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1.
Front Oncol ; 11: 741746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34540702

RESUMO

Accurate orchestration of gene expression is critical for the process of normal hematopoiesis, and dysregulation is closely associated with leukemogenesis. Epigenetic aberration is one of the major causes contributing to acute myeloid leukemia (AML), where chromosomal rearrangements are frequently found. Increasing evidences have shown the pivotal roles of histone deacetylases (HDACs) in chromatin remodeling, which are involved in stemness maintenance, cell fate determination, proliferation and differentiation, via mastering the transcriptional switch of key genes. In abnormal, these functions can be bloomed to elicit carcinogenesis. Presently, HDAC family members are appealing targets for drug exploration, many of which have been deployed to the AML treatment. As the majority of AML events are associated with chromosomal translocation resulting in oncogenic fusion proteins, it is valuable to comprehensively understand the mutual interactions between HDACs and oncogenic proteins. Therefore, we reviewed the process of leukemogenesis and roles of HDAC members acting in this progress, providing an insight for the target anchoring, investigation of hyperacetylated-agents, and how the current knowledge could be applied in AML treatment.

2.
Life Sci ; 284: 119928, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480937

RESUMO

AIMS: Berberine is effective for type 2 diabetes mellitus (T2DM), but has limited use in clinic. This study aims to evaluate the effect of berberine combined with stachyose on glycolipid metabolism and gut microbiota and to explore the underlying mechanisms in diabetic rats. MAIN METHODS: Zucker diabetic fatty (ZDF) rats were orally administered berberine, stachyose and berberine combined with stachyose once daily for 69 days. The oral glucose tolerance and levels of blood glucose, insulin, triglyceride and total cholesterol were determined. The gut microbial profile, colonic miRNA and gene expression were assayed using Illumina sequencing. The quantitative polymerase chain reaction was used to verify the expression of differentially expressed miRNAs and genes. KEY FINDINGS: Repeated treatments with berberine alone and combined with stachyose significantly reduced the blood glucose, improved the impaired glucose tolerance, and increased the abundance of beneficial Akkermansiaceae, decreased that of pathogenic Enterobacteriaceae in ZDF rats. Furthermore, combined treatment remarkably decreased the abundances of Desulfovibrionaceae and Proteobacteria in comparison to berberine. Combined treatment evidently decreased the expression of intestinal early growth response protein 1 (Egr1) and heparin-binding EGF-like growth factor (Hbegf), and significantly increased the expression of miR-10a-5p, but berberine alone not. SIGNIFICANCE: Berberine combined with stachyose significantly improved glucose metabolism and reshaped gut microbiota in ZDF rats, especially decreased the abundance of pathogenic Desulfovibrionaceae and Proteobacteria compared to berberine alone, providing a novel strategy for treating T2DM. The underlying mechanisms may be associated with regulating the expression of intestinal Egr1, Hbegf and miR-10a-5p, but remains further elucidation.


Assuntos
Berberina/farmacologia , Colo/metabolismo , Diabetes Mellitus Experimental/genética , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Glucose/metabolismo , MicroRNAs/genética , Oligossacarídeos/farmacologia , Animais , Colo/efeitos dos fármacos , Colo/microbiologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , MicroRNAs/metabolismo , Análise de Componente Principal , Ratos Zucker , Reprodutibilidade dos Testes , Transcriptoma/genética
3.
J Ethnopharmacol ; 280: 114483, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34339793

