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1.
Bioorg Med Chem Lett ; 40: 127909, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33705900

RESUMO

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.

2.
Bioorg Med Chem ; 37: 116109, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33780813

RESUMO

A novel series of multitargeted molecules were designed and synthesized by combining the pharmacological role of cholinesterase inhibitor and antioxidant of steroid as potential ligands for the treatment of Vascular Dementia (VD). The oxygen-glucose deprivation (OGD) model was used to evaluate these molecules, among which the most potent compound ML5 showed the highest activity. Firstly, ML5 showed appropriate inhibition of cholinesterases (ChEs) at orally 15 mg/kg in vivo. The further test revealed that ML5 promoted the nuclear translocation of Nrf2. Furthermore, ML5 has significant neuroprotective effect in vivo model of bilateral common carotid artery occlusion (BCCAO), significantly increasing the expression of Nrf2 protein in the cerebral cortex. In the molecular docking research, we predicted the ML5 combined with hAChE and Keap1. Finally, compound ML5 displayed normal oral absorption and it was nontoxic at 500 mg/kg, po, dose. We can draw the conclusion that ML5 could be considered as a new potential compound for VD treatment.

3.
Theranostics ; 11(10): 5045-5060, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754043

RESUMO

Background & Aims: Liver cancer stem cells (LCSCs) mediate therapeutic resistance and correlate with poor outcomes in patients with hepatocellular carcinoma (HCC). Fibroblast growth factor (FGF)-19 is a crucial oncogenic driver gene in HCC and correlates with poor prognosis. However, whether FGF19 signaling regulates the self-renewal of LCSCs is unknown. Methods: LCSCs were enriched by serum-free suspension. Self-renewal of LCSCs were characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and tumorigenic potential assays. Ca2+ image was employed to determine the intracellular concentration of Ca2+. Gain- and loss-of function studies were applied to explore the role of FGF19 signaling in the self-renewal of LCSCs. Results: FGF19 was up-regulated in LCSCs, and positively correlated with certain self-renewal related genes in HCC. Silencing FGF19 suppressed self-renewal of LCSCs, whereas overexpressing FGF19 facilitated CSCs-like properties via activation of FGF receptor (FGFR)-4 in none-LCSCs. Mechanistically, FGF19/FGFR4 signaling stimulated store-operated Ca2+ entry (SOCE) through both the PLCγ and ERK1/2 pathways. Subsequently, SOCE-calcineurin signaling promoted the activation and translocation of nuclear factors of activated T cells (NFAT)-c2, which transcriptionally activated the expression of stemness-related genes (e.g., NANOG, OCT4 and SOX2), as well as FGF19. Furthermore, blockade of FGF19/FGFR4-NFATc2 signaling observably suppressed the self-renewal of LCSCs. Conclusions: FGF19/FGFR4 axis promotes the self-renewal of LCSCs via activating SOCE/NFATc2 pathway; in turn, NFATc2 transcriptionally activates FGF19 expression. Targeting this signaling circuit represents a potential strategy for improving the therapeutic efficacy of HCC.

4.
J Appl Psychol ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33630620

RESUMO

This study focuses on the role of emotions in personnel selection and faking research. In particular, we posit that emotions are likely to be activated when applicants receive warning messages from organizations. Drawing on Nabi (Nabi, Communication Theory, 9, 1999, 292) cognitive-functional model of discrete negative emotions, we propose and empirically test the effects of three discrete negative emotions (guilt, fear, and anger) triggered by a warning message during a personality test on personality score accuracy and perceived test fairness. Participants in this within-subjects field experiment were 1,447 applicants for graduate school at a large public university in China. They completed two parallel forms of a personality test: one within a selection context, and another within a developmental context 6 months later as a baseline measure. In the selection context, a warning (or a control) message was randomly assigned to participants during the personality test. Emotions and perceived test fairness were measured after the test was completed. Results indicated that guilt, fear, and anger each played a unique role. Guilt explained how mid-test warnings improved personality score accuracy among fakers, whereas fear accounted for why nonfakers over-corrected their personality scores. Finally, anger explained why the mid-test warnings reduced perceived test fairness for both fakers and nonfakers. Theoretical and practical implications are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

