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BMC Psychiatry May 2024Patients with major depressive disorder (MDD) have an increased risk of breast cancer (BC), implying that these two diseases share similar pathological mechanisms. This...
BACKGROUND
Patients with major depressive disorder (MDD) have an increased risk of breast cancer (BC), implying that these two diseases share similar pathological mechanisms. This study aimed to identify the key pathogenic genes that lead to the occurrence of both triple-negative breast cancer (TNBC) and MDD.
METHODS
Public datasets GSE65194 and GSE98793 were analyzed to identify differentially expressed genes (DEGs) shared by both datasets. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape to identify key PPI genes using cytoHubba. Hub DEGs were obtained from the intersection of hub genes from a PPI network with genes in the disease associated modules of the Weighed Gene Co-expression Network Analysis (WGCNA). Independent datasets (TCGA and GSE76826) and RT-qPCR validated hub gene expression.
RESULTS
A total of 113 overlapping DEGs were identified between TNBC and MDD. The PPI network was constructed, and 35 hub DEGs were identified. Through WGCNA, the blue, brown, and turquoise modules were recognized as highly correlated with TNBC, while the brown, turquoise, and yellow modules were similarly correlated with MDD. Notably, G3BP1, MAF, NCEH1, and TMEM45A emerged as hub DEGs as they appeared both in modules and PPI hub DEGs. Within the GSE65194 and GSE98793 datasets, G3BP1 and MAF exhibited a significant downregulation in TNBC and MDD groups compared to the control, whereas NCEH1 and TMEM45A demonstrated a significant upregulation. These findings were further substantiated by TCGA and GSE76826, as well as through RT-qPCR validation.
CONCLUSIONS
This study identified G3BP1, MAF, NCEH1 and TMEM45A as key pathological genes in both TNBC and MDD.
Topics: Humans; Triple Negative Breast Neoplasms; Depressive Disorder, Major; Female; Protein Interaction Maps; Gene Expression Profiling; Gene Regulatory Networks; Databases, Genetic; Transcriptome
PubMed: 38755543
DOI: 10.1186/s12888-024-05795-z -
Molecular Immunology Jul 2024Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease, of which the pathogens is remains obscure. Viral infection, particularly Epstein Barr viru (EBV)...
OBJECTIVES
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease, of which the pathogens is remains obscure. Viral infection, particularly Epstein Barr viru (EBV) infection, has been considered a common pathogenic factor. This study suggests that c-Maf may be an important target in T cell differentiation during SLE progression, providing a potentially new perspective on the role of viral infection in the pathogenesis of autoimmune diseases.
METHODS
Cytokines of EBV-infected SLE patients were measured by ELISA and assessed in conjunction with their clinical data. IFN-α, c-Maf, and the differentiation of Th17/Treg cells in SLE patients and MRL/LPR mice were analyzed using FCM, WB, RT-PCR, etc. Following the infection of cells and mice with EBV or viral mimic poly (dA:dT), the changes of the aforementioned indicators were investigated. The relationship among IFN-α, STAT3, c-Maf and Th17 cells was determined by si-RNA technique.
RESULTS
Many SLE patients are found to be complicated by viral infections; Further, studies have demonstrated that viral infection, especially EBV, is involved in SLE development. This study showed that viral infections might promote IFN-α secretion, inhibit c-Maf expression by activating STAT3, increase Th17 cell differentiation, and lead to the immune imbalance of Th17/Treg cells, thus playing a role in the onset and progression of SLE.
CONCLUSION
This study demonstrates that EBV infections may contribute to SLE development by activating STAT3 through IFN-α, inhibiting c-Maf, and causing Th17/Treg immune imbalance. Our work provided a new insight into the pathogenesis and treatment of SLE.
Topics: Lupus Erythematosus, Systemic; Th17 Cells; Humans; Animals; Epstein-Barr Virus Infections; T-Lymphocytes, Regulatory; Mice; Interferon-alpha; Female; Adult; Mice, Inbred MRL lpr; Herpesvirus 4, Human; Proto-Oncogene Proteins c-maf; Male; Cell Differentiation; Disease Progression; Middle Aged; STAT3 Transcription Factor; Young Adult
PubMed: 38749236
DOI: 10.1016/j.molimm.2024.05.003 -
BioMed Research International 2024There is no conclusive evidence on the association between interleukin- (IL-) 6 gene polymorphism and type 2 diabetes mellitus (type 2 DM). Thus, this study is aimed at...
BACKGROUND
There is no conclusive evidence on the association between interleukin- (IL-) 6 gene polymorphism and type 2 diabetes mellitus (type 2 DM). Thus, this study is aimed at evaluating the role of and polymorphisms in the pathogenesis of type 2 DM among Ghanaians in the Ho Municipality.
