Comparative analysis of the gut microbiome of ungulate species from Qinghai-Xizang plateau.

Several studies have investigated the gut bacterial composition of wild ungulates in the Qinghai-Xizang Plateau. However, the relationship between their gut microbiome dendrograms and their phylogenetic tree remains unclear. In this study, we analyzed 45 amplicons (V3-V4 region of the 16S rRNA gene) from five wild ungulates-Pseudois nayaur, Pantholops hodgsonii, Gazella subgutturosa, Bos grunniens, and Equus kiang-from the Qinghai-Xizang Plateau to clarify the relationship between their phylogenies and gut microbiome dendrograms. The unweighted pair group method with arithmetic mean analysis and hierarchical clustering analysis indicated that G. subgutturosa is closely related to P. nayaur; however, these results were inconsistent with their phylogenetic trees. Additionally, the indicator genera in the microbiome of each wild ungulate showed strong associations with the diets and habitats of their host. Thus, diet and space niche differentiation may primarily account for the differences between the gut microbiome characteristics of these wild ungulates and their phylogeny. In summary, our research provides insights into the evolutionary factors influencing the gut microbiome of wild ungulates in the Qinghai-Xizang Plateau.

scVGATAE: A Variational Graph Attentional Autoencoder Model for Clustering Single-Cell RNA-seq Data.

Single-cell RNA sequencing (scRNA-seq) is now a successful technology for identifying cell heterogeneity, revealing new cell subpopulations, and predicting developmental trajectories. A crucial component in scRNA-seq is the precise identification of cell subsets. Although many unsupervised clustering methods have been developed for clustering cell subpopulations, the performance of these methods is prone to be affected by dropout, high dimensionality, and technical noise. Additionally, most existing methods are time-consuming and fail to fully consider the potential correlations between cells. In this paper, we propose a novel unsupervised clustering method called scVGATAE (Single-cell Variational Graph Attention Autoencoder) for scRNA-seq data. This method constructs a reliable cell graph through network denoising, utilizes a novel variational graph autoencoder model integrated with graph attention networks to aggregate neighbor information and learn the distribution of the low-dimensional representations of cells, and adaptively determines the model training iterations for various datasets. Finally, the obtained low-dimensional representations of cells are clustered using kmeans. Experiments on nine public datasets show that scVGATAE outperforms classical and state-of-the-art clustering methods.

HYENA detects oncogenes activated by distal enhancers in cancer.

Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm 'HYENA' to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.

Constraints on crustal compositional architecture across the North China-Altaids transition and implications for craton margin reworking.

The phase of secular evolution of continents is manifested as the degree of compositional differentiation, modification and maturation of continental crusts, which is vital in understanding the mechanism of continental evolution but is difficult to quantify. Here we use integrated passive- and active-source seismic profiling to conduct joint analysis and inversion and derive Vs and Vp/Vs section models across the North China Craton (NCC) to southeastern Altaids boundary zone that bears a tectonic transition from a reworked ancient craton margin to a Phanerozoic accretionary orogen. We systematically exploited the imaged multiple physical properties as precise and delicate proxies to constrain the compositional architecture in the crust across this important tectonic transition subject to various crustal evolutional phases. Our Vs and Vp/Vs imaging, together with the existing isotopic data, characterizes the Yin Shan-Yan Shan belt as the northern NCC margin with layered homogeneous compositions that point to an evolved crust. However, the lower-crustal low-Vs/high-Vp/Vs signature that overlaps the shallowly dipping to horizontal reflective fabrics suggests that the crust of the northern NCC margin has undergone considerable reworking through lower-crustal-stretching-assisted melt migration and mixing since the late Paleozoic to Mesozoic eras. The process probably involved crust-mantle interaction and thus resulted in a compositionally modified ancient crustal basement. On the contrary, the southeastern Altaids domain manifests crustal complexity in compositions and structures inferred to be indicative of a juvenile crust of the Phanerozoic accretionary orogen. Our results provide deep physical-property constraints that shed new light on the crustal evolution of a complex craton margin.

Deep Spatial-Spectral Joint-Sparse Prior Encoding Network for Hyperspectral Target Detection.

