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1.
J Exp Med ; 221(8)2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38861480

ABSTRACT

Guard proteins initiate defense mechanisms upon sensing pathogen-encoded virulence factors. Successful viral pathogens likely inhibit guard protein activity, but these interactions have been largely undefined. Here, we demonstrate that the human pathogen herpes simplex virus 1 (HSV-1) stimulates and inhibits an antiviral pathway initiated by NLRP1, a guard protein that induces inflammasome formation and pyroptotic cell death when activated. Notably, HSV-1 infection of human keratinocytes promotes posttranslational modifications to NLRP1, consistent with MAPK-dependent NLRP1 activation, but does not result in downstream inflammasome formation. We identify infected cell protein 0 (ICP0) as the critical HSV-1 protein that is necessary and sufficient for inhibition of the NLRP1 pathway. Mechanistically, ICP0's cytoplasmic localization and function as an E3 ubiquitin ligase prevents proteasomal degradation of the auto-inhibitory NT-NLRP1 fragment, thereby preventing inflammasome formation. Further, we demonstrate that inhibiting this inflammasome is important for promoting HSV-1 replication. Thus, we have established a mechanism by which HSV-1 overcomes a guard-mediated antiviral defense strategy in humans.


Subject(s)
Adaptor Proteins, Signal Transducing , Herpesvirus 1, Human , Inflammasomes , NLR Proteins , Ubiquitin-Protein Ligases , Humans , Inflammasomes/metabolism , Ubiquitin-Protein Ligases/metabolism , Herpesvirus 1, Human/physiology , NLR Proteins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Immediate-Early Proteins/metabolism , HEK293 Cells , Virus Replication , Keratinocytes/virology , Keratinocytes/metabolism , Herpes Simplex/virology , Herpes Simplex/immunology , Herpes Simplex/metabolism , Animals
2.
Microbiologyopen ; 13(3): e23, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38867416

ABSTRACT

The G protein-coupled estrogen receptor, also known as GPER1 or originally GPR30, is found in various tissues, indicating its diverse functions. It is typically present in immune cells, suggesting its role in regulating immune responses to infectious diseases. Our previous studies have shown that G-1, a selective GPER agonist, can limit the pathogenesis mediated by Staphylococcus aureus alpha-hemolysin (Hla). It aids in clearing bacteria in a mouse skin infection model and restricts the surface display of the Hla receptor, ADAM10 (a disintegrin and metalloprotease 10) in HaCaT keratinocytes. In this report, we delve into the modulation of GPER in human immune cells in relation to the NLRP3 inflammasome. We used macrophage-like differentiated THP-1 cells for our study. We found that treating these cells with G-1 reduces ATP release, decreases the activity of the caspase-1 enzyme, and lessens cell death following Hla intoxication. This is likely due to the reduced levels of ADAM10 and NLRP3 proteins, as well as the decreased display of the ADAM10 receptor in the G-1-treated THP-1 cells. Our studies, along with our previous work, suggest the potential therapeutic use of G-1 in reducing Hla susceptibility in humans. This highlights the importance of GPER in immune regulation and its potential as a therapeutic target.


Subject(s)
ADAM10 Protein , Amyloid Precursor Protein Secretases , Bacterial Toxins , Hemolysin Proteins , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Receptors, Estrogen , Receptors, G-Protein-Coupled , Staphylococcus aureus , ADAM10 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Humans , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/metabolism , Hemolysin Proteins/metabolism , Inflammasomes/metabolism , Bacterial Toxins/metabolism , THP-1 Cells , Receptors, Estrogen/metabolism , Amyloid Precursor Protein Secretases/metabolism , Staphylococcus aureus/drug effects , Membrane Proteins/metabolism , Membrane Proteins/agonists , Caspase 1/metabolism , Adenosine Triphosphate/metabolism , Macrophages/immunology , Macrophages/drug effects , Macrophages/metabolism , Macrophages/microbiology , Dipeptides , Hydroxamic Acids
3.
Immun Inflamm Dis ; 12(6): e1317, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38869352