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Morus alba L. (Sangzhi) alkaloids (SZ-A) tablets have been approved by the China National Medical Products Administration for T2DM treatment. Our previous study (Liu et al., 2021) revealed that SZ-A protected against diabetes and inflammation in KKAy mice. However, the mechanism and components in SZ-A exerting anti-inflammatory effects are unclear. AIM OF THE STUDY: Investigate the effects and molecular mechanisms of SZ-A on inflammation, and identify anti-inflammatory active components in SZ-A. MATERIALS AND METHODS: The major ingredients in SZ-A were analyzed by HPLC and sulfuric acid - anthrone spectrophotometry. The inhibitory activities of SZ-A on lipopolysaccharide (LPS)-stimulated inflammation were determined in bone marrow-derived macrophage (BMDM) and RAW264.7 cells. The cytokine levels of IL-6 and TNF-α in cell culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Gene expression levels of IL-6 and TNF-α were detected by qRT-PCR. The levels of protein phosphorylation of p38 MAPK, ERK, and JNK were analyzed by Western blot. RESULTS: The main components in SZ-A were found to be 1-deoxynojirimycin (DNJ), 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), fagomine (FAG), polysaccharide (APS), and arginine (ARG). SZ-A reduced the levels of IL-6 and TNF-α secreted by LPS-induced RAW264.7 and BMDM cells. Simultaneously, the mRNA expression levels of IL-6 and TNF-α were all significantly suppressed by SZ-A in a concentration-dependent manner. Furthermore, SZ-A inhibited the phosphorylation of p38 MAPK, ERK, and JNK in BMDM and the activation of ERK and JNK signaling in RAW264.7 cells. We also observed that DNJ, DAB, FAG, and ARG markedly downregulated IL-6 and TNF-α cytokine levels, while APS did not have an obvious effect. CONCLUSIONS: SZ-A attenuates inflammation at least partly by blocking the activation of p38 MAPK, ERK, and JNK signaling pathways. DNJ, FAG, DAB, and ARG are the main constituents in SZ-A that exert anti-inflammatory effects.

4.
ACS Appl Mater Interfaces ; 13(35): 41657-41668, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34432426

RESUMO

Triboelectric nanogenerators (TENGs) are newly developed energy-harvesting mechanisms, which can efficiently transmute irregular mechanical energy into scarce electrical energy. However, the electrical performance of TENGs shows a decreasing tendency with the increase in temperature, and the negative effect caused by friction heat and operating environmental thermal stresses for the output performance, durability, and reliability are still a bottleneck, restricting the practical application of TENG electronic devices. Especially for wearable TENG devices, the heat-induced temperature rise evokes extreme discomfort and even hazards to human health. To effectively suppress the thermal negative effect and maintain the high-temperature steady electrical performance of TENGs, a novel thermo-regulating TENG (Tr-TENG) based on phase change materials (PCMs) is designed. The results state clearly that the Tr-TENG can maintain steady output performance without deterioration by the introduction of PCMs, during continuous heating and natural cooling, while the output performance of conventional TENG is decayed by 18.33%. More importantly, the Tr-TENG possesses high-efficiency thermal management ability, resulting in its improved durability, reliability, and thermal comfort. This study creates new possibilities for the development of advanced multifunctional TENGs with attractive characteristics and desirable performances and promotes the application of TENG electronic devices in harsh environments.

5.
Clin Sci (Lond) ; 135(14): 1751-1765, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34282832

RESUMO

Epigenetic dysregulation has long been identified as a key driver of leukemogenesis in acute myeloid leukemia (AML). However, epigenetic drugs such as histone deacetylase inhibitors (HDACis) targeting epigenetic alterations in AML have obtained only limited clinical efficiency without clear mechanism. Fortunately, we screened out a novel epigenetic agent named Apigenin-Vorinostat-Conjugate (AVC), which provides us a possibility to handle the heterogeneous malignancy. Its inhibition on HDACs was presented by HDACs expression, enzyme activity, and histone acetylation level. Its efficacy against AML was detected by cell viability assay and tumor progression of AML mouse model. Apoptosis is the major way causing cell death. We found that AVC efficiently suppresses leukemogenesis while sparing the normal human cells. Kasumi-1 cells are at least 20-fold higher sensitive to AVC (IC50 = 0.024 µM) than vorinostat (IC50 = 0.513 µM) and Ara-C (IC50 = 0.4366 µM). Furthermore, it can efficiently regress the tumorigenesis in AML mouse model while keeping the pivotal organs safe, demonstrating a feasibility and favorable safety profile in treatment of AML. Collectively, these preclinical data suggest a promising potential utilizing flavonoid-HDACi-conjugate as a next-generation epigenetic drug for clinical therapy against AML.


