ABSTRACT
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor ß (TGFß) superfamily. BMPs play crucial roles in embryogenesis and bone remodeling. Recently, BMP signaling has been found to have diverse effects on different types of tumors. In this review, we summarized the effects of BMP signaling on gynecologic cancer. BMP signaling has tumor-promoting effects on ovarian cancer (OC) and endometrial cancer (EC), whereas it has tumor-suppressing effects on uterine cervical cancer (UCC). Interestingly, EC has frequent gain-of-function mutations in ACVR1, encoding one of the type I BMP receptors, which are also observed in fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. Little is known about the relationship between BMP signaling and other gynecologic cancers. Tumor-promoting effects of BMP signaling in OC and EC are dependent on the promotion of cancer stemness and epithelial-mesenchymal transition (EMT). In accordance, BMP receptor kinase inhibitors suppress the cell growth and migration of OC and EC. Since both cancer stemness and EMT are associated with chemoresistance, BMP signaling activation might also be an important mechanism by which OC and EC patients acquire chemoresistance. Therefore, BMP inhibitors are promising for OC and EC patients even if they become resistant to standard chemotherapy. In contrast, BMP signaling inhibits UCC growth in vitro. However, the in vivo effects of BMP signaling have not been elucidated in UCC. In conclusion, BMP signaling has a variety of functions, depending on the types of gynecologic cancer. Therefore, targeting BMP signaling should improve the treatment of patients with gynecologic cancer.
Subject(s)
Myositis Ossificans , Neoplasms , Humans , Female , Bone Morphogenetic Proteins/metabolism , Transforming Growth Factor beta/metabolism , Signal Transduction , Myositis Ossificans/genetics , Myositis Ossificans/metabolism , Myositis Ossificans/pathology , Epithelial-Mesenchymal TransitionABSTRACT
Bone morphogenetic proteins (BMPs) play an important role in development. Twisted gastrulation BMP signaling modulator 1 (TWSG1) was initially identified as a regulator of the dorsoventral axis formation in Drosophila. The mechanism of BMP signaling modulation by TWSG1 is complex. TWSG1 inhibits BMP signaling by binding to BMP ligands including BMP4, whereas it enhances signaling by interacting with Chordin, a BMP antagonist. Therefore, TWSG1 can act as both a BMP agonist and antagonist. TWSG1 has various functions ranging from embryogenesis to cancer progression. TWSG1 knockout mice showed neural, craniofacial, and mammary defects. TWSG1 also regulated erythropoiesis and thymocyte development. Furthermore, the relationship between TWSG1 and cancer has been elucidated. Allelic loss of TWSG1 was detected in colorectal cancer. TWSG1 expression was upregulated in papillary thyroid carcinoma and glioblastoma but downregulated in gastric and endometrial cancers. TWSG1 suppressed BMP7-enhanced sphere formation and migration in endometrial cancer cells, indicating its tumor-suppressive role. Further studies are required to clarify the TWSG1 function and its association with BMP signaling in cancer development. Finally, TWSG1 is abundantly expressed in human and mouse ovaries and sustains follicular growth in rodent ovaries. Thus, TWSG1 has various functions ranging from fertility to cancer. Therefore, TWSG1 signaling modulation may be beneficial in treating specific diseases such as cancer.
Subject(s)
Bone Morphogenetic Proteins , Neoplasms , Animals , Mice , Humans , Bone Morphogenetic Proteins/metabolism , Signal Transduction , Mice, Knockout , Embryonic Development/genetics , Neoplasms/geneticsABSTRACT
The patient was a woman in her 90s. Right radical nephrectomy for right renal cell carcinoma had been performed 2 years and 6 months ago. Since then, there had been no recurrence. However, computed tomography during postoperative follow- up period showed a 3 cm mass in the right breast, and the patient was referred to our department. Breast ultrasonography indicated a well-circumscribed, oval, and almost smooth-surfaced tumor, 27 mm in size, located in the D region of the right breast. Results of a core needle biopsy showed metastatic renal cell carcinoma and clear cell carcinoma. Preoperative examination confirmed intramammary metastases of renal cell carcinoma. Given that the patient did not experience systemic metastases, partial mastectomy of the right breast was performed. Metastatic renal cell carcinoma is associated with poor prognosis. Generally, standard treatment in this disease is chemotherapy. However, surgical resection is selected with the aim of improving the prognosis and achieving radical cure of patients with this complication if these patients are in an oligometastatic state and complete resection of metastatic lesions is feasible, as in the present case. To achieve radical cure, the patient underwent partial mastectomy under local anesthesia, which is a relatively minimally invasive surgery.
