ABSTRACT
To identify the role of enterotoxin-related genes in colorectal cancer (CRC) development and progression. Upregulated differentially expressed genes shared by three out of five Gene Expression Omnibus (GEO) data sets were included to screen the key enterotoxin-induced oncogenes (EIOGs) according to criteria oncogene definition, enrichment, and protein-protein interaction (PPI) network analysis, followed by prognosis survival, immune infiltration, and protential drugs analyses was performed via integration of RNA-sequencing data and The Cancer Genome Atlas-derived clinical profiles. We screened nine common key EIOGs from at least three GEO data sets. A Cox proportional hazards regression models verified that more alive cases, decreased overall survival, and highest 4-year survival prediction in CRC patients with high-risk score. Protein tyrosine phosphatase receptor type F polypeptide-interacting protein alpha-4 (PPFIA4), STY11, SCN3B, and SPTBN5 were shared in the same PPI network. Immune infiltration results showed that SCN3B and synaptotagmin 11 expression were obviously associated with B cell, macrophage, myeloid dendritic cell, neutrophils, and T cell CD4+ and CD8+ in both colon adenocarcinoma and rectal adenocarcinoma. CHIR-99021, MLN4924, and YK4-279 were identified as the potential drugs for treatment. Finally, upregulated EIOGs genes PPFIA4 and SCN3B were found in colon adenocarcinoma and PPFIA4 and SCN3B were proved to promote cell proliferation and migration in vitro. We demonstrated here that EIOGs promoting a malignancy phenotype was related with poor survival and prognosis in CRC, which might be served as novel therapeutic targets in CRC management.
Subject(s)
Colorectal Neoplasms , Enterotoxins , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Progression , Gene Expression Regulation, Neoplastic , Protein Interaction MapsABSTRACT
Enterotoxigenic Bacteroides fragilis (ETBF) is believed to promote the malignant process of colorectal cancer (CRC), but the underlying molecular mechanism still needs to be revealed. CRC cells (SW480 and HCT-116) were treated with ETBF strain. Cell proliferation, invasion and, migration were evaluated by cell counting kit 8 assay, EdU assay, colony formation assay, transwell assay, and wound healing assay. Protein expression was analyzed by western blot. MicroRNA (miR)-139-3p and histone deacetylase 3 (HDAC3) expression levels in tissues and cells were determined by qRT-PCR. Xenograft tumor model was conducted to evaluate the effect of miR-139-3p on CRC tumor growth. ETBF treatment could promote CRC cell proliferation, invasion and migration. MiR-139-3p expression was decreased by ETBF, and its overexpression reversed the effect of ETBF on CRC cell progression. HDAC3 negatively regulated miR-139-3p expression, and its overexpression facilitated CRC cell behaviors via reducing miR-139-3p expression. Moreover, HDAC3 expression was increased by ETBF, and its knockdown also abolished ETBF-mediated CRC cell progression. Additionally, miR-139-3p overexpression could reduce CRC tumor growth in vivo. ETBF aggravated CRC proliferation and metastasis via the regulation of HDAC3/miR-139-3p axis. The discovery of ETBF/HDAC3/miR-139-3p axis may provide a new direction for CRC treatment.
ABSTRACT
Aristolochic acid (AA) exposure is a severe public health concern worldwide. AAs damage the kidney with an inevitable acute phase that is similar to acute kidney injury (AKI). Gasdermin E (GSDME) is abundant in the kidney; thus; it-mediated pyroptosis might be essential in connecting cell death and inflammation and promoting AAs-AKI. However, the role and exact mechanism of pyroptosis in AAs-AKI have not been investigated. In this study, aristolochic acid I (AAI) was used to establish AKI models. The expression and translocation results showed GSDME-mediated pyroptosis in AAI-AKI. Knocking down GSDME attenuated AAI-induced cell death and transcription of proinflammatory cytokines. Mechanistic research inhibiting caspase (casp) 3, casp 8, and casp 9 with specific chemical antagonists demonstrated that GSDME was activated by cleaved casp 3. Furthermore, the kinase activity of upstream receptor-interacting protein kinase 1 (RIPK1) was significantly elevated, and inhibiting RIPK1 with specific inhibitors markedly improved AAI-induced cell damage. In addition, the level of autophagy was obviously increased. Pretreatment with a specific autophagic inhibitor (3-methyladenine) or knockdown of autophagic genes (Atg5 or Atg7) evidently reduced the activity of RIPK1 and downstream apoptosis and pyroptosis, thus attenuating AA-induced cell injury, which suggested that RIPK1 was a novel link conferring autophagic promotion of pyroptosis. These findings reveal GSDME-mediated pyroptosis for the first time in AAI-induced AKI, propose its novel role in the transcription of cytokines, and demonstrate that autophagy promotes pyroptosis via the RIPK1-dependent apoptotic pathway. This study promotes the understanding of the toxic effects and exact mechanisms of AAs. This will contribute to evaluating the environmental risk of AA exposure and might provide potential therapeutic targets for AA-AKI.
