Rational design of NIR-II molecule-engineered nanoplatform for preoperative downstaging and imaging-guided surgery of orthotopic hepatic tumor.

Orthotopic advanced hepatic tumor resection without precise location and preoperative downstaging may cause clinical postoperative recurrence and metastasis. Early accurate monitoring and tumor size reduction based on the multifunctional diagnostic-therapeutic integration platform could improve real-time imaging-guided resection efficacy. Here, a Near-Infrared II/Photoacoustic Imaging/Magnetic Resonance Imaging (NIR-II/PAI/MRI) organic nanoplatform IRFEP-FA-DOTA-Gd (IFDG) is developed for integrated diagnosis and treatment of orthotopic hepatic tumor. The IFDG is designed rationally based on the core "S-D-A-D-S" NIR-II probe IRFEP modified with folic acid (FA) for active tumor targeting and Gd-DOTA agent for MR imaging. The IFDG exhibits several advantages, including efficient tumor tissue accumulation, good tumor margin imaging effect, and excellent photothermal conversion effect. Therefore, the IFDG could realize accurate long-term monitoring and photothermal therapy non-invasively of the hepatic tumor to reduce its size. Next, the complete resection of the hepatic tumor in situ lesions could be realized by the intraoperative real-time NIR-II imaging guidance. Notably, the preoperative downstaging strategy is confirmed to lower the postoperative recurrence rate of the liver cancer patients under middle and advanced stage effectively with fewer side effects. Overall, the designed nanoplatform demonstrates great potential as a diagnostic-therapeutic integration platform for precise imaging-guided surgical navigation of orthotopic hepatic tumors with a low recurrence rate after surgery, providing a paradigm for diagnosing and treating the advanced tumors in the future clinical translation application.

Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway.

Acute lung injury (ALI) and sepsis are both serious and complex conditions associated with high mortality, yet there are no effective treatments. Herein, we designed and synthesized a series of diphenyl 6-oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide analogues exhibiting anti-inflammatory activity. The optimal compound J27 decreased the release of TNF-α and IL-6 in mouse and human cells J774A.1 and THP-1 (IL-6 IC50 = 0.22 µM) through the NF-κB/MAPK pathway. J27 demonstrated remarkable protection against ALI and sepsis in vivo and exhibited good safety in subacute toxicity experiments. Pharmacokinetic study indicated that J27 had good bioavailability (30.74%). To our surprise, J27 could target JNK2 with a totally new molecular skeleton compared with the only few JNK2 inhibitors reported. Moreover, there is no report that JNK2 inhibitors could apply for ALI and sepsis. Therefore, this work provides a new lead structure for the study of JNK2 inhibitors and a new target of JNK2 to treat ALI and sepsis.

Design, Synthesis, and Bioevaluation of Novel MyD88 Inhibitor c17 against Acute Lung Injury Derived from the Virtual Screen.

Myeloid differentiation primary response protein 88 (MyD88) is crucial to immune cascades mediated by Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 dysregulation has been linked to a wide variety of inflammatory diseases, making it a promising new target for anti-inflammatory and cancer therapy development. In this study, 46 compounds were designed and synthesized inspired by virtual screen hit. The anti-inflammatory activity of designed compounds was evaluated biologically, and c17 was discovered to have a high binding affinity with MyD88. It inhibited the interaction of TLR4 and MyD88 and suppressed the NF-κB pathway. In addition, c17 treatment led to the accumulation in the lungs of rats and attenuated LPS-induced ALI mice model. Furthermore, c17 showed negligible toxicity in vivo. Together, these findings suggest that c17 may serve as a potential therapeutical method for the treatment of ALI and as a lead structure for the continued development of MyD88 inhibitors.

Synthesis and SAR study of novel diimide skeleton compounds with the anti-inflammatory activities in vitro and in vivo.

Amide bonds widely exist in the structure of natural products and drugs, and play an important role in biological activities. However, due to the limitation of synthesis conditions, there are few studies on biscarbonyl diimides. In this paper, a series of new compounds with diimide skeleton were synthesized by using CDI and NaH as condensation agents. The anti-inflammatory activity and cytotoxicity of the compound in RAW264.7 macrophages were evaluated by ELISA and MTT experiments. The results showed that these compounds had good anti-inflammatory activity in vitro, and the IC50 of compound 4d on inflammatory factors IL-6 and TNF-α reached 1.59 µM and 15.30 µM, respectively. Further structure-activity relationship showed that biscarbonyl diimide and unsaturated double bond played a major role in the anti-inflammatory activity. In addition, compound 4d can alleviate acute lung injury (ALI) induced by LPS in vivo, reduce alveolar cell infiltration, and decrease the expression of ALI inflammatory factors. At the same time, compound 4d can significantly improve the survival rate of LPS-induced sepsis in mice. In short, the design and synthesis of the diimide skeleton provides a potential lead compound for the treatment of inflammatory diseases, and also provides a new idea for the design of amide compounds.

