ABSTRACT
Background: Given the increasing interest in the role of gut microbiota in glioblastoma multiforme (GBM), our objective was to examine the potential causal relationship between gut microbiota and GBM, as well as the mediating effects of specific metabolites. Methods: A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the associations between 196 microbial taxa and GBM. A two-step MR technique was used to identify significant mediators in this relationship. Subsequently, a mediation analysis was performed to explore and quantify the mediating effects of specific metabolites on the causal relationship between gut microbiota and GBM. Results: Five taxa showed significant associations with GBM. Among them, family Victivallaceae [odds ratio (OR): 1.95; 95% confidence interval (CI): 1.21, 3.13; p = 0.005] and genus Lactococcus (OR: 1.81; 95% CI: 1.04, 3.15; p = 0.036) were positively correlated with the risk of GBM, while phylum Cyanobacteria had a protective effect against GBM (OR: 0.45; 95% CI: 0.22, 0.89; p = 0.021). The mediation analysis revealed that the connections among family Victivallaceae, genus Lactococcus, phylum Cyanobacteria and GBM were mediated by Methyl-4-hydroxybenzoate sulfate, phosphoethanolamine and dehydroepiandrosterone sulfate. Each of these accounted for 7.27, 7.98, and 8.65%, respectively. Conclusion: Our study provides evidence supporting a potential causal association between certain gut microbiota taxa and GBM. The study highlights the central role of gut microbiota in GBM pathogenesis and their interactions with vital serum metabolites. This paves the way for potential novel therapeutic interventions in GBM management.
ABSTRACT
Atmospheric precipitation samples were collected in 2018, 2019, and 2021 in Beijing to study the concentrations and changes of the main metal elements and water-soluble ionsï¼ the wet deposition fluxes of heavy metals, water-soluble ions, dissolved inorganic nitrogen, and sulfur in the atmospheric precipitation and their impacts on the ecological environmentï¼ and the scavenging mechanisms of the typical precipitation to atmospheric pollutants during the study period. The results showed that the precipitation in Beijing during the study period was mostly neutral or alkaline, and the frequency of acid rain occurrence was very low, only accounting for 3.06%. The total concentrations of major metal elements in 2018, 2019, and 2021 were ï¼4 787.46 ±4 704.31ï¼, ï¼7 663.07 ±8 395.05ï¼, and ï¼2 629.13 ±2 369.51ï¼ µg·L-1, respectively. The total equivalent concentrations of ions in 2018, 2019, and 2021 were ï¼851.68 ±649.16ï¼, ï¼973.98 ±850.94ï¼, and ï¼644.31 ±531.16ï¼ µeq·L-1, respectively. The interannual changes in major metal elements and ions followed the order of 2019 > 2018 > 2021. The seasonal average total concentrations of major metal elements in spring, summer, autumn, and winter were ï¼9 624.25 ±7 327.92ï¼, ï¼4 088.67 ±5 710.14ï¼, ï¼3 357.68 ±3 995.64ï¼, and ï¼6 203.19 ±3 857.43ï¼ µg·L-1, respectively, and the seasonal average total equivalent concentrations of ions in spring, summer, autumn, and winter were ï¼1 014.71 ±512.21ï¼, ï¼729.83 ±589.90ï¼, ï¼724.35 ±681.40ï¼, and ï¼1 014.03 ±359.67ï¼ µeq·L-1, respectively, all presenting the order of spring > winter > summer > autumn. NO3- and SO42- were the main acid-causing ions in precipitation, whereas NH4+ and Ca2+ were the main acid-neutralizing ions. The wet deposition fluxes of the heavy metal Cd were very low [ï¼0.05 ±0.01ï¼ mg·ï¼m2·aï¼-1], only accounting for ï¼0.13 ±0.04ï¼% of the total wet deposition fluxes of main metal elementsï¼ however, its soil safety years were 291 years, significantly lower than those of other heavy metals, displaying that its ecological risk was relatively the highest. The total wet precipitation flux of water-soluble ions NH4+, Ca2+, NO3-, and SO42- accounted for ï¼85.72 ±2.18ï¼% of the wet precipitation flux of total ions, suggesting that their comprehensive impact on the ecological environment might have been higher. DIN wet deposition flux was mainly characterized by NH4+-N, which had a positive impact on the ecological environment in summer. SO42--S wet deposition flux was higher in summer, so its positive impact on the ecological environment was also greater. The scavenging effects of atmospheric precipitations to pollutants from the air were impacted by various factors, and the synergism effects of these factors could directly influence the scavenging mechanisms of precipitation to pollutants.
