ABSTRACT
The Hippo signaling pathway plays a pivotal role in regulating cell growth and organ size. Its regulatory effects on hepatocellular carcinoma (HCC) encompass diverse aspects, including cell proliferation, invasion and metastasis, tumor drug resistance, metabolic reprogramming, immunomodulatory effects and autophagy. Yesassociated protein 1 (YAP1), a potent transcriptional coactivator and a major downstream target tightly controlled by the Hippo pathway, is influenced by various molecules and pathways. The expression of YAP1 in different cell types within the liver tumor microenvironment exerts varying effects on tumor outcomes, warranting careful consideration. Therefore, research on YAP1targeted therapies merits attention. This review discusses the composition and regulation mechanism of the Hippo/YAP1 signaling pathway and its relationship with HCC, offering insights for future research and cancer prevention strategies.
Subject(s)
Adaptor Proteins, Signal Transducing , Carcinoma, Hepatocellular , Hippo Signaling Pathway , Liver Neoplasms , Protein Serine-Threonine Kinases , Signal Transduction , Transcription Factors , YAP-Signaling Proteins , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Transcription Factors/metabolism , Signal Transduction/drug effects , YAP-Signaling Proteins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Protein Serine-Threonine Kinases/metabolism , Tumor Microenvironment/drug effects , Molecular Targeted Therapy/methods , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Cell Proliferation/drug effects , AnimalsABSTRACT
Previous studies have demonstrated that gut microbiota dysbiosis promotes the development of mastitis. The interaction of the vagus nerve and gut microbiota endows host homeostasis and regulates disease development, but whether the vagus nerve participates in the pathogenesis of mastitis is unclear. Here, vagotomized mice exhibit disruption of the blood-milk barrier and mammary gland inflammation. Notably, mastitis and barrier damage caused by vagotomy are dependent on the gut microbiota, as evidenced by antibiotic treatment and fecal microbiota transplantation. Vagotomy significantly alters the gut microbial composition and tryptophan metabolism and reduces the 5-hydroxyindole acetic acid (5-HIAA) level. Supplementation with 5-HIAA alleviates vagotomy-induced mastitis, which is associated with the activation of the aryl hydrocarbon receptor (AhR) and subsequent inhibition of the NF-κB pathway. Collectively, our findings indicate the important role of the vagus-mediated gut-mammary axis in the pathogenesis of mastitis and imply a potential strategy for the treatment of mastitis by targeting the vagus-gut microbiota interaction.
ABSTRACT
Tick-borne Encephalitis (TBE) is a zoonotic disease caused by the Tick-borne Encephalitis virus (TBEV), which affects the central nervous system of both humans and animals. Currently, there is no specific therapy for patients with TBE, with symptomatic treatment being the primary approach. In this study, the effects of minocycline (MIN), which is a kind of tetracycline antibiotic, on TBEV propagation and cellular protection in TBEV-infected cell lines were evaluated. Indirect immunofluorescence, virus titers, and RT-qPCR results showed that 48 h post-treatment with MIN, TBEV replication was significantly inhibited in a dose-dependent manner. In addition, the inhibitory effect of MIN on different TBEV multiplicities of infection (MOIs) in Vero cells was studied. Furthermore, the transcriptomic analysis and RT-qPCR results indicate that after incubation with MIN, the levels of TBEV and CALML4 were decreased, whereas the levels of calcium channel receptors, such as RYR2 and SNAP25, were significantly increased. MIN also regulated MAPK-ERK-related factors, including FGF2, PDGFRA, PLCB2, and p-ERK, and inhibited inflammatory responses. These data indicate that administering MIN to TBEV-infected cells can reduce the TBEV level, regulate calcium signaling pathway-associated proteins, and inhibit the MAPK-ERK signaling pathway and inflammatory responses. This research offers innovative strategies for the advancement of anti-TBEV therapy.
