Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of BCL6 and BACH2 RNA had significantly shorter overall survival (OS) than high BCL6- and BACH2-expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of BACH2 RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for BACH2 in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology.

Identification of ncRNA-mediated prognostic Value and Immune Infiltration of MTHFD2 in Bladder Cancer

Background: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), one of mitochondrial enzymes, is involved in folate and nucleic acid metabolism and maintains the cellular redox balance. However, the function of MTHFD2 in bladder cancer is still poorly characterized. This study was designed to elucidate the effect and regulatory mechanism of MTHFD2 on bladder cancer cells and explore the relationships between MTHFD2 and immune cell infiltration in tumor microenvironment (TME). Methods: The data from Oncomine, TIMER, The Cancer Genome Atlas (TCGA) and The Human Protein Atlas (HPA) database were extracted to evaluate the expression of MTHFD2 and its prognostic role in pan-cancer, especially in bladder cancer. Enrichment analyses, were utilized to explore the underlying cellular mechanisms. The ncRNA regulatory axis was established by Starbase database, and the PPI network was constructed by Cytoscape software. Ultimately, the relations between the expression of MTHFD2 and immune cell infiltration in bladder cancer was indicated by TCGA and TIMER databases.Results: Our results demonstrated that MTHFD2 expression was generally up-regulated in pan-cancers and its high expression was correlated with poor prognosis of patients with bladder cancer. Specifically, our study revealed that MTHFD2 was a powerful risk factor and involved in the tumor development of bladder cancer. Furthermore, hsa_circ_0046140 and hsa_circ_0006769/miR-383-5p/MTHFD2 axis could also play a significant role in tumorigenesis. Ultimately, a strong correlation was observed between MTHFD2 expression and various immune cell infiltration, which implied that MTHFD2 might serve as an agent in tumor immunotherapy. Conclusion: MTHFD2 is widely overexpressed in pan-cancers, and its expression is related with the prognosis of patients and the multiple immune cell infiltrates in TME. Besides, hsa_circ_0046140 and hsa_circ_0006769/miR-383-5p/MTHFD2 axis are implicated with the proliferation and invasion of tumors.

Survival and Metabolic Modulation of Swimming Crab Portunus trituberculatus During Live Transport

Demand from consumers for small quantities of live swimming crab Portunus trituberculatus is rising with the development of e-commerce. However, it is challenging to keep P. trituberculatus alive post-capture. In this study, a transport bag containing oxygen and seawater (24 ppt) was used to investigate the survival and metabolic changes of P. trituberculatus during transport. The results showed that more than 80% P. trituberculatus could survive at least 24 h in the transport bag. The ability of the crabs to survive may be attributed to adaptive metabolism, as suggested by the switch from an aerobic to an anaerobic pathway for energy generation and a decline in amino acid metabolism, nucleic acid metabolism, and osmoregulation. Our findings suggest that the transport bag could effectively extend the post-capture survival time of P. trituberculatus. Metabolic adaptation – especially energy homeostasis – is crucial for crab survival during transport. Our study provides a promising method for the transport of live P. trituberculatus.

Identification of ncRNA-Mediated Prognostic Value and Functions of MTHFD2 in Bladder Cancer

Background: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), one of mitochondrial enzymes, is involved in folate and nucleic acid metabolism and maintains the cellular redox balance. However, the function of MTHFD2 in bladder cancer is still poorly characterized. This study was designed to elucidate the effect and regulatory mechanism of MTHFD2 on bladder cancer cells and explore the relationships between MTHFD2 and immune cell infiltration in tumor microenvironment (TME). Methods: The data from Oncomine, TIMER, The Cancer Genome Atlas (TCGA) and The Human Protein Atlas (HPA) database were extracted to evaluate the expression of MTHFD2 and its prognostic role in pan-cancer, especially in bladder cancer. Enrichment analyses, were utilized to explore the underlying cellular mechanisms. The ncRNA regulatory axis was established by Starbase database, and the PPI network was constructed by Cytoscape software. Ultimately, the relations between the expression of MTHFD2 and immune cell infiltration in bladder cancer was indicated by TCGA and TIMER databases.Results: Our results demonstrated that MTHFD2 expression was generally up-regulated in pan-cancers and its high expression was correlated with poor prognosis of patients with bladder cancer. Specifically, our study revealed that MTHFD2 was a powerful risk factor and involved in the tumor development of bladder cancer. Furthermore, hsa_circ_0046140 and hsa_circ_0006769/miR-383-5p/MTHFD2 axis could also play a significant role in tumorigenesis. Ultimately, a strong correlation was observed between MTHFD2 expression and various immune cell infiltration, which implied that MTHFD2 might serve as an agent in tumor immunotherapy. Conclusion: MTHFD2 is widely overexpressed in pan-cancers, and its expression is related with the prognosis of patients and the multiple immune cell infiltrates in TME. Besides, hsa_circ_0046140 and hsa_circ_0006769/miR-383-5p/MTHFD2 axis are implicated with the proliferation and invasion of tumors.