ABSTRACT

BACKGROUND: Numerous studies have demonstrated that Absent in Melanoma 2 (AIM2) is upregulated in aortic plaques, especially in Vascular Smooth Muscle Cells in Coronary Artery Disease (CAD), and is related to inflammasome-induced inflammation. However, the underlying mechanism of this phenomenon and the role of AIM2 in atherosclerosis remained unclear. METHODS: This study enrolled 133 CAD patients and 123 controls. We isolated Peripheral Blood Leukocytes (PBLs) and the mRNA expression of AIM2 inflammasome and its downstream genes (ASC, Caspase-1, IL-1ß, and IL-18) were detected by real-time quantitative PCR (qPCR). We assessed correlations between AIM2 expressions and clinical characteristics by multiple linear regression and spearman's correlation. The THP-1 cells cultured in poly(dA:dT), A151, interferon-gamma (IFN-γ), AG490, or JC2-11. And then the mRNA and protein levels of AIM2, ASC, Caspase-1, IL-1ß, IL-18, GSDMD, and STAT1 were analyzed by qPCR and Western blot analysis, respectively. The migration and adhesive capacity of THP-1 cells was assessed using an inverted microscope and an inverted fluorescence microscope, respectively. RESULTS: In this study, we found that expressions of components of AIM2 inflammasome and its downstream genes (ASC, Caspase-1, IL-1ß, and IL-18), were all increased in PBLs of CAD patients, which indicated the inflammasome activation. AIM2 inflammasome activation further induced pyroptosis, and stimulated migration and adhesion in monocyte cell lines, which was regulated by IFN-γ probably through JAK2/STAT1 pathway. In addition, AIM2 expressions were positively correlated with systemic inflammatory indicators as an independent risk factor for CAD. CONCLUSIONS: In conclusion, increased AIM2 expression, induced by the IFN-γ/JAK2/STAT1 signal, orientates monocytes to inflammatory status or even pyroptosis through AIM2 inflammasome activation, which is involved in the development of CAD.


Subject(s)
Coronary Artery Disease , DNA-Binding Proteins , Inflammasomes , Interferon-gamma , Janus Kinase 2 , Monocytes , Pyroptosis , STAT1 Transcription Factor , Signal Transduction , Humans , STAT1 Transcription Factor/metabolism , Coronary Artery Disease/immunology , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Monocytes/metabolism , Monocytes/immunology , Interferon-gamma/metabolism , Male , Inflammasomes/metabolism , Janus Kinase 2/metabolism , Janus Kinase 2/genetics , Female , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Middle Aged , THP-1 Cells , Aged
4.
Int Immunopharmacol ; 136: 112370, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-38823174

ABSTRACT

Reperfusion after myocardial ischemia would aggravate myocardial structural and functional damage, known as myocardial ischemia-reperfusion (MI/R) injury. Cinnamamide derivatives have been reported to exert cardioprotective effects, and we have previously reported that compound 7 played a role in cardioprotection against MI/R via anti-inflammatory effect. However, exact mechanism underlying such beneficial action of compound 7 is still unclear. The protective effect of compound 7 was determined in H9c2 cells under H2O2 stimulation with or without nigerin (NLRP3 activator). Electrocardiogram, echocardiography, myocardial infarction size, histopathology and serum biochemical assay were performed in MI/R rats. Metabolomics in vivo and mRNA or protein levels of NLRP3, ASC, cleaved caspase-1 and its downstream IL-18 and IL-1ß were detected both in vitro and in vivo. Compound 7 significantly ameliorate H2O2-induced cardiomyocyte damage, which was supported by in vivo data determined by improved left ventricular systolic function and histopathological changes, reduced myocardial infarction area and cellular apoptosis in heart tissue. Cardiac differential metabolites demonstrated that compound 7 indeed altered the cardiac reprogramming of inflammation-related metabolites, which was evidenced by down-regulated cardiac inflammation by compound 7. Additionally, compound 7 alleviated myocardial injury by inhibiting the NLRP3 pathway rather than other members of the inflammasome both in vitro and in vivo, which was further evidenced by CETSA assay. Whereas, nigerin blocked the inhibitory activity of compound 7 against NLRP3. Cinnamamide derivative compound 7 ameliorated MI/R injury by inhibiting inflammation via NLRP3.


Subject(s)
Anti-Inflammatory Agents , Myocardial Reperfusion Injury , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Male , Rats , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Cell Line , Cinnamates/pharmacology , Cinnamates/therapeutic use , Rats, Sprague-Dawley , Hydrogen Peroxide/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Myocytes, Cardiac/metabolism , Myocardial Infarction/drug therapy , Myocardial Infarction/pathology , Apoptosis/drug effects , Inflammasomes/metabolism , Disease Models, Animal
5.
Int Immunopharmacol ; 136: 112346, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-38850785

