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1.
Int J Mol Sci ; 25(13)2024 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-39000319

RESUMEN

Liver regeneration induced by partial hepatectomy (PHx) has attracted intensive research interests due to the great significance for liver resection and transplantation. The zebrafish (Danio rerio) is an excellent model to study liver regeneration. In the fish subjected to PHx (the tip of the ventral lobe was resected), the lost liver mass could be fully regenerated in seven days. However, the regulatory mechanisms underlying the liver regeneration remain largely unknown. In this study, gene expression profiles during the regeneration of PHx-treated liver were explored by RNA sequencing (RNA-seq). The genes responsive to the injury of PHx treatment were identified and classified into different clusters based on the expression profiles. Representative gene ontology (GO) enrichments for the early responsive genes included hormone activity, ribosome biogenesis and rRNA processing, etc., while the late responsive genes were enriched in biological processes such as glutathione metabolic process, antioxidant activity and cellular detoxification. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments were also identified for the differentially expressed genes (DEGs) between the time-series samples and the sham controls. The proteasome was overrepresented by the up-regulated genes at all of the sampling time points. Inhibiting proteasome activity by the application of MG132 to the fish enhanced the expression of Pcna (proliferating cell nuclear antigen), an indicator of hepatocyte proliferation after PHx. Our data provide novel insights into the molecular mechanisms underlying the regeneration of PHx-treated liver.


Asunto(s)
Hepatectomía , Regeneración Hepática , Transducción de Señal , Transcriptoma , Pez Cebra , Animales , Pez Cebra/genética , Regeneración Hepática/genética , Hígado/metabolismo , Perfilación de la Expresión Génica , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Ontología de Genes
2.
J Mol Cell Biol ; 15(7)2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37451810

RESUMEN

During ribosome biogenesis, the small subunit (SSU) processome is responsible for 40S assembly. The BMS1/RCL1 complex is a core component of the SSU processome that plays an important role in 18S rRNA processing and maturation. Genetic studies using zebrafish mutants indicate that both Bms1-like (Bms1l) and Rcl1 are essential for digestive organ development. In spite of vital functions of this complex, the mutual dependence of these two nucleolar proteins for the stability and function remains elusive. In this study, we identified an RCL1-interacting domain in BMS1, which is conserved in zebrafish and humans. Moreover, both the protein stability and nucleolar entry of RCL1 depend on its interaction with BMS1, otherwise RCL1 degraded through the ubiquitination-proteasome pathway. Functional studies revealed that overexpression of RCL1 in BMS1-knockdown cells can partially rescue the defects in 18S rRNA processing and cell proliferation, and hepatocyte-specific overexpression of Rcl1 can resume zebrafish liver development in the bms1l substitution mutant bms1lsq163/sq163but not in the knockout mutant bms1lzju1/zju1, which is attributed to the nucleolar entry of Rcl1 in the former mutant. Our data demonstrate that BMS1 and RCL1 interaction is essential for not only pre-rRNA processing but also the communication between ribosome biogenesis and cell cycle regulation.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Pez Cebra , Animales , Humanos , ARN Ribosómico 18S/genética , ARN Ribosómico 18S/metabolismo , Pez Cebra/genética , Proteínas Nucleares/metabolismo , Procesamiento Postranscripcional del ARN , Precursores del ARN/genética , Precursores del ARN/metabolismo , Proteínas de Saccharomyces cerevisiae/genética
3.
Sci China Life Sci ; 67(3): 488-503, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37955780

RESUMEN

Ferroptosis, a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation, has a potential physiological function in tumor suppression, but its underlying mechanisms have not been fully elucidated. Here, we report that the long non-coding RNA (lncRNA) LncFASA increases the susceptibility of triple-negative breast cancer (TNBC) to ferroptosis. As a tumor suppressor, LncFASA drives the formation of droplets containing peroxiredoxin1 (PRDX1), a member of the peroxidase family, resulting in the accumulation of lipid peroxidation via the SLC7A11-GPX4 axis. Mechanistically, LncFASA directly binds to the Ahpc-TSA domain of PRDX1, inhibiting its peroxidase activity by driving liquid-liquid phase separation, which disrupts intracellular ROS homeostasis. Notably, high LncFASA expression indicates favorable overall survival in individuals with breast cancer, and LncFASA impairs the growth of breast xenograft tumors by modulating ferroptosis. Together, our findings illustrate the crucial role of this lncRNA in ferroptosis-mediated cancer development and provide new insights into therapeutic strategies for breast cancer.