Subject(s)
Breast Neoplasms , Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Female , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/secondary , Breast Neoplasms/pathology , Kidney Neoplasms/pathology , Mastectomy/methods , Nephrectomy , Melanoma, Cutaneous MalignantABSTRACT
Modification of the transforming growth factor ß (TGF-ß) signaling components by (de)ubiquitination is emerging as a key regulatory mechanism that controls cell signaling responses in health and disease. Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7/TGF-ß signaling, suggesting that this mode of regulation of TGF-ß signaling is conserved across animal species. The dauer larva-constitutive C. elegans phenotype caused by defective DAF-7/TGF-ß signaling was enhanced and suppressed, respectively, by ubh-1 deletion and overexpression in the loss-of-function genetic backgrounds of daf7, daf-1/TGF-ßRI, and daf4/R-SMAD, but not of daf-8/R-SMAD. This suggested that UBH-1 may stimulate DAF-7/TGF-ß signaling via DAF-8/R-SMAD. Therefore, we investigated the effect of UCH-L1 on TGF-ß signaling via its intracellular effectors, i.e. SMAD2 and SMAD3, in mammalian cells. Overexpression of UCH-L1, but not of UCH-L3 (the other human homolog of UBH1) or of the catalytic mutant UCH-L1C90A, enhanced TGF-ß/SMAD-induced transcriptional activity, indicating that the deubiquitination activity of UCH-L1 is indispensable for enhancing TGF-ß/SMAD signaling. We also found that UCH-L1 interacts, deubiquitinates, and stabilizes SMAD2 and SMAD3. Under hypoxia, UCH-L1 expression increased and TGF-ß/SMAD signaling was potentiated in the A549 human lung adenocarcinoma cell line. Notably, UCH-L1-deficient A549 cells were impaired in tumorigenesis, and, unlike WT UCH-L1, a UCH-L1 variant lacking deubiquitinating activity was unable to restore tumorigenesis in these cells. These results indicate that UCH-L1 activity supports DAF-7/TGF-ß signaling and suggest that UCH-L1's deubiquitination activity is a potential therapeutic target for managing lung cancer.
Subject(s)
Caenorhabditis elegans Proteins/metabolism , Carcinogenesis/metabolism , Transforming Growth Factor beta/metabolism , Ubiquitin Thiolesterase/metabolism , Animals , Caenorhabditis elegans , Cell Transformation, Neoplastic , Deubiquitinating Enzymes , Larva/metabolism , Lung/metabolism , Signal Transduction/genetics , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Ubiquitin Thiolesterase/physiology , UbiquitinationABSTRACT
PURPOSE: The aim of this study was to assess whether the retention index (RI) determined using dual-phase 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) reflects the malignant features of breast cancer. METHODS: A total of 1,523 patients with breast cancer were retrospectively evaluated. PET/CT scans were performed at 1 h and 2 h after FDG administration before treatment. The maximum standardized uptake value (SUVmax) at both time points (SUVmax1 and SUVmax2) in the primary tumour and RI were calculated. Primary tumour tissues were evaluated in terms of biological features, such as histology, nuclear grade, lymphovascular invasion and molecular subtype. RESULTS: Of the 1,523 patients, 463 (30.4%) had luminal A-like, 661 (43.4%) had luminal B-like, 229 (15.0%) had human epidermal growth factor receptor 2-positive (HER2-positive), and 157 (10.3%) triple-negative breast cancer. The median SUVmax1, SUVmax2 and RI values were 2.2, 2.3 and 2.6%, respectively. These metabolic parameters were correlated with tumour size, nodal metastasis, histology, nuclear grade, lymphovascular invasion, and molecular subtype (all P < 0.001). The median RI values were 0% in luminal A-like, 5.3% in luminal B-like, 6.9% in HER2-positive, and 11.4% in triple-negative breast cancer. RI was associated with malignant features when the tumour accumulated a significant amount of FDG. In a subanalysis of patients with tumours of stages T2 to T4, RI was correlated with nodal metastasis, histology, nuclear grade, and molecular subtype (luminal A-like 4.8%, luminal B-like 12.3%, HER2-positive 15.8%, and triple-negative 16.3%). CONCLUSION: RI determined using delayed-phase FDG PET/CT is associated with malignant features in breast cancers with significant FDG uptake. Dual-phase imaging was helpful in distinguishing luminal A-like breast cancer from luminal B-like, HER2-positive, and triple-negative breast cancers.
