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ELife Jan 2024Prostaglandin E (PGE) is a key player in a plethora of physiological and pathological events. Nevertheless, little is known about the dynamics of PGE secretion from a...
Prostaglandin E (PGE) is a key player in a plethora of physiological and pathological events. Nevertheless, little is known about the dynamics of PGE secretion from a single cell and its effect on the neighboring cells. Here, by observing confluent Madin-Darby canine kidney (MDCK) epithelial cells expressing fluorescent biosensors, we demonstrate that calcium transients in a single cell cause PGE-mediated radial spread of PKA activation (RSPA) in neighboring cells. By in vivo imaging, RSPA was also observed in the basal layer of the mouse epidermis. Experiments with an optogenetic tool revealed a switch-like PGE discharge in response to the increasing cytoplasmic Ca concentrations. The cell density of MDCK cells correlated with the frequencies of calcium transients and the following RSPA. The extracellular signal-regulated kinase (ERK) activation also enhanced the frequency of RSPA in MDCK and in vivo. Thus, the PGE discharge is regulated temporally by calcium transients and ERK activity.
Topics: Mice; Animals; Dogs; Extracellular Signal-Regulated MAP Kinases; Calcium; Dinoprostone; Kidney; Phosphorylation
PubMed: 38276879
DOI: 10.7554/eLife.86727 -
Immunity, Inflammation and Disease Jan 2024For the unclear pathogenesis of Sjogren's syndrome (SS), further exploration is necessary. Mesenchymal stem cells (MSCs) and derived exosomes (MSCs-exo) have exhibited...
Human umbilical cord mesenchymal stem cells improve disease characterization of Sjogren's syndrome in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.
BACKGROUND
For the unclear pathogenesis of Sjogren's syndrome (SS), further exploration is necessary. Mesenchymal stem cells (MSCs) and derived exosomes (MSCs-exo) have exhibited promising results in treating SS.
OBJECT
This study aimed to investigate the effect and mechanism of human umbilical cord MSCs (UC-MSCs) on SS.
METHODS
Nonobese Diabetic (NOD) mouse splenic T cells were co-cultured with UC-MSCs and UC-MSCs-exo, and interferon-gamma (IFN-γ), interleukin (IL)-6, IL-10, prostaglandin E2 (PGE2), and transforming growth factor-β1 (TGF-β1) levels in the supernatant were assessed by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Co-cultured T cells were injected into NOD mice via the tail vein. The inflammatory cell infiltration in the intestine and the submandibular gland was characterized by hematoxylin-eosin staining. Treg/Th17 homeostasis within the spleen was determined by flow cytometry. Gut microbiota was detected by 16S rRNA sequencing, and the relationship between differential microbiota and Treg/Th17 cytokines was analyzed by the Pearson correlation coefficient.
RESULTS
UC-MSCs, UC-MSCs-exo, and NOD mouse splenic T cells were successfully cultured and identified. After T cells were co-cultured with UC-MSCs and UC-MSCs-exo, both IFN-γ and IL-6 were decreased while IL-10, PGE2, and TGF-β1 were increased in transcriptional and translational levels. UC-MSCs and UC-MSCs-exo partially restored salivary secretion function, reduced Ro/SSA antibody and α-Fodrin immunoglobulin A levels, reduced inflammatory cell infiltration in the intestine and submandibular gland, raised proportion of Treg cells, decreased IFN-γ, IL-6, IL-2, IL-17, lipopolysaccharide, and tumor necrosis factor-alpha levels, and raised IL-10, Foxp3, and TGF-β1 levels by affecting co-cultured T cells. The intervention of UC-MSCs and UC-MSCs-exo improved intestinal homeostasis in NOD mice by increasing microbiota diversity and richness. Additionally, differential microbiota was significantly associated with Treg/Th17 cytokine levels.
CONCLUSION
Human UC-MSCs and UC-MSCs-exo improved disease characterization of SS in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.