ABSTRACT

Myocardial infarction (MI) is an event of heart attack due to the formation of plaques in the interior walls of the arteries. This study is conducted to explore the role of ubiquitin-specific peptidase 47 (USP47) in cardiac function and inflammatory immunity. MI mouse models were established, followed by an appraisal of cardiac functions, infarct size, pathological changes, and USP47 and NLRP3 levels. MI cell models were established in HL-1 cells using anoxia. Levels of cardiac function-associated proteins, USP7, interferon regulatory factor 1 (IRF1), platelet factor-4 (CXCL4), pyroptotic factors, and neutrophil extracellular traps (NETs) were determined. The bindings of IRF1 to USP47 and the CXCL4 promoter and the ubiquitination of IRF1 were analyzed. USP47 was upregulated in myocardial tissues of MI mice. USP47 inhibition alleviated cardiac functions, and decreased infarct size, pro-inflammatory cytokines, NETs, NLRP3, and pyroptosis. The ubiquitination and expression levels of IRF1 were increased by silencing USP47, and IRF1 bound to the CXCL4 promoter to promote CXCL4. Overexpression of IRF1 or CXCL4 in vitro and injection of Nigericin in vivo reversed the effect of silencing USP47 on alleviating pyroptosis and cardiac functions. Collectively, USP47 stabilized IRF1 and promoted CXCL4, further promoting pyroptosis, impairing cardiac functions, and aggravating immune inflammation through NLRP3 pathways.


Subject(s)
Inflammasomes , Mice, Inbred C57BL , Myocardial Infarction , NLR Family, Pyrin Domain-Containing 3 Protein , Signal Transduction , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Myocardial Infarction/immunology , Myocardial Infarction/metabolism , Mice , Inflammasomes/metabolism , Male , Pyroptosis , Interferon Regulatory Factor-1/metabolism , Interferon Regulatory Factor-1/genetics , Disease Models, Animal , Cell Line , Extracellular Traps/metabolism , Extracellular Traps/immunology , Ubiquitin-Specific Proteases/metabolism , Ubiquitin-Specific Proteases/genetics , Platelet Factor 4/metabolism , Platelet Factor 4/genetics , Ubiquitination , Humans
6.
Nat Commun ; 15(1): 5199, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38890305

ABSTRACT

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.


Subject(s)
Depression , Endoplasmic Reticulum Stress , Endoplasmic Reticulum , Mice, Inbred C57BL , Microglia , Mitochondria , NLR Family, Pyrin Domain-Containing 3 Protein , Social Defeat , Stress, Psychological , Voltage-Dependent Anion Channel 1 , Animals , Mitochondria/metabolism , Depression/metabolism , Microglia/metabolism , Microglia/pathology , Mice , Male , Endoplasmic Reticulum/metabolism , Stress, Psychological/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Voltage-Dependent Anion Channel 1/metabolism , Voltage-Dependent Anion Channel 1/genetics , Hippocampus/metabolism , Hippocampus/pathology , Adenosine Triphosphate/metabolism , Inflammasomes/metabolism , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Inositol 1,4,5-Trisphosphate Receptors/genetics , Calcium/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , Behavior, Animal , Mitochondria Associated Membranes , HSP70 Heat-Shock Proteins
7.
Int J Med Sci ; 21(8): 1438-1446, 2024.
Article in English | MEDLINE | ID: mdl-38903927

ABSTRACT

Background: Exploring potential biomarkers for predicting clinical outcomes and developing targeted therapies for acute myeloid leukemia (AML) is of utmost importance. This study aimed to investigate the expression pattern of the thioredoxin-interacting protein (TXNIP)/nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) pathway and its role in the prognosis of AML patients. Methods: In this study, we examined the prognostic value of TXNIP/NLRP3 pathway in AML patients using microarray data from Gene Expression Omnibus (GEO) and transcriptome data from the Cancer Genome Atlas (TCGA) to develop a prognostic model and validated the results by quantitative real-time PCR (qRT-PCR) in a validation cohort of 26 AML patients and 18 healthy individuals from Jinan University (JNU) database. Results: Analysis of the GSE13159 database revealed that TXNIP, interleukin 1 beta (IL1B) within the TXNIP/NLRP3 pathway were significantly upregulated and caspase1 (CASP1) was downregulated in AML patients (TXNIP, P = 0.031; IL1B, P = 0.042; CASP1, P = 0.038). Compared to high NLRP3 expression, AML patients with low NLRP3 expression had a longer overall survival (OS) in the GSE12417 dataset (P = 0.004). Moreover, both the training and validation results indicated that lower TXNIP, NLRP3, and IL1B expression were associated with favorable prognosis (GSE12417, P = 0.009; TCGA, P = 0.050; JNU, P = 0.026). According to the receiver operating characteristic curve analysis, this model demonstrated a sensitivity of 84% for predicting three-year survival. These data might provide novel predictors for AML outcome and direction for further investigation of the possibility of using TXNIP/NLRP3/IL1B genes in novel targeted therapies for AML.


