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Currently, developing luminescent materials for dual-mode optical thermometry has been becoming a rising topic, and concurrent temperature-sensitive optical parameters hold the key. Still, it is a serious challenge, since distinct activators are generally needed and energy transfer (ET) processes among activators inevitably occur, further leading to severe luminescence quenching. Herein, a spatial separation strategy is proposed for designing dual-phase glass ceramics (GCs) containing ZnGa2O4:Cr3+ and NaYF4:Yb3+,Er3+ nanocrystals (NCs) for dual-mode optical thermometry, in order to integrate diversified activators into one. Structural, morphological, and optical characterizations are examined to verify the partition of Cr3+ into ZnGa2O4 and Er3+ into the NaYF4 lattice in the dual-phase GC. Benefiting from such a spatial separation strategy, the adverse ET processes between Cr3+ and Er3+ could be cut off in the dual-phase GC, contributing to downshifting (DS) and upconversion (UC) luminescence. Furthermore, dual-mode optical thermometry is performed based on the lifetime of Cr3+ and fluorescence intensity ratio (FIR) of Er3+, with high relative sensitivities of 0.95% K-1@450 K and 1.24% K-1@303 K, respectively. It is evidenced that the dual-phase GC holds great potential for dual-mode optical thermometry, and this work also offers a prospective pathway for expanding the practical applications of GC luminescent materials.
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Analgésicos Opioides , Raquianestesia , Cesárea , Injeções Espinhais , Morfina , Dor Pós-Operatória , Humanos , Cesárea/métodos , Feminino , Raquianestesia/métodos , Morfina/administração & dosagem , Gravidez , Injeções Espinhais/métodos , Analgésicos Opioides/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , AdultoRESUMO
Large-leaf Yellow tea (LYT) is a traditional beverage from Camellia Sinensis (L.) O. Kuntze in China and has unusual health-regulating functions. This investigation explored the structural characteristics of a polysaccharide extracted from LYT, which possesses anti-inflammatory activity. The polysaccharide HDCP-2, obtained through ethanol fractional precipitation and then DEAE-52 anion exchange column, followed by DPPH radical scavenging screening, exhibited a yield of 0.19 %. The HPGPC method indicated that the molecular weight of HDCP-2 is approximately 2.9 × 104 Da. Analysis of the monosaccharide composition revealed that HDCP-2 consisted of mannose, glucose, xylose, and galacturonic acid, and their molar ratio is approximately 0.4:0.5:1.2:0.7. The structure motif of HDCP-2 was probed carefully through methylation analysis, FT-IR, and NMR analysis, which identified the presence of ß-d-Xylp(1â, â2, 4)-ß-d-Xylp(1â, â3)-ß-d-Manp(1â, α-d-Glcp(1â and â2, 4)-α-d-GalAp(1â linkages. A CCK-8 kit assay was employed to evaluate the anti-inflammatory action of HDCP-2. These results demonstrated that HDCP-2 could inhibit the migration and proliferation of the MH7A cells and reduce NO production in an inflammatory model induced by TNF-α. The abundant presence of xylose accounted for 39 % of the LYT polysaccharide structure, and its distinctive linking mode (â2, 4)-ß-d-Xylp(1â) appears to be the primary contributing factor to its anti-inflammatory effect.
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Digital light processing (DLP) bioprinting, known for its high resolution and speed, enables the precise spatial arrangement of biomaterials and has become integral to advancing tissue engineering and regenerative medicine. Nevertheless, inherent light scattering presents significant challenges to the fidelity of the manufactured structures. Herein, we introduce a photoinhibition strategy based on Rutin nanoparticles (Rnps), attenuating the scattering effect through concurrent photoabsorption and free radical reaction. Compared to the widely utilized biocompatible photoabsorber tartrazine (Tar), Rnps-infused bioink enhanced printing speed (1.9×), interlayer homogeneity (58% less overexposure), resolution (38.3% improvement), and print tolerance (3× high-precision range) to minimize trial-and-error. The biocompatible and antioxidative Rnps significantly improved cytocompatibility and exhibited resistance to oxidative stress-induced damage in printed constructs, as demonstrated with human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs). The related properties of Rnps facilitate the facile fabrication of multimaterial, heterogeneous, and cell-laden biomimetic constructs with intricate structures. The developed photoinhibitor, with its profound adaptability, promises wide biomedical applications tailored to specific biological requirements.