Mining phosphorus from waste streams at wastewater treatment plants: a review of enrichment, extraction, and crystallization methods.

Two interrelated problems exist: the non-renewability of phosphate rock as a resource and the excess phosphate in the water system lead to eutrophication. Removal and recovery of phosphorus (P) from waste streams at wastewater treatment plants (WWTPs) is one of the promising solutions. This paper reviews strategies for P recovery from waste streams in WWTPs are reviewed, and the main P recovery processes were broken down into three parts: enrichment, extraction, and crystallization. On this basis, the present P recovery technology was summarized and compared. The choice of P recovery technology depends on the process of sewage treatment and sludge treatment. Most P recovery processes can meet the financial requirements since the recent surge in phosphate rock prices. The safety requirements of P recovery products add a high cost to toxic substance removal, so it is necessary to control the discharge of toxic substances such as heavy metals and persistent organic pollutants from the source.

Transformation and fate of non-reactive phosphorus (NRP) in enhanced biological phosphorus removal process with sidestream phosphorus recovery.

Recovery of phosphorus (P) from wastewater can help establish a new P cycle. However, there are many P forms in wastewater, not always in reactive forms, which are the most suitable for direct recovery. The enhanced biological phosphorus removal process with sidestream phosphorus recovery (EBPR-SPR) is an effective way to remove and recover P resources in wastewater, but there is a lack of research on the transformation and fate of non-reactive phosphorus (NRP) in it. This study selected four model NRP to investigate their transformation and fate in an EBPR-SPR process. The transformation of NRP in pure water and activated sludge under anaerobic and aerobic conditions were compared. The effects of Ca/P ratio and pH on NRP recovery were studied, and the recovery products of NRP were characterized. It was found that NRP containing phosphoanhydride and phosphoester bonds were more easily hydrolyzed to reactive P (RP) than that containing PC bonds. NRP will be adsorbed and accumulated by activated sludge, and activated sludge will accelerate the conversion of NRP to RP. Tripolyphosphate can form complex precipitation with Ca2+. When multiform P co-existed, Ca2+ preferably complexed with polyphosphate, which harmed RP recovery. The conversion of NRP should be strengthened to recover more P in wastewater. The effect of NRP should be considered when recovering P from wastewater.

Effects of dissolved organic matter on phosphorus recovery via hydroxyapatite crystallization: New insights based on induction time.

Recovery of phosphorus from sewage can help establish a new phosphorus cycle and hydroxyapatite (HAP) crystallization is a promising way. HAP crystallization is an amorphous calcium phosphate (ACP) mediated process, and its induction time reflects the rate of HAP nucleation, and seriously affects the efficiency of phosphorus recovery. In this study, the effects of different types of dissolved organic matter (DOM) on the induction time and phosphorus recovery performance of ACP-mediated HAP phosphorus recovery were studied, and the mechanism was analyzed by X-Ray Diffraction, Fourier transform infrared spectroscopy, and scanning electron micrograph with energy dispersive spectrometry. The results show that DOM greatly prolongs the induction time of ACP-mediated HAP crystallization and leads to an increase in the yield of microcrystals, thus leading to a decrease in phosphorus recovery efficiency. DOM inhibits ACP-mediated HAP crystallization by complexing lattice ions and occupying active growth sites on the crystal surface. Pre-removal of DOM can not only improve the speed and efficiency of phosphorus recovery by the HAP crystallization process but also improve product quality.

Application of membrane separation processes in phosphorus recovery: A review.

The depletion of phosphorus resources and the excess discharge of phosphorus into waste streams are contrasting problems. The key to solving both problems is to recover phosphorus from the waste streams. Current phosphorus recovery technologies require high phosphorus concentrations and lack the ability to separate toxic substances from recovered phosphorus products. Membrane separation processes such as nanofiltration, forward osmosis, and electrodialysis are examples of effective methods for solving some of these issues. In this paper, the mechanisms, performance, and influential factors affect phosphorus recovery from membrane separation are reviewed. Membrane fouling, energy consumption, and the selectivity of toxic substances in membrane separation processes were evaluated. This work will serve as a basis for future research and development of phosphorus recovery by membrane separation processes and as a response to the increasingly pressing issues of eutrophication and the growing depletion of phosphorus resources.