Subject(s)
Biomarkers, Tumor , Carrier Proteins , Inflammasomes , Interleukin-1beta , Leukemia, Myeloid, Acute , NLR Family, Pyrin Domain-Containing 3 Protein , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Female , Male , Prognosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Middle Aged , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Inflammasomes/metabolism , Inflammasomes/genetics , Signal Transduction/genetics , Adult , Aged , Gene Expression Regulation, Leukemic , Thioredoxins/genetics , Thioredoxins/metabolism
8.
Int J Biol Sci ; 20(8): 2790-2813, 2024.
Article in English | MEDLINE | ID: mdl-38904007

ABSTRACT

Coenzyme Q0 (CoQ0), a quinone derivative from Antrodia camphorata, has antitumor capabilities. This study investigated the antitumor effect of noncytotoxic CoQ0, which included NLRP3 inflammasome inhibition, anti-EMT/metastasis, and metabolic reprogramming via HIF-1α inhibition, in HNSCC cells under normoxia and hypoxia. CoQ0 suppressed hypoxia-induced ROS-mediated HIF-1α expression in OECM-1 and SAS cells. Under normoxia and hypoxia, the inflammatory NLRP3, ASC/caspase-1, NFκB, and IL-1ß expression was reduced by CoQ0. CoQ0 reduced migration/invasion by enhancing epithelial marker E-cadherin and suppressing mesenchymal markers Twist, N-cadherin, Snail, and MMP-9, and MMP-2 expression. CoQ0 inhibited glucose uptake, lactate accumulation, GLUT1 levels, and HIF-1α-target gene (HK-2, PFK-1, and LDH-A) expressions that are involved in aerobic glycolysis. Notably, CoQ0 reduced ECAR as well as glycolysis, glycolytic capability, and glycolytic reserve and enhanced OCR, basal respiration, ATP generation, maximal respiration, and spare capacity in OECM-1 cells. Metabolomic analysis using LC-ESI-MS showed that CoQ0 treatment decreased the levels of glycolytic intermediates, including lactate, 2/3-phosphoglycerate, fructose 1,6-bisphosphate, and phosphoenolpyruvate, and increased the levels of TCA cycle metabolites, including citrate, isocitrate, and succinate. HIF-1α silencing reversed CoQ0-mediated anti-metastasis (N-Cadherin, Snail, and MMP-9) and metabolic reprogramming (GLUT1, HK-2, and PKM-2) under hypoxia. CoQ0 prevents cancer stem-like characteristics (upregulated CD24 expression and downregulated CD44, ALDH1, and OCT4) under normoxia and/or hypoxia. Further, in IL-6-treated SG cells, CoQ0 attenuated fibrosis by inhibiting TGF-ß and Collagen I expression and suppressed EMT by downregulating Slug and upregulating E-cadherin expression. Interesting, CoQ0 inhibited the growth of OECM-1 tumors in xenografted mice. Our results advocate CoQ0 for the therapeutic application against HNSCC.


Subject(s)
Epithelial-Mesenchymal Transition , Hypoxia-Inducible Factor 1, alpha Subunit , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Squamous Cell Carcinoma of Head and Neck , Ubiquinone , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Cell Line, Tumor , Epithelial-Mesenchymal Transition/drug effects , Ubiquinone/analogs & derivatives , Ubiquinone/pharmacology , Animals , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/drug therapy , Mice , Inflammasomes/metabolism , Warburg Effect, Oncologic/drug effects , Mice, Nude , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/drug therapy
9.
Cells ; 13(11)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38891092

ABSTRACT

Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol use on the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) remain unexplored. Here, we show that short-term feeding of a metabolic-dysfunction-associated steatohepatitis (MASH) diet plus daily acute alcohol binges for three days induce liver injury and activation of the NLRP3 inflammasome. We identify that a MASH diet plus acute alcohol binges promote liver inflammation via increased infiltration of monocyte-derived macrophages, neutrophil recruitment, and NET release in the liver. Our results suggest that both monocyte-derived macrophages and neutrophils are activated via NLRP3, while the administration of MCC950, an NLRP3 inhibitor, dampens these effects.In this study, we reveal important intercellular communication between hepatocytes and neutrophils. We discover that the MASH diet plus alcohol induces IL-1ß via NLRP3 activation and that IL-1ß acts on hepatocytes and promotes the production of CXCL1 and LCN2. In turn, the increase in these neutrophils recruits chemokines and causes further infiltration and activation of neutrophils in the liver. In vivo administration of the NLRP3 inhibitor, MCC950, improves the early phase of MetALD by preventing liver damage, steatosis, inflammation, and immune cells recruitment.


