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2.
Front Plant Sci ; 15: 1428394, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38938639

RESUMO

Fresh red waxy corn is consumed worldwide because of its unique flavor and rich nutrients, but it is susceptible to deterioration with a short shelf life. This study explored the effect of slightly acidic electrolyzed water (SAEW) treatment on the quality and antioxidant capacity of fresh red waxy corn during postharvest cold storage up to 40 d. The SAEW treatment exhibited lower weight loss, softer firmness, and higher total soluble solids (TSS) and moisture content than the control group. Correspondingly, the SAEW maintained the microstructure of endosperm cell wall and starch granules of fresh red waxy corn kernels well, contributing to good sensory quality. Furthermore, SAEW effectively reduced the accumulation of H2O2 content, elevated the O2 -· scavenging ability, maintained higher CAT and APX activities, and decreased the decline of the flavonoids and anthocyanin during the storage. These results revealed that the SAEW treatment could be a promising preservation method to maintain higher-quality attributes and the antioxidant capacity of fresh red waxy corn during postharvest cold storage.

3.
J Agric Food Chem ; 72(21): 12240-12250, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38764183

RESUMO

LIM domain binding 3 (LDB3) serves as a striated muscle-specific Z-band alternatively spliced protein that plays an important role in mammalian skeletal muscle development, but its regulatory role and molecular mechanism in avian muscle development are still unclear. In this study, we reanalyzed RNA sequencing data sets of 1415 samples from 21 chicken tissues published in the NCBI GEO database. First, three variants (LDB3-X, LDB3-XN1, and LDB3-XN2) generated by alternative splicing of the LDB3 gene were identified in chicken skeletal muscle, among which LDB3-XN1 and LDB3-XN2 are novel variants. LDB3-X and LDB3-XN1 are derived from exon skipping in chicken skeletal muscle at the E18-D7 stage and share three LIM domains, but LDB3-XN2 lacks a LIM domain. Our results preliminarily suggest that the formation of three variants of LDB3 is regulated by RBM20. The three splice isomers have divergent functions in skeletal muscle according to in vitro and in vivo assays. Finally, we identified the mechanism by which different variants play different roles through interactions with IGF2BP1 and MYHC, which promote the proliferation and differentiation of chicken myoblasts, in turn regulating chicken myogenesis. In conclusion, this study revealed the divergent roles of three LDB3 variants in chicken myogenesis and muscle remodeling and demonstrated their regulatory mechanism through protein-protein interactions.


Assuntos
Processamento Alternativo , Galinhas , Proteínas com Domínio LIM , Desenvolvimento Muscular , Músculo Esquelético , Animais , Galinhas/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/química , Músculo Esquelético/crescimento & desenvolvimento , Desenvolvimento Muscular/genética , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Mioblastos/metabolismo , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Proteínas Aviárias/química , Diferenciação Celular , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/química
4.
Commun Biol ; 7(1): 518, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38698103

RESUMO

Myoblast proliferation and differentiation are essential for skeletal muscle development. In this study, we generated the expression profiles of mRNAs, long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) in different developmental stages of chicken primary myoblasts (CPMs) using RNA sequencing (RNA-seq) technology. The dual luciferase reporter system was performed using chicken embryonic fibroblast cells (DF-1), and functional studies quantitative real-time polymerase chain reaction (qPCR), cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), flow cytometry cycle, RNA fluorescence in situ hybridization (RNA-FISH), immunofluorescence, and western blotting assay. Our research demonstrated that miR-301a-5p had a targeted binding ability to lncMDP1 and ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1). The results revealed that lncMDP1 regulated the proliferation and differentiation of myoblasts via regulating the miR-301a-5p/CHAC1 axis, and CHAC1 promotes muscle regeneration. This study fulfilled the molecular regulatory network of skeletal muscle development and providing an important theoretical reference for the future improvement of chicken meat performance and meat quality.