5.
Environ Microbiol ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33587785

RESUMO

Long non-coding RNAs (lncRNAs) play an important role in biological processes but regulation and function of lncRNAs remain largely unelucidated, especially in fungi. Ustilaginoidea virens is an economically important fungus causing a devastating disease of rice. By combining microscopic and RNA-seq analyses, we comprehensively characterized lncRNAs of this fungus in infection and developmental processes and defined four serial typical stages. RNA-seq analyses revealed 1724 lncRNAs in U. virens, including 1084 long intergenic non-coding RNAs (lincRNAs), 51 intronic RNAs (incRNAs), 566 natural antisense transcripts (lncNATs) and 23 sense transcripts. Gene Ontology enrichment of differentially expressed lincRNAs and lncNATs demonstrated that these were mainly involved in transport-related regulation. Functional studies of transport-related lncRNAs revealed that UvlncNAT-MFS, a cytoplasm localized lncNAT of a putative MFS transporter gene, UvMFS, could form an RNA duplex with UvMFS and was required for regulation of growth, conidiation and various stress responses. Our results were the first to elucidate the lncRNA profiles during infection and development of this important phytopathogen U. virens. The functional discovery of the novel lncRNA, UvlncNAT-MFS, revealed the potential of lncRNAs in regulation of life processes in fungi.

6.
Phytopathology ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33567906

RESUMO

Colletotrichum higginsianum is an important hemibiotrophic fungal pathogen that causes anthracnose disease on various cruciferous plants. Discovery of new virulence factors could lead to strategies for effectively controlling anthracnose. Acyl-CoA binding proteins (ACBPs) are mainly involved in binding and trafficking acyl-CoA esters in eukaryotic cells. However, the functions of this important class of proteins in plant fungal pathogens remain unclear. In this study, we performed an iTRAQ-based quantitative proteomic analysis to identify differentially expressed proteins (DEPs) between a nonpathogenic mutant ΔCh-MEL1 and the wild-type. Based on iTRAQ data, DEPs in the ΔCh-MEL1 mutant were mainly associated with melanin biosynthesis, carbohydrate and energy metabolism, lipid metabolism, redox processes, and amino acid metabolism. Proteomic analysis revealed that many DEPs might be involved in growth and pathogenesis of C. higginsianum. Among them, an acyl-CoA binding protein, ChAcb1, was selected for further functional studies. Deletion of ChAcb1 caused defects in vegetative growth and conidiation. ChAcb1 is also required for response to hyperosmotic and oxidative stresses, and maintenance of cell wall integrity. Importantly, the ΔChAcb1 mutant exhibited reduced virulence, and microscopic examination revealed that it was defective in appressorial penetration and infectious growth. Furthermore, the ΔChAcb1 mutant was impaired in fatty acid and lipid metabolism. Taken together, ChAcb1 was identified as a new virulence gene in this plant pathogenic fungus.

7.
Sci Adv ; 7(4)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523920

RESUMO

Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here, we demonstrated that ANXA1 is modified by SUMOylation, and SUMOylated ANXA1 could promote the beneficial phenotype polarization of microglia. Mechanistically, SUMOylated ANXA1 suppressed nuclear factor κB activation and the production of proinflammatory mediators. Further study revealed that SUMOylated ANXA1 targeted the IκB kinase (IKK) complex and selectively enhanced IKKα degradation. Simultaneously, we detected that SUMOylated ANXA1 facilitated the interaction between IKKα and NBR1 to promote IKKα degradation through selective autophagy. Further work revealed that the overexpression of SUMOylated ANXA1 in microglia/macrophages resulted in marked improvement in neurological function in a mouse model of cerebral ischemia. Collectively, our study demonstrates a previously unidentified mechanism whereby SUMOylated ANXA1 regulates microglial polarization and strongly indicates that up-regulation of ANXA1 SUMOylation in microglia may provide therapeutic benefits for cerebral ischemia.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33555221