Subject(s)
Breast Neoplasms/diagnostic imaging , Fluorodeoxyglucose F18 , Positron Emission Tomography Computed Tomography , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cohort Studies , Female , Humans , Middle Aged , Retrospective Studies , Young AdultABSTRACT
A chemical sensor for cysteine (Cys) was fabricated based on a fluorescent oligo(p-phenylene ethynylene)s (OPEs) and OPE-graphene oxide (GO) composite. OPE with cyanoacrylate terminal groups were synthesized by a Pd-catalyzed Sonogashira coupling reaction and Knoevenagel condensation for use as a chemical sensor for Cys. The optical properties and Cys sensing capability of the cyanoacrylate modified OPE and OPE-GO composite were investigated. In addition of Cys, the fluorescence of OPE was blue-shifted and decreased (fluorescence turn-off), while the fluorescence of the OPE-GO composite was enhanced (fluorescence turn-on). Thus, OPE with cyanoacrylate terminal groups and OPE-GO composite acts a highly sensitive fluorescent chemical sensor for Cys.
Subject(s)
Abnormalities, Multiple/genetics , Eyelids/abnormalities , Finger Phalanges/diagnostic imaging , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Limb Deformities, Congenital/genetics , Metacarpus/diagnostic imaging , Microcephaly/genetics , Tracheoesophageal Fistula/genetics , Adult , Asian People/genetics , Eyelids/pathology , Female , Fertilization in Vitro , Fingers/abnormalities , Hand Deformities, Congenital/diagnostic imaging , Humans , Infant , Intellectual Disability/classification , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Limb Deformities, Congenital/classification , Limb Deformities, Congenital/diagnosis , Limb Deformities, Congenital/pathology , Male , Microcephaly/classification , Microcephaly/diagnosis , Microcephaly/pathology , Polydactyly/diagnostic imaging , Polydactyly/genetics , Sequence Deletion , Thumb/abnormalities , Tracheoesophageal Fistula/classification , Tracheoesophageal Fistula/diagnosis , Tracheoesophageal Fistula/pathologyABSTRACT
PURPOSE: Lamotrigine (LTG) is used to treat epilepsy. The variability of LTG pharmacokinetics among individuals may be attributed to polymorphisms in the genes of uridine diphosphate glucuronosyltransferases (UGTs) 1A4 and UGT2B7 and/or combination with other drugs. In this study, we evaluated the association between LTG concentrations and patient characteristics such as genetic polymorphisms and the co-administration of antiepileptic drugs. METHODS: We recruited 122 patients with epilepsy. LTG concentrations were measured in blood samples from each patient under steady-state condition. We assessed the influence of multiple factors on LTG concentrations and derived a formula for predicting LTG concentrations using multiple linear regression analysis. RESULTS: We derived a formula to predict LTG concentrations that considers the daily dose of LTG, body weight, valproic acid concentration, phenytoin co-administration, and the co-administration of phenobarbital and/or carbamazepine as well as UGT1A4 142T>G and UGT2B7 -161C>T polymorphisms (adjusted coefficients of determination R (2) = 0.734). Furthermore, we used this formula to reveal a strong positive correlation between measured and predicted LTG concentrations (r (2) = 0.76, p < 0.001). CONCLUSION: We derived a formula that will be useful in clinical practice for predicting LTG concentrations in patients with epilepsy.
