Dopamine Uses the DRD5-ARRB2-PP2A Signaling Axis to Block the TRAF6-Mediated NF-κB Pathway and Suppress Systemic Inflammation.

The functional relevance and mechanistic basis of the effects of the neurotransmitter dopamine (DA) on inflammation remain unclear. Here we reveal that DA inhibited TLR2-induced NF-κB activation and inflammation via the DRD5 receptor in macrophages. We found that the DRD5 receptor, via the EFD and IYX(X)I/L motifs in its CT and IC3 loop, respectively, can directly recruit TRAF6 and its negative regulator ARRB2 to form a multi-protein complex also containing downstream signaling proteins, such as TAK1, IKKs, and PP2A, that impairs TRAF6-mediated activation of NF-κB and expression of pro-inflammatory genes. Furthermore, the DA-DRD5-ARRB2-PP2A signaling axis can prevent S. aureus-induced inflammation and protect mice against S. aureus-induced sepsis and meningitis after DA treatment. Collectively, these findings provide the first demonstration of DA-DRD5 signaling acting to control inflammation and a detailed delineation of the underlying mechanism and identify the DRD5-ARRB2-PP2A axis as a potential target for future therapy of inflammation-associated diseases such as meningitis and sepsis.

The Gasdermin D N-terminal fragment acts as a negative feedback system to inhibit inflammasome-mediated activation of Caspase-1/11.

Inflammatory pathways usually utilize negative feedback regulatory systems to prevent tissue damage arising from excessive inflammatory response. Whether such negative feedback mechanisms exist in inflammasome activation remains unknown. Gasdermin D (GSDMD) is the pyroptosis executioner of downstream inflammasome signaling. Here, we found that GSDMD, after its cleavage by caspase-1/11, utilizes its RFWK motif in the N-terminal ß1-ß2 loop to inhibit the activation of caspase-1/11 and downstream inflammation in a negative feedback manner. Furthermore, an RFWK motif-based peptide inhibitor can inhibit caspase-1/11 activation and its downstream substrates GSDMD and interleukin-1ß cleavage, as well as lipopolysaccharide-induced sepsis in mice. Collectively, these findings provide a demonstration of the N-terminal fragment of GSDMD as a negative feedback regulator controlling inflammasome activation and a detailed delineation of the underlying inhibitory mechanism.

Network pharmacology analysis and experimental validation of Anemarrhenae Rhizoma in treating Alzheimer's disease. / çŸ¥æ¯æ²»ç–—é˜¿å°”èŒ¨æµ·é»˜ç— ç½‘ç»œè¯ç†å­¦ç ”ç©¶åŠå®žéªŒéªŒè¯.

OBJECTIVES: To explore the mechanism of Anemarrhenae Rhizoma in treatment of Alzheimer's Disease (AD). METHODS: The active ingredients and targets of Anemarrhenae Rhizoma for treatment of AD were screened with network pharmacology methods, the protein-protein interaction (PPI) network was constructed and the core targets were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriching analysis was performed. The peripheral blood lymphocytes were extracted and lymphoblastoid cell lines (LCL) were constructed and an in vitro cell model of LCL-SKNMC was established. MTT and CCK-8 methods were used to quantify SKNMC/LCL cells, 2 ´, 7 ´-dichlorodihydrofluorescein diacetate (DCFH-DA) probe was used to detect reactive oxygen species (ROS), and immunofluorescence staining was used to detect the generation of Aß1-42 in a co-cultured model. Western blotting was used to detect protein expression in the co-culture model. The lifespan of N2 nematodes was observed under oxidative stress, normal state, and heat stress; ROS generated by N2 nematodes was detected by DCFH-DA probes. The paralysis time of CL4176 N2 nematodes was evaluated by paralysis assay, and Aß deposition in the pharynx was detected by Thioflavin S staining. RESULTS: Through network pharmacology, 15 potential active ingredients and 103 drug-disease targets were identified. PPI analysis showed that the Anemarrhenae Rhizoma might play anti-AD roles through albumin, Akt1, tumor necrosis factor, epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA), mammalian target of rapamycin (mTOR), amyloid precursor protein (APP) and other related targets. KEGG analysis showed that the pharmacological effects of Anemarrhenae Rhizoma might involve the biological processes of Alzheimer's disease, endocrine resistance, insulin resistance; and neuroactive ligand-receptor interaction, phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, calcium signaling pathway, AGE-RAGE signaling pathway in diabetes complications, neurotrophic factor signaling pathway and others. The in vitro cell experiments showed that Anemarrhenae Rhizoma was able to reduce the production of ROS and Aß1-42 (both P<0.01), inhibit the expression of ß-secretase 1 (BACE1), APP and Aß1-42 proteins (all P<0.05), up-regulate the expression of p-PI3K/PI3K, p-AKT/AKT, p-GSK3ß/GSK3ß in SKNMC cells (all P<0.05). The in vivo studies further confirmed that Anemarrhenae Rhizoma prolonged the lifespan of C. elegans under stress and normal conditions, reduced the accumulation of ROS and the toxicity of Aß deposition. CONCLUSIONS: Anemarrhenae Rhizoma may reduce the production of Aß in AD and inhibit its induced oxidative stress, which may be achieved by regulating the PI3K/Akt/GSK-3ß pathway.

