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Asian Pacific Journal of Cancer... Jun 2024This study examined the morphological changes in the colonic mucosa and the presence of inflammation in rats induced with 1,2-dimethylhydrazine (DMH) 30 mg/kg BW over 9,...
OBJECTIVE
This study examined the morphological changes in the colonic mucosa and the presence of inflammation in rats induced with 1,2-dimethylhydrazine (DMH) 30 mg/kg BW over 9, 11, and 13 weeks without a latency period.
METHODS
Hematoxylin and eosin staining was performed to assess the morphology and characteristic alteration of the epitheliocytes in the colon. Immunohistochemistry was employed to assess the expression of tumor necrosis factor (TNF)-α and cyclooxygenase-2 (COX-2). The difference in the severity of inflammation and COX-2 expression was examined using one-way analysis of variance. The correlation of COX-2 expression with the severity of inflammation was analyzed using Spearman's rank correlation test.
RESULT
Until week 13, chronic inflammation and non-hyperplastic and hyperplastic aberrant crypt foci occurred. The severity of inflammation gradually shifted from high moderate to low moderate. TNF-α expression was high in all groups; however, COX-2 expression was gradually lower with longer duration of induction, which corresponded with the severity of inflammation.
CONCLUSION
DMH induction until week 13 without a latency period caused chronic inflammation without the formation of adenoma or adenocarcinoma. A very strong correlation was established between COX-2 expression and inflammation.
Topics: Animals; 1,2-Dimethylhydrazine; Rats; Colorectal Neoplasms; Cyclooxygenase 2; Inflammation; Male; Tumor Necrosis Factor-alpha; Intestinal Mucosa; Carcinogens; Rats, Sprague-Dawley; Aberrant Crypt Foci; Colon; Adenocarcinoma
PubMed: 38918668
DOI: 10.31557/APJCP.2024.25.6.2059 -
PloS One 2024Both psoriasis and metabolic dysfunction-associated steatotic liver disease (MASLD) are immune-mediated chronic inflammatory diseases. Psoriasis manifests itself mainly...
BACKGROUND
Both psoriasis and metabolic dysfunction-associated steatotic liver disease (MASLD) are immune-mediated chronic inflammatory diseases. Psoriasis manifests itself mainly as skin damage, while MASLD mainly involves the liver promoting liver fibrosis, which has a significant impact on patient health and quality of life. Some clinical studies have shown that there are mutually reinforcing mechanisms between these two diseases, but they are not clearly defined, and this paper aims to further explore their common pathogenesis.
METHODS
Gene expression profiling datasets (GSE30999, GSE48452) and single cell datasets (GSE151177, GSE186328) for psoriasis and MASLD were downloaded from the Gene Expression Omnibus (GEO) database. Common differential gene sets were obtained by gene differential analysis, and then functional enrichment of differential genes was performed to find associated transcription factors and PPI protein network analysis. Single-cell datasets were validated for gene expression and explored for cellular communication, gene set differential analysis and immune infiltration analysis.
RESULTS
We identified seven common differential genes, all of which were upregulated.The IL-17 pathway, tumor necrosis factor (TNF-α) pathway were shown in strong association with both diseases, and five transcription factors regulating the differential genes were predicted. Two key genes (MMP9, CXCL10) and three key transcription factors (TF) (IRF1, STAT1, NFKB1) were obtained by PPI protein network analysis. Single cell dataset verified the expression of key genes, and combined with gene set differential analysis, immune infiltration revealed that CD4+ T cells, NK cells and macrophages were heavily infiltrated in both diseases. IL-17, IL-1 and cGAS-STING pathways were highly expressed in both diseases, and both diseases share a similar immune microenvironment.
CONCLUSIONS
Our study reveals the common pathogenesis of psoriasis and MASLD from gene expression to immune cell similarities and differences, identifies key genes and regulatory pathways common to both, and elucidates the similarities in the immune microenvironment of both diseases, providing new ideas for subsequent studies on targeted therapy.
Topics: Psoriasis; Humans; Gene Expression Profiling; Interleukin-17; Protein Interaction Maps; Tumor Necrosis Factor-alpha; Signal Transduction
PubMed: 38917217
DOI: 10.1371/journal.pone.0305217 -
International Journal of... Apr 2024Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), with a high global prevalence and mortality rate. To control the gruesome pathogen, a deep... (Comparative Study)
Comparative Study
BACKGROUND
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), with a high global prevalence and mortality rate. To control the gruesome pathogen, a deep understanding of pathophysiology and host-pathogen interaction is essential for early diagnosis and novel drug development. Cytokines play a crucial role in infection and susceptibility, and their expressions could serve as potential biomarkers to enhance our understanding of Mtb pathophysiology for improved therapeutic approaches. This cross-sectional study investigates the levels of four important T-cell immune-mediated cytokines: interleukins (IL-6 and IL-10), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha in 80 cohort samples, with 20 people in each group.