Subject(s)
Anticonvulsants/pharmacokinetics , Epilepsy/metabolism , Triazines/pharmacokinetics , Adolescent , Adult , Aged , Anticonvulsants/blood , Anticonvulsants/therapeutic use , Asian People/genetics , Child , Child, Preschool , Epilepsy/drug therapy , Epilepsy/genetics , Female , Genotype , Glucuronosyltransferase/genetics , Humans , Infant , Lamotrigine , Male , Middle Aged , Polymorphism, Genetic , Triazines/blood , Triazines/therapeutic use , Young AdultABSTRACT
PURPOSE: We aimed to compare the preventive effect of 5-day administration of aprepitant with single administration of fosaprepitant meglumine against nausea and vomiting symptoms due to highly emetogenic chemotherapy regimens comprising cisplatin (CDDP). METHODS: Subjects were inpatients who underwent chemotherapy for gastric cancer, esophageal cancer, lung cancer, or head and neck cancer with a regimen comprising 60 mg/m(2) or higher dose of CDDP. In this randomised, open-label, controlled study, the subjects were assigned to a group given aprepitant for 5 days or a group given a single administration of fosaprepitant meglumine. The nausea and vomiting symptoms that emerged within 7 days after the first CDDP administration were investigated with a questionnaire form; the results were compared between the two groups. Risk factors affecting nausea and vomiting symptoms were also investigated. RESULTS: Of the 101 patients enrolled, 93 patients were included (48 in the 5-day aprepitant group and 45 in the single fosaprepitant meglumine group). No significant intergroup differences in the complete response rate or the complete control rate were found over the entire period. The nausea score tended to increase from day 3 in both groups, but no significant intergroup difference was observed. Furthermore, the investigation of risk factors affecting moderate or severe nausea symptoms indicated that the fosaprepitant meglumine administration was not a risk factor. CONCLUSIONS: Single administration of fosaprepitant meglumine was not inferior to 5-day administration of aprepitant for preventing acute and delayed nausea and vomiting symptoms occurring after administration of CDDP (60 mg/m(2) or higher).
Subject(s)
Antiemetics/therapeutic use , Cisplatin/adverse effects , Morpholines/therapeutic use , Nausea/prevention & control , Vomiting/prevention & control , Aged , Aprepitant , Cisplatin/therapeutic use , Esophageal Neoplasms/drug therapy , Female , Head and Neck Neoplasms/drug therapy , Humans , Lung Neoplasms/drug therapy , Male , Meglumine , Middle Aged , Nausea/chemically induced , Nausea/drug therapy , Risk Factors , Stomach Neoplasms/drug therapy , Surveys and Questionnaires , Treatment Outcome , Vomiting/chemically induced , Vomiting/drug therapyABSTRACT
Isolation of Bordetella pertussis and detection of the pertussis genome are not always successful because of low bacterial loads in adult patients with pertussis. Antibodies against pertussis toxin (PT) are measured but have low sensitivity in vaccinated subjects. There is no reliable diagnostic method at present. In this study, a fluorescent-EIA against several pertussis antigens and genome detection were investigated to establish clinical laboratory diagnostic methods for pertussis. The study was conducted in an outpatient clinic between September 2007 and 2013. Subjects consisted of 209 patients including adults suspected of pertussis and 35 staff members of the clinic. Loop-mediated isothermal amplification (LAMP) was performed to detect the pertussis genome in 5' UTR of the pertussis toxin (PT) gene. The catalytic region of the adenylate cyclase toxin (catACT), C-terminal of filamentous hemagglutinin (cFHA), and type 3 fimbria (Fim3) were selected, which are not pertussis vaccine component. Conventional PT and FHA antibodies were examined together with type 2 fimbria (Fim2) antibodies, and these are vaccine antigens. Pertussis DNA was detected in 23 (11%) out of 209. Detection sensitivity was high in young infants. Antibodies against Fim3 showed a higher positive rate in all age groups. Staff members at the pediatric outpatient clinic showed serological booster responses in Fim2 and Fim3 antibodies more sensitively than those in PT antibodies during outbreaks. LAMP was useful for detecting the pertussis genome in young infants, whereas a serological assay for fluorescent-EIA against Fim2 and Fim3 was preferable for adolescents and adults.