Microglial AIM2 alleviates antiviral-related neuro-inflammation in mouse models of Parkinson's disease.

Inflammasome involvement in Parkinson's disease (PD) has been intensively investigated. Absent in melanoma 2 (AIM2) is an essential inflammasome protein known to contribute to the development of several neurological diseases. However, a specific role for AIM2 in PD has not been reported. In this study, we investigated the effect of AIM2 in the N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model by use of various knockout and bone marrow chimeric mice. The mechanism of action for AIM2 in PD was assessed by RNA-sequencing and in vitro primary microglial transfection. Results were validated in the A30P transgenic mouse model of PD. In the MPTP mouse model, AIM2 activation was found to negatively regulate neuro-inflammation independent of the inflammasome. Microglial AIM2 deficiency exacerbated behavioral and pathological features of both MPTP-induced and transgenic PD mouse models. Mechanistically, AIM2 reduced cyclic GMP-AMP synthase (cGAS)-mediated antiviral-related inflammation by inhibition of AKT-interferon regulatory factor 3 (IRF3) phosphorylation. These results demonstrate microglial AIM2 to inhibit the antiviral-related neuro-inflammation associated with PD and provide for a foundation upon which to identify new therapeutic targets for treatment of the disease.

Evaluation of Inspection Efficiency of Diatom Artificial Intelligence Search System Based on Scanning Electron Microscope.

OBJECTIVES: To explore the application values of diatom artificial intelligence (AI) search system in the diagnosis of drowning. METHODS: The liver and kidney tissues of 12 drowned corpses were taken and were performed with the diatom test, the view images were obtained by scanning electron microscopy (SEM). Diatom detection and forensic expert manual identification were carried out under the thresholds of 0.5, 0.7 and 0.9 of the diatom AI search system, respectively. Diatom recall rate, precision rate and image exclusion rate were used to detect and compare the efficiency of diatom AI search system. RESULTS: There was no statistical difference between the number of diatoms detected in the target marked by the diatom AI search system and the number of diatoms identified manually (P>0.05); the recall rates of the diatom AI search system were statistically different under different thresholds (P<0.05); the precision rates of the diatom AI system were statistically different under different thresholds(P<0.05), and the highest precision rate was 53.15%; the image exclusion rates of the diatom AI search system were statistically different under different thresholds (P<0.05), and the highest image exclusion rate was 99.72%. For the same sample, the time taken by the diatom AI search system to identify diatoms was only 1/7 of that of manual identification. CONCLUSIONS: Diatom AI search system has a good application prospect in drowning cases. Its automatic diatom search ability is equal to that of experienced forensic experts, and it can greatly reduce the workload of manual observation of images.

Cadmium-induced toxicity to amphibian tadpoles might be exacerbated by alkaline not acidic pH level.

Heavy metal pollution in natural water bodies generally interacting with other environmental stressors produces toxic effects on aquatic organisms. However, toxicological studies exploring interactive effects of these stressors are still limited. Here, tadpoles of the Zhenhai brown frog (Rana zhenhaiensis) were exposed to a 3 × 3 factorial combination, with three cadmium (Cd) concentrations (0, 10 and 100 µg/L) and three pH levels (5.0, 7.23 and 9.0) throughout the developmental period to assess combined toxic effects of Cd × pH on tadpole growth, development and physiology. Nearly all measured traits [including survival, metamorphosis and abnormality rate, metamorphosis time, post-metamorphic size, hepatic metal content, locomotor performance, antioxidant enzyme activity, and erythrocytic nuclear abnormality (ENA) frequency] were affected by Cd exposure, indicating notable Cd-induced toxicity to R. zhenhaiensis tadpoles. The pH level and its interaction with Cd also had significant impacts on most measured traits, such as survival rate, metamorphosis time, froglet jumping distance, hepatic Cd content, ENA frequency. Acidic (or alkaline) environment itself was toxic to tadpoles. However, high pH (but not low pH) level appeared to exacerbate Cd-induced toxicity to tadpoles. Excess free hydrogen ions under acidic environments might inhibit Cd2+ ions binding to cell surface, which reduced Cd accumulation in tissues. Under alkaline environments, other forms of Cd complexes in the aqueous phase probably contributed to promoting Cd accumulation. Our results indicated that Cd exposure could interact with different pH levels, producing diverse combined toxicities to amphibian larvae.