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Bioimpressão , Luz , Nanopartículas , Rutina , Humanos , Rutina/química , Rutina/farmacologia , Nanopartículas/química , Engenharia Tecidual , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
INTRODUCTION: Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. OBJECTIVES: This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. METHODS: Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vitro and in vivo experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. RESULTS: Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin-proteasome degradation, restoring SIRT1's role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. CONCLUSION: Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.
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The recent surge in Internet growth has significantly altered how residents obtain health information and services, underscoring the need to investigate its impact on healthcare perceptions. However, current studies often fail to distinguish between Internet use and involvement, as well as the diverse range of healthcare stakeholders, resulting in incomplete and inconsistent understanding. To address this, this study utilized data from the 2018 China Family Panel Study (CFPS 2018), categorizing attitudes toward healthcare into three dimensions: doctor trust, satisfaction with medical institutions, and perception of systemic healthcare issues. Employing propensity score matching (PSM) to control for thirteen confounding variables, this study examined the Internet's impact on public attitudes toward healthcare among similar demographic, psychological, and health-related variables. Results revealed that both Internet use and involvement affect residents' attitudes toward healthcare to some extent, with involvement having a more pronounced effect. While Internet use increased the perception of systemic healthcare issues, Internet involvement enhanced doctor trust, yet reduced satisfaction with medical institutions and exaggerated the perception of systemic healthcare issues. These findings have significant theoretical and practical implications. They enhance the comprehension of diverse levels and purposes of Internet use, thereby advancing our knowledge of its multi-faced influence on public attitudes toward healthcare. Furthermore, they offer insights for medical institutions to improve service quality, assist Internet media in optimizing information delivery, and illuminate the implications for residents who effectively use the Internet to assess health information.
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Pontuação de Propensão , Humanos , China , Masculino , Feminino , Adulto , Uso da Internet/estatística & dados numéricos , Confiança , Pessoa de Meia-Idade , Atenção à Saúde , Inquéritos e Questionários , Internet , AtitudeRESUMO
BACKGROUND: Post-stroke infection is the most common complication of stroke and poses a huge threat to patients. In addition to prolonging the hospitalization time and increasing the medical burden, post-stroke infection also significantly increases the risk of disease and death. Clarifying the risk factors for post-stroke infection in patients with acute ischemic stroke (AIS) is of great significance. It can guide clinical practice to perform corresponding prevention and control work early, minimizing the risk of stroke-related infections and ensuring favorable disease outcomes. AIM: To explore the risk factors for post-stroke infection in patients with AIS and to construct a nomogram predictive model. METHODS: The clinical data of 206 patients with AIS admitted to our hospital between April 2020 and April 2023 were retrospectively collected. Baseline data and post-stroke infection status of all study subjects were assessed, and the risk factors for post-stroke infection in patients with AIS were analyzed. RESULTS: Totally, 48 patients with AIS developed stroke, with an infection rate of 23.3%. Age, diabetes, disturbance of consciousness, high National Institutes of Health Stroke Scale (NIHSS) score at admission, invasive operation, and chronic obstructive pulmonary disease (COPD) were risk factors for post-stroke infection in patients with AIS (P < 0.05). A nomogram prediction model was constructed with a C-index of 0.891, reflecting the good potential clinical efficacy of the nomogram prediction model. The calibration curve also showed good consistency between the actual observations and nomogram predictions. The area under the receiver operating characteristic curve was 0.891 (95% confidence interval: 0.839-0.942), showing predictive value for post-stroke infection. When the optimal cutoff value was selected, the sensitivity and specificity were 87.5% and 79.7%, respectively. CONCLUSION: Age, diabetes, disturbance of consciousness, NIHSS score at admission, invasive surgery, and COPD are risk factors for post-stroke infection following AIS. The nomogram prediction model established based on these factors exhibits high discrimination and accuracy.
