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Advanced Science (Weinheim,... Jun 2024Lack of liver regenerative capacity is the primary cause of hepatic failure and even mortality in patients undergoing hepatectomy, with no effective intervention...
Lack of liver regenerative capacity is the primary cause of hepatic failure and even mortality in patients undergoing hepatectomy, with no effective intervention strategies currently available. Therefore, identifying efficacious interventions to enhance liver regeneration is pivotal for optimizing clinical outcomes. Recent studies have demonstrated that vagotomy exerts an inhibitory effect on liver regeneration following partial hepatectomy, thereby substantiating the pivotal role played by the vagus nerve in the process of liver regeneration. In recent years, electroacupuncture (EA) has emerged as a non-invasive technique for stimulating the vagus nerve. However, EA on hepatic regeneration remains uncertain. In this study, a 70% partial hepatectomy (PH) mouse model is utilized to investigate the effects of EA on acute liver regeneration and elucidate its underlying molecular mechanisms. It is observed that EA at ST36 acutely activated cholinergic neurons in the dorsal motor nucleus of the vagus nerve (DMV), resulting in increased release of acetylcholine from hepatic vagal nerve endings and subsequent activation of IL-6 signaling in liver macrophages. Ultimately, these events promoted hepatocyte proliferation and facilitated liver regeneration. These findings provide insights into the fundamental brain-liver axis mechanism through which EA promotes liver regeneration, offering a novel therapeutic approach for post-hepatectomy liver regeneration disorders.
PubMed: 38923873
DOI: 10.1002/advs.202402856 -
Chemical Biology & Drug Design Jun 2024The environmental factor aryl hydrocarbon receptor (AhR), a key protein connecting the external environmental signals (e.g., environmental endocrine disruptor TCDD) to...
The environmental factor aryl hydrocarbon receptor (AhR), a key protein connecting the external environmental signals (e.g., environmental endocrine disruptor TCDD) to internal cellular processes, is involved in the activation of peripheral macrophages and inflammatory response in human body. Thus, there is widespread interest in finding compounds to anti-inflammatory response in macrophages by targeting human AhR. Here, ensemble docking based-virtual screening was first used to screen a library (~200,000 compounds) against human AhR ligand binding domain (LBD) and 25 compounds were identified as potential inhibitors. Then, 9 out of the 25 ligands were found to down-regulate the mRNA expression of CYP1A1 (a downstream gene of AhR signaling) in AhR overexpressing macrophages. The most potent compound AE-411/41415610 was selected for further study and found to reduce both mRNA and protein expressions level of CYP1A1 in mouse peritoneal macrophage. Moreover, protein chip signal pathway analysis indicated that AE-411/41415610 play a role in regulating JAK-STAT and AKT-mTOR pathways. In sum, the discovered hits with novel scaffolds provided a starting point for future design of more effective AhR-targeted lead compounds to regulate CYP1A1 expression of inflammatory peritoneal macrophages.
Topics: Receptors, Aryl Hydrocarbon; Cytochrome P-450 CYP1A1; Animals; Ligands; Mice; Humans; Molecular Docking Simulation; Signal Transduction; Macrophages; Macrophages, Peritoneal; Inflammation; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Binding Sites
PubMed: 38923686
DOI: 10.1111/cbdd.14572 -
Toxics May 2024It is well known that Particulate Matter2.5 (PM) has a major adverse effect on the organism. However, the health hazards of livestock farm PM to humans and animals are...
It is well known that Particulate Matter2.5 (PM) has a major adverse effect on the organism. However, the health hazards of livestock farm PM to humans and animals are not yet known, and the role of miRNAs in the cellular damage induced by livestock farm PM is also unclear. Therefore, our study used cowshed PM to stimulate rat alveolar macrophage NR8383 to construct an in vitro injury model to investigate the effect of miR-122-5p on PM-induced apoptosis in the NR8383. The level of apoptosis was quantified by flow cytometry and Hoechst 33342/PI double staining. Furthermore, the potential target gene Collagen type IV alpha () of miR-122-5p was identified through the use of bioinformatics methods. The results demonstrated a decline in cell viability and an increase in apoptosis with rising PM concentrations and exposure durations. The transfection of miR-122-5p mimics resulted in an upregulation of the pro-apoptotic protein Bcl-xL/Bcl-2 and activation of cleaved caspase-3 while inhibiting the anti-apoptotic protein B-cell lymphoma-2. The experimental data indicate that miR-122-5p is involved in the apoptotic process by targeting . Furthermore, the overexpression of was observed to enhance the PM-activated PI3K/AKT/NF-κB signaling pathway, which contributed to the inhibition of apoptosis. This finding offers a promising avenue for the development of therapeutic strategies aimed at mitigating cellular damage induced by PM exposure.