MATERIALS AND METHODS
We recruited into this hospital-based case-control study 174 patients with type 2 DM (75 DM alone and 99 with DM+HTN) and 149 healthy individuals between 2018 and 2020. Demographic, lifestyle, clinical, anthropometric, and haemodynamic variables were obtained. Fasting blood samples were collected for haematological, biochemical, and molecular analyses. Genomic DNA was extracted, amplified using Tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) technique, and genotyped for IL-6 gene polymorphism. Logistic regression analyses were performed to assess the association between IL-6 gene polymorphism and type 2 DM.
RESULTS
The minor allele frequency (MAF) of the and polymorphisms was higher in DM alone (57.5%, 62.0%) and DM with HTN groups (58.3%, 65.3%) than controls (33.1%, 20.0%). Carriers of the rs1800795GC genotype (aOR = 2.35, 95% CI: 1.13-4.90, = 0.022) and mutant C allele (aOR = 2.41, 95% CI: 1.16-5.00, = 0.019) as well as those who carried the rs1800796GC (aOR = 8.67, 95% CI: 4.00-18.90, < 0.001) and mutant C allele (aOR = 8.84, 95% CI: 4.06-19.26, = 0.001) had increased odds of type 2 DM. For both polymorphisms, carriers of the GC genotype had comparable levels of insulin, HOMA-IR, and fasting blood glucose (FBG) with those who carried the GG genotype. IL-6 levels were higher among carriers of the rs1800796GC variant compared to carriers of the rs1800796GG variant ( = 0.023). The polymorphism, dietary sugar intake, and exercise status, respectively, explained approximately 3% ( = 0.046), 3.2% ( = 0.038, coefficient = 1.456), and 6.2% ( = 0.004, coefficient = -2.754) of the variability in IL-6 levels, suggesting weak effect sizes.
CONCLUSION
The GC genotype and mutant C allele are risk genetic variants associated with type 2 DM in the Ghanaian population. The rs1800796 GC variant, dietary sugar intake, and exercise status appear to contribute significantly to the variations in circulating IL-6 levels but with weak effect sizes.
Topics: Humans; Diabetes Mellitus, Type 2; Female; Male; Interleukin-6; Middle Aged; Case-Control Studies; Ghana; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Gene Frequency; Adult; Aged; Genotype; Alleles
PubMed: 38707766
DOI: 10.1155/2024/3610879 -
Nature Communications Apr 2024Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell...
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.
Topics: Pancreatic Neoplasms; Animals; Liver Neoplasms; STAT3 Transcription Factor; Macrophages; Carcinoma, Pancreatic Ductal; Humans; Mice; Cell Line, Tumor; Signal Transduction; Janus Kinases; Mice, Inbred C57BL; Fibroblasts; Male; Cancer-Associated Fibroblasts; Female
PubMed: 38678021
DOI: 10.1038/s41467-024-47949-3 -
Plants (Basel, Switzerland) Apr 2024Protein content (PC) is crucial to the nutritional quality of soybean [ (L.) Merrill]. In this study, a total of 266 accessions were used to perform a genome-wide...
Protein content (PC) is crucial to the nutritional quality of soybean [ (L.) Merrill]. In this study, a total of 266 accessions were used to perform a genome-wide association study (GWAS) in three tested environments. A total of 23,131 high-quality SNP markers (MAF ≥ 0.02, missing data ≤ 10%) were identified. A total of 40 association signals were significantly associated with PC. Among them, five novel quantitative trait nucleotides (QTNs) were discovered, and another 32 QTNs were found to be overlapping with the genomic regions of known quantitative trait loci (QTL) related to soybean PC. Combined with GWAS, metabolome and transcriptome sequencing, 59 differentially expressed genes (DEGs) that might control the change in protein content were identified. Meantime, four commonly upregulated differentially abundant metabolites (DAMs) and 29 commonly downregulated DAMs were found. Remarkably, the soybean gene , which is homologous with Arabidopsis hydroxyproline-rich glycoproteins (HRGPs), may play an important role in improving the PC. Additionally, was divided into two main haplotype in the tested accessions. The PC of haplotype 1 was significantly lower than that of haplotype 2. The results of this study provided insights into the genetic mechanisms regulating protein content in soybean.
PubMed: 38674535
DOI: 10.3390/plants13081128 -
Islets Dec 2024Chronically elevated levels of glucose are deleterious to pancreatic β cells and contribute to β cell dysfunction, which is characterized by decreased insulin...
