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The genome of faba bean was first published in 2023. To promote future molecular breeding studies, we improved the quality of the faba genome based on high-density genetic maps and the Illumina and Pacbio RNA-seq datasets. Two high-density genetic maps were used to conduct the scaffold ordering and orientation of faba bean, culminating in an increased length (i.e., 14.28 Mbp) of chromosomes and a decrease in the number of scaffolds by 45. In gene model mining and optimisation, the PacBio and Illumina RNA-seq datasets from 37 samples allowed for the identification and correction 121,606 transcripts, and the data facilitated a prediction of 15,640 alternative splicing events, 2,148 lncRNAs, and 1,752 fusion transcripts, thus allowing for a clearer understanding of the gene structures underlying the faba genome. Moreover, a total of 38,850 new genes including 56,188 transcripts were identified compared with the reference genome. Finally, the genetic data of the reference genome was integrated and a comprehensive and complete faba bean transcriptome sequence of 103,267 transcripts derived from 54,753 uni-genes was formed.
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Transcriptoma , Vicia faba , Empalme Alternativo , RNA-Seq , Vicia faba/genética , Fitomejoramiento , Mapeo Cromosómico , Genoma de PlantaRESUMEN
Prostate cancer (PCa) is a serious health concern for men due to its high incidence and mortality rate. The first therapy typically adopted is androgen deprivation therapy (ADT). However, patient response to ADT varies, and 20-30% of PCa cases develop into castration-resistant prostate cancer (CRPC). This article investigates the anti-PCa effect of a drug candidate named GL-V9 and highlights the significant mechanism involving the AKT-hexokinase II (HKII) pathway. In both androgen receptor (AR)-expressing 22RV1 cells and AR-negative PC3 cells, GL-V9 suppressed phosphorylated AKT and mitochondrial location of HKII. This led to glycolytic inhibition and mitochondrial pathway-mediated apoptosis. Additionally, GL-V9 inhibited AR activity in 22RV1 cells and disrupted the feedback activation of AKT signaling in condition of AR inhibition. This disruption greatly increased the anti-PCa efficacy of the AR antagonist bicalutamide. In conclusion, we present a novel anti-PCa candidate and combination drug strategies to combat CRPC by intervening in the AR-AKT-HKII signaling network.
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Sesame is an ancient oilseed crop with high oil content and quality. However, the evolutionary history and genetic mechanisms of its valuable agronomic traits remain unclear. Here, we report chromosome-scale genomes of cultivated sesame (Sesamum indicum L.) and six wild Sesamum species, representing all three karyotypes within this genus. Karyotyping and genome-based phylogenic analysis revealed the evolutionary route of Sesamum species from n = 13 to n = 16 and revealed that allotetraploidization occurred in the wild species Sesamum radiatum. Early divergence of the Sesamum genus (48.5-19.7 million years ago) during the Tertiary period and its ancient phylogenic position within eudicots were observed. Pan-genome analysis revealed 9164 core gene families in the 7 Sesamum species. These families are significantly enriched in various metabolic pathways, including fatty acid (FA) metabolism and FA biosynthesis. Structural variations in SiPT1 and SiDT1 within the phosphatidyl ethanolamine-binding protein gene family lead to the genomic evolution of plant-architecture and inflorescence-development phenotypes in Sesamum. A genome-wide association study (GWAS) of an interspecific population and genome comparisons revealed a long terminal repeat insertion and a sequence deletion in DIR genes of wild Sesamum angustifolium and cultivated sesame, respectively; both variations independently cause high susceptibility to Fusarium wilt disease. A GWAS of 560 sesame accessions combined with an overexpression study confirmed that the NAC1 and PPO genes play an important role in upregulating oil content of sesame. Our study provides high-quality genomic resources for cultivated and wild Sesamum species and insights that can improve molecular breeding strategies for sesame and other oilseed crops.