Hyperspectral target detection aims to locate targets of interest in the scene, and deep learning-based detection methods have achieved the best results. However, black box network architectures are usually designed to directly learn the mapping between the original image and the discriminative features in a single data-driven manner, a choice that lacks sufficient interpretability. On the contrary, this article proposes a novel deep spatial-spectral joint-sparse prior encoding network (JSPEN), which reasonably embeds the domain knowledge of hyperspectral target detection into the neural network, and has explicit interpretability. In JSPEN, the sparse encoded prior information with spatial-spectral constraints is learned end-to-end from hyperspectral images (HSIs). Specifically, an adaptive joint spatial-spectral sparse model (AS 2 JSM) is developed to mine the spatial-spectral correlation of HSIs and improves the accuracy of data representation. An optimization algorithm is designed for iteratively solving AS 2 JSM, and JSPEN is proposed to simulate the iterative optimization process in the algorithm. Each basic module of JSPEN one-to-one corresponds to the operation in the optimization algorithm so that each intermediate result in the network has a clear explanation, which is convenient for intuitive analysis of the operation of the network. With end-to-end training, JSPEN can automatically capture the general sparse properties of HSIs and faithfully characterize the features of background and target. Experimental results verify the effectiveness and accuracy of the proposed method. Code is available at https://github.com/Jiahuiqu/JSPEN.

A Principle Design of Registration-Fusion Consistency: Toward Interpretable Deep Unregistered Hyperspectral Image Fusion.

For hyperspectral image (HSI) and multispectral image (MSI) fusion, it is often overlooked that multisource images acquired under different imaging conditions are difficult to be perfectly registered. Although some works attempt to fuse unregistered images, two thorny challenges remain. One is that registration and fusion are usually modeled as two independent tasks, and there is no yet a unified physical model to tightly couple them. Another is that deep learning (DL)-based methods may lack sufficient interpretability and generalization. In response to the above challenges, we propose an unregistered HSI fusion framework energized by a unified model of registration and fusion. First, a novel registration-fusion consistency physical perception model (RFCM) is designed, which uniformly models the image registration and fusion problem to greatly reduce the sensitivity of fusion performance to registration accuracy. Then, an HSI fusion framework (MoE-PNP) is proposed to learn the knowledge reasoning process for solving RFCM. Each basic module of MoE-PNP one-to-one corresponds to the operation in the optimization algorithm of RFCM, which can ensure clear interpretability of the network. Moreover, MoE-PNP captures the general fusion principle for different unregistered images and therefore has good generalization. Extensive experiments demonstrate that MoE-PNP achieves state-of-the-art performance for unregistered HSI and MSI fusion. The code is available at https://github.com/Jiahuiqu/MoE-PNP.

Effect of locomotor preference on the evolution of mitochondrial genes in Bovidae.

Locomotor preferences and habitat types may drive animal evolution. In this study, we speculated that locomotor preference and habitat type may have diverse influences on Bovidae mitochondrial genes. We used selection pressure and statistical analysis to explore the evolution of mitochondrial DNA (mtDNA) protein-coding genes (PCGs) from diverse locomotor preferences and habitat types. Our study demonstrates that locomotor preference (energy demand) drives the evolution of Bovidae in mtDNA PCGs. The habitat types had no significant effect on the rate of evolution in Bovidae mitochondrial genes. Our study provides deep insight into the adaptation of Bovidae.

VAMP2 controls murine epidermal differentiation and carcinogenesis by regulation of nucleophagy.

Differentiation of murine epidermal stem/progenitor cells involves the permanent withdrawal from the cell cycle, the synthesis of various protein and lipid components for the cornified envelope, and the controlled dissolution of cellular organelles and nuclei. Deregulated epidermal differentiation contributes to the development of various skin diseases, including skin cancers. With a genome-wide shRNA screen, we identified vesicle-associated membrane protein 2 (VAMP2) as a critical factor involved in skin differentiation. Deletion of VAMP2 leads to aberrant skin stratification and enucleation in vivo. With quantitative proteomics, we further identified an autophagy protein, focal adhesion kinase family interacting protein of 200 kDa (FIP200), as a binding partner of VAMP2. Additionally, we showed that both VAMP2 and FIP200 are critical for murine keratinocyte enucleation and epidermal differentiation. Loss of VAMP2 or FIP200 enhances cutaneous carcinogenesis in vivo. Together, our findings identify important molecular mechanisms underlying epidermal differentiation and skin tumorigenesis.

