Sesamol serves as a p53 stabilizer to relieve rheumatoid arthritis progression and inhibits the growth of synovial organoids.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease known as a leading cause of disability with considerable mortality. Developing alternative drugs and targets for RA treatment is an urgent issue. Sesamol is a phenolic compound isolated from natural food sesame (Sesamum indicum L.) with various biological activities. PURPOSE: The current research intended to illuminate the bioactivity and mechanisms of sesamol in RA fibroblast-like synoviocytes (FLS), and aimed to estimate the potential clinical application value of sesamol in RA treatment. METHODS: CCK-8, EdU, and flow cytometry assays, as well as transwell tests were applied to observe the effects of sesamol on the abnormal functions of RA-FLS. Moreover, synovial organoids and a collagen-induced arthritis (CIA) mouse model were constructed to further explore the therapeutic capacity of sesamol on RA. Furthermore, RNA sequencing combined with quantitative real-time PCR assay, Western blot as well as co-immunoprecipitation were employed to clarify the mechanism of sesamol in regulating RA progression. RESULTS: Sesamol suppressed the proliferation through inhibiting DNA replication, triggering cell cycle arrest and apoptosis of RA-FLS. Besides, sesamol impaired RA-FLS migration and invasion. Interestingly, sesamol inhibited the growth of constructed synovial organoids and alleviated RA symptoms in CIA mice. Moreover, RNA sequencing further implicated p53 signaling as a downstream pathway of sesamol. Furthermore, sesamol was shown to decrease p53 ubiquitination and degradation, thereby activating p53 signaling. Finally, bioinformatics analyses also highlighted the importance of sesamol-regulated networks in the progression of RA. CONCLUSIONS: Our investigation demonstrated that sesamol served as a novel p53 stabilizer to attenuate the abnormal functions of RA-FLS via facilitating the activation of p53 signaling. Moreover, our study highlighted that sesamol might be an effective lead compound or candidate drug and p53 could be a promising target for the therapy of RA.

Arecoline hydrobromide suppresses PI3K/AKT pathway in rheumatoid arthritis synovial fibroblasts and relieves collagen-induced arthritis in mice.

OBJECTIVE: This study investigated the effectiveness of arecoline hydrobromide (AH) on the functions of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and collagen-induced arthritis (CIA) mice. METHODS: Immunofluorescence was used to identify RA-FLSs. Cell Counting Kit-8 (CCK-8) was used to determine the viability of RA-FLSs and the half maximal inhibitory concentration (IC50) of AH. The 5-ethynyl-2'-deoxyuridine (EdU) assay was used to detect DNA replication in RA-FLSs. Cell cycle and apoptosis were examined by flow cytometry. Migration and invasion, as well as wound healing assays, were employed to determine cell migration and invasion ability. Proteins and mRNA expression levels were investigated using Western blot, quantitative real-time PCR (RT-qPCR), and immunofluorescence. The CIA mice model was used to assess the effect of AH in vivo. RNA-sequencing (RNA-seq) was used to find the potential signaling pathways of AH against RA, and Western blot was used to verify the key signaling pathway of AH on RA-FLSs. Network pharmacology and molecular docking were used to predict drug targets. RESULTS: AH inhibited the proliferation and DNA replication of RA-FLSs, promoted cell cycle arrest by reducing the levels of cyclin-dependent kinase 1 (CDK1), cyclin A2, and cyclin B1, promoted apoptosis by suppressing B-cell lymphoma-2 (Bcl-2) expression, and suppressed migration and invasion by inhibiting vimentin expression in RA-FLSs. AH was also effective in relieving arthritis in vivo. RNA sequencing analyses suggested that AH inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in RA-FLSs, which was also confirmed in Western blot analysis. Furthermore, network pharmacology and molecular docking suggested that F2, MAPK14, SRC, AKT1, and CTSK might be the direct targets of AH. CONCLUSION: AH can modulate the pathological process of RA-FLSs by blocking the PI3K/AKT pathway and relieve CIA in mice, making it a potential new small molecule candidate.

Low-Grade Waste Heat Enables Over 80 L m- 2 h-1 Interfacial Steam Generation Based on 3D Superhydrophilic Foam.

