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Understanding the vascular formation and distribution in metastatic lung tumors is a significant challenge due to autofluorescence, antibody/dye diffusion in dense tumor, and fluorophore stability when exposed to solvent-based clearing agents. Here, an approach is presented that redefines 3D vasculature imaging within metastatic tumor, peritumoral lung tissue, and normal lung. Specifically, a far-red aggregation-induced emission nanoparticle with surface amino groups (termed as TSCN nanoparticle, TSCNNP) is designed for in situ formation of hydrogel (TSCNNP@Gel) inside vasculatures to provide structural support and enhance the fluorescence in solvent-based tissue clearing method. Using this TSCNNP@Gel-reinforced tissue clearing imaging approach, the critical challenges are successfully overcome and comprehensive visualization of the whole pulmonary vasculature up to 2 µm resolution is enabled, including its detailed examination in metastatic tumors. Importantly, features of tumor-associated vasculature in 3D panoramic views are unveiled, providing the potential to determine tumor stages, predict tumor progression, and facilitate the histopathological diagnosis of various tumor types.
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Hidrogeles , Imagenología Tridimensional , Neoplasias Pulmonares , Pulmón , Hidrogeles/química , Animales , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Ratones , Pulmón/diagnóstico por imagen , Pulmón/irrigación sanguínea , Pulmón/patología , Humanos , Nanopartículas/química , Línea Celular Tumoral , Imagen Óptica/métodos , Colorantes Fluorescentes/químicaRESUMEN
Acute myeloid leukaemia (AML) is a collection of genetically diverse diseases characterised by abnormal proliferation of immature haematopoietic cells and disruption of normal haematopoiesis. Myeloid cells and lymphocytes originate from different haematopoietic precursors within the bone marrow. It has been traditionally assumed that myeloid cells cannot produce immunoglobulin (Ig), a marker of B cells and plasma cells. However, in recent years, all five Ig classes have been detected in CD34+ haematopoietic stem cells, mature monocytes and neutrophils, differentiated macrophages and tumour-associated macrophages, acute myeloid leukaemia cell lines, as well as myeloblasts of AML. The rearranged V(D)J sequences exhibit unique restricted or biased V gene usage and evidence of somatic mutation. Furthermore, AML-derived Igs could promote cell proliferation, induce apoptosis, and enhance migration. Elevated levels of Ig expression predict inferior clinical outcomes. These findings indicate that AML-derived Ig plays a role in AML pathogenesis and progression, and could serve as a novel biomarker for risk stratification, disease monitoring, and targeted therapy. In this chapter, we provide a comprehensive review of recent literature on the expression, function, and significance of non B cell-derived Ig in the haematological system, with a focus on AML.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , AnimalesRESUMEN
Eukaryotic cells regulate various cellular processes through membrane-bound and membrane-less organelles, enabling active signal communication and material exchange. Lysosomes and lipid droplets are representative organelles, contributing to cell lipophagy when their interaction and metabolism are disrupted. Our limited understanding of the interacting behaviours and physicochemical properties of different organelles during lipophagy hinders accurate diagnosis and treatment of related diseases. In this contribution, we report a fluorescent probe, PTZ, engineered for dual-targeting of lipid droplets and lysosomes. PTZ can track liquid-liquid phase separation and respond to polarity shifts through ratiometric fluorescence emission, elucidating the lipophagy process from the perspective of organelle behavior and physicochemical properties. Leveraging on the multifunctionality of PTZ, we have successfully tracked the polarity and dynamic changes of lysosomes and lipid droplets during lipophagy. Furthermore, an unknown homogeneous transition of lipid droplets and lysosomes was discovered, which provided a new perspective for understanding lipophagy processes. And this work is expected to serve as a reference for diagnosis and treatment of lipophagy-related diseases.
