ABSTRACT
BACKGROUND & AIMS: Because pancreatic cancer responds poorly to chemotherapy and immunotherapy, it is necessary to identify novel targets and compounds to overcome resistance to treatment. METHODS: This study analyzed genomic single nucleotide polymorphism sequencing, single-cell RNA sequencing, and spatial transcriptomics. Ehf-knockout mice, KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx1-Cre) mice, CD45.1+ BALB/C nude mice, and CD34+ humanized mice were also used as subjects. Multiplexed immunohistochemistry and flow cytometry were performed to investigate the proportion of tumor-infiltrated C-X-C motif chemokine receptor 2 (CXCR2)+ neutrophils. In addition, multiplexed cytokines assays and chromatin immunoprecipitation assays were used to examine the mechanism. RESULTS: The TP53 mutation-mediated loss of tumoral EHF increased the recruitment of CXCR2+ neutrophils, modulated their spatial distribution, and further induced chemo- and immunotherapy resistance in clinical cohorts and preclinical syngeneic mice models. Mechanistically, EHF deficiency induced C-X-C motif chemokine ligand 1 (CXCL1) transcription to enhance in vitro and in vivo CXCR2+ neutrophils migration. Moreover, CXCL1 or CXCR2 blockade completely abolished the effect, indicating that EHF regulated CXCR2+ neutrophils migration in a CXCL1-CXCR2-dependent manner. The depletion of CXCR2+ neutrophils also blocked the in vivo effects of EHF deficiency on chemotherapy and immunotherapy resistance. The single-cell RNA-sequencing results of PDAC treated with Nifurtimox highlighted the therapeutic significance of Nifurtimox by elevating the expression of tumoral EHF and decreasing the weightage of CXCL1-CXCR2 pathway within the microenvironment. Importantly, by simultaneously inhibiting the JAK1/STAT1 pathway, it could significantly suppress the recruitment and function of CXCR2+ neutrophils, further sensitizing PDAC to chemotherapy and immunotherapies. CONCLUSIONS: The study demonstrated the role of EHF in the recruitment of CXCR2+ neutrophils and the promising role of Nifurtimox in sensitizing pancreatic cancer to chemotherapy and immunotherapy.
Subject(s)
Chemokine CXCL1 , Drug Resistance, Neoplasm , Neutrophil Infiltration , Neutrophils , Pancreatic Neoplasms , Receptors, Interleukin-8B , Animals , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/metabolism , Receptors, Interleukin-8B/antagonists & inhibitors , Humans , Neutrophil Infiltration/drug effects , Drug Resistance, Neoplasm/genetics , Neutrophils/immunology , Neutrophils/metabolism , Neutrophils/drug effects , Mice , Chemokine CXCL1/metabolism , Chemokine CXCL1/genetics , Cell Line, Tumor , Mice, Knockout , Tumor Microenvironment , Immunotherapy/methods , Mice, Nude , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Mice, Inbred BALB C , Antineoplastic Agents/pharmacology , Signal Transduction , Mutation , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathologyABSTRACT
Targeting specific molecular drivers of tumor growth is a key approach in cancer therapy. Among these targets, the low-density lipoprotein receptor-related protein 6 (LRP6), a vital component of the Wnt signaling pathway, has emerged as an intriguing candidate. As a cell-surface receptor and vital co-receptor, LRP6 is frequently overexpressed in various cancer types, implicating its pivotal role in driving tumor progression. The pursuit of LRP6 as a target for cancer treatment has gained substantial traction, offering a promising avenue for therapeutic intervention. Here, this comprehensive review explores recent breakthroughs in our understanding of LRP6's functions and underlying molecular mechanisms, providing a profound discussion of its involvement in cancer pathogenesis and drug resistance. Importantly, we go beyond discussing LRP6's role in cancer by discussing diverse potential therapeutic approaches targeting this enigmatic protein. These approaches encompass a wide spectrum, including pharmacological agents, natural compounds, non-coding RNAs, epigenetic factors, proteins, and peptides that modulate LRP6 expression or disrupt its interactions. In addition, also discussed the challenges associated with developing LRP6 inhibitors and their advantages over Wnt inhibitors, as well as the drugs that have entered phase II clinical trials. By shedding light on these innovative strategies, we aim to underscore LRP6's significance as a valuable and multifaceted target for cancer treatment, igniting enthusiasm for further research and facilitating translation into clinical applications.