PubMed: 38922066
DOI: 10.3390/toxics12060386 -
Marine Drugs Jun 2024SeviL, a galactoside-binding lectin previously isolated from the mussel , was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this...
SeviL, a galactoside-binding lectin previously isolated from the mussel , was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel β-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.
Topics: Animals; Mice; Macrophages; RAW 264.7 Cells; Lectins; Bivalvia; Cell Proliferation; Humans; Cytokines; Phenotype; Signal Transduction
PubMed: 38921580
DOI: 10.3390/md22060269 -
Current Issues in Molecular Biology Jun 2024Nonalcoholic steatohepatitis (NASH) is characterized by severe inflammation and fibrosis due to an excessive accumulation of triglycerides (TGs) in the liver with a...
Nonalcoholic steatohepatitis (NASH) is characterized by severe inflammation and fibrosis due to an excessive accumulation of triglycerides (TGs) in the liver with a dysregulated de novo lipogenesis (DNL) pathway. In this study, we aimed to evaluate the effectiveness of YC-1102, an extract obtained from the roots of , as a nutritional supplement in a diet-induced NASH mouse model. C57BL/6 wild-type mice were fed a fructose, palmitate, and cholesterol (FPC)-containing diet for 16 weeks to induce experimental NASH. A daily oral gavage of YC-1102 and obetichoic acid (OCA) was conducted for 9 weeks. After sacrifice, disease parameters related to hepatic lipids, inflammation, and fibrosis were evaluated. The treatment with YC-1102 significantly decreased the liver/body weight ratio, epididymal fat weight, and plasma ALT and AST levels, which are indicators of NASH injuries. YC-1102 attenuated hepatic lipid accumulation by inhibiting the transcription of DNL genes in the livers exhibiting NASH. Additionally, we found that YC-1102 blocked the development of hepatic inflammation and fibrosis by directly disturbing macrophage activation, resulting in an amelioration of hepatic fibrosis. Our findings suggest that YC-1102 could ameliorate NASH progression by inhibiting uncontrolled DNL and inflammation.
PubMed: 38921022
DOI: 10.3390/cimb46060351 -
Cells Jun 2024Multiple sclerosis (MS) is a clinically heterogeneous disease underpinned by inflammatory, demyelinating and neurodegenerative processes, the extent of which varies...
BACKGROUND
Multiple sclerosis (MS) is a clinically heterogeneous disease underpinned by inflammatory, demyelinating and neurodegenerative processes, the extent of which varies between individuals and over the course of the disease. Recognising the clinicopathological features that most strongly associate with disease outcomes will inform future efforts at patient phenotyping.
AIMS
We used a digital pathology workflow, involving high-resolution image acquisition of immunostained slides and opensource software for quantification, to investigate the relationship between clinical and neuropathological features in an autopsy cohort of progressive MS.
METHODS
Sequential sections of frontal, cingulate and occipital cortex, thalamus, brain stem (pons) and cerebellum including dentate nucleus (n = 35 progressive MS, females = 28, males = 7; age died = 53.5 years; range 38-98 years) were immunostained for myelin (anti-MOG), neurons (anti-HuC/D) and microglia/macrophages (anti-HLA). The extent of demyelination, neurodegeneration, the presence of active and/or chronic active lesions and quantification of brain and leptomeningeal inflammation was captured by digital pathology.
RESULTS
Digital analysis of tissue sections revealed the variable extent of pathology that characterises progressive MS. Microglia/macrophage activation, if found at a higher level in a single block, was typically elevated across all sampled blocks. Compartmentalised (perivascular/leptomeningeal) inflammation was associated with age-related measures of disease severity and an earlier death.
CONCLUSION
Digital pathology identified prognostically important clinicopathological correlations in MS. This methodology can be used to prioritise the principal pathological processes that need to be captured by future MS biomarkers.
Topics: Humans; Middle Aged; Female; Male; Multiple Sclerosis; Aged; Adult; Biomarkers; Aged, 80 and over; Inflammation; Brain; Microglia; Macrophages
PubMed: 38920650
DOI: 10.3390/cells13121020 -
Rheumatology Advances in Practice 2024
PubMed: 38919835
DOI: 10.1093/rap/rkae078 -
Frontiers in Immunology 2024Inflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several...