Mitochondrial Genomic Evidence of Selective Constraints in Small-Bodied Terrestrial Cetartiodactyla.

Body size may drive the molecular evolution of mitochondrial genes in response to changes in energy requirements across species of different sizes. In this study, we perform selection pressure analysis and phylogenetic independent contrasts (PIC) to investigate the association between molecular evolution of mitochondrial genome protein-coding genes (mtDNA PCGs) and body size in terrestrial Cetartiodactyla. Employing selection pressure analysis, we observe that the average non-synonymous/synonymous substitution rate ratio (ω) of mtDNA PCGs is significantly reduced in small-bodied species relative to their medium and large counterparts. PIC analysis further confirms that ω values are positively correlated with body size (R2 = 0.162, p = 0.0016). Our results suggest that mtDNA PCGs of small-bodied species experience much stronger purifying selection as they need to maintain a heightened metabolic rate. On the other hand, larger-bodied species may face less stringent selective pressures on their mtDNA PCGs, potentially due to reduced relative energy expenditure per unit mass. Furthermore, we identify several genes that undergo positive selection, possibly linked to species adaptation to specific environments. Therefore, despite purifying selection being the predominant force in the evolution of mtDNA PCGs, positive selection can also occur during the process of adaptive evolution.

Bacterial and fungal community structures in Hulun Lake are regulated by both stochastic processes and environmental factors.

Microorganisms are a crucial component of lake ecosystems and significant contributors to biogeochemical cycles. However, the understanding of how primary microorganism groups (e.g., bacteria and fungi) are distributed and constructed within different lake habitats is lacking. We investigated the bacterial and fungal communities of Hulun Lake using high-throughput sequencing techniques targeting 16S rRNA and Internal Transcribed Spacer 2 genes, including a range of ecological and statistical methodologies. Our findings reveal that environmental factors have high spatial and temporal variability. The composition and community structures vary significantly depending on differences in habitats. Variance partitioning analysis showed that environmental and geographical factors accounted for <20% of the community variation. Canonical correlation analysis showed that among the environmental factors, temperature, pH, and dissolved oxygen had strong control over microbial communities. However, the microbial communities (bacterial and fungal) were primarily controlled by the dispersal limitations of stochastic processes. This study offers fresh perspectives regarding the maintenance mechanism of bacterial and fungal biodiversity in lake ecosystems, especially regarding the responses of microbial communities under identical environmental stress.IMPORTANCELake ecosystems are an important part of the freshwater ecosystem. Lake microorganisms play an important role in material circulation and energy flow owing to their unique enzymatic and metabolic capacity. In this study, we observed that bacterial and fungal communities varied widely in the water and sediments of Hulun Lake. The primary factor affecting their formation was identified as dispersal limitation during stochastic processes. Environmental and geographical factors accounted for <20% of the variation in bacterial and fungal communities, with pH, temperature, and dissolved oxygen being important environmental factors. Our findings provide new insights into the responses of bacteria and fungi to the environment, shed light on the ecological processes of community building, and deepen our understanding of lake ecosystems. The results of this study provide a reference for lake management and conservation, particularly with respect to monitoring and understanding microbial communities in response to environmental changes.

Visible-light-driven alkene dicarboxylation with formate and CO2 under mild conditions.

Low-cost formate salt was used as the reductant and part of the carboxyl source in a visible-light-driven dicarboxylation of diverse alkenes, including simple styrenes. The highly competing hydrocarboxylation side reaction was successfully overridden. Good yields of products were obtained under mild reaction conditions at ambient temperature and pressure of CO2. The dual role of formate salt may stimulate the discovery of a range of new transformations under mild and friendly conditions.

HYENA detects oncogenes activated by distal enhancers in cancer.

Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm "HYENA" to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1,146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.

Nicotinamide mononucleotide alleviates endotoxin-induced acute lung injury by modulating macrophage polarization via the SIRT1/NF-κB pathway.