METHODS
Following proper ethics and patient consent, we collected blood samples and isolated serum from all four groups: TB, type 2 diabetes mellitus (T2DM), type 2 diabetes-TB comorbidity (T2DM + TB), and a healthy individual as a control group (C). Furthermore, cytokine expression was measured in individual serum samples through the enzyme-linked immunosorbent assay method using commercial kits (Diaclone, French). Statistical significance was observed by analyzing triplicate data using t-tests and the one-way ANOVA method with GraphPad Prism 10.
RESULTS
The results showed that all four cytokine levels were higher (P ≤ 0.0001) than the control, especially IL-6, IL-10, and IFN-γ, which were found to be upregulated in T2DM + TB samples (P ≤ 0.0001) than individual TB or T2DM samples.
CONCLUSION
The high levels of cytokines in comorbidity cases raise the risk of insulin resistance and the severity of TB infection. These levels of expression could be used to keep track of the Mtb infection status or severity, aid in early diagnosis as a possible biomarker, and suggest possible treatment plans.
Topics: Humans; Diabetes Mellitus, Type 2; Tuberculosis, Pulmonary; Cross-Sectional Studies; Male; Middle Aged; Female; Adult; Cytokines; Comorbidity; Mycobacterium tuberculosis; Interferon-gamma; Biomarkers; Interleukin-10; Tumor Necrosis Factor-alpha; Interleukin-6; Aged
PubMed: 38916387
DOI: 10.4103/ijmy.ijmy_40_24 -
Microbiology (Reading, England) Jun 2024Bacterial infection is a dynamic process resulting in a heterogenous population of infected and uninfected cells. These cells respond differently based on their...
Bacterial infection is a dynamic process resulting in a heterogenous population of infected and uninfected cells. These cells respond differently based on their bacterial load and duration of infection. In the case of infection of macrophages with Crohn's disease (CD) associated adherent-invasive (AIEC), understanding the drivers of pathogen success may allow targeting of cells where AIEC replicate to high levels. Here we show that stratifying immune cells based on their bacterial load identifies novel pathways and therapeutic targets not previously associated with AIEC when using a traditional homogeneous infected population approach. Using flow cytometry-based cell sorting we stratified cells into those with low or high intracellular pathogen loads, or those which were bystanders to infection. Immune cells transcriptomics revealed a diverse response to the varying levels of infection while pathway analysis identified novel intervention targets that were directly related to increasing intracellular AIEC numbers. Chemical inhibition of identified targets reduced AIEC intracellular replication or inhibited secretion of tumour necrosis factor alpha (TNFα), a key cytokine associated with AIEC infection. Our results have identified new avenues of intervention in AIEC infection that may also be applicable to CD through the repurposing of already available inhibitors. Additionally, they highlight the applicability of immune cell stratification post-infection as an effective approach for the study of microbial pathogens.
Topics: Crohn Disease; Macrophages; Humans; Escherichia coli Infections; Escherichia coli; Tumor Necrosis Factor-alpha; Bacterial Load; Bacterial Adhesion; Host-Pathogen Interactions
PubMed: 38916198
DOI: 10.1099/mic.0.001470 -
Scientific Reports Jun 2024Cryptosporidiosis is a worldwide zoonotic disease. Oxymatrine, an alkaloid extracted and isolated from the plant bitter ginseng, has been reported to have therapeutic...
Cryptosporidiosis is a worldwide zoonotic disease. Oxymatrine, an alkaloid extracted and isolated from the plant bitter ginseng, has been reported to have therapeutic effects on cryptosporidiosis. However, the underlying mechanism of its action remains unclear. In this study, we utilized network pharmacology and experimental validation to investigate the mechanism of oxymatrine in the treatment of cryptosporidiosis. First, the potential targets of drugs and diseases were predicted by TCMSP, Gene Cards, and other databases. Following the intersection of drug-disease targets, the DAVID database was used to implement the enrichment analysis of GO functions and KEGG pathways, and then the network diagram of "intersected target-KEGG" relationship was constructed. Autodock 4.2.6 software was used to carry out the molecular docking of core targets to drug components. Based on the establishment of a mouse model of cryptosporidiosis, the validity of the targets in the TNF/NF-κB signaling pathway was confirmed using Western blot analysis and Quantitative Rea-ltime-PCR. A total of 41 intersectional targets of oxymatrine and Cryptosporidium were generated from the results, and five core targets were screened out by network analysis, including RELA, AKT1, ESR1, TNF, and CASP3. The enrichment analysis showed that oxymatrine could regulate multiple gene targets, mediate TNF, Apoptpsis, IL-17, NF-κB and other signaling pathways. Molecular docking experiments revealed that oxymatrine was tightly bound to core targets with stable conformation. Furthermore, we found through animal experiments that oxymatrine could regulate the mRNA and protein expression of IL-6, NF-κB, and TNF-α in the intestinal tissues of post-infected mice through the TNF/NF-κB signaling pathway. Therefore, it can be concluded that oxymatrine can regulate the inflammatory factors TNF-α, NF-κB, and IL-6 through the TNF/NF-κB signaling pathway for the treatment of cryptosporidiosis. This prediction has also been validated by network pharmacology and animal experiments.