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Colorantes Fluorescentes , Gotas Lipídicas , Lisosomas , Humanos , Lisosomas/metabolismo , Gotas Lipídicas/metabolismo , Transición de Fase , Autofagia/fisiología , Células HeLaRESUMEN
Rice leaf morphology is a pivotal component of the ideal plant architecture, significantly impacting rice yield. The process of leaf development unfolds through three distinct stages: the initiation of leaf primordia, the establishment and maintenance of polarity, and leaf expansion. Genes regulating leaf morphology encompass transcription factors, hormones, and miRNAs. An in-depth synthesis and categorization of genes associated with leaf development, particularly those successfully cloned, hold paramount importance in unraveling the complexity of rice leaf development. Furthermore, it provides valuable insights into the potential for molecular-level manipulation of rice leaf types. This comprehensive review consolidates the stages of rice leaf development, the genes involved, molecular regulatory pathways, and the influence of plant hormones. Its objective is to establish a foundational understanding of the creation of ideal rice leaf forms and their practical application in molecular breeding.
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Myeloid differentiation factor 88 (MyD88) is a universal adaptor protein and plays an important role in the signal transduction of Toll like receptors (TLR) family. In this study, the MyD88 gene from the Haliotis diversicolor (hdMyD88) was identified. The full-length cDNA of hdMyD88 has a 1927 base pairs (bp), with an open reading frame of 1314 bp encoding 437 amino acids including a death domain (DD) at the N-terminus and TIR domain at the C-terminus which are typical features of MyD88 family proteins. Three conserved boxes are also found in the hdMyD88, which are similar to MyD88 in vertebrates. The expression levels of hdMyD88 mRNA at different early embryonic developmental stages of abalone were measured by qPCR revealed that their constitutive expression at all developmental stages analyzed with the considerably highest values at 8 cell stage and the lowest level at the trochosphere stage. Additionally, the mRNA expression of hdMyD88 decreased significantly (P < 0.05) after MyD88-dsRNA soak in the stage of trochosphere and veliger than EGFP-dsRNA group and blank control group. Whole embryo in situ hybridization showed that the positive signals of hdMyD88 were in visceral mass of trochophore larvae and veliger larvae. These results indicate hdMyD88 may could respond to pathogenic infection and may play an important role in early innate immunity in the process of abalone larval development.
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Gastrópodos , Factor 88 de Diferenciación Mieloide , Animales , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Secuencia de Aminoácidos , Transducción de Señal , ARN Mensajero/metabolismoRESUMEN
KEY MESSAGE: A FT/TFL1 subfamily gene, rice CENTRORADIALIS 2, also known as RCN1, regulates seed germination and increase salt tolerance via ABA-mediated pathway. The ABA synthesis and metabolism related genes were changed relative expression levels. Seed germination is a complex biological process that is affected by many factors. Although a number of germination-related genes have been reported, the molecular mechanism of germination regulation has not yet been fully elucidated. Here, we reported that the rice OsCEN2 gene can negatively regulate seed germination. The germination speed of OsCEN2-RNAi seeds was significantly faster while that of OsCEN2-overexpression (OE) seeds was slower than that of the wild type (WT). The results of qRT-PCR showed that the OsCEN2 expression was increased in the early stage of seed germination. Exogenous application of abscisic acid (ABA) on seeds and seedlings showed that OsCEN2-OE seeds and seedlings were highly sensitive to ABA during germination and post-germination growth, respectively. The determination of endogenous ABA content in seeds also showed that the ABA content of OsCEN2-RNAi seeds was lower, while that of OsCEN2-OE seeds was higher. Moreover, the transgenic plants changed salt tolerance because of the altered ABA level. In addition, differences were also observed in the expression of genes related to ABA synthesis and metabolism in the seeds of OsCEN2-transgenic lines. This study reveals that OsCEN2 regulates the germination speed by affecting the content of ABA during seed germination and provides a theoretical basis for research on rice direct seeding.
