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1.
Exp Hematol ; 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32437908

RESUMO

Inhibition of the H3K79 histone methyl-transferase DOT1L has shown encouraging preclinical and early clinical activity in KMT2A (MLL)-rearranged leukemia, supporting the development of combinatorial therapies. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination with a protein synthesis inhibitor. EZH2 is the catalytic subunit in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has reported preclinical activity in KMT2A-r leukemia. When combined with DOT1L inhibition, however, we found both synergistic and antagonistic effects. Interestingly, antagonistic effects were not due to PRC2 mediated de-repression of HOXA9. HOXA cluster genes are key canonical targets of both KMT2A and the PRC2 complex. The independence of the HOXA cluster from PRC2 repression in KMT2A-r leukemia thus affords important insights into leukemia biology. Further studies revealed that EZH2 inhibition counteracted the effect of DOT1L inhibition on ribosomal gene expression. We thus identified a previously unrecognized role of DOT1L in regulating protein production. Decreased translation was one of the earliest effects measurable after DOT1L inhibition and specific to KMT2A-rearranged cell lines. H3K79me2 ChIP-Seq patterns over ribosomal genes were similar to the canonical KMT2A-fusion target genes in primary AML patient samples. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (omacetaxine), supporting further preclinical/clinical development of this combination. In summary, we discovered a novel epigenetic regulation of a metabolic process - protein synthesis - that plays a role in leukemogenesis and affords a combinatorial therapeutic opportunity.

2.
ACS Appl Mater Interfaces ; 12(19): 21779-21787, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32323969

RESUMO

Wearable energy storage and flexible body biomolecule detection are two key factors for real-time monitoring of human health in a practical environment. It would be rather exciting if one wearable system could be used for carrying out both energy storage and biomolecule detection. Herein, carbon fiber-based NiCoO2 nanosheets coated with nitrogen-doped carbon (CF@NiCoO2@N-C) have been prepared via a simple electrochemical deposition method. Interestingly, being a dual-functional active material, CF@NiCoO2@N-C exhibits excellent behaviors as a supercapacitor and prominent electrocatalytic properties, which can be applied for enzyme-free biosensor. It exhibits outstanding energy storage, high capacitive stability (94% capacitive retention after 10,000 cycles), and pre-eminent flexible ability (95% capacitive retention after 10,000 bending cycles), as well as high sensitivity for enzyme-free glucose detection (592  µA mM-1). Moreover, the CF@NiCoO2@N-C-based wearable supercapacitors would be used as self-powered energy systems for enzyme-free biosensors. Integrating with bluetooth, we have successfully developed a wearable self-powered enzyme-free smartsensor, remotely controlled using a smartphone for health monitoring in a practical environment. From this prospective study, it was found that the design of wearable self-powered smartsensors, demonstrating energy storage and enzyme-free biosensing in one system, provides a promising device for detecting body biomolecules, which has the potential to be implemented in the artificial intelligent fields.