CONTEXT: Sepsis-induced acute lung injury (ALI) is a severe condition with limited effective therapeutics; nicotinamide mononucleotide (NMN) has been reported to exert anti-inflammatory activities. OBJECTIVE: This study explores the potential mechanisms by which NMN ameliorates sepsis-induced ALI in vivo and in vitro. MATERIALS AND METHODS: Cultured MH-S cells and a murine model were used to evaluate the effect of NMN on sepsis-induced ALI. MH-S cells were stimulated with LPS (1 µg/mL) and NMN (500 µM) for 12 h grouping as control, LPS, and LPS + NMN. Cell viability, apoptotic status, and M1/2 macrophage-related markers were detected. The mice were pretreated intraperitoneally with NMN (500 mg/kg) and/or EX-527 (5 mg/kg) 1 h before LPS injection and randomized into 7 groups (n = 8): control, LPS, LPS + NMN, NMN, LPS + NMN + EX-527 (a SIRT1 inhibitor), LPS + EX-527, and EX-527. After 12 h, lung histopathology, W/D ratio, MPO activity, NAD+ and ATP levels, M1/2 macrophage-related markers, and expression of the SIRT1/NF-κB pathway were detected. RESULTS: In MH-S cells, NMN significantly decreased the apoptotic rate from 12.25% to 5.74%. In septic mice, NMN improved the typical pathologic findings in lungs and reduced W/D ratio and MPO activity, but increased NAD+ and ATP levels. Additionally, NMN suppressed M1 but promoted M2 polarization, and upregulated the expression of SIRT1, with inhibition of NF-κB-p65 acetylation and phosphorylation. Furthermore, inhibition of SIRT1 reversed the effects of NMN-induced M2 macrophage polarization. CONCLUSIONS: NMN protects against sepsis-induced ALI by promoting M2 macrophage polarization via the SIRT1/NF-κB pathway, it might be an effective strategy for preventing or treating sepsis-induced ALI.

Analysis of the Complete Mitochondrial Genome of Pteronura brasiliensis and Lontra canadensis.

P. brasiliensis and L. canadensis are two otter species, which successfully occupied semi-aquatic habitats and diverged from other Mustelidae. Herein, the full-length mitochondrial genome sequences were constructed for these two otter species for the first time. Comparative mitochondrial genome, selection pressure, and phylogenetic independent contrasts (PICs) analyses were conducted to determine the structure and evolutionary characteristics of their mitochondrial genomes. Phylogenetic analyses were also conducted to confirm these two otter species' phylogenetic position. The results demonstrated that the mitochondrial genome structure of P. brasiliensis and L. canadensis were consistent across Mustelidae. However, selection pressure analyses demonstrated that the evolutionary rates of mitochondrial genome protein-coding genes (PCGs) ND1, ND4, and ND4L were higher in otters than in terrestrial Mustelidae, whereas the evolutionary rates of ND2, ND6, and COX1 were lower in otters. Additionally, PIC analysis demonstrated that the evolutionary rates of ND2, ND4, and ND4L markedly correlated with a niche type. Phylogenetic analysis showed that P. brasiliensis is situated at the base of the evolutionary tree of otters, and then L. canadensis diverged from it. This study suggests a divergent evolutionary pattern of Mustelidae mitochondrial genome PCGs, prompting the otters' adaptation to semi-aquatic habitats.

Structure characteristics of mutation sites in two waxy alleles from Yunnan waxy maize (Zea mays L. var. certaina Kulesh) landraces.

A large number of waxy maize landraces are distributed in Yunnan and surrounding areas, and abundant waxy alleles of different types are distributed in these landraces. The identification of waxy alleles is helpful to the protection and utilization of these waxy landraces. This study introduced structure characteristics of waxy genes from two specific landraces of Yunnan, Zinuoyumi and Myanmar Four-Row Wax. Zinuoyumi has two waxy alleles wx-Cin4 and wx-Cin4-2; Myanmar Four-Row Wax has three waxy alleles wx-D10, wx-Reina and wx-D11. The wx-Cin4-2 and wx-D11 are two types of waxy alleles first reported in this study. The wx-Cin4-2 has two mutation sites, deletion of 30 bp in exon 10, insertion of a 1,267 bp non-long terminal repeat (non-LTR) retrotransposon Cin4 in intron 10, and 13 bp extra sequence were found at 5' end of the Cin4; the mutation site of wx-D11 is a 1,082 bp deletion from exons 11 to 14 of the waxy gene and is replaced with a 72 bp filler sequence. This study enriched the type of waxy allele from Yunnan waxy maize landraces and further discussed the molecular basis for the formation of mutation sites of wx-Cin4-2 and wx-D11.