RESUMO

Identification of transcription factor binding-sites is one of the most important steps in understanding the function of transcription factors and regulatory networks in organisms. The Assay for Transposase Accessible Chromatin Sequencing (ATAC-seq) is a simple protocol for detection of open chromatin, which could be a powerful tool to advance studies of protein:DNA interactions. Although ATAC-seq has been used in systematic identification of cis-regulatory regions in animal and plant genomes, this method has been rarely applied in fungi. Here, we describe a valuable ATAC-seq resource in the genome of an economically important phytopathogen, the rice false smut fungus, Ustilaginoidea virens. The ATAC-seq data of U. virens mycelia collected from potato sucrose broth (PSB) and PSB supplied with rice spikelet extract (RSE) were both generated. This is the first genome-wide profiling of open chromatin and transcription factor binding sites in U. virens.

9.
Chempluschem ; 86(2): 340-346, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33624952

RESUMO

A series of macrocycles that contain two quinoline oligoamide foldamers (QOFs) using various length of alkyl chains as linkers (2, 3, 6, 8 or 12 hydrocarbons) were synthesized. The two QOFs interact with each other through the linkers and the intramolecular helix chiral communications between the two QOFs were studied by 1 H NMR spectroscopy and crystal structures. Investigations show that the intensity of the intramolecular helix chiral communications between the two QOFs is dependent on the length of the linkers, and the interaction between the two QOFs increases with decreasing length of the linkers. When the length of the linkers decreased to C2 linkers, only one conformer is present in solution. Moreover, increasing the length of the foldamers would enhance the intramolecular helix chiral communication if the linkers are short, indicating that the length of the foldamers also has significant impact on intramolecular helix chiral communication.

11.
J Integr Plant Biol ; 63(2): 409-425, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33427395

RESUMO

Lysine 2-hydroxyisobutyrylation (Khib ) is a newly identified post-translational modification (PTM) that plays important roles in transcription and cell proliferation in eukaryotes. However, its function remains unknown in phytopathogenic fungi. Here, we performed a comprehensive assessment of Khib in the rice false smut fungus Ustilaginoidea virens, using Tandem Mass Tag (TMT)-based quantitative proteomics approach. A total of 3 426 Khib sites were identified in 977 proteins, suggesting that Khib is a common and complex PTM in U. virens. Our data demonstrated that the 2-hydroxyisobutyrylated proteins are involved in diverse biological processes. Network analysis of the modified proteins revealed a highly interconnected protein network that included many well-studied virulence factors. We confirmed that the Zn-binding reduced potassium dependency3-type histone deacetylase (UvRpd3) is a major enzyme that removes 2-hydroxyisobutyrylation and acetylation in U. virens. Notably, mutations of Khib sites in the mitogen-activated protein kinase (MAPK) UvSlt2 significantly reduced fungal virulence and decreased the enzymatic activity of UvSlt2. Molecular dynamics simulations demonstrated that 2-hydroxyisobutyrylation in UvSlt2 increased the hydrophobic solvent-accessible surface area and thereby affected binding between the UvSlt2 enzyme and its substrates. Our findings thus establish Khib as a major post-translational modification in U. virens and point to an important role for Khib in the virulence of this phytopathogenic fungus.

12.
Ecotoxicol Environ Saf ; 208: 111687, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396019

RESUMO

Manganese (Mn) is demonstrated to be essential for plants. Ion homeostasis is maintained in plant cells by specialized transporters. PbMTP8.1, which encodes a putative Mn-CDF transporter in Pyrus bretschneideri Rehd, was expressed mainly in leaves and complemented the Mn hypersensitivity of the Mn-sensitive yeast mutant △pmr1 in previous research conducted by our laboratory. In the present study, we report that the expression of PbMTP8.1 can enhance Mn tolerance and accumulation in Saccharomyces cerevisiae. Subcellular localization analysis of the PbMTP8.1-GFP fusion protein indicated that PbMTP8.1 was targeted to the pre-vacuolar compartment (PVC). In addition, the overexpression of PbMTP8.1 in Arabidopsis thaliana conferred increased resistance to plants under toxic Mn levels, as indicated by increased fresh and dry weights of shoots and roots. Mn accumulation in vacuoles of PbMTP8.1-overexpressing plants was significantly increased when compared with that in wild-type plants under Mn stress. This suggests that a considerable proportion of Mn enters into the vacuoles through a PbMTP8.1-dependent mechanism. Taken together, these results indicate PbMTP8.1 is a Mn-specific transporter that is localized to the PVC, and confers Mn tolerance by sequestering Mn into the vacuole.


