Your browser doesn't support javascript.
loading
: 20 | 50 | 100
1 - 20 de 10.431
1.
Anim Reprod Sci ; 249: 107198, 2023 Feb.
Article En | MEDLINE | ID: mdl-36791599

The soft-shelled turtle, Pelodiscus sinensis, is an important economic aquaculture species. Its reproduction exhibits seasonality; however, there is a lack of systematic studies focused on sperm maturation and epididymal storage. The testes and epididymides of P. sinensis were sampled from March to December. The seasonal reproduction and maturation of the spermatozoa were examined by anatomy, hematoxylin and eosin staining, AB-PAS staining, and immunohistochemistry. Spermatogenesis exhibited obvious seasonality in P. sinensis. It was found that the spermatogenic epithelium was most active during June to September, whereas the diameter of the epididymal tubules was smallest during June to October. As key enzymes of ATP metabolism, creatine kinases were highly expressed in the epididymal tubule epithelium during the breeding season, which may be important for the regulation of sperm maturation. In addition, the epididymal tubule epithelium changed with the season in June to September, the epididymal tubule epithelium proliferated to form villous structures, and secreted a large number of glycoproteins, which may be related to the rapid maturation of sperm during the breeding season. In conclusion, this study provided insights into the spermatogenesis of P. sinensis through histological analysis and enriched our understanding of reproduction in reptiles.


Creatine Kinase , Epididymis , Spermatogenesis , Turtles , Seasons , Male , Animals , Epididymis/cytology , Epididymis/growth & development , Epididymis/metabolism , Creatine Kinase/genetics , Creatine Kinase/metabolism , Gene Expression/physiology , Epithelium/anatomy & histology , Epithelium/growth & development
2.
Blood Adv ; 7(6): 893-899, 2023 03 28.
Article En | MEDLINE | ID: mdl-36240289

We investigated the clinicopathologic features of 5 follicular lymphomas (FLs) that transformed (tFL) morphologically to diffuse large B-cell lymphomas (DLBCLs) and had a primary mediastinal large B-cell lymphoma (PMBL)-like gene expression profile (tFL-PMBLsig-pos). None of the tFL-PMBLsig-pos cases arose in the mediastinum, all cases tested had a germinal center B-cell phenotype, 20% were CD30+, 60% CD23+, 80% MAL+, 20% CD200+, and 0% CD273/PDL2+. Whole-exome sequencing detected alterations in genes associated with both FL/DLBCL (CREBBP, KMT2C, KMT2D, ARID1A, HIST1 members, and TNFRSF14) and PMBL (JAK-STAT pathway genes, B2M, and CD58). Copy number (CN) analysis detected gains/amplification of REL and STAT6 in 60%, gains of SOCS1 in 40%, and gains of chromosome 16, including IL4R, in 40% of the cases. CN gains/amplification of BCL6 and MYC and loss of TNFRSF14 and TNFAIP3 were identified in 20% of the cases. Three of 5 cases lacked a BCL2 rearrangement. Despite having some features that are less common in DLBCL (MAL and CD23 expression and JAK-STAT activation), these tFL-PMBLsig-pos cases lack the most characteristic CN alteration seen in PMBL (9p24.1 gain/amplification). This cohort expands the biologic heterogeneity of tFL, illustrating a subset with gene expression and some genetic features reminiscent of PMBL, with potential treatment implications that include the use of novel targeted therapies.


Lymphoma, Follicular , Lymphoma, Large B-Cell, Diffuse , Transcriptome , Humans , Janus Kinases , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Signal Transduction , STAT Transcription Factors , Lymphoma, Follicular/genetics , Lymphoma, Follicular/metabolism , Lymphoma, Follicular/pathology , Gene Expression/genetics , Gene Expression/physiology
3.
PLoS Genet ; 18(12): e1010535, 2022 12.
Article En | MEDLINE | ID: mdl-36508455

Noise in expression of individual genes gives rise to variations in activity of cellular pathways and generates heterogeneity in cellular phenotypes. Phenotypic heterogeneity has important implications for antibiotic persistence, mutation penetrance, cancer growth and therapy resistance. Specific molecular features such as the presence of the TATA box sequence and the promoter nucleosome occupancy have been associated with noise. However, the relative importance of these features in noise regulation is unclear and how well these features can predict noise has not yet been assessed. Here through an integrated statistical model of gene expression noise in yeast we found that the number of regulating transcription factors (TFs) of a gene was a key predictor of noise, whereas presence of the TATA box and the promoter nucleosome occupancy had poor predictive power. With an increase in the number of regulatory TFs, there was a rise in the number of cooperatively binding TFs. In addition, an increased number of regulatory TFs meant more overlaps in TF binding sites, resulting in competition between TFs for binding to the same region of the promoter. Through modeling of TF binding to promoter and application of stochastic simulations, we demonstrated that competition and cooperation among TFs could increase noise. Thus, our work uncovers a process of noise regulation that arises out of the dynamics of gene regulation and is not dependent on any specific transcription factor or specific promoter sequence.