Assuntos
Epigênese Genética/efeitos dos fármacos , Flavonoides/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos
6.
J Orthop Surg Res ; 16(1): 392, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140036

RESUMO

BACKGROUND: Osteoarthritis (OA) is responsible for the impotent disability in old people. Circular RNA (circRNA) has been reported to be related to the development of diseases. The lack of research on the role of circRNA spastic paraplegia 11 (circ-SPG11) results in conducting this study. METHODS: The expression of circ-SPG11, microRNA-337-3p (miR-337-3p), and aggrecanases like a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was used to measure the protein expression of extracellular matrix (ECM) degradation-related markers and ADAMTS5. Ribonuclease R (RNase R) was applied to test the stability of circ-SPG11 in CHON-001 cells. The viability, apoptosis, TNF-α and IL-6 production were determined by cell counting kit-8 (CCK-8) assay, flow cytometry assay, and enzyme-linked immunosorbent assay (ELISA), respectively. Meanwhile, the interaction between miR-337-3p and circ-SPG11 or ADAMTS5 was respectively predicted by Circinteractome or Starbase2.0, which was further verified by dual-luciferase reporter system and RNA binding protein immunoprecipitation (RIP) assay. RESULTS: Circ-SPG11 and ADAMTS5 were upregulated and miR-337-3p was downregulated in OA tissues and OA model cells. Circ-SPG11 knockdown allayed interleukin 1ß (IL-1ß)-induced restraint in viability and promotion in apoptosis, TNF-α, and IL-6 generation and ECM degradation in CHON-001 cells. Anti-miR-337-3p or ADAMTS5 overexpression correspondingly reversed si-circ-SPG11 or miR-337-3p overexpression-mediated facilitation in viability, and inhibition in apoptosis, TNF-α and IL-6 generation and ECM degradation in OA model cells. Moreover, anti-miR-337-3p ameliorated si-circ-SPG11-mediated inhibition in ADAMTS5 mRNA and protein expression in OA model cells. CONCLUSION: Circ-SPG11 facilitated OA development via regulating miR-337-3p/ADAMTS5 axis. This finding might contribute to the improvement of OA therapy.


Assuntos
Proteína ADAMTS5/genética , Proteína ADAMTS5/metabolismo , Técnicas de Silenciamento de Genes , Interleucina-1beta/efeitos adversos , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite do Joelho/genética , Proteínas/genética , RNA Circular/genética , Linhagem Celular , Progressão da Doença , Regulação para Baixo/genética , Regulação da Expressão Gênica/genética , Humanos , Osteoartrite do Joelho/etiologia , Proteínas/fisiologia , RNA Circular/fisiologia , Regulação para Cima/genética
7.
Front Pharmacol ; 12: 642400, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935735

RESUMO

The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.