Subject(s)
Interleukin-1beta , Liver , NLR Family, Pyrin Domain-Containing 3 Protein , Neutrophil Infiltration , Neutrophils , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Animals , Liver/pathology , Liver/metabolism , Liver/drug effects , Interleukin-1beta/metabolism , Neutrophil Infiltration/drug effects , Male , Neutrophils/metabolism , Neutrophils/drug effects , Mice, Inbred C57BL , Mice , Inflammasomes/metabolism , Binge Drinking/pathology , Binge Drinking/complications , Hepatocytes/metabolism , Hepatocytes/drug effects , Hepatocytes/pathology , Cell Communication/drug effects , Sulfones/pharmacology , Sulfonamides/pharmacology , Macrophages/metabolism , Macrophages/drug effects , Furans/pharmacology , Humans , Indenes/pharmacology , Diet , Signal Transduction/drug effects , Extracellular Traps/metabolism , Extracellular Traps/drug effects , Fatty Liver/pathology , Fatty Liver/metabolism , Sulfoxides/pharmacology
10.
Int J Mol Sci ; 25(11)2024 May 29.
Article in English | MEDLINE | ID: mdl-38892148

ABSTRACT

The primary emphasis of photoimmunology is the impact of nonionizing radiation on the immune system. With the development of terahertz (THz) and sub-terahertz (sub-THz) technology, the biological effects of this emerging nonionizing radiation, particularly its influence on immune function, remain insufficiently explored but are progressively attracting attention. Here, we demonstrated that 0.1 sub-THz radiation can modulate the immune system and alleviate symptoms of arthritis in collagen-induced arthritis (CIA) mice through a nonthermal manner. The application of 0.1 sub-THz irradiation led to a decrease in proinflammatory factors within the joints and serum, reducing the levels of blood immune cells and the quantity of splenic CD4+ T cells. Notably, 0.1 sub-THz irradiation restored depleted Treg cells in CIA mice and re-established the Th17/Treg equilibrium. These findings suggested that sub-THz irradiation plays a crucial role in systemic immunoregulation. Further exploration of its immune modulation mechanisms revealed the anti-inflammatory properties of 0.1 sub-THz on LPS-stimulated skin keratinocytes. Through the reduction in NF-κB signaling and NLRP3 inflammasome activation, 0.1 sub-THz irradiation effectively decreased the production of inflammatory factors and immune-active substances, including IL-1ß and PGE2, in HaCaT cells. Consequently, 0.1 sub-THz irradiation mitigated the inflammatory response and contributed to the maintenance of immune tolerance in CIA mice. This research provided significant new evidence supporting the systemic impacts of 0.1 sub-THz radiation, particularly on the immune system. It also enhanced the field of photoimmunology and offered valuable insights into the potential biomedical applications of 0.1 sub-THz radiation for treating autoimmune diseases.


Subject(s)
Arthritis, Experimental , Animals , Arthritis, Experimental/immunology , Arthritis, Experimental/radiotherapy , Arthritis, Experimental/pathology , Mice , Terahertz Radiation , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Male , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Inflammasomes/metabolism , Inflammasomes/immunology , NF-kappa B/metabolism , Mice, Inbred DBA , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/radiation effects , Humans , Signal Transduction/radiation effects , Keratinocytes/radiation effects , Keratinocytes/immunology , Keratinocytes/metabolism
11.
Int J Mol Sci ; 25(11)2024 May 31.
Article in English | MEDLINE | ID: mdl-38892264

ABSTRACT

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy.


Subject(s)
Anticonvulsants , Drug Discovery , Epilepsy , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Humans , Animals , Drug Discovery/methods , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Inflammasomes/metabolism , Inflammasomes/antagonists & inhibitors , Drug Development
12.
Invest Ophthalmol Vis Sci ; 65(6): 13, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38848078

ABSTRACT

Purpose: Fungal keratitis (FK) is an invasive corneal infection associated with significant risk to vision. Although the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway has been recognized for its role in defending against viral infections, its involvement in FK still remains largely unclear. This study sought to elucidate the contribution of the cGAS/STING signaling pathway to the pathogenesis of FK. Methods: The expression of cGAS/STING signaling components was assessed in a murine model of Candida albicans keratitis through RNA sequencing, western blot analysis, immunofluorescence staining, and real-time PCR. Both genetic (utilizing Sting1gt/gt mice) and pharmacological (using C176) interventions were employed to inhibit STING activity, allowing for the evaluation of resultant pathogenic alterations in FK using slit-lamp examination, clinical scoring, hematoxylin and eosin (H&E) staining, fungal culture, and RNA sequencing. Subconjunctival administration of the NOD-like receptor protein 3 (NLRP3) inflammasome inhibitor MCC950 was performed to evaluate FK manifestations following STING activity blockade. Furthermore, the impact of the STING agonist diABZI on FK progression was investigated. Results: Compared to uninfected corneas, those infected with C. albicans exhibited increased expression of cGAS/STING signaling components, as well as its elevated activity. Inhibiting cGAS/STING signaling exacerbated the advancement of FK, as evidenced by elevated clinical scores, augmented fungal load, and heightened inflammatory response, including NLRP3 inflammasome activation and pyroptosis. Pharmacological inhibition of the NLRP3 inflammasome effectively mitigated the exacerbated FK by suppressing STING activity. Conversely, pre-activation of STING exacerbated FK progression compared to the PBS control, characterized by increased fungal burden and reinforced inflammatory infiltration. Conclusions: This study demonstrates the essential role of the cGAS/STING signaling pathway in FK pathogenesis and highlights the necessity of its proper activation for the host against FK.