3.
Cells ; 9(3)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32244921

RESUMO

Softening of fruit during the postharvest storage, which is mainly associated with both compositional and spatial changes of polysaccharides within cell wall, affects the texture and quality of fruit. Current research on the fruit softening mechanism lacks an understanding of the overall softening at the cell level. The objective of this work was to investigate the change in the spatial distribution of cell wall polysaccharides in peach flesh cells at both single- and multiple-cell levels in a label-free way during the postharvest storage. Nonmelting peaches (Prunus persica L. Batsch cv."Zhonghuashoutao") at commercial maturity were stored at 0 °C and 20 °C. Firmness measurement and chemical analysis were performed at each storage time. In addition, three molecular imaging techniques, namely confocal Raman microspectroscopy (CRM), Fourier transform infrared microspectroscopy (FTIRM), and stimulated Raman scattering microscopy (SRS) were used to visualize changes in the spatial distribution of cell wall polysaccharides of peach fruit in a label-free way during the postharvest storage. The combination of CRM and FTIRM provided complementary spectral information to visualize the spatial changes of cellulose, hemicellulose, and pectin in the cell wall of peach flesh during softening at the single-cell level, and found that the cell wall polysaccharides tended to be concentrated in the cell corner of parenchymal cells at the late stage. Furthermore, SRS, which is an ultrafast Raman imaging technique (approximately three or four orders of magnitude faster than CRM), was used for high-throughput cell wall phenotypes measurement. Different degradation degrees of parenchymal cells during fruit softening were found based on the gray-scale statistical analysis of SRS data. In general, cell wall polysaccharides decreased during softening and tended to be concentrated in the cell corner for most parenchymal cells at the late stage, but there were also some cells not in line with the whole softening trends. The results show that there were differences in the content and spatial changes of cell wall polysaccharides among parenchymal cells of peach fruit during the softening process, and the hybrid use of CRM, FTIRM, and SRS is a promising method for simultaneous visualization of changes in cell wall polysaccharides of peach.

4.
Anal Chem ; 92(8): 5897-5903, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32207617

RESUMO

A wearable screen-printed electrochemical smartsensor with excellent selectivity for methanol quantification has been developed. This smartsensor consists of a printable sensing system modified with platinum (Pt) confined in a reduced graphene oxide (rGO) matrix, as well as a compact electronic interface for data collection. The real-time electrochemical signal from methanol could be remotely detected and transmitted to a smartphone by blue tooth. It performs good environmental adaptability of vapor/liquid amphibious behaviors. Owing to the uniform distribution of Pt loading on the rGO nanosheets, this sensor demonstrates high selectivity, sensitivity, stability, and recoverability both in vapor and liquid during temperature or humidity diversification, compared with other resistance-based sensors. It also achieves good bending and stretching performance, and it could be a possible candidate device for the quantification of methanol in different environments.

5.
Influenza Other Respir Viruses ; 14(2): 129-141, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31701647

RESUMO

BACKGROUND: The development of serologic assays that can rapidly assess human exposure to novel influenza viruses remains a public health need. Previously, we developed an 11-plex magnetic fluorescence microsphere immunoassay (MAGPIX) by using globular head domain recombinant hemagglutinins (rHAs) with serum adsorption using two ectodomain rHAs. METHODS: We compared sera collected from two cohorts with novel influenza exposures: animal shelter staff during an A(H7N2) outbreak in New York City in 2016-2017 (n = 119 single sera) and poultry workers from a live bird market in Bangladesh in 2012-2014 (n = 29 pairs). Sera were analyzed by microneutralization (MN) assay and a 20-plex MAGPIX assay with rHAs from 19 influenza strains (11 subtypes) combined with serum adsorption using 8 rHAs from A(H1N1) and A(H3N2) viruses. Antibody responses were analyzed to determine the novel influenza virus exposure. RESULTS: Among persons with novel influenza virus exposures, the median fluorescence intensity (MFI) against the novel rHA from exposed influenza virus had the highest correlation with MN titers to the same viruses and could be confirmed by removal of cross-reactivity from seasonal H1/H3 rHAs following serum adsorption. Interestingly, in persons with exposures to novel influenza viruses, age and MFIs against exposed novel HA were negatively correlated, whereas in persons without exposure to novel influenza viruses, age and MFI against novel HAs were positively correlated. CONCLUSIONS: This 20-plex high-throughput assay with serum adsorption will be a useful tool to detect novel influenza virus infections during influenza outbreak investigations and surveillance, especially when well-paired serum samples are not available.

