Metabolic heterogeneity of cancer contributes significantly to its poor treatment outcomes and prognosis. As a result, studies continue to focus on identifying new biomarkers and metabolic ...vulnerabilities, both of which depend on the understanding of altered metabolism in cancer. In the recent decades, the rise of mass spectrometry imaging (MSI) enables the
in situ
detection of large numbers of small molecules in tissues. Therefore, researchers look to using MSI-mediated spatial metabolomics to further study the altered metabolites in cancer patients. In this review, we examined the two most commonly used spatial metabolomics techniques, MALDI-MSI and DESI-MSI, and some recent highlights of their applications in cancer studies. We also described AFADESI-MSI as a recent variation from the DESI-MSI and compare it with the two major techniques. Specifically, we discussed spatial metabolomics results in four types of heterogeneous malignancies, including breast cancer, esophageal cancer, glioblastoma and lung cancer. Multiple studies have effectively classified cancer tissue subtypes using altered metabolites information. In addition, distribution trends of key metabolites such as fatty acids, high-energy phosphate compounds, and antioxidants were identified. Therefore, while the visualization of finer distribution details requires further improvement of MSI techniques, past studies have suggested spatial metabolomics to be a promising direction to study the complexity of cancer pathophysiology.
Immune-related genes (IRGs) have been identified as critical drivers of the initiation and progression of hepatocellular carcinoma (HCC). This study is aimed at constructing an IRG signature for HCC ...and validating its prognostic value in clinical application. The prognostic signature was developed by integrating multiple IRG expression data sets from TCGA and GEO databases. The IRGs were then combined with clinical features to validate the robustness of the prognostic signature through bioinformatics tools. A total of 1039 IRGs were identified in the 657 HCC samples. Subsequently, the IRGs were subjected to univariate Cox regression and LASSO Cox regression analyses in the training set to construct an IRG signature comprising nine immune-related gene pairs (IRGPs). Functional analyses revealed that the nine IRGPs were associated with tumor immune mechanisms, including cell proliferation, cell-mediated immunity, and tumorigenesis signal pathway. Concerning the overall survival rate, the IRGPs distinctly grouped the HCC samples into the high- and low-risk groups. Also, we found that the risk score based on nine IRGPs was related to clinical and pathologic factors and remained a valid independent prognostic signature after adjusting for tumor TNM, grade, and grade in multivariate Cox regression analyses. The prognostic value of the nine IRGPs was further validated by forest and nomogram plots, which revealed that it was superior to the tumor TNM, grade, and stage. Our findings suggest that the nine-IRGP signature can be effective in determining the disease outcomes of HCC patients.
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, and its pathogenetic mechanism is far from being understood. In this study, we aimed to explore the cellular and molecular ...mechanisms that lead to pathogenesis of this disease.
We applied single-cell RNA sequencing (scRNA-seq) to 57,288 peripheral blood mononuclear cells (PBMCs) from five patients with pSS and five healthy controls. The immune cell subsets and susceptibility genes involved in the pathogenesis of pSS were analyzed. Flow cytometry was preformed to verify the result of scRNA-seq.
We identified two subpopulations significantly expand in pSS patients. The one highly expressing cytotoxicity genes is named as CD4
CTLs cytotoxic T lymphocyte, and another highly expressing T cell receptor (TCR) variable gene is named as CD4
TRAV13-2+ T cell. Flow cytometry results showed the percentages of CD4
CTLs, which were profiled with CD4
and GZMB
staining; the total T cells of 10 patients with pSS were significantly higher than those of 10 healthy controls (
= 0.008). The expression level of IL-1β in macrophages, TCL1A in B cells, as well as interferon (IFN) response genes in most cell subsets was upregulated in the patients with pSS. Susceptibility genes including HLA-DRB5, CTLA4, and AQP3 were highly expressed in patients with pSS.
Our data revealed disease-specific immune cell subsets and provided some potential new targets of pSS. Specific expansion of CD4
CTLs may be involved in the pathogenesis of pSS, which might give valuable insights for therapeutic interventions of pSS.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects thousands of people worldwide. Recently, alterations in metabolism and gut microbiome have emerged as key regulators ...of SLE pathogenesis. However, it is not clear about the coordination of gut commensal bacteria and SLE metabolism. Here, by integrating 16S sequencing and metabolomics data, we characterized the gut microbiome and fecal and serum metabolome alterations in patients with SLE. Microbial diversity sequencing revealed gut microflora dysbiosis in SLE patients with significantly increased beta diversity. The metabolomics profiling identified 43 and 55 significantly changed metabolites in serum and feces samples in SLE patients. Notably, lipids accounted for about 65% altered metabolites in serum, highlighted the disruption of lipid metabolism. Integrated correlation analysis provided a link between the gut microbiome and lipid metabolism in patients with SLE, particularly according to regulate the conversion of primary bile acids to secondary bile acids. Overall, our results illustrate the perturbation of the gut microbiome and metabolome in SLE patients which may facilitate the development of new SLE interventions.
Inactivation of tumor suppressor gene played critical roles in the development and progression of human hepatocellular carcinoma (HCC). Zic family member 4 (ZIC4) is transcription factor and plays an ...important role in the developmental process. However, the expression and biological role of ZIC4 in HCC is poorly understood. Here, bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database revealed an aberrant hypermethylation of ZIC4 in HCC. ZIC4 is frequently hypermethylated in promoter region and down expressed in HCC cells and tissues. Functionally, ZIC4 inhibition facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, ZIC4 overexpression reduced proliferation and invasiveness of HCC cells. In addition, ZIC4 inhibition rescued the antitumor effect induced by enhancer of zeste homolog 2 (EZH2) knockdown or EZH2 inhibitor. Mechanistically, EZH2 knockdown or EZH2 inhibitor reduced the enrichment of EZH2 and H3K27me3 in ZIC4 promoter region and leading to the upregulation of ZIC4. Altogether, these data indicate that epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in HCC and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.
