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Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence ß-Galactosidase Staining (SA-ß-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-ß-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.
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Senescencia Celular , Diabetes Mellitus Experimental , Inflamasomas , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Fenantrenos , Transducción de Señal , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Ratones , FN-kappa B/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Fenantrenos/farmacología , Senescencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Catalasa/metabolismo , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacosRESUMEN
A fundamental understanding of the underlying mechanisms involved in biological invasions is crucial to developing effective risk assessment and control measures against invasive species. The fall armyworm (FAW), Spodoptera frugiperda, is a highly invasive pest that has rapidly spread from its native Americas into much of the Eastern Hemisphere, with a highly homogeneous nuclear genetic background. However, the exact mechanism behind its rapid introduction and propagation remains unclear. Here, a systematic investigation is conducted into the population dynamics of FAW in China from 2019 to 2021 and found that FAW individuals carrying "rice" mitochondria (FAW-mR) are more prevalent (>98%) than that with "corn" mitochondria (FAW-mC) at the initial stage of the invasion and in newly-occupied non-overwintering areas. Further fitness experiments show that the two hybrid-strains of FAW exhibit different adaptions in the new environment in China, and this may have been facilitated by amino acid changes in mitochondrial-encoded proteins. FAW-mR used increases energy metabolism, faster wing-beat frequencies, and lower wing loadings to drive greater flight performance and subsequent rapid colonization of new habitats. In contrast, FAW-mC individuals adapt with more relaxed mitochondria and shuttle energetics into maternal investment, observed as faster development rate and higher fecundity. The presence of two different mitochondria types within FAW has the potential to significantly expand the range of damage and enhance competitive advantage. Overall, the study describes a novel invasion mechanism displayed by the FAW population that facilitates its expansion and establishment in new environments.
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BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.
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Modelos Animales de Enfermedad , Inflamasomas , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Proteína con Dominio Pirina 3 de la Familia NLR , Fenantrenos , Transducción de Señal , Quinasa Syk , Vasodilatación , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Quinasa Syk/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Fenantrenos/farmacología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Vasodilatación/efectos de los fármacos , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/fisiopatología , Vasodilatadores/farmacología , Fosforilación , Ratones , Aorta/efectos de los fármacos , Aorta/fisiopatología , Aorta/metabolismo , Aorta/enzimología , Apolipoproteínas ERESUMEN
Perineural invasion (PNI) is an adverse prognostic feature of pancreatic ductal adenocarcinoma (PDAC). However, the understanding of the interactions between tumors and neural signaling within the tumor microenvironment is limited. In the present study, we found that MUC21 servers as an independent risk factor for poor prognosis in PDAC. Furthermore, we demonstrated that MUC21 promoted the metastasis and PNI of PDAC cells by activating JNK and inducing epithelial-mesenchymal transition (EMT). Mechanistically, glial cell-derived neurotrophic factor, secreted by Schwann cells, phosphorylates the intracellular domain S543 of MUC21 via CDK1 in PDAC cells, facilitating the interaction between MUC21 and RAC2. This interaction leads to membrane anchoring and activation of RAC2, which in turn activates the JNK/ZEB1/EMT axis, ultimately enhancing the metastasis and PNI of PDAC cells. Our results present a novel mechanism of PNI, suggesting that MUC21 is a potential prognostic marker and therapeutic target for PDAC.