Assuntos
Galinhas , Perfilação da Expressão Gênica , MicroRNAs , Desenvolvimento Muscular , RNA Longo não Codificante , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Desenvolvimento Muscular/genética , Galinhas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Diferenciação Celular/genética , Proliferação de Células , Mioblastos/metabolismo , Mioblastos/citologia , Embrião de Galinha
5.
Foods ; 13(6)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38540809

RESUMO

The nonantimicrobial properties and relatively poor mechanical properties of hydroxyethyl cellulose (HEC) limit its use in packaging. Sulfated rice bran polysaccharides (SRBP) possess significant antioxidant and antimicrobial activities. The purpose of this study was to investigate the effect of different concentrations of SRBP on the physical and mechanical properties and the functional characteristics of HEC/SRBP films. The physical properties of the HEC/20% SRBP films, such as water resistance, water vapor barrier, light barrier, and tensile strength, improved significantly (p < 0.05) compared with those of the HEC films. Scanning electron microscopy and Fourier transform infrared spectrometry showed that HEC formed hydrogen bonds with SRBP and exhibited better compatibility. Thermogravimetric analysis revealed that the addition of SRBP was beneficial to the thermal stability of the films. In addition, the antioxidant and bacteriostatic properties of the films were enhanced by the addition of SRBP to HEC, with the 20% SRBP films showing the most significant enhancement in activity. Therefore, the HEC/20% SRBP films show potential for development for use as active food packaging.

6.
Food Chem ; 446: 138777, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38402763

RESUMO

Seven novel antioxidant peptides (AWF, LWQ, WIY, YLW, LAYW, LPWG, and LYFY) exhibiting a superior activity compared to trolox were identified through in silico screening. Among these, the four peptides (WIY, YLW, LAYW, and LYFY) displayed notably enhanced performance, with ABTS activity 2.58-3.26 times and ORAC activity 5.19-8.63 times higher than trolox. Quantum chemical calculations revealed that the phenolic hydroxyl group in tyrosine and the nitrogen-hydrogen bond in the indole ring of tryptophan serve as the critical sites for antioxidant activity. These findings likely account for the potent chemical antioxidant activity. The corn peptides also exerted a protective effect against AAPH-induced cytomorphologic changes in human erythrocytes by modulating the antioxidant system. Notably, LAYW exhibited the most pronounced cytoprotective effects, potentially due to its high content of hydrophobic amino acids.


Assuntos
Antioxidantes , Glutens , Humanos , Antioxidantes/química , Glutens/química , Zea mays/química , Peptídeos/química , Fenóis
7.
Poult Sci ; 103(3): 103407, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38198913

RESUMO

During myogenesis and regeneration, the proliferation and differentiation of myoblasts play key regulatory roles and may be regulated by many genes. In this study, we analyzed the transcriptomic data of chicken primary myoblasts at different periods of proliferation and differentiation with protein‒protein interaction network, and the results indicated that there was an interaction between cyclin-dependent kinase 1 (CDK1) and ribonucleotide reductase regulatory subunit M2 (RRM2). Previous studies in mammals have a role for RRM2 in skeletal muscle development as well as cell growth, but the role of RRM2 in chicken is unclear. In this study, we investigated the effects of RRM2 on skeletal muscle development and regeneration in chickens in vitro and in vivo. The interaction between RRM2 and CDK1 was initially identified by co-immunoprecipitation and mass spectrometry. Through a dual luciferase reporter assay and quantitative real-time PCR, we identified the core promoter region of RRM2, which is regulated by the SP1 transcription factor. In this study, through cell counting kit-8 assays, 5-ethynyl-2'-deoxyuridine incorporation assays, flow cytometry, immunofluorescence staining, and Western blot analysis, we demonstrated that RRM2 promoted the proliferation and inhibited the differentiation of myoblasts. In vivo studies showed that RRM2 reduced the diameter of muscle fibers and slowed skeletal muscle regeneration. In conclusion, these data provide preliminary insights into the biological functions of RRM2 in chicken muscle development and skeletal muscle regeneration.


Assuntos
Galinhas , Oxirredutases , Animais , Galinhas/genética , Fibras Musculares Esqueléticas , Proliferação de Células , Regeneração , Mamíferos
8.
Int J Biol Macromol ; 259(Pt 2): 129229, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38211913

RESUMO

The medicinal Dendrobium species of Orchidaceae possess significant pharmaceutical value, and modern pharmacological research has shown that Dendrobium contains many important active ingredients. Alkaloids, the crucial components of medicinal Dendrobium, demonstrate beneficial healing properties in cardiovascular, cataract, gastrointestinal, and respiratory diseases. Members of the cytochrome P450 monooxygenase (CYP) gene family play essential roles in alkaloid synthesis, participating in alkaloid terpene skeleton construction and subsequent modifications. Although studies of the CYP family have been conducted in some species, genome-wide characterization and systematic analysis of the CYP family in medicinal Dendrobium remain underexplored. In this study, we identified CYP gene family members in the genomes of four medicinal Dendrobium species recorded in the Pharmacopoeia: D. nobile, D. chrysotoxum, D. catenatum, and D. huoshanense. Further, we analyzed the motif composition, gene replication events, and selection pressure of this family. Syntenic analysis revealed that members of the clan 710 were present on chromosome 18 in three medicinal Dendrobium species, except for D. nobile, indicating a loss of clan 710 occurring in D. nobile. We also conducted an initial screening of the CYP genes involved in alkaloid synthesis through transcriptome sequencing. Quantitative real-time reverse transcription PCR showed that the expression of DnoNew43 and DnoNew50, homologs of secologanin synthase involved in the alkaloid synthesis pathway, was significantly higher in the stems than in the leaves. This result coincided with the distribution of dendrobine content in Dendrobium stems and leaves, indicating that these two genes might be involved in the dendrobine synthesis pathway. Our results give insights into the CYP gene family evolution analysis in four medicinal Dendrobium species for the first time and identify two related genes that may be involved in alkaloid synthesis, providing a valuable resource for further investigations into alkaloid synthesis pathway in Dendrobium and other medicinal plants.