BACKGROUND
Inflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several chronic inflammatory diseases. However, increased liver fibrosis has been reported in mice lacking IL-15 receptor alpha chain (IL-15Rα), suggesting an anti-fibrogenic role for IL-15. As myeloid cells are key players in liver fibrosis and IL-15 signaling can occur independently of IL-15Rα, we investigated the requirement of IL-15 and IL-15Rα in liver fibrosis.
METHODS
We induced liver fibrosis in , and wildtype C57BL/6 mice by the administration of carbon tetrachloride (CCl). Liver fibrosis was evaluated by Sirius red and Mason's trichrome staining and α-smooth muscle acting immunostaining of myofibroblasts. Gene expression of collagens, matrix modifying enzymes, cytokines and chemokines was quantified by RT-qPCR. The phenotype and the numbers of intrahepatic lymphoid and myeloid cell subsets were evaluated by flow cytometry.
RESULTS
Both and mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content. mice showed further reduction in collagen deposition compared to mice. However, and genes were similarly induced in the fibrotic livers of wildtype, and mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected, and mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45 immune cells and CD68 macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and anti-inflammatory monocyte subsets compared to wildtype mice.
CONCLUSION
Our findings indicate that IL-15 exerts its profibrogenic role in the liver by promoting macrophage activation and that this requires trans-presentation of IL-15 by IL-15Rα.
Topics: Animals; Interleukin-15; Mice; Carbon Tetrachloride; Interleukin-15 Receptor alpha Subunit; Liver Cirrhosis; Mice, Knockout; Mice, Inbred C57BL; Disease Models, Animal; Male; Liver; Cytokines; Receptors, Interleukin-15
PubMed: 38919611
DOI: 10.3389/fimmu.2024.1404891 -
Frontiers in Immunology 2024Therapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit...
INTRODUCTION
Therapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit cytotoxic responses against malignant B cells. However, efficacy is often compromised due to a suppressive microenvironment that interferes with cellular immune responses. To overcome this suppression, agonists of pattern recognition receptors have been studied which promote direct cytotoxicity or elicit anti-tumoral immune responses. NOD2 is an intracellular pattern recognition receptor that participates in the detection of peptidoglycan, a key component of bacterial cell walls. This detection then mediates the activation of multiple signaling pathways in myeloid cells. Although several NOD2 agonists are being used worldwide, the potential benefit of these agents in the context of antibody therapy has not been explored.
METHODS
Primary cells from healthy-donor volunteers (PBMCs, monocytes) or CLL patients (monocytes) were treated with versus without the NOD2 agonist L18-MDP, then antibody-mediated responses were assessed. In vivo, the Eµ-TCL1 mouse model of CLL was used to test the effects of L18-MDP treatment alone and in combination with anti-CD20 antibody.
RESULTS
Treatment of peripheral blood mononuclear cells with L18-MDP led to activation of monocytes from both healthy donors and CLL patients. In addition, there was an upregulation of activating FcγR in monocytes and a subsequent increase in antibody-mediated phagocytosis. This effect required the NF-κB and p38 signaling pathways. Treatment with L18-MDP plus anti-CD20 antibody in the Eµ-TCL model of CLL led to a significant reduction of CLL load, as well as to phenotypic changes in splenic monocytes and macrophages.
CONCLUSIONS
Taken together, these results suggest that NOD2 agonists help overturn the suppression of myeloid cells, and may improve the efficacy of antibody therapy for CLL.
Topics: Nod2 Signaling Adaptor Protein; Animals; Humans; Receptors, IgG; Mice; Macrophages; Leukemia, Lymphocytic, Chronic, B-Cell; Acetylmuramyl-Alanyl-Isoglutamine; Female; Mice, Inbred C57BL; Signal Transduction; Phagocytosis; Rituximab
PubMed: 38919608
DOI: 10.3389/fimmu.2024.1409333 -
Journal of Neuroinflammation Jun 2024The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal...
BACKGROUND
The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models.
METHODS AND RESULTS
We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls.
CONCLUSION
These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.
Topics: Female; Pregnancy; Microglia; Humans; Placenta; COVID-19; Macrophages; Pregnancy Complications, Infectious; SARS-CoV-2; Fetus; Adult; Brain; Mice; Animals
PubMed: 38918792
DOI: 10.1186/s12974-024-03157-w