Subject(s)
Candida albicans , Candidiasis , Disease Models, Animal , Eye Infections, Fungal , Membrane Proteins , Nucleotidyltransferases , Signal Transduction , Animals , Membrane Proteins/metabolism , Membrane Proteins/genetics , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/genetics , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/metabolism , Mice , Candida albicans/physiology , Candidiasis/microbiology , Candidiasis/metabolism , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction , Keratitis/microbiology , Keratitis/metabolism , Blotting, Western , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Female , Corneal Ulcer/microbiology , Corneal Ulcer/metabolism , Inflammasomes/metabolism
13.
Proc Natl Acad Sci U S A ; 121(25): e2316551121, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38865260

ABSTRACT

The NLRP3 inflammasome, a pivotal component of innate immunity, has been implicated in various inflammatory disorders. The ubiquitin-editing enzyme A20 is well known to regulate inflammation and maintain homeostasis. However, the precise molecular mechanisms by which A20 modulates the NLRP3 inflammasome remain poorly understood. Here, our study revealed that macrophages deficient in A20 exhibit increased protein abundance and elevated mRNA level of NIMA-related kinase 7 (NEK7). Importantly, A20 directly binds with NEK7, mediating its K48-linked ubiquitination, thereby targeting NEK7 for proteasomal degradation. Our results demonstrate that A20 enhances the ubiquitination of NEK7 at K189 and K293 ubiquitinated sites, with K189 playing a crucial role in the binding of NEK7 to A20, albeit not significantly influencing the interaction between NEK7 and NLRP3. Furthermore, A20 disrupts the association of NEK7 with the NLRP3 complex, potentially through the OTU domain and/or synergistic effect of ZnF4 and ZnF7 motifs. Significantly, NEK7 deletion markedly attenuates the activation of the NLRP3 inflammasome in A20-deficient conditions, both in vitro and in vivo. This study uncovers a mechanism by which A20 inhibits the NLRP3 inflammasome.


Subject(s)
Inflammasomes , NIMA-Related Kinases , NLR Family, Pyrin Domain-Containing 3 Protein , Tumor Necrosis Factor alpha-Induced Protein 3 , Ubiquitination , NIMA-Related Kinases/metabolism , NIMA-Related Kinases/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Inflammasomes/metabolism , Animals , Mice , Tumor Necrosis Factor alpha-Induced Protein 3/metabolism , Tumor Necrosis Factor alpha-Induced Protein 3/genetics , Humans , Macrophages/metabolism , Macrophages/immunology , HEK293 Cells , Mice, Knockout , Protein Binding
14.
Arthritis Res Ther ; 26(1): 119, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38863059

ABSTRACT

OBJECTIVE: In gout, monosodium urate crystals are taken up by macrophages, triggering the activation of the NLRP3 inflammasome and the maturation of IL-1ß. This study aimed to investigate the role of integrin CD11b in inflammasome activation in macrophages stimulated by MSU. METHODS: BMDM from WT and CD11b KO mice were stimulated in vitro with MSU crystals. Cellular supernatants were collected to assess the expression of the inflammatory cytokines by enzyme-linked immunosorbent assay and western blot methods. The role of integrin CD11b in MSU-induced gouty arthritis in vivo was investigated by intra-articular injection of MSU crystals. Real-time extracellular acidification rate and oxygen consumption rate of BMDMs were measured by Seahorse Extracellular Flux Analyzer. RESULTS: We demonstrate that CD11b-deficient mice developed exacerbated gouty arthritis with increased recruitment of leukocytes in the joint and higher IL-1ß levels in the sera. In macrophages, genetic deletion of CD11b induced a shift of macrophage metabolism from oxidative phosphorylation to glycolysis, thus decreasing the overall generation of intracellular ATP. Upon MSU stimulation, CD11b-deficient macrophages showed an exacerbated secretion of IL-1ß. Treating wild-type macrophages with a CD11b agonist, LA1, inhibited MSU-induced release of IL-1ß in vitro and attenuated the severity of experimental gouty arthritis. Importantly, LA1, was also effective in human cells as it inhibited MSU-induced release of IL-1ß by peripheral blood mononuclear cells from healthy donors. CONCLUSION: Our data identified the CD11b integrin as a principal cell membrane receptor that modulates NLRP3 inflammasome activation by MSU crystal in macrophages, which could be a potential therapeutic target to treat gouty arthritis in human patients.