6.
J Cell Biochem ; 121(3): 2704-2712, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31692058

RESUMO

Bedsore is a familiar disease, which fearfully harms the health of the patients. We investigated the efficacy and mechanism of circular RNA circANKRD36 on HaCaT cell in inflammatory damage. CCK-8 and flow cytometry were respectively used to investigate the efficacies of lipopolysaccharide (LPS), circANKRD36, and microRNA (miR)-15 on cell viability and apoptosis. Moreover, circANKRD36 and miR-15 expression were changed by cell transfection and investigated by reverse transcription-quantitative polymerase chain reaction. Furthermore, the levels of Bax, pro caspase-3, cleaved caspase-3, interleukin (IL)-1ß, IL-6, and proteins of the pathway were investigated by Western blot. Otherwise, the levels of IL-1ß and IL-6 were investigated by enzyme-linked immunosorbent assay. Reactive oxygen species (ROS) was investigated by ROS assay. The relation between myeloid differentiation factor 88 (MyD88) and miR-15 was investigated by luciferase assay. LPS caused inflammatory damage and upregulated circANKRD36. circANKRD36 was silenced in cells and si-circANKRD36 remitted inflammatory damage. Furthermore, si-circANKRD36 negatively regulated miR-15 and miR-15 inhibitor could reverse the efficacies of si-circANKRD36. Besides, si-circANKRD36 restrained the NF-κB pathway by upregulating miR-15. Finally, MyD88 was authenticated as a target of miR-15. circANKRD36 remitted cell inflammatory damage upregulating miR-15/MyD88 via the NF-κB pathway in HaCaT cells.

7.
Polymers (Basel) ; 11(12)2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31810368

RESUMO

In previous research, sucrose and citric acid were used to synthesize an eco-friendly plywood adhesive. Herein, further research was performed to determine the optimal hot-pressing conditions and curing behavior of a sucrose-citric acid (SC) adhesive. The results of dry and wet shear strength measurements showed that the optimal hot-pressing temperature, hot-pressing time, and spread rate of plywood samples bonded by the SC adhesive were 190 °C, 7 min, and 140 g/m2, respectively. When plywood was bonded at the optimal hot-pressing conditions, the wet shear strength met the requirements of the China National Standard GB/T 9846-2015. Thermal analysis showed that the thermal degradation and endothermic reaction temperatures of the SC 25/75 adhesive were lower than either sucrose or citric acid individually. In addition, the insoluble mass proportion increased with the heating temperature and time. The Pyrolysis Gas Chromatography and Mass Spectrometr (Py-GC/MS) analysis confirmed that the SC adhesive was cured by the reaction between furan compounds, saccharide, and citric acid, and the resulting polymer appeared to be joined by ether linkages.