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Arabidopsis , Oryza , Ácido Abscísico/metabolismo , Germinación/genética , Tolerancia a la Sal/genética , Semillas/genética , Arabidopsis/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
As a subtype of kainite receptors (KARs), GluK2 plays a role in the perception of cold in the periphery sensory neuron. However, the molecular mechanism for gluk2 on the cold stress in fish has not been reported. In this article, real-time PCR assays showed that gluk2 was highly expressed in the brain and eyes of adult zebrafish. To study the functions of gluk2, gene knockout was carried out using the CRISPR/Cas9 system. According to RNA-seq analysis, we selected the differentially expressed genes (DEGs) that had significant differences in at least three tissues of the liver, gill, intestine, skin, brain, and eyes. Gene Ontology (GO) enrichment analysis revealed that cry1ba, cry2, per1b, per2, hsp70.1, hsp70.2, hsp70l, hsp90aa1.1, hsp90aa1.2, hspb1, trpv1, slc27a1b, park2, ucp3, and METRNL were significantly enriched in the 'Response to temperature stimulus' pathway. Through behavioral phenotyping assay, the gluk2-/- larval mutant displayed obvious deficiency in cold stress. Furthermore, TUNEL (TdT-mediated dUTP Nick-End Labeling) staining proved that the gill apoptosis of gluk2-/- mutant was increased approximately 60 times compared with the wild-type after gradient cooling to 8 °C for 15 h. Overall, our data suggested that gluk2 was necessary for cold tolerance in zebrafish.
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Transcriptoma , Pez Cebra , Animales , Sistemas CRISPR-Cas , Técnicas de Inactivación de Genes , Larva/genética , Proteínas Circadianas Period , Transcriptoma/genética , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
Immunoglobulin (Ig), a characteristic marker of B cells, is a multifunctional evolutionary conserved antibody critical for maintaining tissue homeostasis and developing fully protective humoral responses to pathogens. Increasing evidence revealed that Ig is widely expressed in non-immune cells; moreover, Ig produced by different lineages cells plays different biological roles. Recently, it has been reported that monocytes or macrophages also express Ig. However, its function remains unclear. In this study, we further identified that Ig, especially Ig mu heavy chain (IgM), was mainly expressed in mice macrophages. We also analyzed the IgM repertoire characteristic in macrophages and found that the VHDJH rearrangements of macrophage-derived IgM showed a restricted and conservative VHDJH pattern, which differed from the diverse VHDJH rearrangement pattern of the B cell-expressed IgM in an individual. Functional investigation showed that IgM knockdown significantly promoted macrophage migration and FAK/Src-Akt axis activation. Furthermore, some inflammatory cytokines such as MCP1 and IL-6 increased after IgM knockdown under LPS stimulation. A mechanism study revealed that the IgM interacted with binding immunoglobulin protein (Bip) and inhibited inflammatory response and unfolded protein response (UPR) activation in macrophages. Our data elucidate a previously unknown function of IgM in macrophages that explains its ability to act as a novel regulator of Bip to participate in endoplasmic reticulum stress and further regulate the inflammatory response.
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Estrés del Retículo Endoplásmico , Inmunoglobulina M/inmunología , Inflamación/inmunología , Macrófagos/metabolismo , Envejecimiento/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Endorribonucleasas/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Inflamación/patología , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Unión Proteica/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células RAW 264.7 , Empalme del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 de Unión a la X-Box/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
Psoriasis is an inflammatory skin disease with substantial morbidity. Numerous patients with psoriasis experience recurrence after therapy. The underlying mechanism about psoriasis is still not fully understood. Some evidences suggest that innate immunity may play an unexpected and important role in active severe psoriasis. In this work, the deconvolution algorithm CIBERSORT was conducted to identify the infiltration of innate immune cells and related core genes in psoriatic plaque. Datasets from the Gene Expression Omnibus, including skin samples from 405 psoriasis patients and 91 healthy donors, were downloaded for analysis. Considerable differences of the innate immune cell composition were uncovered between psoriatic plaque and control skin. Results revealed that γδ T cells, resting NK cells, M0 macrophages, M1 macrophages, activated dendritic cells, and neutrophils were significantly increased in psoriatic skin, while resting mast cells and active NK cells were significantly decreased. Moreover, the proportion of M0 macrophages or resting mast cells was found to be associated with disease severity. Spearman correlation analysis suggests that RORC and S100A12 genes were related to disease severity, while genes including S100A12, CLEC4C, IL-19, AIM2, IL-17F, and PPARGC1A were correlated with biologic treatment response. In conclusion, this work displays innate immune status in psoriatic skin and provides novel clues for clinical decisions and mechanism study.