Asunto(s)
Ferroptosis , Neoplasias Mamarias Animales , ARN Largo no Codificante , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ferroptosis/genética , Separación de Fases , ARN Largo no Codificante/genética , Peroxidasas , Peroxirredoxinas/genética
4.
Circulation ; 149(8): 605-626, 2024 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-38018454

RESUMEN

BACKGROUND: A better understanding of the molecular mechanism of aortic valve development and bicuspid aortic valve (BAV) formation would significantly improve and optimize the therapeutic strategy for BAV treatment. Over the past decade, the genes involved in aortic valve development and BAV formation have been increasingly recognized. On the other hand, ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family members have been reported to be able to modulate cardiovascular development and diseases. The present study aimed to further investigate the roles of ADAMTS family members in aortic valve development and BAV formation. METHODS: Morpholino-based ADAMTS family gene-targeted screening for zebrafish heart outflow tract phenotypes combined with DNA sequencing in a 304 cohort BAV patient registry study was initially carried out to identify potentially related genes. Both ADAMTS gene-specific fluorescence in situ hybridization assay and genetic tracing experiments were performed to evaluate the expression pattern in the aortic valve. Accordingly, related genetic mouse models (both knockout and knockin) were generated using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) method to further study the roles of ADAMTS family genes. The lineage-tracing technique was used again to evaluate how the cellular activity of specific progenitor cells was regulated by ADAMTS genes. Bulk RNA sequencing was used to investigate the signaling pathways involved. Inducible pluripotent stem cells derived from both BAV patients and genetic mouse tissue were used to study the molecular mechanism of ADAMTS. Immunohistochemistry was performed to examine the phenotype of cardiac valve anomalies, especially in the extracellular matrix components. RESULTS: ADAMTS genes targeting and phenotype screening in zebrafish and targeted DNA sequencing on a cohort of patients with BAV identified ADAMTS16 (a disintegrin and metalloproteinase with thrombospondin motifs 16) as a BAV-causing gene and found the ADAMTS16 p. H357Q variant in an inherited BAV family. Both in situ hybridization and genetic tracing studies described a unique spatiotemporal pattern of ADAMTS16 expression during aortic valve development. Adamts16+/- and Adamts16+/H355Q mouse models both exhibited a right coronary cusp-noncoronary cusp fusion-type BAV phenotype, with progressive aortic valve thickening associated with raphe formation (fusion of the commissure). Further, ADAMTS16 deficiency in Tie2 lineage cells recapitulated the BAV phenotype. This was confirmed in lineage-tracing mouse models in which Adamts16 deficiency affected endothelial and second heart field cells, not the neural crest cells. Accordingly, the changes were mainly detected in the noncoronary and right coronary leaflets. Bulk RNA sequencing using inducible pluripotent stem cells-derived endothelial cells and genetic mouse embryonic heart tissue unveiled enhanced FAK (focal adhesion kinase) signaling, which was accompanied by elevated fibronectin levels. Both in vitro inducible pluripotent stem cells-derived endothelial cells culture and ex vivo embryonic outflow tract explant studies validated the altered FAK signaling. CONCLUSIONS: Our present study identified a novel BAV-causing ADAMTS16 p. H357Q variant. ADAMTS16 deficiency led to BAV formation.