ABSTRACT
Cobalt is a transition element that abundantly exists in the environment. Besides direct hypoxia stress, cobalt ions indirectly induce hypoxia-reoxygenation injury (HRI), the main cause of acute kidney injury (AKI), a life-threatening clinical syndrome characterized by the necrosis of the proximal tubular epithelial cells (PTECs) and inflammation. Pyroptosis, a type of inflammatory programmed cell death, might play an essential role in HRI-AKI. However, whether pyroptosis is involved in cobalt chloride (CoCl2)-induced HRI-AKI remains unknown. Autophagy is a cellular biological process maintaining cell homeostasis that is involved in cell damage in AKI, yet the underlying regulatory mechanism of autophagy on pyroptosis has not been fully understood. In this study, the in vitro and in vivo models of CoCl2-induced HRI-AKI were established with HK-2 cell line and C57BL/6J mouse. Pyroptosis-related markers were detected with western blotting and immunofluorescence assays, and results showed that gasdermin E (GSDME)-mediated pyroptosis was involved in the cell damage in HRI-AKI. Specific chemical inhibitors of caspase 3, caspase 8, and caspase 9 significantly inhibited GSDME-mediated pyroptosis, verifying that GSDME-mediated pyroptosis was induced via the activation of caspase 3/8/9. The western blotting and immunofluorescence assays were adopted to detect the accumulation of the autophagosomes, and results suggested that HRI increased the autophagic level. The effects of autophagy on apoptosis and pyroptosis were evaluated using lentivirus transfection assays to knock down autophagy-specific genes atg5 and fip200, and results demonstrated that autophagy induced GSDME-mediated pyroptosis via apoptotic pathways in HRI-AKI. Our results revealed the involvement of GSDME-mediated pyroptosis in CoCl2-induced HRI-AKI and promoted the understanding of the regulatory mechanism of GSDME cleavage. Our study might provide a potential therapeutic target for HRI-AKI, and will be helpful for the risk evaluation of cobalt exposure.
Subject(s)
Acute Kidney Injury , Pyroptosis , Acute Kidney Injury/chemically induced , Animals , Apoptosis , Autophagy , Caspase 3/metabolism , Cobalt/toxicity , Humans , Hypoxia , Mice , Mice, Inbred C57BL , Pore Forming Cytotoxic ProteinsABSTRACT
Truffle cultivation has drawn more and more attention for its high economic and ecological values in the world. To select symbionts suitable for cultivation purposes, we conducted greenhouse-based mycorrhization trials of two Tuber species (T. formosanum and T. pseudohimalayense) with five broad-leaved tree species (Corylus yunnanensis, Quercus aliena var. acutiserrata, Q. acutissima, Q. robur, Q. variabilis) and one conifer species (Pinus armandii). Axenically germinated seedlings of all tree species were either inoculated, or not, with spore suspensions of these two truffles in the greenhouse. Eight months after inoculation, T. formosanum or T. pseudohimalayense ectomycorrhizae were successfully formed on these six tree species, as evidenced by both morphological and molecular analyses. All selected trees showed good receptivity to mycorrhization by both fungi, with average colonization rates visually estimated at 40-50%. Plant growth, photosynthesis, and nutrient uptake were assessed 2 years after inoculation and were mainly affected by host species. Mycorrhization by both fungi significantly improved P uptake of the hosts, and the interaction between truffle species and host plant species had significant effects on leaf water and leaf K concentrations. In addition, a significantly negative correlation between leaf Ca and leaf C concentration was found across all the seedlings. In addition, mycorrhization had slightly increased plant stem and canopy, but had no significant effects on plant photosynthesis. Overall, these results suggest that the effects of these two Tuber ECMF on plant growth and nutrient acquisition depend on the identity of the host species. Moreover, all selected plant species could be symbiotic partners with either T. pseudohimalayense or T. formosanum for field cultivation purposes.