Topics: Quinolizines; Cryptosporidiosis; Animals; Signal Transduction; Alkaloids; Mice; NF-kappa B; Network Pharmacology; Molecular Docking Simulation; Tumor Necrosis Factor-alpha; Disease Models, Animal; Humans; Matrines
PubMed: 38914662
DOI: 10.1038/s41598-024-65362-0 -
Scientific Reports Jun 2024NLRP3 inflammasome has been implicated in neutrophil polarization and extrusion of neutrophil extracellular traps (NETs) in vitro and facilitates secretion of Il1-beta...
NLRP3 inflammasome has been implicated in neutrophil polarization and extrusion of neutrophil extracellular traps (NETs) in vitro and facilitates secretion of Il1-beta (IL-1β). Permanent ligation of the left anterior descending artery was used to induce MI in WT and NLRP3 mice as well as in NLRP3 recipient mice transfused with either WT or NLRP3 neutrophils. NLRP3 deficiency reduced infarct size to roughly a third of WT heart injury and preserved left ventricular (LV) function at 12 h after MI as assessed by echocardiography and triphenyltetrazolium chloride staining of live tissue. Transfusion of WT but not NLRP3 neutrophils after MI increased infarct size in NLRP3 mice and significantly reduced LV function. The key features of myocardial tissue in WT neutrophil transfused recipients were increased H3Cit-positive deposits with NET-like morphology and increased tissue levels of IL-1β and plasma levels of von Willebrand Factor (VWF). Flow cytometry analysis also revealed that neutrophil NLRP3 increased the number of labeled and transfused neutrophils in the bone marrow of recipient mice following MI. Our data suggest a key role for neutrophil NLRP3 in the production of IL-1β and deposition of NETs in cardiac tissue exacerbating injury following MI. We provide evidence for a link between neutrophil NLRP3 and VWF release likely enhancing thromboinflammation in the heart. Neutrophil NLRP3 deficiency conferred similar cardioprotective effects to general NLRP3 deletion in MI rendering anti-neutrophil NLRP3 therapy a promising target for early cardioprotective treatment.
Topics: Animals; NLR Family, Pyrin Domain-Containing 3 Protein; Neutrophils; Interleukin-1beta; Myocardial Infarction; Mice; Extracellular Traps; Myocardium; Mice, Knockout; von Willebrand Factor; Mice, Inbred C57BL; Male; Inflammasomes; Disease Models, Animal
PubMed: 38914598
DOI: 10.1038/s41598-024-64710-4 -
Scientific Reports Jun 2024The rapid perfusion of cerebral arteries leads to a significant increase in intracranial blood volume, exposing patients with traumatic brain injury to the risk of...
Assessment of cerebrovascular alterations induced by inflammatory response and oxidative-nitrative stress after traumatic intracranial hypertension and a potential mitigation strategy.
The rapid perfusion of cerebral arteries leads to a significant increase in intracranial blood volume, exposing patients with traumatic brain injury to the risk of diffuse brain swelling or malignant brain herniation during decompressive craniectomy. The microcirculation and venous system are also involved in this process, but the precise mechanisms remain unclear. A physiological model of extremely high intracranial pressure was created in rats. This development triggered the TNF-α/NF-κB/iNOS axis in microglia, and released many inflammatory factors and reactive oxygen species/reactive nitrogen species, generating an excessive amount of peroxynitrite. Subsequently, the capillary wall cells especially pericytes exhibited severe degeneration and injury, the blood-brain barrier was disrupted, and a large number of blood cells were deposited within the microcirculation, resulting in a significant delay in the recovery of the microcirculation and venous blood flow compared to arterial flow, and this still persisted after decompressive craniectomy. Infliximab is a monoclonal antibody bound to TNF-α that effectively reduces the activity of TNF-α/NF-κB/iNOS axis. Treatment with Infliximab resulted in downregulation of inflammatory and oxidative-nitrative stress related factors, attenuation of capillary wall cells injury, and relative reduction of capillary hemostasis. These improved the delay in recovery of microcirculation and venous blood flow.