Subject(s)
Antineoplastic Agents , Low Density Lipoprotein Receptor-Related Protein-6 , Molecular Targeted Therapy , Neoplasms , Animals , Humans , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Low Density Lipoprotein Receptor-Related Protein-6/antagonists & inhibitors , Neoplasms/drug therapy , Neoplasms/metabolism , Wnt Signaling Pathway/drug effectsABSTRACT
Objective: This meta-analysis aimed to assess and evaluate the effect of nurse-led health management on the quality of life of patients with atrial fibrillation. Methods: We compared the outcomes of patients who received nurse-led intervention during hospitalization with those who did not, using a systematic retrospective and randomized controlled trial (RCT) analysis. We searched the studies in Cochrane Central Register, including PubMed, EmBase, Web of Science, Cochrane Library, WAN Data, CBM, CNKI, etc. Bias risks included in the study were evaluated by Cochrane Bias risk tool , and combined risk estimates were calculated. The main endpoints are the SF-36 and HADS scores and endpoints after surgery. We used a random effects model to combine the data. For continuous variables (such as SF-36 and HADS scores), we used standard mean difference for analysis, and for binary variables (such as the presence or absence of mental health problems), we used hazard ratio for analysis. The data are based on fixed or stochastic effects models, with standard mean differences and risk ratios for continuous and heterotaxic variables. Results: 3064 patients from 7 clinical studies were included in this meta-analysis. Postoperative SF-36 scores at 6 months in the nurse-led group were significantly higher than those in the routine nursing group in Role-Physical and Mental health. Postoperative SF-36 scores at 12 months in the nurse-led group were not significantly higher than those in the routine nursing group. The nurse-led group had a significantly lower HADS depression score than the conventional care group, but there was no significant difference in HADS anxiety score between the two groups. Conclusion: The main findings of this meta-analysis are that the nurse-led comprehensive management of atrial fibrillation can significantly improve the role-physical and mental health status of SF-36, reduce the HADS depression score, the incidence of cardiovascular hospitalization and atrial fibrillation at 6 months atrial fibrillation surgery. Additional high-quality RCTs should be conducted in the future. nurse-led interventions have the potential to significantly impact the care of patients with atrial fibrillation. By providing comprehensive management, education, and support, nurses can improve patient outcomes, enhance quality of life, and reduce healthcare burdens for both patients and providers. While this meta-analysis provides valuable insights, there are limitations that should be considered. Standardizing interventions and outcome measures, conducting larger studies with longer follow-up periods, including diverse populations and settings, and assessing the economic impact of nurse-led interventions are potential directions for future research in this field. Addressing these limitations would provide a more comprehensive understanding of the role of nurse-led interventions in the care of patients with atrial fibrillation.
Subject(s)
Atrial Fibrillation , Humans , Nurse's Role , Quality of Life , Randomized Controlled Trials as TopicABSTRACT
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumour with limited treatment options. Here, we identified syndecan binding protein (SDCBP), also known as syntenin1, as a novel targetable factor in promoting PDAC tumour progression. We also explored a therapeutic strategy for suppressing SDCBP expression. DESIGN: We used samples from patients with PDAC, human organoid models, LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse models, and PDX mouse models. Immunostaining, colony formation assay, ethynyl-2-deoxyuridine incorporation assay, real-time cell analysis, cell apoptosis assay, automated cell tracking, invadopodia detection and gelatin degradation assays, coimmunoprecipitation, and pull-down assays were performed in this study. RESULTS: The median overall survival and recurrence-free survival rates in the high-SDCBP group were significantly shorter than those in the low-SDCBP group. In vitro and in vivo studies have demonstrated that SDCBP promotes PDAC proliferation and metastasis. Mechanically, SDCBP inhibits CK1δ/ε-mediated YAP-S384/S387 phosphorylation, which further suppresses ß-TrCP-mediated YAP1 ubiquitination and proteasome degradation by directly interacting with YAP1. SDCBP interacts with the TAD domain of YAP1, mainly through its PDZ1 domain. Preclinical KPC mouse cohorts demonstrated that zinc pyrithione (ZnPT) suppresses PDAC tumour progression by suppressing SDCBP. CONCLUSIONS: SDCBP promotes the proliferation and metastasis of PDAC by preventing YAP1 from ß-TrCP-mediated proteasomal degradation. Therefore, ZnPT could be a promising therapeutic strategy to inhibit PDAC progression by suppressing SDCBP.