Asunto(s)
Enfermedad de la Válvula Aórtica Bicúspide , Cardiopatías Congénitas , Enfermedades de las Válvulas Cardíacas , Humanos , Animales , Ratones , Pez Cebra/genética , Enfermedades de las Válvulas Cardíacas/metabolismo , Células Endoteliales/metabolismo , Desintegrinas/genética , Desintegrinas/metabolismo , Hibridación Fluorescente in Situ , Válvula Aórtica/metabolismo , Cardiopatías Congénitas/complicaciones , Matriz Extracelular/metabolismo , Trombospondinas/metabolismo , Metaloproteasas/metabolismo , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo
5.
Small ; : e2308383, 2023 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-38073323

RESUMEN

Acidic residues (Asp and Glu) have a high prevalence on protein surfaces, but cross-linking reactions targeting these residues are limited. Existing methods either require high-concentration coupling reagents or have low structural compatibility. Here a previously reported "plant-and-cast" strategy is extended to develop heterobifunctional cross-linkers. These cross-linkers first react rapidly with Lys sidechains and then react with Asp and Glu sidechains, in a proximity-enhanced fashion. The cross-linking reaction proceeds at neutral pH and room temperature without coupling reagents. The efficiency and robustness of cross-linking using model proteins, ranging from small monomeric proteins to large protein complexes are demonstrated. Importantly, it is shown that this type of cross-linkers are efficient at identifying protein-protein interactions involving acidic domains. The Cross-linking mass spectrometry (XL-MS) study with p53 identified 87 putative binders of the C-terminal domain of p53. Among them, SARNP, ZRAB2, and WBP11 are shown to regulate the expression and alternative splicing of p53 target genes. Thus, these carboxylate-reactive cross-linkers will further expand the power of XL-MS in the analysis of protein structures and protein-protein interactions.

6.
Front Bioeng Biotechnol ; 11: 1294074, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37929188

RESUMEN

Introduction: Photothermal therapy (PTT) holds significant potential for the treatment of malignant tumors. However, conventional single PTT often struggles to effectively inhibit tumor metastasis and recurrence. In this study, we constructed a MOF nanoparticle with a synergistic therapeutic effect combining photothermal and immunotherapy, enabling selective blocking of the PD-1/PD-L1 pathway within the tumor microenvironment. Methods: Firstly, MOF nanoparticles were synthesized using NH2-TPDC as ligands and Zr+4 as metal ions. Subsequently, NH2 was modified to N3 via azide transfer reagents. Through a copper free catalytic click chemical reaction, the PD-1/PD-L1 blocking agent AUNP-12 functionalized with disulfide bonds of DBCO was covalently introduced into MOF nanoparticles which were then loaded with the photothermal agent indocyanine green (ICG) to successfully obtain uniformly sized and stable ICG-MOF-SS-AUNP12 nanoparticles. Results and discussion: ICG-MOF-SS-AUNP12 exhibited GSH-triggered release of PD-1/PD-L1 blockers while demonstrating potent photothermal effects capable of efficiently killing tumor cells. Under 808 nm near-infrared (NIR) irradiation, ICG-MOF-SS-AUNP12 effectively promoted the maturation of DC cells and activated immune responses. This study presents a novel method for constructing MOF-based nanodrugs and offers new possibilities for the synergistic treatment of tumors involving photothermal combined with immunotherapy.

7.
Biochem Biophys Res Commun ; 686: 149182, 2023 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-37922575

RESUMEN

The specification of endoderm cells to prospective hepatoblasts is the starting point for hepatogenesis. However, how a prospective hepatoblast gains the hepatic fate remains elusive. Previous studies have shown that loss-of-function of either hhex or prox1a alone causes a small liver phenotype but without abolishing the hepatocyte differentiation, suggesting that absence of either Hhex or Prox1a alone is not sufficient to block the hepatoblast differentiation. Here, via genetic studies of the zebrafish two single (hhex-/- and prox1a-/-) and one double (hhex-/-prox1a-/-) mutants, we show that simultaneous loss-of-function of the hhex and prox1a two genes does not block the endoderm cells to gain the hepatoblast potency but abolishes the hepatic differentiation from the prospective hepatoblast. Consequently, the hhex-/-prox1a-/- double mutant displays a liverless phenotype that cannot be rescued by the injection of bmp2a mRNA. Taken together, we provide strong evidences showing that Hhex teams with Prox1a to act as a master control of the differentiation of the prospective hepatoblasts towards hepatocytes.