Assuntos
Alcaloides , Dendrobium , Dendrobium/genética , Alcaloides/genética , Alcaloides/análise , Vias Biossintéticas/genética , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Terpenos/metabolismo
9.
Int J Mol Sci ; 24(24)2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38139020

RESUMO

Organic phosphorus (OP) is an essential component of the soil P cycle, which contributes to barley nutrition after its mineralization into inorganic phosphorus (Pi). However, the dynamics of OP utilization in the barley rhizosphere remain unclear. In this study, phytin was screened out from six OP carriers, which could reflect the difference in OP utilization between a P-inefficient genotype Baudin and a P-efficient genotype CN4027. The phosphorus utilization efficiency (PUE), root morphological traits, and expression of genes associated with P utilization were assessed under P deficiency or phytin treatments. P deficiency resulted in a greater root surface area and thicker roots. In barley fed with phytin as a P carrier, the APase activities of CN4027 were 2-3-fold lower than those of Baudin, while the phytase activities of CN4027 were 2-3-fold higher than those of Baudin. The PUE in CN4027 was mainly enhanced by activating phytase to improve the root absorption and utilization of Pi resulting from OP mineralization, while the PUE in Baudin was mainly enhanced by activating APase to improve the shoot reuse capacity. A phosphate transporter gene HvPHT1;8 regulated P transport from the roots to the shoots, while a purple acid phosphatase (PAP) family gene HvPAPhy_b contributed to the reuse of P in barley.


Assuntos
6-Fitase , Hordeum , Fósforo/metabolismo , Hordeum/genética , Hordeum/metabolismo , 6-Fitase/metabolismo , Ácido Fítico/metabolismo , Genótipo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo
10.
Nat Commun ; 14(1): 7827, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38030613

RESUMO

The dominant mutational signature in colorectal cancer genomes is C > T deamination (COSMIC Signature 1) and, in a small subgroup, mismatch repair signature (COSMIC signatures 6 and 44). Mutations in common colorectal cancer driver genes are often not consistent with those signatures. Here we perform whole-genome sequencing of normal colon crypts from cancer patients, matched to a previous multi-omic tumour dataset. We analyse normal crypts that were distant vs adjacent to the cancer. In contrast to healthy individuals, normal crypts of colon cancer patients have a high incidence of pks + (polyketide synthases) E.coli (Escherichia coli) mutational and indel signatures, and this is confirmed by metagenomics. These signatures are compatible with many clonal driver mutations detected in the corresponding cancer samples, including in chromatin modifier genes, supporting their role in early tumourigenesis. These results provide evidence that pks + E.coli is a potential driver of carcinogenesis in the human gut.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Escherichia coli/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação , Carcinogênese/genética
11.
Foods ; 12(17)2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37685089

RESUMO

Cherry tomatoes are easily damaged due to their high moisture content. A composite coating was developed to delay deterioration and prolong storage by mixing antibacterial sulfated rice bran polysaccharides (SRBP) and edible hydroxyethyl cellulose (HEC) with film-forming properties. The effects of HEC, HEC-5% SRBP, and HEC-20% SRBP preservative coatings on the maintenance of the quality of cherry tomatoes (LycopersivonesculentumMill., Xiaohuang F2) during cold storage were investigated. The HEC-20% SRBP coating significantly reduced tomato deterioration and weight loss, delayed firmness loss, decreased polyphenol oxidase activity, and increased peroxidase activity. Furthermore, cherry tomatoes treated with HEC-20% SRBP maintained high levels of titratable acid, ascorbic acid, total phenols, and carotenoids. Cherry tomatoes coated with HEC-SRBP also had higher levels of volatile substances and a greater variety of these substances compared to uncoated tomatoes. In conclusion, the HEC-20% SRBP coating effectively delayed deterioration and preserved cherry tomatoes' nutrient and flavor qualities during postharvest cold storage, suggesting it could be a novel food preservation method.