8.
J Transl Med ; 19(1): 215, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006295

RESUMO

BACKGROUND: The fecal microbiota in pancreatic ductal adenocarcinoma (PDAC) and in autoimmune pancreatitis (AIP) patients remains largely unknown. We aimed to characterize the fecal microbiota in patients with PDAC and AIP, and explore the possibility of fecal microbial biomarkers for distinguishing PDAC and AIP. METHODS: 32 patients with PDAC, 32 patients with AIP and 32 age- and sex-matched healthy controls (HC) were recruited and the fecal microbiotas were analyzed through high-throughput metagenomic sequencing. Alterations of fecal short-chain fatty acids were measured using gas chromatographic method. RESULTS: Principal coordinate analysis (PCoA) revealed that microbial compositions differed significantly between PDAC and HC samples; whereas, AIP and HC individuals tended to cluster together. Significant reduction of phylum Firmicutes (especially butyrate-producing bacteria, including Eubacterium rectale, Faecalibacterium prausnitzii and Roseburia intestinalis) and significant increase of phylum Proteobacteria (especially Gammaproteobacteria) were observed only among PDAC samples. At species level, when compared with HC samples, we revealed 24 and 12 differently enriched bacteria in PDAC and AIP, respectively. Functional analysis showed a depletion of short-chain fatty acids synthesis associated KO modules (e.g. Wood-Ljungdahl pathway) and an increase of KO modules associated with bacterial virulence (e.g. type II general secretion pathway). Consistent with the downregulation of butyrate-producing bacteria, gas chromatographic analysis showed fecal butyrate content was significantly decreased in PDAC group. Eubacterium rectale, Eubacterium ventrisum and Odoribacter splanchnicus were among the most important biomarkers in distinguishing PDAC from HC and from AIP individuals. Receiver Operating Characteristic analysis showed areas under the curve of 90.74% (95% confidence interval [CI] 86.47-100%), 88.89% (95% CI 73.49-100%), and 76.54% (95% CI 52.5-100%) for PDAC/HC, PDAC/AIP and AIP/HC, respectively. CONCLUSIONS: In conclusion, alterations in fecal microbiota and butyrate of patients with PDAC suggest an underlying role of gut microbiota for the pathogenesis of PDAC. Fecal microbial and butyrate as potential biomarkers may facilitate to distinguish patients with PDAC from patients with AIP and HCs which worth further validation.


Assuntos
Doenças Autoimunes , Pancreatite Autoimune , Neoplasias Pancreáticas , Doenças Autoimunes/diagnóstico , Bacteroidetes , Clostridiales , Diagnóstico Diferencial , Fezes , Humanos , Neoplasias Pancreáticas/diagnóstico
9.
J Mater Chem B ; 9(21): 4365-4379, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34013945

RESUMO

As a radiotherapy sensitizer, gold-based nanomaterials can significantly enhance radiotherapy efficacy. However, the severe hypoxia and the low accumulation of nanomedicine at the tumor site caused by poor perfusion have seriously affected the effect of radiotherapy. Tumor vascular normalization has emerged as a new strategy for increasing the efficacy of radiotherapy due to its ability to relieve hypoxia and increase perfusion. However, a commonly used approach of blocking a single growth factor to induce vascular normalization is limited by the compensation effect of evasive drug resistance. In this work, we developed a strategy to simultaneously reduce the expression of multi-angiogenic growth factors by suppressing the oxidative stress effects in tumor. Herein, gold nanoparticles (Au NPs) were modified with 8-hydroxyquinoline (HQ) to obtain AuHQ. This system has a simple structure and could inhibit the production of reactive oxygen species in tumor cells by chelating iron ions, and attenuating the expression of angiopoietin-2, vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells. In vivo, AuHQ treatment increased pericyte coverage, modulated tumor leakage while alleviating tumor hypoxia and increased blood perfusion, thereby inducing tumor vascular normalization. Consequently, Au accumulation of the AuHQ group increased by 1.94 fold compared to that in the control group. Furthermore, the antitumor efficacy of radiotherapy was increased by 38% compared to the Au NPs-treated group. Therefore, AuHQ may be a promising nanomedicine for future cancer treatment.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Neoplasias/irrigação sanguínea , Oxiquinolina/química , Radiossensibilizantes/farmacologia , Radioterapia/métodos , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células Hep G2 , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos ICR , Neoplasias/metabolismo , Neoplasias/patologia , Radiossensibilizantes/química , Radioterapia/normas , Espécies Reativas de Oxigênio/metabolismo
10.
Exp Hematol Oncol ; 10(1): 26, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33789763

RESUMO

Aberrant DNA methylation is often related to the diagnosis, prognosis, and therapeutic response of acute myeloid leukemia (AML); however, relevant studies on the relationship between bone marrow myeloblast percentage and the DNA methylation level in AML have not been reported. We evaluated the effects of AML blast percentage on DNA methylation level using the MethylC-capture sequencing (MCC-Seq) approach based on next-generation sequencing (NGS) and found that the methylation level of both genome-wide and promoter regions significantly increased when the percentage of AML blasts reached ≥ 40%, indicating that an accurate DNA methylation level in cancer cells can be obtained when the bone marrow samples of AML patients have more than 40% myeloblasts.