Asunto(s)
Hígado , Pez Cebra , Animales , Diferenciación Celular/genética , Hepatocitos , Estudios Prospectivos , Proteínas Represoras , Pez Cebra/genética , Proteínas de Pez Cebra/genética
8.
Cell Death Discov ; 9(1): 227, 2023 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-37407577

RESUMEN

Food digestion requires the cooperation of different digestive organs. The differentiation of digestive organs is crucial for larvae to start feeding. Therefore, during digestive organogenesis, cell identity and the tissue morphogenesis must be tightly coordinated but how this is accomplished is poorly understood. Here, we demonstrate that WD repeat domain 5 (Wdr5)-mediated H3K4 tri-methylation (H3K4me3) coordinately regulates cell differentiation, proliferation and apoptosis in zebrafish organogenesis of three major digestive organs including intestine, liver, and exocrine pancreas. During zebrafish digestive organogenesis, some of cells in these organ primordia usually undergo differentiation without apoptotic activity and gradually reduce their proliferation capacity. In contrast, cells in the three digestive organs of wdr5-/- mutant embryos retain progenitor-like status with high proliferation rates, and undergo apoptosis. Wdr5 is a core member of COMPASS complex to implement H3K4me3 and its expression is enriched in digestive organs from 2 days post-fertilization (dpf). Further analysis reveals that lack of differentiation gene expression is due to significant decreases of H3K4me3 around the transcriptional start sites of these genes; this histone modification also reduces the proliferation capacity in differentiated cells by increasing the expression of apc to promote the degradation of ß-Catenin; in addition, H3K4me3 promotes the expression of anti-apoptotic genes such as xiap-like, which modulates p53 activity to guarantee differentiated cell survival. Thus, our findings have discovered a common molecular mechanism for cell fate determination in different digestive organs during organogenesis, and also provided insights to understand mechanistic basis of human diseases in these digestive organs.

9.
iScience ; 26(7): 107220, 2023 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-37456842

RESUMEN

Copper is an essential component in the mitochondrial respiratory chain complex IV (cytochrome c oxidases). However, whether any nucleolar factor(s) is(are) involved in regulating the mitochondrial copper homeostasis remains unclear. The nucleolar localized Def-Capn3 protein degradation pathway cleaves target proteins, including p53, in both zebrafish and human nucleoli. Here, we report that hepatic depletion of mDEF in mice causes an excessive copper accumulation in the mitochondria. We find that mDEF-depleted hepatocytes show an exclusion of CAPN3 from the nucleoli and accumulate p53 and NRF1 proteins in the nucleoli. Furthermore, we find that NRF1 is a CAPN3 substrate. Elevated p53 and NRF1 enhances the expression of Sco2 and Cox genes, respectively, to allow more copper acquirement in the mDefloxp/loxp, Alb:Cre mitochondria. Our findings reveal that the mDEF-CAPN3 pathway serves as a novel mechanism for regulating the mitochondrial copper homeostasis through targeting its substrates p53 and NRF1.

10.
Front Bioeng Biotechnol ; 11: 1199922, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37288355

RESUMEN

Age-related macular degeneration (AMD) is the predominant threat to human vision and ultimately results in blindness. With the increase in the aging population, it has become a more crucial issue to human health. AMD is a multifactorial disease with the unique feature of uncontrollable angiogenesis during initiation and progression. Although increasing evidence indicates that AMD is largely hereditary, the predominant efficient treatment is antiangiogenesis, which mainly involves VEGF and HIF-α as therapeutic targets. The repeated administration of this treatment over the long term, generally through intravitreal injection, has called for the introduction of long-term drug delivery systems, which are expected to be achieved by biomaterials. However, the clinical results of the port delivery system indicate that the optimization of medical devices toward prolonging the activities of therapeutic biologics in AMD therapy seems more promising. These results indicate that we should rethink the possibility and potential of biomaterials as drug delivery systems in achieving long-term, sustained inhibition of angiogenesis in AMD therapy. In this review, the etiology, categorization, risk factors, pathogenesis, and current clinical treatments of AMD are briefly introduced. Next, the development status of long-term drug delivery systems is discussed, and the drawbacks and shortages of these systems are emphasized. By comprehensively considering the pathological aspect and the recent application of drug delivery systems in AMD therapy, we hope to find a better solution for the further development of long-term therapeutic strategies for AMD.

