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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 -
European Journal of Immunology Apr 2024Cenicriviroc, a dual CCR2/CCR5 antagonist, initially developed as an anti-HIV drug, has shown promising results in nonalcoholic steatohepatitis phase 2 clinical trials....
Cenicriviroc, a dual CCR2/CCR5 antagonist, initially developed as an anti-HIV drug, has shown promising results in nonalcoholic steatohepatitis phase 2 clinical trials. It inhibits the infiltration and activation of CCR2/CCR5 monocytes and macrophages to the site of liver injury, preventing liver fibrosis. However, the role of Cenicriviroc in the modulation of helper T cell differentiation and functions remains to be explored. In inflamed colons of Crohn's disease patients, CCR2 and CCR5 CD4+ T cells are enriched. Considering the role of CCR2 and CCR5 T cells in IBD pathogenesis, we investigated the potential role of Cenicriviroc in colitis. Our in vitro studies revealed that Cenicriviroc inhibits Th1-, Th2-, and Th17-cell differentiation while promoting the generation of type 1 regulatory T cells (Tr1), known for preventing inflammation through induction of IL-10. This study is the first to report that Cenicriviroc promotes Tr1 cell generation by up-regulating the signature of Tr1 cell transcription factors such as c-Maf, Prdm1, Irf-1, Batf, and EGR-2. Cenicriviroc displayed a protective effect in experimental colitis models by preventing body weight loss and intestinal inflammation and preserving epithelial barrier integrity. We show that Cenicriviroc induced IL-10 and inhibited the generation of pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and IL-1β during colitis. Based on our data, we propose Cenicriviroc as a potential therapeutic in controlling tissue inflammation by inhibiting the generation and functions of effector T cells and promoting the induction of anti-inflammatory Tr1 cells.
PubMed: 38643381
DOI: 10.1002/eji.202350847 -
Nature Immunology May 2024
Topics: Animals; Positive Regulatory Domain I-Binding Factor 1; Colitis; Mice; Proto-Oncogene Proteins c-maf; Mice, Knockout; Humans; Signal Transduction; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38641721
DOI: 10.1038/s41590-024-01823-y -
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 -
The Egyptian Journal of Immunology Apr 2024Multiple sclerosis (MS) is a multifactorial polygenic disease; results from autoimmune and neurodegenerative processes which lead to multifocal lesions of the central...
Multiple sclerosis (MS) is a multifactorial polygenic disease; results from autoimmune and neurodegenerative processes which lead to multifocal lesions of the central nervous system. Axonal degeneration was found to be prominent in the inflammation period of MS and contribute to the progression of disability. Soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) complex plays a vital role in the release of neurotransmitter by synaptic vesicle fusion. Stx-1A protein (Stx-1A), a major component of the SNARE complex, is widely expressed in brain tissue. This study intended to evaluate the prevalence of the Stx-1A gene polymorphism (rs1569061) in the Egyptian population with MS and to investigate its association with various clinical factors. This study included 65 adult Egyptian MS patients and 35 age- and sex-matched normal control subjects. Diagnosis of MS was made by an experienced neurologist according to revised McDonald criteria. All Patients underwent full history taking, included Age of onset of MS, disease duration, disease course and degree of disability according to the Expanded Disability Status Scale (EDSS) and family history of neurological diseases. Stx-1A gene polymorphism (rs1569061) genotyping was performed by TaqMan assay based quantitative real time (qPCR) and verified by sanger sequencer. Genotype and allele frequencies of (rs1569061) did not differ significantly between case and control groups. No difference was detected when comparing the genotype frequency and the allele frequency to different disease parameters. Discrepancy of the minor allele frequency (MAF) of Stx-1A gene (rs1569061) between different populations was noted. In conclusion, our study in Stx-1A gene polymorphism (rs1569061) and MS showed that no difference between the patient and control as regards gene frequency and allele frequency. Predicting no association between the studied polymorphism and MS in the Egyptian population. However, discrepancy between different population was noted as regards the MAF for Stx-1A gene (rs1569061).
Topics: Adult; Humans; Egypt; Gene Frequency; Multiple Sclerosis; Polymorphism, Genetic; SNARE Proteins; Syntaxin 1; North African People
PubMed: 38615201
DOI: No ID Found -
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