Subject(s)
Encephalitis Viruses, Tick-Borne , Minocycline , Virus Replication , Animals , Encephalitis Viruses, Tick-Borne/drug effects , Encephalitis Viruses, Tick-Borne/physiology , Minocycline/pharmacology , Chlorocebus aethiops , Vero Cells , Virus Replication/drug effects , Humans , Antiviral Agents/pharmacology , Encephalitis, Tick-Borne/virology , Encephalitis, Tick-Borne/drug therapy , Cell Line , Signal Transduction/drug effectsABSTRACT
Research indicates that COVID-19 has had adverse effects on the mental health of adolescents, exacerbating their negative psychological states. The purpose of this study is to investigate the impact of Physical Literacy (PL) on Negative Mental State caused by COVID-19 (NMSC) and identify potential factors related to NMSC and PL in Chinese adolescents. This cross-sectional study involved a total of 729 Chinese high school students with an average age of 16.2 ± 1.1 years. Participants' demographic data, PL data, and NMSC data were collected. PL and NMSC were measured using the self-reported Portuguese Physical Literacy Assessment Questionnaire (PPLA-Q), the Stress and Anxiety to Viral Epidemics-6 (SAVE-6), and the Fear of COVID-19 Scale (FCV-19). Adolescents in the current study demonstrated higher levels of NMSC and lower PL, with average scores of 3.45 and 2.26, respectively (on a scale of 5). Through multiple linear regression analysis, Motivation (MO), Confidence (CO), Emotional Regulation (ER), and Physical Regulation (PR) were identified as factors influencing NMSC in adolescents. The study findings contribute to providing guidance for actions aimed at alleviating NMSC among adolescents.
Subject(s)
COVID-19 , Resilience, Psychological , Adolescent , Female , Humans , Male , China/epidemiology , COVID-19/psychology , COVID-19/epidemiology , COVID-19/prevention & control , Cross-Sectional Studies , East Asian People , Health Literacy/statistics & numerical data , Mental Health , Surveys and QuestionnairesABSTRACT
Premature ovarian failure (POF) is a complex and heterogeneous disease that causes infertility and subfertility. However, the molecular mechanism of POF has not been fully elucidated. Here, we show that the loss of adenylyl cyclase III (Adcy3) in female mice leads to POF and a shortened reproductive lifespan. We found that Adcy3 is abundantly expressed in mouse oocytes. Adcy3 knockout mice exhibited the excessive activation of primordial follicles, progressive follicle loss, follicular atresia, and ultimately POF. Mechanistically, we found that mitochondrial oxidative stress in oocytes significantly increased with age in Adcy3-deficient mice and was accompanied by oocyte apoptosis and defective folliculogenesis. In contrast, compared with wild-type female mice, humanized ADCY3 knock-in female mice exhibited improved fertility with age. Collectively, these results reveal that the previously unrecognized Adcy3 signaling pathway is tightly linked to female ovarian aging, providing potential pharmaceutical targets for preventing and treating POF.
ABSTRACT
Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies.
Subject(s)
High-Temperature Requirement A Serine Peptidase 1 , High-Temperature Requirement A Serine Peptidase 1/metabolism , High-Temperature Requirement A Serine Peptidase 1/genetics , Animals , Humans , Mice , Protein Conformation , Protein Multimerization , HEK293 Cells , Brain/metabolism , Brain/pathology , Mutation , Loss of Function MutationABSTRACT
A novel sheet-like tin-based metal-organic framework exhibited a specific capacity for lithium storage as high as 1033.3 mAh g-1 at 200 mA g-1 with excellent cycling stability. This framework, due to its unique porous structure and multiple lithium storage sites, could better cope with challenges occurring during lithium insertion/extraction than could traditional tin materials.