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Carcinoma Ductal Pancreático , Transición Epitelial-Mesenquimal , Invasividad Neoplásica , Neoplasias Pancreáticas , Proteína RCA2 de Unión a GTP , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Fosforilación , Animales , Línea Celular Tumoral , Ratones , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Proteínas de Unión al GTP rac/metabolismo , Proteínas de Unión al GTP rac/genética , Pronóstico , Metástasis de la Neoplasia , Masculino , Femenino , Ratones DesnudosRESUMEN
It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Fragilidad , Lenalidomida , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Anciano , Estudios Prospectivos , Masculino , Femenino , Anciano de 80 o más Años , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Lenalidomida/uso terapéutico , Lenalidomida/administración & dosificación , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Medicina de Precisión/métodos , Anciano Frágil , Evaluación Geriátrica/métodos , Anticuerpos MonoclonalesRESUMEN
Bitter taste perception plays a critical role in deterring animals from consuming harmful and toxic substances. To characterize the evolution of primate Tas2r, test the generality of Tas2r duplication in Cercopithecidae species, and examine whether dietary preferences have shaped the Tas2r repertoire of primate species, we identified Tas2r in the genomes of 35 primate species, including 16 Cercopithecidae, 6 Hominidae, 4 Cebidae, 3 Lemuridae, and 6 other species. The results showed that the total number of primate Tas2r ranged from 27 to 51, concentrating on 2 to 4 scaffolds of each species. Closely related genes were tandemly duplicated in the same scaffold. Phylogenetic construction revealed that Tas2r can be divided into 21 clades, including anthropoid-, Strepsirrhini-, and Cercopithecidae-specific Tas2r duplications. Phylogenetically independent contrast analysis revealed that the number of intact Tas2r significantly correlated with feeding preferences. Altogether, our data support diet as a driver of primate Tas2r evolution, and Cercopithecidae species have developed some specific Tas2r duplication during evolution. These results are probably because most Cercopithecidae species feed on plants containing many toxins, and it is necessary to develop specialized Tas2r to protect them from poisoning.
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Dieta , Evolución Molecular , Filogenia , Primates , Receptores Acoplados a Proteínas G , Animales , Receptores Acoplados a Proteínas G/genética , Primates/genética , Duplicación de Gen , Gusto/genética , HumanosRESUMEN
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-ß-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-ß-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.
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Senescencia Celular , Diabetes Mellitus Experimental , Factores de Crecimiento de Fibroblastos , Inflamasomas , Ratones Endogámicos C57BL , Músculo Liso Vascular , Proteína con Dominio Pirina 3 de la Familia NLR , PPAR gamma , Transducción de Señal , Quinasa Syk , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Quinasa Syk/metabolismo , Quinasa Syk/genética , PPAR gamma/metabolismo , PPAR gamma/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Inflamasomas/metabolismo , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Masculino , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patologíaRESUMEN
The regenerative microenvironment after peripheral nerve injury is imbalanced and difficult to rebalance, which is mainly affected by inflammation, oxidative stress, and inadequate blood supply. The difficulty in remodeling the nerve regeneration microenvironment is the main reason for slow nerve regeneration. Traditional drug treatments have certain limitations, such as difficulty in penetrating the blood-nerve barrier and lack of pleiotropic effects. Therefore, there is an urgent need to build multifunctional nerve grafts that can effectively regulate the regenerative microenvironment and promote nerve regeneration. Nitric oxide (NO), a highly effective gas transmitter with diatomic radicals, is an important regulator of axonal growth and migration, synaptic plasticity, proliferation of neural precursor cells, and neuronal survival. Moreover, NO provides potential anti-inflammation, anti-oxidation, and blood vessel promotion applications. However, excess NO may cause cell death and neuroinflammatory cell damage. The prerequisite for NO treatment of peripheral nerve injury is that it is gradually released over time. In this study, we constructed an injectable NO slow-release system with two main components, including macromolecular NO donor nanoparticles (mPEG-P(MSNO-EG) nanoparticles, NO-NPs) and a carrier for the nanoparticles, mPEG-PA-PP injectable temperature-sensitive hydrogel. Due to the multiple physiological regulation of NO and better physiological barrier penetration, the conduit effectively regulates the inflammatory response and oxidative stress of damaged peripheral nerves, promotes nerve vascularization, and nerve regeneration and docking, accelerating the nerve regeneration process. STATEMENT OF SIGNIFICANCE: The slow regeneration speed of peripheral nerves is mainly due to the destruction of the regeneration microenvironment. Neural conduits with drug delivery capabilities have the potential to improve the microenvironment of nerve regeneration. However, traditional drugs are hindered by the blood nerve barrier and cannot effectively target the injured area. NO, an endogenous gas signaling molecule, can freely cross the blood nerve barrier and act on target cells. However, excessive NO can lead to cell apoptosis. In this study, a NO sustained-release system was constructed to regulate the microenvironment of nerve regeneration through various pathways and promote nerve regeneration.