11.
Infect Drug Resist ; 14: 1415-1422, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33880046

RESUMO

Background: ST11 is the most prevalent sequence type of clinical Klebsiella pneumoniae in China. Methods: We investigated the characteristics of the ST11 subclones using core genome multi-locus sequence typing (cgMLST). Ninety-three carbapenemase-producing K. pneumoniae isolates were collected at Shenzhen People's Hospital. Then, whole-genome sequencing and cgMLST were used to discriminate apparent subclones within the ST11 group. Results: We analyzed the prevalence and genetic relationships of these subclones. ST11 and K. pneumoniae carbapenemase (KPC-2) were the predominant genotype and carbapenemase, respectively, in the clinical carbapenemase-producing K. pneumoniae strains. cgMLST scheme genotyping divided the ST11 group into two clades across seven complex types (CTs). CT1313 was the most prevalent subclone. The deletion of galF and a high frequency of SNPs in genes associated with the stress- and SOS-responses were found in CT1291 and CT2405 over time, respectively. Conclusion: Our results indicated that the subclones of the ST11 group had different patterns of prevalence. Highly discriminatory genotyping techniques, such as cgMLST scheme, should be used in further molecular epidemiology investigations.

12.
Front Oncol ; 11: 579881, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33928020

RESUMO

The occurrence of gene mutation is a major contributor to the initiation and propagation of acute myeloid leukemia (AML). Accumulating evidence suggests that genes encoding cohesin subunits have a high prevalence of mutations in AML, especially in the t(8;21) subtype. Therefore, it is important to understand how cohesin mutations contribute to leukemogenesis. However, the fundamental understanding of cohesin mutation in clonal expansion and myeloid transformation in hematopoietic cells remains ambiguous. Previous studies briefly introduced the cohesin mutation in AML; however, an in-depth summary of mutations in AML was not provided, and the correlation between cohesin and AML1-ETO in t (8;21) AML was also not analyzed. By summarizing the major findings regarding the cohesin mutation in AML, this review aims to define the characteristics of the cohesin complex mutation, identify its relationships with co-occurring gene mutations, assess its roles in clonal evolution, and discuss its potential for the prognosis of AML. In particular, we focus on the function of cohesin mutations in RUNX1-RUNX1T1 fusion.

13.
Front Cell Infect Microbiol ; 11: 640309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777850

RESUMO

To characterize the salivary microbiota in patients at different progressive histological stages of gastric carcinogenesis and identify microbial markers for detecting gastric cancer, two hundred and ninety-three patients were grouped into superficial gastritis (SG; n = 101), atrophic gastritis (AG; n = 93), and gastric cancer (GC; n = 99) according to their histology. 16S rRNA gene sequencing was used to access the salivary microbiota profile. A random forest model was constructed to classify gastric histological types based on the salivary microbiota compositions. A distinct salivary microbiota was observed in patients with GC when comparing with SG and AG, which was featured by an enrichment of putative proinflammatory taxa including Corynebacterium and Streptococcus. Among the significantly decreased oral bacteria in GC patients including Haemophilus, Neisseria, Parvimonas, Peptostreptococcus, Porphyromonas, and Prevotella, Haemophilus, and Neisseria are known to reduce nitrite, which may consequently result in an accumulation of carcinogenic N-nitroso compounds. We found that GC can be distinguished accurately from patients with AG and SG (AUC = 0.91) by the random forest model based on the salivary microbiota profiles, and taxa belonging to unclassified Streptophyta and Streptococcus have potential as diagnostic biomarkers for GC. Remarkable changes in the salivary microbiota functions were also detected across three histological types, and the upregulation in the isoleucine and valine is in line with a higher level of these amino acids in the gastric tumor tissues that reported by other independent studies. Conclusively, bacteria in the oral cavity may contribute gastric cancer and become new diagnostic biomarkers for GC, but further evaluation against independent clinical cohorts is required. The potential mechanisms of salivary microbiota in participating the pathogenesis of GC may include an accumulation of proinflammatory bacteria and a decline in those reducing carcinogenic N-nitroso compounds.


