Combined single cell and spatial transcriptome analysis reveals cellular heterogeneity of hedgehog pathway in gastric cancer.

Gastric cancer (GC) is one of the most common and deadly malignancies in the world. Abnormal activation of hedgehog pathway is closely related to tumor development and progression. However, potential therapeutic targets for GC based on the hedgehog pathway have not been clearly identified. In the present study, we combined single-cell sequencing data and spatial transcriptomics to deeply investigate the role of hedgehog pathway in GC. Based on a comprehensive scoring algorithm, we found that fibroblasts from GC tumor tissues were characterized by a highly enriched hedgehog pathway. By analyzing the development process of fibroblasts, we found that CCND1 plays an important role at the end stage of fibroblast development, which may be related to the formation of tumor-associated fibroblasts. Based on spatial transcriptome data, we deeply mined the role of CCND1 in fibroblasts. We found that CCND1-negative and -positive fibroblasts have distinct characteristics. Based on bulk transcriptome data, we verified that highly infiltrating CCND1 + fibroblasts are a risk factor for GC patients and can influence the immune and chemotherapeutic efficacy of GC patients. Our study provides unique insights into GC and hedgehog pathways and also new directions for cancer treatment strategies.

Hedgehog signaling-related genomics signature for the accurate progress and prognosis prediction in gastric cancer.

The Hedgehog pathway is thought to be closely associated with the progression of GC; however, a specific link between the Hedgehog pathway on the prognosis and immune infiltration of gastric cancer is still lacking. This study collected Hedgehog pathway-related genes. The Hedgehog pathway-related pattern were identified by consensus cluster analysis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were used to identify the biological functions which were significantly altered between predefined Cluster1 and Cluster2 in consensus clustering. The risk model of gastric cancer based on Hedgehog signaling pathway was constructed by univariate and multivariate COX regression, and the nomogram was constructed. The results showed that there were significant differences in the expression of Hedgehog pathway-related genes between the two groups. In addition, the constructed risk model was significantly correlated with the clinical prognosis and immune cell infiltration level of patients with gastric cancer. The model effectively predicted the efficacy of chemotherapy in GC patients and the sensitivity of drug treatment between groups. We systematically revealed the mechanism of Hedgehog pathway in gastric cancer and selected biomarkers with biological significance from a new perspective, providing potential direction for the treatment of gastric cancer.

Nrf2-miR-129-3p-mTOR Axis Controls an miRNA Regulatory Network Involved in HDACi-Induced Autophagy.

Histone deacetylase inhibitors (HDACis) are the recommended treatment for many solid tumors; however, resistance is a major clinical obstacle for their efficacy. High levels of the transcription factor nuclear factor erythroid 2 like-2 (Nrf2) in cancer cells suggest a vital role in chemoresistance, and regulation of autophagy is one mechanism by which Nrf2 mediates chemoresistance. Although the molecular mechanisms underlying this activity are unclear, understanding them may ultimately improve therapeutic outcomes following HDACi treatment. In this study, we found that HDACi treatment increased Nrf2 mRNA and protein levels and enhanced Nrf2 transcriptional activity. Conversely, Nrf2 knockdown or inhibition blocked HDACi-induced autophagy. In addition, a microRNA (miRNA) array identified upregulation of miR-129-3p in response to Nrf2 overexpression. Chromatin immunoprecipitation assays confirmed miR-129-3p to be a direct Nrf2 target. RepTar and RNAhybrid databases indicated mammalian target of rapamycin (mTOR) as a potential miR-129-3p target, which we experimentally confirmed. Finally, Nrf2 inhibition or miR-129-3p in combination with HDACis increased cell death in vitro and in vivo. Collectively, these results demonstrated that Nrf2 regulates mTOR during HDACi-induced autophagy through miRNA-129-3p and inhibition of this pathway could enhance HDACi-mediated cell death.

Vat Photopolymerization of Sepiolite Fiber and 316L Stainless Steel-Reinforced Alumina with Functionally Graded Structures.

Alumina (Al2O3) ceramics are widely used in electronics, machinery, healthcare, and other fields due to their excellent hardness and high temperature stability. However, their high brittleness limits further applications, such as artificial ceramic implants and highly flexible protective gear. To address the limitations of single-phase toughening in Al2O3 ceramics, some researchers have introduced a second phase to enhance these ceramics. However, introducing a single phase still limits the range of performance improvement. Therefore, this study explores the printing of Al2O3 ceramics by adding two different phases. Additionally, a new gradient printing technique is proposed to overcome the limitations of single material homogeneity, such as uniform performance and the presence of large residual stresses. Unlike traditional vat photopolymerization printing technology, this study stands out by generating green bodies with varying second-phase particle ratios across different layers. This study investigated the effects of different contents of sepiolite fiber (SF) and 316L stainless steel (SS) on various aspects of microstructure, phase composition, physical properties, and mechanical properties of gradient-printed Al2O3. The experimental results demonstrate that compared to Al2O3 parts without added SF and 316L SS, the inclusion of these materials can significantly reduce porosity and water absorption, resulting in a denser structure. In addition, the substantial improvements, with an increase of 394.4% in flexural strength and an increase of 316.7% in toughness, of the Al2O3 components enhanced by incorporating SF and 316L SS have been obtained.