Subject(s)
Arthritis, Gouty , CD11b Antigen , Inflammasomes , Macrophages , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Uric Acid , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Macrophages/metabolism , CD11b Antigen/metabolism , Inflammasomes/metabolism , Arthritis, Gouty/chemically induced , Arthritis, Gouty/metabolism , Mice , Male
15.
Eur J Pharmacol ; 976: 176693, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38834095

ABSTRACT

ß-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of ß-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and ß-arrestin2-/- mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the ß-arrestin2-/- CMS group, these results of the ß-arrestin2-/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out ß-arrestin2. Mass spectrometry implying that FLX promoted the binding of ß-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to ß-arrestin2. We further found that the lack of ß-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, ß-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT2BR-ß-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.


Subject(s)
Antidepressive Agents , Astrocytes , Depression , Disease Models, Animal , Fluoxetine , Pyroptosis , Stress, Psychological , beta-Arrestin 2 , Animals , Fluoxetine/pharmacology , Fluoxetine/therapeutic use , Pyroptosis/drug effects , beta-Arrestin 2/metabolism , Mice , Depression/drug therapy , Depression/metabolism , Stress, Psychological/drug therapy , Stress, Psychological/metabolism , Male , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Astrocytes/drug effects , Astrocytes/metabolism , Mice, Inbred C57BL , Hippocampus/drug effects , Hippocampus/metabolism , Mice, Knockout , Behavior, Animal/drug effects , Inflammasomes/metabolism , Chronic Disease
16.
Cell Death Dis ; 15(6): 407, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38862500

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent of acute bacterial skin and skin-structure infections (ABSSSI), one of the major challenges to the health system worldwide. Although the use of antibiotics as the first line of intervention for MRSA-infected wounds is recommended, important side effects could occur, including cytotoxicity or immune dysregulation, thus affecting the repair process. Here, we show that the oxazolidinone antibiotic linezolid (LZD) impairs wound healing by aberrantly increasing interleukin 1 ß (IL-1ß) production in keratinocytes. Mechanistically, LZD triggers a reactive oxygen species (ROS)-independent mitochondrial damage that culminates in increased tethering between the endoplasmic reticulum (ER) and mitochondria, which in turn activates the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex by promoting its assembly to the mitochondrial surface. Downregulation of ER-mitochondria contact formation is sufficient to inhibit the LZD-driven NLRP3 inflammasome activation and IL-1ß production, restoring wound closure. These results identify the ER-mitochondria association as a key factor for NLRP3 activation and reveal a new mechanism in the regulation of the wound healing process that might be clinically relevant.


Subject(s)
Endoplasmic Reticulum , Inflammasomes , Interleukin-1beta , Mitochondria , NLR Family, Pyrin Domain-Containing 3 Protein , Wound Healing , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Mitochondria/metabolism , Mitochondria/drug effects , Wound Healing/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/drug effects , Humans , Animals , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Reactive Oxygen Species/metabolism , Mice , Keratinocytes/metabolism , Keratinocytes/drug effects , Mice, Inbred C57BL
17.
Expert Opin Ther Targets ; 28(5): 401-418, 2024 May.
Article in English | MEDLINE | ID: mdl-38871633

ABSTRACT

INTRODUCTION: Inflammasome complexes, especially NLRP3, have gained great attention as a potential therapeutic target in mood disorders. NLRP3 triggers a caspase 1-dependent release of the inflammatory cytokines IL-1ß and IL-18, and seems to interact with purinergic and kynurenine pathways, all of which are implicated in mood disorders development and progression. AREAS COVERED: Emerging evidence supports NLRP3 inflammasome as a promising pharmacological target for mood disorders. We discussed the available evidence from animal models and human studies and provided a reflection on drawbacks and perspectives for this novel target. EXPERT OPINION: Several studies have supported the involvement of NLRP3 inflammasome in MDD. However, most of the evidence comes from animal models. The role of NLRP3 inflammasome in BD as well as its anti-manic properties is not very clear and requires further exploration. There is evidence of anti-manic effects of P2×R7 antagonists associated with reduction in the brain levels of IL-1ß and TNF-α in a murine model of mania. The involvement of other NLRP3 inflammasome expressing cells besides microglia, like astrocytes, and of other inflammasome complexes in mood disorders also deserves further investigation. Preclinical and clinical characterization of NLRP3 and other inflammasomes in mood disorders is needed before considering translational approaches, including clinical trials.