Chronically elevated levels of glucose are deleterious to pancreatic β cells and contribute to β cell dysfunction, which is characterized by decreased insulin production and a loss of β cell identity. The Krüppel-like transcription factor, Glis3 has previously been shown to positively regulate insulin transcription and mutations within the Glis3 locus have been associated with the development of several pathologies including type 2 diabetes mellitus. In this report, we show that Glis3 is significantly downregulated at the transcriptional level in INS1 832/13 cells within hours of being subjected to high glucose concentrations and that diminished expression of Glis3 is at least partly attributable to increased oxidative stress. CRISPR/Cas9-mediated knockdown of Glis3 indicated that the transcription factor was required to maintain normal levels of both insulin and MafA expression and reduced Glis3 expression was concomitant with an upregulation of β cell disallowed genes. We provide evidence that Glis3 acts similarly to a pioneer factor at the insulin promoter where it permissively remodels the chromatin to allow access to a transcriptional regulatory complex including Pdx1 and MafA. Finally, evidence is presented that Glis3 can positively regulate MafA transcription through its pancreas-specific promoter and that MafA reciprocally regulates Glis3 expression. Collectively, these results suggest that decreased Glis3 expression in β cells exposed to chronic hyperglycemia may contribute significantly to reduced insulin transcription and a loss of β cell identity.
Topics: Animals; Rats; Cell Line; DNA-Binding Proteins; Down-Regulation; Glucose; Homeodomain Proteins; Insulin; Insulin-Secreting Cells; Maf Transcription Factors, Large; Oxidative Stress; Repressor Proteins; Trans-Activators
PubMed: 38652652
DOI: 10.1080/19382014.2024.2344622 -
MBio May 2024The Hippo kinases MST1 and MST2 initiate a highly conserved signaling cascade called the Hippo pathway that limits organ size and tumor formation in animals....
UNLABELLED
The Hippo kinases MST1 and MST2 initiate a highly conserved signaling cascade called the Hippo pathway that limits organ size and tumor formation in animals. Intriguingly, pathogens hijack this host pathway during infection, but the role of MST1/2 in innate immune cells against pathogens is unclear. In this report, we generated knockout macrophages to investigate the regulatory activities of the Hippo kinases in immunity. Transcriptomic analyses identified differentially expressed genes (DEGs) regulated by MST1/2 that are enriched in biological pathways, such as systemic lupus erythematosus, tuberculosis, and apoptosis. Surprisingly, pharmacological inhibition of the downstream components LATS1/2 in the canonical Hippo pathway did not affect the expression of a set of immune DEGs, suggesting that MST1/2 control these genes alternative inflammatory Hippo signaling. Moreover, MST1/2 may affect immune communication by influencing the release of cytokines, including TNFα, CXCL10, and IL-1ra. Comparative analyses of the single- and double-knockout macrophages revealed that MST1 and MST2 differentially regulate TNFα release and expression of the immune transcription factor MAF, indicating that the two homologous Hippo kinases individually play a unique role in innate immunity. Notably, both MST1 and MST2 can promote apoptotic cell death in macrophages upon stimulation. Lastly, we demonstrate that the Hippo kinases are critical factors in mammalian macrophages and single-cell amoebae to restrict infection by , , and . Together, these results uncover non-canonical inflammatory Hippo signaling in macrophages and the evolutionarily conserved role of the Hippo kinases in the anti-microbial defense of eukaryotic hosts.
IMPORTANCE
Identifying host factors involved in susceptibility to infection is fundamental for understanding host-pathogen interactions. Clinically, individuals with mutations in the MST1 gene which encodes one of the Hippo kinases experience recurrent infection. However, the impact of the Hippo kinases on innate immunity remains largely undetermined. This study uses mammalian macrophages and free-living amoebae with single- and double-knockout in the Hippo kinase genes and reveals that the Hippo kinases are the evolutionarily conserved determinants of host defense against microbes. In macrophages, the Hippo kinases MST1 and MST2 control immune activities at multiple levels, including gene expression, immune cell communication, and programmed cell death. Importantly, these activities controlled by MST1 and MST2 in macrophages are independent of the canonical Hippo cascade that is known to limit tissue growth and tumor formation. Together, these findings unveil a unique inflammatory Hippo signaling pathway that plays an essential role in innate immunity.
Topics: Animals; Protein Serine-Threonine Kinases; Signal Transduction; Mice; Serine-Threonine Kinase 3; Hippo Signaling Pathway; Macrophages; Immunity, Innate; Phagocytes; Mice, Knockout; Bacterial Infections; Gene Expression Profiling; Mice, Inbred C57BL; Pseudomonas aeruginosa
PubMed: 38624208
DOI: 10.1128/mbio.03429-23 -
International Journal of Molecular... Apr 2024A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We...