In Situ Decoration of Selenide on Copper Foam for the Efficient Immobilization of Gaseous Elemental Mercury.

Mercury emission from industrial activities is a great threat to public health and ecosystems. Developing new strategies and materials to remove mercury still remains a serious task. Herein, selenide-decorated copper foam prepared by a heating-stirring method (Cu-hs) was used as a monolithic mercury adsorption material. The Cu-hs exhibited much better adsorption of elemental mercury (Hg0) compared with the selenide-decorated cordierite honeycomb prepared by the same method (Cordierite-hs). Nearly 100% Hg0 adsorption efficiency was obtained under a high gaseous hourly space velocity of 6.0 × 104. Excellent Hg0 adsorption capacity was obtained in a wide range of reaction temperatures from 40 to 120 °C, suggesting the good adaptability of Cu-hs in different operating conditions. The Cu-hs exhibited high selectivity for Hg0 against H2O and SO2, which is advantageous for real applications in industrial flue gas. The Hg0 adsorption capacity of Cu-hs reached 3743 g/m3, about 14 times higher than the 243 g/m3 of Cordierite-hs. The excellent Hg0 adsorption performance of Cu-hs was attributed to the high affinity of the selenium in Cu2Se for mercury, the homogeneous distribution of Cu2Se, and the superior fluid characteristics of the Cu foam substrate. The adsorption performance of the spent Cu-hs could be effectively recovered by HCl solution leaching and subsequent reselenization. The utilization of recyclable Cu-hs provides a cost-effective and environmentally friendly method for removing mercury from industrial flue gas.

Evaluation of the sensitivity of Microhyla fissipes tadpoles to aqueous cadmium.

Cadmium (Cd) exposure is harmful to amphibians in natural environments and the Cd concentration is a key parameter in water monitoring. Cd pollution has been a severe issue in the Yangtze River and its southern reaches in recent years. Acute toxicity assays were employed to determine the tolerance limits of Cd for Microhyla fissipes tadpoles and five different concentrations of Cd (0, 50, 100, 200 and 300 µg/L) were involved to detect its chronic effects on metamorphosis, growth, locomotion, genotoxicity and enzymatic activities of M. fissipes tadpoles. The results showed that the 24-h and 48-h LC50 values of Cd on M. fissipes tadpoles were 2591.3 µg/L and 1567.9 µg/L, respectively, and the presumable non-lethal concentration obtained was 172.2 µg/L. During the 70-day chronic toxicity assays, Cd showed negative impacts on survival, growth, metamorphosis and the frequency of erythrocytes nuclear abnormality of M. fissipes tadpoles. However, the Cd exposure caused the increased body size and condition of tadpoles at complete metamorphosis (GS46). The tadpoles exposed to 200 µg/L of Cd exhibited degraded locomotor performance at GS46. Weight increments of tadpoles were inhibited at Day 14 and massive deaths were observed over the next 14 days. The enzymatic activities of tadpoles experienced a shock response stage (GS30-GS35) and a complete recovery stage (GS36-GS41) in all treatments. However, the enzymatic activities (except alkaline phosphatase) of tadpoles at GS46 increased after Cd exposure, especially at high concentrations. In summary, Cd is a threat to M. fissipes tadpoles as that causes reduced fitness.

Thermal dependence of feeding performance and resting metabolic expenditure in different altitudinal populations of toad-headed lizards.