Gene Expression , Transcription Factors , Binding Sites/genetics , Gene Expression/genetics , Gene Expression/physiology , Nucleosomes/metabolism , Protein Binding , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
4.
Int J Cancer ; 151(5): 770-782, 2022 09 01.
Article En | MEDLINE | ID: mdl-35583991

Acute myeloid leukemia (AML) results from aberrant hematopoietic processes and these changes are frequently initiated by chromosomal translocations. One particular subtype, AML with translocation t(7;12)(q36;p13), is found in children diagnosed before 2 years of age. The mechanisms for leukemogenesis induced by t(7;12) is not understood, in part because of the lack of efficient methods to reconstruct the leukemia-associated genetic aberration with correct genomic architecture and regulatory elements. We therefore created induced pluripotent stem cell (iPSC) lines that carry the translocation t(7;12) using CRISPR/Cas9. These t(7;12) iPSC showed propensity to differentiate into all three germ layers, confirming retained stem cell properties. The potential for differentiation into hematopoietic stem and progenitor cells (HSPC) was shown by expression of CD34, CD43 and CD45. Compared with the parental iPSC line, a significant decrease in cells expressing CD235a and CD41a was seen in the t(7;12) iPSC-derived HSPC (iHSPC), suggesting a block in differentiation. Moreover, colony formation assay showed an accumulation of cells at the erythroid and myeloid progenitor stages. Gene expression analysis revealed significant down-regulation of genes associated with megakaryocyte differentiation and up-regulation of genes associated with myeloid pathways but also genes typically seen in AML cases with t(7;12). Thus, this iPSC t(7;12) leukemia model of the t(7;12) AML subtype constitutes a valuable tool for further studies of the mechanisms for leukemia development and to find new treatment options.


Cell Differentiation , Homeodomain Proteins , Induced Pluripotent Stem Cells , Leukemia, Myeloid, Acute , Megakaryocyte-Erythroid Progenitor Cells , Transcription Factors , Cell Differentiation/genetics , Child , Gene Expression/genetics , Gene Expression/physiology , Gene Expression Profiling , Hematopoietic Stem Cells/physiology , Homeodomain Proteins/genetics , Humans , Induced Pluripotent Stem Cells/metabolism , Leukemia, Myeloid, Acute/genetics , Megakaryocyte-Erythroid Progenitor Cells/physiology , Megakaryocytes/physiology , Transcription Factors/genetics , Translocation, Genetic
5.
Sci Rep ; 12(1): 2890, 2022 02 21.
Article En | MEDLINE | ID: mdl-35190586

Malignant melanoma is the main cause of death in patients with skin cancer. Overexpression of Proteolipid protein 2 (PLP2) increased tumor metastasis and the knockdown of PLP2 inhibited the growth and metastasis of melanoma cells. In the present work, we studied the antitumor activity of peptide Rb4 derived from protein PLP2. In vitro, Rb4 induced F-actin polymerization, prevented F-actin depolymerization and increased the ER-derived cytosolic calcium. Such effects were associated with necrosis of murine melanoma B16F10-Nex2 cells and with inhibition of the viability of human cancer cell lines. Loss of plasma membrane integrity, dilation of mitochondria, cytoplasm vacuolation and absence of chromatin condensation characterized tumor cell necrosis. Cleavage of PARP-1 and inhibition of RIP1 expression were also observed. In vivo, peptide Rb4 reduced the lung metastasis of tumor cells and delayed the subcutaneous melanoma growth in a syngeneic model. Rb4 induced the expression of two DAMPs molecules, HMGB1 and calreticulin, in B16F10-Nex2. Our results suggest that peptide Rb4 acts directly on tumor cells inducing the expression of DAMPs, which trigger the immunoprotective effect in vivo against melanoma cells. We suggest that peptide Rb4 is a promising compound to be developed as an anticancer drug.


Cell Death/genetics , Gene Expression/genetics , Gene Expression/physiology , MARVEL Domain-Containing Proteins/genetics , MARVEL Domain-Containing Proteins/pharmacology , Melanoma/genetics , Melanoma/pathology , Poly (ADP-Ribose) Polymerase-1/physiology , Proteolipids/genetics , Proteolipids/pharmacology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Animals , Antineoplastic Agents , Calreticulin/genetics , Calreticulin/metabolism , Cell Line, Tumor , Gene Expression/drug effects , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Humans , MARVEL Domain-Containing Proteins/metabolism , MARVEL Domain-Containing Proteins/physiology , Mice , Necrosis , Nuclear Pore Complex Proteins/genetics , Nuclear Pore Complex Proteins/metabolism , Peptides , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , Proteolipids/metabolism , Proteolipids/physiology , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism
6.
Cell Rep ; 38(5): 110329, 2022 02 01.
Article En | MEDLINE | ID: mdl-35108527