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Mice , Animals , beta-Transducin Repeat-Containing Proteins/metabolism , Pancreatic Neoplasms/pathology , Pancreas/pathology , Carcinoma, Pancreatic Ductal/pathology , Cell Proliferation , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Syntenins/metabolism , Pancreatic NeoplasmsABSTRACT
BACKGROUND AND AIMS: The crosstalk between cancer stem cells (CSCs) and their niche is required for the maintenance of stem cell-like phenotypes of CSCs. Here, we identified E26 transformation-specific homologous factor (EHF) as a key molecule in decreasing the sensitivity of pancreatic cancer (PC) cells to CSCs' niche stimulus. We also explored a therapeutic strategy to restore the expression of EHF. DESIGN: We used a LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model and samples from patients with PC. Immunostaining, flow cytometry, sphere formation assays, anchorage-independent growth assay, in vivo tumourigenicity, reverse transcription PCR, chromatin immunoprecipitation (ChIP) and luciferase analyses were conducted in this study. RESULTS: CXCL12 derived from pancreatic stellate cells (PSCs) mediates the crosstalk between PC cells and PSCs to promote PC stemness. Tumorous EHF suppressed CSC stemness by decreasing the sensitivity of PC to CXCL12 stimulus and inhibiting the crosstalk between PC and CSC-supportive niches. Mechanically, EHF suppressed the transcription of the CXCL12 receptor CXCR4. EHF had a cell autonomous role in suppressing cancer stemness by inhibiting the transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppressed PC stemness and inhibited the crosstalk between PC and PSCs by upregulating EHF. Preclinical KPC mouse cohorts demonstrated that rosiglitazone sensitised PDAC to gemcitabine therapy. CONCLUSIONS: EHF decreased the sensitivity of PC to the stimulus from PSC-derived CSC-supportive niche by negatively regulating tumorous CXCR4. Rosiglitazone could be used to target PC stem cells and the crosstalk between CSCs and their niche by upregulating EHF.
Subject(s)
Neoplastic Stem Cells/drug effects , Pancreatic Neoplasms/pathology , Pancreatic Stellate Cells/drug effects , Receptors, CXCR4/metabolism , Rosiglitazone/pharmacology , Transcription Factors/metabolism , Animals , Cohort Studies , Disease Models, Animal , Humans , Hypoglycemic Agents/pharmacology , Mice , Mice, Inbred BALB C , Neoplastic Stem Cells/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Stellate Cells/metabolismABSTRACT
Fungi sense environmental signals and coordinate growth, development, and metabolism accordingly. Calcium-calmodulin-calcineurin signaling is a conserved cascade pathway in fungi. One of the most important downstream targets of this pathway is the transcription factor Crz1/CrzA, which plays an essential role in various cellular processes. The putative collaborators of Penicillium oxalicum CrzA (PoCrzA) were found, through tandem affinity purification followed by mass spectrometric analysis (TAP-MS). A total of 50 protein-protein interaction collaborators of PoCrzA were observed. Among them, some collaborators, such as the catalytic subunit of calcineurin (Cna1, calcineurin A), the regulatory catalytic subunit of calcineurin (Cnb1, calcineurin B), and a 14-3-3 protein Bmh1, which were previously reported in yeast, were identified. Some putative collaborators, including two karyopherins (exportin Los1 and importin Srp1), two kinases (Fus3 and Slt2p), and a general transcriptional corepressor (Cyc8), were also found. The CrzA deletion mutant ΔPocrzA exhibited slow hyphal growth, impaired conidiogenesis, and reduced extracellular cellulase synthesis. Phenotype and transcriptome analysis showed that PoCrzA regulated fungal development in a Flbs-BrlA-dependent manner and participated in cellulase synthesis by modulating cellulolytic gene expression. On the basis of the results of TAP-MS, transcriptome, and phenotypic analysis in P. oxalicum, our study was the first to draft the calcineurin-CrzA pathway in cellulolytic fungi.
