Fabric structure and polymer composition as key contributors to micro(nano)plastic contamination in face masks.

The surge in face mask use due to COVID-19 has raised concerns about micro(nano)plastics (MNPs) from masks. Herein, focusing on fabric structure and polymer composition, we investigated MNP generation characteristics, mechanisms, and potential risks of surgical polypropylene (PP) and fashionable polyurethane (PU) masks during their wearing and photoaging based on stereomicroscope, µ-Fourier transform infrared spectroscopy (µ-FTIR), and scanning electron microscope (SEM) techniques. Compared with new PP and PU masks (66 ± 16 MPs/PP-mask, 163 ± 83 MPs/PU-mask), single- and multiple-used masks exhibited remarkably increased MP type and abundance (600-1867 MPs/PP-mask, 607-2167 MPs/PU-mask). Disinfection exacerbated endogenous MP generation in masks, with washing (416 MPs/PP-mask, 30,708 MPs/PU-mask) being the most prominent compared to autoclaving (219 MPs/PP-mask, 553 MPs/PU-mask) and alcohol spray (162 MPs/PP-mask, 18,333 MPs/PU-mask). Photoaging led to massive generation of MPs (8.8 × 104-3.7 × 105 MPs/PP-layer, 1.0 × 105 MPs/PU-layer) and NPs (5.2 × 109-3.6 × 1013 NPs/PP-layer, 3.5 × 1012 NPs/PU-layer) from masks, presenting highly fabric structure-dependent aging modes as "fragmentation" for fine fiber-structure PP mask and "erosion" for 3D mesh-structure PU mask. The MNPs derived from PP/PU mask caused significant deformities of Zebrafish (Danio rerio) larvae. These findings underscore the potential adverse effects of masks on humans and aquatic organisms, advocating to enhance proper use and rational disposal for masks.

Control of Hybrid Exciton Lifetime in MoSe2/WS2 Moiré Heterostructures.

Hybrid excitons, characterized by their strong oscillation strength and long lifetimes, hold great potential as information carriers in semiconductors. They offer promising applications in exciton-based devices and circuits. MoSe2/WS2 heterostructures represent an ideal platform for studying hybrid excitons, but how to regulate the exciton lifetime has not yet been explored. In this study, layer hybridization is modulated by applying electric fields parallel or antiparallel to the dipole moment, enabling us to regulate the exciton lifetime from 1.36 to 4.60 ns. Furthermore, the time-resolved photoluminescence decay traces are measured at different excitation power. A hybrid exciton annihilation rate of 8.9 × 10-4 cm2 s-1 is obtained by fitting. This work reveals the effects of electric fields and excitation power on the lifetime of hybrid excitons in MoSe2/WS2 1.5° moiré heterostructures, which play important roles in high photoluminescence quantum yield optoelectronic devices based on transition-metal dichalcogenides heterostructures.

Twist angle-dependent interlayer hybridized exciton lifetimes in van der Waals heterostructures.

The interlayer twist angle has a direct effect on exciton lifetimes in van der Waals heterostructures. At small angles, the interlayer and intralayer excitons in MoSe2/WS2 heterostructures are hybridized, resulting in hybridized excitons with long lifetimes and strong resonance. However, the study of twist-angle modulation of hybridized exciton lifetimes is still insufficient, leading to an unclear understanding of the mechanism through which the twist angle between layers influences the lifetime of hybridized excitons. Here, we observed the formation of hybridized excitons by constructing MoSe2/WS2 heterostructures with different twist angles. The exciton lifetime is found to increase from 0.5 ns to 3.3 ns when the twist angle is reduced from 12° to 1°. This work provides a new perspective on the modulation of the exciton lifetime, enabling further exploration in improving the efficiency of optoelectronic devices.

Soil-dwelling grub larvae of Protaetia brevitarsis biodegrade polystyrene: Responses of gut microbiome and host metabolism.