A little-appreciated feature of early pregnancy is that embryo implantation and placental outgrowth do not evoke wound-healing responses in the decidua, the specialized endometrial tissue that surrounds the conceptus. Here, we provide evidence that this phenomenon is partly due to an active program of gene silencing mediated by EZH2, a histone methyltransferase that generates repressive histone 3 lysine 27 trimethyl (H3K27me3) histone marks. We find that pregnancies in mice with EZH2-deficient decidual stromal cells frequently fail by mid-gestation, with the decidua showing ectopic myofibroblast formation, peri-embryonic collagen deposition, and gene expression profiles associated with transforming growth factor ß (TGF-ß)-driven fibroblast activation and fibrogenic extracellular matrix (ECM) remodeling. Analogous responses are observed when the mutant decidua is surgically wounded, while blockade of TGF-ß receptor signaling inhibits the defects and improves reproductive outcomes. Together, these results highlight a critical feature of reproductive success and have implications for the context-specific control of TGF-ß-mediated wound-healing responses elsewhere in the body.


Embryo Implantation/physiology , Gene Silencing/physiology , Placenta/metabolism , Transforming Growth Factor beta/genetics , Wound Healing/physiology , Animals , Decidua/metabolism , Embryo, Mammalian/metabolism , Enhancer of Zeste Homolog 2 Protein/metabolism , Female , Gene Expression/physiology , Histones/metabolism , Humans , Mice, Inbred C57BL , Pregnancy , Stromal Cells/metabolism , Transforming Growth Factor beta/metabolism
7.
Pathol Res Pract ; 231: 153804, 2022 Mar.
Article En | MEDLINE | ID: mdl-35183824

OBJECTIVE: to assess whether immunohistochemical (IHC) algorithms used to classify the cell of origin (COO) of nodal Diffuse Large B-cell lymphoma (nDLBCL) in Germinal Center type (GCB) and non-GCB subtypes may be applied to Primary Cutaneous B-cell lymphoma (PCBCL) too, and which of these algorithms performs better on PCBCL. DESIGN: Retrospective case control study. SETTING: Pathology Department of the University Hospital "San Giovanni di Dio e Ruggi d'Aragona" Salerno, Italy. PARTICIPANTS: Fourteen PCBCL, including Primary Cutaneous follicle centre lymphoma (PCFCL) and primary cutaneous diffuse large B-cell lymphoma, Leg type (PCDLBCL-LT) and 14 nDLBCL were evaluated for 7-year period (January 2011 to December 2017). Primary cutaneous marginal zone cell lymphoma (PCMZL) cases were not included in the present study. INTERVENTION: Evaluation of immunohistochemical CD10, BCL6, MUM1/IRF4, BCL2, MYC and Ki-67 expression and classification according to three different algorithms. Gene expression profiling (GEP) was performed on the same series using Lymph2Cx assay (Nanostring). The data obtained were compared and analysed. RESULTS: All the IHC algorithms showed 13 GCB and 15 non-GCB. GEP showed 12 GCB, 12 activated B cell-type and 4 unclassified. CONCLUSIONS: The PCBCL were classifiable as GCB and non-GCB like the nDLBCL as IHC algorithms were concordant to GEP and produced the same results.


Algorithms , Gene Expression/genetics , Lymphoma, B-Cell/genetics , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Biomarkers, Tumor/blood , Case-Control Studies , Female , Gene Expression/physiology , Humans , Immunohistochemistry/methods , Immunohistochemistry/statistics & numerical data , Italy/epidemiology , Lymphoma, B-Cell/diagnosis , Lymphoma, B-Cell/epidemiology , Male , Middle Aged , Retrospective Studies
8.
Pathol Res Pract ; 231: 153791, 2022 Mar.
Article En | MEDLINE | ID: mdl-35124548

BACKGROUND AND AIMS: TEAD4 transcription factor belonging to TEAD-family, is a key downstream element of the Hippo Signalling pathway and is very important for YAPinduced tumor progression. YAP-TEAD interaction is required to promote tumor progression and metastasis in various cancers. This study aims to investigate the role of TEAD4 in CRC progression and to compare the TEAD4 expression with different clinicopathological parameters of the study population. We also aim to explore the expression pattern of miR-4269 and miR-1343-3p and their functional role in TEAD4 mediated CRC progression. Furthermore, we intend to evaluate the prognostic significance of TEAD4, miR-4269, and miR-1343-3p in colorectal carcinoma. METHODS: Real-time PCR, Immunohistochemical Staining, and Western Blotting were performed on 71 human CRC tissue specimens and their adjacent normal tissues to evaluate the TEAD4 expression and the results were statistically analyzed against the clinicopathological variables of patient data and also with survival data using STATA software. miRNA expression was analyzed by quantitative real-time PCR. RESULTS: TEAD4 expression levels in tumor specimens were significantly higher than their paired normal specimens. The higher protein expression levels showed a significant association with TNM stage, Duke Stage, tumor grade, invasion depth, node status, necrosis of tumor tissue, lymphovascular and perineural invasion. As per the cox-regression model and classification tree analysis, TNM stage and perineural invasion were important predictors for TEAD4 expression and prognosis of CRC patients. Survival analysis indicated that TEAD4 overexpression was associated with poorer overall and disease-free survival. miR-4269 and miR-1343-3p were downregulated in CRC tumors and showed a negative correlation with TEAD4. The nuclear overexpressed TEAD4 and downregulated miR-4269 and miR-1343-3p evaluated for the first time in CRC, are believed to serve as important prognostic markers in CRC. CONCLUSION: Expression of TEAD4 was increased in CRC and was negatively regulated by miR-4269 and miR-1343-3p. The overexpression of TEAD4 is linked with poor overall and disease-free survival of CRC patients. These findings support prior observations and thus TEAD4 may be a possible prognostic marker in CRC.