Assuntos
Gastrite , Microbiota , Neoplasias Gástricas , Humanos , RNA Ribossômico 16S
14.
Curr Oncol ; 28(2): 1077-1093, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652996

RESUMO

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.


Assuntos
Células Matadoras Naturais , Neoplasias , Humanos , Imunoterapia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T
15.
J Child Psychol Psychiatry ; 62(10): 1246-1254, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33738808

RESUMO

BACKGROUND: Symptom improvement in children with tic disorder (TD) following fecal microbiota transplantation led us to investigate the gut microbiota in TD. This exploratory study aims to depict the gut microbial profile in patients with TD and explore the impact of dopamine receptor antagonist (DRA) drugs on the composition and metabolic function of the gut microbiota. METHODS: The gut microbiota were profiled in fecal samples of 49 children with TD and 50 matched healthy controls (HC) using shotgun metagenomic sequencing. A random forest (RF) model was constructed using the gut bacterial species to distinguish TD from HC. Associations between clinical metadata and microbial abundance or function were analyzed using MaAsLin2 and Spearman correlation. RESULTS: The gut microbiota in children with TD was featured by higher abundances of Bacteroides plebeius and Ruminococcus lactaris (a potential pro-inflammatory taxon) and lower abundances of Prevotella stercorea and Streptococcus lutetiensis compared to HC. The constructed RF model accurately distinguished TD from HC based on the gut microbiota profile, resulting in an AUC of 0.884. Significant correlations were observed between tic symptom severity and the abundances of multiple bacterial species and gut microbiota metabolic functions. Multivariate analysis identified an upregulation of 4-aminobutanoate (GABA) degradation in the gut microbiota associated with TD status. The gut microbiota of DRA-treated TD children showed a distinct gut microbiota compared to the treatment-naïve group, represented by an increase in some potential enteric pathogens such as Escherichia coli, a decline in several species including Akkermansia muciniphila, and alterations in various metabolic functions. CONCLUSIONS: Bacterial species promoting inflammatory responses and those modulating neurotransmitters such as GABA may be involved in the pathogenesis of TD. The use of DRA drugs is likely to induce overgrowth of some enteric pathogens and alter the gut microbiota metabolism.


Assuntos
Microbioma Gastrointestinal , Transtornos de Tique , Bacteroides , Criança , Humanos , Prevotella , Ruminococcus , Streptococcus
16.
Sci Total Environ ; 776: 145730, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33639460

RESUMO

Biodiversity drives ecosystem functioning across grassland ecosystems. However, few studies have examined how grazing intensity affects ecosystem multifunctionality (EMF) via its effects on plant diversity and soil microbial diversity in dry grasslands. We conducted a 12-year experiment manipulating sheep grazing intensity in a desert steppe of northern China. Through measuring plant species diversity, soil microbial diversity (bacteria diversity) and multiple ecosystem functions (i.e., aboveground net primary productivity, belowground biomass of plant community, temporal stability of ANPP, soil organic matter, moisture, available nitrogen and phosphorus, ecosystem respiration and gross ecosystem productivity), we aimed to understand how grazing intensity affected EMF via changing the diversity of plants and microbes. Our results showed that increasing grazing intensity significantly reduced EMF and most individual ecosystem functions, as well as the diversity of plants and microbes, while EMF and most individual functions were positively related to plant diversity and soil microbial diversity under all grazing intensities. In particular, soil microbial diversity in shallow soil layers (0-5 cm depth) had stronger positive correlations with plant diversity and EMF than in deeper soil layers. Furthermore, structural equation modeling (SEM) showed that grazing reduced EMF mainly via reducing plant diversity, rather than by reducing soil microbial diversity. Thus, plant diversity played a more important role in mediating the response of EMF to grazing disturbance. This study highlights the critical role of above- and belowground diversity in mediating the response of EMF to grazing intensity, which has important implications for biodiversity conservation and sustainability in arid grasslands.