8.
Zhongguo Gu Shang ; 32(11): 1014-1020, 2019 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-31870049

RESUMO

OBJECTIVE: To compare clinical effect of modified anterolateral approach combined with modified posteromedial approach and conventional posterolateral approach combined with medial-aided in treating trimalleolar fractures. METHODS: From January 2015 to August 2017, 108 patients with trimalleolar fractures were enrolled and randomly divided into modified approaches (experimental group) and conventional approaches(control group). There were 53 patients in experimental group including 31 males and 22 females aged from 18 to 67 years old with an average of(40.2±16.4) years old; 19 patients on the left side and 34 patients on the right side; 39 patients were supination external rotation and 14 patients were pronation-external rotation; preoperative waiting time ranged from 6 to 14 d with an average of(9.6±3.1) d; performed operation through modified anterolateral approach combined with modified posteromedial approach. There were 55 patients in control group, including 34 males and 21 females aged from 19 to 69 years old with an average of (42.1±15.3) years old; 18 patients on the left side and 37 patients on the right side; 42 patients were supination external rotation and 13 patients were pronation-external rotation; preoperative waiting time ranged from 7 to 16 d with an average of (10.3±3.4) d; performed operation through conventional posterolateral approach combined with medial-aided. Operation time, intraoperative blood loss, postoperative drainage volume, cases of incision complications and excellent-good reduction, fracture healing time, cases of nerve injury and muscular flexor contracture, cases of incision complications between two groups were compared; AOFAS score were used to evaluate clinical efficacy at 1 year after operation. RESULTS: All patients were followed up from 12 to 24 months with an average of (16.4 ±7.5) months. Operation time, intraoperative blood loss, postoperative drainage volume and incision complication in experimental group were (95.3±22.6) min, (114.7±68.7) ml, (127.5±87.8) ml and 1 case, respectively; while in control group were (112.5±53.8) min, (155.2±79.6) ml, (178.4±73.8) ml and 3 cases respectively; the data in experimental group were better than that of control group. In experimental group, 36 cases got excellent results, 14 good and 3 poor on the quality of reduction, while 30 patients got excellent results, 15 good and 10 poor in control group; the experimental group was better than control group. Fracture healing time in experimental group were(5.5±1.6) months, 2 patients occurred incision complications, while(6.7±2.1) months, 12 patients in control group; the experiment group were better than control group. Postoperative AOFAS score at 12 months in experimental group was 92.9±18.4, and better than control group 80.3±38.3; 32 patients got excellent results, 17 good, 3 moderate and 1 poor in experimental group; 25 patients got excellent results, 18 good, 8 moderate and 4 poor in control group; there was statistical difference between two groups. CONCLUSIONS: Both of modified anterolateral approach combined with modified posteromedial approach and conventional posterolateral approach combined with medial-aided in treating trimalleolar fractures could receive good clinical effect. While compared with conventional posterolateral approach combined with medial-aided, modified anterolateral approach combined with modified posteromedial approach is more fit for blood supply of local soft tissue, and has advantages of less trauma, safety operation and clearly exposure.


Assuntos
Fraturas do Tornozelo , Adolescente , Adulto , Idoso , Fraturas do Tornozelo/terapia , Estudos de Casos e Controles , Feminino , Fixação Interna de Fraturas , Consolidação da Fratura , Humanos , Masculino , Pessoa de Meia-Idade , Supinação , Resultado do Tratamento , Adulto Jovem
9.
Z Gerontol Geriatr ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31602508

RESUMO

Previous studies have demonstrated the damaging effect of alcohol (ALH) consumption on bone tissue and bone metabolism. Alpha-lipoic acid (ALA) promotes osteoblast proliferation and inhibits osteoclast proliferation, and positively affects bone regeneration; however, reports about effects of ALA on bone loss for aged female rats with ALH consumption are limited. This study was designed to investigate the impact of treatment with ALA on bone loss for aged female rats with ALH consumption. In this study 30 female Sprague-Dawley rats (22 months old), weighing approximately 520 g, were incorporated. The animals were randomly divided into three groups: group CON, group ALH and group ALH + ALA and received saline, ALH, ALH plus ALA treatment until death at 16 weeks, respectively. The results of maintaining bone mass and bone strength in senile female rats with ALH consumption were evaluated by histology, microcomputerized tomography, gene expression analysis and biomechanical tests. Results from this study indicated that ALH + ALA had stronger effects on the prevention and treatment of osteoporosis in senile female rats with ALH consumption. The ALH + ALA produced stronger effects on the bone volume ratio (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular separation (Tb.Sp), BMD and strength of distal femurs, and regulation of osteogenesis and bone resorption-related gene expression. These results seem to indicate that ALA intervention prevents bone loss in senile female rats with ALH consumption.

10.
Nat Commun ; 10(1): 4415, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562329

RESUMO

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores CXCR5/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos B/metabolismo , Antígenos CD40/genética , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/genética , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Tolerância Imunológica/genética , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Fator de Transcrição STAT5/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
11.
Biosens Bioelectron ; 144: 111637, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494509

