scholarly journals Gp37 Regulates the Pathogenesis of Avian Leukosis Virus Subgroup J via Its C Terminus

2020 ◽  
Vol 94 (11) ◽  
Author(s):  
Tuofan Li ◽  
Xiaohui Yao ◽  
Chunping Li ◽  
Jun Zhang ◽  
Quan Xie ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Antiviral Drug ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Significant Loss ◽  
Viral Shedding ◽  
C Terminus ◽  
New Perspective

ABSTRACT Different from other subgroups of avian leukosis viruses (ALVs), ALV-J is highly pathogenic. It is the main culprit causing myeloid leukemia and hemangioma in chickens. The distinctiveness of the env gene of ALV-J, with low homology to those of other ALVs, is linked to its unique pathogenesis, but the underlying mechanism remains unclear. Previous studies show that env of ALV-J can be grouped into three species based on the tyrosine motifs in the cytoplasmic domain (CTD) of Gp37, i.e., the inhibitory, bifunctional, and active groups. To explore whether the C terminus or the tyrosine motifs in the CTD of Gp37 affect the pathogenicity of ALV-J, a set of ALV-J infectious clones containing different C termini of Gp37 or the mutants at the tyrosine sites were tested in vitro and in vivo. Viral growth kinetics indicated not only that ALV-J with active env is the fastest in replication and ALV-J with inhibitory env is the lowest but also that the tyrosine sites essentially affected the replication of ALV-J. Moreover, in vivo studies demonstrated that chickens infected by ALV-J with active or bifunctional env showed higher viremia, cloacal viral shedding, and viral tissue load than those infected by ALV-J with inhibitory env. Notably, the chickens infected by ALV-J with active or bifunctional env showed significant loss of body weight compared with the control chickens. Taken together, these findings reveal that the C terminus of Gp37 plays a vital role in ALV-J pathogenesis, and change from inhibitory env to bifunctional or active env increases the pathogenesis of ALV-J. IMPORTANCE ALV-J can cause severe immunosuppression and myeloid leukemia in infected chickens. However, no vaccine or antiviral drug is available against ALV-J, and the mechanism for ALV-J pathogenesis needs to be elucidated. It is generally believed that gp85 and LTR of ALV contribute to its pathogenesis. Here, we found that the C terminus and the tyrosine motifs (YxxM, ITIM, and ITAM-like) in the CTD of Gp37 of ALV-J could affect the pathogenicity of ALV-J in vitro and in vivo. The pathogenicity of ALV-J with Gp37 containing ITIM only was significantly less than ALV-J with Gp37 containing both YxxM and ITIM and ALV-J with Gp37 containing both YxxM and ITAM-like. This study highlights the vital role of the C terminus of Gp37 in the pathogenesis of ALV-J and thus provides a new perspective to elucidate the interaction between ALV-J and its host and a molecular basis to develop efficient strategies against ALV-J.

scholarly journals Circ_0001367 inhibits glioma proliferation, migration and invasion by sponging miR-431 and thus regulating NRXN3

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Liang Liu ◽  
Peng Zhang ◽  
Xuchen Dong ◽  
Haoran Li ◽  
Suwen Li ◽  
...  
Keyword(s):  
Close Correlation ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Dependent Manner ◽  
Glioma Growth

AbstractMany studies have reported that circular RNAs play a vital role in the malignant progression of human cancers. However, the role and underlying mechanism of circRNAs in the development of gliomas have not been fully clarified. In this study, we found that circ_0001367 was downregulated in glioma tissues and showed a close correlation with glioma patient survival. Functional assays demonstrated that upregulation of circ_0001367 could suppress the proliferation, migration and invasion of glioma cells in vitro and inhibit glioma growth in vivo. Furthermore, bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation assay indicated that circ_0001367 can serve as a sponge for miR-431 and that miR-431 acts as an oncogene by regulating neurexin 3 (NRXN3). In addition, rescue experiments verified that circ_0001367 could regulate both the expression and function of NRXN3 in a miR-431-dependent manner. In conclusion, circ_0001367 functions as an suppressor in glioma by targeting the miR-431/NRXN3 axis and may be a promising therapeutic target against gliomas.

scholarly journals C-Terminal Domain of ABL Family Kinases, ABL and ARG, Defines Their Distinct Leukemogenic Activities in Vivo

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2368-2368 ◽  
Author(s):  
Asumi Yokota ◽  
Hideyo Hirai ◽  
Tsukimi Shoji ◽  
Taira Maekawa ◽  
Keiko Okuda
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Tyrosine Kinase ◽  
Fusion Proteins ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Terminal Domain ◽  
C Terminus