Avian Influenza A (H5N6) Virus causes severe influenza disease in humans and is manifested by acute respiratory distress syndrome, multi-organ failure, and high mortality rates. T cells recognize ...antigens specifically through a membrane protein T cell receptor (TCR). To ward off a wide variety of pathogens, the human adaptive immune system harbors a vast array of TCRs, which are collectively referred to as the TCR repertoire. The B cell receptor (BCR) is involved in inducing the humoral immune response. The generation of a diverse T cell and B cell repertoire is essential for protection against infection. In this study, multiplex PCR based on genomic DNA amplicons and Illumina high-throughput sequencing (HTS) were applied to study the characteristics and polymorphisms of the TRB and IGH repertoire in the peripheral blood mononuclear cells (PBMCs) from two H5N6 AIV patients and six healthy donors (NC). The CDR3 average length in the AIV group was different from the NC group. The TRBV12-3, TRBV12-4, and TRBV15 gene segments and TRBV30/TRBJ1-2, TRBV12-3/TRBJ1-1 and IGHV3-11/IGHJ6 gene segment pairings also exhibited a higher usage in the PBMCs of AIV donors and may provide more information for generating more effective T/B cell targeted diagnosis/protection strategies.
Mesenchymal stem cells (MSCs) and their released extracellular vesicles (Evs) have shown protective effects against kidney diseases. This study aims to study the functions of umbilical cord ...MSCs-released Evs (ucMSC-Evs) and their implicated molecules in mesangial proliferative glomerulonephritis (MsPGN).
A rat model of MsPGN was induced by anti-Thy-1.1, and rat mesangial cells (rMCs) HBZY-1 were treated with PDGF-BB/DD to mimic MsPGN condition in vitro. Rats and cells were treated with different doses of ucMSC-Evs, and then the pathological changes in renal tissues and proliferation of rMCs were determined. Differentially expressed microRNAs (miRNAs) after Evs treatment were screened by microarray analysis. The interactions among miR-378, PSMD14, and TGFBR1 were analyzed. Gain- and loss-of function studies of miR-378 and PSMD14 were performed to explore their effects on tissue hyperplasia and rMC proliferation and their interactions with the TGF-β1/Smad2/3 signaling pathway.
The ucMSC-Evs treatment ameliorated mesangial hyperplasia and fibrosis in rat renal tissues and suppressed the aberrant proliferation of rMCs in a dose-dependent manner. miR-378 was the most upregulated miRNA in tissues and cells after ucMSC-Evs treatment. miR-378 directly targeted PSMD14, and PSMD14 maintained the stability of TGFBR1 through deubiquitination modification, which led to TGF-β1/Smad2/3 activation. Either miR-378 knockdown or PSMD14 overexpression diminished the protective functions of ucMSC-Evs by activating the TGF-β1/Smad2/3 signaling pathway.
UcMSC-Evs ameliorate pathological process in MsPGN through the delivery of miR-378, which suppresses PSMD14-mediated TGFBR1 stability and inactivates the TGF-β1/Smad2/3 signaling pathway to reduce tissue hyperplasia and rMC proliferation. Video abstract.
Post-translational modifications (PTMs) are at the heart of many cellular signaling events, which changes the function of protein. Crotonylation, one of the most important and common PTMs, plays a ...crucial role in the regulation of various biological processes. However, no study has evaluated the role of lysine crotonylation modification in chronic renal failure (CRF) patients.
Here, we comparatively evaluated the crotonylation proteome of normal controls and chronic renal failure patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with highly sensitive immune-affinity purification.
A total of 1109 lysine modification sites were identified, of which 772 sites were up-regulated and 69 sites were down-regulated. This suggested that crotonylation modification maintains high levels in the patients with chronic renal failure. Gene ontology(GO) enrichment analysis showed that the crotonylated proteins were significantly enriched in the platelet alpha granule lumen, platelet degradulation, and cell adhesion molecule binding. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG)-based functional enrichment analysis in the Kyoto encyclopedia showed that crotonylated protein was enriched in CD36, which is closely linked to renal failure.
This is the first report of the global crotonylation proteome in chronic renal failure patients. Crotonylation of histone and non-histone may play important roles in delaying the continuous deterioration of renal function in patients with chronic renal failure.
The immune cells and the repertoire of T cells and B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Exploring their expression and distribution in SLE can ...help us better understand this lethal autoimmune disease. In this study, we used a single-cell 5' RNA sequence and single-cell T cell receptor (TCR)/B cell receptor (BCR) to study the immune cells and the repertoire from ten SLE patients and the paired normal controls (NC). The results showed that 9732 cells correspondence to 12 cluster immune cell types were identified in NC, whereas 11042 cells correspondence to 16 cluster immune cell types were identified in SLE. The results demonstrated that neutrophil, macrophage, and dendritic cells were accumulated in SLE by annotating the immune cell types. Besides, the bioinformatics analysis of differentially expressed genes (DEGs) in these cell types indicates their role in inflammation response. In addition, patients with SLE showed increased TCR and BCR clonotypes compared with the healthy controls. Furthermore, patients with SLE showed biased usage of TCR and BCR V(D)J genes. Taken together, we characterized the transcriptome and TCR/BCR immune repertoire profiles of SLE patients, which may provide a new avenue for the diagnosis and treatment of SLE.
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