RESUMO

The wearable smart detection of body biomolecules and biomarkers is being of significance in the practical fields. Hydrogen peroxide (H2O2) is a product of some enzyme-catalyzed biomolecular reactions. The detection of H2O2 could reflect the concentration information of the enzyme reaction biomolecule substrate such as glucose. A high-performance berlin green (BG) carbon ink for monitoring H2O2 was prepared in this work. And we have successfully developed the wearable smartsensors for detecting H2O2 and glucose based on one-step fabricated BG arrays by screen-printing technology. Comparing with other detection methods, these sensors are wearable, movable, flexible and biocompatible for monitoring biomolecules. As a result, the sensors exhibited good sensitivity, specificity, stability and reproductivity towards H2O2 and glucose. Additionally, there also received stable response after near one hundred times stretching and thousands of bending. Moreover, the wearable sensors could be easily remotely controlled by a smart phone, when integrated with wireless into the device. In prospective studies, the one-step fabricated wearable smartsensors is of great significance in developing a straightforward, highly-efficient and low-cost method for actual detection of biomolecules reflecting body health status, and would potentially be applied in the artificial intelligence (AI) fields.

13.
Front Psychol ; 10: 1709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396136

RESUMO

The rift between evolutionary psychology and the biosocial model of gender relations impedes a fuller understanding of gender roles and gender inequality. In a novel evolutionary account that complements both existing theories, we highlight life history strategies as intermediate mechanism linking distal environmental forces to variations in gender relations. Specifically, traditional versus modernized gender roles are seen as shaped by present-oriented versus future-oriented reproductive strategies, which are sensitive to uncontrollable morbidity-mortality risks. Gender inequality stems from a combination of present-oriented reproductive strategies adapted to high-risk environments and dominance hierarchies resulting from societal competition (i.e., the probability of obtaining resources desired by others through personal efforts). By contrast, gender egalitarian values develop as people increasingly enact future-oriented reproductive strategies in a competitive but orderly and controllable environment, which is conducive to prestige hierarchies. The current account provides novel interpretations of phenomena ranging from sex differences in mate preference, sociosexuality, and sexism to cross-cultural variability in marital systems and cultural practices. All of these serve to support the view that gender relations are evolved, changeable, and influenced by the interaction between ecological and social environments in ways predicted by the life history mechanism.

14.
J Orthop Surg (Hong Kong) ; 27(3): 2309499019864722, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366284

RESUMO

BACKGROUND: Traditional anteromedial incision for pilon fractures would further increase the damage to the subcutaneous tissues anterior and medial to tibia. In this study, we retrospectively evaluated the method and the outcomes of lateral approach for surgical treatment of Gustilo type-I and type-II open pilon fractures with medial soft tissue injuries. METHODS: From May 2014 to September 2017, 35 patients with Gustilo type-I and type-II open pilon fractures were treated with standard protocol using a lateral approach. The initial wound debridement and application of a spanning external fixator or traction of calcaneal tubercle were performed within 24 h and a definitive fixation was performed when the wound was healed. The mean time from primary surgery to definite surgery was 11.8 (range: 8-16) days. Postoperative radiographs, complications, bone union, and American Orthopedic Foot and Ankle Society (AOFAS) ankle/hind foot score were recorded. RESULTS: The mean follow-up period was 17 months (range: 13-23). The average time to bone union was 22 weeks (range: 18-25). In 35 patients, 2 patients had a superficial wound infection and another 1 patient showed limitation of ankle joint motion. No cases of deep infection, skin necrosis, and symptomatic implant reported. The mean AOFAS score was 89.8 (range: 84-95). On final outcome, 25 patients come under excellent and 10 patients had good result. CONCLUSION: From the results of this study, we can conclude that the lateral approach to treat Gustilo type-I and type-II open pilon fractures was a safe option with a low complication rate. On the other hand, it provides sufficient exposure to restore anatomic articulation, which is worthy of clinical recommendation.