ABSTRACT
Structural variations (SVs) are a major source of domestication and improvement traits. We present the first duck pan-genome constructed using five genome assemblies capturing â¼40.98 Mb new sequences. This pan-genome together with high-depth sequencing data (â¼46.5×) identified 101,041 SVs, of which substantial proportions were derived from transposable element (TE) activity. Many TE-derived SVs anchoring in a gene body or regulatory region are linked to duck's domestication and improvement. By combining quantitative genetics with molecular experiments, we, for the first time, unraveled a 6945 bp Gypsy insertion as a functional mutation of the major gene IGF2BP1 associated with duck bodyweight. This Gypsy insertion, to our knowledge, explains the largest effect on bodyweight among avian species (27.61% of phenotypic variation). In addition, we also examined another 6634 bp Gypsy insertion in MITF intron, which triggers a novel transcript of MITF, thereby contributing to the development of white plumage. Our findings highlight the importance of using a pan-genome as a reference in genomics studies and illuminate the impact of transposons in trait formation and livestock breeding.
ABSTRACT
BACKGROUND: To explore the anti-tumor and anti-virus key active ingredients of Sini Decoction Plus Ginseng Soup (SNRS) and their mechanisms. METHODS: The main ingredients of SNRS were analyzed by network pharmacology, and quercetin was identified as the key active ingredient. Then, we obtained the targets of quercetin by using Drugbank, PharmMapper, and SwissTargetPrediction databases. Then, the targets of HBV-related hepatocellular carcinoma (HBV-related HCC) were obtained by using Genecards database. In addition, using the gene expression profiles of HBV-related HCC patients in GEO database and the genes with the greatest survival difference in GEPIA 2 database identified the potential targets of quercetin. In addition, the mechanism of potential genes was studied through GO, KEGG analysis, and PPI network. Using AUC and survival analysis to evaluate the diagnostic and prognostic value of cyclin-dependent kinase 1 (CDK1) and CCNB1. Finally, the effects of quercetin on proliferation of Hep3B and HepG2215 cells and the level of CDK1 and CCNB1 were verified in vitro. ELISA was used to measure the expression levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) after the intervention by quercetin for 24 h and 48 h in HepG2215 cell. RESULTS: The first 10 key ingredients of SNRS were identified, and quercetin was the most key ingredient. The 101 potential quercetin targets were identified for the treatment of HBV-related HCC. GO and KEGG showed that 101 potential target enrichment in cancer and cell cycle regulation. By Venn analysis, CDK1 and CCNB1 were intersection targets, which could be used as potential targets for the action of quercetin on HBV-related HCC. Moreover, the expression of CDK1 and CCNB1 was highly expressed in the high-risk group, while the OS rate was low. The 1-year, 3-year and 5-year area under the curve (AUC) curves of CDK1 and CCNB1 were 0.724, 0.676, 0.622 and 0.745, 0.678, 0.634, respectively. Moreover, experimental results also showed that quercetin inhibited cell proliferation and reduced CDK1 expression in Hep3B and HepG2215 cells. The expressions of HBsAg and HBeAg in HepG2215 cell supernatant and cell gradually decreased with the increase of intervention time of quercetin and CDK1 inhibitor. CONCLUSIONS: Quercetin is a key ingredient of anti-HBV-related HCC activity and inhibits HBV replication in SNRS by inhibiting CDK1.
Subject(s)
CDC2 Protein Kinase , Drugs, Chinese Herbal , Liver Neoplasms , Panax , Quercetin , Virus Replication , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , CDC2 Protein Kinase/drug effects , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin B1/drug effects , Cyclin B1/metabolism , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Hep G2 Cells , Hepatitis B virus/drug effects , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/virology , Panax/chemistry , Quercetin/pharmacology , Virus Replication/drug effectsABSTRACT
Migrasomes, enriched with signaling molecules such as chemokines, cytokines and angiogenic factors, play a pivotal role in the spatially defined delivery of these molecules, influencing critical physiological processes including organ morphogenesis and angiogenesis. The mechanism governing the accumulation of signaling molecules in migrasomes has been elusive. In this study, we show that secretory proteins, including signaling proteins, are transported into migrasomes by secretory carriers via both the constitutive and regulated secretion pathways. During cell migration, a substantial portion of these carriers is redirected to the rear of the cell and actively transported into migrasomes, driven by the actin-dependent motor protein Myosin-5a. Once at the migrasomes, these carriers fuse with the migrasome membrane through SNARE-mediated mechanisms. Inhibiting migrasome formation significantly reduces secretion, suggesting migrasomes as a principal secretion route in migrating cells. Our findings reveal a specialized, highly localized secretion paradigm in migrating cells, conceptually paralleling the targeted neurotransmitter release observed in neuronal systems.