Abstract ARG (ABL2) is a member of ABL family kinases and highly homologous to ABL (ABL1) except the C-terminal domain adjacent to the kinase domain. TEL/ARG that consists of ARG fused to TEL (ETV6) has been found in AML M3, M4 or T-ALL patients, with additional chromosomal abnormalities of t(15;17)(q12;q21), inv(16)(p13;q12) or t(1;10;12)(q25;q23;p13) translocation, respectively. The structure of TEL/ARG is similar to that of TEL/ABL, which has been found in patients with T-ALL, B-ALL, AML and CML. TEL mediates homo-oligomerization of these fusion proteins, TEL/ABL and TEL/ARG, resulting in constitutive activation of the tyrosine kinases. Although ABL fusion proteins such as BCR/ABL and TEL/ABL have been intensively investigated, the involvement of TEL/ARG in leukemogenesis is not fully elucidated yet. We have recently reported that in vitro transforming activity of TEL/ARG was significantly lower than that of TEL/ABL although their kinase activities were almost identical. Interestingly, the in vitro transforming activities of C-terminus-swapped mutants, TEL/ABL with C-terminal domain of ARG [TEL-ABL (ARG-C)] or TEL/ARG with C-terminal domain of ABL [TEL/ARG (ABL-C)], were comparable to those of TEL/ARG or TEL/ABL, respectively, while kinase activities in the swapped mutants were not altered. These results suggest that C-termini of ABL family kinases contain some functional domain that defines their distinct transforming activities. The purpose of this study is to compare the in vivo leukemogenic activities of TEL/ABL and TEL/ARG, and evaluate the impact of the C-terminal domains. First, we investigated whether TEL/ABL or TEL/ARG caused leukemia in mice. Each fusion gene together with GFP gene was retrovirally transduced into the bone marrow cells harvested from C57BL/6 mice treated with 5-fluorouracil, and the transduced cells were transplanted into lethally irradiated mice. Similar to BCR/ABL, transplantation of TEL/ABL-transduced cells induced rapid myeloproliferative status accompanied by hepatomegaly and/or splenomegaly, and all the recipient mice died within 33 days after transplantation, indicating the development of myeloid leukemia. In contrast, the recipient mice transplanted with TEL/ARG-transduced cells did not develop myeloid leukemia but infiltrative mastocytosis, and died around 200 days after transplantation (Figure 1). Hemophagocytic mast cells accumulating in the bone marrow, and mast cells circulating in the peripheral blood were also observed in these mice. Next we investigated the roles of C-terminal domains of ABL and ARG in their in vivo leukemogenic activities. C-terminus-swapped mutants, TEL/ABL (ARG-C) and TEL/ARG (ABL-C) were retrovirally transduced into bone marrow cells and the transduced cells were transplanted as described above. Intriguingly, TEL/ABL (ARG-C) mutant failed to cause myeloproliferative status or leukemia at day 153 (Figure 2A). On the other hand, TEL/ARG (ABL-C) induced lethal myeloid leukemia in 4 out of 13 mice (30.8%) within 111 days after transplantation (Figure 2B). Collectively, the in vivo phenotypes induced by TEL/ABL (ARG-C) or TEL/ARG (ABL-C) resembled those induced by TEL/ARG or TEL/ABL, respectively. Mastocytosis, a characteristic of TEL-ARG-induced phenotype, has not been observed so far in any of the recipients of TEL/ABL (ARG-C) or TEL/ARG (ABL-C). In conclusion, these results indicate that C-terminal domain of ABL family kinases defines their distinct leukemogenic activities in vivo through modulating both proliferation and differentiation. Notably, C-terminus of ARG strongly suppressed the in vivo leukemogenic activity of TEL/ABL without impairing the tyrosine kinase activity. Further clarification of the molecular mechanisms underlying the suppressive activity of C-terminus of ARG will lead to development of a novel therapeutic strategy, especially for patients with CML harboring mutations, which are resistant to tyrosine kinase inhibitors. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

The C-Terminus of the CBFβ-SMMHC Fusion Protein Is Required for the Myeloblastic Transformation of inv16 Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3799-3799
Author(s):  
Yasuhiko Kamikubo ◽  
Lisa Garrett-Beal ◽  
Martha Kirby ◽  
Pu Paul Liu
Keyword(s):  
Fusion Protein ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Homozygous Deletion ◽  
Double Positive ◽  
Developmental Defects ◽  
C Terminus ◽  
Almost All