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Preparaciones de Acción Retardada , Regeneración Nerviosa , Óxido Nítrico , Animales , Óxido Nítrico/metabolismo , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Regeneración Nerviosa/efectos de los fármacos , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/terapia , Traumatismos de los Nervios Periféricos/patología , Traumatismos de los Nervios Periféricos/metabolismo , Ratas Sprague-Dawley , Ratas , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/patología , Nanopartículas/química , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/uso terapéutico , Masculino , Hidrogeles/química , Nervio Ciático/efectos de los fármacosRESUMEN
Objective: This study aims to develop and validate a suitable scale for assessing the level of nurses' knowledge and practice of perioperative pulmonary rehabilitation. Methods: We divided the study into two phases: scale development and validation. In Phase 1, the initial items were generated through a literature review. In Phase 2, a cross-sectional survey was conducted involving 603 thoracic nurses to evaluate the scale's validity, reliability, and difficulty and differentiation of items. Item and exploratory factor analyses were performed for item reduction. Thereafter, their validity, reliability, difficulty, and differentiation of items were assessed using Cronbach's α coefficient, retest reliability, content validity, and item response theory (IRT). Results: The final questionnaire comprised 34 items, and exploratory factor analysis revealed 3 common dimensions with internal consistency coefficients of 0.950, 0.959, and 0.965. The overall internal consistency of the scale was 0.966, with a split-half reliability of 0.779 and a retest reliability Pearson's correlation coefficient of 0.936. The content validity of the scale was excellent (item-level content validity index = 0.875-1.000, scale-level content validity index = 0.978). The difficulty and differentiation of item response theory were all verified to a certain extent (average value = 2.391; threshold ß values = -1.393-0.820). Conclusions: The knowledge-attitudes-practices questionnaire for nurses can be used as a tool to evaluate knowledge, attitudes, and practices among nurses regarding perioperative pulmonary rehabilitation for patients with lung cancer.
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The fall armyworm (FAW), Spodoptera frugiperda, has colonized and caused consistent damage in the Eastern hemisphere. The identification of various FAW strains is essential for developing precise prevention and control measures. The triosephosphate isomerase (Tpi) gene is recognized as an effective marker closely linked to FAW subpopulations. However, most current studies primarily focus on the comparison of variations in specific gene sites of this gene. In this study, we conducted full-length sequencing of the Tpi genes from 5 representative FAW groups. Our findings revealed that the Tpi genes varied in length from 1220 to 1420 bp, with the primary variation occurring within 4 introns. Notably, the exon lengths remained consistent, at 747 bp, with 37 observed base variations; however, no amino acid variations were detected. Through sequence alignment, we identified 8 stable variation sites that can be used to distinguish FAW strains in the Eastern hemisphere. Additionally, we performed strain identification on 1569 FAW samples collected from 19 provinces in China between 2020 and 2021. The extensive analysis indicated the absence of the rice strain in the samples. Instead, we only detected the presence of the corn strain and the Zambia strain, with the Zambia strain being distributed in a very low proportion (3.44%). Furthermore, the corn strain could be further categorized into 2 subgroups. This comprehensive study provides a valuable reference for enhancing our understanding of FAW population differentiation and for improving monitoring and early warning efforts.