Colorectal Neoplasms/genetics , Gene Expression/physiology , MicroRNAs/metabolism , TEA Domain Transcription Factors/genetics , Cell Line, Tumor/metabolism , Female , Humans , Male , MicroRNAs/analysis , Middle Aged , Nuclear Localization Signals/genetics , Prognosis , Proportional Hazards Models , TEA Domain Transcription Factors/analysis , TEA Domain Transcription Factors/metabolism
9.
Cell Prolif ; 55(3): e13183, 2022 Mar.
Article En | MEDLINE | ID: mdl-35137485

OBJECTIVE: Paravertebral muscle asymmetry may be involved in the pathogenesis of adolescent idiopathic scoliosis (AIS), and the Tent5a protein was recently identified as a novel active noncanonical poly(A) polymerase. We, therefore, explored the function of the AIS susceptibility gene Tent5a in myoblasts. MATERIALS AND METHODS: RNA-seq of AIS paravertebral muscle was performed, and the molecular differences in paravertebral muscle were investigated. Twenty-four AIS susceptibility genes were screened, and differential expression of Tent5a in paravertebral muscles was confirmed with qPCR and Western blot. After the knockdown of Tent5a, the functional effects of Tent5a on C2C12 cell proliferation, migration, and apoptosis were detected by Cell Counting Kit-8 assay, wound-healing assay, and TUNEL assay, respectively. Myogenic differentiation markers were tested with immunofluorescence and qPCR in vitro, and muscle fiber formation was compared in vivo. RESULTS: The AIS susceptibility gene Tent5a was differentially expressed in AIS paravertebral muscles. Tent5a knockdown inhibited the proliferation and migration of C2C12 cells and inhibited the maturation of type I muscle fibers in vitro and in vivo. Mechanistically, the expression of myogenin was decreased along with the suppression of Tent5a. CONCLUSIONS: Tent5a plays an important role in the proliferation and migration of myoblasts, and it regulates muscle fiber maturation by maintaining the stability of myogenin. Tent5a may be involved in the pathogenesis of AIS by regulating the formation of muscle fiber type I.


Muscle Fibers, Skeletal/metabolism , Myoblasts/cytology , Myogenin/metabolism , Polynucleotide Adenylyltransferase/metabolism , Adolescent , Cell Differentiation/genetics , Child , Female , Gene Expression/physiology , Humans , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/metabolism , Myogenin/genetics , RNA, Messenger/metabolism , Scoliosis/genetics
10.
Pathol Res Pract ; 231: 153779, 2022 Mar.
Article En | MEDLINE | ID: mdl-35151033

CIC-DUX4 fusion gene associated sarcoma is a new emerging subgroup of round cell sarcoma with Ewing sarcoma-like morphology. Distinguishing these tumors from Ewing sarcoma family tumors (ESFT) is critical because of the clinical impact but is still challenging due to the overlapped histological and immunohistochemical phenotypes of each subtype. The present study investigated small round cell sarcoma to identify CIC-DUX4 fusion positive sarcoma, examined clinical, histopathologic and immunohistochemical characteristics of CIC-DUX4 sarcoma, and evaluated parameters to differentiate Ewing sarcoma family tumors. Seventy patients with undifferentiated round cell sarcoma or Ewing-like sarcoma were retrieved. Molecular tests including EWSR1, CIC break apart FISH, and RT-PCR for CIC-DUX4 gene fusion were performed and immunohistochemistry was performed. Six cases (8.6%) of CIC-DUX4 sarcomas were detected. Histologically, CIC-DUX4 sarcomas composed of heterogeneous round, plasmacytoid, and spindle cells and more commonly showed cytologic pleomorphism with bizarre nuclei and multinucleated cells and myxoid stoma unlike ESFT. CIC-DUX4 sarcomas didn't show overall survival differences (p = 0.325) compared to ESFT but they demonstrated short disease-free survival (p = 0.034) and poor response to treatment (p = 0.007). Therefore, molecular analysis to detect the distinctive genetic alteration is mandatory in tumors with atypical histologic, immunohistochemical and/or clinical presentation for accurate diagnosis and treatment.