Plastic pollution poses a significant threat to terrestrial ecosystems, yet the potential for soil fauna to contribute to plastic biodegradation remains largely unexplored. In this study, we reveal that soil-dwelling grubs, Protaetia brevitarsis larvae, can effectively biodegrade polystyrene (PS) plastics. Over a period of 4 weeks, these grubs achieved a remarkable 61.5 % reduction in PS foam mass. This biodegradation was confirmed by the depolymerization of ingested PS, formation of oxidative functional groups, noticeable chemical modifications, and an increase of δ13C of residual PS in frass. Additionally, antibiotic treatment to suppress gut microbes led to variations in the biodegradation process. PS ingestion induced a significant shift in the gut microbiome, promoting the growth of degradation-related bacteria such as Promicromonosporaceae, Bacillaceae, and Paenibacillaceae. Furthermore, the digestion of plastic triggered extensive metabolomic reprogramming of grubs' intestines, enhancing redox capabilities and facilitating PS biodegradation. These results indicate that responsive adaptation of both the gut microbiome and the host's intestinal metabolism contributes to PS degradation. Collectively, these findings demonstrate P. brevitarsis larvae's capability to alleviate soil plastic pollution, and highlight the potential of researching soil fauna further for sustainable plastic waste management solutions.

Induced dual-target rebalance simultaneously enhances efficient therapeutical efficacy in tumors.

Multiple gene abnormalities are major drivers of tumorigenesis. NF-κB p65 overactivation and cGAS silencing are important triggers and genetic defects that accelerate tumorigenesis. However, the simultaneous correction of NF-κB p65 and cGAS abnormalities remains to be further explored. Here, we propose a novel Induced Dual-Target Rebalance (IDTR) strategy for simultaneously correcting defects in cGAS and NF-κB p65. By using our IDTR approach, we showed for the first time that oncolytic adenovirus H101 could reactivate silenced cGAS, while silencing GAU1 long noncoding RNA (lncRNA) inhibited NF-κB p65 overactivation, resulting in efficient in vitro and in vivo antitumor efficacy in colorectal tumors. Intriguingly, we further demonstrated that oncolytic adenoviruses reactivated cGAS by promoting H3K4 trimethylation of the cGAS promoter. In addition, silencing GAU1 using antisense oligonucleotides significantly reduced H3K27 acetylation at the NF-κB p65 promoter and inhibited NF-κB p65 transcription. Our study revealed an aberrant therapeutic mechanism underlying two tumor defects, cGAS and NF-κB p65, and provided an alternative IDTR approach based on oncolytic adenovirus and antisense oligonucleotides for efficient therapeutic efficacy in tumors.

Comprehensive understanding of electron mobility and superior performance in sub-10 nm DG ML tetrahex-GeC2 n-type MOSFETs.

In this study, we have investigated the electron mobility of monolayered (ML) tetrahex-GeC2 by solving the linearized Boltzmann transport equation (BTE) with the normalized full-band relaxation time approximation (RTA) using density functional theory (DFT). Contrary to what the deformation potential theory (DPT) suggested, the ZA acoustic mode was determined to be the most restrictive for electron mobility, not the LA mode. The electron mobility at 300 K is 803 cm2 (V s)-1, exceeding the 400 cm2 (V s)-1 of MoS2 which was calculated using the same method and measured experimentally. The ab initio quantum transport simulations were performed to assess the performance limits of sub-10 nm DG ML tetrahex-GeC2 n-type MOSFETs, including gate lengths (Lg) of 3 nm, 5 nm, 7 nm, and 9 nm, with the underlap (UL) effect considered for the first two. For both high-performance (HP) and low-power (LP) applications, their on-state currents (Ion) can meet the requirements of similar nodes in the ITRS 2013. In particular, the Ion is more remarkable for HP applications than that of the extensively studied MoS2. For LP applications, the Ion values at Lg of 7 and 9 nm surpass those of arsenene, known for having the largest Ion among 2D semiconductors. Subthreshold swings (SSs) as low as 69/53 mV dec-1 at an Lg of 9 nm were observed for HP/LP applications, and 73 mV dec-1 at an Lg of 5 nm for LP applications, indicating the excellent gate control capability. Moreover, the delay time τ and power dissipation (PDP) at Lg values of 3 nm, 5 nm, 7 nm, and 9 nm are all below the upper limits of the ITRS 2013 HP/LP proximity nodes and are comparable to or lower than those of typical 2D semiconductors. The sub-10 nm DG ML tetrahex-GeC2 n-type MOSFETs can be down-scaled to 9 nm and 5 nm for HP and LP applications, respectively, displaying desirable Ion, delay time τ, and PDP in the ballistic limit, making them a potential choice for sub-10 nm transistors.

Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice.

Overactivation of the NLRP3 inflammasomes induces production of pro-inflammatory cytokines and drives pathological processes. Pharmacological inhibition of NLRP3 is an explicit strategy for the treatment of inflammatory diseases. Thus far no drug specifically targeting NLRP3 has been approved by the FDA for clinical use. This study was aimed to discover novel NLRP3 inhibitors that could suppress NLRP3-mediated pyroptosis. We screened 95 natural products from our in-house library for their inhibitory activity on IL-1ß secretion in LPS + ATP-challenged BMDMs, found that Britannin exerted the most potent inhibitory effect with an IC50 value of 3.630 µM. We showed that Britannin (1, 5, 10 µM) dose-dependently inhibited secretion of the cleaved Caspase-1 (p20) and the mature IL-1ß, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. We demonstrated that Britannin specifically inhibited the activation step of NLRP3 inflammasome in BMDMs via interrupting the assembly step, especially the interaction between NLRP3 and NEK7. We revealed that Britannin directly bound to NLRP3 NACHT domain at Arg335 and Gly271. Moreover, Britannin suppressed NLRP3 activation in an ATPase-independent way, suggesting it as a lead compound for design and development of novel NLRP3 inhibitors. In mouse models of MSU-induced gouty arthritis and LPS-induced acute lung injury (ALI), administration of Britannin (20 mg/kg, i.p.) significantly alleviated NLRP3-mediated inflammation; the therapeutic effects of Britannin were dismissed by NLRP3 knockout. In conclusion, Britannin is an effective natural NLRP3 inhibitor and a potential lead compound for the development of drugs targeting NLRP3.

Enhanced vessel wall magnetic resonance imaging in the follow-up of intracranial aneurysms treated with flow diversion.

OBJECTIVE: This study aimed to compare the efficacy of enhanced 3D T1-weighted black-blood fast-spin-echo vessel wall magnetic resonance imaging (eVW-MRI) and time-of-flight magnetic resonance angiography (TOF MRA) for follow-up evaluation of aneurysms treated with flow diversion (FD). METHODS: Our study enrolled 77 patients harboring 84 aneurysms treated with FD. Follow-up was by MRI (eVW-MRI and TOF MRA) and digital subtraction angiography (DSA). Two radiologists, blinded to DSA examination results, independently evaluated the images of aneurysm occlusion and parent artery patency using the Kamran-Byrne Scale. Interobserver diagnostic agreement and intermodality diagnostic agreement were acquired. Pretreatment and follow-up aneurysm wall enhancement (AWE) patterns were collected. RESULTS: Based on the Kamran-Byrne Scale, the intermodality agreement between eVW-MRI and DSA was better than TOF MRA versus DSA for aneurysm remnant detection (weighted ĸ = 0.891 v. 0.553) and parent artery patency (ĸ = 0.950 v. 0.221). Even with the coil artifact, the consistency of eVW-MRI with DSA for aneurysm remnant detection was better than that of TOF MRA (weighted ĸ = 0.891 v. 0.511). The artifact of adjunctive coils might be more likely to affect the accuracy in evaluating parent artery patency with TOF MRA than with eVW-MRI (ĸ = 0.077 v. 0.788). The follow-up AWE patterns were not significantly associated with pretreatment AWE patterns and aneurysm occlusion. CONCLUSIONS: The eVW-MRI outperforms TOF MRA as a reliable noninvasive and nonionizing radioactive imaging method for evaluating aneurysm remnants and parent artery patency after FD. The significance of enhancement patterns on eVW-MRI sequences needs more exploration. CLINICAL RELEVANCE STATEMENT: The application of enhanced vessel wall magnetic resonance imaging has proven to be a promising tool to depict aneurysm remnant and parent artery stenosis in order to tailor the antiplatelet therapy strategy in patients after flow diversion. KEY POINTS: • Enhanced vessel wall magnetic resonance imaging has an emerging role in depicting aneurysm remnant and parent artery patency after flow diversion. • With or without the artifact from adjunctive coils, enhanced vessel wall magnetic resonance imaging was better than TOF MRA in detecting aneurysm residual and parent artery stenosis by using DSA imaging as the standard. • Enhanced vessel wall magnetic resonance imaging holds potential to be used as an alternative to DSA for routine aneurysm follow-up after flow diversion.