Assuntos
Arabidopsis/metabolismo , Proteínas de Transporte de Cátions/genética , Poluentes Ambientais/toxicidade , Manganês/toxicidade , Pyrus/metabolismo , Saccharomyces cerevisiae/metabolismo , Adaptação Biológica/genética , Arabidopsis/genética , Poluentes Ambientais/metabolismo , Manganês/metabolismo , Células Vegetais/metabolismo , Folhas de Planta/genética , Folhas de Planta/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Pyrus/genética , Saccharomyces cerevisiae/genética , Vacúolos/metabolismo
13.
AIDS Care ; : 1-10, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33487029

RESUMO

We evaluated health-related quality of life (QoL) and self-reported incomplete adherence as predictors of early second-line antiretroviral (ART) virological failure (VF). ACTG A5273 study participants completed the ACTG SF-21 measure which has 8 QoL domains. We used exact logistic regression to assess the association of QoL at baseline and week 4 with early VF adjusted for self-reported adherence. Of 500 individuals (51% women, median age 39 years) in this analysis, 79% and 75% self-reported complete adherence (no missing doses in the past month) at weeks 4 and 24, respectively. Early VF was experienced by 7% and more common among those who self-reported incomplete adherence. Participants with low week 4 QoL scores had higher rates of early VF than participants with high scores. After adjusting for self-reported adherence at week 4, VL and CD4 at baseline, cognitive functioning, pain and mental health domains were significantly associated with subsequent early VF. In this post-hoc analysis, poorer QoL adds to self-reported incomplete adherence after 4 weeks of second-line ART in predicting VF at week 24. Evaluation is needed to assess whether individuals with poorer QoL might be targeted for greater support to reduce risk of VF. Trial registration: ClinicalTrials.gov identifier: NCT01352715.

14.
Yonsei Med J ; 62(1): 29-40, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33381932

RESUMO

PURPOSE: The aim of this study was to compare the efficacy of liver transplantation (LT) and liver resection (LR) for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) and to investigate risk factors affecting prognosis. MATERIALS AND METHODS: A total of 94 HCC patients with PVTT type I (segmental PVTT) and PVTT type II (lobar PVTT) were involved and divided into LR (n=47) and LT groups (n=47). Recurrence-free survival (RFS) and overall survival (OS) were compared before and after inverse probability of treatment weighting (IPTW). Prognostic factors for RFS and OS were explored. RESULTS: Two treatment groups were well-balanced using IPTW. In the entire cohort, LT provided a better prognosis than LR. Among patients with PVTT type I, RFS was better with LT (p=0.039); OS was not different significantly between LT and LR (p=0.093). In subgroup analysis of PVTT type I patients with α-fetoprotein (AFP) levels >200 ng/mL, LT elicited significantly longer median RFS (18.0 months vs. 2.1 months, p=0.022) and relatively longer median OS time (23.6 months vs. 9.8 months, p=0.065). Among patients with PVTT type II, no significant differences in RFS and OS were found between LT and LR (p=0.115 and 0.335, respectively). Multivariate analyses showed treatment allocation (LR), tumor size (>5 cm), AFP and aspartate aminotransferase (AST) levels to be risk factors of RFS and treatment allocation (LR), AFP and AST as risk factors for OS. CONCLUSION: LT appeared to afford a better prognosis for HCC with PVTT type I than LR, especially in patients with AFP levels >200 ng/mL.