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It remains unclear how ambient air pollution may affect the prevalence of obstructive ventilatory dysfunction (OVD) among workers. We aim to assess the association of a comprehensive set of ambient air pollutants with OVD prevalence in workers and to explore the potential interactive effects of the occupational factors. This is a population-based cross-sectional study among 305,022 participants from the Guangdong Province, China. Mixed-effects models were used to obtain differences in the OVD risk associated with a 10 µg/m3 increase in ambient air pollution. We found that for each 10 µg/m3 increase in PM2.5, PM10, PM coarse, O3, and NO2 concentrations, the odds ratio (OR) for OVD in workers is 1.324 (95 % confidence interval (CI), 1.282-1.367), 1.292 (95 % CI, 1.268-1.315),1.666 (95 % CI, 1.614-1.719), 1.153 (95 % CI, 1.142-1.165), and 1.023 (95 % CI, 1.012-1.033). We observed that young participants (18-38 years old), women, participants with longer years of service (>48 months), participants working in large enterprises, professional skills workers, and production and manufacturing workers have higher estimated effects. In addition, we also found that workers exposed to high temperatures have higher estimated effects under air pollutants exposure, while workers exposed to noise have higher estimated effects under PM2.5, PM10, NO2, and O3 exposure. Workers exposed to dust have a lower risk of developing OVD under exposure to ambient air pollutants compared to those not exposed. Our results indicate that ambient air pollution increases the risk of OVD in workers. Moreover, air pollutants exhibit a greater estimated effect among workers exposed to high temperatures or noise. Our research findings highlight the importance of fully considering the impact of ambient air pollution on protecting the respiratory health of workers.
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Poluentes Atmosféricos , Poluição do Ar , Exposição Ocupacional , Humanos , Adulto , China/epidemiologia , Feminino , Masculino , Poluição do Ar/estatística & dados numéricos , Exposição Ocupacional/estatística & dados numéricos , Estudos Transversais , Poluentes Atmosféricos/análise , Adulto Jovem , Material Particulado/análise , Pessoa de Meia-Idade , AdolescenteRESUMO
Photocatalytic carbon dioxide (CO2) conversion and simultaneous pollutant oxidation in a single system are promising approaches to mitigate energy and environmental challenges. However, the limited availability of active photocatalyst sites led to slow reaction kinetics and poor selectivity. Current research has predominantly focused on ground-state reactive sites of semiconductors, with less emphasis on active sites in their excited states. Therefore, gaining insights into the active sites in the excited state of semiconductors could provide a significant breakthrough in understanding the photocatalytic reaction mechanism. In this study, cobalt-doped bismuth oxychloride nanosheets containing abundant oxygen vacancies (OVs) were used as a model to investigate the active sites in excited states. These nanosheets were used to integrate CO2 reduction with tetracycline (TC) oxidation. Combining theoretical calculations with in situ characterizations revealed that under excited-state conditions photogenerated electrons transfer from cobalt (Co) dopants to OVs and subsequently to bismuth (Bi) atoms, forming Bi(3-x)+ sites enriched with excited electrons. These excited-electron-rich Bi(3-x)+ sites and electron-deficient Co sites contribute to CO2 reduction and TC oxidation, respectively. This study provides a comprehensive understanding of active sites in the excited state in doped semiconductors at the atomic level, reinforcing their potential for synergistic CO2 reduction and pollutant degradation.
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Short-term exposure to PM2.5 or O3 can increase mortality risk; however, limited studies have evaluated their interaction. A multicity time series study was conducted to investigate the synergistic effect of PM2.5 and O3 on mortality in China, using mortality data and high-resolution pollutant predictions from 272 cities in 2013-2015. Generalized additive models were applied to estimate associations of PM2.5 and O3 with mortality. Modification and interaction effects were explored by stratified analyses and synergistic indexes. Deaths attributable to PM2.5 and O3 were evaluated with or without modification of the other pollutant. The risk of total nonaccidental mortality increased by 0.70% for each 10 µg/m3 increase in PM2.5 when O3 levels were high, compared to 0.12% at low O3 levels. The effect of O3 on total nonaccidental mortality at high PM2.5 levels (1.26%) was also significantly higher than that at low PM2.5 levels (0.59%). Similar patterns were observed for cardiovascular or respiratory diseases. The relative excess risk of interaction and synergy index of PM2.5 and O3 on nonaccidental mortality were 0.69% and 1.31 with statistical significance, respectively. Nonaccidental deaths attributable to short-term exposure of PM2.5 or O3 when considering modification of the other pollutant were 28% and 31% higher than those without considering modification, respectively. Our results found synergistic effects of short-term coexposure to PM2.5 and O3 on mortality and suggested underestimations of attributable risks without considering their synergistic effects.