Liposarcoma, Myxoid/genetics , Liposarcoma, Myxoid/pathology , Oncogene Proteins, Fusion/analysis , Sarcoma, Ewing/genetics , Sarcoma, Ewing/pathology , Adolescent , Adult , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Diagnosis, Differential , Female , Gene Expression/genetics , Gene Expression/physiology , Humans , Immunohistochemistry/methods , Immunohistochemistry/statistics & numerical data , Male , Middle Aged , Oncogene Proteins, Fusion/genetics , Optical Imaging/methods , Optical Imaging/statistics & numerical data , Real-Time Polymerase Chain Reaction/methods , Real-Time Polymerase Chain Reaction/statistics & numerical data
11.
Pathol Res Pract ; 231: 153781, 2022 Mar.
Article En | MEDLINE | ID: mdl-35121362

This study aimed to investigate the expression and prognostic significance of the signal transducer and activator of transcription protein 6 (STAT6YE361) and EB virus encoding a small molecule RNA (EBER) in Hodgkin lymphoma (HL), as well as their correlation with clinical parameters. The expression of STAT6YE361 and EBER was investigated in HL via immunohistochemistry and in situ hybridization. Patient clinical data were retrospectively collected from archival libraries, and statistical analysis was performed. Overall, the nuclear positive expression rate of STAT6YE361 was 46%, and the EBER positive expression rate was 57%. STAT6YE361 was specifically expressed on the nucleus in cHL tissues. EBER was overexpressed in HL and had correlations with several clinical data, including age, gender, ethnicity, and primary cancer site. Interestingly, nuclear STAT6YE361 expression was correlated with EBER expression. Based on survival analysis, the nuclear expression of STAT6YE361 and female patients were associated with poor prognosis and were independent prognostic factors for five-year OS. These findings suggest that STAT6YE361 is a potential valuable index in the differential diagnosis and prognosis of HL. The mechanism of STAT6YE361 is related to Epstein-Barr virus infection.


Gene Expression/genetics , Hodgkin Disease/diagnosis , STAT6 Transcription Factor/analysis , Adolescent , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Child , Child, Preschool , Female , Gene Expression/physiology , Hodgkin Disease/genetics , Humans , Immunohistochemistry/methods , Immunohistochemistry/statistics & numerical data , Male , Middle Aged , Prognosis , Proportional Hazards Models , STAT6 Transcription Factor/genetics
12.
Sci Rep ; 12(1): 3018, 2022 02 22.
Article En | MEDLINE | ID: mdl-35194064

Worker reproduction in social insects is often regulated by the queen, but can be regulated by the brood and nestmates, who may use different mechanisms to induce the same outcomes in subordinates. Analysis of brain gene expression patterns in bumble bee workers (Bombus impatiens) in response to the presence of the queen, the brood, both or neither, identified 18 differentially expressed genes, 17 of them are regulated by the queen and none are regulated by the brood. Overall, brain gene expression differences in workers were driven by the queen's presence, despite recent studies showing that brood reduces worker egg laying and provides context to the queen pheromones. The queen affected important regulators of reproduction and brood care across insects, such as neuroparsin and vitellogenin, and a comparison with similar datasets in the honey bee and the clonal raider ant revealed that neuroparsin is differentially expressed in all species. These data emphasize the prominent role of the queen in regulating worker physiology and behavior. Genes that serve as key regulators of workers' reproduction are likely to play an important role in the evolution of sociality.


Bees/genetics , Bees/physiology , Behavior, Animal/physiology , Brain/metabolism , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Gene Expression/genetics , Gene Expression/physiology , Reproduction/genetics , Reproduction/physiology , Animals , Insect Hormones/metabolism , Pheromones/metabolism , Social Behavior , Vitellogenins/metabolism
13.
Sci Rep ; 12(1): 2999, 2022 02 22.
Article En | MEDLINE | ID: mdl-35194087

The present study was designed to assess whether raised Serine protease inhibitor Kazal type 1 (SPINK1) expressions modulates angiogenesis. Human umbilical vein endothelial cells (HUVECs) exposed to SPINK1 were noted to exhibit raised expressions of interleukin-8 (IL-8) as well as VCAM-1 and ICAM-1 cell adhesion molecules in a dose-dependent manner. In co-culture system of HUVECs and Acute lymphoblastic leukemia (ALL) cells, SPINK1 exposure also resulted in enhanced endothelial cell motility and ALL cells trans-endothelial migration. High concentrations of SPINK1 caused in vitro cellular reorganization into tubes in Matrigel-cultured HUVECs and induced in vivo vascularization and brain infiltration of NOD/SCID ALL model mice. The further transcriptomic analysis indicated that SPINK1 treatment altered several biological processes of endothelial cells and led to activation of the MAPK pathway. This study is the first to determine the neovascularization effects of raised SPINK1.