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Sesamum , Sesamum/genética , Sesamum/metabolismo , Estudio de Asociación del Genoma Completo , Fenotipo , Genómica , Evolución MolecularRESUMEN
KEY MESSAGE: A 4.43-Kb structural variation in the sesame genome results in the deletion of the Siofp1 gene and induces the long capsule length trait. Capsule length (CL) has a positive effect on seed weight and yield in various agronomically important species; however, the molecular mechanism underlying long capsule trait regulation in sesame remains unknown. The inheritance analysis showed that long capsule traits (CL > 4.0 cm) were dominant over normal length (average CL = 3.0 cm) and were controlled by a single gene pair. Association mapping with a RIL population and 259 natural sesame germplasm accessions indicated that the target interval was 52,830-730,961 bp of SiChr.10 in sesame. Meanwhile, the structural variation (SV) of the association mapping revealed that only SV_414325 on chromosome 10 was significantly associated with the CL trait, with a P value of 1.1135E-19. SV_414325 represents a 4430-bp deletion from 414,325 to 418,756 bp on SiChr.10, covering Sindi_2155000 (named SiOFP1). In the normal length type, Siofp1 encodes 411 amino acids of the ovate family proteins and is highly expressed in the leaf, stem, bud, and capsule tissues of sesame. In accordance with the transcriptional repressor character, Siofp1 overexpression in transgenic Arabidopsis (T0 and T1 generations) induced a 25-39% greater shortening of silique length than the wild type (P < 0.05), as well as round cauline leaves and short carpels. These results confirm that SiOFP1 plays a key role in regulating CL trait in sesame and other flowering plants. These findings provide a theoretical and material basis for sesame capsule development and high-yield breeding research.
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Sesamum , Sesamum/genética , Mapeo Cromosómico/métodos , Fitomejoramiento , Fenotipo , Patrón de HerenciaRESUMEN
Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.
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Dinámicas Mitocondriales , Neoplasias , Humanos , Transportador de Glucosa de Tipo 1 , Sirtuina 1/genética , Mitocondrias , Glucosa , Proteínas Mitocondriales , MetaloproteasasRESUMEN
Drug resistance represents one of the greatest challenges in cancer treatment. Cancer stem cells (CSCs) are thought to be the major cause of failure in cancer therapy due to their considerable resistance to most chemotherapeutic agents, resulting in tumor recurrence and eventually metastasis. Here, we report a treatment strategy for osteosarcoma using hydrogel-microspheres (Gel-Mps) complex mainly composed of collagenase (Col) and PLGA microspheres (Mps) carrying Pioglitazone (Pio) and Doxorubicin (Dox). Col was encapsulated in the thermosensitive gel to preferentially degrade tumor extracellular matrix (ECM), ensuring subsequent drug penetration, while Mps with Pio and Dox were co-delivered to synergistically inhibit tumor growth and metastasis. Our results showed that the Gel-Mps dyad functions as a highly biodegradable, extremely efficient, and low-toxic reservoir for sustained drug release, displaying potent inhibition of tumor proliferation and subsequent lung metastasis. Selective PPARγ agonist Pio reversed drug resistance to Dox by significantly down-regulating the expression of stemness markers and P-glycoprotein (P-gp) in osteosarcoma cells. The Gel@Col-Mps@Dox/Pio exhibited advanced therapeutic efficacy in vivo, demonstrating its great potential to serve a novel osteosarcoma therapy, which not only inhibits the growth of, but also attenuates the stemness of osteosarcoma. The dual effects reinforce the sensitivity and efficacy of chemotherapy.