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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has a high mortality rate and incidence of complications. The pathophysiology of ALI/ARDS is still not fully understood. The lipopolysaccharide (LPS)-induced mouse model of ALI has been widely used to study human ALI/ARDS. Sulfasalazine (SASP) has antibacterial and anti-inflammatory effects and is used for treating inflammatory bowel and rheumatic diseases. However, the effect of SASP on LPS-induced ALI in mice has not yet been reported. Therefore, we aimed to investigate the effect of SASP on LPS-induced ALI in mice. Mice were intraperitoneally injected with SASP 2 h before or 4 h after LPS modeling. Pulmonary pathological damage was measured based on inflammatory factor expression (malondialdehyde and superoxide dismutase levels) in the lung tissue homogenate and alveolar lavage fluid. The production of inflammatory cytokines and occurrence of oxidative stress in the lungs induced by LPS were significantly mitigated after the prophylactic and long-term therapeutic administration of SASP, which ameliorated ALI caused by LPS. SASP reduced both the production of inflammatory cytokines and occurrence of oxidative stress in RAW264.7 cells, which respond to LPS. Moreover, its mechanism contributed to the suppression of NF-κB and nuclear translocation. In summary, SASP treatment ameliorates LPS-induced ALI by mediating anti-inflammatory and antioxidant effects, which may be attributed to the inhibition of NF-κB activation and promotion of antioxidant defenses. Thus, SASP may be a promising pharmacologic agent for ALI therapy.
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Lesión Pulmonar Aguda , Síndrome de Dificultad Respiratoria , Ratones , Humanos , Animales , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Sulfasalazina/efectos adversos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Pulmón/patología , Estrés Oxidativo , Antiinflamatorios/farmacología , Citocinas/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patologíaRESUMEN
To further understand the complexation and fragmentation during the extraction process, the formation of 2,9-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-12,4-benzotriazin-3-yl)-1,10-phenanthroline (CyMe4-BTPhen) complexes with lanthanides (Ln = La, Ce, Nd, Sm, Eu, Yb) and actinides (UO22+, Th4+) was observed by electrospray ionization mass spectrometry (ESI-MS) technique and density functional theory (DFT) calculations. Mass spectrometry titrations showed the variation relationship of different complexes in acetonitrile. For lanthanides, the major complexes were 1:2 species ([Ln(L)2]3+ and [Ln(L)2(NO3)]2+) with a ratio of 1:2, which were observed at the initial addition of Ln3+, whereas the species ([Ln(L)(NO3)2]+) with a ratio of 1:1 was detected when the [Ln]/[L] concentration ratio reached 1.0. For UO22+ and Th4+ complexes, 1:1 or 1:2 species ([UO2L(NO3)]+, Th(L)2(NO3)3+ and Th(L)2(NO3)22+) were formed. The fragmentation chemistry of both the ligand and the complex cations was characterized in detail by collision-induced dissociation. The fragmentation process of CyMe4-BTPhen was unfolded sequentially on both sides of the ligand by cleavage of C-C and C-N bonds. DFT calculations provided a detailed analysis of the structures and thermodynamics of those complexes, which indicated that the stable complexes formed in acetonitrile solution were consistent with the ESI-MS results.
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As one of novel hallmarks of cancer, lipid metabolic reprogramming has recently been becoming fascinating and widely studied. Lipid metabolic reprogramming in cancer is shown to support carcinogenesis, progression, distal metastasis, and chemotherapy resistance by generating ATP, biosynthesizing macromolecules, and maintaining appropriate redox status. Notably, increasing evidence confirms that lipid metabolic reprogramming is under the control of dysregulated non-coding RNAs in cancer, especially lncRNAs and circRNAs. This review highlights the present research findings on the aberrantly expressed lncRNAs and circRNAs involved in the lipid metabolic reprogramming of cancer. Emphasis is placed on their regulatory targets in lipid metabolic reprogramming and associated mechanisms, including the clinical relevance in cancer through lipid metabolism modulation. Such insights will be pivotal in identifying new theranostic targets and treatment strategies for cancer patients afflicted with lipid metabolic reprogramming.