Vat Photopolymerization of Ceramic Parts: Effects of Carbon Fiber Additives on Microstructure and Mechanical Performance.

Vat photopolymerization (VPP), as an additive manufacturing (AM) technology, can conveniently produce ceramic parts with high resolution and excellent surface quality. However, due to the inherent brittleness and low toughness of ceramic materials, manufacturing defect-free ceramic parts remains a challenge. Many researchers have attempted to use carbon fibers as additives to enhance the performance of ceramic parts, but these methods are mostly applied in processes like fused deposition modeling and hot pressing. To date, no one has applied them to VPP-based AM technology. This is mainly because the black carbon fibers reduce laser penetration, making it difficult to cure the ceramic slurry and thus challenging to produce qualified ceramic parts. To address this issue, our study has strictly controlled the amount of carbon fibers by incorporating trace amounts of carbon fiber powder into the original ceramic slurry with the aim to investigate the impact of these additions on the performance of ceramic parts. In this study, ceramic slurries with three different carbon fiber contents (0 wt.%, 0.1 wt.%, 0.2 wt.%, and 0.3 wt.%) were used for additive manufacturing. A detailed comparative analysis of the microstructure, physical properties, and mechanical performance of the parts was conducted. The experimental results indicate that the 3D-printed alumina parts with added carbon fibers show varying degrees of improvement in multiple performance parameters. Notably, the samples prepared with 0.2 wt.% carbon fiber content exhibited the most significant performance enhancements.

Inhibitory effect of isavuconazole, ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro.

The aim of this study was to investigate the possible effect of orally administered isavuconazole, ketoconazole, or voriconazole on the pharmacokinetics of methadone in rats. Twenty Sprague-Dawley (SD) rats were divided randomly into four groups: Group A (control), group B (5 mg/kg isavuconazole), group C (5 mg/kg ketoconazole), and group D (5 mg/kg voriconazole). A single dose of methadone was administrated half an hour later. Methadone in plasma concentrations and its metabolite EDDP in microsomes were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS), and pharmacokinetic parameters were calculated by DAS version 3.0. The Cmax of methadone in groups C and D increased to 2.7-fold and 5-fold, respectively. While AUC increased in three groups and group D increased the most. Also, isavuconazole, ketoconazole, and voriconazole showed inhibitory effect on human and rat microsomes. The inhibition ratios of isavuconazole, ketoconazole, and voriconazole in rat liver microsome were 97.87%, 96.74% and 78.9%, respectively (p < 0.01), while in human liver microsome, inhibition ratios were 86.97%, 96.46%, and 53.11%, respectively. And the IC50 for inhibition activity of isavuconazole, ketoconazole, and voriconazole in rat microsomes were 7.76 µM, 8.33 µM, and 4.45 µM, respectively. Our study indicated that taking methadone combine with ketoconazole, isavuconazole, or voriconazole could reduce the metabolism rate of methadone and prolong the pharmacological effects in vivo and in vitro.

The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases.

Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.

A novel curcumin derivative CL-6 exerts antitumor effect in human gastric cancer cells by inducing apoptosis through Hippo-YAP signaling pathway.

PURPOSE: Gastric carcinoma is the second most frequently diagnosed cancer and leading cause of cancer death in China. As a new generation of cancer therapeutic drug, CL-6, a curcumin derivative, shows better bioavailability than curcumin, which has shown anticancer effects in gastric cancer (GC). However, whether CL-6 shows similar activities in GC has not been examined. MATERIALS AND METHODS: Cell proliferation assay, colony-forming assay, flow cytometric analysis, wound healing assay, and Transwell invasion assay were performed to examine the effects of CL-6 on proliferation, apoptosis, migration, and invasion on human AGS and MGC-803 cell lines. Western blot was used to evaluate protein levels of Bax, Bcl-2, YAP, p-YAP, and Lats, and gene expression was measured by real-time quantitative PCR (RT-qPCR). RESULTS: CL-6 dose dependently reduced proliferation, increased apoptosis, and inhibited the migration and invasion abilities of AGS and MGC-803 cells. CL-6 also increased levels of pro-apoptotic protein Bax, decreased levels of antiapoptotic protein Bcl-2, and increased the Bax/Bcl-2 ratio. CL-6 treatment also inhibited YAP and YAP protein and mRNA expression, while it induced the expression of Lats and p-YAP (Ser127). CONCLUSION: CL-6 induces apoptosis of GC cells by activating the Hippo-YAP signaling pathway. These results indicate the therapeutic potential of the novel curcumin derivative CL-6 in GC.

[Interactive effect of irrigation and nitrogen application on physiological characteristics of flag leaf and grain yield of winter wheat in dry years].

The field studies indicated that in dry years, both irrigation and nitrogen application had a marked yield increment effect, but irrigation played a more important role. Irrigation at jointing and booting stages could induce a higher grain yield, but irrigation at jointing, booting and grain-filling stages had a less yield increment effect if nitrogen was applied as base fertilizer. Insufficient irrigation reduced the nitrogen efficiency and yield, which could be compensated to some extent by increasing the nitrogen application rate. Only a suitable combination of irrigation and nitrogen application could effectively coordinate the relationship between yield components and increase grain yield.