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Poluentes Atmosféricos , Cidades , Ozônio , Material Particulado , China/epidemiologia , Humanos , Poluentes Atmosféricos/toxicidade , Exposição Ambiental , MortalidadeRESUMO
Despite the superior efficacy of radiotherapy in esophageal squamous cell carcinoma (ESCC), radioresistance by cancer stem cells (CSCs) leads to recurrence, metastasis, and treatment failure. Therefore, it is necessary to develop CSC-based therapies to enhance radiotherapy. miR-339-5p (miR339) is involved in stem cell division and DNA damage checkpoint signaling pathways based on ESCC cohort. miR339 inhibited ESCC cell stemness and enhanced radiation-induced DNA damage by targeting USP8, suggesting that it acts as a potential CSC regulator and radiosensitizer. Considering the limited circulating periods and poor tumor-targeting ability of miRNA, a multifunctional nanoplatform based on bismuth sulfide nanoflower (Bi@PP) is developed to efficiently deliver miR339 and improve radioresistance. Intriguingly, Bi@PP encapsulates more miR339 owing to their flower-shaped structure, delivering more than 1000-fold miR339 into cells, superior to free miR339 alone. Besides being used as a carrier, Bi@PP is advantageous for dynamically monitoring the distribution of delivered miR339 in vivo while simultaneously inhibiting tumor growth. Additionally, Bi@PP/miR339 can significantly enhance radiotherapy efficacy in patient-derived xenograft models. This multifunctional platform, incorporating higher miRNA loading capacity, pH responsiveness, hypoxia relief, and CT imaging, provides another method to promote radiosensitivity and optimize ESCC treatment.
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Bismuto , Neoplasias Esofágicas , MicroRNAs , Células-Tronco Neoplásicas , Sulfetos , Bismuto/química , Bismuto/farmacologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Sulfetos/química , Sulfetos/farmacologia , Animais , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Camundongos , Tolerância a Radiação/efeitos dos fármacos , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Camundongos Nus , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/genéticaRESUMO
BACKGROUND AND AIMS: An imbalance in lipid metabolism is the main cause of NAFLD. While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of IL-22 protects against NAFLD; however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. APPROACH AND RESULTS: This study shows that hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly 3 beta-hydroxy-5-cholestenoic acid (3ß HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3ß HCA deposition through the activating transcription factor 3/oxysterol 7 alpha-hydroxylase axis. Notably, 3ß HCA facilitates lipogenesis in mouse primary hepatocytes and human liver organoids by activating liver X receptor-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring oxysterol 7 alpha-hydroxylase or silencing hepatic activating transcription factor 3 reduces both hepatic 3ß HCA and lipid contents in hepatocyte-specific Il22ra1 knockout mice. CONCLUSIONS: These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an activating transcription factor 3/oxysterol 7 alpha-hydroxylase-dependent manner and establish a link between 3ß HCA and hepatic lipid homeostasis.
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Routine pediatric vaccination is one of the most effective public health inter-ventions for the control of a number of fatal diseases. However, during the coronavirus disease 2019 pandemic, routine pediatric vaccination rates were severely affected by disruptions of health services and vaccine confidence issues. Governments and the United Nations have taken measures to re-establish routine pediatric vaccination, while additional efforts are needed to catch up and develop plans to ensure routine vaccination services for the future pandemics.
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BACKGROUND: The ginseng endophyte Paenibacillus polymyxa Pp-7250 (Pp-7250) has multifaceted roles such as preventing ginseng diseases, promoting growth, increasing ginsenoside accumulation, and degrading pesticide residues, however, these effects still have room for improvements. Composite fungicides are an effective means to improve the biocontrol effect of fungicides, but the effect of Pp-7250 in combination with its symbiotic bacteria on ginseng needs to be further investigated, and its mechanism of action has not been elucidated. In this study, a series of experiments was conducted to elucidate the effect of Paenibacillus polymyxa and Bacillus cereus co-bacterial agent on the yield and quality of understory ginseng, and to investigate their mechanism of action. RESULTS: The results indicated that P. polymyxa and B. cereus co-bacterial agent (PB) treatment improved ginseng yield, ginsenoside accumulation, disease prevention, and pesticide degradation. The mechanism is that PB treatment increased the abundance of beneficial microorganisms, including Rhodanobacter, Pseudolabrys, Gemmatimonas, Bacillus, Paenibacillus, Cortinarius, Russula, Paecilomyces, and Trechispora, and decreased the abundance of pathogenic microorganisms, including Ellin6067, Acidibacter, Fusarium, Tetracladium, Alternaria, and Ilyonectria in ginseng rhizosphere soil. PB co-bacterial agents enhanced the function of microbial metabolic pathways, biosynthesis of secondary metabolites, biosynthesis of antibiotics, biosynthesis of amino acids, carbon fixation pathways in prokaryotes, DNA replication, and terpenoid backbone biosynthesis, and decreased the function of microbial plant pathogens and animal pathogens. CONCLUSION: The combination of P. polymyxa and B. cereus may be a potential biocontrol agent to promote the resistance of ginseng to disease and improve the yield, quality, and pesticide degradation.