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Neoplasias , ARN Largo no Codificante , Humanos , ARN Circular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Reprogramación Metabólica , Neoplasias/genética , Neoplasias/metabolismo , Epigénesis Genética/genética , LípidosRESUMEN
In this study, the disrupting effects of glyphosate (GLY), aminomethylphosphonic acid (AMPA), and three glyphosate-based herbicides (GBHs) on vitellogenesis in a non-concentration-dependent manner are reported for the first time in 120 h of acute exposure of zebrafish at environmentally relevant concentrations. GBHs are commonly used worldwide in weed control management. Due to their extensive application, they frequently occur in aquatic ecosystems and may affect various organisms. The active substance GLY and its major by-product, AMPA, are the most thoroughly studied chemicals; however, the adverse effects of the complex formulas of GBHs with diverse and unknown content of co-formulants are still not sufficiently researched. This study focused on the embryotoxicity, sublethal malformations, and estrogenic potency of GLY, AMPA, and four commonly used GBHs on zebrafish embryos using a wild type and an estrogen-sensitive, transgenic zebrafish line (Tg(vtg1:mCherry)). After 120 h of exposition, AMPA did not cause acute toxicity, while the LC50 of GLY was 160 mg/L. The GBHs were more toxic with LC50 values ranging from 31 to 111 GLY active equivalent (a.e.) mg/L. Exposure to 0.35-2.8 mg/L GBHs led to sublethal abnormalities: typical symptoms were structural deformation of the lower jaw and anomalies in the olfactory region. Deformity rates were 10-30% in the treated groups. In vivo, fluorescently expressed vtg1 mCherry protein in embryonic liver was detected by a non-invasive microscopic method indicating estrogenic action through vitellogenin production by GLY, AMPA, and GBHs. To confirm the in vivo findings, RT-qPCR method was performed to determine the levels of the estrogenicity-related vtg1 mRNA. After 120 h of exposure to GLY, AMPA, and three GBHs at a concentration of 0.35 mg/L, the expression of vtg1 gene was significantly up-regulated. Our results highlight the risk that short-term GLY and GBH exposure can cause developmental malformations and disrupt the hormonal balance in zebrafish embryos.
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Glifosato , Herbicidas , Organofosfonatos , Animales , Pez Cebra , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico , Glicina/toxicidad , Ecosistema , Herbicidas/toxicidad , Animales Modificados Genéticamente , EstronaRESUMEN
Peripheral nerve regeneration is a complex physiological process. Single-function nerve scaffolds often struggle to quickly adapt to the imbalanced regenerative microenvironment, leading to slow nerve regeneration and limited functional recovery. In this study, we demonstrate a "pleiotropic gas transmitter" strategy based on endogenous reactive oxygen species (ROS), which trigger the on-demand H2S release at the defect area for transected peripheral nerve injury (PNI) repair through concurrent neuroregeneration and neuroprotection processing. This H2S delivery system consists of an H2S donor (peroxyTCM) encapsulated in a ROS-responsive polymer (mPEG-PMet) and loaded into a temperature-sensitive poly (amino acid) hydrogel (mPEG-PA-PP). This multi-effect combination strategy greatly promotes the regeneration of PNI, attributed to the physiological effects of H2S. These effects include the inhibition of inflammation and oxidative stress, protection of nerve cells, promotion of angiogenesis, and the restoration of normal mitochondrial function. The adaptive release of pleiotropic messengers to modulate the tissue regeneration microenvironment offers promising peripheral nerve repair and tissue engineering opportunities.