ABSTRACT
Cyclic GMP-AMP synthase (cGAS) is a key innate immune sensor that recognizes cytosolic DNA to induce immune responses against invading pathogens. The role of cGAS is conventionally recognized as a nucleotidyltransferase to catalyze the synthesis of cGAMP upon recognition of cytosolic DNA, which leads to the activation of STING and production of type I/III interferon to fight against the pathogen. However, given that hepatocytes are lack of functional STING expression, it is intriguing to define the role of cGAS in hepatocellular carcinoma (HCC), the liver parenchymal cells derived malignancy. In this study, we revealed that cGAS was significantly downregulated in clinical HCC tissues, and its dysregulation contributed to the progression of HCC. We further identified cGAS as an immune tyrosine inhibitory motif (ITIM) containing protein, and demonstrated that cGAS inhibited the progression of HCC and increased the response of HCC to sorafenib treatment by suppressing PI3K/AKT/mTORC1 pathway in cellular and animal models. Mechanistically, cGAS recruits SH2-containing tyrosine phosphatase 1 (SHP1) via ITIM, and dephosphorylates p85 in phosphatidylinositol 3-kinase (PI3K), which leads to the suppression of AKT-mTORC1 pathway. Thus, cGAS is identified as a novel tumor suppressor in HCC via its function independent of its conventional role as cGAMP synthase, which indicates a novel therapeutic strategy for advanced HCC by modulating cGAS signaling.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Nucleotidyltransferases , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Nucleotidyltransferases/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Humans , Animals , Mice , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Male , Signal Transduction , Proto-Oncogene Proteins c-akt/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Mice, Nude , Mechanistic Target of Rapamycin Complex 1/metabolism , Nucleotides, Cyclic/metabolismABSTRACT
Helicobacter pylori (H. pylori) infection is considered to be an important factor in gastric cancer (GC). Long noncoding RNA (lncRNA) and m6A modification are involved in the occurrence and development of GC, but the role of lncRNA m6A modification in the development of GC mediated by H. pylori is still unclear. Here, we found that H. pylori infection downregulated the expression of lnc-PLCB1 through METTL14-mediated m6A modification and IRF2-mediated transcriptional regulation. Overexpression of lnc-PLCB1 inhibited the proliferation and migration of GC cells, while downregulation of lnc-PLCB1 promoted the proliferation and migration ability of GC cells. In addition, clinical analysis showed that lnc-PLCB1 is lower in GC tissues than in normal tissues. Further study found that lnc-PLCB1 reduced the protein stability of its binding protein DEAD-box helicase 21 (DDX21) and then downregulated the expression of CCND1 and Slug, thereby playing tumour suppressing role in the occurrence and development of GC. In conclusion, the METTL14/lnc-PLCB1/DDX21 axis plays an important role in H. pylori-mediated GC, and lnc-PLCB1 can be used as a new target for GC treatment.
Subject(s)
Adenine , Helicobacter Infections , Helicobacter pylori , RNA, Long Noncoding , Stomach Neoplasms , Humans , Helicobacter pylori/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Stomach Neoplasms/pathology , Down-Regulation , Helicobacter Infections/complications , Helicobacter Infections/genetics , Cell Proliferation , DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , Phospholipase C beta/genetics , Phospholipase C beta/metabolism , Methyltransferases/genetics , Methyltransferases/metabolismABSTRACT
Drug addiction can seriously damage human physical and mental health, while detoxification is a long and difficult process. Although studies have reported changes in the oral microbiome of methamphetamine (METH) users, the role that the microbiome plays in the process of drug addiction is still unknown. This study aims to explore the function of the microbiome based on analysis of the variations in the oral microbiome and metabolome of METH users. We performed the 16S rRNA sequencing analysis based on the oral saliva samples collected from 278 METH users and 105 healthy controls (CTL). In addition, the untargeted metabolomic profiling was conducted based on 220 samples. Compared to the CTL group, alpha diversity was reduced in the group of METH users and the relative abundances of Peptostreptococcus and Gemella were significantly increased, while the relative abundances of Campylobacter and Aggregatibacter were significantly decreased. Variations were also detected in oral metabolic pathways, including enhanced tryptophan metabolism, lysine biosynthesis, purine metabolism, and steroid biosynthesis. Conversely, the metabolic pathways of porphyrin metabolism, glutathione metabolism, and pentose phosphate were significantly reduced. It was speculated that four key microbial taxa, i.e., Peptostreptococcus, Gemella, Campylobacter, and Aggregatibacter, could be involved in the toxicity and addiction mechanisms of METH by affecting the above metabolic pathways. It was found that with the increase of drug use years, the content of tryptamine associated with neuropsychiatric disorders was gradually increased. Our study provides novel insights into exploring the toxic damage and addiction mechanisms underlying the METH addiction.IMPORTANCEIt was found that with the increase of drug use years, the content of tryptamine associated with neuropsychiatric disorders gradually increased. The prediction models based on oral microbiome and metabolome could effectively predict the methamphetamine (METH) smoking. Our study provides novel insights into the exploration of the molecular mechanisms regulating the toxic damage and addiction of METH as well as new ideas for early prevention and treatment strategies of METH addiction.