Subject(s)
Ascomycota , Mycorrhizae , Quercus , Quercus/microbiology , Seedlings/microbiology , Trees/microbiologyABSTRACT
Microbial communities and environmental conditions are both of great importance for efficient utilization of agroforestry resources. Nevertheless, knowledge about the role of soluble nutrients and enzymatic properties, and their inner links with microbial communities remain limited. This is especially the case for the co-composting of agricultural and forestry biowaste. Here, we investigate the succession of key microbes during co-composting (sawdust + cow manure, SA; straw + cow manure, ST), employing amplicon sequencing, enzyme assays, and physicochemical analyses. N-fixing bacteria (Pseudomonas) and C-degrading fungi (Acaulium) have been identified as dominant taxa during such co-composting. Although eight antibiotic resistance genes were found to persist during composting, pathogenic microbes declined with composting time. NO3--N content was screened as a determinant structuring the bacterial and fungal communities, with importance also shown for C-degrading enzymes such as cellulose, laccase, and peroxidase activity. These results identify the key microbial taxa and their main interactive environmental factors, which are potentially valuable for the development of a mixed microbial inoculant to accelerate the maturation of agroforestry biowastes composting.
Subject(s)
Composting , Mycobiome , Animals , Female , Cattle , Manure/microbiology , Soil/chemistry , Bacteria/geneticsABSTRACT
BACKGROUND The aim of this study was to investigate distribution rules of radial peripapillary capillaries (RPCs) density and correlations with retinal nerve fiber layers (RNFL) thickness in normal subjects. MATERIAL AND METHODS We included 78 eyes of 78 healthy subjects examined by optical coherence tomography angiography (OCTA). RPCs density and RNFL thickness were measured automatically. Distributions of RPCs density and RNFL thickness were analyzed at different locations. Correlations of these 2 parameters and relationship with large vessels were evaluated by Spearman test. RESULTS Average density for overall, peripapillary, and inside disc RCPs was 56.12±2.51%, 58.56±2.84%, and 60.16±4.01%, respectively. Overall and peripapillary RCPs density were positively correlated with RNFL thickness (r=0.595, P.
Subject(s)
Capillaries/cytology , Nerve Fibers/physiology , Optic Disk/blood supply , Retinal Vessels/cytology , Adult , Female , Follow-Up Studies , Healthy Volunteers , Humans , Male , Middle Aged , Visual Fields , Young AdultABSTRACT
Heart failure (HF), a clinical syndrome with high morbidity and mortality, is becoming a growing public health problem. Dilated cardiomyopathy (DCM) is one of the major causes of HF, yet the molecular mechanisms underlying DCM-mediated HF are not completely understood. Previous studies have shown that dysregulation of arachidonic acid (AA) metabolism could contribute to the development of HF. To explore the roles of microRNAs (miRNAs) in regulating AA metabolism in HF, we used two public datasets to analyze the expression changes of miRNAs in the patients of DCM-mediated HF. A total of 101 and 88 miRNAs with significant abundance alterations in the two dataset were obtained, respectively. Around 1/3 of these miRNAs were predicted to target AA metabolic pathway genes. We also investigated the distribution of known single nucleotide polymorphisms (SNPs) within the sequences of miRNAs dysregulated in DCM-mediated HF patients, and identified miRNAs harboring high number of SNPs in either the seed regions or the entire sequences. These information could provide clues for further functional studies of miRNAs in the pathogeny of DCM-mediated HF.