FTY720 attenuates acute colitis via colonic T cells reduction and inhibition of M1 macrophages polarization independent of CCR2-mediated monocytes input.

Ulcerative colitis (UC) is a complex multifactorial disease, of which the exact etiology is not fully understood. The inappropriate aggressive inflammatory response is closely related to the disease progression of UC. FTY720 is a sphingosine-1-phosphate receptor agonist and acts as a key immunomodulator in inflammation. This study aims to investigate the protective influence of FTY720 on inflammation in the DSS-induced colitis model. In the present study, the C57BL/6 mice and the CCR2-/- mice were exposed to 5% Dextran Sodium Sulfate (DSS) drinking water for 6 days followed by an injection of FTY720 (1 mg/kg/d) or vehicle (PBS) 6 times starting on the next day. The body weight, stool consistency, and occult blood were assessed daily. The inflammatory cytokines level in colon tissues and serum were assessed. Leukocyte subsets of bone marrow (BM), spleen, and colon were analyzed by flow cytometry. Our results demonstrated that FTY720 ameliorated the aberrant immune responses by trapping T cells and inhibiting the polarization of M1 macrophages in colitis mice. The effect of FTY720 on the increased number of colonic macrophages did not dependent on CCR2-mediated monocyte influx, despite most monocytes being reduced after DSS administration in the inflamed colon of CCR2-/- mice. Rather, depletion of CCR2 did not impact the protective influence of FTY720 on colonic injury in acute colitis. All these findings unravel a beneficial function of FTY720 in the inflammatory response to DSS-induced acute colitis, provided further insights into monocyte migration and might provide potential opportunities for UC therapeutic intervention.

Wireless-Powering Deep Brain Stimulation Platform Based on 1D-Structured Magnetoelectric Nanochains Applied in Antiepilepsy Treatment.

Electrical deep brain stimulation (DBS) is a top priority for pharmacoresistant epilepsy treatment, while less-invasive wireless DBS is an urgent priority but challenging. Herein, we developed a conceptual wireless DBS platform to realize local electric stimulation via 1D-structured magnetoelectric Fe3O4@BaTiO3 nanochains (FBC). The FBC was facilely synthesized via magnetic-assisted interface coassembly, possessing a higher electrical output by inducing larger local strain from the anisotropic structure and strain coherence. Subsequently, wireless magnetoelectric neuromodulation in vitro was synergistically achieved by voltage-gated ion channels and to a lesser extent, the mechanosensitive ion channels. Furthermore, FBC less-invasively injected into the anterior nucleus of the thalamus (ANT) obviously inhibited acute and continuous seizures under magnetic loading, exhibiting excellent therapeutic effects in suppressing both high voltage electroencephalogram signals propagation and behavioral seizure stage and neuroprotection of the hippocampus mediated via the Papez circuit similar to conventional wired-in DBS. This work establishes an advanced antiepilepsy strategy and provides a perspective for other neurological disorder treatment.

Magnetic manipulation of Fe3O4@BaTiO3 nanochains to regulate extracellular topographical and electrical cues.

Magnetic fields play an essential role in material science and biomedical engineering. Magnetic-responsive materials can be arranged orderly in matrix to realize the construction of an aligned scaffold under magnetic induction. However, a single topological cue is insufficient to activate neural tissue regeneration, demanding more cues to promote regeneration synergistically, such as electrical stimulation and a biomimetic matrix. Herein, we propose one-dimensional (1D) magnetoelectric Fe3O4@BaTiO3 nanochains with controllable lengths under the regulation of a magnetic field. These nanochains can be oriented in the biomimetic hydrogel under magnetic guidance and induce the hydrogel microfiber to align along the direction of the nanochains, which is beneficial for cell-oriented outgrowth. This aligned hydrogel enabled wireless electrical stimulation mediated by magnetoelectric nanochains under magnetic stimulation, thereby activating the voltage-gated ion channel. Consequently, topological and electrical cues in this multifunctional biomimetic hydrogel synergistically enhanced the expression of neural functional proteins, facilitating synapse remodeling and neural regeneration. Predictably, the construction of multifunctional hydrogels based on low-cost and facile synthesis of magnetoelectric nanochains is an emerging patient-friendly and effective therapeutic strategy for neural or other tissue regeneration. STATEMENT OF SIGNIFICANCE: A facile and controllable magnetic strategy is established to manipulate 1D nanomaterial growth, matrix topography, and wireless electrical stimulation of cells. First, the magnetic-assisted interface co-assembly was used to control the length of Fe3O4@BaTiO3 nanochains with enhanced magnetoelectric effect. Then, the motion of the magnetic-induced nanochains guided the orientation of nanofibers in a 3D biomimetic hydrogel matrix. Finally, wireless electrical signals and topological cues in the biomimetic matrix synergistically promoted orderly aligned cell outgrowth and membrane depolarization by Ca2+ influx, thus enhancing nerve cell synaptic plasticity and functional expression. Consequently, this work provides a conceptual strategy from material design to extracellular matrix signal manipulation and synergistic induction of tissue regeneration.