Assuntos
Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/cirurgia , Hepatectomia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Trombose/complicações , Adulto , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Veia Porta/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , alfa-Fetoproteínas/metabolismo
15.
Cell Rep ; 33(11): 108502, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33326789

RESUMO

Changes in antibody glycosylation are linked to inflammation across several diseases. Alterations in bulk antibody galactosylation can predict rheumatic flares, act as a sensor for immune activation, predict gastric cancer relapse, track with biological age, shift with vaccination, change with HIV reservoir size on therapy, and decrease in HIV and HCV infections. However, whether changes in antibody Fc biology also track with reservoir rebound time remains unclear. The identification of a biomarker that could forecast viral rebound time could significantly accelerate the downselection and iterative improvement of promising HIV viral eradication strategies. Using a comprehensive antibody Fc-profiling approach, the level of HIV-specific antibody Fc N-galactosylation is significantly associated with time to rebound after treatment discontinuation across three independent cohorts. Thus virus-specific antibody glycosylation may represent a promising, simply measured marker to track reservoir reactivation.

16.
Iran J Immunol ; 17(4): 275-282, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33382384

RESUMO

BACKGROUND: T helper 17 (Th17) cells and the related cytokines, interleukin (IL)- 17 and IL-23, were proved to play pivotal roles during the development of allergic rhinitis (AR). IL-27, an anti-inflammatory cytokine, has been reported to promote the production of IL-12R and induce Th1 cell responses. However, its effect on Th17 responses was not fully understood. OBJECTIVE: We conducted the present research to explore the role of IL-27 in the regulation of Th17 responses in AR. METHODS: Thirty confirmed AR patients and 20 controls were recruited for the study. The mRNA expression and protein levels of IL-27 were analyzed employing quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively, and their correlations with Th17 cytokines were analyzed. We utilized ELISA and qPCR to analyze the effect of IL-27 on the differentiation of Th17 cells and the production of IL-17 and IL-23 from peripheral blood mononuclear cells (PBMCs). RESULTS: We found that the IL-27 levels in AR were downregulated and negatively related to IL-17 and IL-23 levels. The recombinant IL-27 inhibited the mRNA expression of RORγt and the protein expression of IL-17 and IL-23 in PBMCs through MEK, NF-κB, and JNK pathways. CONCLUSION: Our data demonstrated that IL-27 suppressed Th17 responses through MEK, NF-κB, and JNK pathways.

17.
J Genet Genomics ; 47(9): 523-534, 2020 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-33309167

RESUMO

Apolipoprotein M (apoM) participates in both high-density lipoprotein and cholesterol metabolism. Little is known about how apoM affects lipid composition of the liver and serum. In this study, we systemically investigated the effects of apoM on liver and plasma lipidomes and how apoM participates in lipid cycling, via apoM knockout in mice and the human SMMC-7721 cell line. We used integrated mass spectrometry-based lipidomics approaches to semiquantify more than 600 lipid species from various lipid classes, which include free fatty acids, glycerolipids, phospholipids, sphingolipids, glycosphingolipids, cholesterol, and cholesteryl esters (CEs), in apoM-/- mouse. Hepatic accumulation of neutral lipids, including CEs, triacylglycerols, and diacylglycerols, was observed in apoM-/- mice; while serum lipidomic analyses showed that, in contrast to the liver, the overall levels of CEs and saturated/monounsaturated fatty acids were markedly diminished. Furthermore, the level of ApoB-100 was dramatically increased in the liver, whereas significant reductions in both ApoB-100 and low-density lipoprotein (LDL) cholesterol were observed in the serum of apoM-/- mice, which indicated attenuated hepatic LDL secretion into the circulation. Lipid profiles and proinflammatory cytokine levels indicated that apoM-/- leads to hepatic steatosis and an overall state of metabolic distress. Taken together, these results revealed that apoM knockout leads to hepatic steatosis, impaired lipid secretion, and an overall state of metabolic distress.