Subject(s)
Amphetamine-Related Disorders , Methamphetamine , Microbiota , Humans , Methamphetamine/adverse effects , RNA, Ribosomal, 16S/genetics , Amphetamine-Related Disorders/complications , Metabolome , Microbiota/genetics , TryptaminesABSTRACT
Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors. The microenvironment of GBM is characterized by its highly immunosuppressive nature with infiltration of immunosuppressive cells and the expression levels of cytokines. Efferocytosis is a biological process in which phagocytes remove apoptotic cells and vesicles from tissues. Efferocytosis plays a noticeable function in the formation of immunosuppressive environment. This study aimed to develop an efferocytosis-related prognostic model for GBM. The bioinformatic methods were utilized to analyze the transcriptomic data of GBM and normal samples. Clinical and RNA-seq data were sourced from TCGA database comprising 167 tumor samples and 5 normal samples, and 167 tumor samples for which survival information was available. Transcriptomic data of 1034 normal samples were collected from the Genotype-Tissue Expression (GTEx) database as a control sample supplement to the TCGA database. In the end, 167 tumor samples and 1039 normal samples were obtained for transcriptome analysis. Efferocytosis-related differentially expressed genes (ERDEGs) were obtained by intersecting 7487 differentially expressed genes (DEGs) between GBM and normal samples along with 1189 hub genes. Functional enrichment analyses revealed that ERDEGs were mainly involved in cytokine-mediated immune responses. Moreover, 9 prognosis-related genes (PRGs) were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis, and a prognostic model was therefore developed. The nomogram combining age and risk score could effectively predict GBM patients' prognosis. GBM patients in the high-risk group had higher immune infiltration, invasion, epithelial-mesenchymal transition, angiogenesis scores and poorer tumor purity. In addition, the high-risk group exhibited higher half maximal inhibitory concentration (IC50) values for temozolomide, carmustine, and vincristine. Expression analysis indicated that PRGs were overexpressed in GBM cells. PDIA4 knockdown reduced efferocytosis in vitro. In summary, the proposed prognostic model for GBM based on efferocytosis-related genes exhibited a robust performance.
Subject(s)
Glioblastoma , Humans , Glioblastoma/genetics , Prognosis , Efferocytosis , Carmustine , Temozolomide , Cytokines , Tumor Microenvironment/geneticsABSTRACT
Road silt loading (sL) is an important parameter in the fugitive road dust (FRD) emissions. In this study, the improved Testing Re-entrained Aerosol Kinetic Emissions from Roads (TRAKER) combined with the AP-42 method was firstly developed to quickly measure and estimate the sLs of paved roads in Beijing, China. The annual average sLs in Beijing was 0.59±0.31 g/m2 in 2020, and decreased by 22.4% compared with that in 2019. The seasonal variations of sLs followed the order of spring > winter > summer > autumn in the two years. The seasonal mean road sLs on the same type road in the four seasons presented a decline trend from 2019 to 2020, especially on the Express way, decreasing 47.4%-72.7%. The road sLs on the different type roads in the same season followed the order of Major arterial â¼ Minor arterial â¼ Branch road > Express road, and Township road â¼ Country highway > Provincial highway â¼ National highway. The emission intensities of PM10 and PM2.5 from FRD in Beijing in 2020 were lower than those in 2019. The PM10 and PM2.5 emission intensities at the four planning areas in the two years all presented the order of the capital functional core area > the urban functional expansion area > the urban development new area > the ecological conservation and development area. The annual emissions of PM10 and PM2.5 from FRD in Beijing in 2020 were 74,886 ton and 18,118 ton, respectively, decreasing by â¼33.3% compared with those in 2019.
