Characterization of a small molecule inhibitor of the NLRP3 inflammasome and its potential use for acute lung injury.

Accumulating data support the key roles of the NLRP3 inflammasome, an essential component of the innate immune system, in human pathophysiology. As an emerging drug target and a potential biomarker for human diseases, small molecule inhibitors of the NLRP3 inflammasome have been actively pursued. Our recent studies identified a small molecule, MS-II-124, as a potent NLRP3 inhibitor and potential imaging probe. In this report, MS-II-124 was further characterized by an unbiased and comprehensive analysis through Eurofins BioMAP Diversity PLUS panel that contains 12 human primary cell-based systems. The analysis revealed promising activities of MS-II-124 on inflammation and immune functions, further supporting the roles of the NLRP3 inflammasome in these model systems. Further studies of MS-II-124 in mouse model of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and NLRP3 knockout mice demonstrated its target engagement, efficacy to suppress inflammatory cytokines and infiltration of immune cells in the lung tissues. In summary, the results support the therapeutic potential of MS-II-124 as a NLRP3 inhibitor and warrant future studies of this compound and its analogs to develop therapeutics for ALI/ARDS.

Chiral MoS2@BC fibrous membranes selectively promote peripheral nerve regeneration.

BACKGROUND: Molybdenum disulfide (MoS2) has excellent physical and chemical properties. Further, chiral MoS2 (CMS) exhibits excellent chiroptical and enantioselective effects, and the enantioselective properties of CMS have been studied for the treatment of neurodegenerative diseases. Intriguingly, left- and right-handed materials have different effects on promoting the differentiation of neural stem cells into neurons. However, the effect of the enantioselectivity of chiral materials on peripheral nerve regeneration remains unclear. METHODS: In this study, CMS@bacterial cellulose (BC) scaffolds were fabricated using a hydrothermal approach. The CMS@BC films synthesized with L-2-amino-3-phenyl-1-propanol was defined as L-CMS. The CMS@BC films synthesized with D-2-amino-3-phenyl-1-propanol was defined as D-CMS. The biocompatibility of CMS@BC scaffolds and their effect on Schwann cells (SCs) were validated by cellular experiments. In addition, these scaffolds were implanted in rat sciatic nerve defect sites for three months. RESULTS: These chiral scaffolds displayed high hydrophilicity, good mechanical properties, and low cytotoxicity. Further, we found that the L-CMS scaffolds were superior to the D-CMS scaffolds in promoting SCs proliferation. After three months, the scaffolds showed good biocompatibility in vivo, and the nerve conducting velocities of the L-CMS and D-CMS scaffolds were 51.2 m/s and 26.8 m/s, respectively. The L-CMS scaffolds showed a better regenerative effect than the D-CMS scaffolds. Similarly, the sciatic nerve function index and effects on the motor and electrophysiological functions were higher for the L-CMS scaffolds than the D-CMS scaffolds. Finally, the axon diameter and myelin sheath thickness of the regenerated nerves were improved in the L-CMS group. CONCLUSION: We found that the CMS@BC can promote peripheral nerve regeneration, and in general, the L-CMS group exhibited superior repair performance. Overall, the findings of this study reveal that CMS@BC can be used as a chiral nanomaterial nerve scaffold for peripheral nerve repair.

Type I gamma phosphatidylinositol phosphate 5-kinase i5 controls cell sensitivity to interferon.

The interferon signaling pathway is critical for host defense by serving diverse functions in both innate and adaptive immune responses. Here, we show that type I gamma phosphatidylinositol phosphate 5-kinase i5 (PIPKIγi5), an enzyme that synthesizes phosphatidylinositol-4,5-bisphosphate (PI4,5P2), controls the sensitivity to interferon in both human and mouse cells. PIPKIγi5 directly binds to the interferon-gamma (IFN-γ) downstream effector signal transducer and activator of transcription 1 (STAT1), which suppresses the STAT1 dimerization, IFN-γ-induced STAT1 nuclear translocation, and transcription of IFN-γ-responsive genes. Depletion of PIPKIγi5 significantly enhances IFN-γ signaling and strengthens an antiviral response. In addition, PIPKIγi5-synthesized PI4,5P2 can bind to STAT1 and promote the PIPKIγi5-STAT1 interaction. Similar to its interaction with STAT1, PIPKIγi5 is capable of interacting with other members of the STAT family, including STAT2 and STAT3, thereby suppressing the expression of genes mediated by these transcription factors. These findings identify the function of PIPKIγi5 in immune regulation.

Occurrence and mechanism of sulfamethoxazole in alginate-like extracellular polymers from excess sludge.

The recovery of biopolymers, particularly alginate-like extracellular polymers, from municipal sludge represents a promising step toward sustainable sludge treatment practices. Originating from wastewater plants in complexly polluted environments, alginate-like extracellular polymers carry potential environmental risks concerning their reuse. This study employs ultrahigh-performance liquid chromatography-tandem mass spectrometry to investigate the distribution coefficients and occurrence of alginate-like extracellular polymers and sulfamethoxazole. Results demonstrate a negative distribution coefficient, suggesting an inhibitory effect on sulfamethoxazole dissolution. The ethanol-extracted alginate-like extracellular polymers exhibits higher sulfamethoxazole levels (approximately 52%) than those obtained via dialysis extraction. Three-dimensional excitation-emission matrix analysis and adsorption studies indicate the absence of tyrosine-like substances in the alginate-like extracellular polymers, unlike in other extracellular polymeric substances. This absence diminishes hydrophobic interactions, highlighting that electrostatic interactions play a more important role. These insights are crucial for understanding the adsorption behavior of alginate-like extracellular polymers and optimizing their large-scale extraction processes.

Biopterin metabolism and nitric oxide recoupling in cancer.

Tetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in the field of cancer immunology and immunotherapy due to its involvement in the cytotoxic T cell response. Past research has demonstrated that when the availability of BH4 is low, as it is in chronic inflammatory conditions and tumors, electron transfer in the active site of nitric oxide synthase becomes uncoupled from the oxidation of arginine. This results in the production of radical species that are capable of a direct attack on tetrahydrobiopterin, further depleting its local availability. This feedforward loop may act like a molecular switch, reinforcing low tetrahydrobiopterin levels leading to altered NO signaling, restrained immune effector activity, and perpetual vascular inflammation within the tumor microenvironment. In this review, we discuss the evidence for this underappreciated mechanism in different aspects of tumor progression and therapeutic responses. Furthermore, we discuss the preclinical evidence supporting a clinical role for tetrahydrobiopterin supplementation to enhance immunotherapy and radiotherapy for solid tumors and the potential safety concerns.