Direct Visualization of Dark Interlayer Exciton Transport in Moiré Superlattices.

Moiré superlattices have emerged as an unprecedented manipulation tool for engineering correlated quantum phenomena in van der Waals heterostructures. With moiré potentials as a naturally configurable solid-state that sustains high exciton density, interlayer excitons in transition metal dichalcogenide heterostructures are expected to achieve high-temperature exciton condensation. However, the exciton degeneracy state is usually optically inactive due to the finite momentum of interlayer excitons. Experimental observation of dark interlayer excitons in moiré potentials remains challenging. Here we directly visualize the dark interlayer exciton transport in WS2/h-BN/WSe2 heterostructures using femtosecond transient absorption microscopy. We observe a transition from classical free exciton gas to quantum degeneracy by imaging temperature-dependent exciton transport. Below a critical degeneracy temperature, exciton diffusion rates exhibit an accelerating downward trend, which can be explained well by a nonlinear quantum diffusion model. These results open the door to quantum information processing and high-precision metrology in moiré superlattices.

The value of the cinematic volume rendering technique: magnetic resonance imaging in diagnosing tumors associated with the brachial plexus.

PURPOSE: To examine the diagnostic advantages and clinical application value of the cinematic volume rendering technique (cVRT) when evaluating the relationship between the brachial plexus, peripheral tumor lesions, and blood vessels. MATERIALS AND METHODS: Seventy-nine patients with brachial plexus tumors between November 2012 and July 2022 were enrolled in our study. All patients underwent T1WI, T2WI, three-dimensional short recovery time reversal recovery fast spin-echo imaging (3D-STIR-SPACE), and the T1WI enhancement sequence. In addition, cVRT was used to render and obtain a three-dimensional model that clearly showed the location and tissue structure of the brachial plexus nerves and the tumor in all directions. RESULTS: Seventy-one patients (mean age, 47.1 years; 33 males, 38 females) with tumors around the brachial plexus were included in the study. The brachial plexus nerve, surrounding tumor lesions, and vascular anatomy of all patients were well displayed with cVRT. The tumors of 37 patients manifested as unilateral or bilateral growths along the brachial plexus nerve and were fusiform, spherical, or multiple beaded; seven patients' tumors pushed against the brachial plexus nerve and were circular, lobular, or irregular; sixteen patients' tumors encircled the brachial plexus nerve and were spherical; and eleven patients' tumors infiltrated the brachial plexus nerve and had irregular morphology. The mass has a moderately uniform or uneven signal on T1WI and a high or mixed signal on T2WI. After enhancement, the signal was evenly or unevenly strengthened. CONCLUSIONS: cVRT clearly showed the origin of tumors associated with the brachial plexus and their relationship with the nerves and peripheral blood vessels, providing reliable information for clinical diagnosis and treatment.

The guiding value of the cinematic volume rendering technique in the preoperative diagnosis of brachial plexus schwannoma.