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Neoplasias Óseas , Osteosarcoma , Humanos , Pioglitazona/farmacología , Pioglitazona/uso terapéutico , Hidrogeles/uso terapéutico , Microesferas , Recurrencia Local de Neoplasia/tratamiento farmacológico , Doxorrubicina , Osteosarcoma/patología , Neoplasias Óseas/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Hepatocellular carcinoma (HCC) is a malignant tumor, frequently causing both intrahepatic and extrahepatic metastases. The overall prognosis of patients with metastatic HCC is poor. Recently, single-cell (sc) polarity is proved to be an innate feature of some tumor cells in liquid phase, and directly involved in the cell adhesion to blood vessel and tumor metastasis. Here, we characterize the maintained sc polarity of HCC cells in a suspension culture, and investigate its roles and regulatory mechanisms during metastasis. We demonstrate that transient receptor potential vanilloid 4 (TRPV4) is a promoting regulator of sc polarity via activating Ca2+-dependent AMPK/MLC/ERM pathway. This attenuates the adhesion of metastatic HCC cells to vascular endothelial cells. The reduction of cancer metastases can result from TRPV4 inhibition, which not only impacts the migration and invasion of tumor cells, but also prevents the adhesion to vascular endothelial cells. Additionally, we discover a brand-new TRPV4 inhibitor called GL-V9 that modifies the degree of sc polarization and significantly decreases the metastatic capacity of HCC cells. Taken together, our data shows that TRPV4 and calcium signal are significant sc polarity regulators in metastatic HCC, and that the pharmacological intervention that results in HCC cells becoming depolarized suggests a promising treatment for cancer metastasis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Canales Catiónicos TRPV/genética , Polaridad Celular , Células Endoteliales/metabolismo , Línea Celular Tumoral , Movimiento Celular , Metástasis de la Neoplasia/patologíaRESUMEN
Faba bean (Vicia faba L.) is a valuable legume crop and data on its seed-related traits is required for yield and quality improvements. However, basic research on faba bean is lagging compared to that of other major crops. In this study, an F2 faba bean population, including 121 plants derived from the cross WY7×TCX7, was genotyped using the Faba_bean_130 K targeted next-generation sequencing genotyping platform. The data were used to construct the first ultra-dense faba bean genetic map consisting of 12,023 single nucleotide polymorphisms markers covering 1,182.65 cM with an average distance of 0.098 cM. The map consisted of 6 linkage groups, which is consistent with the 6 faba bean chromosome pairs. A total of 65 quantitative trait loci (QTL) for seed-related traits were identified (3 for 100-seed weight, 28 for seed shape, 12 for seed coat color, and 22 for nutritional quality). Furthermore, 333 candidate genes that are likely to participate in the regulation of seed-related traits were also identified. Our research findings can provide a basis for future faba bean marker-assisted breeding and be helpful to further modify and improve the reference genome.
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HCC remains one of the most prevalent and deadliest cancers. Serum AFP level is a biomarker for clinical diagnosis of HCC, instead the contribution of AFP to HCC development is clearly highly complex. Here, we discussed the effect of AFP deletion in the tumorigenesis and progression of HCC. AFP deletion in HepG2 cells inhibited the cell proliferation by inactivating PI3K/AKT signaling. Surprisingly, AFP KO HepG2 cells appeared the increasing metastatic capacity and EMT phenotype, which was attributed to the activation of WNT5A/ß-catenin signal. Further studies revealed that the activating mutations of CTNNB1 was closely related with the unconventional pro-metastatic roles of AFP deletion. Consistently, the results of DEN/CCl4-induced HCC mouse model also suggested that AFP knockout suppressed the growth of HCC primary tumors, but promoted lung metastasis. Despite the discordant effect of AFP deletion in HCC progression, a drug candidate named OA showed the potent suppression of HCC tumor growth by interrupting AFP-PTEN interaction and, importantly, reduced the lung metastasis of HCC via angiogenesis suppression. Thus, this study demonstrates an unconventional effect of AFP in HCC progression, and suggests a potent candidate strategy for HCC therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Animales , Ratones , alfa-Fetoproteínas/genética , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Neoplasias Hepáticas/patología , Mutación , Fosfatidilinositol 3-Quinasas/genética , HumanosRESUMEN
The protein conformation of soymilk is the key to affecting the instant solubility of soymilk flour. This study aimed to evaluate the effect of cavitation jet treatment time (0, 2, 4, 6, and 8 min) on the instant solubility of soymilk flour based on the conformational changes of protein in soymilk. The results showed that the cavitation jet treatment for 0-4 min significantly unfolded the protein structure of soymilk and increased the content of soluble protein, which reduced the particle size and increased the electrostaticrepulsion and the viscosity of soymilk. This was beneficial for soymilk droplets fully atomized and repolymerized in the spray drying tower, forming soymilk flour particles with large size, smooth surface, and uniform distribution. When the cavitation jet treatment time was 4 min, the wettability (from 127.3 ± 2.5 s to 84.7 ± 2.1 s), dispersibility (from 70.0 ± 2.0 s to 55.7 ± 2.1 s), and solubility (from 56.54% to 78.10%) of soymilk flour were significantly improved. However, when the time of the cavitation jet treatment was extended to 8 min, the protein of soymilk aggregated and the stability of soymilk decreased, which reduced the particle size and hurt the surfacecharacteristics of soymilk flour after spraydrying. It resulted in a decrease in the instant solubility of soymilk flour. Therefore, the cavitationjet treatment with proper time increases the instant solubility of soymilk flour by improving the protein conformation of soymilk.