Subject(s)
Air Pollutants , Dust , Dust/analysis , Beijing , Particulate Matter/analysis , Air Pollutants/analysis , Environmental Monitoring , China , Seasons , Vehicle Emissions/analysisABSTRACT
Re-suspended road dust RRD as RRD2.5 and RRD10 can even more easily enter the atmospheric environment, showing a kind of significant potential to influence atmospheric environment. A campaign of sampling RRD samples at 53 sites and aerosol samples at a representative urban site in Beijing in October 2014, January, April and July 2015 was accomplished, and combined with RRD in 2003, and 2016-2018 periods to investigate the seasonal variations of chemical components in RRD2.5 and RRD10, long-term evolutions of RRD characteristics in 2003-2018, and source composition changes of RRD. Meanwhile a technique based on Mg/Al indicator for effectively estimating contributions of RRD to PM was developed. It is found that pollution elements and water-soluble ions in RRD were largely enriched in RRD2.5. The pollution elements presented an obvious seasonal variation in RRD2.5, however showed various seasonal variations in RRD10. These pollution elements in RRD, due to being mainly impacted by both increasing traffic activities and atmospheric pollution control measures, almost display a single-peak change in 2003-2018. The water-soluble ions in RRD2.5 and RRD10 presented various seasonal variations, and displayed an evident increase in 2003-2015. The source composition of RRD in 2003-2015 posed a significant change that traffic activities, crustal soil, secondary pollution species and biomass combustion became significant contributors to RRD. The contributions of RRD2.5/RRD10 to mineral aerosols in PM2.5/PM10 presented a similar seasonal variation. The synergistic effects of meteorological factors and anthropogenic activities in different seasons were significant motive force influencing the contributions of RRD to the mineral aerosols. The pollution elements Cr and Ni in RRD2.5 were the significant contributors to PM2.5, however, Cr, Ni, Cu, Zn, and Pb in RRD10 were the important contributors to PM10. The research will provide a new significant scientific guide for further controlling atmospheric pollution and improving air quality.
Subject(s)
Air Pollutants , Dust , Dust/analysis , Beijing , Air Pollutants/analysis , Environmental Monitoring/methods , Seasons , Aerosols/analysis , Ions , Water , Particulate Matter/analysis , Vehicle Emissions/analysisABSTRACT
Cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, plays a crucial role in antiviral immunity, and its overactivation induces excess inflammation and tissue damage. Macrophage polarization is critically involved in inflammation; however, the role of cGAS in macrophage polarization during inflammation remains unclear. In this study, we demonstrated that cGAS was upregulated in the LPS-induced inflammatory response via the TLR4 pathway, and cGAS signaling was activated by mitochondria DNA in macrophages isolated from C57BL/6J mice. We further demonstrated that cGAS mediated inflammation by acting as a macrophage polarization switch, which promoted peritoneal macrophages and the bone marrow-derived macrophages to the inflammatory phenotype (M1) via the mitochondrial DNA-mTORC1 pathway. In vivo studies verified that deletion of Cgas alleviated sepsis-induced acute lung injury by promoting macrophages to shift from the M1 phenotype to the M2 phenotype. In conclusion, our study demonstrated that cGAS mediated inflammation by regulating macrophage polarization through the mTORC1 pathway, and it further provided a potential therapeutic strategy for inflammatory diseases, especially sepsis-induced acute lung injury.