This study aimed to explore and compare the guiding value of Maximum Intensity Projection (MIP) and Cinematic Volume Rendering Technique (cVRT) in the preoperative diagnosis of brachial plexus schwannomas. We retrospectively analyzed the clinical and imaging data of 45 patients diagnosed with brachial plexus schwannomas at the First Affiliated Hospital of Zhengzhou University between January 2020 and December 2022. The enhanced three-dimensional short recovery time inversion-recovery fast spin-echo imaging (3D-STIR-SPACE) sequence served as source data for the reconstruction of MIP and cVRT. Two independent observers scored the image quality and evaluated the location of the tumor and the relationship between the tumor and the brachial plexus. The image quality scores of the two reconstruction methods were compared using the nonparametric Wilcoxon signed-rank test, and the consistency between the image and surgical results was assessed using the weighted kappa. Compared to MIP images, cVRT images had a better performance of overall image quality (p < 0.001), nerve and lump visualization (p < 0.001), spatial positional relationship conspicuity (p < 0.001), and diagnostic confidence (p < 0.001). Additionally, the consistency between the cVRT image results and surgical results (kappa =0.913, P<0.001) was higher than that of the MIP images (kappa =0.829, P<0.001). cVRT provides a high guiding value in the preoperative diagnosis of brachial plexus schwannomas and is an important basis for formulating surgical plans.

In-depth understanding of higher-order genome architecture in orphan cancer.

The human genome is intertwined, folded, condensed, and gradually constitutes the 3D architecture, thereby affecting transcription and widely involving in tumorigenesis. Incidence and mortality rates for orphan cancers increase due to poor early diagnosis and lack of effective medical treatments, which are now getting attention. In-depth understanding in tumorigenesis has fast-tracked over the last decade, however, the further role and mechanism of 3D genome organization in variant orphan tumorigenesis remains to be fully understood. We summarize for the first time that higher-order genome organization can provide novel insights into the occurrence mechanisms of orphan cancers, and discuss probable future research directions for drug development and anti-tumor therapies.

Efficacy and safety of flow diverter combined with coil embolization and evidence-based antithrombotic regimen in the treatment of ruptured aneurysms.

OBJECTIVE: The use of a flow diverter (FD) in the treatment of ruptured aneurysms is limited due to the increased risk of perioperative ischemia and hemorrhagic complications. Adjunctive coil embolization and an evidence-based antithrombotic regimen may improve therapeutic safety, although evidence from relevant clinical research is limited. The authors' aim was to further assess the perioperative safety and long-term efficacy of this strategy. METHODS: Data on patients with FD insertion and coil embolization were collected retrospectively at two centers. The perioperative antithrombotic regimen consists of intraoperative tirofiban and continues for 24 hours postoperatively, with the initiation of an orally administered dual-antiplatelet regimen 4 hours prior to tirofiban cessation, rather than purposeful preoperative antiplatelet therapy. Perioperative cerebral ischemia and hemorrhagic complications and long-term aneurysm occlusion rates were recorded to evaluate the safety and efficacy of the procedure, respectively. RESULTS: In total, 67 cases were screened and 41 cases were ultimately included in this study. A total of 2 cases (4.9%) of perioperative cerebral hemorrhagic events occurred, 1 of which (2.4%) was attributable to rerupture of the aneurysm. Cerebral ischemic events were reported in 3 patients, including 1 with cortical thromboembolism and 2 with perforator occlusion of the basilar artery. A median 8-month follow-up was attained in 25 patients (61.0%), with a 92% complete or near-complete occlusion rate. CONCLUSIONS: FD insertion combined with coil embolization is a potentially safe and effective therapeutic strategy for ruptured aneurysms when accompanied with perioperative evidence-based antithrombotic therapy.

Ergolide covalently binds NLRP3 and inhibits NLRP3 inflammasome-mediated pyroptosis.