18.
Clin Infect Dis ; 2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33382405

RESUMO

BACKGROUND: Antiretroviral therapy (ART) initiation during acute and early HIV infection (AEHI) limits HIV reservoir formation and may facilitate post-ART control but is logistically challenging. We evaluated the performance of new AEHI diagnostic criteria from a multi-national prospective study of ART initiation during AEHI. METHODS: ACTG 5354 enrolled adults at 30 sites in the Americas, Africa, and Asia who met any one of six criteria based on combinations of results of HIV RNA, HIV antibody, Western blot or Geenius assay, and/or the signal-to-cutoff (S/CO) ratio of the ARCHITECT HIV Combo Ag/Ab CMIA or GS HIV COMBO Ag/Ab EIA. HIV infection and Fiebig stage were subsequently confirmed by centralized testing. RESULTS: From 2017-2019, 195 participants were enrolled with median age 27 (interquartile range 23-39) years. Thirty (15.4%) were female. ART was started by 171 (87.7%) on the day of enrollment and 24 (12.3%) the next day. AEHI was confirmed in 188 (96.4%) participants after centralized testing, four (2.0%) participants were retrospectively found to have chronic infection, and three (1.5%) found not to have HIV discontinued ART and were withdrawn. Retrospectively, a nonreactive or indeterminate HIV antibody on the Geenius assay combined with ARCHITECT S/CO ≥10 correctly identified 99 of 122 (81.2%) Fiebig II-IV AEHI cases with no false-positive results. CONCLUSIONS: Novel AEHI criteria incorporating ARCHITECT S/CO into diagnostic algorithms facilitated rapid and efficient ART initiation without waiting for an HIV RNA result. These new criteria may facilitate AEHI diagnosis, staging, and immediate ART initiation in future research studies and clinical practice.

19.
J Infect Dis ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33349862

RESUMO

BACKGROUND: Romidepsin (RMD) is a histone deacetylase inhibitor reported to reverse HIV-1 latency. We sought to identify doses of RMD that were safe and induced HIV-1 expression. METHODS: Enrollees had HIV-1 RNA <40 copies/ml on ART. Measurements included RMD levels, plasma viremia by single copy HIV-1 RNA assay, HIV-1 DNA, cell-associated unspliced HIV-1 RNA (CA-RNA), acetylation of histone H3-lysine-9 (H3K9ac+) and phosphorylation of transcription factor P-TEFb. Wilcoxon tests were used for comparison. RESULTS: 43 participants enrolled in the single dose Cohorts 1-3 of 0.5, 2, and 5 mg/m 2 (36 RMD; 7 placebo) and 16 enrolled in the multi-dose Cohort 4 of 5 mg/m 2 (13 RMD; 3 placebo). One grade 3 event (neutropenia) was possibly treatment-related. No significant changes in viremia were observed in Cohorts 1-4 compared to placebo. In Cohort 4, observed pharmacodynamic effects of RMD were reduced proportions of CD4+ T cells 24 hours after infusions 2, 3, and 4 (median -3.5% to -4.5%) vs. placebo (+0.5% to 1%; p≤0.022) and increases in H3K9ac+ and phosphorylated P-TEFb in CD4 + T cells compared to placebo (p≤0.02). CONCLUSIONS: RMD infusions were safe but did not increase plasma viremia or unspliced CA-RNA despite pharmacodynamic effects on CD4 + T cells. The trial is registered with ClinicalTrials.gov, number NCT01933594.

20.
Vet Microbiol ; : 108919, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33191002

RESUMO

Marek's disease virus serotype 1 (MDV-1) is an important oncogenic α-herpesvirus that induces immunosuppressive and rapid-onset T-cell lymphomatous disease in poultry commonly referred to as Marek's disease (MD). As an excellent biomodel for the study of virally-induced cancers in natural hosts, MDV-1 encoded microRNAs (miRNAs) have been previously demonstrated with the potential roles to act as critical regulators in virus replication, latency, pathogenesis and especially in oncogenesis. Similar to the oncogenic γ-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), miR-M4-5p, the cellular microRNA-155 (miR-155) ortholog encoded by MDV-1, is also involved in MD oncogenesis. In lymphoblastoid cell lines derived from MDV-induced T-cell lymphomas, miR-M4-5p has been shown to be highly expressed and participate in inducing MD lymphomagenesis by regulating multiple signal pathways. Herein we report the new identification of the host WW domain-containing oxidoreductase (WWOX) as a biological target for miR-M4-5p. Further experiments revealed that as a critical oncomiRNA, miR-M4-5p promotes the proliferations of both chicken embryo fibroblast (CEF) and MSB-1 cells via suppressing cell apoptosis by targeting WWOX, a well-known tumor suppressor. Our data presents a novel insight in elucidating the regulatory mechanisms mediated by the viral analog of miR-155 that potentially contribute to MD tumorigenesis.

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