Subject(s)
Cardiomyopathy, Dilated , Heart Failure , MicroRNAs , Arachidonic Acid , Cardiomyopathy, Dilated/genetics , Heart Failure/genetics , Humans , MicroRNAs/geneticsABSTRACT
Mitochondria play a central role in the maintenance of the naive state of embryonic stem cells. Many details of the mechanism remain to be fully elucidated. Solute carrier family 25 member 36 (Slc25a36) might regulate mitochondrial function through transporting pyrimidine nucleotides for mtDNA/RNA synthesis. Its physical role in this process remains unknown; however, Slc25a36 was recently found to be highly expressed in naive mouse embryonic stem cells (mESCs). Here, the function of Slc25a36 was characterized as a maintenance factor of mESCs pluripotency. Slc25a36 deficiency (via knockdown) has been demonstrated to result in mitochondrial dysfunction, which induces the differentiation of mESCs. The expression of key pluripotency markers (Pou5f1, Sox2, Nanog, and Utf1) decreased, while that of key TE genes (Cdx2, Gata3, and Hand1) increased. Cdx2-positive cells emerged in Slc25a36-deficient colonies under trophoblast stem cell culture conditions. As a result of Slc25a36 deficiency, mtDNA of knockdown cells declined, leading to impaired mitochondria with swollen morphology, decreased mitochondrial membrane potential, and low numbers. The key transcription regulators of mitochondrial biogenesis also decreased. These results indicate that mitochondrial dysfunction leads to an inability to support the pluripotency maintenance. Moreover, down-regulated glutathione metabolism and up-regulated focal adhesion reinforced and stabilized the process of differentiation by separately enhancing OCT4 degradation and promoting cell spread. This study improves the understanding of the function of Slc25a36, as well as the relationship of mitochondrial function with naive pluripotency maintenance and stem cell fate decision.
Subject(s)
Glutathione/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Proteins/metabolism , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/metabolism , Nucleotide Transport Proteins/metabolism , Animals , CDX2 Transcription Factor/metabolism , Cell Differentiation/genetics , Cells, Cultured , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Focal Adhesions , Gene Expression Regulation , Gene Knockdown Techniques , Mice , Mitochondria/metabolism , Mitochondria/ultrastructure , Mitochondrial Membrane Transport Proteins/antagonists & inhibitors , Mitochondrial Membrane Transport Proteins/genetics , Mitochondrial Proteins/antagonists & inhibitors , Mitochondrial Proteins/genetics , Nucleotide Transport Proteins/antagonists & inhibitors , Nucleotide Transport Proteins/genetics , Octamer Transcription Factor-3/metabolismABSTRACT
Roots and root-released organic anions play important roles in uptake of phosphorus (P), an essential macronutrient for food production. Oat, ranking sixth in the world's cereal production, contains valuable nutritional compounds and can withstand poor soil conditions. Our aim was to investigate root transcriptional and metabolic responses of oat grown under P-deficient and P-sufficient conditions. We conducted a hydroponic experiment and measured root morphology and organic anion exudation, and analysed changes in the transcriptome and metabolome. Oat roots showed enhanced citrate and malate exudation after 4 weeks of P deficiency. After 10 d of P deficiency, we identified 9371 differentially expressed transcripts with a 2-fold or greater change (P<0.05): 48 sequences predicted to be involved in organic anion biosynthesis and efflux were consistently up-regulated; 24 up-regulated transcripts in oat were also found to be up-regulated upon P starvation in rice and wheat under similar conditions. Phosphorylated metabolites (i.e. glucose-6-phosphate, myo-inositol phosphate) were reduced dramatically, while citrate and malate, some sugars and amino acids increased slightly in P-deficient oat roots. Our data are consistent with a strategy of increased organic anion efflux and a shift in primary metabolism in response to P deficiency in oat.
Subject(s)
Avena/genetics , Metabolome , Phosphorus/deficiency , Transcriptome , Anions/metabolism , Avena/metabolism , Plant Roots/genetics , Plant Roots/metabolismABSTRACT
Large numbers of lipids exist in the porcine oocytes and early embryos and have the positive effects on their development, suggesting that the lipids may play an important role in pluripotency establishment and maintenance in pigs. However, the effects of lipids and their metabolites, such as fatty acids on reprogramming and the pluripotency gene expression of porcine-induced pluripotent stem cells (iPSCs), are unclear. Here, we generated the porcine iPSCs that resemble the mouse embryonic stem cells (ESCs) under lipid and fatty-acid-enriched cultural conditions (supplement of AlbuMAX). These porcine iPSCs show positive for the ESCs pluripotency markers and have the differentiation abilities to all three germ layers, and importantly, have the capability of aggregation into the inner cell mass (ICM) of porcine blastocysts. We further confirmed that lipid and fatty acid enriched condition can promote the cell proliferation and improve reprogramming efficiency by elevating cAMP levels. Interestingly, this lipids supplement promotes mesenchymal-epithelial transition (MET) through the cAMP/PKA/CREB signal pathway and upregulates the E-cadherin expression during porcine somatic cell reprogramming. The lipids supplement also makes a contribution to lipid droplets accumulation in the porcine iPSCs that resemble porcine preimplantation embryos. These findings may facilitate understanding of the lipid metabolism in porcine iPSCs and lay the foundation of bona fide porcine embryonic stem cell derivation.