A novel immunohistochemical score predicts the postoperative prognosis of gastric cancer patients.

BACKGROUND AND AIM: Immunohistochemistry indicators are increasingly being used to predict the survival prognosis of cancer patients after surgery. This study aimed to combine some markers to establish an immunohistochemical score (MSI-P53-Ki-67[MPK]) and stratify postoperative patients with gastric cancer according to the score. METHODS: We used 245 patients who underwent surgery at one center as the training cohort and 111 patients from another center as the validation cohort. All patients were treated between January 2012 and June 2018. The training cohort was screened for prognostic factors, and MPK scores were established using univariate and multifactorial COX risk proportional models. Patients were prognostically stratified according to the MPK score after gastrectomy for gastric cancer. Overall survival (OS) and recurrence-free survival (RFS) rates were compared among low-, intermediate-, and high-risk groups using the Kaplan-Meier method, and survival curves were plotted. Finally, the MPK score was validated using the validation cohort. RESULTS: In the training group, there were statistically significant differences in OS and RFS in the low, medium, and high-risk groups (P < 0.001). Thirty patients were in the high-risk group (12.2%). The median survival times of the three groups were 64.0, 44.0, and 23.0, respectively, and median times to recurrence were 54.0, 35.0, and 16.0 months, respectively. In the validation group, the prognosis in the three risk groups remained significantly different (P < 0.001). CONCLUSIONS: The novel MPK score could effectively predict the postoperative OS and RFS of gastric cancer patients, risk-stratify postoperative patients, and identify postoperative high-risk patients for refined management.

5-Methoxytryptophan ameliorates endotoxin-induced acute lung injury in vivo and in vitro by inhibiting NLRP3 inflammasome-mediated pyroptosis through the Nrf2/HO-1 signaling pathway.

BACKGROUND AND AIM: Endotoxin-induced acute lung injury (ALI) is a complicated and fatal condition with no specific or efficient clinical treatments. 5-Methoxytryptophan (5-MTP), an endogenous metabolite of tryptophan, was revealed to block systemic inflammation. However, the specific mechanism by which 5-MTP affects ALI still needs to be clarified. The purpose of this study was to determine whether 5-MTP protected the lung by inhibiting NLRP3 inflammasome-mediated pyroptosis through the Nrf2/HO-1 signaling pathway. METHODS AND RESULTS: We used lipopolysaccharide (LPS)-stimulated C57BL/6 J mice and MH-S alveolar macrophages to create models of ALI, and 5-MTP (100 mg/kg) administration attenuated pathological lung damage in LPS-exposed mice, which was associated with decreased inflammatory cytokines and oxidative stress levels, upregulated protein expression of Nrf2 and HO-1, and suppressed Caspase-1 activation and NLRP3-mediated pyroptosis protein levels. Moreover, Nrf2-deficient mice or MH-S cells were treated with 5-MTP to further confirm the protective effect of the Nrf2/HO-1 pathway on lung damage. We found that Nrf2 deficiency partially eliminated the beneficial effect of 5-MTP on reducing oxidative stress levels and inflammatory responses and abrogating the inhibition of NLRP3-mediated pyroptosis induced by LPS. CONCLUSION: These findings suggested that 5-MTP could effectively ameliorate ALI by inhibiting NLRP3-mediated pyroptosis via the Nrf2/HO-1 signaling pathway.