Subject(s)
Acute Lung Injury , Macrophages , Mechanistic Target of Rapamycin Complex 1 , Nucleotidyltransferases , Sepsis , Animals , Mice , DNA, Mitochondrial/metabolism , Inflammation , Macrophages/metabolism , Mice, Inbred C57BL , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Phenotype , Mechanistic Target of Rapamycin Complex 1/metabolismABSTRACT
This study mainly developed an estimate method for photochemical ozone (O3) production from urban plumes in hot season, through simulating O3 evolution from precursors locally emitted and determining the real-field O3 increment reactivity (IR) of volatile organic compounds (VOCs) based on the box chemical model. Our simulation on June-2019 indicated that Beijing local emissions produced O3 at the rate of 0.7-9.2 ppb/h and led to an O3 increase of 48.9 ppb during 05:00-18:00, accounting for 68.3% of the observed O3 increase. The maximum level and production rate of simulated O3 showed a linear response to VOCs, therefore we can use VOCs levels in urban plumes to quantify O3 formation in summer. The IR (g O3 formed per g VOCs) was calculated on the actual precursor and meteorology condition of this megacity, 0.12-4.90 g/g for individual VOCs and 1.49 g/g for comprehensive TVOCs. The weighted average of individual IRs agreed well with that of TVOCs, but these IRs were 34.5% of MIR values that were widely used in references. It's noteworthy that these IRs had greater sensitivity to precursor levels, and broadly remained stable under the fixed VOCs:NOx. Considering the synchronous reductions of precursors in Beijing, we applied these IRs to quantify chemical O3 evolution from Beijing local emissions in summer of recent years, declining from 63.5 ppb in 2016 to 44.0 ppb in 2020 for June. The contributions of the diagnosed chemical O3 to Beijing O3 better matched with the atmospheric transport paths on daily basis, higher than 100% when the transport paths starting from the clean neighbor cities, but lower to 45%-66% when the transport paths originating from the highly-polluted neighbor cities. This consistence indicated the reliability of our IR calculation method for quickly estimating chemical O3 production of urban plumes in summer.
Subject(s)
Air Pollutants , Ozone , Volatile Organic Compounds , Beijing , Volatile Organic Compounds/analysis , Air Pollutants/analysis , Seasons , Reproducibility of Results , Environmental Monitoring/methods , China , Ozone/analysisABSTRACT
PURPOSE: Postoperative delirium (POD) commonly occurs after major abdominal surgery and is associated with increased morbidity and mortality. There have been many studies on the relationship between POD and various surgeries, but research on POD after pancreatic cancer surgery is limited. The aim of this study was to identify the incidence and risk factors of POD after pancreatic cancer surgery. METHODS: The subjects of this retrospective analysis were 196 patients who were transferred for postoperative care after pancreatic cancer surgery, to a 12-bed critical care medicine ward at Shandong Provincial Hospital, affiliated with Shandong First Medical University, between January 2015 and December 2019. The patients were divided according to whether they suffered POD into a delirium group and a non-delirium group. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit and two independent medical practitioners analyzed all the data. Univariate and multiple logistic regression analyses were performed. RESULTS: The overall delirium incidence was 20.41%, which increased to 29.03% for patients aged ≥ 70 years. POD was associated with age, smoking, the American Society of Anesthesiologists classification, the Acute Physiology and Chronic Health Evaluation II score, and the TNM stage of the cancer. The variables concerning sex, drinking, hypertension, a history of cerebral disease, surgery type, operation time, amount of bleeding, and the intraoperative use of dexmedetomidine did not differ significantly between the two groups. There was no significant difference in the length of ICU stay, with the exclusion of long-term stay for complications, between the groups, but POD tended to prolong the postoperative hospital stay and increase the risk of mortality. There was also a gradual decline in the incidence of POD between 2015 and 2019, especially from 2015 to 2018, after preventive measures were implemented. CONCLUSION: POD is related to many risk factors and worthy of attention. Appropriate management can reduce its incidence or at least shorten its duration.
Subject(s)
Emergence Delirium , Pancreatic Neoplasms , Humans , Retrospective Studies , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Incidence , Risk Factors , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/complications , Pancreatic NeoplasmsABSTRACT
Tripartite motif protein (TRIM) 50 is a new member of the tripartite motif family, and its biological function and the molecular mechanism it is involved in remain largely unknown. The NOD-like receptor family protein (NLRP)3 inflammasome is actively involved in a wide array of biological processes while mechanisms of its regulation remain to be fully clarified. Here, we demonstrate the role of TRIM50 in NLRP3 inflammasome activation. In contrast to the conventional E3 ligase functions of TRIM proteins, TRIM50 mediates direct oligomerization of NLRP3, thereby suppressing its ubiquitination and promoting inflammasome activation. Mechanistically, TRIM50 directly interacts with NLRP3 through its RING domain and induces NLRP3 oligomerization via its coiled-coil domain. Finally, we show that TRIM50 promotes NLRP3 inflammasome-mediated diseases in mice. We thus reveal a novel regulatory mechanism of NLRP3 via TRIM50 and suggest that modulating TRIM50 might represent a therapeutic strategy for NLRP3-dependent pathologies.
Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Tripartite Motif Proteins , Animals , Mice , Inflammasomes/metabolism , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Tripartite Motif Proteins/genetics , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , UbiquitinationABSTRACT
Ras-related C3 botulinum toxin substrate 1 (RAC1) overexpressiosn and hyperactivation are correlated with aggressive growth and other malignant characteristics in a wide variety of cancers including hepatocellular carcinoma (HCC). However, the regulatory mechanism of RAC1 expression and activation in HCC is not fully understood. Here, we demonstrated that E3 ubiquitin ligase MG53 (also known as tripartite motif 72, TRIM72) acted as a direct inhibitor of RAC1, and it catalyzed the ubiquitination of RAC1 and further inhibited RAC1 activity in HCC cells. Mechanistically, MG53 directly bound with RAC1 through its coiled-coil domain and suppressed RAC1 activity by catalyzing the Lys48 (K48)-linked polyubiquitination of RAC1 at Lys5 residue in HCC cells. We further demonstrated that MG53 significantly suppressed the malignant behaviors of HCC cells and enhanced the chemosensitivity of HCC cells to sorafenib treatment by inhibiting RAC1-MAPK signaling axis. In summary, we identified MG53 as a novel RAC1 inhibitor and tumor suppressor in HCC, and it suppressed HCC progression by inducing K48-linked polyubiquitination of RAC1 and further inhibiting the RAC1-MAPK signaling. Altogether, our investigation provided a new therapeutic strategy for RAC1 overactivated tumors by modulating MG53.
ABSTRACT
Hepatocellular carcinoma (HCC), a heterogeneous cancer with high mortality, is resistant to single targeted therapy; thus, combination therapy based on synthetic lethality is a promising therapeutic strategy for HCC. Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) is the most recognized target for synthetic lethality; however, the therapeutic effect of PARP1 inhibition on HCC is disappointing. Therefore, exploring new synthetic lethal partners for the efficient manipulation of HCC is urgently required. In this study, we identified Src and PARP1 as novel synthetic lethal partners, and the combination therapy produced significant anti-tumor effects without causing obvious side effects. Mechanistically, Src interacted with PARP1 and phosphorylated PARP1 at the Y992 residue, which further mediated resistance to PARP1 inhibition. Overall, this study revealed that Src-mediated PARP1 phosphorylation induced HCC resistance to PARP1 inhibitors and indicated a therapeutic window of the Y992 phosphorylation of PARP1 for HCC patients. Moreover, synthetic lethal therapy by co-targeting PARP1 and Src have the potential to broaden the strategies for HCC and might benefit HCC patients with high Src activation and resistance to PARP1 inhibitors alone.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Dasatinib/administration & dosage , Dasatinib/pharmacology , Dimethyl Sulfoxide/administration & dosage , Dimethyl Sulfoxide/pharmacology , Disease Models, Animal , Hep G2 Cells , Humans , Liver Neoplasms/metabolism , Male , Mice , Mice, Inbred NOD , Phosphorylation , Phthalazines/administration & dosage , Phthalazines/pharmacology , Piperazines/administration & dosage , Piperazines/pharmacology , Poly (ADP-Ribose) Polymerase-1/metabolism , Up-Regulation , Xenograft Model Antitumor Assays , Zebrafish , src-Family Kinases/metabolismABSTRACT
During the progression of coronavirus disease 2019 (COVID-19), immune response and inflammation reactions are dynamic events that develop rapidly and are associated with the severity of disease. Here, we aimed to develop a predictive model based on the immune and inflammatory response to discriminate patients with severe COVID-19. COVID-19 patients were enrolled, and their demographic and immune inflammatory reaction indicators were collected and analyzed. Logistic regression analysis was performed to identify the independent predictors, which were further used to construct a predictive model. The predictive performance of the model was evaluated by receiver operating characteristic curve, and optimal diagnostic threshold was calculated; these were further validated by 5-fold cross-validation and external validation. We screened three key indicators, including neutrophils, eosinophils, and IgA, for predicting severe COVID-19 and obtained a combined neutrophil, eosinophil, and IgA ratio (NEAR) model (NEU [109/liter] - 150×EOS [109/liter] + 3×IgA [g/liter]). NEAR achieved an area under the curve (AUC) of 0.961, and when a threshold of 9 was applied, the sensitivity and specificity of the predicting model were 100% and 88.89%, respectively. Thus, NEAR is an effective index for predicting the severity of COVID-19 and can be used as a powerful tool for clinicians to make better clinical decisions. IMPORTANCE The immune inflammatory response changes rapidly with the progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is responsible for clearance of the virus and further recovery from the infection. However, the intensified immune and inflammatory response in the development of the disease may lead to more serious and fatal consequences, which indicates that immune indicators have the potential to predict serious cases. Here, we identified both eosinophils and serum IgA as prognostic markers of COVID-19, which sheds light on new research directions and is worthy of further research in the scientific research field as well as clinical application. In this study, the combination of NEU count, EOS count, and IgA level was included in a new predictive model of the severity of COVID-19, which can be used as a powerful tool for better clinical decision-making.