11.
Cell Discov ; 9(1): 63, 2023 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-37369707

RESUMEN

Genetic compensation responses (GCRs) can be induced by deleterious mutations in living organisms in order to maintain genetic robustness. One type of GCRs, homology-dependent GCR (HDGCR), involves transcriptional activation of one or more homologous genes related to the mutated gene. In zebrafish, ~80% of the genetic mutants produced by gene editing technology failed to show obvious phenotypes. The HDGCR has been proposed to be one of the main reasons for this phenomenon. It is triggered by mutant mRNA bearing a premature termination codon and has been suggested to depend on components of both the nonsense mRNA-mediated degradation (NMD) pathway and the complex of proteins associated with Set1 (COMPASS). However, exactly which specific NMD factor is required for HDGCR remains disputed. Here, zebrafish leg1 deleterious mutants are adopted as a model to distinguish the role of the NMD factors Upf1 and Upf3a in HDGCR. Four single mutant lines and three double mutant lines were produced. The RNA-seq data from 71 samples and the ULI-NChIP-seq data from 8 samples were then analyzed to study the HDGCR in leg1 mutants. Our results provide strong evidence that Upf3a, but not Upf1, is essential for the HDGCR induced by nonsense mutations in leg1 genes where H3K4me3 enrichment appears not to be a prerequisite. We also show that Upf3a is responsible for correcting the expression of hundreds of genes that would otherwise be dysregulated in the leg1 deleterious mutant.

12.
Biomaterials ; 295: 122036, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36804660

RESUMEN

Osteoarthritis (OA) is a common joint condition that is a leading cause of disability worldwide. There are currently no disease-modifying treatments for osteoarthritis, which is associated with multiple kinds of inflammatory cytokines produced by M1 macrophages in the synovium of the joint. Despite recent therapeutic advancements with anti-cytokine biologics, the OA therapy response rate continues to be inadequate. To treat OA, the pro-inflammatory and anti-inflammatory responses of synoviocytes and macrophages must be controlled simultaneously. Therefore, the immune regulation capabilities of an ideal nano-drug should not only minimize pro-inflammatory responses but also effectively boost anti-inflammatory responses. In this paper, an M2H@RPK nanotherapeutic system was developed, KAFAK and shRNA-LEPR were condensed with polyethylenimine (PEI) to form a complex, which was then modified with hyaluronic acid (HA) to negatively charge to cover the M2 membrane. It was discovered that the repolarization of macrophages from the M1 to the M2 phenotype lowered pro-inflammatory responses while enhancing anti-inflammatory responses in macrophages and synoviocytes. In vitro and in vivo studies demonstrate that M2H@RPK dramatically decreases proinflammatory cytokines, controls synovial inflammation, and provides significant therapeutic efficacy by reducing joint damage. Overall, it has been demonstrated that M2H@RPK provides inflammation-targeted therapy by macrophage repolarization, and it represents a promising OA therapeutic strategy.


Asunto(s)
Nanopartículas , Osteoartritis , Sinovitis , Humanos , Osteoartritis/tratamiento farmacológico , Sinovitis/tratamiento farmacológico , Sinovitis/complicaciones , Inflamación , Macrófagos , Membrana Sinovial , Citocinas , Antiinflamatorios/farmacología , Nanopartículas/uso terapéutico
13.
Comput Struct Biotechnol J ; 21: 105-119, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36544475