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Harina , Leche de Soja , Solubilidad , Fenómenos Químicos , Leche de Soja/química , Conformación ProteicaRESUMEN
Mitophagy is a type of selective macroautophagy/autophagy that degrades dysfunctional or excessive mitochondria. Regulation of this process is critical for maintaining cellular homeostasis and has been closely implicated in acquired drug resistance. However, the regulatory mechanisms and influences of mitophagy in cancer are still unclear. Here, we reported that inhibition of CDK9 blocked PINK1-PRKN-mediated mitophagy in HCC (hepatocellular carcinoma) by interrupting mitophagy initiation. We demonstrated that CDK9 inhibitors promoted dephosphorylation of SIRT1 and promoted FOXO3 protein degradation, which was regulated by its acetylation, leading to the transcriptional repression of FOXO3-driven BNIP3 and impairing the BNIP3-mediated stability of the PINK1 protein. Lysosomal degradation inhibitors could not rescue mitophagy flux blocked by CDK9 inhibitors. Thus, CDK9 inhibitors inactivated the SIRT1-FOXO3-BNIP3 axis and PINK1-PRKN pathway to subsequently block mitophagy initiation. Moreover, CDK9 inhibitors facilitated mitochondrial dysfunction. The dual effects of CDK9 inhibitors resulted in the destruction of mitochondrial homeostasis and cell death in HCC. Importantly, a novel CDK9 inhibitor, oroxylin A (OA), from Scutellaria baicalensis was investigated, and it showed strong therapeutic potential against HCC and a striking capacity to overcome drug resistance by downregulating PINK1-PRKN-mediated mitophagy. Additionally, because of the moderate and controlled inhibition of CDK9, OA not led to extreme repression of general transcription and appeared to overcome the inconsistent anti-HCC efficacy and high normal tissue toxicity that was associated with existing CDK9 inhibitors. All of the findings reveal that mitophagy disruption is a promising strategy for HCC treatment and OA is a potential candidate for the development of mitophagy inhibitors.Abbreviations: BNIP3: BCL2 interacting protein 3; CCCP: carbonyl cyanide p-trichloromethoxy-phenylhydrazone; CDK9: cyclin dependent kinase 9; CHX: cycloheximide; CQ, chloroquine; DFP: deferiprone; DOX: doxorubicin; EBSS: Earle's balanced salt solution; E64d: aloxistatin; FOXO3: forkhead box O3; HCC: hepatocellular carcinoma; HepG2/ADR: adriamycin-resistant HepG2 cells; MMP: mitochondrial membrane potential; mito-Keima: mitochondria-targeted and pH-sensitive fluorescent protein; MitoSOX: mitochondrial reactive oxygen species; OA: oroxylin A; PB: phosphate buffer; PDX: patient-derived tumor xenograft; PINK1: PTEN induced kinase 1; POLR2A: RNA polymerase II subunit A; p-POLR2A-S2: Ser2 phosphorylation of RNA polymerase II subunit A; PRKN: parkin RBR E3 ubiquitin protein ligase; SIRT1: sirtuin 1.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Autofagia , Carcinoma Hepatocelular/patología , Quinasa 9 Dependiente de la Ciclina/metabolismo , Proteína Forkhead Box O3 , Humanos , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Mitofagia/genética , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , ARN Polimerasa II/metabolismo , ARN Polimerasa II/farmacología , Sirtuina 1/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is one of the most lethal tumours worldwide. However, the effects of first-line sorafenib treatment in advanced HCC fail to prolong patients' survival due to the highly heterogeneous characteristics of HCC etiology. Cyclin-dependent kinase 9 (CDK9) is an important target in the continuous development of cancer therapy. Here, we demonstrate that CDK9 is closely associated with the progression of HCC and can serve as an HCC therapeutic target by modulating the recovery of wild-type p53 (wt-p53) function. We prove that mouse double minute 2 homologue (MDM2) and Sirtuin 1 (SIRT1) are phosphorylated by CDK9 at Ser166 and Ser47, respectively. Inhibition of CDK9 not only reduces the MDM2-mediated ubiquitination and degradation of wt-p53 but also increases wt-p53 stability by suppressing deacetylase activity of SIRT1. Thus, inhibition of CDK9 promotes the wt-p53 stabilization and prevents HCC