Subject(s)
Calcineurin , Penicillium , Calcineurin/genetics , Calcineurin/metabolism , Fungal Proteins/genetics , Fungal Proteins/metabolism , Gene Expression Regulation, Fungal , Penicillium/genetics , Penicillium/metabolism , Phenotype , TranscriptomeABSTRACT
Generally, people prefer to dine in beautiful environments. Previous studies have reported that environmental factors affect an individual's perception of food; however, little is known about the effect of environmental aesthetics on food perception. In Experiment 1, we used photographs of restaurant (1a) or non-restaurant (1b) environments with high or low aesthetic value, paired with images of foods, and participants were asked to rate the visual, olfactory, and gustatory aesthetic value of the food. Results showed significantly higher ratings for food perception in all three sensory modalities in the high aesthetic value environment, together with positive emotion and the desire to eat, compared with the low aesthetic environment. Experiment 2 extended the study to two real-world environments (one high and one low aesthetic value) and actual food consumption. The results also found higher aesthetic ratings in the olfactory and gustatory systems and greater desire to eat again in an environment with high aesthetic value than in an environment with low aesthetic value. This research also explored the mediating role of emotion in the relationship between environmental aesthetics and food perception and found a significant mediating relationship. In conclusion, environmental aesthetics play an important role in food perception, and these findings provide insights into increasing positive food perception in daily life.
ABSTRACT
BACKGROUND: Emotional eaters eat to relieve their emotions. However, food also contains esthetic information. People generally perceive ugly food as unhealthy and unpalatable. Does the esthetic information of food influence an emotional eater's desire for food in a negative emotional state? In particular, do they have the same lower eating intentions for low esthetic food as non-emotional eaters? OBJECTIVE/DESIGN/MEASURES: Based on these questions, the present study examined whether the esthetic value of food influences emotional eaters' desires for food. The experiment used a 2 (eating type: emotional eating vs. non-emotional eating) × 2 (food style: high esthetic vs. low esthetic) mixed experimental design. We measured the emotional and non-emotional eaters' eating intentions for different esthetic foods when experiencing negative emotions. RESULTS: The results showed that emotional eaters have higher intention to eat high esthetic foods. However, they did not have a high eating intention for all foods, and their eating intention did not differ from that of non-emotional eaters when faced with low esthetic food. CONCLUSION: In conclusion, food esthetic value can affect individual eating intentions. Even for emotional eaters who are in a negative mood, they also did not have a higher eating intention for low esthetic food compared with no-emotional eater. LEVEL OF EVIDENCE: Level II: controlled trial without randomization.
Subject(s)
Eating , Intention , Eating/psychology , Emotions , Esthetics , Food , HumansABSTRACT
Pancreatic cancer has a low survival rate, and most patients have lymph node metastasis and distant metastasis at the time of diagnosis. Despite efforts to improve overall survival (OS) and recurrence free survival (RFS), the prognosis of pancreatic cancer remains poor, underscoring the importance of identifying new biomarkers to predict metastasis in patients with pancreatic cancer. Leukemia inhibitory factor (LIF) is overexpressed in many types of cancer and is involved in the development of various malignancies including pancreatic cancer. However, the role of LIF as a biomarker to predict metastasis in pancreatic cancer remains unclear. In this study, univariate and multivariate Cox regression analyses identified LIF expression in pancreatic tumor tissues as an independent risk factor related to worse OS and RFS. LIF overexpression was related to poor clinicopathological features such as lymph node metastasis and Pathological stage (pTNM) stage. Serum LIF levels were higher in pancreatic cancer patients than in healthy controls. The area under the receiver operating characteristic curve indicated that serum LIF is more effective than other biomarkers (CA199 and CEA) for predicting lymph node and distant metastasis.
Subject(s)
Biomarkers, Tumor/biosynthesis , Leukemia Inhibitory Factor/biosynthesis , Pancreatic Neoplasms/metabolism , Antigens, Tumor-Associated, Carbohydrate/blood , Biomarkers, Tumor/blood , Carcinoembryonic Antigen/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Leukemia Inhibitory Factor/blood , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/pathology , Prognosis , ROC CurveABSTRACT
In this study, we isolated a novel virulent Escherichia phage, SRT7. Its genome is a double-stranded linear DNA molecule containing 39,883 bp. Direct terminal repeats with a length of 175 bp, are present at both ends of the genome. The G+C content is 50.54%. Forty-seven putative protein coding genes were identified. No tRNA or rRNA genes were identified. Comparative genomic analysis revealed that phage SRT7 is a novel member of the T7-like phage cluster, but it forms a singleton subcluster.
