application in various problem soils.

Due to the synergistic effects of biochar and compost/composting, the combined application of biochar and compost (biochar-compost) has been recognized as a highly promising and efficient method of soil improvement. However, the willingness to apply biochar-compost for soil improvement is still low compared to the use of biochar or compost alone. This paper collects data on the application of biochar-compost in several problem soils that are well-known and extensively investigated by agronomists and scientists, and summarizes the effects of biochar-compost application in common problem soils. These typical problem soils are classified based on three different characteristics: climatic zones, abiotic stresses, and contaminants. The improvement effect of biochar-compost in different soils is assessed and directions for further research and suggestions for application are made. Generally, biochar-compost mitigates the high mineralization rate of soil organic matter, phosphorus deficiency and aluminum toxicity, and significantly improves crop yields in most tropical soils. Biochar-compost can help to achieve long-term sustainable management of temperate agricultural soils by sequestering carbon and improving soil physicochemical properties. Biochar-compost has shown positive performance in the remediation of both dry and saline soils by reducing the threat of soil water scarcity or high salinity and improving the consequent deterioration of soil conditions. By combining different mechanisms of biochar and compost to immobilize or remove contaminants, biochar-compost tends to perform better than biochar or compost alone in soils contaminated with heavy metals (HMs) or organic pollutants (OPs). This review aims to improve the practicality and acceptability of biochar-compost and to promote its application in soil. Additionally, the prospects, challenges and future directions for the application of biochar-compost in problem soil improvement were foreseen.

Tuning the intrinsic catalytic sites of magnetite to concurrently enhance the reduction of H2O2 and O2: Mechanism analysis and application potential evaluation.

Heterogeneous Fenton-like process based on H2O2 activation has been widely tested for water purification, but its application still faces some challenges such as the use of high doses of chemicals (including catalysts and H2O2). Herein, a facile co-precipitation method was utilized for small-scale production (∼50 g) of oxygen vacancies (OVs)-containing Fe3O4 (Vo-Fe3O4) for H2O2 activation. Experimental and theoretical results collaboratively verified that H2O2 adsorbed on the Fe site of Fe3O4 tended to lose electrons and generate O2•-. While the localized electron from OVs of Vo-Fe3O4 could assist in donating electrons to H2O2 adsorbed on OVs sites, this allowed more H2O2 to be activated to •OH, which was 3.5 folds higher than Fe3O4/H2O2 system. Moreover, the OVs sites promoted dissolved oxygen activation and decreased the quenching of O2•- by Fe(III), thus promoting the generation of 1O2. Consequently, the fabricated Vo-Fe3O4 achieved much higher oxytetracycline (OTC) degradation rate (91.6%) than Fe3O4 (35.4%) at a low catalyst (50 mg/L) and H2O2 dosage (2 mmol/L). Importantly, further integration of Vo-Fe3O4 into fixed-bed Fenton-like reactor could effectively eliminate OTC (>80%) and chemical oxygen demand (COD) (21.3%∼50%) within the running period. This study provides promising strategies for enhancing the H2O2 utilization of Fe mineral.

Electrospun Nanofibrous Membranes Accelerate Biofilm Formation and Probiotic Enrichment: Enhanced Tolerances to pH and Antibiotics.

Biofilms are the oldest, most successful, and most widely distributed form of microorganism life on earth, existing even in extreme environments. Presently, probiotics in biofilm phenotype are thought as the most advanced fourth-generation probiotics. However, high-efficiency and large-scale biofilm enrichment in an artificial way is difficult. Here, fibrous membranes as probiotic biofilm-enriching materials are studied. Electrospun cellulose acetate nanofibrous membranes with nano-sized fibers show outstanding superiority over fibrous membranes with micron-sized fibers in Lactobacillus paracasei biofilm enrichment. The special 3D structure of electrospun nanofibrous membranes makes other facilitating biofilm formation factors insignificant. With a suitable scaffold/culture medium ratio, nearly 100% of L. paracasei cells exist as biofilm phenotype on the membrane from the very beginning, not planktonic state. L. paracasei biofilms possess a potential for long-term survival and high tolerances toward strong acidic and alkali conditions and antibiotics. RNA sequencing results explain why L. paracasei biofilms possess high tolerances toward harsh environments as compared to planktonic L. paracasei. Electrospun nanofibrous membranes can serve as powerful biofilm-enriching scaffolds for probiotics and other valuable microbes.

Sludge char-to-fuel approaches based on the pyrolysis III: Adding protein without dehydration.

Urban expansion has led to the accumulation of sludge, and its disposal has to meet increasingly stringent requirements. Therefore, pyrolysis has become an alternative option. However, it was still unclear which part of the sludge could be pyrolyzed to generate the product with a higher heating value, and therefore we divided sludge into extracellular polymeric substances (EPS) and cell phase and measured their heating values respectively. The obtained results showed that the high heating value (HHV) of the pyrolysis cell phase accounted for 85% of the sludge pyrolysis, and the addition of protein significantly increased the heating value of each component. Although the HHV of the pyrolysis cell phase increased by 1.8 MJ kg-1 for every 1% increase in protein, the HHV of the pyrolysis sludge and EPS increased by only 1.2 MJ kg-1. It is therefore suggested that EPS may contain substances that inhibit heat release. Properly increasing the cellular or protein components in the sludge could significantly increase the HHV produced by pyrolysis. Based on the measurement of fatty acids (FAs) and alcohol content and FTIR results, the addition of protein could increase the saturated FAs and accelerate the replacement of oxygen with nitrogen in the pyrolysis product, resulting in higher HHV. If the sludge was not dehydrated, more volatile compounds were carbonized and the HHV increased from 12 MJ kg-1 to 19 MJ kg-1. In short, since the HHV of the sludge was mainly derived from the cell phase, the HHV generation could be improved by increasing the cell phase or protein content without dehydration.

An approach using ensemble empirical mode decomposition to remove noise from prototypical observations on dam safety.

It is very important for dam safety control to identify reasonably dam behavior according to the prototypical observations on deformation, seepage, stress, etc. However, there are many cases in which the noise corrupts the prototypical observations, and it must be removed from the data. Considering the nonlinear and non-stationary characteristics of data series with signal intermittency, an ensemble empirical mode decomposition (EEMD)-based method is presented to remove noise from prototypical observations on dam safety. Its basic principle and implementation process are discussed. The key parameters and rules, which can adapt the noise removal requirements of prototypical observations on dam safety, are given. The displacement of one actual dam is taken as an example. The noise removal capability of EEMD-based method is assessed. It is indicated that the dam displacement feature can be reflected more clearly by removing noise from prototypical observations on dam displacement. The statistical model, which is built according to noise-removed data series, can provide the more precise forecast for structural behavior.