Subject(s)
Cell Movement , Humans , Animals , Signal Transduction , Protein Transport , Myosin Type V/metabolism , SNARE Proteins/metabolism , MiceABSTRACT
The branch number is a crucial factor that influences density tolerance and is closely associated with the yield of soybean. However, its molecular regulation mechanisms remain poorly understood. This study cloned a candidate gene GmSPL9d for regulating the soybean branch number based on the rice OsSPL14 homologous gene. Meanwhile, the genetic diversity of the GmSPL9d was analyzed using 3599 resequencing data and identified 55 SNP/InDel variations, which were categorized into seven haplotypes. Evolutionary analysis classified these haplotypes into two groups: GmSPL9d H-I and GmSPL9d H-II. Soybean varieties carrying the GmSPL9d H-II haplotype exhibited a significantly lower branch number compared with those carrying the GmSPL9d H-I haplotype. Association analysis between the variation sites and branch number phenotypes revealed a significant correlation between the promoter variations and the branch number. Promoter activity assays demonstrated that the GmSPL9d H-II promoter displayed significantly higher activity than the GmSPL9d H-I promoter. Transgenic experiments confirmed that the plants that carried the GmSPL9d H-II promoter exhibited a significantly lower branch number compared with those that carried the GmSPL9d H-I promoter. These findings indicate that the variation in the GmSPL9d promoter affected its transcription level, leading to differences in the soybean branch number. This study provides valuable molecular targets for improving the soybean plant structure.
Subject(s)
Gene Expression Regulation, Plant , Glycine max , Haplotypes , Plant Proteins , Promoter Regions, Genetic , Glycine max/genetics , Plant Proteins/genetics , Plant Proteins/metabolism , Polymorphism, Single Nucleotide , Plants, Genetically Modified/genetics , Genetic Variation , PhenotypeABSTRACT
The development of distinct dendritic cell (DC) subsets, namely, plasmacytoid DCs (pDCs) and conventional DC subsets (cDC1s and cDC2s), is controlled by specific transcription factors. IRF8 is essential for the fate specification of cDC1s. However, how the expression of Irf8 is regulated is not fully understood. In this study, we identified TRIM33 as a critical regulator of DC differentiation and maintenance. TRIM33 deletion in Trim33fl/fl Cre-ERT2 mice significantly impaired DC differentiation from hematopoietic progenitors at different developmental stages. TRIM33 deficiency downregulated the expression of multiple genes associated with DC differentiation in these progenitors. TRIM33 promoted the transcription of Irf8 to facilitate the differentiation of cDC1s by maintaining adequate CDK9 and Ser2 phosphorylated RNA polymerase II (S2 Pol II) levels at Irf8 gene sites. Moreover, TRIM33 prevented the apoptosis of DCs and progenitors by directly suppressing the PU.1-mediated transcription of Bcl2l11, thereby maintaining DC homeostasis. Taken together, our findings identified TRIM33 as a novel and crucial regulator of DC differentiation and maintenance through the modulation of Irf8 and Bcl2l11 expression. The finding that TRIM33 functions as a critical regulator of both DC differentiation and survival provides potential benefits for devising DC-based immune interventions and therapies.