Subject(s)
CREB-Binding Protein/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Cyclic AMP/metabolism , Dietary Supplements , Induced Pluripotent Stem Cells/metabolism , Lipid Metabolism , Lipids , Signal Transduction , Animals , Cell Differentiation , Cell Proliferation , Cells, Cultured , Cellular Reprogramming , Fatty Acids/metabolism , Fibroblasts , Induced Pluripotent Stem Cells/drug effects , Lipids/pharmacology , Models, Biological , Proto-Oncogene Proteins c-met/genetics , SwineABSTRACT
The hepatitis C virus (HCV) is a major etiologic agent for severe liver diseases (e.g. cirrhosis, fibrosis and hepatocellular carcinoma). Approximately 140 million people have chronic HCV infections and about 500 000 die yearly from HCV-related liver pathologies. To date, there is no licensed vaccine available to prevent HCV infection and production of a HCV vaccine remains a major challenge. Here, we report the successful production of the HCV E1E2 heterodimer, an important vaccine candidate, in an edible crop (lettuce, Lactuca sativa) using Agrobacterium-mediated transient expression technology. The wild-type dimer (E1E2) and a variant without an N-glycosylation site in the E2 polypeptide (E1E2∆N6) were expressed, and appropriate N-glycosylation pattern and functionality of the E1E2 dimers were demonstrated. The humoral immune response induced by the HCV proteins was investigated in mice following oral administration of lettuce antigens with or without previous intramuscular prime with the mammalian HEK293T cell-expressed HCV dimer. Immunization by oral feeding only resulted in development of weak serum levels of anti-HCV IgM for both antigens; however, the E1E2∆N6 proteins produced higher amounts of secretory IgA, suggesting improved immunogenic properties of the N-glycosylation mutant. The mice group receiving the intramuscular injection followed by two oral boosts with the lettuce E1E2 dimer developed a systemic but also a mucosal immune response, as demonstrated by the presence of anti-HCV secretory IgA in faeces extracts. In summary, our study demonstrates the feasibility of producing complex viral antigens in lettuce, using plant transient expression technology, with great potential for future low-cost oral vaccine development.
Subject(s)
Lactuca/genetics , Viral Envelope Proteins/immunology , Viral Hepatitis Vaccines/administration & dosage , Viral Hepatitis Vaccines/immunology , Administration, Oral , Animals , Female , HEK293 Cells , Humans , Immunity, Humoral , Mice, Inbred BALB C , Plants, Genetically Modified , Protein Engineering/methods , Protein Multimerization , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/isolation & purification , Viral Envelope Proteins/genetics , Viral Hepatitis Vaccines/geneticsABSTRACT
Dengue fever is a disease in many parts of the tropics and subtropics and about half the world's population is at risk of infection according to the World Health Organization. Dengue is caused by any of the four related dengue virus serotypes DEN-1, -2, -3 and -4, which are transmitted to people by Aedes aegypti mosquitoes. Currently there is only one vaccine (Dengvaxia(®)) available (limited to a few countries) on the market since 2015 after half a century's intensive efforts. Affordable and accessible vaccines against dengue are hence still urgently needed. The dengue envelop protein domain III (EDIII), which is capable of eliciting serotype-specific neutralizing antibodies, has become the focus for subunit vaccine development. To contribute to the development of an accessible and affordable dengue vaccine, in the current study we have used plant-based vaccine production systems to generate a dengue subunit vaccine candidate in tobacco. Chloroplast genome engineering was applied to express serotype-specific recombinant EDIII proteins in tobacco chloroplasts using both constitutive and ethanol-inducible expression systems. Expression of a tetravalent antigen fusion construct combining EDIII polypeptides from all four serotypes was also attempted. Transplastomic EDIII-expressing tobacco lines were obtained and homoplasmy was verified by Southern blot analysis. Northern blot analyses showed expression of EDIII antigen-encoding genes. EDIII protein accumulation levels varied for the different recombinant EDIII proteins and the different expression systems, and reached between 0.8 and 1.6 % of total cellular protein. Our study demonstrates the suitability of the chloroplast compartment as a production site for an EDIII-based vaccine candidate against dengue fever and presents a Gateway(®) plastid transformation vector for inducible transgene expression.