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Células Dendríticas/inmunología , Regulación de la Expresión Génica/inmunología , Inmunidad Innata , Leucocitos/inmunología , Psoriasis/inmunología , Piel/inmunología , Bases de Datos de Ácidos Nucleicos , Células Dendríticas/patología , Humanos , Leucocitos/patología , Psoriasis/genética , Psoriasis/patología , Piel/patologíaRESUMEN
Visualization of cerebrovascular networks is crucial for understanding the pathogenesis of many neurological diseases. Recently developed optical clearing techniques offer opportunities in deep tissue imaging, and have been successfully applied in many research studies. The development of nanotechnology enables the labeling of brain vessels with functionalized micro/nanoparticles embedded with fluorescent dyes. We herein report an efficient method, named LIMPID (Labeled and Interlinked Micro/nanoparticles for Imaging and Delipidation), specific for the precise fluorescence imaging of vascular networks in clearing-treated tissues. This robust vessel labeling technique replaces conventional fluorescence dyes with functionalized polymer micro/nanoparticles that are able to cross-link with polyacrylamide to form dense hydrogels in vessels. LIMPID shows high-robustness during the clearing process without sacrificing fluorescence signals and clearing performance. LIMPID enables three dimension (3D) visualization of elaborate vascular networks in mouse brains and is compatible with other fluorescence-labeling techniques. We have successfully applied this method to acquire cortical vasculature images simultaneously with the neurons or microglia, as well as to evaluate vascular damage in a mouse model of stroke. The LIMPID method provides a novel tool for the precise analysis of vascular dysfunction and vascular diseases.
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Sistema Cardiovascular , Imagenología Tridimensional , Animales , Encéfalo/diagnóstico por imagen , Colorantes Fluorescentes , Ratones , Microscopía FluorescenteRESUMEN
Immunoglobulins (Ig) are important immune molecules that possess highly diverse variable region sequences enabling antigen recognition. According to classical immune theory, B lymphocytes have been considered the only source of Ig production (B-Igs). However, accumulating evidence have suggested that Igs are also produced by many non-B cells (non-B Igs), including epithelial cells, neurons, germ cells, as well as myeloid cells of hemopoietic system. Besides acting as bona fide antibodies, Non-B Igs have alternative cellular functions, such as promotion of cell survival, adhesion and migration. More importantly, Unlike the unlimited sequence diversity of B-Igs, the non-B Igs exhibit conserved V(D)J patterns across the same lineages. To support the analysis and comparison of variable region sequences from Igs, produced by B and non-B cells, we established a database (NBIGV) constituted by a non-B Ig variable region repertoire, which includes 727,989 VHDJH and VκJκ recombination sequences of non-B Igs sequenced from mouse samples. Upon database search, users can view, browse and investigate the variable region sequences of non-B Igs according to respective mice strains and tissues as well as Ig classes. Moreover, users can easily download selected sequences and/or compare sequences of interest with known non-B Ig sequences present in the database using NCBI-BLAST algorithms. Additionally, our database integrates a submission page and supplementary sample information. The NBIGV database may serve as a valuable resource for sequence analyses of Non-B Igs. NBIGV database is freely available at http://nbigv.org.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/metabolismo , Algoritmos , Animales , Adhesión Celular , Movimiento Celular , Supervivencia Celular , Bases de Datos Genéticas , Humanos , Ratones , Análisis de Secuencia de ADN , Recombinación V(D)JRESUMEN
As stated in the classic Kirchhoff's circuit laws, the total conductance of two parallel channels in an electronic circuit is the sum of the individual conductance. However, in molecular circuits, the quantum interference (QI) between the individual channels may lead to apparent invalidity of Kirchhoff's laws. Such an effect can be very significant in single-molecule circuits consisting of partially overlapped multiple transport channels. Herein, an investigation on how the molecular circuit conductance correlates to the individual channels is conducted in the presence of QI. It is found that the conductance of multi-channel circuit consisting of both constructive and destructive QI is significantly smaller than the addition of individual ones due to the interference between channels. In contrast, the circuit consisting of destructive QI channels exhibits an additive transport. These investigations provide a new cognition of transport mechanism and manipulation of transport in multi-channel molecular circuits.