Subject(s)
Bcl-2-Like Protein 11 , Cell Differentiation , Dendritic Cells , Homeostasis , Interferon Regulatory Factors , Mice, Inbred C57BL , Transcription Factors , Animals , Interferon Regulatory Factors/metabolism , Interferon Regulatory Factors/genetics , Dendritic Cells/metabolism , Dendritic Cells/cytology , Mice , Transcription Factors/metabolism , Transcription Factors/genetics , Bcl-2-Like Protein 11/metabolism , Bcl-2-Like Protein 11/genetics , Transcription, Genetic , Apoptosis , RNA Polymerase II/metabolism , Cyclin-Dependent Kinase 9/metabolism , Trans-Activators/metabolism , Trans-Activators/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Mice, Knockout , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/cytologyABSTRACT
Diarrhea is a common gastrointestinal disorder in horses, with diet-induced diarrhea being an emerging challenge. This study aimed to investigate the gut microbiota differences in healthy and diet-induced diarrheic horses and evaluate the effectiveness of fecal microbiota transplantation (FMT) and carbonate buffer mixture (CBM) as potential therapeutic approaches. Twenty healthy horses were included in the study, with four groups: Control, Diarrhea, CBM, and FMT. Diarrhea was induced using oligofructose, and fecal samples were collected for microbiota analysis. FMT and CBM treatments were administered orally using donor fecal matter, and formula mixture, respectively. Clinical parameters, serum levels, intestinal tissue histopathology, and fecal microbiota profiles were evaluated. The results showed that diarrhea induction disbalanced the gut microbiota with decreased diversity and richness, affected clinical parameters including elevated body temperature and diarrhea score, and decreased fecal pH, increased inflammatory responses such as increased serum LPS, IL-17A, lactic acid and total protein, and caused damage in the colon tissue. CBM and FMT treatments altered the gut microbiota composition, restoring it towards a healthier profile compared to diarrheic, restored the gut microbiota composition to healthier states, improved clinical symptoms including decreased body temperature and diarrhea score, and increased fecal pH, decreased inflammatory responses such as increased serum LPS, IL-17A, lactic acid and total protein, and repaired tissue damage. CBM and FMT Spearman correlation analysis identified specific bacterial taxa associated with host parameters and inflammation. FMT and CBM treatments showed promising therapeutic effects in managing oligofructose-induced diarrhea in horses. The findings provide valuable insights into the management and treatment of diarrhea in horses and suggest the potential of combined CBM and FMT approaches for optimal therapeutic outcomes.
ABSTRACT
A specialized population of mast cells residing within epithelial layers, currently known as intraepithelial mast cells (IEMCs), was originally observed over a century ago, yet their physiological functions have remained enigmatic. In this study, we unveil an unexpected and crucial role of IEMCs in driving gasdermin C-mediated type 2 immunity. During helminth infection, αEß7 integrin-positive IEMCs engaged in extensive intercellular crosstalk with neighboring intestinal epithelial cells (IECs). Through the action of IEMC-derived proteases, gasdermin C proteins intrinsic to the epithelial cells underwent cleavage, leading to the release of a critical type 2 cytokine, interleukin-33 (IL-33). Notably, mast cell deficiency abolished the gasdermin C-mediated immune cascade initiated by epithelium. These findings shed light on the functions of IEMCs, uncover a previously unrecognized phase of type 2 immunity involving mast cell-epithelial cell crosstalk, and advance our understanding of the cellular mechanisms underlying gasdermin C activation.
Subject(s)
Interleukin-33 , Mast Cells , Phosphate-Binding Proteins , Pore Forming Cytotoxic Proteins , Animals , Mice , Cell Communication/immunology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Interleukin-33/metabolism , Interleukin-33/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/immunology , Mast Cells/immunology , Mast Cells/metabolism , Mice, Inbred C57BL , Mice, Knockout , Phosphate-Binding Proteins/metabolism , Pore Forming Cytotoxic Proteins/immunology , Pore Forming Cytotoxic Proteins/metabolismABSTRACT
Alpha-enolase (ENO1), a multifunctional protein with carcinogenic properties, has emerged as a promising cancer biomarker because of its differential expression in cancer and normal cells. On the basis of this characteristic, we designed a cell-targeting peptide that specifically targets ENO1 and connected it with the drug doxorubicin (DOX) by aldehyde-amine condensation. A surface plasmon resonance (SPR) assay showed that the affinity for ENO1 was stronger (KD = 2.5 µM) for the resulting cell-targeting drug, DOX-P, than for DOX. Moreover, DOX-P exhibited acid-responsive capabilities, enabling precise release at the tumor site under the guidance of the homing peptide and alleviating DOX-induced cardiotoxicity. An efficacy experiment confirmed that, the targeting ability of DOX-P toward ENO1 demonstrated superior antitumor activity against colorectal cancer than that of DOX, while reducing its toxicity to cardiomyocytes. Furthermore, in vivo metabolic distribution results indicated low accumulation of DOX-P in nontumor sites, further validating its targeting ability. These results showed that the ENO1-targeted DOX-P peptide has great potential for application in targeted drug-delivery systems for colorectal cancer therapy.