Subject(s)
Bacteriophages/isolation & purification , Escherichia/virology , Genome, Viral , Bacteriophages/classification , Bacteriophages/genetics , Base Composition , Base Sequence , Open Reading Frames , Phylogeny , Whole Genome SequencingABSTRACT
PURPOSE: Syntenin1/SDCBP (syndecan binding protein), also known as melanoma differentiation associated gene-9 (MDA-9), is a PDZ domain-containing molecule, which was initially identified as a key oncogene in melanoma. However, the role of syntenin1 in triple-negative breast cancer (TNBC), especially in suppression of antitumour immune response, remains unknown. METHODS AND RESULTS: One hundred TNBC tissues were obtained after radical resection and used for analysis. High syntenin1 expression was associated with increased tumour size (r = 0.421, P < 0.001), presence of lymph node metastasis (r = 0.221, P = 0.044) and poor overall survival (P = 0.01) and recurrence-free survival (P = 0.007). Syntenin1 overexpression significantly promoted 4T1 tumour growth and lung metastasis in BALB/c mice by affecting CD8+ T cells. Western blot and flow cytometry analyses demonstrated that syntenin1 induced CD8+ T cell apoptosis in vitro and in vivo through upregulating PD-L1. Western blot demonstrated that syntenin1 upregulated PD-L1 expression by inducing Tyr705 stat3 phosphorylation, which was further confirmed by stat3 inhibition study. The correlation between syntenin1 and PD-L1 was further confirmed using tumour tissues derived from patients with TNBC (r = 0.509, P < 0.001). Efficacy studies indicated that 4T1-scramble tumour benefitted from anti-PD-L1 therapy (P < 0.001); however, 4T1-syntenin1-KD demonstrated no response to anti-PD-L1 treatment (P = 0.076). CONCLUSIONS: Syntenin1 exhibits a profound function in mediating T cells apoptosis by upregulating PD-L1 and thus could be used as a prognostic biomarker of TNBC. Tumoural syntenin1 expression corelated with anti-PD-L1 treatment efficacy. Targeting syntenin1-mediated T-cell suppression could be a potential strategy for improving the prognosis of patients with TNBC.
Subject(s)
B7-H1 Antigen/genetics , Gene Expression Regulation, Neoplastic , Immune Evasion/genetics , Syntenins/metabolism , Triple Negative Breast Neoplasms/immunology , Triple Negative Breast Neoplasms/metabolism , Adult , Aged , Animals , Apoptosis , B7-H1 Antigen/metabolism , Biomarkers, Tumor , Cell Line, Tumor , Female , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Middle Aged , Neoplasm Grading , Neoplasm Staging , STAT3 Transcription Factor/metabolism , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathologyABSTRACT
In this study, an Escherichia coli virulent phage, SRT8, was isolated from sewage sludge samples collected from Jinan, Shandong Province, China. The genome of phage SRT8 consists of 49,579 bp with 47.83% G+C content. The phage genome contains 84 putative protein-coding genes, and no rRNA or tRNA genes. Comparative genomics analysis showed that the E. coli phage SRT8 is a member of a new species and belongs to the subfamily Tunavirinae, which includes T1-like phages.
Subject(s)
Coliphages/genetics , Escherichia coli/virology , Genome, Viral , Open Reading Frames , Siphoviridae/genetics , Base Composition , China , Chromosome Mapping , Coliphages/classification , Coliphages/isolation & purification , Coliphages/pathogenicity , Founder Effect , Genome Size , Humans , Sewage/microbiology , Sewage/virology , Siphoviridae/classification , Siphoviridae/isolation & purification , Siphoviridae/pathogenicity , Virulence , Whole Genome SequencingABSTRACT
As the universal methyl donor for methylation reactions, S-adenosylmethionine (AdoMet) plays an indispensable role in most cellular metabolic processes. AdoMet is synthesized by AdoMet synthetase. We identified the only one AdoMet synthetase (PoSasA) in filamentous fungus Penicillium oxalicum. PoSasA was widely distributed in mycelium at different growth stages. The absence of PoSasA was lethal for P. oxalicum. The misregulation of the PoSasA encoding gene affected the synthesis of extracellular cellulolytic enzymes. The expression levels of cellobiohydrolase encoding gene cbh1/cel7A, ß-1-4 endoglucanase eg1/cel7B, and xylanase encoding gene xyn10A were remarkably downregulated as a result of decreased PosasA gene expression. The production of extracellular cellulases and hemicellulases was also reduced. By contrast, the overexpression of PosasA improved the production of extracellular cellulases and hemicellulases. A total of 133 putative interacting proteins with PoSasA were identified using tandem affinity purification and mass spectrometry. The results of functional enrichment on these proteins showed that they were mainly related to ATP binding, magnesium ion binding, and ATP synthetase activity. Several methyltransferases were also observed among these proteins. These results were consistent with the intrinsic feature of AdoMet synthetase. This work reveals the indispensable role of PoSasA in various biological processes.