RESUMEN

Obesity affects the function of multiple organs/tissues including the exocrine organ salivary glands. However, the effects of obesity on transcriptomes and cell compositions in the salivary glands have yet been studied by bulk RNA-sequencing and single-cell RNA-sequencing. Besides, the cell types in the sublingual gland, one of the three major salivary glands, have yet been characterized by the approach of single-cell RNA-sequencing. In this report, we find that the histological structure of the three major salivary glands are not obviously affected in the obese mice. Bulk RNA-sequencing analysis shows that the most prominent changes observed in the three major salivary glands of the obese mice are the mobilization of transcriptomes related to the immune response and down-regulation of genes related to the secretory function of the salivary glands. Based on single-cell RNA-sequencing analysis, we identify and annotate 17 cell clusters in the sublingual gland for the first time, and find that obesity alters the relative compositions of immune cells and secretory cells in the major glands of obese mice. Integrative analysis of the bulk RNA-sequencing and single-cell RNA-sequencing data confirms the activation of immune response genes and compromise of secretory function in the three major salivary glands of obese mice. Consequently, the secretion of extracellular matrix proteins is significantly reduced in the three major salivary glands of obese mice. These results provide new molecular insights into understanding the effect of obesity on salivary glands.

14.
J Genet Genomics ; 49(12): 1101-1113, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36460297

RESUMEN

In mammals, the expression of the homeobox family member Cdx2/CDX2 is restricted within the intestine. Conditional ablation of the mouse Cdx2 in the endodermal cells causes a homeotic transformation of the intestine towards the esophagus or gastric fate. In this report, we show that null mutants of zebrafish cdx1b, encoding the counterpart of mammalian CDX2, could survive more than 10 days post fertilization, a stage when the zebrafish digestive system has been well developed. Through RNA sequencing (RNA-seq) and single-cell sequencing (scRNA-seq) of the dissected intestine from the mutant embryos, we demonstrate that the loss-of-function of the zebrafish cdx1b yields hepatocyte-like intestinal cells, a phenotype never observed in the mouse model. Further RNA-seq data analysis, and genetic double mutants and signaling inhibitor studies reveal that Cdx1b functions to guard the intestinal fate by repressing, directly or indirectly, a range of transcriptional factors and signaling pathways for liver specification. Finally, we demonstrate that heat shock-induced overexpression of cdx1b in a transgenic fish abolishes the liver formation. Therefore, we demonstrate that Cdx1b is a key repressor of hepatic fate during the intestine specification in zebrafish.


Asunto(s)
Diferenciación Celular , Proteínas de Homeodominio , Intestinos , Hígado , Animales , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Intestinos/metabolismo , Hígado/metabolismo , Mamíferos/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Transducción de Señal/genética , Diferenciación Celular/genética
15.
Cells ; 11(20)2022 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-36291156

RESUMEN

The zebrafish intestine and liver, as in other vertebrates, are derived from the endoderm. Great effort has been devoted to deciphering the molecular mechanisms controlling the specification and development of the zebrafish intestine and liver; however, genome-wide comparison of the transcriptomes between these two organs at the larval stage remains unexplored. There is a lack of extensive identification of feature genes marking specific cell types in the zebrafish intestine and liver at 5 days post-fertilization, when the larval fish starts food intake. In this report, through RNA sequencing and single-cell RNA sequencing of intestines and livers separately dissected from wild-type zebrafish larvae at 5 days post-fertilization, together with the experimental validation of 47 genes through RNA whole-mount in situ hybridization, we identified not only distinctive transcriptomes for the larval intestine and liver, but also a considerable number of feature genes for marking the intestinal bulb, mid-intestine and hindgut, and for marking hepatocytes and cholangiocytes. Meanwhile, we identified 135 intestine- and 97 liver-enriched transcription factor genes in zebrafish larvae at 5 days post-fertilization. Our findings provide rich molecular and cellular resources for studying cell patterning and specification during the early development of the zebrafish intestine and liver.


