Dysregulation of phosphoenolpyruvate carboxykinase in cancers: A comprehensive analysis.

BACKGROUND: Phosphoenolpyruvate carboxykinase (PEPCK) plays a crucial role in gluconeogenesis, glycolysis, and the tricarboxylic acid cycle by converting oxaloacetate into phosphoenolpyruvate. Two distinct isoforms of PEPCK, specifically cytosolic PCK1 and mitochondrial PCK2, have been identified. Nevertheless, the comprehensive understanding of their dysregulation in pan-cancer and their potential mechanism contributing to signaling transduction pathways remains elusive. METHODS: We conducted comprehensive analyses of PEPCK gene expression across 33 diverse cancer types using data from The Cancer Genome Atlas (TCGA). Multiple public databases such as HPA, TIMER 2.0, GEPIA2, cBioPortal, UALCAN, CancerSEA, and String were used to investigate protein levels, prognostic significance, clinical associations, genetic mutations, immune cell infiltration, single-cell sequencing, and functional enrichment analysis in patients with pan-cancer. PEPCK expression was analyzed about different clinical and genetic factors of patients using data from TCGA, GEO, and CGGA databases. Furthermore, the role of PCK2 in Glioma was examined using both in vitro and in vivo experiments. RESULTS: The analysis we conducted revealed that the expression of PEPCK is involved in both clinical outcomes and immune cell infiltration. Initially, we verified the high expression of PCK2 in GBM cells and its role in metabolic reprogramming and proliferation in GBM. CONCLUSION: Our study showed a correlation between PEPCK (PCK1 and PCK2) expression with clinical prognosis, gene mutation, and immune infiltrates. These findings identified two possible predictive biomarkers across different cancer types, as well as a comprehensive analysis of PCK2 expression in various tumors, with a focus on GBM.

Microglia-mediated inflammatory destruction of neuro-cardiovascular dysfunction after stroke.

Stroke, a serious systemic inflammatory disease, features neurological deficits and cardiovascular dysfunction. Neuroinflammation is characterized by the activation of microglia after stroke, which disrupts the cardiovascular-related neural network and the blood-brain barrier. Neural networks activate the autonomic nervous system to regulate the cardiac and blood vessels. Increased permeability of the blood-brain barrier and the lymphatic pathways promote the transfer of the central immune components to the peripheral immune organs and the recruitment of specific immune cells or cytokines, produced by the peripheral immune system, and thus modulate microglia in the brain. In addition, the spleen will also be stimulated by central inflammation to further mobilize the peripheral immune system. Both NK cells and Treg cells will be generated to enter the central nervous system to suppress further inflammation, while activated monocytes infiltrate the myocardium and cause cardiovascular dysfunction. In this review, we will focus on microglia-mediated inflammation in neural networks that result in cardiovascular dysfunction. Furthermore, we will discuss neuroimmune regulation in the central-peripheral crosstalk, in which the spleen is a vital part. Hopefully, this will benefit in anchoring another therapeutic target for neuro-cardiovascular dysfunction.

Lighting a Fire: Gasdermin-Mediated Pyroptosis Remodels the Glioma Microenvironment and Promotes Immune Checkpoint Blockade Response.

Pyroptosis is a proinflammatory programmed cell death pathway mediated by gasdermins. Exploring the role of pyroptosis can provide new insights into tumor malignancy. The most recent studies on pyroptosis have focused on tumor cells. However, the effects of pyroptosis on the tumor microenvironment (TME), immunotherapeutic responses, and efficacy have been neglected, especially in case of glioma. In this study, four independent glioma cohorts comprising 1,339 samples and a pan-cancer cohort comprising 10,535 tumor samples were analyzed. The relationships among pyroptosis status, prognosis, microenvironment cellular components, and clinical and biological phenotypes were investigated through the identification of pyroptosis subtypes, construction of a gasdermin-related prognostic index (GPI), and evaluation of immunological characteristics in glioma. The Genomics of Drug Sensitivity in Cancer database and "pRRophetic" package in R were used to estimate temozolomide (TMZ) sensitivity. The "Submap" package and external immunotherapy cohorts were used to investigate and confirm the role of GPI in response to and efficacy of immunotherapy in glioma. Finally, potential small-molecule compounds related to GPI were identified using the connectivity map database and mode-of-action analysis. We identified three different pyroptosis subtypes: cluster 1 (C1) characterized by a higher GPI, while cluster 2 (C2) and cluster 3 (C3) characterized by a lower GPI. The high GPI of C1 was associated with glioma progression and worse prognoses, whereas the low GPI of subtype C2 and C3 was associated with better prognoses. However, patients with high GPIs were found to be more sensitive to TMZ and immune checkpoint blockade than those with low GPIs. Furthermore, gasdermin D may be a principal potential biomarker and play key roles in pyroptosis-inducible therapy combined with immunotherapy in glioma. This study provides a clinical, biological, and molecular landscape of pyroptosis and suggests that pyroptosis of glioma cells may perform the dual function of promoting both tumorigenesis and antitumor immunity.