progression. However, excessive inhibition by high concentrations of specific CDK9 inhibitors counteracts the promotion of p53 stability and reduces their anti-HCC activity because of extreme general transcription repression. The effects of a novel CDK9 inhibitor named oroxylin A (OA) from Scutellaria baicalensis are explored, with the results indicating that OA shows moderate and controlled inhibition of CDK9 activity and expression, and stabilizes wt-p53 by inhibiting CDK9-regulated MDM2 and SIRT1 signaling. These outcomes indicate the high therapeutic potential of OA against HCC and its low toxicity in normal tissue. This study demonstrates a novel mechanism for the regulation of wt-p53 by CDK9 and indicates that OA is a potential candidate for HCC therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Apoptosis , Carcinoma Hepatocelular/patología , Quinasa 9 Dependiente de la Ciclina/metabolismo , Flavonoides , Humanos , Neoplasias Hepáticas/patología , Ratones , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Background: Neuronal death is a major hallmark of Alzheimer's disease (AD). Necroptosis, as a programmed necrotic process, is activated in AD. However, what signals and factors initiate necroptosis in AD is largely unknown. Methods: We examined the expression levels of critical molecules in necroptotic signaling pathway by immunohistochemistry (IHC) staining and immunoblotting using brain tissues from AD patients and AD mouse models of APP/PS1 and 5×FAD. We performed brain stereotaxic injection with recombinant TNF-α, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 mice. For in vitro studies, we used TNF-α combined with zVAD-fmk and Smac mimetic to establish neuronal necroptosis models and utilized pharmacological or molecular biological approaches to study the signaling pathways. Results: We find that activated neuronal necroptosis is dependent on upstream TNF-α/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-α stimulation, accumulated p62 recruits RIPK1 and induces its self-oligomerization, and activates downstream RIPK1/RIPK3/MLKL cascade, leading to neuronal necroptosis. Ectopic accumulation of p62 is caused by impaired autophagy flux, which is mediated by UVRAG downregulation during the TNF-α-promoted necroptosis. Notably, UVRAG overexpression inhibits neuronal necroptosis in cell and mouse models of AD. Conclusions: We identify a finely controlled regulation of neuronal necroptosis in AD by coordinated TNF-α signaling, RIPK1/3 activity and autophagy machinery. Strategies that could fine-tune necroptosis and autophagy may bring in promising therapeutics for AD.
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Enfermedad de Alzheimer/fisiopatología , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Supresoras de Tumor/fisiología , Enfermedad de Alzheimer/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagia/efectos de los fármacos , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Ratones , Necroptosis/fisiología , Necrosis/metabolismo , Neuronas/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Transducción de Señal/efectos de los fármacos , Transcriptoma/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, and its mortality rate is the third-highest, after lung cancer and colorectal cancer. Currently, systematic targeted therapies for HCC mainly include multiple kinase inhibitors and immunotherapy. However, these drugs carry a black-box warning about the potential for inducing severe toxicity, and they do not significantly prolong the survival period of patients due to the highly heterogeneous characteristics of HCC etiology. In order to improve the prediction, effective treatment and prognosis of HCC, the tools and different biomarkers in clinical practices are recommended. Alpha-fetoprotein (AFP) is the earliest and the most widely used serum marker in the detection of HCC. Interestingly, serum AFP and cytoplasmic AFP show different, even opposite, roles in the cancer progression of HCC. This review focuses on biological characteristics, regulatory mechanisms for gene expression, emerging influences of AFP in HCC and its possible implications in HCC-targeted therapy.