15.
J Nat Prod ; 82(7): 1917-1922, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31276403

RESUMO

A phytochemical investigation on the leaves of Callistemon viminalis resulted in the isolation of two unusual compounds, callistemonols A (1) and B (2). Callistemonol A (1) possesses a novel skeleton of a furan ring fusing both an α,ß-triketone and a phloroglucinol unit, while callistemonol B (2) is an acylphloroglucinol derivative featuring two methyl substituents on a five-membered ring and an isovaleryl side chain. Their structures were fully characterized on the basis of extensive spectroscopic analysis, including 1D and 2D NMR parameters, as well as the IR and HRESIMS data. Callistemonol A (1) represents an example of a natural dibenzofuran with two phenyl moieties, and a plausible biogenetic pathway to generate this novel dibenzofuran through a C-C bond-forming radical SAM enzyme is proposed. Moreover, antimicrobial assays, in conjunction with time-killing and biophysical studies, revealed that 1 and 2 exert potent bactericidal activities against a panel of methicillin-resistant pathogenic microbes.

16.
Hortic Res ; 6: 72, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231530

RESUMO

The lignification triggered by biotic or abiotic stresses hardens fruits and vegetables and eventually influences their consumer appeal. Extensive prior efforts have been made to unveil the underlying mechanism of flesh lignification, primarily focused on its physicochemical and molecular biological properties. Nevertheless, most of these studies used destroyed and homogenized bulk tissues as analytes; as a result, potentially valuable spatial information was lost. In this study, the deposition of lignin in loquat flesh during lignification was visualized from the tissue level to the single-cell level by combining the advantages of stimulated Raman scattering (SRS) and spontaneous Raman microscopy using label-free in situ molecular imaging. SRS has the advantages of being fast and providing large-area chemical imaging to reveal the spatial heterogeneity of lignin and cell wall polysaccharide distribution in loquat flesh. After 2 days of storage at 0 °C, increased lignins were observed by large-area SRS imaging. In addition, microscopic SRS images of the flesh cells indicated that the increased lignins were trapped in the cell corner (CC) and middle lamella (ML). Furthermore, the compositional and structural features of lignified cells (LCs), CC and ML of loquat flesh were investigated by spontaneous Raman microscopy, and the results showed that the LCs were a combination of lignin, cellulose, and hemicellulose, whereas CC and ML showed only deposited lignin and pectin without cross-linked cellulose and hemicellulose. This result further suggests that the lignins in the CC and ML regions of loquats were later synthesized alone during postharvest storage. This innovative combination of SRS and spontaneous Raman microscopy allows the label-free macroscale and fine chemical imaging of plant cell walls and will enhance our fundamental understanding of the structures and functions of the plant cell wall.

17.
Blood Adv ; 3(9): 1499-1511, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31076406

RESUMO

JMJD1C, a member of the lysine demethylase 3 family, is aberrantly expressed in mixed lineage leukemia (MLL) gene-rearranged (MLLr) leukemias. We have shown previously that JMJD1C is required for self-renewal of acute myeloid leukemia (AML) leukemia stem cells (LSCs) but not normal hematopoietic stem cells. However, the domains within JMJD1C that promote LSC self-renewal are unknown. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) negative-selection screening and identified a requirement for the catalytic Jumonji (JmjC) domain and zinc finger domain for leukemia cell survival in vitro and in vivo. In addition, we found that histone H3 lysine 36 methylation (H3K36me) is a marker for JMJD1C activity at gene loci. Moreover, we performed single cell transcriptome analysis of mouse leukemia cells harboring a single guide RNA (sgRNA) against the JmjC domain and identified increased activation of RAS/MAPK and the JAK-STAT pathway in cells harboring the JmjC sgRNA. We discovered that upregulation of interleukin 3 (IL-3) receptor genes mediates increased activation of IL-3 signaling upon JMJD1C loss or mutation. Along these lines, we observed resistance to JMJD1C loss in MLLr AML bearing activating RAS mutations, suggesting that RAS pathway activation confers resistance to JMJD1C loss. Overall, we discovered the functional importance of the JMJD1C JmjC domain in AML leukemogenesis and a novel interplay between JMJD1C and the IL-3 signaling pathway as a potential resistance mechanism to targeting JMJD1C catalytic activity.

