iScience
·
2023
·
IF 5.8
Yao Li,Zi-Yu Liang,Hai-Lin Wang
Summary Red blood cells supply the oxygen required for all human cells and are in demand for emerging blood-loss therapy. Here we identified N6-methyl-2′-deoxyadenosine (6mdA) as an agonist that promotes the hyperproliferation of burst-forming unit erythroid (BFU-E) progenitor cells. In addition, 6mdA represses the apoptosis of erythroid progenitor cells (EPCs). Combined use of with SCF and EPO enabled cultures of isolated BFU-E to be expanded up to 5,000-fold. Transcriptome analysis showed that 6mdA upregulates the expression of the EPC-associated factors c-Kit, Myb, and Gata2 and downregulates that of the erythroid maturation-related transcription factors Gata1, Spi1, and Klf1. Mechanistic studies suggested that 6mdA enhances and prolongs the activation of erythropoiesis-associated master gene c-Kit and its downstream signaling, leading to expansion and accumulation of EPCs. Collectively, we demonstrate that 6mdA can efficiently stimulate the EPC hyperproliferation and provide a new regenerative medicine recipe to improve ex vivo generation of red blood cells.
研究领域:
血液学
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分子生物学
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再生医学
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细胞生物学
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DOI
PubMed
高影响因子
BRAIN
·
2021
·Vol. 144
·期 9
·2759-2770
·
IF 13.501
Zhang Yalun,Zhang Yi,Aman Yahyah,Ng Cheung Toa,Chau Wing-Hin,Zhang Zhigang,Yue Ming,Bohm Christopher,Jia Yizhen,Li Siwen,Yuan Qiuju,Griffin Jennifer,Chiu Kin,Wong Dana S M,Wang Binbin,Jin Dongyan,Rogaeva Ekaterina,Fraser Paul E,Fang Evandro F,St George-Hyslop Peter,Song You-Qiang
The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer’s disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention.
研究领域:
神经科学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
Crop Journal
·
2025
·
IF 5.6
Yunlong Pang,Shanshan Li,Qiang Yan,Pingping Zhang,Yu Lu,Cunyuan Zhao,Tao Li,Hailiang Zhao,Shanyi Sun,Tingting Zhou,Xiaoqian Wang,Huaqiang Zhu,Yong Li,Lingrang Kong,Guihua Bai,Shubing Liu,Yuye Wu
Wheat grains contain various bioactive substances, of which, condensed tannins (CT) are polymeric flavan-3-ols that accumulate in wheat seed coat influencing the end-use quality and nutritional value. However, the genetic architecture underlying CT biosynthesis in wheat grain remains unclear. Here, we studied the deposition and genetic regulation of CT in wheat grains, and found that CT deposited specifically in the testa layer of red-grained wheat as catechin- and epicatechin-formed polymers. Genome-wide association study identified 22 genetic loci affecting CT content, one of which, TaTAN , a single dominant gene controlling CT presence, was mapped to chromosome 3A in a segregation population. Further pan-genome analysis, transcriptome profiling and ethyl methanesulfonate induced mutants sequencing revealed a R2R3-MYB transcription factor, TaMYB10-3A , as the causal gene . Three loss-of-function alleles in TaMYB10-3A caused by large fragment inversion-deletion and insertion were identified which abolish both CT deposition and red pigmentation, demonstrating the pleiotropic effect of TaMYB10-3A on CT presence and grain color. TaMYB10-3A directly trans -activates core flavonoid genes such as chalcone synthase and dihydroflavonol 4-reductase to initiate CT biosynthesis. Our investigation provides a comprehensive understanding of CT presence in wheat grains and lays a solid foundation for manipulating CT metabolites to improve wheat grain end-use quality and nutrition values in wheat.