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Solid tumors often exhibit hypoxia in their centers, which has been associated with a marked reduction in the sensitivity of the tumor cells to anti-tumor and chemotherapeutic interventions. Here, we found that the occurrence and progress of hypoxic insensitivity to paclitaxel in non-small cell lung cancer (NSCLC) are closely associated with the HIF-1α pathway. The HIF-1α protein upregulated the expression of adipose differentiation-related protein (ADRP), fatty acid synthase (FASN), and sterol regulatory element binding protein 1(SREBP1), while simultaneously downregulating carnitine palmitoyltransferase 1 (CPT1), thereby leading to a more pronounced uptake of lipids and reduced oxidation of fatty acids. Diminished levels of fatty acids led to reduced Wnt pathway activation and ß-catenin nuclear translocation, leading to G2/M cell cycle arrest. In this study, FV-429, a derivative of the natural flavonoid wogonin, reprogrammed metabolism of cancer cells and decreased fatty acid levels. Moreover, paclitaxel-induced G2/M phase arrest in hypoxia-resistant NSCLC was hampered but FV-429 improved the sensitivity of these cancer cells to paclitaxel. FV-429 activated and modulated fatty acid metabolism in NSCLC cells, significantly reduced levels of fatty acids within cells and increased the oxidation of these fatty acids. The results of our study demonstrated that FV-429 could reshape fatty acid metabolism in hypoxia-induced paclitaxel-resistant NSCLC and enhance the sensitivity of NSCLC cells to paclitaxel through G2/M phase arrest deterioration, by inactivating the Wnt pathway, and suggested the possibility of using FV-429 as a promising candidate therapeutic agent for advanced NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Flavonoides/administración & dosificación , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Paclitaxel/administración & dosificación , Células A549 , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Línea Celular Tumoral , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Ácidos Grasos/metabolismo , Flavonoides/toxicidad , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Paclitaxel/toxicidad , Hipoxia Tumoral/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismoRESUMEN
Seed coat color is an important seed quality trait in sesame. However, the genetic mechanism of seed coat color variation remains elusive in sesame. We conducted a QTL mapping of the seed coat color trait in sesame using an F2 mapping population. With the aid of the newly constructed superdense genetic linkage map comprised of 22,375 bins distributed in 13 linkage groups (LGs), 17 QTLs of the three indices (i.e., L, a, and b values) of seed coat color were detected in seven intervals on four LGs, with a phenotype variance explanation rate of 4.46-41.53%. A new QTL qSCa6.1 on LG 6 and a QTL hotspot containing at least four QTLs on LG 9 were further identified. Variants screening of the target intervals showed that there were 84 genes which possessed the variants that were high-impact and co-segregating with the seed coat color trait. Meanwhile, we performed the transcriptome comparison of the developing seeds of a white- and a black-seeded variety, and found that the differentially expressed genes were significantly enriched in 37 pathways, including three pigment biosynthesis related pathways. Integration of variants screening and transcriptome comparison results suggested that 28 candidate genes probably participated in the regulation of the seed coat color in sesame; of which, 10 genes had been proved or suggested to be involved in pigments biosynthesis or accumulation during seed formation. The findings gave the basis for the mechanism of seed coat color regulation in sesame, and exhibited the effects of the integrated approach of genome resequencing and transcriptome analysis on the genetics analysis of the complex traits.
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Cancer cells prefers to rely on aerobic glycolysis than pyruvate oxidation to meet the high demand of energy for rapidly proliferation. Peroxisome proliferator-activated receptors (PPARs) are a kind of important ligand-inducible transcription factors and play crucial roles in glucose and lipid metabolism. Careful designing of novel agonists for PPARs, may show improvement with the side effects and also increase the therapeutic value for cancer and other metabolic disorder diseases. Compared with normal human liver cells, lower expression or acitivity of PPARs is observed in hepatocellular carcinoma (HCC). In this study, we show that oroxyloside (OAG) is a new dual agonist of PPARγ/É, and inhibits cell proliferation of HCC based on metabolic switch. Via both PPAR-dependent and PPAR-independent regulations on glycolipid metabolic enzymes, OAG shuts down the catabolism of glucose and promotes fatty acids oxidation to generate acetyl-CoA for TCA cycle and oxidative phosphorylation. The metabolic switch induced by OAG results in a marked increase of reactive oxygen species (ROS) levels, leading to rapid dephosphorylation of RB and cell-cycle arrest in G1 phase. Pyruvate dehydrogenase kinase 4 (PDK4) and ß-Oxidation are required for the suppression of cell cycle progression by OAG. Together, our findings provide a new drug candidate and a viable therapeutic strategy for HCC based on metabolic reprogram.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Puntos de Control del Ciclo Celular , Flavonas , Glucurónidos , Glucolípidos , Humanos , Metabolismo de los Lípidos , Neoplasias Hepáticas/tratamiento farmacológico , PPAR gamma/metabolismo , Especies Reactivas de OxígenoRESUMEN