In Planta Transcriptome and Proteome Profiles of Spongospora subterranea in Resistant and Susceptible Host Environments Illuminates Regulatory Principles Underlying Host–Pathogen Interaction

Spongospora subterranea is an obligate biotrophic pathogen, causing substantial economic loss to potato industries globally. Currently, there are no fully effective management strategies for the control of potato diseases caused by S. subterranea. To further our understanding of S. subterranea biology during infection, we characterized the transcriptome and proteome of the pathogen during the invasion of roots of a susceptible and a resistant potato cultivar. A total of 7650 transcripts from S. subterranea were identified in the transcriptome analysis in which 1377 transcripts were differentially expressed between two cultivars. In proteome analysis, we identified 117 proteins with 42 proteins significantly changed in comparisons between resistant and susceptible cultivars. The functional annotation of transcriptome data indicated that the gene ontology terms related to the transportation and actin processes were induced in the resistant cultivar. The downregulation of enzyme activity and nucleic acid metabolism in the resistant cultivar suggests a probable influence of these processes in the virulence of S. subterranea. The protein analysis results indicated that the majority of differentially expressed proteins were related to the metabolic processes and transporter activity. The present study provides a comprehensive molecular insight into the multiple layers of gene regulation that contribute to S. subterranea infection and development in planta and illuminates the role of host immunity in affecting pathogen responses.

Current Progress and Perspectives on Using Gold Compounds for the Modulation of Tumor Cell Metabolism

Altered cellular metabolism, which is essential for the growth and survival of tumor cells in a specific microenvironment, is one of the hallmarks of cancer. Among the most significant changes in the metabolic pattern of tumor cells is the shift from oxidative phosphorylation to aerobic glycolysis for glucose utilization. Tumor cells also exhibit changes in patterns of protein and nucleic acid metabolism. Recently, gold compounds have been shown to target several metabolic pathways and a number of metabolites in tumor cells. In this review, we summarize how gold compounds modulate glucose, protein, and nucleic acid metabolism in tumor cells, resulting in anti-tumor effects. We also discuss the rationale underlying the anti-tumor effects of these gold compounds and highlight how to effectively utilize against various types of tumors.

HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing

Heterogeneous nuclear ribonucleoproteins (HnRNPs) are a group of ubiquitously expressed RNA-binding proteins implicated in the regulation of all aspects of nucleic acid metabolism. HnRNP K is a member of this highly versatile hnRNP family. Pathological redistribution of hnRNP K to the cytoplasm has been linked to the pathogenesis of several malignancies but, until now, has been underexplored in the context of neurodegenerative disease. Here we show hnRNP K mislocalisation in pyramidal neurons of the frontal cortex to be a novel neuropathological feature that is associated with both frontotemporal lobar degeneration and ageing. HnRNP K mislocalisation is mutually exclusive to TDP-43 and tau pathological inclusions in neurons and was not observed to colocalise with mitochondrial, autophagosomal or stress granule markers. De-repression of cryptic exons in RNA targets following TDP-43 nuclear depletion is an emerging mechanism of potential neurotoxicity in frontotemporal lobar degeneration and the mechanistically overlapping disorder amyotrophic lateral sclerosis. We silenced hnRNP K in neuronal cells to identify the transcriptomic consequences of hnRNP K nuclear depletion. Intriguingly, by performing RNA-seq analysis we find that depletion of hnRNP K induces 101 novel cryptic exon events. We validated cryptic exon inclusion in an SH-SY5Y hnRNP K knockdown and in FTLD brain exhibiting hnRNP K nuclear depletion. We, therefore, present evidence for hnRNP K mislocalisation to be associated with FTLD and for this to induce widespread changes in splicing.