BACKGROUND: NLR family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis plays a key role in various acute and chronic inflammatory diseases. Targeted inhibition of NLRP3-mediated pyroptosis may be a potential therapeutic strategy for various inflammatory diseases. Ergolide (ERG) is a sesquiterpene lactone natural product derived from the traditional Chinese medicinal herb, Inula britannica. ERG has been shown to have anti-inflammatory and anti-cancer activities, but the target is remains unknown. HYPOTHESIS/PURPOSE: This study performed an in-depth investigation of the anti-inflammatory mechanism of ERG in NLRP3-mediated pyroptosis and NLPR3 inflammasome related sepsis and acute lung injury model. METHODS: ELISA and Western blot were used to determine the IL-1ß and P20 levels. Co-immunoprecipitation assays were used to detect the interaction between proteins. Drug affinity response target stability (DARTS) assays were used to explore the potential target of ERG. C57BL/6J mice were intraperitoneally injected with E. coli DH5α (2 × 109 CFU/mouse) to establish a sepsis model. Acute lung injury was induced by intratracheal administrationof lipopolysaccharide in wild-type mice and NLRP3 knockout mice with or without ERG treatment. RESULTS: We showed that ERG is an efficient inhibitor of NLRP3-mediated pyroptosis in the first and second signals of NLRP3 inflammasome activation. Furthermore, we demonstrated that ERG irreversibly bound to the NACHT domain of NLRP3 to prevent the assembly and activation of the NLRP3 inflammasome. ERG remarkably improved the survival rate of wild-type septic mice. In lipopolysaccharide-induced acute lung injury model, ERG alleviated acute lung injury of wild-type mice but not NLRP3 knockout mice. CONCLUSION: Our results revealed that the anti-pyroptosis effect of ERG are dependent on NLRP3 and NLRP3 NACHT domain is ERG's direct target. Therefore, ERG can serve as a precursor drug for the development of novel NLRP3 inhibitors to treat NLRP3 inflammasome mediated inflammatory diseases.

Tanshinone IIA analogue 15a inhibits NLRP3-mediated inflammation by activating mitophagy in macrophages to alleviate acute tubular necrosis.

BACKGROUND: Acute tubular necrosis (ATN) is a common type of acute renal failure. Recent studies have shown that NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in macrophages plays a crucial role in the progression of ATN. Previously, we synthesized an anti-inflammatory compound 15a based on Tanshinone IIA (Tan IIA). In the present study, we found that compound 15a exhibited a greater inhibitory effect on NLRP3-mediated pyroptosis than Tan IIA in vitro. METHODS: C57BL/6 and NLRP3-knockout (NLRP3-KO) mice were intraperitoneally injected with LPS or folic acid (FA) to develop ATN. In vitro, bone marrow-derived macrophages (BMDMs) were treated with LPS for 3 h and then treated with ATP for 0.5 h. RESULTS: We explored the mechanism by which compound 15a inhibited NLRP3 inflammasome in BMDMs as well as its renal protective effect against ATN in mice. We found that compound 15a exhibited a protective effect on mitochondria and reduced the production of mitochondrial reactive oxygen species (mtROS). Moreover, we revealed that compound 15a remarkably reduced the production of mtROS by promoting mitophagy, which resulted in the inhibition of NLRP3 inflammasome to alleviates ATN in mice. CONCLUSION: In summary, compound 15a inhibited NLRP3-mediated inflammation by activating mitophagy in macrophages to alleviate ATN. Our results identified compound 15a as a promising candidate for the treatment of NLRP3-driven ATN.

Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases.

The NLRP3 inflammasome's core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS's great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.

Doublecortin-like kinase 1 activates NF-κB to induce inflammatory responses by binding directly to IKKß.

Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis, and its levels are elevated in various human cancers. Recent studies suggest that DCLK1 may relate to inflammatory responses in the mouse model of colitis. However, cellular pathways engaged by DCLK1, and potential substrates of the kinase remain undefined. To understand how DCLK1 regulates inflammatory responses, we utilized the well-established lipopolysaccharide (LPS)-stimulated macrophages and mouse model. Through a range of macrophage-based and cell-free platforms, we discovered that DCLK1 binds directly with the inhibitor of κB kinase ß (IKKß) and induces IKKß phosphorylation on Ser177/181 to initiate nuclear factor-κB (NF-κB) pathway. Deficiency in DCLK1, achieved by silencing or through pharmacological inhibition, prevented LPS-induced NF-κB activation and cytokine production in macrophages. We further show that mice with myeloid-specific DCLK1 knockout or DCLK1 inhibitor treatment are protected against LPS-induced acute lung injury and septic death. Our studies report a novel functional role of macrophage DCLK1 as a direct IKKß regulator in inflammatory signaling and suggest targeted therapy against DCLK1 for inflammatory diseases.

Tabersonine, a natural NLRP3 inhibitor, suppresses inflammasome activation in macrophages and attenuate NLRP3-driven diseases in mice.

Aberrant activation of NLRP3 inflammasome causes the progression of various inflammation-related diseases, but the small-molecule inhibitors of NLRP3 are not currently available for clinical use. Tabersonine (Tab) is a natural product derived from a traditional Chinese herb Catharanthus roseus that is usually used as an anti-tumor agent. In this study we investigated the anti-inflammatory effects and molecular targets of Tab. We first screened 151 in-house natural compounds for their inhibitory activity against IL-1ß production in BMDMs. We found that Tab potently inhibited NLRP3-mediated IL-1ß production with an IC50 value of 0.71 µM. Furthermore, we demonstrated that Tab suppressed the assembly of NLRP3 inflammasome, especially the interaction between NLRP3 and ASC. Interestingly, we found that Tab directly bound to NLRP3 NACHT domain, thereby reducing the self-oligomerization of NLRP3. In addition, we showed that administration of Tab significantly ameliorated NLRP3-driven diseases, such as peritonitis, acute lung injury, and sepsis in mouse models. The preventive effects of Tab were not observed in the models of NLRP3 knockout mouse. In conclusion, we have identified Tab as a natural NLRP3 inhibitor and a lead compound for the design and discovery of novel NLRP3 inhibitors.

Discovery of alantolactone as a naturally occurring NLRP3 inhibitor to alleviate NLRP3-driven inflammatory diseases in mice.

BACKGROUND AND PURPOSE: The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is activated in many inflammatory conditions. So far, no low MW compounds inhibiting NLRP3 have entered clinical use. Identification of naturally occurring NLRP3 inhibitors may be beneficial to the design and development of compounds targeting NLRP3. Alantolactone is a phytochemical from a traditional Chinese medicinal plant with anti-inflammatory activity, but its precise target remains unclear. EXPERIMENTAL APPROACH: A bank of phytochemicals was screened for inhibitors of NLRP3-driven production of IL-1ß in cultures of bone-marrow-derived macrophages from female C57BL/6 mice. Models of gouty arthritis and acute lung injury in male C57BL/6J mice were used to determine the in vivo effects of the most potent compound. KEY RESULTS: Among the 150 compounds screened in vitro, alantolactone exhibited the highest inhibitory activity against LPS + ATP-induced production of IL-1ß in macrophages, suppressing IL-1ß secretion, caspase-1 activation and pyroptosis. Alantolactone directly bound to the NACHT domain of NLRP3 to inhibit activation and assembly of NLRP3 inflammasomes. Molecular simulation analysis suggested that Arg335 in NLRP3 was a critical residue for alantolactone binding, leading to suppression of NLRP3-NEK7 interaction. In vivo studies confirmed significant alleviation by alantolactone of two NLRP3-driven inflammatory conditions, acute lung injury and gouty arthritis. CONCLUSION AND IMPLICATIONS: The phytochemical alantolactone inhibited activity of NLRP3 inflammasomes by directly targeting the NACHT domain of NLRP3. Alantolactone shows great potential in the treatment of NLRP3-driven diseases and could lead to the development of novel NLRP3 inhibitors.