Effect of host breeds on gut microbiome and serum metabolome in meat rabbits.

BACKGROUND: Gut microbial compositional and functional variation can affect health and production performance of farm animals. Analysing metabolites in biological samples provides information on the basic mechanisms that affect the well-being and production traits in farm animals. However, the extent to which host breeds affect the gut microbiome and serum metabolome in meat rabbits is still unknown. In this study, the differences in phylogenetic composition and functional capacities of gut microbiota in two commercial rabbit breeds Elco and Ira were determined by 16S rRNA gene and metagenomic sequencing. The alternations in serum metabolome in the two rabbit breeds were detected using ultra-performance liquid chromatography system coupled with quadrupole time of flight mass spectrometry (UPLC-QTOFMS). RESULTS: Sequencing results revealed that there were significant differences in the gut microbiota of the two breeds studied, suggesting that host breeds affect structure and diversity of gut microbiota. Numerous breed-associated microorganisms were identified at different taxonomic levels and most microbial taxa belonged to the families Lachnospiraceae and Ruminococcaceae. In particular, several short-chain fatty acids (SCFAs) producing species including Coprococcus comes, Ruminococcus faecis, Ruminococcus callidus, and Lachnospiraceae bacterium NK4A136 could be considered as biomarkers for improving the health and production performance in meat rabbits. Additionally, gut microbial functional capacities related to bacterial chemotaxis, ABC transporters, and metabolism of different carbohydrates, amino acids, and lipids varied greatly between rabbit breeds. Several fatty acids, amino acids, and organic acids in the serum were identified as breed-associated, where certain metabolites could be regarded as biomarkers correlated with the well-being and production traits of meat rabbits. Correlation analysis between breed-associated microbial species and serum metabolites revealed significant co-variations, indicating the existence of cross-talk among host-gut microbiome-serum metabolome. CONCLUSIONS: Our study provides insight into how gut microbiome and serum metabolome of meat rabbits are affected by host breeds and uncovers potential biomarkers important for breed improvement of meat rabbits.

A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma.

Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and "stepAIC" algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the "pRRophetic" and "TIDE" algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4+ T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4+ T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.

EEF1D Promotes Glioma Proliferation, Migration, and Invasion through EMT and PI3K/Akt Pathway.

Eukaryotic translation elongation factor 1δ (EEF1D), a subunit of the elongation factor 1 complex of proteins, mediates the elongation process of protein synthesis. Besides this canonical role, EEF1D was found overexpressed in many tumors, like hepatocarcinomas and medulloblastomas. In the present study, we demonstrated for the first time that EEF1D may interact with other putative proteins to regulate cell proliferation, migration, and invasion through PI3K/Akt and EMT pathways in glioma. Furthermore, knockdown of EEF1D could reduce cell proliferation and impaired epithelial-mesenchymal transition (EMT) phenotypes, including cell invasion. Taken together, these results indicate that EEF1D and its partner proteins might play a critical role in glioma and serve as a potential therapeutic target of glioma.

Effects of Gut Microbiome and Short-Chain Fatty Acids (SCFAs) on Finishing Weight of Meat Rabbits.

Understanding how the gut microbiome and short-chain fatty acids (SCFAs) affect finishing weight is beneficial to improve meat production in the meat rabbit industry. In this study, we identified 15 OTUs and 23 microbial species associated with finishing weight using 16S rRNA gene and metagenomic sequencing analysis, respectively. Among these, butyrate-producing bacteria of the family Ruminococcaceae were positively associated with finishing weight, whereas the microbial taxa related to intestinal damage and inflammation showed opposite effects. Furthermore, interactions of these microbial taxa were firstly found to be associated with finishing weight. Gut microbial functional capacity analysis revealed that CAZymes, such as galactosidase, xylanase, and glucosidase, could significantly affect finishing weight, given their roles in regulating nutrient digestibility. GOs related to the metabolism of several carbohydrates and amino acids also showed important effects on finishing weight. Additionally, both KOs and KEGG pathways related to the membrane transportation system and involved in aminoacyl-tRNA biosynthesis and butanoate metabolism could act as key factors in modulating finishing weight. Importantly, gut microbiome explained nearly 11% of the variation in finishing weight, and our findings revealed that a subset of metagenomic species could act as predictors of finishing weight. SCFAs levels, especially butyrate level, had critical impacts on finishing weight, and several finishing weight-associated species were potentially contributed to the shift in butyrate level. Thus, our results should give deep insights into how gut microbiome and SCFAs influence finishing weight of meat rabbits and provide essential knowledge for improving finishing weight by manipulating gut microbiome.