Subject(s)
Antibiotics, Antineoplastic , Colorectal Neoplasms , Doxorubicin , Drug Delivery Systems , Phosphopyruvate Hydratase , Tumor Suppressor Proteins , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Phosphopyruvate Hydratase/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Animals , Tumor Suppressor Proteins/metabolism , Humans , Mice , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacology , Drug Delivery Systems/methods , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/administration & dosage , Mice, Inbred BALB C , Mice, Nude , Male , Cell Line, Tumor , HCT116 Cells , Xenograft Model Antitumor Assays/methods , Biomarkers, TumorABSTRACT
In this paper, a magnetic sequencing batch reactor (SBR) was constructed, and the influence rule of magnetic particle dosing performance of denitrification was investigated. The diversity, structure, and potential functions of the microbial community were comprehensively explored. The results showed that the particle size and the dosage of Fe3O4 magnetic particles were the main parameters affecting the sedimentation performance of activated sludge. The start-up phase of the SBR reactor with Fe3O4 magnetic particles was 5 days less than the control. Moreover, total nitrogen removal efficiency during the start-up phase was improved, with the maximum value reaching 91.93%, surpassing the control by 9.7% with the Fe3O4 dosage of 1.2 g L-1. In addition, the activated sludge concentration and dehydrogenase activity were improved, compared to the control. High-throughput sequencing showed that the denitrifying bacterium Saccharimonadales dominated the reactor and was enriched by magnetic particles. According to predicted functions, the abundance of genes for denitrification increased with the addition of magnetic particles, suggesting the capacity of nitrogen removal was enhanced in the microbial community. Overall, the Fe3O4 magnetic particles provide great potential for enhanced wastewater nitrogen removal.
Subject(s)
Bioreactors , Denitrification , Nitrogen , Nitrogen/chemistry , Nitrogen/metabolism , Sewage/microbiology , Bacteria/metabolism , Bacteria/genetics , Wastewater/microbiology , Wastewater/chemistry , Magnetite Nanoparticles/chemistryABSTRACT
In brief: The mechanism underlying the accumulation of γδT cells in the decidua, which helps maintain maternal-fetal immunotolerance in early pregnancy, is unknown. This study reveals that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. Abstract: Decidual γδT (dγδT) cells help maintain maternal-fetal immunotolerance in early pregnancy. However, the mechanism underlying the accumulation of γδT cells in the decidua is unknown. Previous work showed that RANKL upregulated intercellular adhesion molecule 1 (ICAM-1) in decidual stromal cells (DSCs), and Rankl knockout mice had limited dγδT cell populations. In this study, we measured the expression levels of RANKL/RANK and ICAM-1 in DSCs, in addition to the integrins of ICAM-1 on dγδT cells, and the number of dγδT cells from patients with recurrent spontaneous abortion (RSA) and normal pregnant women in the first trimester. RSA patients showed significantly decreased RANKL/RANK and ICAM-1/CD11a signaling in decidua, and a decreased percentage of dγδT cells, which was positively correlated with DSC-derived RANKL and ICAM-1. Next, an in vitro adhesion experiment showed that the enhanced attraction of human DSCs to dγδT cells after RANKL overexpression was almost completely aborted by anti-ICAM-1. Furthermore, Rankl knockout mice showed a significant reduction in NF-κB activity compared with wild-type controls. Finally, we applied a selective NF-κB inhibitor named PDTC to validate the role of NF-κB in RANKL-mediated ICAM-1 upregulation. Taken together, our data show that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. A reduction in RANKL/ICAM-1 signaling in DSCs may result in insufficient accumulation of γδT cells in decidua and, in turn, RSA.