Inter-population variations in growth rate can result from independent or interactive effects of genetic and environmental factors, and be induced by some physiological differences as well. Toad-headed lizards (Phrynocephalus vlangalii) from a higher-elevation population were shown to have a higher growth rate than those from a lower-elevation population. The physiological basis of growth rate variation in this species is not well understood. Here, we investigated the feeding performance and resting metabolic rate (RMR) of lower- and higher-elevation individuals at different test ambient temperatures to evaluate the role of differences in energy intake, assimilation efficiency and metabolic expenditure on growth rate variations. Within the range of 25-35 °C, lizard RMR increased with increasing test ambient temperature, but food intake, apparent digestive coefficient (ADC, food energy minus faecal energy divided by food energy), and assimilation efficiency (AE, food energy minus faecal and urinary energy divided by food energy) were less thermally sensitive in both populations. Higher-elevation lizards tended to eat more food and have a lower RMR than lower-elevation ones, despite the lack of differences in ADC and AE. Our result showed that more energy intake and reduced maintenance cost may be associated with the higher growth rate of higher-elevation lizards. Accordingly, inter-population differences in energy acquisition and expenditure could act as potential sources for geographic variation in growth rate.

Altitude influences thermal ecology and thermal sensitivity of locomotor performance in a toad-headed lizard.

Population differentiation in ectotherm physiological performance may be driven by adapting to different thermal environments. In this study, we measured locomotor performance in two different altitude populations of the Qinghai toad-headed lizards (Phrynocephalus vlangalii) at different test temperatures to assess between-population differences in thermal sensitivity of sprint speed. Low-elevation lizards ran faster than high-elevation lizards at most test temperatures. Sprint speed varied with test temperature similarly between populations, but the thermal sensitivity (performance breadth) differed significantly. Low-elevation lizards had a lower optimal temperature (Topt) for sprint speed and narrower performance breadth than high-elevation lizards as inferred from the thermal performance curves constructed for each individual. We also measured the body temperature of active lizards (Tb) in the field and selected temperature (Tsel) in the laboratory. Low-elevation lizards had a lower Tsel, and less variable Tb than high-elevation lizards. In both populations, Tsel was lower than Topt for sprint speed, which was inconsistent with the prediction for a match between thermal preference and Topt. Our results suggest that lower thermal sensitivity and weaker locomotor ability for high-elevation lizards may be an adaptive response to the local environmental conditions (e.g., greater thermal variability, higher food availability, and lower predator pressure).

Ferroptosis: Iron-mediated cell death linked to disease pathogenesis.

Ferroptosis is an iron-mediated regulatory cell death pattern characterized by oxidative damage. The molecular regulating mechanisms are related to iron metabolism, lipid peroxidation, and glutathione metabolism. Additionally, some immunological signaling pathways, such as the cyclic GMP-AMP synthase-stimulator ofinterferon genes axis, Janus kinase-signal transducer and activator of transcription 1 axis, and transforming growth factor beta 1-Smad3 axis may also participate in the regulation of ferroptosis. Studies have shown that ferroptosis is closely related to many diseases such as cancer, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases. Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases, the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of the aforementioned conditions.

Synthesis of spherical CaO pellets incorporated with Mg, Y, and Ce inert carriers for CO2 capture.

Sintering and elutriation are two main problems of the calcium looping process for high-temperature CO2 capture. In the process of CO2 capture, the operation temperature is generally higher than the Taman temperature, resulting in the agglomeration and sintering of the sorbents. The traditional sorbent powers need to be granulated for practical application in a circulating fluidized bed to avoid elutriation. By using a new agar-assisted technology to granulate CaO powder incorporated with Mg, Y, and Ce inert supports, the problems of sintering and elutriation can be mitigated within one step. The incorporated inert supports are uniformly dispersed in the CaO/CaCO3 particles as an inert scaffold, and the inert scaffold is used as a skeleton to resist sintering, alleviate its agglomeration phenomenon, and keep the specific surface area to a certain extent. The Ce-incorporated CaO pellets have been proven to exhibit the best carbonation conversion and sorption capacity. The sorption capacity of 10% CeO2-incorporated CaO pellets reached 0.574 g CO2/g sorbent, more than 43% higher than that of the pure CaO pellets. In addition, the effects of the solid-liquid ratio during the preparation stage on CO2 performance were also investigated, demonstrating that a solid-liquid ratio of 1:5 was the optimal ratio to produce satisfying sorbents. The mitigated sintering and achieved spherical CaO pellets greatly promote the practical application of the calcium looping process for CO2 capture.

Experimental verification about treatment of Bu-Shen-Yi-Jing-Fang in Alzheimer's disease by the analysis of the feasible signaling pathway of network pharmacology.