Subject(s)
Gene Expression Regulation, Fungal , Methionine Adenosyltransferase , Microbial Viability , Penicillium , Cellulases/genetics , Cellulases/metabolism , Gene Expression Regulation, Fungal/genetics , Methionine Adenosyltransferase/genetics , Methionine Adenosyltransferase/metabolism , Microbial Viability/genetics , Penicillium/enzymology , Penicillium/geneticsABSTRACT
OBJECTIVE: Gang-Qing-Ning (GQN) is a traditional Chinese medicine formula that has been used in the treatment of hepatocellular carcinoma (HCC) in the folk population for decades. However, scientific validation is still necessary to lend credibility to the traditional use of GQN against HCC. This study investigates the antitumor effect of GQN on H22 tumor-bearing mice and its possible mechanism. METHODS: Fifty H22 tumor-bearing mice were randomly assigned to five groups. Three groups were treated with high, medium, and low dosages of GQN (27.68, 13.84, and 6.92 g/kg, respectively); the positive control group was treated with cytoxan (CTX) (20 mg/kg) and the model group was treated with normal saline. After 10 days' treatment, the tumor inhibitory rates were calculated. Pathological changes in tumor tissue were observed, and the key proteins and genes of the mitochondrial apoptosis pathway were measured, as well as the mRNA expression levels of VEGF in tumor tissue. RESULTS: The tumor inhibitory rates of high, medium, and low dosages of GQN groups were 47.39%, 38.26%, and 22.17%, respectively. The high dosage of the GQN group significantly increased the protein and mRNA expression levels of Bax, Cyt-C, and cleaved Caspase 3 (or Caspase 3) (P < 0.01) but decreased the expression levels of Bcl-2, VEGF, and microvessel density (MVD) (P < 0.01). CONCLUSIONS: The high dosage of GQN can significantly inhibit the tumor growth in H22 tumor-bearing mice. It exerts the antitumor effect by enhancing proapoptotic factors and inhibiting the antiapoptotic factor of the mitochondrial apoptosis pathway and inhibiting tumor angiogenesis.
ABSTRACT
Increasing evidence indicates that depression affects bone metabolism to some extent, but the specific mechanisms are still unclear. Numerous studies have confirmed that a variety of signaling molecules are involved in depression's impact on fracture healing, including serum monoamine neurotransmitters, cytokines, inflammatory markers, growth factors, and metabolites. This article comprehensively discusses the effects of depression-associated signaling molecules on bone metabolism and their underlying mechanisms to provide a basis for early preventive intervention for delayed fracture healing in patients with depression.
Subject(s)
Bone and Bones/metabolism , Depression/metabolism , Animals , HumansABSTRACT
Histone methylation is associated with transcription regulation, but its role for glycoside hydrolase (GH) biosynthesis is still poorly understood. We identified the histone H3 lysine 79 (H3K79)-specific methyltransferase PoDot1 in Penicillium oxalicum. PoDot1 affects conidiation by regulating the transcription of key regulators (BrlA, FlbC, and StuA) of asexual development and is required in normal hyphae septum and branch formation by regulating the transcription of five septin-encoding genes, namely, aspA, aspB, aspC, aspD, and aspE. Tandem affinity purification/mass spectrometry showed that PoDot1 has no direct interaction with transcription machinery, but it affects the expressions of extracellular GH genes extensively. The expression of genes (amy15A, amy13A, cel7A/cbh1, cel61A, chi18A, cel3A/bgl1, xyn10A, cel7B/eg1, cel5B/eg2, and cel6A/cbh2) that encode the top 10 GHs was remarkably downregulated by Podot1 deletion (ΔPodot1). Consistent with the decrease in gene transcription level, the activities of amylases and cellulases were significantly decreased in ΔPodot1 mutants in agar (solid) and fermentation (liquid) media. The repression of GH gene expressions caused by PoDot1 deletion was not mediated by key transcription factors, such as AmyR, ClrB, CreA, and XlnR, but was accompanied by defects in global demethylated H3K79 (H3K79me2) and trimethylated H3K79 (H3K79me3). The impairment of H3K79me2 on specific GH gene loci was observed due to PoDot1 deletion. The results implies that defects of H3K79 methylation is the key reason of the downregulated transcription level of GH-encoding genes and reveals the indispensable role of PoDot1 in extracellular GH biosynthesis.