Clean water scarcity and energy shortage have become urgent global problems due to population growth and human industrial development. Low-grade waste heat (LGWH) is a widely available and ubiquitous byproduct of human activities worldwide, which can provide effective power to address the fresh water crisis without additional energy consumption and carbon emissions. In this regard, 3D superhydrophilic polyurethane/sodium alginate (PU/SA) foam and LGWH-driven interfacial water evaporation systems are developed, which can precipitate over 80 L m-2  h-1 steam generation from seawater and has favorable durability for purification of high salinity wastewater. The excellent water absorption ability, unobstructed water transport, and uniform thin water layer formed on 3D skeletons of PU/SA foam ensure the strong heat exchange between LGWH and fluidic water. As a result, the heat-localized PU/SA foam enables the efficient energy utilization and ultrafast water evaporation once LGWH is introduced into PU/SA foam as heat flow. In addition, the precipitated salt on PU/SA foam can be easily removed by mechanical compression, and almost no decrease in water evaporation rate after salt precipitation and removal for many times. Meanwhile, the collected clean water has high rejection of ions of 99.6%, which meets the World Health Organization (WHO) standard of drinking water. Above all, this LGWH-driven interfacial water evaporation system presents a promising and easily accessible solution for clean water production and water-salt separation without additional energy burden for the society.

A novel sorbicillinoid compound as a potent anti-inflammation agent through inducing NLRP3 protein degradation.

BACKGROUND AND PURPOSE: Chronic inflammation is pathogenic and contributes to human diseases, causing a significant threat to public health. The NLR family pyrin domain-containing protein 3 (NLRP3) is the best-characterized factor regulating inflammation. Therefore, targeting NLRP3 has the potential to treat inflammatory diseases and improve human health. EXPERIMENTAL APPROACH: Lipopolysaccharide was used to induce inflammation in cell cultures. Lipopolysaccharide/d-galactosamine and dextran sulfate sodium salt were used to induce acute liver inflammation and ulcerative colitis respectively in C57BL/6J mice. Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the activation of the inflammatory response in cell cultures and in mice. KEY RESULTS: JNUTS013, a novel sorbicillinoid compound recently synthesized by us, significantly inhibited inflammation both in cell cultures and in mouse models. Mechanistically, JNUTS013 induced proteasome-dependent degradation of NLRP3. Hence, it suppressed the formation of the NLRP3 inflammasome and the production of downstream inflammatory cytokines and chemokines. The inhibitory effect of JNUTS013 on NLRP3 protein expression was confirmed in mice. Importantly, JNUTS013 failed to ameliorate bowel inflammation in Nlrp3-/- knockout mice, supporting NLRP3 as the biological target by which JNUTS013 inhibits inflammation. Further studies revealed critical chemical moieties of JNUTS013 required for inducing NLRP3 degradation. CONCLUSION AND IMPLICATIONS: This study identifies a novel compound JNUTS013 that inhibits inflammation through inducing NLRP3 protein degradation in vitro and in vivo, which not only supports the development of JNUTS013 as an anti-inflammation agent but also creates a new way for the treatment of inflammation by chemically inducing NLRP3 degradation.

A reconfigurable and magnetically responsive assembly for dynamic solar steam generation.

Interfacial solar vapor generation is a promising technique to efficiently get fresh water from seawater or effluent. However, for the traditional static evaporation models, further performance improvement has encountered bottlenecks due to the lack of dynamic management and self-regulation on the evolving water movement and phase change in the evaporation process. Here, a reconfigurable and magnetically responsive evaporator with conic arrays is developed through the controllable and reversible assembly of graphene wrapped Fe3O4 nanoparticles. Different from the traditional structure-rigid evaporation architecture, the deformable and dynamic assemblies could reconfigure themselves both at macroscopic and microscopic scales in response to the variable magnetic field. Thus, the internal water transportation and external vapor diffusion are greatly promoted simultaneously, leading to a 23% higher evaporation rate than that of static counterparts. Further, well-designed hierarchical assembly and dynamic evaporation system can boost the evaporation rate to a record high level of 5.9 kg m-2 h-1. This proof-of-concept work demonstrates a new direction for development of high performance water evaporation system with the ability of dynamic reconfiguration and reassembly.

Electric Power Generation through the Direct Interaction of Pristine Graphene-Oxide with Water Molecules.

Converting ubiquitous environmental energy into electric power holds tremendous social and financial interests. Traditional energy harvesters and converters are limited by the specific materials and complex configuration of devices. Herein, it is presented that electric power can be directly produced from pristine graphene oxide (GO) without any pretreatment or additives once encountering the water vapor, which will generate an open-circuit-voltage of up to 0.4-0.7 V and a short-circuit-current-density of 2-25 µA cm-2 on a single piece of GO film. This phenomenon results from the directional movement of charged hydrogen ions through the GO film. The present work demonstrates and provides an extremely simple method for electric energy generation, which offers more applications of graphene-based materials in green energy converting field.