Subject(s)
Antigens, Viral/biosynthesis , Chloroplasts/genetics , Dengue Virus/immunology , Genetic Techniques , Nicotiana/genetics , Amino Acid Sequence , Antigens, Viral/chemistry , Antigens, Viral/metabolism , Ethanol/pharmacology , Genetic Vectors/metabolism , Plants, Genetically Modified , Protein Domains , Recombinant Proteins/metabolism , Regeneration , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/metabolismABSTRACT
Phototropins (phot1 and phot2), the blue light receptors in plants, regulate hypocotyl phototropism in a fluence-dependent manner. Especially under high fluence rates of blue light (HBL), the redundant function mediated by both phot1 and phot2 drastically restricts the understanding of the roles of phot2. Here, systematic analysis of phototropin-related mutants and overexpression transgenic lines revealed that HBL specifically induced a transient increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in Arabidopsis (Arabidopsis thaliana) hypocotyls and that the increase in [Ca(2+)]cyt was primarily attributed to phot2. Pharmacological and genetic experiments illustrated that HBL-induced Ca(2+) increases were modulated differently by phot1 and phot2. Phot2 mediated the HBL-induced increase in [Ca(2+)]cyt mainly by an inner store-dependent Ca(2+)-release pathway, not by activating plasma membrane Ca(2+) channels. Further analysis showed that the increase in [Ca(2+)]cyt was possibly responsible for HBL-induced hypocotyl phototropism. An inhibitor of auxin efflux carrier exhibited significant inhibitions of both phototropism and increases in [Ca(2+)]cyt, which indicates that polar auxin transport is possibly involved in HBL-induced responses. Moreover, PHYTOCHROME KINASE SUBSTRATE1 (PKS1), the phototropin-related signaling element identified, interacted physically with phototropins, auxin efflux carrier PIN-FORMED1 and calcium-binding protein CALMODULIN4, in vitro and in vivo, respectively, and HBL-induced phototropism was impaired in pks multiple mutants, indicating the role of the PKS family in HBL-induced phototropism. Together, these results provide new insights into the functions of phototropins and highlight a potential integration point through which Ca(2+) signaling-related HBL modulates hypocotyl phototropic responses.
Subject(s)
Arabidopsis Proteins/metabolism , Calcium/metabolism , Cytosol/metabolism , Phosphoproteins/metabolism , Phototropism/physiology , Arabidopsis/metabolism , Arabidopsis/physiology , Arabidopsis Proteins/genetics , Calmodulin/genetics , Calmodulin/metabolism , Gene Expression Regulation, Plant , Hypocotyl/physiology , Indoleacetic Acids/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Light , Membrane Proteins , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mutation , Phosphoproteins/genetics , Plants, Genetically Modified , Protein Serine-Threonine Kinases , Signal TransductionABSTRACT
Penetrating injuries with reinforced screwed steel bar in the skull base represent a unique challenge for oral maxillofacial surgeons. Management of these injuries is complicated by associated injuries and the proximity to vital neurovascular structures. A 35-year-old man was admitted to our hospital because of injury due to a downward fall upon a reinforced steel rod. Radiologic studies of the skull base revealed that the steel bar traversed the temporomandibular space between the left cervical spine and the mastoid process to the space between the inner side of the left mandibular ramus and the maxilla. We performed osteotomy of the left mastoid process tip and the left mandibular ramus to take out the steel bar from the maxilla and repaired the left mandible with internal fixation. Appropriate preoperative planning, including three-dimensional computed tomographic images, is integral in the surgical approach for the safe removal of such objects.