Biofunctional significance of multi-herbal combination against paracetamol-induced hepatotoxicity in Wistar rats

A multi-herbal combination (MHC) of five herbs, namely Punica granatum L., Putranjiva roxburghii Wall., Swertia chirata Buch.-Ham., Tinospora cordifolia (Willd.) Miers and Trigonella corniculata L., was assessed against the paracetamol-induced acute hepatotoxicity in female Wistar rats. The animals were randomly assorted into seven groups with six animals in each group. The rats were pre-treated with MHC (50, 100, and 200 mg/kg bw) and silymarin (50 mg/kg bw) once daily for seven consecutive days via oral route followed by administration of paracetamol (3 g/kg bw) on day 7, an hour after the last administration of MHC and silymarin. It was observed that MHC administration significantly (p ≤ 0.05) overturned the paracetamol-induced increase in serum liver function biomarkers (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, and total bilirubin), phase I reaction enzymes (NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase), and oxidant biomarkers (lactate dehydrogenase, lipid peroxidation, lipid hydroperoxides, and protein content). MHC administration also reinstated the paracetamol-induced significant decrease (p ≤ 0.05) in haematological indices (haematocrit, haemoglobin, red and white blood cells, and platelets), phase II reaction enzymes (glutathione-S-transferase and DT-diaphorase), membrane-bound enzymes (Na+/K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase), and antioxidant biomarkers (reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase). Overall, MHC at 200 mg/kg bw dose significantly (p ≤ 0.05) sheltered the red blood cells from the assault of free radicals, stabilized the structural and functional integrity of hepatocytes, hindered APAP biotransformation to its toxic metabolites, and endorsed conjugating abilities to detoxify toxic entities. Further, MHC significantly (p ≤ 0.05) activated enzymatic machinery to scavenge/inhibit the formation of reactive oxygen species, regulated nucleic acid metabolism, surface potential, and membrane fluidity, attenuated tissue breakdown, quenched peroxyl radicals, and provided protection against tissue injury. The necroinflammatory scores revealed strong evidence of MHC (200 mg/kg bw) effectiveness against the paracetamol-induced hepatotoxicity in rats at p ≤ 0.05. The synergistic effect of major inherent phytoconstituents (kaempferol, ellagic acid, and gallic acid), detected by HPLC-PDA, in MHC might have overturned the paracetamol-induced biochemical toxic alterations in rat liver.

Identification of Cancer Trait Genes and their Association Analysis through Pan-Cancer Analysis

Background: Different cancers have different sites of origin, cell types, and forms of genetic mutations that manifest different forms of cancers. Therefore, identifying genes associated with cancer traits and analyzing their functions in different cancers is important for understanding the mechanism of cancers. Objective: The purpose of this paper is to make up for the shortcomings of single tumor analysis and realize the discovery and identification of genes related to each cancer trait at the level of multiple tumors, and their association analysis. Method: In this paper, we use a structural equation model to quantitatively identify genes associated with cancer traits for five cancers. We verify the correctness and effectiveness of the method through correlation analysis. Then we analyze the functions of genes and the biological processes involved through GO and KEGG pathways. Finally, we further analyze and verify the experimental results through protein interaction network and survival analysis. Results: Through five types of cancer data, we identify 44 genes related to cancer traits. We verify the combined effects of these genes and the biological processes that they participate in and we find key gene pathways and two significant gene functional modules. Conclusion: The results show that the structural equation model has unique advantages in quantifying the combined effects of genes. Many of the genes we have identified are tumor metastasis genes and are related to many cancers; there are strong potential commonalities among cancers. Four cancer genes are not only related to protein metabolism but also related to the regulation of nucleobase, nucleoside, nucleotide, and nucleic acid metabolism, which are of great significance for cancer treatment.

Melatonin Is a Promising Silage Additive: Evidence From Microbiota and Metabolites

The safe and effective storage of forage are very important. As an important storage method, ensiling can keep fresh forage for a long time with less nutritional loss. Melatonin has antioxidant and bacteriostasis, usually used as a natural preservative. The influence of melatonin on silage microbial or fermentation quality has not been clarified. In the present study, we aimed to clarify whether melatonin affected stylo (Stylosanthes guianensis) silage quality via microbiota and metabolites. Melatonin addition significantly improved the silage fermentation quality, including the increased contents of lactic acid and total acid (244.18–255.81% and 63.95–78.97%, respectively), as well as the decreased in pH and butyric acid content compare with control group. Moreover, 16S rRNA sequencing indicated that melatonin addition enhanced the silage microbial diversity indices (such as increase in Shannon indices but decrease in Simpson indices), and significantly shaped the composition of silage microbiota (such as increased abundances of Pantoea, Stenotrophomonas, Sphingobacterium, and Pseudomonas, and decreased abundance of Weissella). Melatonin addition also dramatically affected the metabolites of sylo silage, such as raised malonic acid and some amino acid metabolism(glycine, threonine, methionine and ornithine), while reduced nucleic acid metabolism(2-deoxyuridine and thymine) and carbon metabolism(allose and 2-deoxy-D-glucose). Collectively, our results confirmed that the lowest melatonin addition (5 mg/kg) could improve the fermentation quality, and the potential mechanisms might be associated with the microbiota and metabolites in stylo.