The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome activation, but compounds ...directly and specifically targeting NLRP3 are still not available, so it is unclear whether NLRP3 itself can be targeted to prevent or treat diseases. Here we show that the compound CY-09 specifically blocks NLRP3 inflammasome activation. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation. Importantly, treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes. Furthermore, CY-09 is active ex vivo for monocytes from healthy individuals or synovial fluid cells from patients with gout. Thus, our results provide a selective and direct small-molecule inhibitor for NLRP3 and indicate that NLRP3 can be targeted in vivo to combat NLRP3-driven diseases.
Abstract
TLR4 signaling plays key roles in the innate immune response to microbial infection. Innate immune cells encounter different mechanical cues in both health and disease to adapt their ...behaviors. However, the impact of mechanical sensing signals on TLR4 signal-mediated innate immune response remains unclear. Here we show that TLR4 signalling augments macrophage bactericidal activity through the mechanical sensor Piezo1. Bacterial infection or LPS stimulation triggers assembly of the complex of Piezo1 and TLR4 to remodel F-actin organization and augment phagocytosis, mitochondrion-phagosomal ROS production and bacterial clearance and genetic deficiency of Piezo1 results in abrogation of these responses. Mechanistically, LPS stimulates TLR4 to induce Piezo1-mediated calcium influx and consequently activates CaMKII-Mst1/2-Rac axis for pathogen ingestion and killing. Inhibition of CaMKII or knockout of either Mst1/2 or Rac1 results in reduced macrophage bactericidal activity, phenocopying the Piezo1 deficiency. Thus, we conclude that TLR4 drives the innate immune response via Piezo1 providing critical insight for understanding macrophage mechanophysiology and the host response.
Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a ...central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori's anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.
The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory, metabolic and neurodegenerative diseases, but ...medications targeting the NLRP3 inflammasome are not available for clinical use. RRx-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials, but its effects on inflammatory diseases are not known. Here, we show that RRx-001 is a highly selective and potent NLRP3 inhibitor that has strong beneficial effects on NLRP3-driven inflammatory diseases. RRx-001 inhibits the activation of the canonical, noncanonical, and alternative NLRP3 inflammasomes but not the AIM2, NLRC4 or Pyrin inflammasomes. Mechanistically, RRx-001 covalently binds to cysteine 409 of NLRP3 via its bromoacetyl group and therefore blocks the NLRP3-NEK7 interaction, which is critical for the assembly and activation of the NLRP3 inflammasome. More importantly, RRx-001 treatment attenuates the symptoms of lipopolysaccharide (LPS)-induced systemic inflammation, dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our study identifies RRx-001 as a new potential therapeutic agent for NLRP3-driven diseases.
Coupled magmatic and tectonic activity plays an important role in high-temperature hydrothermal circulation at mid-ocean ridges. The circulation patterns for such systems have been elucidated by ...microearthquakes and geochemical data over a broad spectrum of spreading rates, but such data have not been generally available for ultra-slow spreading ridges. Here we report new geophysical and fluid geochemical data for high-temperature active hydrothermal venting at Dragon Horn area (49.7°E) on the Southwest Indian Ridge. Twin detachment faults penetrating to the depth of 13 ± 2 km below the seafloor were identified based on the microearthquakes. The geochemical composition of the hydrothermal fluids suggests a long reaction path involving both mafic and ultramafic lithologies. Combined with numerical simulations, our results demonstrate that these hydrothermal fluids could circulate ~ 6 km deeper than the Moho boundary and to much greater depths than those at Trans-Atlantic Geotraverse and Logachev-1 hydrothermal fields on the Mid-Atlantic Ridge.
The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not ...available in clinic. Here, we show that tranilast (TR), an old anti‐allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization. In vivo experiments show that TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome‐related human diseases, including gouty arthritis, cryopyrin‐associated autoinflammatory syndromes, and type 2 diabetes. Furthermore, TR is active ex vivo for synovial fluid mononuclear cells from patients with gout. Thus, our study identifies the old drug TR as a direct NLRP3 inhibitor and provides a potentially practical pharmacological approach for treating NLRP3‐driven diseases.
Synopsis
Tranilast (TR), an anti‐allergic clinical drug, is here reported as a NLRP3 inflammasome inhibitor with beneficial effects for NLRP3‐driven diseases. By direct binding to NLRP3, it inhibits its oligomerization and subsequent inflammasome assembly, caspase‐1 activation and IL‐1β production.
TR specifically inhibits NLRP3 inflammasome activation in both human and mouse cells.
TR binds to NLRP3 and inhibits its oligomerization and inflammasome complex formation.
TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3‐driven diseases.
Tranilast (TR), an anti‐allergic clinical drug, is here reported as a NLRP3 inflammasome inhibitor with beneficial effects for NLRP3‐driven diseases. By direct binding to NLRP3, it inhibits its oligomerization and subsequent inflammasome assembly, caspase‐1 activation and IL‐1β production.
Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects
. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a ...major role in its mechanism of action
; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation
. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase
, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase
, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
Transshipment of compacted soybean is characterized by labor-intensive processes, long operating times, and a great amount of dust that cannot be collected by sealed devices. This dust significantly ...reduces air quality of the workshop and represents a great threat to human health. Solving this problem has been a great challenge in the soybean storage industry. For this reason, in the present study the concept of a transshipment system for soybean clearance was proposed. This system can simultaneously achieve real-time transshipment of falling materials and air curtain control of fugitive dust. The main factors influencing the performance of the air curtain dust control system were investigated using numerical simulation, and the effects of the exhaust-to-pressure ratio K and air curtain outlet velocity V on dust control efficiency were determined. Results showed that the width of the dust-collecting paths increased with increasing K and V values. We also found out that dust-escape paths were mainly concentrated in the transition height between the complete air curtains and local air curtains. At the beginning of the process, dust control efficiency rapidly increased and the increment rate became slower as K increased. When K = 1.5 and V = 5–6 m/s, dust control efficiency reached values up to 95.54–96.27%. Based on numerical simulation results, the prototype transshipment system for soybean clearance was developed, and the effectiveness of air curtain dust control was validated via smoke tracing experiments. After the application of the developed system, occupational lung disease can be significantly reduced, and transshipment efficiency per clearance can be enhanced by approximately 67% (about 50,113￥ can be saved in terms of energy consumption and labor resources). An extra granary can be saved after using the newly developed system for 36.5–52.1 clearances.
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•An effective method to solve the soybean blanking dust collection is proposed.•The dust collection method ensures smooth ventilation inside the granary.•Dust collection efficiency reaches 95.54%.•The method is validated by industrial experiments.
The SLC12A cation-Cl
cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ...ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.
A simplified pulse width modulation (PWM) strategy for a neutral-point-clamped three-level converter with unbalanced dc links is proposed in this paper to achieve high-quality line-to-line output ...voltages and to maximize the linear modulation range. The simplified strategy takes the direct output voltage modulation by calculating the special solutions of the voltage-second balance equations without detecting the position of the reference vector in the asymmetrical and complicated space voltage vector diagrams to reduce the calculation time. A novel solution based on the state transition is proposed to extend the maximum linear modulation index to 1.15. Furthermore, the asymmetric control of the split dc link by the proposed PWM is implemented by adjusting the special solutions. The difference between the conventional space vector PWM and the proposed strategy is conducted to illustrate the advantages of the simplified strategy. The effectiveness of the proposed modulation strategy is verified by simulation and experiment results.
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