Subject(s)
Construction Materials , Foreign Bodies/diagnosis , Foreign Bodies/surgery , Mandibular Injuries/diagnosis , Mandibular Injuries/surgery , Maxilla/injuries , Maxilla/surgery , Maxillary Sinus/injuries , Neck Injuries/surgery , Occupational Injuries/diagnosis , Occupational Injuries/surgery , Skull Base/injuries , Skull Base/surgery , Steel , Wounds, Penetrating/diagnosis , Wounds, Penetrating/surgery , Adult , Fracture Fixation, Internal , Humans , Imaging, Three-Dimensional , Male , Maxillary Sinus/surgery , Neck Injuries/diagnosis , Osteotomy/methods , Tomography, X-Ray Computed/methodsABSTRACT
BACKGROUND: Xuebijing (XBJ) is widely applied in the treatment of Acute Lung Injury (ALI). This study focused on the potential mechanism of XBJ in Lipopolysaccharide (LPS)-induced ALI. METHODS: The rat ALI model was established by injection of LPS (10 mg/kg) and pretreated with XBJ (4 mL/kg) three days before LPS injection. BEAS-2B cell line was stimulated with LPS (1 µg/mL) and ATP (5 mM) to induce pyroptosis, and XBJ (2 g/L) was pretreated 24h before induction. The improvement effects of XBJ on pulmonary edema, morphological changes, and apoptosis in ALI lung tissue were evaluated by lung wet/dry weight ratio, HE-staining, and TUNEL staining. Inflammatory cytokines in lung tissue and cell supernatant were determined by ELISA. pyroptosis was detected by flow cytometry. Meanwhile, the expressions of miR-181d-5p, SPP1, p-p65, NLRP3, ASC, caspase-1, p20, and GSDMD-N in tissues and cells were assessed by RT-qPCR and immunoblotting. The relationship between miR-181d-5p and SPP1 in experimental inflammation was reported by dual luciferase assay. RESULTS: XBJ could improve inflammation and pyroptosis of ALI by inhibiting contents of inflammatory cytokines, and levels of inflammation- and pyroptosis-related proteins. Mechanistically, XBJ could up-regulate miR-181d-5p and inhibit SPP1 in ALI. miR-181d-5p can target the regulation of SPP1. Depressing miR-181d-5p compensated for the ameliorative effect of XBJ on ALI, and overexpressing SPP1 suppressed the attenuating effect of XBJ on LPS-induced inflammation and pyroptosis. CONCLUSION: XBJ can regulate the miR-181d-5p/SPP1 axis to improve inflammatory response and pyroptosis in ALI.
Subject(s)
Acute Lung Injury , Drugs, Chinese Herbal , MicroRNAs , Rats , Animals , Pyroptosis , Lipopolysaccharides , MicroRNAs/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Inflammation/drug therapy , CytokinesABSTRACT
Osteosarcoma is an aggressive bone malignancy, molecularly characterized by acquired genome complexity and frequent loss of TP53 and RB1. Obtaining a molecular understanding of the initiating mutations of osteosarcomagenesis has been challenged by the difficulty of parsing between passenger and driver mutations in genes. Here, a forward genetic screen in a genetic mouse model of osteosarcomagenesis initiated by Trp53 and Rb1 conditional loss in pre-osteoblasts identified that Arid1a loss contributes to OS progression. Arid1a is a member of the canonical BAF (SWI/SNF) complex and a known tumor suppressor gene in other cancers. We hypothesized that the loss of Arid1a increases the rate of tumor progression and metastasis. Phenotypic evaluation upon in vitro and in vivo deletion of Arid1a validated this hypothesis. Gene expression and pathway analysis revealed a correlation between Arid1a loss and genomic instability, and the subsequent dysregulation of genes involved in DNA DSB or SSB repair pathways. The most significant of these transcriptional changes was a concomitant decrease in DCLRE1C. Our findings suggest that Arid1a plays a role in genomic instability in aggressive osteosarcoma and a better understanding of this correlation can help with clinical prognoses and personalized patient care.
ABSTRACT
Disulfidptosis, a novel form of regulated cell death, occurs due to the aberrant accumulation of intracellular cystine and other disulfides. Moreover, targeting disulfidptosis could identify promising approaches for cancer treatment. Long non-coding RNAs (lncRNAs) are known to be critically implicated in clear cell renal cell carcinoma (ccRCC) development. Currently, the involvement of disulfidptosis-related lncRNAs in ccRCC is yet to be elucidated. This study primarily dealt with identifying and validating a disulfidptosis-related lncRNAs-based signature for predicting the prognosis and immune landscape of individuals with ccRCC. Clinical and RNA sequencing data of ccRCC samples were accessed from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was conducted for the identification of the disulfidptosis-related lncRNAs. Additionally, univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator Cox regression, and stepwise multivariate Cox analysis were executed to develop a novel risk prognostic model. The prognosis-predictive capacity of the model was then assessed using an integrated method. Variation in biological function was noted using GO, KEGG, and GSEA. Additionally, immune cell infiltration, the tumor mutational burden (TMB), and tumor immune dysfunction and exclusion (TIDE) scores were calculated to investigate differences in the immune landscape. Finally, the expression of hub disulfidptosis-related lncRNAs was validated using qPCR. We established a novel signature comprised of eight lncRNAs that were associated with disulfidptosis (SPINT1-AS1, AL121944.1, AC131009.3, AC104088.3, AL035071.1, LINC00886, AL035587.2, and AC007743.1). Kaplan-Meier and receiver operating characteristic curves demonstrated the acceptable predictive potency of the model. The nomogram and C-index confirmed the strong correlation between the risk signature and clinical decision-making. Furthermore, immune cell infiltration analysis and ssGSEA revealed significantly different immune statuses among risk groups. TMB analysis revealed the link between the high-risk group and high TMB. It is worth noting that the cumulative effect of the patients belonging to the high-risk group and having elevated TMB led to decreased patient survival times. The high-risk group depicted greater TIDE scores in contrast with the low-risk group, indicating greater potential for immune escape. Finally, qPCR validated the hub disulfidptosis-related lncRNAs in cell lines. The established novel signature holds potential regarding the prognosis prediction of individuals with ccRCC as well as predicting their responses to immunotherapy.