12.
Animals (Basel) ; 13(14)2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37508090

RESUMO

Skeletal muscle is an essential tissue in meat-producing animals, and meat-producing traits have been a hot topic in chicken genetic breeding research. Current research shows that creatine kinase M-type-like (CKM) is one of the most abundant proteins in skeletal muscle and plays an important role in the growth and development of skeletal muscle, but its role in the development of chicken skeletal muscle is still unclear. Via RNA sequencing (RNA-seq), we found that CKM was highly expressed in chicken breast muscle tissue. In this study, the expression profile of CKM was examined by quantitative real-time PCR (qPCR), and overexpression and RNA interference techniques were used to explore the functions of CKM in the proliferation, apoptosis and differentiation of chicken primary myoblasts (CPMs). It was shown that CKM was specifically highly expressed in breast muscle and leg muscle and was highly expressed in stage 16 embryonic muscle, while CKM inhibited proliferation, promoted the apoptosis and differentiation of CPMs and was involved in regulating chicken myogenesis. Transcriptome sequencing was used to identify genes that were differentially expressed in CPMs after CKM disruption, and bioinformatics analysis showed that CKM was involved in regulating chicken myogenesis. In summary, CKM plays an important role in skeletal muscle development during chicken growth and development.

13.
Int J Biol Macromol ; 236: 123851, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36863670

RESUMO

This study aimed to investigate the structural characterization, conformational properties, and hepatoprotective activity of corn silk acidic polysaccharide (CSP-50E). CSP-50E with molecular weights of 1.93 × 105 g/mol was composed of Gal, Glc, Rha, Ara, Xyl, Man and uronic acid with a weight ratio of 12:25:1:2:2:5:21. Structural analysis with methylation indicated that CSP-50E mainly contained T-Manp, 4-substituted-D-Galp/GalpA, and 4-substituted-D-Glcp. CSP-50E presented random coils conformation in an aqueous solution based on the analysis of HPSEC. In vitro experiments showed that CSP-50E exhibited significant hepatoprotective effects, CSP-50E reduce IL-6, TNF-α content, and AST, ALT activity to protect ethanol-induced damage liver cells (HL-7702), while the polysaccharide functioned mainly through the caspase cascade and mediate the mitochondrial apoptosis pathway. In this study, we describe a novel acidic polysaccharide from corn silk with hepatoprotective activity that facilitates the development and utilization of corn silk resources.


Assuntos
Polissacarídeos , Zea mays , Humanos , Polissacarídeos/farmacologia , Polissacarídeos/química , Etanol , Seda
14.
Food Chem X ; 18: 100653, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-36993870

RESUMO

Citrus reticulatae pericarpium (CRP) is regarded as a valuable functional food in many countries due to its pharmacological activities and unique aroma. In this study, CRP was treated by different A. niger to accelerate aging. Headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) fingerprinting was adopted to rapidly and comprehensively evaluate the flavor compounds of CRP and to identify their dynamic changes at different storage time. Results revealed that the hesperidin content of DOL groups reduced more clearly than other groups during storage. A total of 134 volatile flavor compounds were identified. The volatile organic compounds (VOCs) showed that the lemon, sweet with the musk aroma of CRP, changed to apple, pineapple, and coffee odors during storage. The principal component analysis (PCA) and fingerprint similarity analysis (FSA) results showed that the CRP was clearly distinguished at different storage time. DOL-3 and DOS-6 differ the most from the DOW-3,6, respectively. This work provided helpful information for accelerating the aging of CRP and has great potential for industrial application.