研究领域:
作物遗传学
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植物生物化学
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分子生物学
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功能基因组学
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代谢调控
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谷物品质改良
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植物次生代谢
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产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Li Yan,Ge Jingping,Yin Yuanyuan,He Juan,Shang Longcheng
Background: This study aimed to explore the regulatory effect of anserine on HUVEC cell injury and thrombosis in deep venous thrombosis (DVT) rats, and to elucidate the underlying molecular mechanisms.Methods: Non-targeted metabolomics data analyses were conducted using an ultra-performance liquid chromatography system Vanquish UHPLC and mass spectrometer to detect plasma metabolism profiles. The transcriptome sequencing and gene intervention experiments were performed to verify the regulatory effect. Further in vivo and in vitro experiments were performed. Enzyme-linked immunosorbent assay was used to detect the levels of P-selectin, E-selectin, and vWF, hematoxylin-eosin (HE) staining was performed to observe thrombotic and inflammatory cell infiltration, flow cytometry and TUNEL assays were performed to detect apoptosis, and qPCR and WB assays were conducted to determine the gene and protein expression.Results: Anserine alleviated HUVECs injury, reduced adhesion molecule expression, and inflammation. It decreased P-selectin, E-selectin, vWF, THBD, TFPI levels, and apoptosis while promoting NOS3, ET-1, and NO release in HUVECs. In DVT rats, anserine reduced P-selectin, E-selectin, vWF, thrombosis, cell infiltration, apoptosis, and promoted NO release. Transcriptome sequencing and gene intervention confirmed anserine’s regulation of the PI3K-Akt pathway and coagulation via MYB. CARNMT1, a regulatory enzyme for anserine metabolism, increased anserine content, inhibiting coagulation, thrombosis, cell infiltration, and promoting NO release in rats.Conclusion: This study confirmed anserine could alleviate DVT by improving the inflammatory response, inhibiting blood agglutination, and promoting vasodilation, providing new potential therapeutic targets, important scientific evidence for the development of DVT management, and new clues for an in-depth understanding of its molecular mechanisms.
研究领域:
药理学
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分子生物学
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心血管疾病
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血栓
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DOI
PubMed
高影响因子
SEED SCIENCE RESEARCH
·
2021
·Vol. 31
·期 2
·136-148
·
IF 2.25
Chengshuai Li,Lijing Zhang,Decao Niu,Shuzhen Nan,Xiumei Miao,Xiaowei Hu,Hua Fu
Flavonoids are a group of phenolic secondary metabolites in plants that have important physiological, ecological and economic value. In this study, using the desert plant Artemisia sphaerocephala Krasch. as the sample material, the content and components of the total flavonoids in its seeds at seven different developmental stages were determined. In addition, the genes involved in flavonoid metabolism were identified by full-length transcriptome sequencing (third-generation sequencing technology based on PacBio RS II). Their expression levels were analysed by RNA-seq short reading sequencing, to reveal the patterns and regulation mechanisms of flavonoid accumulation during seed development. The key results were as follows: the content of total flavonoids in mature seeds was 15.05 mg g−1, including five subclasses: flavonols, chalcones, flavones, flavanones and proanthocyanidins, among which flavonols accounted for 45.78%. The period of rapid accumulation of flavonoids was 40–70 d following anthesis. The high expression of phenylalanine ammonia-lyase (PAL), 4-coumarate-CoA ligase (4CL) and UDP-glucose:flavonoids 3-o-glucosyltransferase (UF3GT) promoted the accumulation of total flavonoids, while the high expression of flavonoids 3′-hydroxylase (F3′H) and flavonols synthase (FLS) made flavanols the main component. Transcription factors such as the MYB-bHLH-WDR (MBW) complex and Selenium-binding protein (SBP) directly regulated the structural genes of flavonoid metabolism, while C2H2-type zinc finger (C2H2), Zinc-finger transcription factor (GATA), Dehydration-responsive element binding (DREB), Global Transcription factor Group E protein (GTE), Trihelix DNA-binding factors (Trihelix) and Phytochrome-interacting factor (PIF) indirectly promoted the synthesis of flavonoids through hormones such as brassinoidsteroids (BRs) and abscisic acid (ABA). These results provided valuable resources for the application of related genes in genetics and breeding.
研究领域:
植物生理学
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分子生物学
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生物化学
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基因组学
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产品关联
DOI
高影响因子
DALTON TRANSACTIONS
·
2025
·
IF 3.3
Yulu Ru,Jiahui Chen,Qinxin Li,Qiyao Chen,Sihui Huang,Jiahuan Zhou,Dandan Wang,Xiaoshun Zhou,Yong Shao
Folding of nucleic acids is strongly dependent on metal ions. For example, G-quadruplex (G4) structures are usually determined by the specific K+/Na+ coordination. However, G4 constructs highly selective to high-valent metal ions (for instance, trivalent metal ions) have not been found due to their strong and nonspecific phosphate backbone interactions. Herein, a higher-order G4 structure having a heptad junction formed by GGA repeats (for example, GGA8 with eight repeats) of the human c-myb promoter region was found to stoichiometrically recruit three Tb3+ ions. The junction binding of Tb3+ did not affect the global G4 structure of GGA8 because of its high stability in K+. The three context A/A contacts with a proper stacking orientation and an appropriate interbase distance were proved to be the specific binding sites of Tb3+ (A/Tb3+/A). Other high-valent metal ions were unable to interfere with this specific Tb3+ binding, suggestive of the potential of GGA8 serving as an aptamer-like DNA for Tb3+. This A/Tb3+/A binding was also found in another KRAS promoter G4 structure with the same A/A contact, indicating the potential of Tb3+ in selectively probing G4 structures. This work will also inspire more interest in searching higher-order G4 structures for selectively coordinating high-valent metal ions with the purpose of their detection, enrichment, and recovery.