Topics: Animals; Oxidative Stress; Rats; Intracranial Hypertension; Male; Tumor Necrosis Factor-alpha; Inflammation; Microcirculation; Cerebrovascular Circulation; Rats, Sprague-Dawley; Brain Injuries, Traumatic; Infliximab; Disease Models, Animal; Blood-Brain Barrier; Reactive Oxygen Species; Reactive Nitrogen Species; Microglia
PubMed: 38914585
DOI: 10.1038/s41598-024-64940-6 -
Journal of Applied Biomedicine Jun 2024Resveratrol (RSV) is a polyphenol antioxidant that has been shown to have neuroprotective effects. We sought molecular mechanisms that emphasize the anti-inflammatory...
Resveratrol (RSV) is a polyphenol antioxidant that has been shown to have neuroprotective effects. We sought molecular mechanisms that emphasize the anti-inflammatory activity of RSV in traumatic brain injury (TBI) in mice associated with endoplasmic reticulum stress (ERS). After establishing three experimental groups (sham, TBI, and TBI+RSV), we explored the results of RSV after TBI on ERS and caspase-12 apoptotic pathways. The expression levels of C/EBP homologous protein (CHOP), glucose regulated protein 78kD (GRP78), caspase-3, and caspase-12 in cortical brain tissues were assessed by western blotting. The qPCR analysis was also performed on mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in cortical brain tissue. In addition, the expression of GRP78 in microglia (ionized calcium binding adaptor molecule 1; Iba-1) and neurons (neuronal nuclei; NeuN) was identified by immunofluorescence staining. The neurological function of mice was assessed by modified neurological severity scores (mNSS). After drug treatment, the expression of CHOP, GRP78, caspase-3 and caspase-12 decreased, and qPCR results showed that TNF-α and IL-1β were down-regulated. Immunofluorescence staining showed down-regulation of Iba-1+/GRP78+ and NeuN+/GRP78+ cells after RSV treatment. The mNSS analysis confirmed improvement after RSV treatment. RSV improved apoptosis by downregulating the ERS signaling pathway and improved neurological prognosis in mice with TBI.
Topics: Animals; Brain Injuries, Traumatic; Resveratrol; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Mice; Male; Apoptosis; Prognosis; Neuroprotective Agents; Neurons; Interleukin-1beta; Caspase 12; Heat-Shock Proteins; Tumor Necrosis Factor-alpha; Mice, Inbred C57BL; Cell Death; Microglia; Transcription Factor CHOP
PubMed: 38912865
DOI: 10.32725/jab.2024.008 -
Communications Biology Jun 2024Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation,...
Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.
Topics: Mechanistic Target of Rapamycin Complex 1; Ras Homolog Enriched in Brain Protein; Humans; Animals; Mice; Signal Transduction; Tuberous Sclerosis Complex 2 Protein; Liver Diseases, Alcoholic; Interleukin-1; Mice, Inbred C57BL; Male; HEK293 Cells
PubMed: 38907105
DOI: 10.1038/s42003-024-06427-8 -
PloS One 2024At present, the mechanism of fluorosis-induced damage to the hepatic system is unclear. Studies have shown that excess fluoride causes some degree of damage to the...
At present, the mechanism of fluorosis-induced damage to the hepatic system is unclear. Studies have shown that excess fluoride causes some degree of damage to the liver, including inflammation. The SDF-1/CXCR4 signaling axis has been reported to have an impact on the regulation of inflammation in human cells. In this study, we investigated the role of the SDF-1/CXCR4 signaling axis and related inflammatory factors in fluorosis through in vitro experiments on human hepatic astrocytes (LX-2) cultured with sodium fluoride. CCK-8 assays showed that the median lethal dose at 24 h was 2 mmol/l NaF, and these conditions were used for subsequent enzyme-linked immunosorbent assays (ELISAs) and quantitative real-time polymerase chain reaction (qPCR) analysis. The protein expression levels of SDF-1/CXCR4 and the related inflammatory factors nuclear factor-κB (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) were detected by ELISAs from the experimental and control groups. The mRNA expression levels of these inflammatory indicators were also determined by qPCR in both groups. Moreover, the expression levels of these factors were significantly higher in the experimental group than in the control group at both the protein and mRNA levels (P < 0.05). Excess fluorine may stimulate the SDF-1/CXCR4 signaling axis, activating the inflammatory NF-κB signaling pathway and increasing the expression levels of the related inflammatory factors IL-6, TNF-α and IL-1β. Identification of this mechanism is important for elucidating the pathogenesis of fluorosis-induced liver injury.
Topics: Receptors, CXCR4; Humans; Chemokine CXCL12; Sodium Fluoride; Hepatocytes; Signal Transduction; NF-kappa B; Cell Line; Interleukin-1beta; Tumor Necrosis Factor-alpha; Interleukin-6; Inflammation
PubMed: 38905184
DOI: 10.1371/journal.pone.0302530