Topics: Animals; Mice; Humans; Gastrointestinal Microbiome; T-Lymphocytes, Regulatory; Mice, Inbred NOD; Interleukin-10; Interleukin-6; Dinoprostone; RNA, Ribosomal, 16S; Sjogren's Syndrome; Transforming Growth Factor beta1; Cytokines; Mesenchymal Stem Cells; Immunity, Cellular; Umbilical Cord
PubMed: 38270310
DOI: 10.1002/iid3.1139 -
International Immunopharmacology Feb 2024Lung macrophages (LMs) are critically involved in respiratory diseases. The primary objective of the present study was to determine whether or not an adenosine analog...
BACKGROUND AND PURPOSE
Lung macrophages (LMs) are critically involved in respiratory diseases. The primary objective of the present study was to determine whether or not an adenosine analog (NECA) and prostaglandin E (PGE) affected the interleukin (IL)-4- and IL-13-induced release of M2a chemokines (CCL13, CCL17, CCL18, and CCL22) by human LMs.
EXPERIMENTAL APPROACH
Primary macrophages isolated from resected human lungs were incubated with NECA, PGE, roflumilast, or vehicle and stimulated with IL-4 or IL-13 for 24 h. The levels of chemokines and PGE in the culture supernatants were measured using ELISAs and enzyme immunoassays.
KEY RESULTS
Exposure to IL-4 (10 ng/mL) and IL-13 (50 ng/mL) was associated with greater M2a chemokine production but not PGE production. PGE (10 ng/mL) and NECA (10 M) induced the production of M2a chemokines to a lesser extent but significantly enhanced the IL-4/IL-13-induced production of these chemokines. At either a clinically relevant concentration (10 M) or at a concentration (10 M) that fully inhibited phosphodiesterase 4 (PDE4) activity, roflumilast did not increase the production of M2a chemokines and did not modulate their IL-13-induced production, regardless of the presence or absence of PGE.
CONCLUSIONS
NECA and PGE enhanced the IL-4/IL-13-induced production of M2a chemokines. The inhibition of PDE4 by roflumilast did not alter the production of these chemokines. These results contrast totally with the previously reported inhibitory effects of NECA, PGE, and PDE4 inhibitors on the lipopolysaccharide-induced release of tumor necrosis factor alpha and M1 chemokines in human LMs.
Topics: Humans; Dinoprostone; Adenosine; Interleukin-4; Interleukin-13; Adenosine-5'-(N-ethylcarboxamide); Chemokines; Macrophages; Tumor Necrosis Factor-alpha; Chemokine CCL17; Lung; Cells, Cultured; Aminopyridines; Benzamides; Cyclopropanes
PubMed: 38266451
DOI: 10.1016/j.intimp.2024.111557 -
Cellular and Molecular Life Sciences :... Jan 2024In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its...
In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its antagonist, the tumor-suppressor microRNA (miRNA) let-7, play a key role in maintaining pluripotency. Muse cells are non-tumorigenic pluripotent-like stem cells residing in the bone marrow, peripheral blood, and organ connective tissues as pluripotent surface marker SSEA-3(+). They express pluripotency genes, differentiate into triploblastic-lineage cells, and self-renew at the single cell level. Muse cells do not express LIN28 but do express let-7 at higher levels than in iPSCs. In Muse cells, we demonstrated that let-7 inhibited the PI3K-AKT pathway, leading to sustainable expression of the key pluripotency regulator KLF4 as well as its downstream genes, POU5F1, SOX2, and NANOG. Let-7 also suppressed proliferation and glycolysis by inhibiting the PI3K-AKT pathway, suggesting its involvement in non-tumorigenicity. Furthermore, the MEK/ERK pathway is not controlled by let-7 and may have a pivotal role in maintaining self-renewal and suppression of senescence. The system found in Muse cells, in which the tumor suppressor let-7, but not LIN28, tunes the expression of pluripotency genes, might be a rational cell system conferring both pluripotency-like properties and a low risk for tumorigenicity.
Topics: Alprostadil; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Embryonic Stem Cells; Gene Expression
PubMed: 38261036
DOI: 10.1007/s00018-023-05089-9 -
Advanced Science (Weinheim,... Mar 2024Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy....
Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single-component dual-functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)-generated HOCl. A representative prodrug (DHU-CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU-CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU-CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase-2 (COX-2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX-2. Downstream prostaglandins E and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU-CBA2 promotes infiltration and function of CD8 T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single-component dual-functional prodrug activated by TME-specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX-2 inhibitor.
Topics: Humans; Photosensitizing Agents; Photochemotherapy; Lung Neoplasms; Cyclooxygenase 2; CD8-Positive T-Lymphocytes; Spinal Neoplasms; Prodrugs; Indomethacin; Tumor Microenvironment
PubMed: 38224203
DOI: 10.1002/advs.202303981 -
NPJ Systems Biology and Applications Jan 2024Traditional Chinese medicine is one of the most commonly used complementary and alternative medicine therapies for depression. Integrated Chinese-western therapies have... (Meta-Analysis)
Meta-Analysis
Traditional Chinese medicine is one of the most commonly used complementary and alternative medicine therapies for depression. Integrated Chinese-western therapies have been extensively applied in numerous diseases due to their superior efficiency in individual treatment. We used the meta-analysis, network pharmacology, and bioinformatics studies to identify the putative role of Longya Lilium combined with Fluoxetine in depression. Depression-like behaviors were mimicked in mice after exposure to the chronic unpredictable mild stress (CUMS). The underlying potential mechanism of this combination therapy was further explored based on in vitro and in vivo experiments to analyze the expression of COX-2, PGE2, and IL-22, activation of microglial cells, and neuron viability and apoptosis in the hippocampus. The antidepressant effect was noted for the combination of Longya Lilium with Fluoxetine in mice compared to a single treatment. COX-2 was mainly expressed in hippocampal CA1 areas. Longya Lilium combined with Fluoxetine reduced the expression of COX-2 and thus alleviated depression-like behavior and neuroinflammation in mice. A decrease of COX-2 curtailed BV-2 microglial cell activation, inflammation, and neuron apoptosis by blunting the PGE2/IL-22 axis. Therefore, a combination of Longya Lilium with Fluoxetine inactivates the COX-2/PGE2/IL-22 axis, consequently relieving the neuroinflammatory response and the resultant depression.
Topics: Mice; Animals; Fluoxetine; Depression; Lilium; Cyclooxygenase 2; Dinoprostone; Antidepressive Agents
PubMed: 38218856
DOI: 10.1038/s41540-024-00329-5 -
Nature Structural & Molecular Biology Apr 2024Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a...
Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules derived from unsaturated fatty acids. To better understand the basis of the substrate selectivity of MRP4, we used cryogenic-electron microscopy to determine six structures of nanodisc-reconstituted MRP4 at various stages throughout its transport cycle. Substrate-bound structures of MRP4 in complex with PGE, PGE and the sulfonated-sterol DHEA-S reveal a common binding site that accommodates a diverse set of organic anions and suggest an allosteric mechanism for substrate-induced enhancement of MRP4 ATPase activity. Our structure of a catalytically compromised MRP4 mutant bound to ATP-Mg is outward-occluded, a conformation previously unobserved in the MRP subfamily and consistent with an alternating-access transport mechanism. Our study provides insights into the endogenous function of this versatile efflux transporter and establishes a basis for MRP4-targeted drug design.
Topics: Prostaglandins; Multidrug Resistance-Associated Proteins; Biological Transport; Dinoprostone; Membrane Transport Proteins
PubMed: 38216659
DOI: 10.1038/s41594-023-01176-4 -
International Journal of Molecular... Jan 2024The aim of this study was to evaluate the possible relationships between polymorphisms in the interleukin-1 () , , and genes and concentrations of the inflammatory...
The Influence of Genetic Polymorphisms on the Expression of Interleukin-1beta, Prostaglandin E2 and Tumor Necrosis Factor Alpha in Peri-Implant Crevicular Fluid: A Cross-Sectional Study.