研究领域:
生物化学
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分子生物学
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无机化学
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结构生物学
·
核酸研究
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产品关联
DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2022
·
IF 6.449
Shu Diao,Yini Zhang,Qifu Luan,Xianyin Ding,Jiaming Sun,Jingmin Jiang
Oleoresin terpenoids have been widely used in the food , pharmaceutical, and chemical industries. A thorough understanding of oleoresin terpenoid biosynthesis is important for the metabolic engineering of high-valued terpenoid products in plants and microbes and the improvement of oleoresin traits using molecular breeding strategies. TPS-d subfamily members, specific to conifers, determine the oleoresin terpenoid compound diversity. Here, we aimed to identify the TPS-d genes in slash pine ( Pinus elliottii ) and characterize their function and expression patterns in population. Our study reveals two main results: (1) A total of 52 terpene synthase (TPS) candidate genes were identified based on long-read transcripts of slash pine, 12 of which were successfully cloned from the secondary developing xylem RNA. Two levopimaradiene/abietadiene synthases (LAS), one monofunctional isopimaradiene synthase (mISO1)-like, and two α-pinene synthases were identified by comparing with previously known TPS. Next, the two α-pinene synthases and one β-pinene synthase producing multiple products were validated through heterologous expression and in vitro enzyme activity assays, which showed different product profiles from previously identified TPS. (2) The expression status of the cloned TPS genes in 240 slash pine individuals were analyzed. Four exhibited very low expression levels, including those identical to copalyl diphosphate synthases, hemiterpene synthases, diterpene synthases without activity, and one obtained without soluble protein in the heterologous expression. The expression levels of eight TPS genes participating in slash pine oleoresin biosynthesis varied in different individuals and were highly correlated with multiple transcriptional regulators, namely, MYB and MYC. The expression of two α-pinene synthase genes was significantly higher than that of the other TPS genes. Some TPS gene expression levels were positively correlated with the corresponding oleoresin component content. Our results provide an essential reference for exploring the mechanisms of terpene biosynthesis and regulation.
研究领域:
植物生物化学
·
分子生物学
·
遗传学
·
代谢工程
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2020
·
IF 4.192
Da Li,Cun-Yu Li,Ci-Jie Hu,Yu-Si Yang,Chen Lin,Dong Zhao,Qing-Sheng Li,Jian-Hui Ye,Xin-Qiang Zheng,Yue-Rong Liang,Jian-Liang Lu
Amino acids are very important for oolong tea brisk-smooth mouthfeel which is mainly associated with bruising and withering treatment (BWT). In this study, metabolome and transcriptome analyses were performed to comprehensively investigate the changes in abundance of amino acids and the expression pattern of relevant genes during BWT of oolong tea manufacturing. Levels of most amino acids increased during BWT in the leaves harvested from 4 cultivars, while expression of the relevant function genes responsible for synthesis and transformation of amino acids up-regulated accordingly. Upstream hub genes including receptor-like protein kinase IKU2, serine/threonine-protein kinase PBL11, MYB transcription factor MYB2, ethylene-responsive transcription factor ERF114, WRKY transcription factor WRKY71, aspartate aminotransferase AATC, UDP-glycosyltransferase U91D1, and 4-hydroxy-4-methyl-2-oxoglutarate aldolase 2 RRAA2, were predicted to be involved in regulation of the function genes expression and the amino acids metabolism through weighted gene coexpression network analysis. A modulation mechanism for accumulation of amino acids during BWT was also proposed. These findings give a deep insight into the metabolic reprogramming mechanism of amino acids during BWT of oolong tea.
研究领域:
植物学
·
分子生物学
·
茶叶科学
·
植物代谢
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）