Subject(s)
COVID-19 Testing/methods , COVID-19/diagnosis , COVID-19/immunology , Clinical Decision Rules , Severity of Illness Index , Adult , Aged , Biomarkers/blood , COVID-19/blood , Clinical Decision-Making/methods , Disease Progression , Eosinophils/metabolism , Female , Humans , Immunoglobulin A/blood , Inflammation/blood , Inflammation/diagnosis , Inflammation/virology , Logistic Models , Male , Middle Aged , Neutrophils/metabolism , Predictive Value of Tests , Prognosis , Sensitivity and SpecificityABSTRACT
Cyclic GMP-AMP synthase (cGAS) functions as an essential DNA sensor, which senses the cytoplasmic double-stranded DNA and activates the antiviral response. However, the posttranslational modification of cGAS remains to be fully understood and whether it has arginine methylation modification remains unknown. Here, we identified protein arginine methyltransferase 5 (PRMT5) as a direct binding partner of cGAS, and it catalyzed the arginine symmetrical dimethylation of cGAS at the Arg124 residue. Further investigation demonstrated that methylation of cGAS by PRMT5 attenuated cGAS-mediated antiviral immune response by blocking the DNA binding ability of cGAS. Oral administration of PRMT5 inhibitors significantly protected mice from HSV-1 infection and prolonged the survival time of these infected mice. Therefore, our findings revealed an essential regulatory effect of PRMT5 on cGAS-mediated antiviral immune response and provided a promising potential antiviral strategy by modulating PRMT5.
Subject(s)
Herpes Simplex , Protein-Arginine N-Methyltransferases/metabolism , Animals , Antiviral Agents/pharmacology , Arginine/metabolism , Herpes Simplex/genetics , Immunity , Intracellular Signaling Peptides and Proteins , Mice , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Protein-Arginine N-Methyltransferases/geneticsABSTRACT
The prevalence of colorectal cancer (CRC) continues to increase. Treatment of CRC remains a significant clinical challenge, and effective therapies for advanced CRC are desperately needed. Increasing attention and ongoing research efforts have focused on krill oil that may provide health benefits to the human body. Here we report that krill oil exerts in vitro anticancer activity through a direct inhibition on proliferation, colony formation, migration, and invasion of mouse colon cancer cells. Krill oil inhibited the proliferation and colony formation of CT-26 colon cancer cells by causing G0/G1 cell cycle arrest and apoptosis. Cell cycle arrest was attributable to reduction of cyclin D1 levels in krill oil-treated cells. Further studies revealed that krill oil induced mitochondrial-dependent apoptosis of CT-26 cells, including loss of mitochondrial membrane potential, increased cytosolic calcium levels, activation of caspase-3, and downregulation of anti-apoptotic proteins MCL-1 and BCL-XL. Krill oil suppressed migration of CT-26 cells by disrupting the microfilaments and microtubules. Extracellular signal-regulated protein kinase (ERK) plays crucial roles in regulating proliferation and migration of cancer cells. We found that krill oil attenuated the activation of ERK signaling pathway to exert the effects on cell cycle, apoptosis, and migration of colon cancer cells. We speculate that polyunsaturated fatty acids of krill oil may dampen ERK activation by decreasing the phospholipid saturation of cell membrane. Although findings from in vitro studies may not necessarily translate in vivo, our study provides insights into the possibility that krill oil or its components could have therapeutic potential in colon cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Colonic Neoplasms/drug therapy , Euphausiacea/chemistry , Fish Oils/pharmacology , Animals , Cell Movement/drug effects , Cell Proliferation/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Drug Screening Assays, Antitumor , MAP Kinase Signaling System/drug effects , Mice , Tumor Cells, CulturedABSTRACT
The anemia of inflammation is related in part to abnormal erythropoiesis in bone marrow. G-CSF regulates granulopoiesis and is increased during systemic inflammation. Here, we have showed that high levels of G-CSF are associated with repression of bone marrow erythropoiesis and expansion of splenic erythropoiesis in Escherichia coli-infected mice and lipopolysaccharide-treated mice. Under lipopolysaccharide-induced systemic inflammatory conditions in mice, G-CSF neutralization with antibody alleviated the blockage of bone marrow erythropoiesis, prevented the enhancement of splenic erythropoiesis, ameliorated splenomegaly, and reduced the brittleness of spleen. We further demonstrated that after lipopolysaccharide treatment, TLR4-knockout mice display low levels of G-CSF, healthy bone marrow erythropoiesis, almost no stress erythropoiesis in the spleen, and normal size and toughness of spleen. In addition, we found HIF-mediated erythropoietin production is essential for splenic erythropoiesis in the setting of G-CSF-induced suppression of bone marrow erythropoiesis. Our findings identify G-CSF as a critical mediator of inflammation-associated erythropoiesis dysfunction in bone marrow and offer insight into the mechanism of G-CSF-induced splenic erythropoiesis. We provide experimentally significant dimension to the biology of G-CSF.