Cell Movement/genetics , Gene Expression/genetics , Gene Expression/physiology , Neovascularization, Pathologic/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Trypsin Inhibitor, Kazal Pancreatic/genetics , Trypsin Inhibitor, Kazal Pancreatic/physiology , Animals , Coculture Techniques , Disease Models, Animal , Endothelial Cells/pathology , Female , Human Umbilical Vein Endothelial Cells , Humans , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , MAP Kinase Signaling System/genetics , MAP Kinase Signaling System/physiology , Mice , Mice, Inbred NOD , Mice, SCID , Neovascularization, Pathologic/pathology , Trypsin Inhibitor, Kazal Pancreatic/metabolism , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/metabolism
14.
Sci Rep ; 12(1): 2597, 2022 02 16.
Article En | MEDLINE | ID: mdl-35173215

In vertebrates dysregulation of the antioxidant defense system has a detrimental impact on male fertility and reproductive physiology. However, in insects, especially mosquitoes the importance of sperm quality has been poorly studied. Since long-term storage of healthy and viable sperm earmarks male reproductive competency, we tested whether the heme peroxidase, a member of antioxidant enzyme family proteins, and abundantly expressed in the testis, also influence male fertility in the mosquito An. stephensi. Here, we show that a heme peroxidase 12 (HPX12), is an important cellular factor to protect the sperms from oxidative stress, and maintains semen quality in the male mosquito reproductive organ. We demonstrate that knockdown of the HPX12 not only impairs the sperm parameters such as motility, viability but also causes a significant down-regulation of MAG expressing transcripts such as ASTEI02706, ASTEI00744, ASTEI10266, likely encoding putative Accessory gland proteins. Mating with HPX12 knockdown male mosquitoes, resulted in ~ 50% reduction in egg-laying, coupled with diminished larval hatchability of a gravid female mosquito. Our data further outlines that increased ROS in the HPX12 mRNA depleted mosquitoes is the ultimate cause of sperm disabilities both qualitatively as well as quantitatively. Our data provide evidence that testis expressing AsHPX12 is crucial for maintaining optimal homeostasis for storing and protecting healthy sperms in the male mosquito's reproductive organs. Since, high reproductive capacity directly influences the mosquito population, manipulating male mosquito reproductive physiology could be an attractive tool to combat vector-borne diseases.


Anopheles/physiology , Fertility/genetics , Fertility/physiology , Insect Proteins/physiology , Peroxidase/genetics , Peroxidase/physiology , Testis/metabolism , Animals , Gene Expression/genetics , Gene Expression/physiology , Gene Knockdown Techniques , Insect Proteins/genetics , Insect Proteins/metabolism , Male , Mosquito Vectors , Peroxidase/metabolism , Sperm Motility/genetics , Vector Borne Diseases/prevention & control
15.
Pathol Res Pract ; 231: 153795, 2022 Mar.
Article En | MEDLINE | ID: mdl-35134625

Heterogeneous nuclear ribonucleic protein K (hnRNPK) regulates the expression of various genes, but has contradictory roles as a tumor promoter and a tumor suppressor. We recently reported that the expression of hnRNPK is negatively associated with malignant behavior of breast cancer where it was induced by estrogen, and bound to estrogen receptor α (ERα) in the nucleus of breast cancer cells. However, the significance of hnRNPK in endometrial cancer, also an estrogen-dependent cancer, remains unclear. In this study, we first examined the localization of hnRNPK and ERα in normal endometrium and endometrial cancer. hnRNPK and ERα immunoreactivity was detected in the nuclei of endometrial glandular and carcinoma cells. In normal endometria, hnRNPK labeling index/immuno-intensity was significantly higher in the proliferative phase than in the secretory phase. In endometrial cancer tissues, hnRNPK labeling index/immuno-intensity was significantly higher in the adjacent non-malignant glandular cells compared to that in carcinoma cells. Immunohistochemistry results for ERα were identical to that of hnRNPK both in normal endometrium and endometrial cancer. In normal and cancerous tissues, the median value of the hnRNPK labeling index was significantly higher in the ERα-high group. Intratumoral estrogen, but not androgen, measured using liquid chromatography-tandem mass spectrometry, was significantly positively correlated with the hnRNPK labeling index in endometrial cancer tissues. Database analysis revealed that the hnRNPK high expression group had a significantly better prognosis for both overall and disease-free survival. These results suggest that hnRNPK interacts with ERα to regulate endometrial changes during the menstrual cycle and suppress the malignant behavior of endometrial cancer.