Assuntos
Ecossistema , Solo , Animais , Biodiversidade , Biomassa , China , Pradaria , Plantas , Ovinos
17.
J Transl Med ; 19(1): 65, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579308

RESUMO

BACKGROUND: Rho GTPase activating protein 9 (ARHGAP9) is expressed in various types of cancers and can inactivate Rho GTPases that mainly regulate cytoskeletal dynamics. However, the exact role of ARHGAP9 in acute myeloid leukemia (AML) has yet to be clarified. METHODS: We compared the transcriptional expression, prognosis, differentially expressed genes, functional enrichment, and hub genes in AML patients on the basis of the data published in the following databases: UALCAN, GEPIA, Gene Expression Omnibus, the Human Protein Atlas, Cancer Cell Line Encyclopedia, LinkedOmics, Metascape, and String. Data from the Cancer Genome Atlas database was used to evaluate the correlations between ARHGAP9 expression and various clinicopathological parameters, as well as the significantly different genes associated with ARHGAP9 expression. RESULTS: We found that ARHGAP9 expression was higher in the tissues and cell lines extracted from patients with AML than corresponding control tissues and other cancer types. ARHGAP9 overexpression was associated with decreased overall survival (OS) in AML. Compared with the ARHGAP9low group, the ARHGAP9high group, which received only chemotherapy, showed significantly worse OS and event-free survival (EFS); however, no significant difference was observed after treatment with autologous or allogeneic hematopoietic stem cell transplantation (auto/allo-HSCT). The ARHGAP9high patients undergoing auto/allo-HSCT also had a significantly better prognosis with respect to OS and EFS than those receiving only chemotherapy. Most overlapping genes of the significantly different genes and co-expression genes exhibited enriched immune functions, suggesting the immune regulation potential of ARHGAP9 in AML. A total of 32 hub genes were identified from the differentially expressed genes, within which the KIF20A had a significant prognostic value for AML. CONCLUSIONS: ARHGAP9 overexpression was associated with poor OS in AML patients and can be used as a prognostic biomarker. AML patients with ARHGAP9 overexpression can benefit from auto/allo-HSCT rather than chemotherapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Proteínas Ativadoras de GTPase/genética , Humanos , Leucemia Mieloide Aguda/genética , Prognóstico , Intervalo Livre de Progressão
18.
Gut Microbes ; 13(1): 1-18, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33430702

RESUMO

Gut microbial dysbiosis and altered metabonomics have been implicated in the pathogenesis of Crohn's disease (CD). The aim of our study was to characterize the gut microbiome structure and metabolic activities in pediatric CD patients with different clinical outcomes after infliximab (IFX) therapy. Fecal samples were collected from 20 healthy children and 29 newly diagnosed pediatric CD patients. 16S rRNA/ITS2 gene sequencing and targeted metabolomics analysis were applied to profile the gut bacterial microbiome, mycobiome, and metabolome, respectively. Pediatric CD patients exhibited lower relative abundances of short-chain fatty acids (SCFAs)-producing bacteria including Faecalibacterium, Clostridium clusters IV and XIVb, Roseburia, and Ruminococcus, which were correlated with reduced fecal levels of SCFAs. Decreased unconjugated bile acids (BAs) pool size and a lower unconjugated/conjugated BAs ratio were associated with reduced relative abundances of Bifidobacterium and Clostridium clusters IV and XIVb which contain bile salt hydrolases (BSH) genes. IFX treatment enriched the BSH-producing bacteria in CD subjects, which may explain a decreased level of conjugated BAs and an increase in unconjugated BAs as well as the unconjugated/conjugated BAs ratio. Furthermore, a sustained response (SR) of IFX therapy was associated with higher abundances of Methylobacterium, Sphingomonas, Staphylococcus, and Streptococcus, and higher fecal concentrations of amino acids, including L-aspartic acid, linoleic acid, and L-lactic acid at baseline. Our study suggests that the effects of IFX might be partially mediated by enriching bacteria taxa that producing SCFAs and BSH thereby inhibiting inflammation and restoring the BA metabolism. Some fecal bacteria and metabolites may be predictive of outcomes of IFX therapy for pediatric CD patients.