The aim of this study was to evaluate the possible relationships between polymorphisms in the interleukin-1 () , , and genes and concentrations of the inflammatory mediators IL-1β, tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) in peri-implant crevicular fluid (PICF). A cross-sectional analytical study was conducted on 51 patients with dental implants. Samples from the buccal mucosa were obtained, and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for and and PCR and restriction fragment length polymorphism analysis for . For the biochemical analysis, the concentrations of IL-1β and TNF-α were analyzed using multiplexed fluorescent sphere immunoassays, and PGE2 by enzyme-linked immunosorbent assay. In patients with detected polymorphism, there was an increase in the concentration of the three mediators with statistically significant differences in the mean values of TNF-α and PGE2, regardless of peri-implant health status ( = 0.002 and = 0.049, respectively). The concentrations of all three mediators were positively and significantly correlated (IL-1β vs. TNF-α Rho = 0.480, < 0.001; IL-1β vs. PGE2 Rho = 0.382, = 0.006; and TNF-α vs. PGE2 Rho = 0.528, < 0.001). We can conclude that the polymorphism exerts an influence on the PICF immune response, which may explain the influence of this genetic polymorphism on the occurrence of peri-implantitis.
Topics: Humans; Cross-Sectional Studies; Dinoprostone; Interleukin-1beta; Polymorphism, Genetic; Tumor Necrosis Factor-alpha; Interleukin 1 Receptor Antagonist Protein; Gingival Crevicular Fluid; Dental Implants
PubMed: 38203822
DOI: 10.3390/ijms25010651 -
International Journal of Molecular... Dec 2023Lactobacilli have been widely used as probiotics because of their benefits for intestinal health and physiological functions. Among a variety of genera, has been...
Lactobacilli have been widely used as probiotics because of their benefits for intestinal health and physiological functions. Among a variety of genera, has been studied for its ability to exert anti-inflammatory functions and its role in controlling metabolic disorders, as well as the production of the antimicrobial compound reuterin. However, the effects and mechanisms of on enhancing immune responses in the immunosuppressed states have been relatively understudied. In this study, we isolated an immunomodulatory strain, namely, KBL346 (KBL346), from a fecal sample of a 3-month-old infant in Korea. We evaluated the immunostimulatory activity and hematopoietic function of KBL346 in macrophages and cyclophosphamide (CPA)-induced immunosuppressed mice. KBL346 increased the phagocytic activity against MYA-4788 in macrophages, and as biomarkers for this, increased secretions of nitric oxide (NO) and prostaglandin E (PGE) were confirmed. Also, the secretions of innate cytokines (TNF-α, IL-1β, and IL-6) were increased. In CPA-induced immunosuppressed mice, KBL346 at a dosage of 10 CFU/kg protected against spleen injury and suppressed levels of immune-associated parameters, including NK cell activity, T and B lymphocyte proliferation, CD4 and CD8 T cell abundance, cytokines, and immunoglobulins in vivo. The effects were comparable or superior to those in the Korean red ginseng positive control group. Furthermore, the safety assessment of KBL346 as a probiotic was conducted by evaluating its antibiotic resistance, hemolytic activity, cytotoxicity, and metabolic characteristics. This study demonstrated the efficacy and safety of KBL346, which could potentially be used as a supplement to enhance the immune system.
Topics: Humans; Infant; Animals; Mice; Limosilactobacillus reuteri; Immunocompromised Host; Lactobacillus; Lymphocyte Activation; Cyclophosphamide; Cytokines; Dinoprostone
PubMed: 38203313
DOI: 10.3390/ijms25010141 -
Nature Communications Jan 2024Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8 T cells to the intestinal microenvironment...
Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8 T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8 T cell pool. CD8 T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8 T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E (PGE), which drives mitochondrial depolarization in CD8 T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE sensing promotes CD8 T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE-autophagy-glutathione axis defines the metabolic adaptation of CD8 T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; Autophagy; Dinoprostone; Genes, Mitochondrial; Glutathione
PubMed: 38200005
DOI: 10.1038/s41467-024-44689-2