Asunto(s)
Transcriptoma , Pez Cebra , Animales , Pez Cebra/metabolismo , Larva/genética , Larva/metabolismo , Transcriptoma/genética , Intestinos , Hígado/metabolismo , ARN/metabolismo , Factores de Transcripción/metabolismo
16.
Biochem Biophys Res Commun ; 623: 66-73, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35878425

RESUMEN

Digestive-organ expansion factor (Def) is a nucleolar protein that recruits cysteine proteinase Calpain3 (CAPN3) into the nucleolus to form the Def-CAPN3 complex in both human and zebrafish. This complex mediates the degradation of the tumor suppressor p53 and ribosome biogenesis factor mitotic phosphorylated protein 10 (Mpp10) in nucleolus, demonstrating the importance of this complex in regulating cell cycle and ribosome biogenesis. However, the Def and CAPN3 interacting motifs have yet been identified. In this report, by using a series of truncated or internally deleted human CAPN3 (hCAPN3) derivatives we identify that an essential motif of 86 amino acids (86-aa) (430-515aa) in hCAPN3 for its interaction with human Def (hDef), and this 86-aa motif is highly conserved in zebrafish Capn3b (zCapn3b) and is also required for the interaction between zebrafish Def (zDef) and zCapn3b. We further identify the 2/3 C-terminus of hDef is responsible for mediating the hDef-hCAPN3 interaction, and the corresponding region is conserved for the zDef and zCapn3b interaction. Our results lay the ground to resolve the structure of the Def-CAPN3 complex in the future.


Asunto(s)
Nucléolo Celular , Pez Cebra , Secuencias de Aminoácidos , Aminoácidos/metabolismo , Animales , Calpaína/genética , Calpaína/metabolismo , Ciclo Celular , Nucléolo Celular/metabolismo , Humanos , Proteínas Musculares/metabolismo , Pez Cebra/metabolismo
17.
ACS Appl Mater Interfaces ; 14(26): 29563-29576, 2022 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-35730906

RESUMEN

Free radicals, including reactive oxygen species (ROS), play a critical role in determining cell's fate. When the level of free radicals is increased to a fatal value, it causes cancer cells to undergo senescence or cell death. Strategies that target this mechanism offer promising therapies against cancer. However, efficient and sustainable systems that generate free radicals, especially oxygen-independent systems, remain deficient. Herein, functionalized PLGA-based nanocomposites that efficiently co-deliver magnetic nanoparticles and 2,2'-azobis[2-(2-imidazolin-2-yl) propane]-dihydrochloride (AIPH) were fabricated to achieve photothermal-induced thermodynamic therapy combined with macrophage polarization strategies; this therapy targets hypoxic tumors through the generation of an oxygen-independent free-radical cascade. These hybrid NPs can accumulate in the tumor microenvironment, and the encapsulated MNPs not only serve as contrast agents for enhanced magnetic resonance imaging but also exhibit the expected photothermal conversion and trigger the decomposition of AIPH to generate free radicals, thus causing cancer cell death. More importantly, the cell debris from apoptotic or necrotic cancer cells carries nondegraded MNPs, which can be endocytosed by recruited TAMs. MNPs can further induce TAMs to polarize to the M1 subtype to subsequently generate ROS. This study provides an alternative method for the generation of an oxygen-independent free-radical cascade for tumor co-therapy guided by magnetic resonance imaging PTT/TDT.


Asunto(s)
Nanopartículas , Neoplasias , Línea Celular Tumoral , Radicales Libres/química , Humanos , Hipoxia , Imagen por Resonancia Magnética , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Oxígeno/metabolismo , Especies Reactivas de Oxígeno , Termodinámica , Microambiente Tumoral
18.
Carbohydr Polym ; 278: 118952, 2022 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-34973769

RESUMEN

Polysaccharide hydrogels have been widely utilized in tissue engineering. They interact with the organismal environments, modulating the cargos release and realizing of long-term survival and activations of living cells. In this review, the potential strategies for modification of polysaccharides were introduced firstly. It is not only used to functionalize the polysaccharides for the consequent formation of hydrogels, but also used to introduce versatile side groups for the regulation of cell behavior. Then, techniques and underlying mechanisms in inducing the formation of hydrogels by polysaccharides or their derivatives are briefly summarized. Finally, the applications of polysaccharide hydrogels in vivo, mainly focus on the performance for alleviation of foreign-body response (FBR) and as cell scaffolds for tissue regeneration, are exemplified. In addition, the perspectives and challenges for further research are addressed. It aims to provide a comprehensive framework about the potentials and challenges that the polysaccharide hydrogels confronting in tissue engineering.