Cutaneous squamous-cell carcinoma (cSCC) is one of most common type of non-black skin cancer. The malignancy degree and the death risk of cSCC patients are significantly higher than basal cell carcinoma patients. GL-V9 is a synthesized flavonoid derived from natural active ingredient wogonin and shows potent growth inhibitory effects in liver and breast cancer cells. In this study, we investigated the anti-cSCC effect and the underlying mechanism of GL-V9. The results showed that GL-V9 induced both apoptosis and autophagy in human cSCC cell line A431 cells, and prevented the growth progression of chemical induced primary skin cancer in mice. Metabolomics assay showed that GL-V9 potentially affected mitochondrial function, inhibiting glucose metabolism and Warburg effect. Further mechanism studies demonstrated that AKT played important roles in the anti-cSCC effect of GL-V9. On one hand, GL-V9 suppressed AKT-modulated mitochondrial localization of HK2 and promoted the protein degradation of HK2, resulting in cell apoptosis and glycolytic inhibition. On the other hand, GL-V9 induced autophagy via inhibiting Akt/mTOR pathway. Interestingly, though the autophagy induced by GL-V9 potentially antagonized its effect of apoptosis induction, the anti-cSCC effect of GL-V9 was not diluted. All above, our studies suggest that GL-V9 is a potent candidate for cSCC treatment.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Carcinoma de Células Escamosas , Flavonoides/farmacología , Neoplasias Cutáneas , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Femenino , Flavonoides/química , Humanos , Ratones , Ratones Desnudos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Here, we characterized a flap endonuclease 1 (FEN1) plus hairpin DNA probe (hpDNA) system, designated the HpSGN system, for both DNA and RNA editing without sequence limitation. The compact size of the HpSGN system make it an ideal candidate for in vivo delivery applications. In vitro biochemical studies showed that the HpSGN system required less nuclease to cleave ssDNA substrates than the SGN system we reported previously by a factor of â¼40. Also, we proved that the HpSGN system can efficiently cleave different RNA targets in vitro. The HpSGN system cleaved genomic DNA at an efficiency of â¼40% and â¼20% in bacterial and human cells, respectively, and knocked down specific mRNAs in human cells at a level of â¼25%. Furthermore, the HpSGN system was sensitive to the single base mismatch at the position next to the hairpin both in vitro and in vivo. Collectively, this study demonstrated the potential of developing the HpSGN system as a small, effective, and specific editing tool for manipulating both DNA and RNA without sequence limitation.
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Archaeoglobus fulgidus/enzimología , Endonucleasas de ADN Solapado/metabolismo , Edición Génica/métodos , Secuencias Invertidas Repetidas , Edición de ARN , Archaeoglobus fulgidus/genética , Disparidad de Par Base , ADN/química , Sondas de ADN/química , Sondas de ADN/genética , ADN de Cadena Simple , Escherichia coli/genética , Endonucleasas de ADN Solapado/química , Endonucleasas de ADN Solapado/genética , Endonucleasas de ADN Solapado/aislamiento & purificación , Células HEK293 , Humanos , Técnicas In Vitro , Conformación de Ácido Nucleico , ARN/química , Especificidad por SustratoRESUMEN
Prostate cancer (PCa) depends on androgen receptor (AR) signaling to regulate cell metabolism, including glycolysis, and thereby promotes tumor growth. Glycolysis is overactive in PCa and associated with poor prognosis, but the therapeutic efficacy of glycolysis inhibitors has thus far been limited by their inability to induce cell death. FV-429, a flavonoid derivative of Wogonin, is a glycolysis inhibitor that has shown anti-cancer promise. In this study, we used FV-429 as an anti-PCa agent and investigated its mechanisms of action. In vitro, both the glycolytic ability and the viability of PCa cells were inhibited by FV-429. We found that FV-429 could induce mitochondrial dysfunction and apoptosis, with AKT-HK2 signaling pathway playing a key role. In addition, FV-429 had a pro-apoptotic effect on human prostate cancer cells that relied on the inhibition of AR expression and activity. In vivo, FV-429 exerted significant tumor-repressing activity with high safety in the xenograft model using LNCaP cells. In summary, we demonstrated that FV-429 induced glycolysis inhibition and apoptosis in human prostate cancer cells by downregulating the AR-AKT-HK2 signaling network, making FV-429 a promising candidate as one therapeutic agent for advanced PCa.