CONTEXT: Bu-shen-yi-jing-fang (BSYJF) has been reported to reduce amyloid-ß (Aß)1-42 deposition in the brain of APP/PS1 mice and ameliorate cognitive function. However, its neuroprotective mechanism remains unclear. OBJECTIVE: This study aims to investigate whether BSYJF exerts a protective effect on Aß1-42-induced oxidative stress injury and explore its possible mechanism. MATERIALS AND METHODS: The platform databases TCMSP, Swiss, TTD, DrugBank, and GeneCards were used to mine the targets of Alzheimer's disease (AD) and BSYJF. The platform databases STRING and Metascape were used to build the interaction network of the target protein, and Cytoscape software was used to analyze this network and screen out the key pathways. Aß1-42-treated SKNMC cells were established to verify the mechanism of BSYJF and the key proteins. The downstream proteins and antioxidants as well as apoptosis and ferroptosis of the PI3K/AKT/Nrf2 signaling pathway were validated using an in vitro SKNMC cell model experiment. The expression levels of related proteins were detected using Western blotting. Flow cytometry and immunofluorescence staining were used to analyze apoptosis and ferroptosis. RESULTS: Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis considered the key signal pathways, mainly involving the PI3K/AKT signaling pathway. Experimental validation demonstrated that BSYJF treatment markedly increased the activity of the PI3K/AKT pathway, which could exert anti-AD effects. CONCLUSIONS: Our data provided compelling evidence that the protective effects of BSYJF might be associated with their regulation of the PI3K/AKT/Nrf2 signaling pathway. These studies offered a potential therapy for natural herbal medicine treatment of AD.

GSDMD protects intestinal epithelial cells against bacterial infections through its N-terminal activity impacting intestinal immune homeostasis.

The intestinal mucosal barrier serves as a vital guardian for gut health, maintaining a delicate equilibrium between gut microbiota and host immune homeostasis. Recent studies have found the intricate roles of Gasdermin D (GSDMD), a key executioner of pyroptosis downstream of the inflammasome, within the intestine, including controlling colitis in intestinal macrophage and the regulatory function in goblet cell mucus secretion. Thus, the exact role and nature of GSDMD's regulatory function in maintaining intestinal immune homeostasis and defending against pathogens remain elucidation. Here, we uncover that GSDMD plays a key role in defending against intestinal Citrobacter rodentium infection, with high expression in intestinal epithelial and lamina propria myeloid cells. Our results show that GSDMD specifically acts in intestinal epithelial cells to fight the infection, independently of its effects on antimicrobial peptides or mucin secretion. Instead, the resistance is mediated through GSDMD's N-terminal fragments, highlighting its importance in intestinal immunity. However, the specific underlying mechanism of GSDMD N-terminal activity in protection against intestinal bacterial infections still needs further study to clarify in the future.

ECSIT facilitates memory CD8+ T cell development by mediating fumarate synthesis during viral infection and tumorigenesis.

Memory CD8+ T cells play a crucial role in infection and cancer and mount rapid responses to repeat antigen exposure. Although memory cell transcriptional programmes have been previously identified, the regulatory mechanisms that control the formation of CD8+ T cells have not been resolved. Here we report ECSIT as an essential mediator of memory CD8+ T cell differentiation. Ablation of ECSIT in T cells resulted in loss of fumarate synthesis and abrogated TCF-1 expression via demethylation of the TCF-1 promoter by the histone demethylase KDM5, thereby impairing memory CD8+ T cell development in a cell-intrinsic manner. In addition, ECSIT expression correlated positively with stem-like memory progenitor exhausted CD8+ T cells and the survival of patients with cancer. Our study demonstrates that ECSIT-mediated fumarate synthesis stimulates TCF-1 activity and memory CD8+ T cell development during viral infection and tumorigenesis and highlights the utility of therapeutic fumarate analogues and PD-L1 inhibition for tumour immunotherapy.

Pore reconstruction mechanism of wheat straw-templated Li4SiO4 pellets for CO2 capture.