Abstract Inv(16)(p13q22) is found in almost all human acute myeloid leukemia (AML) subtype M4Eo cases and forms a fusion gene CBFB-MYH11, which encodes a fusion protein CBFβ–SMMHC. CBFβ forms a heterodimeric transcription factor with RUNX1 and both are required for embryonic hematopoiesis, while SMMHC is the smooth muscle myosin heavy chain. Using knock-in mouse strategy, we previously demonstrated that Cbfb+/MYH11 F1 embryos have severe blockage of definitive hematopoiesis and die from CNS hemorrhage. The phenotype was similar to that of embryos with homozygous deletion of Cbfb or Runx1, suggesting that Cbfb-MYH11 dominantly represses Runx1/CBFb function. We further demonstrated that Cbfb-MYH11 is necessary but not sufficient for leukemia to develop, as the Cbfb+/MYH11 mice required additional mutations for leukemogenesis. Several hypotheses have been proposed, based on in vitro studies, to explain how CBFβ-SMMHC dominantly inhibits RUNX1/CBFβ. The C-terminal region of CBFβ-SMMHC is responsible for multimerization and also interacts with corepressors; thus this region might be critical for RUNX1 repression. To determine the importance of this multimerization domain in vivo, we generated knock-in mice expressing CBFβ-SMMHC with a 95 aa C-terminal deletion (CBFβ-SMMHCdC95), which truncates this multimerization/repression domain. CBFβ-SMMHCdC95 expressing F1 heterozygous embryos (Cbfb+/MYH11dC95) developed normally with no hematopoietic defects and no hemorrhage. Hematopoiesis was normal in the adult Cbfb+/MYH11dC95 mice except for mild increase of mature neutrophils and minor T cell developmental defects in the first year. However, the mice proceeded to a lethal myeloproliferative disorder (MPD) during their second year of life. There was a significant increase of Mac1/Gr1 double positive cells in the peripheral blood and the spleen, which were negative for the stem cell/progenitor cell marker, c-kit. Morphologically the erythrocytes and neutrophils were dysplastic, and the mice developed severe splenomegaly. ENU treatment of the Cbfb+/MYH11dC95 mice accelerated the development of the MPD phenotype but could not induce overt, transplantable, myeloid leukemia. These data suggest that the multimerizatin domain of SMMHC is important for both hematopoiesis blockage and leukemogenesis, especially the blastic transformation of inv16 leukemia.

scholarly journals Schistosoma japonicum Infection Leads to the Reprogramming of Glucose and Lipid Metabolism in the Colon of Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoying Yang ◽  
Weimin Ding ◽  
Xinyu Qian ◽  
Pengfei Jiang ◽  
Qingqing Chen ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Schistosoma Japonicum ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Metabolic Reprogramming ◽  
Downstream Signaling ◽  
Tensin Homolog ◽  
Glucose And Lipid Metabolism

The deposition of Schistosoma japonicum (S. japonicum) eggs commonly induces inflammation, fibrosis, hyperplasia, ulceration, and polyposis in the colon, which poses a serious threat to human health. However, the underlying mechanism is largely neglected. Recently, the disorder of glucose and lipid metabolism was reported to participate in the liver fibrosis induced by the parasite, which provides a novel clue for studying the underlying mechanism of the intestinal pathology of the disease. This study focused on the metabolic reprogramming profiles of glucose and lipid in the colon of mice infected by S. japonicum. We found that S. japonicum infection shortened the colonic length, impaired intestinal integrity, induced egg-granuloma formation, and increased colonic inflammation. The expression of key enzymes involved in the pathways regulating glucose and lipid metabolism was upregulated in the colon of infected mice. Conversely, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and its downstream signaling targets were significantly inhibited after infection. In line with these results, in vitro stimulation with soluble egg antigens (SEA) downregulated the expression of PTEN in CT-26 cells and induced metabolic alterations similar to that observed under in vivo results. Moreover, PTEN over-expression prevented the reprogramming of glucose and lipid metabolism induced by SEA in CT-26 cells. Overall, the present study showed that S. japonicum infection induces the reprogramming of glucose and lipid metabolism in the colon of mice, and PTEN may play a vital role in mediating this metabolic reprogramming. These findings provide a novel insight into the pathogenicity of S. japonicum in hosts.

scholarly journals Comprehensive RNA Editome Reveals Azin1 As a Functional Regulator in Hematopoietic Stem and Progenitor Cells

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Fengjiao Wang ◽  
Jiahuan He ◽  
Yanni Ma ◽  
Sha Hao ◽  
Siqi Liu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Rna Editing ◽  
Conflicts Of Interest ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Dynamic Landscape