Subject(s)
Disease Models, Animal , Inflammasomes , Molecular Targeted Therapy , Mood Disorders , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Mood Disorders/drug therapy , Mood Disorders/physiopathology , Mice , Bipolar Disorder/drug therapy , Bipolar Disorder/physiopathology , Purinergic P2X Receptor Antagonists/pharmacology , Purinergic P2X Receptor Antagonists/administration & dosage , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/physiopathology
18.
Nat Commun ; 15(1): 5170, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38886341

ABSTRACT

The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.


Subject(s)
CARD Signaling Adaptor Proteins , Colorectal Neoplasms , Immunologic Surveillance , Inflammasomes , Reactive Oxygen Species , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Inflammasomes/metabolism , Animals , Humans , Mice , CARD Signaling Adaptor Proteins/metabolism , CARD Signaling Adaptor Proteins/genetics , Reactive Oxygen Species/metabolism , Disease Progression , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NADPH Oxidases/metabolism , NADPH Oxidases/genetics , Mice, Knockout , Interleukin-18/metabolism , Mice, Inbred C57BL , Male , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Female , Phosphorylation , Cell Line, Tumor
19.
Biomed Pharmacother ; 176: 116856, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38852510

ABSTRACT

Fibromyalgia is characterised by widespread chronic pain and is often accompanied by comorbidities such as sleep disorders, anxiety, and depression. Because it is often accompanied by many adverse symptoms and lack of effective treatment, it is important to search for the pathogenesis and treatment of fibromyalgia. Astaxanthin, a carotenoid pigment known for its anti-inflammatory and antioxidant properties, has demonstrated effective analgesic effects in neuropathic pain. However, its impact on fibromyalgia remains unclear. Therefore, in this study, we constructed a mouse model of fibromyalgia and investigated the effect of astaxanthin on chronic pain and associated symptoms through multiple intragastrical injections. We conducted behavioural assessments to detect pain and depression-like states in mice, recorded electroencephalograms to monitor sleep stages, examined c-Fos activation in the anterior cingulate cortex, measured activation of spinal glial cells, and assessed levels of inflammatory factors in the brain and spinal cord, including interleukin (IL)-1ß, IL-6, and tumour necrosis factor- α(TNF-α).Additionally, we analysed the expression levels of IL-6, IL-10, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), Apoptosis-associated speck-like protein containing CARD, and Caspase-1 proteins. The findings revealed that astaxanthin significantly ameliorated mechanical and thermal pain in mice with fibromyalgia and mitigated sleep disorders and depressive-like symptoms induced by pain. A potential mechanism underlying these effects is the anti-inflammatory action of astaxanthin, likely mediated through the inhibition of the NLRP3 inflammasome, which could be one of the pathways through which astaxanthin alleviates fibromyalgia. In conclusion, our study suggests that astaxanthin holds promise as a potential analgesic medication for managing fibromyalgia and its associated symptoms.


Subject(s)
Depression , Fibromyalgia , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Xanthophylls , Animals , Xanthophylls/pharmacology , Fibromyalgia/drug therapy , Fibromyalgia/complications , Fibromyalgia/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Inflammasomes/metabolism , Inflammasomes/antagonists & inhibitors , Depression/drug therapy , Depression/metabolism , Mice , Male , Mice, Inbred C57BL , Disease Models, Animal , Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Chronic Pain/drug therapy , Chronic Pain/metabolism , Cytokines/metabolism , Spinal Cord/drug effects , Spinal Cord/metabolism , Behavior, Animal/drug effects
20.
Redox Biol ; 74: 103238, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38870780

ABSTRACT

Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP]5+ (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1ß, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, Gpx1, GRP78, and Chop to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, Nlrp3, and Caspase1 in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface.


Subject(s)
Hypothyroidism , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Oxidative Stress , Animals , Pregnancy , Female , Rats , Hypothyroidism/drug therapy , Hypothyroidism/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxidative Stress/drug effects , Inflammasomes/metabolism , Disease Models, Animal , Placenta/metabolism , Placenta/drug effects , Placentation/drug effects , Antioxidants/pharmacology , Endoplasmic Reticulum Stress/drug effects , Fetal Development/drug effects , Manganese , Metalloporphyrins/pharmacology , Endoplasmic Reticulum Chaperone BiP
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