Endometrial Neoplasms/genetics , Estrogen Receptor alpha/analysis , Heterogeneous-Nuclear Ribonucleoprotein K/analysis , Endometrial Neoplasms/diagnosis , Estrogen Receptor alpha/genetics , Female , Gene Expression/genetics , Gene Expression/physiology , Heterogeneous-Nuclear Ribonucleoprotein K/genetics , Humans , Japan
16.
Int J Mol Sci ; 23(4)2022 Feb 14.
Article En | MEDLINE | ID: mdl-35216228

Currently, the mechanism of progression of atopic dermatitis (AD) is not well understood because there is no physiologically appropriate disease model in terms of disease complexity and multifactoriality. Type 2 inflammation, mediated by interleukin (IL)-4 and IL-13, plays an important role in AD. In this study, full-thickness human skin equivalents consisting of human-derived cells were fabricated from pumpless microfluidic chips and stimulated with IL-4 and IL-13. The morphological properties, gene expression, cytokine secretion and protein expression of the stimulated human skin equivalent (HSE) epidermis were investigated. The results showed epidermal and spongy formations similar to those observed in lesions in AD, and decreased expression of barrier-related filaggrin, loricrin and involucrin genes and proteins induced by IL-4Rα signaling. In addition, we induced the expression of carbonic anhydrase II (CAII), a gene specifically expressed in the epidermis of patients with AD. Thus, AD human skin equivalents can be used to mimic the key pathological features of atopic dermatitis, overcoming the limitations of existing studies that rely solely on mouse models and have been unable to translate their effects to humans. Our results will be useful for future research on the development of therapeutic agents for atopic dermatitis.


Dermatitis, Atopic/metabolism , Interleukin-13/metabolism , Interleukin-4/metabolism , Skin/metabolism , Animals , Dermatitis, Atopic/drug therapy , Eczema/drug therapy , Eczema/metabolism , Eczema/pathology , Epidermis/drug effects , Epidermis/metabolism , Epidermis/pathology , Gene Expression/drug effects , Gene Expression/physiology , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Keratinocytes/drug effects , Keratinocytes/metabolism , Keratinocytes/pathology , Lab-On-A-Chip Devices , Membrane Proteins/pharmacology , Rats , Skin/drug effects , Skin/pathology
17.
FASEB J ; 36(2): e22157, 2022 02.
Article En | MEDLINE | ID: mdl-35032404

Congenital hepatic fibrosis (CHF) is a developmental liver disease that is caused by mutations in genes that encode ciliary proteins and is characterized by bile duct dysplasia and portal fibrosis. Recent work has demonstrated that mutations in ANKS6 can cause CHF due to its role in bile duct development. Here, we report a novel ANKS6 mutation, which was identified in an infant presenting with neonatal jaundice due to underlying biliary abnormalities and liver fibrosis. Molecular analysis revealed that ANKS6 liver pathology is associated with the infiltration of inflammatory macrophages to the periportal fibrotic tissue and ductal epithelium. To further investigate the role of macrophages in CHF pathophysiology, we generated a novel liver-specific Anks6 knockout mouse model. The mutant mice develop biliary abnormalities and rapidly progressing periportal fibrosis reminiscent of human CHF. The development of portal fibrosis in Anks6 KO mice coincided with the accumulation of inflammatory monocytes and macrophages in the mutant liver. Gene expression and flow cytometric analysis demonstrated the preponderance of M1- over M2-like macrophages at the onset of fibrosis. A critical role for macrophages in promoting peribiliary fibrosis was demonstrated by depleting the macrophages with clodronate liposomes which effectively reduced inflammatory gene expression and fibrosis, and ameliorated tissue histology and biliary function in Anks6 KO livers. Together, this study demonstrates that macrophages play an important role in the initiation of liver fibrosis in ANKS6-deficient livers and their therapeutic elimination may provide an avenue to mitigate CHF in patients.


Carrier Proteins/metabolism , Cholestasis/pathology , Liver Cirrhosis/metabolism , Liver/metabolism , Macrophages/metabolism , Animals , Disease Models, Animal , Gene Expression/physiology , Inflammation/metabolism , Inflammation/pathology , Liver/pathology , Liver Cirrhosis/pathology , Macrophages/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/metabolism , Monocytes/pathology
18.
FASEB J ; 36(2): e22133, 2022 02.
Article En | MEDLINE | ID: mdl-35032416