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Ginsenosídeos , Paenibacillus polymyxa , Panax , Doenças das Plantas , Rizosfera , Panax/microbiologia , Panax/crescimento & desenvolvimento , Panax/efeitos dos fármacos , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Bacillus cereus/efeitos dos fármacos , Bacillus cereus/crescimento & desenvolvimento , Microbiologia do Solo , Endófitos/fisiologia , Endófitos/efeitos dos fármacos , Microbiota/efeitos dos fármacosRESUMO
Glycosylation and phosphorylation rank as paramount post-translational modifications, and their analysis heavily relies on enrichment techniques. In this work, a facile approach was developed for the one-step simultaneous enrichment and stepwise elution of glycoproteins and phosphoproteins. The core of this approach was the application of the novel titanium (IV) ion immobilized poly(glycidyl methacrylate) microparticles functionalized with dendrimer polyethylenimine and phytic acid. The microparticles possessed dual enrichment capabilities due to their abundant titanium ions and hydroxyl groups on the surface. They demonstrate rapid adsorption equilibrium (within 30 min) and exceptional adsorption capacity for ß-casein (1107.7 mg/g) and horseradish peroxidase (438.6 mg/g), surpassing that of bovine serum albumin (91.7 mg/g). Furthermore, sodium dodecyl sulfate-polyacrylamide gel electrophoresis was conducted to validate the enrichment capability. Experimental results across various biological samples, including standard protein mixtures, non-fat milk, and human serum, demonstrated the remarkable ability of these microparticles to enrich low-abundance glycoproteins and phosphoproteins from biological samples.
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Dendrímeros , Glicoproteínas , Fosfoproteínas , Polietilenoimina , Ácidos Polimetacrílicos , Titânio , Glicoproteínas/química , Fosfoproteínas/química , Polietilenoimina/química , Dendrímeros/química , Humanos , Titânio/química , Ácidos Polimetacrílicos/química , Interações Hidrofóbicas e Hidrofílicas , Propriedades de Superfície , Animais , Tamanho da Partícula , Adsorção , BovinosRESUMO
Regulator of G-protein signaling (RGS) proteins exhibit GTPase-accelerating protein activities to govern G-protein function. In the rice blast fungus Magnaporthe oryzae, there is a family of at least eight RGS and RGS-like proteins (MoRgs1 to MoRgs8), each exhibiting distinct or shared functions in the growth, appressorium formation, and pathogenicity. MoRgs3 recently emerged as one of the crucial regulators that senses intracellular oxidation during appressorium formation. To explore this unique regulatory mechanism of MoRgs3, we identified the nucleoside diphosphate kinase MoNdk1 that interacts with MoRgs3. MoNdk1 phosphorylates MoRgs3 under induced intracellular reactive oxygen species levels, and MoRgs3 phosphorylation is required for appressorium formation and pathogenicity. In addition, we showed that MoRgs3 phosphorylation determines its interaction with MoCrn1, a coronin-like actin-binding protein homolog, which regulates MoRgs3 internalization. Finally, we provided evidence demonstrating that MoRgs3 functions in MoMagA-mediated cAMP signaling to regulate normal appressorium induction. By revealing a novel signal perception mechanism, our studies highlighted the complexity of regulation during the appressorium function and pathogenicity of the blast fungus. IMPORTANCE: We report that MoRgs3 becomes phosphorylated in an oxidative intracellular environment during the appressorium formation stage. We found that this phosphorylation is carried out by MoNdk1, a nucleoside diphosphate kinase. In addition, this phosphorylation leads to a higher binding affinity between MoRgs3 and MoCrn1, a coronin-like actin-binding protein that was implicated in the endocytic transport of several other RGS proteins of Magnaporthe oryzae. We further found that the internalization of MoRgs3 is indispensable for its GTPase-activating protein function toward the Gα subunit MoMagA. Importantly, we characterized how such cellular regulatory events coincide with cAMP signaling-regulated appressorium formation and pathogenicity in the blast fungus. Our studies uncovered a novel intracellular reactive oxygen species signal-transducing mechanism in a model pathogenic fungus with important basic and applied implications.