Subject(s)
Antibodies, Bacterial/blood , Antigens, Bacterial/immunology , Bordetella pertussis/immunology , Fimbriae Proteins/immunology , Virulence Factors, Bordetella/immunology , Whooping Cough/diagnosis , Whooping Cough/immunology , 5' Untranslated Regions , Adenylate Cyclase Toxin/immunology , Adhesins, Bacterial/immunology , Adolescent , Adult , Ambulatory Care Facilities , Bordetella pertussis/genetics , Catalytic Domain/immunology , Child , Child, Preschool , DNA, Bacterial/blood , Enzyme-Linked Immunosorbent Assay , Fimbriae, Bacterial/immunology , Fluorescence , Health Personnel , Humans , Infant , Middle Aged , Nucleic Acid Amplification Techniques , Pertussis Toxin/genetics , Pertussis Toxin/immunology , Whooping Cough/blood , Young AdultABSTRACT
SHANK3 is a synaptic scaffolding protein enriched in the post-synaptic density of excitatory synapses. Since several SHANK3 mutations have been identified in a particular phenotypic group of patients with autism spectrum disorder (ASD), SHANK3 is strongly suspected of being involved in the pathogenesis and neuropathology of ASD. Several SHANK3 isoforms are known to be produced in the developing brain, but they have not been fully investigated. Here, we identified two different amino-terminus truncated Shank3 transcripts. One transcript, designated as Shank3c-3, produces an isoform that contains the entire carboxyl-terminus, but the other transcript, designated as Shank3c-4, produces a carboxyl-terminus truncated isoform. During development, expression of the novel Shank3 transcripts increased after birth, transiently decreased at P14 and then gradually increased again thereafter. We also determined that methyl CpG-binding protein 2 (MeCP2) is involved in regulating expression of the novel Shank3 transcripts. MeCP2 is a transcriptional regulator that has been identified as the causative molecule of Rett syndrome, a neurodevelopmental disorder that includes autistic behavior. We demonstrated a difference between the expression of the novel Shank3 transcripts in wild-type mice and Mecp2-deficient mice. These findings suggest that the SHANK3 isoforms may be implicated in the synaptic abnormality in Rett syndrome. SHANK3 is a synaptic scaffolding protein and is suspected of being implicated in the pathogenesis and neuropathology of ASD. We here identified two different amino-terminus truncated Shank3 transcripts, Shank3c-3 and Shank3c-4, expressed from the intron 10 of the Shank3 gene, and also suggested the epigenetic regulation of their expression via methyl CpG-binding protein 2 (MeCP2) that has been identified as the causative molecule of Rett syndrome.