Asunto(s)
Materiales Biocompatibles/química , Hidrogeles/química , Polisacáridos/química , Ingeniería de Tejidos , Andamios del Tejido/química , Animales , Humanos
19.
J Mol Cell Biol ; 13(12): 902-917, 2022 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-34791311

RESUMEN

18S, 5.8S, and 28S ribosomal RNAs (rRNAs) are cotranscribed as a pre-ribosomal RNA (pre-rRNA) from the rDNA by RNA polymerase I whose activity is vigorous during the S-phase, leading to a conflict with rDNA replication. This conflict is resolved partly by replication-fork-barrier (RFB)-sites sequences located downstream of the rDNA and RFB-binding proteins such as Ttf1. However, how Ttf1 is displaced from RFB-sites to allow replication fork progression remains elusive. Here, we reported that loss-of-function of Bms1l, a nucleolar GTPase, upregulates rDNA transcription, causes replication-fork stall, and arrests cell cycle at the S-to-G2 transition; however, the G1-to-S transition is constitutively active characterized by persisting DNA synthesis. Concomitantly, ubf, tif-IA, and taf1b marking rDNA transcription, Chk2, Rad51, and p53 marking DNA-damage response, and Rpa2, PCNA, Fen1, and Ttf1 marking replication fork stall are all highly elevated in bms1l mutants. We found that Bms1 interacts with Ttf1 in addition to Rc1l. Finally, we identified RFB-sites for zebrafish Ttf1 through chromatin immunoprecipitation sequencing and showed that Bms1 disassociates the Ttf1‒RFB complex with its GTPase activity. We propose that Bms1 functions to balance rDNA transcription and replication at the S-phase through interaction with Rcl1 and Ttf1, respectively. TTF1 and Bms1 together might impose an S-phase checkpoint at the rDNA loci.


Asunto(s)
GTP Fosfohidrolasas , Pez Cebra , Animales , Replicación del ADN , ADN Ribosómico/genética , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , ARN Polimerasa I/metabolismo , ARN Ribosómico/genética , Pez Cebra/genética
20.
Biomaterials ; 281: 121328, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34953333

RESUMEN

Chemotherapy drugs play important roles in clinical treatment, and most first-line regimens of cancer therapy contain chemotherapy drugs. In particular, some chemotherapeutic drugs can also produce ICD effect and enhance the immune response of the body. However, most chemotherapy drugs do not specifically target tumors or the complex tumor microenvironment, which renders their curative effect insufficient. Therefore, we constructed a tumor microenvironment-responsive drug delivery system (Ag2S-PAsp-cRGD) combined with doxorubicin (DOX) for tumor therapy. Firstly, Ag2S nanoparticles (NPs) were modified with polymer aspartic acid (PAsp) to construct the drug-loading platform. Then, an active targeting ligand (cRGD) was coupled through an amide reaction to enhance the functional targeting ability of the drug delivery system. In vivo imaging of the system showed that the nanoparticles accumulated in the tumor site, which facilitated the delivery of the chemotherapy drug DOX to the targeted tumor site. Furthermore, the photothermal effect of Ag2S NPs can effectively killed tumor cells, and also helped the release of DOX from nanoparticles into tumor tissue, thus enhancing the chemotherapeutic effect. Moreover, combined with the ICD effect jointly induced by photothermal therapy (PTT) and DOX, the treatment further activated the host immune response against tumors by enhancing the presentation of antigens and promoting the differentiation of T cells. This strategy of photo-chemo-immunotherapy showed excellent antitumor effect, not only eliminating the primary tumor but also preventing recurrence and inhibiting metastasis.


Asunto(s)
Nanopartículas , Fotoquimioterapia , Ácido Aspártico , Línea Celular Tumoral , Doxorrubicina , Inmunidad , Polímeros/farmacología , Microambiente Tumoral
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