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Sulfuro de Hidrógeno , Traumatismos de los Nervios Periféricos , Humanos , Sulfuro de Hidrógeno/farmacología , Especies Reactivas de Oxígeno , Polietilenglicoles , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Regeneración NerviosaRESUMEN
BACKGROUND: Exposure to general anesthesia influences neuronal functions during brain development. Recently, interneurons were found to be involved in developmental neurotoxicity by anesthetic exposure. But the underlying mechanism and long-term consequences remain elusive. METHODS: Pregnant mice received 2.5% sevoflurane for 6-h on gestational day 14.5. Pentylenetetrazole (PTZ)-induced seizure, anxiety- and depression-like behavior tests were performed in 30- and 60-day-old male offspring. Cortical interneurons were labeled using Rosa26-EYFP/-; Nkx2.1-Cre mice. Immunofluorescence and electrophysiology were performed to determine the cortical interneuron properties. Q-PCR and in situ hybridization (ISH) were performed for the potential mechanism, and the finding was further validated by in utero electroporation (IUE). RESULTS: In this study, we found that maternal sevoflurane exposure increased epilepsy susceptibility by using pentylenetetrazole (PTZ) induced-kindling models and enhanced anxiety- and depression-like behaviors in adolescent offspring. After sevoflurane exposure, the highly ordered cortical interneuron migration was disrupted in the fetal cortex. In addition, the resting membrane potentials of fast-spiking interneurons in the sevoflurane-treated group were more hyperpolarized in adolescence accompanied by an increase in inhibitory synapses. Both q-PCR and ISH indicated that CXCL12/CXCR4 signaling pathway downregulation might be a potential mechanism under sevoflurane developmental neurotoxicity which was further confirmed by IUE and behavioral tests. Although the above effects were obvious in adolescence, they did not persist into adulthood. CONCLUSIONS: Our findings demonstrate that maternal anesthesia impairs interneuron migration through the CXCL12/CXCR4 signaling pathway, and influences the interneuron properties, leading to the increased epilepsy susceptibility in adolescent offspring. Our study provides a novel perspective on the developmental neurotoxicity of the mechanistic link between maternal use of general anesthesia and increased susceptibility to epilepsy.
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Epilepsia , Pentilenotetrazol , Humanos , Embarazo , Femenino , Ratones , Animales , Masculino , Sevoflurano/metabolismo , Sevoflurano/farmacología , Pentilenotetrazol/toxicidad , Pentilenotetrazol/metabolismo , Exposición Materna/efectos adversos , Interneuronas/metabolismo , Epilepsia/inducido químicamenteRESUMEN
BACKGROUND: UTE has been used to depict lung parenchyma. However, the insufficient discussion of its performance in pediatric pneumonia compared with conventional sequences is a gap in the existing literature. The objective of this study was to compare the diagnostic value of 3D-UTE with that of 3D T1-GRE and T2-FSE sequences in young children diagnosed with pneumonia. METHODS: Seventy-seven eligible pediatric patients diagnosed with pneumonia at our hospital, ranging in age from one day to thirty-five months, were enrolled in this study from March 2021 to August 2021. All patients underwent imaging using a 3 T pediatric MR scanner, which included three sequences: 3D-UTE, 3D-T1 GRE, and T2-FSE. Subjective analyses were performed by two experienced pediatric radiologists based on a 5-point scale according to six pathological findings (patchy shadows/ground-glass opacity (GGO), consolidation, nodule, bulla/cyst, linear opacity, and pleural effusion/thickening). Additionally, they assessed image quality, including the presence of artifacts, and evaluated the lung parenchyma. Interrater agreement was assessed using intraclass correlation coefficients (ICCs). Differences among the three sequences were evaluated using the Wilcoxon signed-rank test. RESULTS: The visualization of pathologies in most parameters (patchy shadows/GGO, consolidation, nodule, and bulla/cyst) was superior with UTE compared to T2-FSE and T1 GRE. The visualization scores for linear opacity were similar between UTE and T2-FSE, and both were better than T1-GRE. In the case of pleural effusion/thickening, T2-FSE outperformed the other sequences. However, statistically significant differences between UTE and other sequences were only observed for patchy shadows/GGO and consolidation. The overall image quality was superior or at least comparable with UTE compared to T2-FSE and T1-GRE. Interobserver agreements for all visual assessments were significant and rated "substantial" or "excellent." CONCLUSIONS: In conclusion, UTE MRI is a useful and promising method for evaluating pediatric pneumonia, as it provided better or similar visualization of most imaging findings compared with T2-FSE and T1-GRE. We suggest that the UTE MRI is well-suited for pediatric population, especially in younger children with pneumonia who require longitudinal and repeated imaging for clinical care or research and are susceptible to ionizing radiation.