A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived transcriptomic signatures for M2 (M2, ; ; ; ; ; ; ; ; ; ) and M1 (M1, ; ; ; ; ; ; ) macrophages, and cytolytic T-lymphocytes (CTL, ; ; ; ; ). Primary GC in a TCGA stomach cancer dataset was evaluated for signature expressions, and a log-rank test determined overall survival (OS) and the disease-free interval (DFI). In 341 TCGA GC entries, high M2 expression was associated with histological types and later stages. Low M2 expression was associated with significantly better 5-year OS and DFI. We validated M2 in prospectively collected peritoneal fluid of a GC patient cohort ( = 28). Single-cell RNA sequencing was used for signature expression in cells and the log-rank test compared OS. GC patients with high M2 in cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2 was significantly and independently associated with survival. As an independent predictor of poor survival, M2 may be prognostic in primary tumors and peritoneal fluid of GC patients.
Topics: Humans; Stomach Neoplasms; Peritoneum; Macrophages, Peritoneal; Biomarkers; Macrophages; Tumor Microenvironment; Fibrinogen
PubMed: 38612926
DOI: 10.3390/ijms25074117 -
Nature Immunology May 2024Intestinal immune responses to microbes are controlled by the cytokine IL-10 to avoid immune pathology. Here, we use single-cell RNA sequencing of colon lamina propria...
Intestinal immune responses to microbes are controlled by the cytokine IL-10 to avoid immune pathology. Here, we use single-cell RNA sequencing of colon lamina propria leukocytes (LPLs) along with RNA-seq and ATAC-seq of purified CD4 T cells to show that the transcription factors Blimp-1 (encoded by Prdm1) and c-Maf co-dominantly regulate Il10 while negatively regulating proinflammatory cytokines in effector T cells. Double-deficient Prdm1MafCd4 mice infected with Helicobacter hepaticus developed severe colitis with an increase in T1/NK/ILC1 effector genes in LPLs, while Prdm1Cd4 and MafCd4 mice exhibited moderate pathology and a less-marked type 1 effector response. LPLs from infected MafCd4 mice had increased type 17 responses with increased Il17a and Il22 expression and an increase in granulocytes and myeloid cell numbers, resulting in increased T cell-myeloid-neutrophil interactions. Genes over-expressed in human inflammatory bowel disease showed differential expression in LPLs from infected mice in the absence of Prdm1 or Maf, revealing potential mechanisms of human disease.
Topics: Animals; Positive Regulatory Domain I-Binding Factor 1; Mice; Proto-Oncogene Proteins c-maf; Colitis; Mice, Knockout; Humans; Helicobacter hepaticus; Helicobacter Infections; Mice, Inbred C57BL; Intestinal Mucosa; Inflammatory Bowel Diseases; Gene Expression Regulation; Disease Models, Animal
PubMed: 38609547
DOI: 10.1038/s41590-024-01814-z -
Heliyon Apr 2024Coronary artery disease (CAD) is the most common reason for mortality and disability-adjusted life years (DALYs) lost globally. This study aimed to suggest a new gene...
BACKGROUND
Coronary artery disease (CAD) is the most common reason for mortality and disability-adjusted life years (DALYs) lost globally. This study aimed to suggest a new gene list for the treatment of CAD by a systematic review of bioinformatics analyses of pharmacogenomics impacts of potential genes and variants.
METHODS
PubMed search was filtered by the title including Coronary Artery Disease during 2020-2023. To find the genes with pharmacogenetic impact on the CAD, additional filtrations were considered according to the variant annotations. Protein-Protein Interactions (PPIs), Gene-miRNA Interactions (GMIs), Protein-Drug Interactions (PDIs), and variant annotation assessments (VAAs) performed by STRING-MODEL (ver. 12), Cytoscape (ver. 3.10), miRTargetLink.2., NetworkAnalyst (ver 0.3.0), and PharmGKB.
RESULTS
Results revealed 5618 publications, 1290 papers were qualified, and finally, 650 papers were included. 4608 protein-coding genes were extracted, among them, 1432 unique genes were distinguished and 530 evidence-based repeated genes remained. 71 genes showed a pharmacogenetics-related variant annotation in at least (entirely 6331 annotations). Variant annotation assessment (VAA) showed 532 potential variants for the final report, and finally, the concluding PGs list represented 175 variants. Based on the function and MAF, 57 nonsynonymous variants of 29 Pharmacogenomics-related genes were associated with CAD.
CONCLUSION
Conclusively, evaluating circulating miR33a in individuals' plasma with CAD, and genotyping of rs2230806, rs2230808, rs2487032, rs12003906, rs2472507, rs2515629, and rs4149297 (ABCA1 variants) lead to precisely prescribing of well-known drugs. Also, the findings of this review can be used in both whole-genome sequencing (WGS) and whole-exome sequencing (WES) analysis in the prognosis and diagnosis of CAD.
PubMed: 38601677
DOI: 10.1016/j.heliyon.2024.e28983