ABSTRACT
Novel 2D porous MnIn2Se4 nanosheet photocatalysts have been synthesized for the first time via a simple hydrothermal method, which exhibit promising activity for photocatalytic water splitting without any sacrificial agent due to their large specific surface area, 2D layered morphology, porous structure and suitable energy gap.
ABSTRACT
OBJECTIVE: Stromal interaction molecule 1 (STIM1) overexpression has been reported to play an important role in progression of several cancers. However, the mechanism of STIM1 overexpression and its relationship with hypoxia in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: STIM1 and HIF-1α expression was tested using immunohistochemistry in tissue microarray (TMA) including pancreatic cancer and matched normal pancreatic tissues, and their relationships with clinicopathological parameters were statistically analyzed. q-PCR, Western blot, ChIP, and luciferase assay were employed to 030 analyze transcriptional regulation between HIF-1α and STIM1 in pancreatic cancer PANC-1 cells. RESULTS: Both STIM1 and HIF-1α showed higher positive rates and up-regulated expression in cancer tissues compared to that of normal tissues (P < 0.05). The Kaplan-Meier method revealed that higher HIF-1α and STIM1 expression levels were significantly correlated with decreased disease-free survival ( P = 0.025 and P = 0.029, respectively). The expression of HIF-1α showed a significant positive correlation with that of STIM1 in cancer tissues (rs = 0.3343, P = 0.0011) and pancreatic cancer cell lines. Furthermore, ChIP and luciferase assays confirmed that HIF-1α bound to the STIM1 promoter and regulated its expression in PANC-1 cells. CONCLUSIONS: In hypoxia microenvironment, up-regulated expression of STIM1 mediated by HIF-1α promotes PDAC progression. HIF-1α and STIM1 are potential prognostic markers and/or therapeutic targets for PDAC treatment.
ABSTRACT
BACKGROUND: Enzymatic hydrolysis of lignocellulose by fungi is a key step in global carbon cycle and biomass utilization. Cellulolytic enzyme production is tightly controlled at a transcriptional level. Here, we investigated the roles of different histone lysine methylation modifications in regulating cellulolytic enzyme gene expression, as histone lysine methylation is an important process of chromatin regulation associated with gene transcription. RESULTS: PoSet1 and PoSet2 in Penicillium oxalicum, orthologs of Set1 and Set2 in budding yeast, were associated with the methylation of histone H3 lysine 4 (H3K4) and lysine 36 (H3K36). Cellulolytic enzyme production was extensively upregulated by the disruption of PoSet2, but was significantly downregulated by the disruption of PoSet1. We revealed that the activation of cellulolytic enzyme genes was accompanied by the increase of H3K4me3 signal, as well as the decrease of H3K36me1 and H3K36me3 signal on specific gene loci. The repression of cellulolytic enzyme genes was accompanied by the absence of global H3K4me1 and H3K4me2. An increase in the H3K4me3 signal by Poset2 disruption was eliminated by the further disruption of Poset1 and accompanied by the repressed cellulolytic enzyme genes. The active or repressed genes were not always associated with transcription factors. CONCLUSION: H3K4 methylation is an active marker of cellulolytic enzyme production, whereas H3K36 methylation is a marker of repression. A crosstalk occurs between H3K36 and H3K4 methylation, and PoSet2 negatively regulates cellulolytic enzyme production by antagonizing the PoSet1-H3K4me3 pathway. The balance of H3K4 and H3K36 methylation is required for the normal transcription of cellulolytic enzyme genes. These results extend our previous understanding that cellulolytic enzyme gene transcription is primarily controlled by transcription factors.
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFß1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.