Subject(s)
Carcinoma, Renal Cell , Carcinoma , Kidney Neoplasms , RNA, Long Noncoding , Humans , Carcinoma, Renal Cell/genetics , Prognosis , RNA, Long Noncoding/genetics , Kidney Neoplasms/geneticsABSTRACT
BACKGROUND: To investigate whether low-intensity ultrasound accelerates healing in bone tissues close to dental implants with osteoradionecrosis (ORN) of the mandible and is suitable for development as a therapy in patients with dental implants receiving radiotherapy. MATERIALS AND METHODS: Dog models of radiative bone injury surrounding dental implants in both sides of mandible were established by four treatment methods of radiotherapy, each 15Gy. After radiative treatment, antibiotics were administered and the left injury was treated with ultrasound and the right with debridement. Measures for evaluation included spiral computed tomography (SCT), Micro-CT, microvessel density, and pull-out experiment, and data were collected and analyzed. RESULTS: After 4months of radiotherapy, both sides of mandible displayed preclinic symptom of radiative osteonecrosis. Microvessel density of the side treated by ultrasound was 6.2152±0.6508 and that of the debridement side was 3.8490±0.8954 (P<0.05). Micro-CT results showed that bone volume fraction of trabecula, thickness of trabecula, trabecula spacing, ratio of bone surface area to bone volume, and trabecula number of the ultrasound-treated mandible were 0.3605±0.0337, 0.0287±0.0045, 0.0369±0.0073, 71.6124±14.1649, and 7.2915±1.4937, whereas those of the debridement side were 0.1779±0.0178, 0.0151±0.0021, 0.6623±0.1125, 33.2686±5.949, and 5.0689±0.5028, respectively; statistical significance was observed (P<0.05). Pull-out experiment suggested that pull-out strength of the ultrasound-treated side was 0.5793±0.1066 whereas that of the debridement side was 0.2980±0.0243, representing a statistical significance (P<0.05). CONCLUSIONS: Low-intensity ultrasound can accelerate the healing of bone tissues surrounding dental implants in osteoradionecrosis of the mandible animals.
Subject(s)
Dental Implants , Mandible/physiology , Mandible/surgery , Osteoradionecrosis/therapy , Ultrasonic Therapy/methods , Wound Healing/physiology , Animals , Anti-Bacterial Agents/therapeutic use , Disease Models, Animal , Dogs , Mandible/diagnostic imaging , Osteogenesis/physiology , Osteoradionecrosis/physiopathology , Periodontal Debridement , Radiotherapy , Tomography, X-Ray ComputedABSTRACT
PURPOSE: To investigate the effect of low-intensity ultrasound on mandibular osteoradionecrosis. MATERIALS AND METHODS: Using a canine model, radiotherapy was delivered to the mandible at doses of 25 and 28 Gy. The microstructure of the mandible and changes in microvascular density in the low-intensity ultrasound treatment (group A) and nontreatment (group B) groups were determined and compared with those of the control group. RESULTS: At a single dose of 28 Gy, the canines developed epilation of the mandibular skin, ulcers, and small pieces of oral sequestered material. The microvascular density in group A was significantly greater than that in group B (P<.05). Most osteocytes in group B had disappeared, with atrophy of the cancellous bone trabeculae. In contrast, in group A, a substantial amount of bone had been formed, with increasing amounts of bone trabeculae and a large number of osteoblasts. CONCLUSIONS: Low-intensity ultrasound effectively improves the healing of irradiated bone.