Subject(s)
Bone Marrow/metabolism , Erythropoiesis/drug effects , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/metabolism , Signal Transduction/drug effects , Spleen/metabolism , Systemic Inflammatory Response Syndrome/metabolism , Animals , Bone Marrow/drug effects , Erythropoiesis/genetics , Erythropoietin/biosynthesis , Escherichia coli , Escherichia coli Infections/metabolism , Escherichia coli Infections/microbiology , Injections, Subcutaneous , Lipopolysaccharides/adverse effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/genetics , Spleen/drug effects , Systemic Inflammatory Response Syndrome/chemically induced , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/geneticsABSTRACT
Nucleotide binding oligomerization domain 2 (NOD2) is a recognized innate immune sensor which can initiate potent immune response against pathogens. Many innate immune sensors have been reported to be of great importance in carcinogenesis. However, the role of NOD2 in cancer is not well understood. Here we investigated the role of NOD2 in the development of hepatocellular carcinoma (HCC). We demonstrated that NOD2 deficiency promoted hepatocarcinogenesis in N-nitrosodiethylamine (DEN)/carbon tetrachloride (CCl4) induced HCC mice model and xenograft tumor model. In vitro investigation showed that NOD2 acted as a tumor suppressor and inhibited proliferation, colony formation and invasion of HCC cells. Clinical investigation showed that NOD2 expression was completely lost or significantly downregulated in clinical HCC tissues, and loss of NOD2 expression was significantly correlated with advanced disease stages. Further investigation showed that NOD2 exerted its anti-tumor effect through activating adenosine 5'-monophosphate (AMP) -activated protein kinase (AMPK) signaling pathway, and NOD2 significantly enhanced the sensitivity of HCC cells to sorafenib, lenvatinib and 5-FU treatment through activating AMPK pathway induced apoptosis. Moreover, we demonstrated that NOD2 activated AMPK pathway by directly binding with AMPKα-LKB1 complex, which led to autophagy-mediated apoptosis of HCC cells. Altogether, this study showed that NOD2 acted as a tumor suppressor as well as a chemotherapeutic regulator in HCC cells by directly activating AMPK pathway, which indicated a potential therapeutic strategy for HCC treatment by upregulating NOD2-AMPK signaling axis.
Subject(s)
AMP-Activated Protein Kinases/drug effects , Carcinoma, Hepatocellular/drug therapy , Nod2 Signaling Adaptor Protein/metabolism , Nod2 Signaling Adaptor Protein/pharmacology , Sorafenib/pharmacology , AMP-Activated Protein Kinases/metabolism , Animals , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , MiceABSTRACT
Aberrant Src kinase activity is known to be involved in a variety of human malignancies, whereas the regulatory mechanism of Src has not been completely clarified. Here, we demonstrated that tripartite motif containing 7 (TRIM7) directly interacted with Src, induced Lys48-linked polyubiquitination of Src and reduced the abundance of Src protein in hepatocellular carcinoma (HCC) cells. We further identified TRIM7 as a tumor suppressor in HCC cells through its negative modulation of the Src-mTORC1-S6K1 axis in vivo and in vitro in several HCC models. Moreover, we verified the dysregulated expression of TRIM7 in clinical liver cancer tissues and its negative correlation with Src protein in clinical HCC specimens. Overall, we demonstrated that TRIM7 suppressed HCC progression through its direct negative regulation of Src and modulation of the Src-mTORC1-S6K1 axis; thus, we provided a novel insight into the development of HCC and defined a promising therapeutic strategy for cancers with overactive Src by modulating TRIM7.