Shift-workers show an increased incidence of type 2 diabetes mellitus (T2DM). A possible mechanism is the disruption of the circadian timing of glucose homeostasis. Skeletal muscle mitochondrial function is modulated by the molecular clock. We used time-restricted feeding (TRF) during the inactive phase to investigate how mistimed feeding affects muscle mitochondrial metabolism. Rats on an ad libitum (AL) diet were compared to those that could eat only during the light (inactive) or dark (active) phase. Mitochondrial respiration, metabolic gene expressions, and metabolite concentrations were determined in the soleus muscle. Rats on AL feeding or dark-fed TRF showed a clear daily rhythm in muscle mitochondrial respiration. This rhythm in mitochondrial oxidative phosphorylation capacity was abolished in light-fed TRF animals and overall 24h respiration was lower. The expression of several genes involved in mitochondrial biogenesis and the fission/fusion machinery was altered in light-fed animals. Metabolomics analysis indicated that light-fed animals had lost rhythmic levels of α-ketoglutarate and citric acid. Contrastingly, lipidomics showed that light-fed animals abundantly gained rhythmicity in levels of triglycerides. Furthermore, while the RER shifted entirely with the food intake in the light-fed animals, many measured metabolic parameters (e.g., activity and mitochondrial respiration) did not strictly align with the shifted timing of food intake, resulting in a mismatch between expected metabolic supply/demand (as dictated by the circadian timing system and light/dark-cycle) and the actual metabolic supply/demand (as dictated by the timing of food intake). These data suggest that shift-work impairs mitochondrial metabolism and causes metabolic inflexibility, which can predispose to T2DM.


Cell Respiration/physiology , Circadian Clocks/physiology , Circadian Rhythm/physiology , Fasting/physiology , Mitochondria/physiology , Muscle, Skeletal/physiology , Animals , Diabetes Mellitus, Type 2/physiopathology , Diet/methods , Eating/physiology , Energy Metabolism/physiology , Feeding Behavior/physiology , Gene Expression/physiology , Male , Organelle Biogenesis , Oxidative Phosphorylation , Photoperiod , Rats , Rats, Wistar
19.
PLoS One ; 17(1): e0253406, 2022.
Article En | MEDLINE | ID: mdl-35025862

Early-life adversity (ELA) causes long-lasting structural and functional changes to the brain, rendering affected individuals vulnerable to the development of psychopathologies later in life. Immediate-early genes (IEGs) provide a potential marker for the observed alterations, bridging the gap between activity-regulated transcription and long-lasting effects on brain structure and function. Several heterogeneous studies have used IEGs to identify differences in cellular activity after ELA; systematically investigating the literature is therefore crucial for comprehensive conclusions. Here, we performed a systematic review on 39 pre-clinical studies in rodents to study the effects of ELA (alteration of maternal care) on IEG expression. Females and IEGs other than cFos were investigated in only a handful of publications. We meta-analyzed publications investigating specifically cFos expression. ELA increased cFos expression after an acute stressor only if the animals (control and ELA) had experienced additional hits. At rest, ELA increased cFos expression irrespective of other life events, suggesting that ELA creates a phenotype similar to naïve, acutely stressed animals. We present a conceptual theoretical framework to interpret the unexpected results. Overall, ELA likely alters IEG expression across the brain, especially in interaction with other negative life events. The present review highlights current knowledge gaps and provides guidance to aid the design of future studies.


Gene Expression/physiology , Genes, Immediate-Early/genetics , Stress, Psychological , Animals , Brain/metabolism , Cytoskeletal Proteins/genetics , Early Growth Response Protein 1/genetics , Male , Nerve Tissue Proteins/genetics , Proto-Oncogene Proteins c-fos/genetics , Rodentia
20.
Can J Physiol Pharmacol ; 100(2): 158-166, 2022 Feb.
Article En | MEDLINE | ID: mdl-35080988

Nasopharyngeal carcinoma (NC) poses a threat to the life of patients. Long non-coding RNA (LncRNA) is a novel kind of non-coding RNA, which plays a pivotal role through sponge microRNA (miRNA). Abnormal expression of small nucleolar RNA host gene 8 (SNHG8) is involved in various tumors; however, the role of SNHG8 in NC remains unknown. Quantitative real-time PCR (qRT-PCR) and Western blotting was employed to detect the expression levels of SNHG8, miR-588, and high mobility group A2 (HMGA2). Cell proliferation, migration, and invasion were analyzed by CCK-8 and transwell assays. miR-588 binding sites in SNHG8 were predicted by LncBase analysis. Luciferase reporter and RNA pull-down assay were used to confirm the interaction of SNHG8 and miR-588. SNHG8 was highly expressed in NC cells. The prognosis of the patients with NC in the high expression levels of SNHG8 was poorer than that in the low expression levels. The expression of SNHG8 was closely related to tumor size, TNM stage, and distal metastasis. Knockdown of SNHG8 inhibited cell proliferation, migration, and invasion of NC. SNHG8 targeted miR-588. Inhibition of miR-588 could partially reverse the knockdown of SNHG8 in NC cells, and miR-588 targeted HMGA2. In conclusion, SNHG8 promotes proliferation, migration, and invasion of NC cells through miR-588/HMGA2 in NC as an oncogene.


Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/physiology , Gene Expression/genetics , Gene Expression/physiology , HMGA2 Protein/genetics , HMGA2 Protein/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/pathology , Neoplasm Invasiveness/genetics , Oncogenes/genetics , Oncogenes/physiology , RNA, Long Noncoding/genetics , RNA, Long Noncoding/physiology , Cell Line, Tumor , Female , Humans , Male , Middle Aged , RNA, Long Noncoding/metabolism
...