Subject(s)
Neocortex/metabolism , Nerve Tissue Proteins/metabolism , Animals , Cell Line , CpG Islands , Female , Humans , Introns , Male , Methyl-CpG-Binding Protein 2/genetics , Methyl-CpG-Binding Protein 2/metabolism , Methylation , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Transgenic , Microfilament Proteins , Neocortex/embryology , Neocortex/growth & development , Nerve Tissue Proteins/genetics , Neurons/metabolism , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/metabolism , Transcription Initiation Site , Transcription, GeneticABSTRACT
BACKGROUND: Valproic acid (VPA) is widely used to treat various types of epilepsy. Interindividual variability in VPA pharmacokinetics may arise from genetic polymorphisms of VPA-metabolizing enzymes. This study aimed to examine the relationships between plasma VPA concentrations and the -161C>T single nucleotide polymorphism in uridine diphosphate glucuronosyltransferase (UGT) 2B7 genes in pediatric epilepsy patients. METHODS: This study included 78 pediatric epilepsy patients carrying the cytochrome P450 (CYP) 2C9*1/*1 genotype and who were not treated with the enzyme inducers (phenytoin, phenobarbital, and carbamazepine), lamotrigine, and/or topiramate. CYP2C9*3 and UGT2B7 -161C>T polymorphisms were identified using methods based on polymerase chain reaction-restriction fragment length polymorphism. Blood samples were drawn from each patient under steady-state conditions, and plasma VPA concentrations were measured. RESULTS: Significant differences in adjusted plasma VPA concentrations were observed between carriers of CC, CT, and TT genotypes in the UGT2B7 -161C>T polymorphism (P = 0.039). Patients with the CC genotype had lower adjusted plasma VPA concentrations than those with CT or TT genotype (P = 0.028). CONCLUSIONS: These data suggest that the UGT2B7 -161C>T polymorphism in pediatric epilepsy patients carrying the CYP2C9*1/*1 genotype affects VPA concentration.
Subject(s)
Anticonvulsants/pharmacokinetics , Epilepsy/drug therapy , Glucuronosyltransferase/genetics , Valproic Acid/pharmacokinetics , Age Factors , Anticonvulsants/blood , Anticonvulsants/therapeutic use , Body Weight , Child , Child, Preschool , Cytochrome P-450 CYP2C9/genetics , Drug Therapy, Combination , Female , Genotype , Humans , Male , Polymorphism, Single Nucleotide , Sex Factors , Valproic Acid/blood , Valproic Acid/therapeutic useABSTRACT
Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multiomics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIPseq) and RNA sequencing (RNAseq). The expression of PRMT6 in EC was analyzed using reverse transcriptionquantitative polymerase chain reaction (RTqPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIPseq of H3K27ac antibodies and RNAseq. Finally, the downstream targets identified by multiomics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIPseq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNAseq data demonstrated altered interferonrelated pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide3kinase regulatory subunit 1, following PRMT6KD. RTqPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.
Subject(s)
Endometrial Neoplasms , Histones , Male , Female , Humans , Histones/metabolism , Nuclear Proteins/genetics , Protein-Arginine N-Methyltransferases/genetics , Protein-Arginine N-Methyltransferases/metabolism , Histone Code , Endometrial Neoplasms/genetics , Apoptosis , InterferonsABSTRACT
Activated microglia are observed in various neurodegenerative diseases and are thought to be involved in the processes of neuronal cell death. Motoneuron damage in the facial nuclei after facial nerve avulsion is accelerated in presymptomatic transgenic rats expressing human mutant Cu(2+) /Zn(2+) superoxide dismutase 1 (SOD1), compared with that in wild-type rats. To reveal the functional role of microglia in motoneuronal death, we investigated the microglial response after facial nerve avulsion in presymptomatic mutant SOD1(H46R) (mSOD1(H46R) ) rats. At 3 days after avulsion, microglial clusters were observed in the facial nuclei of both wild-type and mSOD1(H46R) rats. The numbers of microglial clusters, proliferating microglia, and microglial attachments to motoneurons were significantly higher in mSOD1(H46R) rats, compared with those in wild-type rats. Immunopositive signals for the phagocytic marker ED1 were significantly stronger in mSOD1(H46R) rats, compared with that in wild-type rats, at 2 weeks after