Asunto(s)
Quistes , Derrame Pleural , Neumonía , Preescolar , Humanos , Recién Nacido , Vesícula , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Neumonía/diagnóstico por imagen , LactanteRESUMEN
Electrospray Ionization Mass Spectrometry (ESI-MS) technique and density functional theory (DFT) calculations were combined to study the formation of the complexes of lanthanides (Ln = La, Ce, Nd, Sm, Eu, Yb) and actinides (UO2 2+ , Th4+ ) with CyMe4 -BTBP (6,6'-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-benzo-[1,2,4-]triazin-3-yl)-[2,2']bipyridine) to understand the mechanisms during the extraction process. Mass spectrometry titrations showed the formation of the complexation in acetonitrile. For lanthanides, only 1:2 complexes ([Ln(L)2 ]3+ , [Ln(L)2 (CH3 CN)]3+ ), [Ln(L)2 (NO3 )]2+ ) were found at low [Ln]/[L] concentration ratios, whereas the 1:1 complexes ([Ln(L)(NO3 )2 ]+ ) were observed when the [Ln]/[L] concentration ratio reached 1.0. For uranyl complexes, 1:1 complex ([UO2 L(NO3 )]+ ) was the only species within the measuring range. Th4+ complexes had two compositions: 1:1 and 1:2, in which 1:2 species was the dominant complex. Collision-induced dissociation (CID) was employed to characterize the fragmentation process. The fragmentation process was unfolded sequentially on both sides of CyMe4 -BTBP ligand with the loss of alkyl groups and cleavage of triazinyl rings. The CID results of CyMe4 -BTBP complexes revealed a slight difference depending on the metal center. The DFT calculations showed that the stable complexes formed in acetonitrile solution were consistent with the ESI-MS results.
RESUMEN
Bitter taste perception plays an important role in preventing animals from digesting poisonous and harmful substances. In primates, especially the Cercopithecidae species, most species feed on plants; thus, it is reasonable to speculate that most of the bitter taste receptor genes (T2Rs) of primates are under purifying selection to maintain the functional stability of bitter taste perception. Gene duplication has happened in T2Rs frequently, and what will be the fate of T2Rs copies is another question we are concerned about. To answer these questions, we selected the T2Rs of primates reported in another study and conducted corresponding selective pressure analyses to determine what kind of selective pressure was acting on them. Further, we carried out selective pressure analyses on gene copies and their corresponding ancestors by considering several possible situations. The results showed that among the 25 gene groups examined here, 15 groups are subject to purifying selection and others are under relaxed selection, with many positively selected sites detected. Gene copies existed in several groups, but only some groups (clade1_a1-b2, clade1_c-c2, clade1_d1-d3, clade1_f1-f2, T2R10, T2R13, and T2R42) have positively selected sites, inferring that they may have some relation to functional divergence. Taken together, T2Rs in primates are under diverse selective pressures, and most gene copies are subject to the same selective pressures. In such cases, the copies may be just to keep the function conservative, and more copies can increase the quantity of the bitter taste receptor, raise the efficiency of bitter substance recognition, and finally enhance the fitness of feeding during the evolutionary course of primates. This study can improve our understanding of T2Rs evolution in primates.