18.
J Photochem Photobiol B ; 195: 27-32, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31051327

RESUMO

Platinum and Curcumin conjugation using green chemistry is an attempt to enhance the curcumin effectiveness as an anti-fibrosis. In this study, Platinum and curcumin were conjugated to direct curcumin into the liver. Curcumin platinum nanoparticles (C-PtNPs) were formed by changing curcumin concentration at pH 10. The successful formation of C-PtNPs was recognized with the help of Fourier transform infrared (FTIR) and UV-visible spectrophotometers. The particle size and morphology were studied with the help of dynamic light scattering (DLS) and High-resolution transmission electron microscopy (HR-TEM) respectively. The antimicrobial activity of C-PtNPs, was examined against gram positive and gram negative bacteria. Moreover, the NIH/3 T3 cells were used to test the C-PtNPs activity of modifying initial fibrosis indication. The favorable condition for the synthesis of CPt-NPs was by using curcumin 1.5 mM at pH 10. When compared with free curcumin, C-Pt-NPs exhibited higher activity for decreased production of collagen by NIH/3 T3 cells. Altogether, the formation of C-PtNPs by conjugation of platinum to curcumin is assuring for the curcumin directing to treat the hepatic fibrosis.


Assuntos
Anti-Infecciosos/síntese química , Curcumina/química , Nanopartículas Metálicas/química , Platina/química , Animais , Anti-Infecciosos/farmacologia , Sobrevivência Celular , Curcumina/farmacologia , Curcumina/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Cirrose Hepática/prevenção & controle , Camundongos , Microscopia Eletrônica de Transmissão , Células NIH 3T3 , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Best Pract Res Clin Haematol ; 32(1): 31-39, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927973

RESUMO

Therapy-related myeloid neoplasms are unintended and unwanted complications of cytotoxic chemotherapy and radiation. Unlike other environmental toxin-induced malignancies, exposure to the inciting agent is required to eradicate a primary and life-threatening cancer. In this review, we will focus on the biochemical mechanisms that lead to therapy-induced myeloid malignancy. This includes discussion of known mechanisms by which cytotoxic chemotherapy and radiation induce genetic mutations and promote evolution and expansion of malignant hematopoietic clones. Mechanisms by which the hematopoietic stem and progenitor microenvironment may be injured during the course of chemotherapy and radiation therapy will also be presented. While prevention strategies have not yet been brought into clinical testing or practice, there is active basic research relevant to prevention of t-MNs which is also included in our attempt to answer the question of whether we can do better to prevent stem cell injury after chemotherapy and radiation.


Assuntos
Neoplasias Hematológicas , Células-Tronco Hematopoéticas , Mutação , Transtornos Mieloproliferativos , Nicho de Células-Tronco , Microambiente Tumoral , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Radioterapia/efeitos adversos , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/genética , Nicho de Células-Tronco/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos da radiação
20.
J Nat Prod ; 82(4): 919-927, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30869892

RESUMO

Ten new sesquiterpene lactones, carlipsines A-J (1-10), and 12 known analogues (11-22) were isolated from the whole plant of Carpesium lipskyi. Their structures were elucidated by using 1D and 2D NMR and HRESIMS analyses, and their absolute configurations were confirmed by X-ray diffraction studies. All compounds were identified as germacranolides with diverse substructural features. Compounds 1-4 are 2,5-hemiacetal-linked germacranolides. Compounds 5 and 6 possess a 1,2-epoxy moiety. Compounds 7 and 8 represent unusual 1,5-hemiacetal-linked germacranolides. Compounds 9 and 10 contain a tetrahydrofuran unit with the oxygen atom bridging C-1 and C-8. Compounds 6, 7, 8, 19, 20, 21, and 22 showed cytotoxicity against HL-60 and A-549 cell lines with IC50 values ranging from 2.8 to 10.3 µM.

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