Subject(s)
Decidua , Intercellular Adhesion Molecule-1 , NF-kappa B , RANK Ligand , Up-Regulation , Adult , Animals , Female , Humans , Mice , Pregnancy , Decidua/metabolism , Intercellular Adhesion Molecule-1/metabolism , Intercellular Adhesion Molecule-1/genetics , Mice, Knockout , NF-kappa B/metabolism , RANK Ligand/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Signal Transduction , Stromal Cells/metabolism , T-Lymphocytes/metabolismABSTRACT
Long-term coal mining could lead to a serious of geo-environmental problems. However, less comprehensive identification of factors controlling the groundwater dynamics were involved in previous studies. This study focused on 68 groundwater samples collected before and after mining activities, Self-Organizing Maps (SOM) combining with Principal Component Analysis (PCA) derived that the groundwater samples were classified into five clusters. Clusters 1-5 (C1-C5) represented the groundwater quality affected by different hydrochemical processes, mainly including mineral (carbonate and evaporite) dissolution and cation exchange, which were controlled by the hydrochemical environment at different stages of mining activities. Combining with the time-series data, the Extreme Gradient Boosting Decision Trees (XGBoost) derived that the mine water inflow (feature relative importance of 40.0%) and unit goaf area (feature relative importance of 29.2%) were dominant factors affecting the confined groundwater level, but had less or lagged impact on phreatic groundwater level. This was closely related to the height of the water flow fractured zone and hydraulic connection between aquifers. The results of this study on the coupled evolution of groundwater dynamics could enhance our understanding of the effects of mining on aquifer systems and contribute to the prevention of water hazards in the coalfields.
Subject(s)
Coal Mining , Environmental Monitoring , Groundwater , Machine Learning , Groundwater/chemistry , China , Environmental Monitoring/methods , Water Pollutants, Chemical/analysis , Principal Component AnalysisABSTRACT
The coordination between odontoblastic differentiation and directed cell migration of mesenchymal progenitors is necessary for regular dentin formation. The synthesis and degradation of hyaluronan (HA) in the extracellular matrix create a permissive niche that directly regulates cell behaviors. However, the role and mechanisms of HA degradation in dentin formation remain unknown. In this work, we present that HA digestion promotes odontoblastic differentiation and cell migration of mouse dental papilla cells (mDPCs). Hyaluronidase 2 (HYAL2) is responsible for promoting odontoblastic differentiation through degrading HA, while hyaluronidase 1 (HYAL1) exhibits negligible effect. Silencing Hyal2 generates an extracellular environment rich in HA, which attenuates F-actin and filopodium formation and in turn inhibits cell migration of mDPCs. In addition, activating PI3K/Akt signaling significantly rescues the effects of HA accumulation on cytodifferentiation. Taken together, the results confirm the contribution of HYAL2 to HA degradation in dentinogenesis and uncover the mechanism of the HYAL2-mediated HA degradation in regulating the odontoblastic differentiation and migration of mDPCs.
Subject(s)
Cell Differentiation , Cell Movement , Dental Papilla , Hyaluronic Acid , Hyaluronoglucosaminidase , Odontoblasts , Animals , Hyaluronoglucosaminidase/metabolism , Hyaluronoglucosaminidase/genetics , Mice , Hyaluronic Acid/metabolism , Odontoblasts/metabolism , Odontoblasts/cytology , Dental Papilla/cytology , Dental Papilla/metabolism , Signal Transduction , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Cells, Cultured , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/geneticsABSTRACT
BACKGROUND: Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. METHODS: Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. RESULTS: Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn't reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G > C, c.4977C > G, and c.5444A > G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. CONCLUSION: Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants.