Acute myeloid leukemia (AML) is the most aggressive hematopoietic malignancy characterized by uncontrolled proliferation of myeloid progenitor cells within the bone marrow. Tumor suppressor ...cylindromatosis (CYLD) is a deubiquitinating enzyme, which suppresses inflammatory response in macrophages. Macrophages have a central role in the defense against foreign substances and circulating cancer cells by their professional phagocytic capacity. Little is known about contributions of CYLD to changes in biological properties of human macrophages and its involvement in AML. The present study, therefore, explored whether macrophage functions in healthy individuals and AML patients are influenced by CYLD. To this end, ninety-two newly diagnosed AML patients and 80 healthy controls were recruited. The mRNA expression levels of inflammation-related genes were evaluated by real-time PCR, cell maturation, phagocytosis and apoptosis assays by flow cytometry and secretion of inflammatory cytokines by ELISA. As a result, AML patients with the low CYLD expression were significantly higher in M4/M5 than other subtypes according to the FAB type. The low CYLD expression was also closely associated with older patients and enhanced level of LDH in AML. Moreover, treatment of normal macrophages with CYLD siRNA enhanced activation of STAT-1, leading to increases in expressions of maturation markers and IL-6 production as well as suppression in cell apoptosis and phagocytosis, while macrophage phagocytosis from AML M4/M5b was higher than that from healthy controls upon CYLD siRNA transfection through STAT1 signalling. In conclusion, the inhibitory effects of CYLD on macrophage functions are expected to affect the immune response in AML.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polycythemia vera (PV) is characterized by increased proliferation and accumulation of erythroid and mature myeloid cells and megakaryocyte in the bone marrow and peripheral blood. The JAK2V617F ...mutation is present in most PV patients. Deubiquitinase (DUB) genes, including TNFAIP3 (A20), CYLD and Cezanne, function as negative regulators of inflammatory reaction through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ęB) signaling.
To determine single nucleotide polymorphisms (SNPs) profiling and gene expression of the DUB genes as well as the immunophenotype of PV cells.
Seventy-seven patients with PV and 55 healthy individuals with well-characterized clinical profiles were enrolled. Gene expression profile was determined using quantitative real-time polymerase chain reaction (qRT-PCR), the immunophenotype with flow cytometry, secretion of cytokines using enzyme-linked immunosorbent assay (ELISA), and gene polymorphisms using direct DNA sequencing.
Inactivation of A20, CYLD and Cezanne, and increases in interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-á) levels, as well as the enhanced number of CD25+CD4 T, Th1 and regulatory T cells were observed in PV patients. The genetic analysis of the CYLD gene identified 11 SNPs, in which a novel W736G nsSNP in exon 15 and a SNP c.2483+6 T>G in intron 15 were observed in PV cases with the frequencies of 18.2% and 5.2%, respectively. The W736G non-synonymous SNP (nsSNP) was found to be most likely to exert deleterious effect and the intronic SNP c.2483+6 T>G was identified as aberrant splicing. Sequencing of Cezanne gene identified 7 SNPs in intron 10 and PV carriers of the SNPs had at least 2 SNPs in this gene. Importantly, PV carriers of the W736G nsSNP had multiple SNPs in CYLD, but not in A20 or Cezanne gene.
Two identified SNPs, including the W736G nsSNP and the SNP c.2483+6 T>G, in CYLD gene might be associated with a risk of PV disease, in which the deleterious effect of the W736G nsSNP in CYLD gene could contribute to the pathogenesis of PV.
Chikungunya virus (ChikV) infection is characterized by persistent infection in joints and lymphoid organs. The ChikV Capsid protein plays an important role in regulating virus replication. In this ...study, we hypothesized that capsid protein may stimulate dendritic cell (DC) activation and maturation and trigger an inflammatory response in mice.
Mice were intraperitoneally injected with capsid protein and examined for changes in immunophenotype in lymph nodes (LNs). Next, DCs were treated with capsid protein or LPS and then expression of maturation markers, cytokine production, and ability to stimulate CD4
T cells in allo-MLR were analyzed.
Injection of mice with capsid protein led to recruitment of myeloid cells and increased activation of T lymphocytes in LNs. Importantly, treatment of DCs with capsid protein prolonged the activation of IKB-α and up-regulated the number of CD11c
CD86
DCs and release of TNF-α and IL-12p70 as well as reducing DC apoptosis, all effects were abolished in the presence of Bay 11-7082. In addition, IL-2 production was higher by CD4
T cells stimulated with capsid-treated as compared with LPS-induced DCs.
The observations revealed that capsid protein participates in the regulation of NF-κB signaling and maturation of DCs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Our recent work demonstrated that chitin treatment modulated the expression of 118 transcription factor (TF) genes in Arabidopsis. To investigate the potential roles of these TF in chitin signaling ...and plant defense, we initiated an interaction study among these TF proteins, as well as two chitin-activated mitogen-activated protein kinases (MPK3 and MPK6), using a yeast two-hybrid system. This study revealed interactions among the following proteins: three ethylene-responsive element-binding factors (ERF), five WRKY transcription factors, one scarecrow-like (SCL), and the two MPK, in addition to many other interactions, reflecting a complex TF interaction network. Most of these interactions were subsequently validated by other methods, such as pull-down and in planta bimolecular fluorescence complementation assays. The key node ERF5 was shown to interact with multiple proteins in the network, such as ERF6, ERF8, and SCL13, as well as MPK3 and MPK6. Interestingly, ERF5 appeared to negatively regulate chitin signaling and plant defense against the fungal pathogen Alternaria brassicicola and positively regulate salicylic acid signaling and plant defense against the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. Therefore, ERF5 may play an important role in plant innate immunity, likely through coordinating chitin and other defense pathways in plants in response to different pathogens.
•Deflection signal’s static and dynamic elements using deep learning are devised.•The static elements determine quantity and location of defects in structures.•The dynamic elements evaluate growth ...rate of defects during structural operation.•Original signals were analyzed directly using wavelet analysis.•This study concurrently identifies all three criteria of quantity, location and growth rate.
This article aims to identify multiple cracks of a structure under the act of moving load by using wavelet analysis based on displacement signal. Among many researches on this topic, the current study presents three new salient points. Firstly, the breakthrough is the combination of two independent algorithms in wavelet analysis of deflection signal’s static and dynamic elements using deep learning. The static elements allow determining quantity as well as location of defects in structures while the dynamic elements help to assess growth rate of defects during structural operation. Secondly, wavelet analysis is conducted based on deflection signal, which is rarely used but has a great deal of information proving the existence of cracks in a structure. This signal can also be applied to various types of structures such as plate, beam, bar and pivot. Thirdly, original signals are analyzed directly using wavelet analysis without any intermediate algorithm. This gives simpler and more accurate assessment of crack status, therefore, helps to increase sensitivity as well as data accuracy during identification process, especially for structures with multiple cracks. This study concurrently identifies all three criteria of defect assessment, namely: quantity, location and growth rate. In addition, the results have high potential for practical application to most structures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic myelogenous leukemia (CML) is characterised by the translocation of regions of the BCR and ABL genes, leading to the fusion gene BCR-ABL forming the Philadelphia (Ph) chromosome. Vinblastine ...(Vinb) and Vincristine (Vinc) are Vinca alkaloids and frequently used in combination chemotherapy in leukemias and lymphomas. Deubiquitinating enzyme (DUB) genes such as A20, Otubain 1 and CYLD are known as inhibitors of functional activation of immune cells mediated through the NF-κB/STAT pathway. Little is known about the regulatory role of Vinb/Vinc on the function of CML cells and the contribution of the DUBs to those effects. In the end, the gene expression profile was determined by quantitative RT-PCR, physiological properties of CML cells by flow cytometry and cytokine production by ELISA. As a result, inactivated expression of the DUBs A20, CYLD, Otubain 1 and Cezanne and enhanced activation of CD11b+ and CD4T cells were observed in CML patients. Importantly, Vinc enhanced the expression of A20 and CYLD and inhibited the proliferation and survival of CML (K562) cells. The effects were abolished in the presence of A20 siRNA, while cell proliferation only depended on the presence of CYLD. In conclusion, the up-regulation of A20 by Vinc could involve inhibitory effects on the proliferation and survival of K562 cells. The events might contribute to the anticancer effect of Vinc on A20-sensitive CML cells.
Dendritic cells (DCs) are professional antigen presenting cells (APCs) that represent the essential link between innate and acquired immunity. Otubain (OTUB) 1 is shown to deubiquitinate TRAFs to ...suppress virus‐induced inflammatory response. MAPK, a downstream molecule of TRAFs, is involved in regulating LPS‐induced immune reactions and its activation is sensitive to the presence of OTUB1. Little is known about contributions of OTUB1 to changes in biological properties of DCs. The present study, therefore, explored whether DC functions are influenced by OTUB1. To this end, DCs were isolated and cultured with GM‐CSF to attain bone marrow‐derived DCs (BMDCs) and followed by treatment with lipopolysaccharide (LPS) in the presence or absence of OTUB1 siRNA. Expression of markers of cellular maturation and proliferation were analyzed by flow cytometry, and secretion of inflammatory cytokines and ability to stimulate CD4+ T‐cells in allogenic mixed leukocyte reaction (allo‐MLR) by ELISA, cell migration by a transwell migration assay and phagocytic capacity by FITC‐dextran uptake measurement. As a result, treatment of the cells with OTUB1 siRNA prolonged activation of p38MAPK, increased CD54 expression and IL‐6 release and reduced FITC‐dextran uptake. Moreover, cytokine release produced from CD4+ T‐cells in allo‐MLR was different. The enhanced level of IFN‐γ, but not other cytokine production was observed in the presence of siRNA OTUB1. All the effects were completely abolished when the cells were exposed with p38MAPK inhibitor SB203580. In conclusion, OTUB1 prevents the prolonged activation of p38MAPK, which in turn compromises DC functions.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Two new lignans (7S,7′R,8S,8′R)-3,3′-dimethoxy-7,7′-epoxylignan-4,4′,9-triol 4-O-β-D-glucopyranoside (1) and 9-O-formylaviculin (2) together with other thirteen known secondary metabolites were ...isolated from the leaves of Antidesma hainanensis. Their chemical structures were determined using NMR, electrospray ionization (ESI)-MS, circular dichroism (CD) spectroscopic methods, and as well as by comparison with those reported in the literature. Neuro-inflammatory activity of isolated compounds was evaluated by their inhibition on nitric oxide (NO) production in activated BV2 microglial cells. At concentration of 40 µM, compounds 1–3, 5, 7, 8, 9, 14, and 15 exhibited inhibitory effects over 50%, suggesting that they could be potential candidate drugs for the cure of neuro-inflammation. In addition, compounds 1, 8, 14, and 15 significantly inhibited 16.23, 27.76, 21.23, and 29.44% NO production at diluted concentration as low as 2.5 µM.
To date, endophytic actinomycetes have been well-documented as great producers of novel antibiotics and important pharmaceutical leads. The present study aimed to evaluate potent bioactivities of ...metabolites synthesized by the strain LCP18 residing in the Vietnamese medicinal plant
Litsea cubeba
(Lour.) Pers towards human pathogenic bacteria and human cancer cell lines. Endophytic actinomycete strain LCP18 showed considerable inhibition against seven bacterial pathogens and three human tumor cell lines and was identified as species
Streptomyces variabilis
. Strain
S. variabilis
LCP18 was phenotypically resistant to fosfomycin, trimethoprim-sulfamethoxazole, dalacin, cefoxitin, rifampicin, and fusidic acid and harbored the two antibiotic biosynthetic genes such as PKS-II and NRPS. Further purification and structural elucidation of metabolites from the LCP18 extract revealed five plant-derived bioactive compounds including isopcrunetin, genistein, daidzein, syringic acid, and daucosterol. Among those, isoprunetin, genistein, and daidzein exhibited antibacterial activity against
Salmonella typhimurium
ATCC 14,028 and methicillin-resistant
Staphylococcus epidermidis
ATCC 35,984 with the MIC values ranging from 16 to 128 µg/ml. These plant-derived compounds also exhibited cytotoxic effects against human lung cancer cell line A549 with IC
50
values of less than 46 μM. These findings indicated that endophytic
S. variabilis
LCP18 can be an alternative producer of plant-derived compounds which significantly show potential applications in combating bacterial infections and inhibition against lung cancer cell lines.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Taxifolin (dihydroquercetin) and its derivatives are medicinally important flavanonols with a wide distribution in plants. These compounds have been isolated from various plants, such as milk ...thistle, onions, french maritime, and tamarind. In general, they are commercially generated in semisynthetic forms. Taxifolin and related compounds are biosynthesized via the phenylpropanoid pathway, and most of the biosynthetic steps have been functionally characterized. The knowledge gained through the detailed investigation of their biosynthesis has provided the foundation for the reconstruction of biosynthetic pathways. Plant‐ and microbial‐based platforms are utilized for the expression of such pathways for generating taxifolin‐related compounds, either by whole‐cell biotransformation or through reconfiguration of the genetic circuits. In this review, we summarize recent advances in the biotechnological production of taxifolin and its derivatives.
Biochemistry and biotechnological production of taxifolin and its derivatives.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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