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BACKGROUND: Sjögren syndrome (SS) is a rare disease in pediatrics, and little attention has been paid to the clinical feature in these patients. To date, there are few cases concern about neurological and nephrological disorders in childhood Sjögren syndrome. We describe a case of Sjögren syndrome in a 12-year-old girl who developed neurological disorders and interstitial nephritis and review the literature currently available on this topic. CASE PRESENTATION: A 12-year-old girl was admitted to our hospital for arthritis and glucosuria. She was required to do labial gland and renal biopsy, because the positive for anti-nuclear antibody and anti-Sjögren syndrome B (anti-SSB) antibody. Then the biopsy was performed revealing the lymphocytic infiltrate in the small area and renal tubular interstitial damage,thus the diagnosis of Sjögren syndrome with tubular interstitial damage was made. Three months later, she presented again with headache, fever, nausea, vomiting and was recovered without drug therapy. Based on the patient's medical history, laboratory and imaging examination, and treatment, we speculate that the disorders of the nervous system were caused by the Sjögren syndrome. The girl has stable renal function and no residual nervous system damage in the next 1.5 years, but she underwent low dose prednisone therapy because of persistent renal glucosuria. CONCLUSIONS: Nephrological disorders and neurological involvement are rare manifestations of Sjögren syndrome in children, and rarely presented as the initial symptoms. It should be suspected in children presenting with unexplained renal diseases, neurological abnormalities, or unexplained fever. Although there is no guidelines on the diagnosis and treatment of children Sjögren syndrome are currently available, early recognition and the appropriate treatment of renal damage and neurologic involvement would improve prognosis and prevent complications.
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Artritis/fisiopatología , Meningitis Aséptica/fisiopatología , Nefritis Intersticial/fisiopatología , Síndrome de Sjögren/fisiopatología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Anticuerpos Antinucleares/inmunología , Artritis/etiología , Niño , Femenino , Glucosuria/etiología , Humanos , Meningitis Aséptica/etiología , Nefritis Intersticial/etiología , Nefritis Intersticial/patología , Nefritis Intersticial/orina , Glándulas Salivales Menores/patología , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patologíaRESUMEN
The epidermal growth factor receptortyrosine kinase inhibitor (EGFRTKI), gefitinib, is used widely to treat nonsmall cell lung cancer (NSCLC) with EGFRactivating mutations. Unfortunately, the acquired drug resistance promoted by epithelialmesenchymal transition (EMT) markedly limits the clinical effects and remains a major barrier to a cure. Our previous isobaric tags for relative and absolute quantitationbased proteomics analysis revealed that the Ecadherin protein level was markedly upregulated by triptolide (TP). The present study aimed to determine whether TP reverses the gefitinib resistance of human lung cancer cells by regulating EMT. It was revealed that TP combined with gefitinib synergistically inhibited the migration and invasion of lung adenocarcinoma cell line A549; the combination treatment had a significantly better outcome than that of TP and gefitinib alone. Moreover, TP effectively increased the sensitivity of drug resistant A549 cells to gefitinib by upregulating Ecadherin protein expression and downregulating the MMP9, SNAIL, and vimentin expression levels. The dysregulated Ecadherin expression of gefitinibsensitive cells induced gefitinib resistance, which could be overcome by TP. Finally, TP combined with gefitinib significantly inhibited the growth of xenograft tumors induced using gefitinibresistant A549 cells, which was associated with EMT reversal and Ecadherin signaling activation in vivo. The present results indicated that the combination of TP and TKIs may be a promising therapeutic strategy to treat patients with NSCLCs harboring EGFR mutations.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Diterpenos/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos , Gefitinib/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Fenantrenos/administración & dosificación , Células A549 , Adenocarcinoma del Pulmón/genética , Animales , Antígenos CD/genética , Cadherinas/genética , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diterpenos/farmacología , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/farmacología , Gefitinib/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Masculino , Ratones , Fenantrenos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Lung cancer has one of the highest mortalities of any cancer worldwide. Triptolide (TP) is a promising tumor suppressor extracted from the Chinese herb Tripterygium wilfordii. Our previous proteomics analysis revealed that TP significantly interfered with the ribosome biogenesis pathway; however, the underlying molecular mechanism remains poorly understood. The aim of the present study was to determine the molecular mechanism of TP's anticancer effect by investigating the association between ribosomal stress and p53 activation. It was found that TP induces nucleolar disintegration together with RNA polymerase I (Pol I) and upstream binding factor (UBF) translocation. TP interrupted ribosomal (r)RNA synthesis through inhibition of RNA Pol I and UBF transcriptional activation. TP treatment increased the binding of ribosomal protein L23 (RPL23) to mouse double minute 2 protein (MDM2), resulting in p53 being released from MDM2 and stabilized. Activation of p53 induced apoptosis and cell cycle arrest by enhancing the activation of p53 upregulated modulator of apoptosis, caspase 9 and caspase 3, and suppressing BCL2. In vivo experiments showed that TP significantly reduced xenograft tumor size and increased mouse body weight. Immunohistochemical assays confirmed that TP significantly increased the p53 level and induced nucleolus disintegration, during which nucleolin distribution moved from the nucleolus to the nucleoplasm, and RPL23 clustered at the edge of the cell membrane. Therefore, it was proposed that TP induces ribosomal stress, which leads to nucleolus disintegration, and inhibition of rRNA transcription and synthesis, resulting in increased binding of RPL23 with MDM2. Consequently, p53 is activated, which induces apoptosis and cell cycle arrest.
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Antineoplásicos Alquilantes/administración & dosificación , Diterpenos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Fenantrenos/administración & dosificación , ARN Ribosómico/metabolismo , Transducción de Señal/efectos de los fármacos , Células A549 , Animales , Antineoplásicos Alquilantes/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diterpenos/farmacología , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Fenantrenos/farmacología , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Ribosómicas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Two-photon fluorescence (TPF) imaging holds great promise for real-time monitoring of cerebral ischemia-reperfusion injury, which is important for the clinical diagnosis of stroke. However, biocompatible and photostable NIR-emitting probes for TPF imaging of ischemic stroke are lacking. Herein, we report the first NIR-emitting TPF probe (named NESPN) prepared using semiconducting polymers for TPF imaging of cerebral ischemia. By virtue of its excellent biocompatibility with the nervous system and bright fluorescence NIR emission, NESPN enables the real-time imaging of mouse brain vasculature with micrometer-scale spatial resolution, realizing clear visualization of ultrafine capillaries (â¼3.16 µm). Moreover, NESPN can be utilized in the dynamic monitoring of cerebral blood flow velocity. Microangiography using NESPN was successfully used to indicate the openness of the penumbra area in the mouse brain stroke model. More importantly, this technique allows us to continuously monitor the whole process of ischemic stroke and subsequent reperfusion. This work provides a new and versatile tool for vascular research and diagnosis of vascular diseases.
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Encéfalo/diagnóstico por imagen , Circulación Cerebrovascular , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Nanopartículas/administración & dosificación , Polímeros/administración & dosificación , Daño por Reperfusión/diagnóstico por imagen , Animales , Encéfalo/irrigación sanguínea , Fluorenos/administración & dosificación , Colorantes Fluorescentes/administración & dosificación , Ratones , Imagen Óptica/métodos , Semiconductores , Tiadiazoles/administración & dosificación , Imagen de Cuerpo EnteroRESUMEN
In this study, the entire mitogenome sequence of the O. macrolepis has been sequenced. However, its systematic classification is still undetermined. The complete mitochondrial genome is 16,621bp, which includes 37 genes (13 protein-coding genes, 2 rRNA genes and 22 tRNA genes) and 1 control region.The overall base composition is 34.52% A, 19.01% T, 25.58% C, 20.89% G, showing AT rich feature (55.76%). Its structure type is similar to the mitogenome of Cyprinidae. Phylogenetic tree showed that O. macrolepis belong to Barbinae.