RNA editing, adenosine (A)-to-inosine (I), plays a vital role in many biological processes. Our previous study has demonstrated that the hematopoietic stem and progenitor cells (HSPCs) deficient in adenosine deaminase acting on RNA 1 (Adar1), an RNA-editing enzyme, cannot reconstitute the irradiated recipients in vivo and form colonies in vitro (Xufeng R et al, PNAS 2009). However, the overall profile of RNA editome in hematopoiesis has not been established and the underlying mechanism how RNA editing governs the function of HSPCs is poorly defined. In this study, we sorted 12 murine adult hematopoietic cell populations and performed RNA sequencing. We depicted the landscape of RNA editome in hematopoietic cells and identified 30,796 editing sites in total. The dynamic landscape of RNA editome comprised of stage/group-specific as well as house-keeping editing patterns. Notably, antizyme inhibitor 1 (Azin1) was uncovered to be highly edited in HSPCs. To understand whether edited Azin1 was required for functioning of HSPCs, we transduced c-Kit+ HSPCs with the lentivirus carrying Azin1 cDNAs with distinct editing frequencies. c-Kit+ cells transduced with fully edited Azin1 showed enhanced reconstitution, compared to that transduced with partially edited or non-edited Azin1. Specifically, inability of RNA editing in Azin1 blocked the differentiation of hematopoietic stem cells (HSCs) in vivo. Moreover, a similar finding was obtained when Azin1 was knocked down. In conclusion, RNA editing of Azin1 (i) results in amino acid change to induce AZIN1 translocation to the nucleus, (ii) enhances AZIN1 binding affinity for DEAD box polypeptide 1 (DDX1) to alter the DDX1 chromatin distribution, and (iii) changes the expression of multiple hematopoietic regulators to ultimately promote HSPC differentiation. This work provides a valuable resource for studying RNA editing and delineates an essential role of Azin1 RNA editing in HSPCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Oxytocin involves in chronic stress-evoked melanoma metastasis via β-arrestin 2-mediated ERK signaling pathway

2019 ◽  
Vol 40 (11) ◽  
pp. 1395-1404 ◽  
Author(s):  
Haoyi Ji ◽  
Na Liu ◽  
Jing Li ◽  
Dawei Chen ◽  
Dan Luo ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Lung Metastasis ◽  
Restraint Stress ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Melanoma Metastasis ◽  
Chronic Restraint Stress ◽  
Increased Risk

Abstract Stress is associated with an increased risk of lung metastasis in melanoma. However, the underlying mechanism is elusive. Oxytocin (OXT), a neurohormone produced by the hypothalamus, plays a vital role in laboring induction and lactation. Emerging evidence suggests that OXT also regulates human emotions, social cognition, social behaviors and stress-related disorders. Here, we reported that a significant up-regulation of oxytocin receptors (OXTRs) was observed in malignant melanoma. The activation of OXTRs dramatically promoted migration, invasion and angiogenesis but not the proliferation of melanoma cells in vitro and in vivo via β-arrestin 2-dependent ERK-VEGF/MMP-2 pathway. Next, chronic restraint stress significantly elevated the plasma level of OXT. Notably, 21 days chronic restraint stress facilitated lung metastasis of melanoma and reduced overall survival in mice, which were largely abrogated by knocking down either OXTR or β-arrestin 2. These findings provide evidence that chronic stress hormone-OXT promotes lung metastasis of melanoma via a β-arrestin 2-dependent mechanism and suggest that OXT, a novel pro-metastasis factor, is a potential therapeutic target for melanoma.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals A Peptide Found in Human Serum, Derived from the C-Terminus of Albumin, Shows Antifungal Activity In Vitro and In Vivo

2020 ◽  
Vol 8 (10) ◽  
pp. 1627
Author(s):  
Tecla Ciociola ◽  
Pier Paolo Zanello ◽  
Tiziana D’Adda ◽  
Serena Galati ◽  
Stefania Conti ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Human Serum ◽  
Fungicidal Activity ◽  
Galleria Mellonella ◽  
Serum Proteins ◽  
Morphological Alterations ◽  
C Terminus ◽  
Different Sources

The growing problem of antimicrobial resistance highlights the need for alternative strategies to combat infections. From this perspective, there is a considerable interest in natural molecules obtained from different sources, which are shown to be active against microorganisms, either alone or in association with conventional drugs. In this paper, peptides with the same sequence of fragments, found in human serum, derived from physiological proteins, were evaluated for their antifungal activity. A 13-residue peptide, representing the 597–609 fragment within the albumin C-terminus, was proved to exert a fungicidal activity in vitro against pathogenic yeasts and a therapeutic effect in vivo in the experimental model of candidal infection in Galleria mellonella. Studies by confocal microscopy and transmission and scanning electron microscopy demonstrated that the peptide penetrates and accumulates in Candida albicans cells, causing gross morphological alterations in cellular structure. These findings add albumin to the group of proteins, which already includes hemoglobin and antibodies, that could give rise to cryptic antimicrobial fragments, and could suggest their role in anti-infective homeostasis. The study of bioactive fragments from serum proteins could open interesting perspectives for the development of new antimicrobial molecules derived by natural sources.

scholarly journals GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002383
Author(s):  
Jin-Li Wei ◽  
Si-Yu Wu ◽  
Yun-Song Yang ◽  
Yi Xiao ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Sequencing Data ◽  
Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

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