avulsion. Furthermore, primary microglia prepared from mSOD1(H46R) rats showed enhanced phagocytic activity, compared with that in wild-type rats. The expression of P2Y(12) mRNA was higher in the facial nuclei of mSOD1(H46R) rats, compared with that in wild-type rats. A laser microdissection system revealed that the expression of ATF3 mRNA was higher in the motoneurons of mSOD1(H46R) rats, compared with that in wild-type rats, at 2 days after avulsion. These results indicate that microglial activation in response to early neuronal damage increased in mSOD1(H46R) rats and suggest that the enhanced activation of microglia may lead to an increase in the vulnerability of motoneurons after avulsion in mSOD1(H46R) rats.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Disease Models, Animal , Facial Nerve Injuries/metabolism , Microglia/metabolism , Motor Neurons/metabolism , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Animals , Animals, Newborn , Cells, Cultured , Facial Nerve Injuries/genetics , Facial Nerve Injuries/pathology , Humans , Microglia/pathology , Motor Neurons/pathology , Rats , Rats, Sprague-Dawley , Rats, Transgenic , Superoxide Dismutase/biosynthesis , Superoxide Dismutase/genetics , Superoxide Dismutase-1ABSTRACT
The extension of microglial processes toward injured sites in the brain is triggered by the stimulation of the purinergic receptor P2Y(12) by extracellular ATP. We recently showed that P2Y(12) stimulation by ATP induces microglial process extension in collagen gels. In the present study, we found that a P2Y(12) agonist, 2-methylthio-ADP (2MeSADP), failed to induce the process extension of microglia in collagen gels and that co-stimulation with adenosine, a phosphohydrolytic derivative of ATP, and 2MeSADP restored the chemotactic process extension. An adenosine A3 receptor (A3R)-selective agonist restored the chemotactic process extension, but other receptor subtype agonists did not. The removal of adenosine by adenosine deaminase and the blocking of A3R by an A3R-selective antagonist inhibited ADP-induced process extension. The A3R antagonist inhibited ADP-induced microglial migration, and an A3R agonist promoted 2MeSADP-stimulated migration. ADP and the A3R agonist activated Jun N-terminal kinase in microglia, and a Jun N-terminal kinase inhibitor inhibited the ADP-induced process extension. An RT-PCR analysis showed that A1R and A3R were expressed by microglia sorted from adult rat brains and that the A2AR expression level was very low. These results suggested that A3R signaling may be involved in the ADP-induced process extension and migration of microglia.
Subject(s)
Adenosine Diphosphate/pharmacology , Cell Movement/drug effects , Microglia/drug effects , Receptor, Adenosine A3/physiology , Adenosine/pharmacology , Adenosine A3 Receptor Agonists/pharmacology , Adenosine Deaminase Inhibitors/pharmacology , Adenosine Diphosphate/analogs & derivatives , Animals , Animals, Newborn , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Chemotaxis/drug effects , Collagen , Flow Cytometry , Indicators and Reagents , JNK Mitogen-Activated Protein Kinases/physiology , Purinergic P2Y Receptor Agonists/pharmacology , Rats , Rats, Wistar , Real-Time Polymerase Chain Reaction , Receptor, Adenosine A1/biosynthesis , Receptor, Adenosine A3/drug effects , Receptors, Purinergic P2Y12/drug effects , Thionucleotides/pharmacologyABSTRACT
It is known that the onset of major depressive disorder (MDD) would be associated with genetic factors. To investigate the susceptibility to psychiatric disorders, e.g. MDD, schizophrenia etc., it is necessary to compare the genetic differences of objective polymorphisms between in patients and in relative contol subjects. Recently, an increasing number of studies focused on the role of cyclic adenosine monophosphate response element binding protein 1 (CREB1) and Piccolo (PCLO) on MDD. However, there was no report about genetic characterization of polymorphisms in between MDD patients and healthy subjects in Japanese population. We analized genotype distributions and allele frequencies of CREB1 rs4675690 and PCLO rs2522833 polymorphisms in 267 Japanese subjects, respectively. In CREB1 rs4675690, C allele frequency (0.41) was lower than T allele (0.59). While in PCLO rs2522833, A allele frequency (0.45) was lower than C allele (0.55). Our findings may be useful for investigating the genetic factors concerning the susceptibility to MDD in Japanese population.