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CCDC134 (coiled-coil domain containing 134), a cytokine-like molecule, was previously reported to exert antitumor effects by augmenting CD8+ T-cell mediated immunity. However, the dynamic changes in CCDC134 expression patterns in the spinal cord that may be involved in the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, remains unclear. In this study, we found that CCDC134 expression was markedly increased in the spinal cord during the progression of EAE. Furthermore, we demonstrated that CCDC134 significantly reduced the severity and slowed the progression of EAE, which correlated with reduced spinal cord inflammation and demyelination. The underlying mechanism of CCDC134-induced effects involved inhibition of T helper (Th)-1 and Th17 cell differentiation and secretion of its key effector molecules IFN-γ and IL-17A via regulation of JAK/STAT signaling. These findings indicate that CCDC134 exerts potent anti-inflammatory effects through the selective modulation of pathogenic Th1 and Th17 cells by targeting critical signaling pathways. The study provides insights into the role of CCDC134 as a unique therapeutic agent for the treatment of autoimmune diseases.
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Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Proteínas de la Membrana/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/metabolismo , Transducción de Señal/efectos de los fármacos , Médula Espinal/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/fisiología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/fisiologíaRESUMEN
Coiled-coil domain containing 134 (CCDC134), a characterized secreted protein, may serve as an immune cytokine and illustrates its potent antitumor effects by augmenting CD8+ T-cell-mediated immunity. Additionally, CCDC134 may also act as a novel regulator of human alteration/deficiency in activation 2a, and be involved in the p300-CBP-associated factor complex and affect its acetyltransferase activity. To clarify the biological and pathological function of CCDC134, the present study generated a viable and fertile Ccdc134fl/fl mouse strain that allowed temporal and spatial control of gene ablation. Ccdc134-/- embryos generated by crossing of Ccdc134fl/fl mice with human ß-actin-Cre or zona pellucida 3-Cre transgenic mice were embryonic lethal from embryonic day (E)12.5 to birth. Ccdc134 loss was associated with severe hemorrhages in the brain ventricular space and neural tube, pale and abnormal livers, cardiac hypertrophy and placental distress. Furthermore, it was demonstrated that a fraction of E13.5 fetal livers and brains exhibited reduced cell proliferation and vascular endothelial cell defects. CCDC134 also exhibited a dynamic and specific expression pattern during embryo development. The present results suggest that Ccdc134 may have specific biological functions in regulating mouse embryonic development.
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Desarrollo Embrionario/genética , Hemorragias Intracraneales/genética , Proteínas de la Membrana/genética , Animales , Proliferación Celular/genética , Femenino , Regulación del Desarrollo de la Expresión Génica , Humanos , Hemorragias Intracraneales/embriología , Hemorragias Intracraneales/patología , Hígado/embriología , Hígado/patología , Ratones , Ratones Transgénicos , EmbarazoRESUMEN
Numerous studies have demonstrated that free Ig light chain (FLC), a novel inflammation mediator, participates in many inflammatory diseases by activating mast cells and extending the survival of neutrophils. However, it remains unclear whether FLC is involved in colitis and colitis-associated colon carcinogenesis (CAC). In this study, we found a significant increase in FLC in murine models of DSS (Dextran Sulfate Sodium Salt)-induced colitis and CAC compared to controls. Peptide F991, a functional blocker of FLC, significantly attenuated colitis progression, which included abrogating the development of diarrhea and tumor burden, elevating survival rate, greatly reducing the infiltration of inflammatory cells (such as ROS+ active neutrophils), especially reducing tumorigenesis in CAC. Furthermore, we demonstrated that F991 inhibited the activation of the inflammasome by reducing the expression of cleaved caspase-1 and the maturation of IL-1ß and IL-18. Altogether, our findings demonstrate that FLC can promote the pathogenesis of colitis and CAC and may be used as novel biomarker for the diagnosis of inflammatory bowel disease. Additionally, F991 may become a potential therapeutic option for colitis or colorectal cancer.