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AMP Cíclico , Proteínas Fúngicas , Doenças das Plantas , Espécies Reativas de Oxigênio , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , AMP Cíclico/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Fosforilação , Doenças das Plantas/microbiologia , Oryza/microbiologia , Proteínas RGS/metabolismo , Proteínas RGS/genética , Regulação Fúngica da Expressão Gênica , Núcleosídeo-Difosfato Quinase/metabolismo , Núcleosídeo-Difosfato Quinase/genética , Ascomicetos/genética , Ascomicetos/metabolismo , Ascomicetos/patogenicidade , VirulênciaRESUMO
Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, â¼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.
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Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Fatores de Transcrição , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Animais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genéticaRESUMO
In brief: SORBS2, an RNA-binding protein, is identified as a regulator of aerobic glycolysis, which is essential for trophoblast migration and placental development. Reduced SORBS2 expression in preeclampsia may impair trophoblast migration by affecting mRNA stability and glycolysis, suggesting its role in the disease's pathogenesis. Abstract: Insufficient trophoblast migration and impaired uterine spiral artery remodeling are implicated in the pathogenesis of preeclampsia, contributing to inadequate placentation. However, the molecular mechanism underlying this process remains unclear. Aerobic glycolysis, which produces substantial lactate, is crucial for establishing a favorable microenvironment for early uterine preparation and supporting embryo implantation and trophoblast migration. In the present study, we have demonstrated that SORBS2, an RNA-binding protein, regulated aerobic glycolysis and significantly improved trophoblast migration in vitro. Our results showed that SORBS2 expression was significantly reduced in human PE placentas and trophoblasts during hypoxia. Overexpression of SORBS2 enhanced cell proliferation and migration, whereas knockdown of SORBS2 decreased these functions in HTR-8/SVneo cells. Mechanistic studies have demonstrated that SORBS2 directly interacts with the 3' untranslated regions (UTRs) of key glycolysis-related genes, specifically HK2. This interaction results in enhanced stability of HK2 and activation of glycolysis. Moreover, silencing HK2 abrogated the enhancement of proliferation and migration of HTR-8/SVneo cells induced by SORBS2. In conclusion, our findings suggest that the downregulation of SORBS2 may contribute to the pathogenesis of preeclampsia by regulating mRNA stability and inhibiting trophoblast migration during placentation.
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Movimento Celular , Glicólise , Hexoquinase , Pré-Eclâmpsia , Estabilidade de RNA , RNA Mensageiro , Proteínas de Ligação a RNA , Trofoblastos , Humanos , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Trofoblastos/metabolismo , Trofoblastos/patologia , Feminino , Gravidez , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Hexoquinase/metabolismo , Hexoquinase/genética , Adulto , Proliferação de CélulasRESUMO
To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC50 values were 24.53 ± 0.32 µM in rat liver microsomes and 18.24 ± 0.12 µM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC(0-t), Cmax of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism.
Assuntos
Crizotinibe , Citocromo P-450 CYP3A , Interações Medicamentosas , Microssomos Hepáticos , Polimorfismo Genético , Ratos Sprague-Dawley , Crizotinibe/farmacocinética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Animais , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Piridinas/farmacocinética , Pirazóis/farmacocinética , Pirazóis/farmacologiaRESUMO
The Hungarian White Goose (Anser anser domesticus) is an excellent European goose breed, with high feather and meat production. Despite its importance in the poultry industry, no available genome assembly information has been published. This study aimed to present Chromosome-level and functional genome sequencing of the Hungarian White Goose. The results showed that the genome assembly has a total length of 1115.82 Mb, 39 pairs of chromosomes, 92.98% of the BUSCO index, and contig N50 and scaffold N50 were up to 2.32 Mb and 60.69 Mb, respectively. Annotation of the genome assembly revealed 19550 genes, 286 miRNAs, etc. We identified 235 expanded and 1,167 contracted gene families in this breed compared with the other 16 species. We performed a positive selection analysis between this breed and four species of Anatidae to uncover the genetic information underlying feather follicle development. Further, we detected the function of miR-199-x, miR-143-y, and miR-23-z on goose embryonic skin fibroblast. In summary, we have successfully generated a highly complete genome sequence of the Hungarian white goose, which will provide a great resource to improve our understanding of gene functions and enhance the studies on feather follicle development at the genomic level.