Subject(s)
Cyclic AMP Response Element-Binding Protein/genetics , Cytoskeletal Proteins/genetics , Neuropeptides/genetics , Adult , Asian People/genetics , Depressive Disorder, Major/genetics , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Young AdultABSTRACT
Osteoactivin is a type I transmembrane protein upregulated by unloading stresses, including denervation, prolonged bed rest, and space flight, but the regulatory mechanisms of its expression and activation under these conditions remain undefined. Here we report that osteoactivin protein exists in two forms: an intact transmembrane form and a secreted form. The secreted form, the extracellular fragment of osteoactivin, was produced by ectodomain shedding and was released into a culture medium. Amino acid sequence analysis of the carboxy-terminal fragment of osteoactivin (OA-CTF) revealed that cleavage of osteoactivin by proteases occurred both at the cell surface and within the cell membrane. Localization analysis demonstrated translocalization of OA-CTF to the nucleus and the endoplasmic reticulum. Moreover, RNA binding proteins, which regulate pre-mRNA splicing, were identified as OA-CTF binding proteins. These results suggest that OA-CTF formed by ectodomain shedding is involved in the regulation of pre-mRNA splicing.
Subject(s)
Cell Nucleus/metabolism , Intracellular Space/metabolism , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , RNA-Binding Proteins/metabolism , Active Transport, Cell Nucleus , Amino Acid Sequence , Animals , COS Cells , Cell Membrane/metabolism , Chlorocebus aethiops , Endoplasmic Reticulum/metabolism , HEK293 Cells , Humans , Molecular Sequence Data , Protein Binding , Protein Structure, Tertiary , ProteolysisABSTRACT
Fish possess one olfactory organ called the olfactory epithelium (OE), by which various chemical substances are detected. On the other hand, tetrapods possess two independent olfactory organs called the main olfactory epithelium (MOE) and vomeronasal organ (VNO), each of which mainly detects general odorants and pheromones, respectively. Traditionally, the VNO, so-called concentrations of vomeronasal neurons, was believed to have originated in tetrapods. However, recent studies have identified a primordial VNO in lungfish, implying that the origin of the VNO was earlier than traditionally expected. In this study, we examined the presence/absence of the VNO in the olfactory organ of bichir (Polypterus senegalus), which is the most ancestral group of extant bony vertebrates. In particular, we conducted a transcriptomic evaluation of the accessory olfactory organ (AOO), which is anatomically separated from the main olfactory organ (MOO) in bichir. As a result, several landmark genes specific to the VNO and MOE in tetrapods were both expressed in the MOO and AOO, suggesting that these organs were not functionally distinct in terms of pheromone and odorant detection. Instead, differentially expressed gene (DEG) analysis showed that DEGs in AOO were enriched in genes for cilia movement, implying its additional and specific function in efficient water uptake into the nasal cavity other than chemosensing. This transcriptomic study provides novel insight into the long-standing question of AOO function in bichir and suggests that VNO originated in the lineage of lobe-finned fish during vertebrate evolution.
ABSTRACT
Positive peritoneal cytology is a poor prognostic factor in patients with advanced endometrial cancer. Suspicious positive peritoneal cytology (class III) is commonly encountered in clinical practice. However, no standard treatment protocol exists for its management. Here, we investigated a possible relationship between suspicious positive peritoneal cytology, disease stage, risk factors, and endometrial cancer prognosis. We included patients diagnosed with endometrial cancer who underwent total hysterectomy and peritoneal cytology at the University of Tokyo Hospital between 2008 and 2022. Overall, 670 patients were included in the analyses; both demographic and clinical data of the patients were collected. The proportion of patients with lymph node metastasis was significantly different between peritoneal cytology groups, showing lymph node metastasis to be more extensive in patients with positive or suspicious positive peritoneal cytology than in patients with negative peritoneal cytology (p < 0.05). Thirty-nine patients had suspicious positive peritoneal cytology. Omental resection and biopsy were performed in 16 cases. No case of omental metastasis was found. Among patients with suspected ascites cytology, no patient experienced symptom recurrence or death. Therefore, monitoring lymph node metastasis in suspicious positive cases is essential. Moreover, a change of treatment method based on the finding of suspected positive peritoneal cytology is not necessary.