15.
Genes (Basel) ; 14(2)2023 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-36833266

RESUMO

A growing number of studies have shown that members of the ankyrin repeat and suppressors of cytokine signaling (SOCS) box-containing protein (ASB) family are extensively involved in biological processes such as cell growth, tissue development, insulin signaling, ubiquitination, protein degradation, and skeletal muscle membrane protein formation, while the specific biological role of ankyrin-repeat and SOCS box protein 9 (ASB9) remains unclear. In this study, a 21 bp indel in the intron of ASB9 was identified for the first time in 2641 individuals from 11 different breeds and an F2 resource population, and differences were observed among individuals with different genotypes (II, ID, and DD). An association study of a cross-designed F2 resource population revealed that the 21-bp indel was significantly related to growth and carcass traits. The significantly associated growth traits were body weight (BW) at 4, 6, 8, 10, and 12 weeks of age; sternal length (SL) at 4, 8, and 12 weeks of age; body slope length (BSL) at 4, 8, and 12 weeks of age; shank girth (SG) at 4 and 12 weeks of age; tibia length (TL) at 12 weeks of age; and pelvic width (PW) at 4 weeks of age (p < 0.05). This indel was also significantly correlated with carcass traits including semievisceration weight (SEW), evisceration weight (EW), claw weight (CLW), breast muscle weight (BMW), leg weight (LeW), leg muscle weight (LMW), claw rate (CLR), and shedding weight (ShW) (p < 0.05). In commercial broilers, the II genotype was the dominant genotype and underwent extensive selection. Interestingly, the ASB9 gene was expressed at significantly higher levels in the leg muscles of Arbor Acres broilers than those of Lushi chickens, while the opposite was true for the breast muscles. In summary, the 21-bp indel in the ASB9 gene significantly influenced the expression of the ASB9 gene in muscle tissue and was associated with multiple growth and carcass traits in the F2 resource population. These findings suggested that the 21-bp indel within the ASB9 gene could be used in marker-assisted selection breeding for traits related to chicken growth.


Assuntos
Galinhas , Animais , Galinhas/genética , Fenótipo , Genótipo
16.
Foods ; 12(3)2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36766168

RESUMO

Rice bran is a "treasure house of natural nutrition". Even so, utilization of rice bran is often ignored, and this has resulted in the wastage of nutrients. Polysaccharides are one of the active substances in rice bran that have gained widespread attention for their antioxidant, antitumor, immune-enhancing, antibacterial, and hypoglycemic properties. This review summarizes the extraction methods, structural characterization, bioactivity, and application of rice bran polysaccharides that have been developed and studied in recent years, laying a foundation for its development into foods and medicines. In addition, we also discuss the prospects for future research on rice bran polysaccharides.

17.
J Phys Chem A ; 127(1): 286-299, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36580040

RESUMO

Bio-hybrid fuels are a promising solution to accomplish a carbon-neutral and low-emission future for the transportation sector. Two potential candidates are the heterocyclic acetals 1,3-dioxane (C4H8O2) and 1,3-dioxolane (C3H6O2), which can be produced from the combination of biobased feedstocks, carbon dioxide, and renewable electricity. In this work, comprehensive experimental and numerical investigations of 1,3-dioxane and 1,3-dioxolane were performed to support their application in internal combustion engines. Ignition delay times and laminar flame speeds were measured to reveal the combustion chemistry on the macroscale, while speciation measurements in a jet-stirred reactor and ethylene-based counterflow diffusion flames provided insights into combustion chemistry and pollutant formation on the microscale. Comparing the experimental and numerical data using either available or proposed kinetic models revealed that the combustion chemistry and pollutant formation differ substantially between 1,3-dioxane and 1,3-dioxolane, although their molecular structures are similar. For example, 1,3-dioxane showed higher reactivity in the low-temperature regime (500-800 K), while 1,3-dioxolane addition to ethylene increased polycyclic aromatic hydrocarbons and soot formation in high-temperature (>800 K) counterflow diffusion flames. Reaction pathway analyses were performed to examine and explain the differences between these two bio-hybrid fuels, which originate from the chemical bond dissociation energies in their molecular structures.


Assuntos
Dioxolanos , Poluentes Ambientais , Hidrocarbonetos Policíclicos Aromáticos , Dioxolanos/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Dioxanos/análise
18.
Heliyon ; 8(12): e12064, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36544829

RESUMO

Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3. We found that pralatrexate significantly inhibited the growth of BxPC-GEM-20. The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM. Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell. Additionally, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92% in vivo. This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice. Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy. Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate. Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway. Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer. In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future.

19.
Nature ; 611(7937): 733-743, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36289335

RESUMO

Colorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4-7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.


Assuntos
Neoplasias Colorretais , Epigenoma , Genoma Humano , Mutação , Humanos , Adenoma/genética , Adenoma/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Cromatina/genética , Cromatina/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Epigenoma/genética , Oncogenes/genética , Fatores de Transcrição/metabolismo , Genoma Humano/genética , Interferons
20.
Nature ; 611(7937): 744-753, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36289336

RESUMO

Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather 'plastic'. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.


Assuntos
Adaptação Fisiológica , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Fenótipo , Humanos , Adaptação Fisiológica/genética , Células Clonais/metabolismo , Células Clonais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação , Sequenciamento do Exoma , Transcrição Gênica
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