The traditional Li4SiO4-based CO2 sorbent pellets prepared from mechanical granulation methods usually presented densified microstructures. Hence, wheat straw, an agricultural waste featured with huge production and low cost, was used as porosity creator to improve the microstructures and CO2 capture performance of Li4SiO4 pellets. The results indicated that wheat straw effectively enhanced the cyclic CO2 sorption capacity of the pellets. In particular, 30 wt% wheat straw-templated Li4SiO4 pellets (LA-WS30) exhibited the capacity of ~0.15 g/g that is almost twice as high as that of unmodified pellets. The enriched porosity and improved porous structures resulted from the quick release of burning gases was considered as the main reason for the performance enhancement. In addition, the alkaline (K and Na) salts in wheat straw played a positive role in CO2 sorption of Li4SiO4 pellets due to the reduced diffusion resistance. However, the pore plugging of residual wheat straw ashes after high-temperature treatment decreased the contact areas and, thus, led to the capacity reduction. To conclude, the comprehensive performance of wheat straw-templated Li4SiO4 pellets is the result of the combined effects of porosity creation, alkali doping and pore plugging by ashes.

Natural restoration alters soil microbial community structure, but has contrasting effects on the diversity of bacterial and fungal assemblages in salinized grasslands.

Natural restoration has often been considered an effective measure for rehabilitating degraded ecosystems. However, its impact on the structure and diversity of soil microbial communities, particularly within a salinized grassland during its restoration succession, remains unclear. In this study, we examined the effects of natural restoration on the Shannon-Wiener diversity index, Operational Taxonomic Units (OTU) richness, and structure of the soil microbial community of a sodic-saline grassland in China using high-throughput amplicon sequencing data from representative successional chronosequences. Our results indicated that natural restoration resulted in a significant mitigation of the grassland salinization (pH from 9.31 to 8.32 and electrical conductivity from 393.33 to 136.67 µs·cm-1) and a significant alteration of the soil microbial community structure of the grassland (p < 0.01). However, the effects of natural recovery differed in terms of the abundance and diversity of bacteria and fungi. For example, the relative abundance of the bacterial phyla Acidobacteria increased by 116.45 % in the topsoil and 339.03 % in the subsoil, while that of the fungal phyla Ascomycota decreased by 8.86 % in the topsoil and 30.18 % in the subsoil. There was no significant effect of restoration on bacterial diversity, but fungal diversity increased by 15.02 % in the Shannon-Wiener index and 62.20 % in the OTU richness in the topsoil. Model-selection analysis further corroborated that the alteration of the soil microbial structure by natural restoration may be due to the fact that the bacteria could adapt to the alleviated salinized grassland soil and the fungi could adapt to the improved soil fertility of the grasslands. Overall, our results contribute to an in-depth understanding of the impacts of natural restoration on soil microbial diversity and community structure in salinized grasslands during the long-term successional course. This may also help to apply natural restoration as a greener practice option for managing degraded ecosystems.

ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein.

The intestinal epithelium is the fastest renewing tissue in mammals and its regenerative process must be tightly controlled to minimize the risk of dysfunction and tumorigenesis. The orderly expression and activation of Yes-associated protein (YAP) are the key steps in driving intestinal regeneration and crucial for intestinal homeostasis. However, the regulatory mechanisms controlling this process remain largely unknown. Here, it is discovered that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a multi-functional protein, is enriched along the crypt-villus axis. Intestinal cell-specific ablation of ECSIT results in the dysregulation of intestinal differentiation unexpectedly accompanied with enhanced YAP protein dependent on translation, thus transforming intestinal cells to early proliferative stem "-like" cells and augmenting intestinal tumorigenesis. Loss of ECSIT leads to metabolic reprogramming in favor of amino acid-based metabolism, which results in demethylation of genes encoding the eukaryotic initiation factor 4F pathway and their increased expression that further promotes YAP translation initiation culminating in intestinal homeostasis imbalance and tumorigenesis. It is also shown that the expression of ECSIT is positively correlated with the survival of patients with colorectal cancer. Together, these results demonstrate the important role of ECSIT in regulating YAP protein translation to control intestinal homeostasis and tumorigenesis.

Pyroptosis, and its Role in Central Nervous System Disease.

Pyroptosis is an inflammatory form of cell death executed by transmembrane pore-forming proteins known as gasdermins and can be activated in an inflammasome-dependent or -independent manner. Inflammasome-dependent pyroptosis is triggered in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and has emerged as an important player in the pathogenesis of multiple inflammatory diseases, mainly by releasing inflammatory contents. More recently, numerous studies have revealed the intricate mechanisms of pyroptosis and its role in the development of neuroinflammation in central nervous system (CNS) diseases. In this review, we summarize current understandings of the molecular and regulatory mechanisms of pyroptosis. In addition, we discuss how pyroptosis can drive different forms of neurological diseases and new promising therapeutic strategies targeting pyroptosis that can be leveraged to treat neuroinflammation.