19.
Front Pharmacol ; 11: 580817, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33162889

RESUMO

Objectives: Umbilical cord blood transplantation (UCBT) is associated with a relatively high rate of engraftment failure. This study aimed at exploring whether any fecal microbiota could be associated with engraftment failure following UCBT in Crohn's disease patients with IL10RA deficiency. Methods: Thirteen patients were recruited and their 230 fecal samples were collected longitudinally from immediately before conditioning chemotherapy to 8 weeks post the UCBT. The V3-V4 regions of the bacterial 16S rRNA gene were amplified by PCR and sequenced, followed by bioinformatics analyses. Results: Following the UCBT, 7 out of 13 patients achieved neutrophil and platelet engraftment with a median of 21 and 28 days, respectively (S group), while 6 patients failed to achieve engraftment (F group). In comparison with that in the S group, significantly lower Shannon diversity values on the UCBT day (P = 0.0176) and less abundance of Bifidobacterium longum, Bifidobacterium pseudolongum, Enterobacteriaceae_538000, and one taxon of Lachnospiraceae family was detected in the F group, accompanied by significantly higher abundances of four taxa including Lautropia, Pseudomonas, and species Microvirgula aerodenitrificans during the chemotherapy period as well as UCBT. The abundances of thirty OTUs were correlated significantly with clinical indices. Conclusions: Microbial indicators of reduced diversity of microbiota and signatures of specific bacterial abundances, such as a lower abundance of Bifidobacterium longum, for engraftment failure would require validation. These indicators may help for the risk stratification in patients with IL10RA deficiency undergoing UCBT.

20.
Clin Sci (Lond) ; 134(23): 3079-3091, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33201243

RESUMO

The AML1-ETO oncoprotein, which results from t(8;21) translocation, is considered an initial event of t(8;21) acute myeloid leukemia (AML). However, the precise mechanisms of the oncogenic activity of AML1-ETO is yet to be fully determined. The present study demonstrates that AML1-ETO triggers the heterochromatic silencing of microRNA-564 (miR564) by binding at the AML1 binding site along the miR564 promoter region and recruiting chromatin-remodeling enzymes. Suppression of miR564 enhances the oncogenic activity of the AML1-ETO oncoprotein by directly inhibiting the expression of CCND1 and the DNMT3A genes. Ectopic expression of miR564 can induce retardation of G1/S transition, reperform differentiation, promote apoptosis, as well as inhibit the proliferation and colony formation of AML1-ETO+ leukemia cells in vitro. Enhanced miR564 levels can significantly inhibit the tumor proliferation of t(8;21)AML in vivo. We first identify an unexpected and important epigenetic circuitry of AML1-ETO/miR564/CCND1/DNMT3A that contributes to the leukemogenesis in vitro/vivo of AML1-ETO+ leukemia, indicating that miR564 enhancement could provide a potential therapeutic method for AML1-ETO+ leukemia.


Assuntos
Carcinogênese/genética , Epigênese Genética , Inativação Gênica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , MicroRNAs/metabolismo , Translocação Genética , Animais , Apoptose/genética , Sequência de Bases , Carcinogênese/patologia , Pontos de Checagem do Ciclo Celular/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Ciclina D1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Proteínas de Fusão Oncogênica/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Regulação para Cima/genética
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