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Accurate and early detection of atherosclerosis (AS) is imperative for their effective treatment. However, fluorescence probes for efficient diagnosis of AS often encounter insufficient deep tissue penetration, which hinders the reliable assessment of plaque vulnerability. In this work, a reactive oxygen species (ROS) activated near-infrared (NIR) fluorescence and photoacoustic (FL/PA) dual model probe TPA-QO-B is developed by conjugating two chromophores (TPA-QI and O-OH) and ROS-specific group phenylboronic acid ester. The incorporation of ROS-specific group not only induces blue shift in absorbance, but also inhibits the ICT process of TPA-QO-OH, resulting an ignorable initial FL/PA signal. ROS triggers the convertion of TPA-QO-B to TPA-QO-OH, resulting in the concurrent amplification of FL/PA signal. The exceptional selectivity of TPA-QO-B towards ROS makes it effectively distinguish AS mice from the healthy. The NIR emission can achieve a tissue penetration imaging depth of 0.3 cm. Moreover, its PA775 signal possesses the capability to penetrate tissues up to a thickness of 0.8 cm, ensuring deep in vivo imaging of AS model mice in early stage. The ROS-triggered FL/PA dual signal amplification strategy improves the accuracy and addresses the deep tissue penetration problem simultaneously, providing a promising tool for in vivo tracking biomarkers in life science and preclinical applications.
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Corantes Fluorescentes , Técnicas Fotoacústicas , Placa Aterosclerótica , Espécies Reativas de Oxigênio , Animais , Espécies Reativas de Oxigênio/metabolismo , Técnicas Fotoacústicas/métodos , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/metabolismo , Corantes Fluorescentes/química , Camundongos , Imagem Óptica/métodos , Camundongos Endogâmicos C57BL , Humanos , MasculinoRESUMO
BACKGROUND: Currently, there are no reliable methods for predicting and preventing atrial fibrillation (AF) in its early stages. This study aimed to identify plasma proteins associated with AF to discover biomarkers and potential drug targets. METHODS: The UK Biobank Pharma Proteomics Project examined 2923 circulating proteins using the Olink platform, forming the basis of this prospective cohort study. The UK Biobank Pharma Proteomics Project included a randomly selected discovery cohort and the consortium-selected replication cohort. The study's end point was incident AF, identified using International Classification of Diseases, Tenth Revision codes. The association between plasma proteins and incident AF was evaluated using Cox proportional hazard models in both cohorts. Proteins present in both cohorts underwent Mendelian randomization analysis to delineate causal connections, utilizing cis-protein quantitative trait loci as genetic tools. The predictive efficacy of the identified proteins for AF was assessed using the area under the receiver operating characteristic curve, and their druggability was explored. RESULTS: Data from 53â 032 participants were included in this study. Incident AF cases were identified in the discovery cohort (1894; 5.5%) within a median follow-up of 14.5 years and in the replication cohort (451; 10.6%) within a median follow-up of 14.4 years. Twenty-one proteins linked to AF were identified in both cohorts. Specifically, COL4A1 (collagen IV α-1; odds ratio, 1.11 [95% CI, 1.04-1.19]; false discovery rate, 0.016) and RET (proto-oncogene tyrosine-protein kinase receptor Ret; odds ratio, 0.96 [95% CI, 0.94-0.98]; false discovery rate, 0.013) demonstrated a causal link with AF, and RET is druggable. COL4A1 improved the short- and long-term predictive performance of established AF models, as evidenced by significant enhancements in the area under the receiver operating characteristic, integrated discrimination improvement, and net reclassification index, all with P values below 0.05. CONCLUSIONS: COL4A1 and RET are associated with the development of AF. RET is identified as a potential drug target for AF prevention, while COL4A1 serves as a biomarker for AF prediction. Future studies are needed to evaluate the effectiveness of targeting these proteins to reduce AF risk.
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Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using Iodiconazole as the lead compound. Among them, compound 19g is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus, with a MIC80 value of 0.0625 µg/mL. In addition, compounds 19e, 19f, 19g, 19h, 19i and 19k exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC80 values ranging from 0.0625 µg/mL to 32 µg/mL. Since compound 19g had optimal in vitro antifungal activity, we selected 19g for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound 19g on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound 19g on the filamentation of Candida albicans and determined the mechanism of action by sterol composition analysis.
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BACKGROUND: Methyl jasmonate (MeJA) can affect the balance of hormones and regulate the disease resistance of plants. Exploring the application and mechanism of MeJA in inducing the tolerance of Pinus koraiensis to pine wood nematode (PWN) infection is of great significance for developing new strategies for pine wilt disease control. RESULTS: Different concentrations (0.1, 1, 5 and 10 mm) of MeJA treatment groups showed differences in relative tolerance index and relative anti-nematode index of P. koraiensis seedlings to PWN infection. The treatment of 5 mm MeJA solution induced the best tolerance effect, followed by the 1 mm MeJA solution. Transcriptome analysis indicated that many plant defense-related genes upregulated after treatment with 1, 5 and 10 mm MeJA solutions. Among them, genes such as jasmonate ZIM domain-containing protein, phenylalanine ammonia-lyase and peroxidase also continuously upregulated after PWN infection. Metabolome analysis indicated that jasmonic acid (JA) was significantly increased at 7 days postinoculation with PWN, and after treatment with both 1 and 5 mm MeJA solutions. Integrated analysis of transcriptome and metabolome indicated that differences in JA accumulation might lead to ubiquitin-mediated proteolysis, and expression changes in trans-caffeic acid and trans-cinnamic acid-related genes, leading to the abundance differences of these two metabolisms and the formation of multiple lignin and glucosides. CONCLUSIONS: MeJA treatment could activate the expression of defense-related genes that correlated with JA, regulate the abundance of defense-related secondary metabolites, and improve the tolerance of P. koraiensis seedlings to PWN infection. © 2024 Society of Chemical Industry.
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Developing biochar with large specific surface area (SSA), heteroatom doping, and porous structure is attracting substantial attention to absorb electromagnetic wave (EMW) in recent. Herein, a novel method of ethanol and KOH co-treatment is used to produce the biomass carbon deriving from pitaya peels. The obtained carbon possesses the high SSA of 1580 m2/g, successful N/O atoms co-doping, and massive pores with different size. The results of EMW absorption measurement show that the prepared biochar could achieve over 99% absorpition to EMW, which the highest reflection loss is of ca. -45.25 dB at 7.54 GHz with an effective absorption bandwidth (EAB) of ca. 4.87 GHz. The execellent microwave absorption property is caused by the surface defects, dipole and interface polarizations of the synthesized biochar owning unique microstructure and N/O atoms co-doping. Hence, this avenue provides a new reference for fabricating low-cost and eco-friendly biochar as a microwave absorber.
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To develop a promising selenium supplement that overcomes the instability and poor water dispersibility of selenium nanoparticles (SeNPs), we synthesized a series of amphiphilic octenyl succinic anhydride starch (OSAS) through esterification. As the degree of substitution (DS) increased, the particle size of OSAS micelles and the critical micelle concentration (CMC) decreased. FTIR and XRD analysis confirmed the successful introduction of octenyl succinic anhydride groups onto starch. Subsequently, OSAS micelles were used as carriers to synthesize SeNPs via in situ chemical reduction, forming SeNPs-loaded self-assembled starch nano-micelles (OSAS-SeNPs). The OSAS-SeNPs exhibited spherical dispersion in water with an average diameter of 116.1 ± 2.3 nm, contributed to enhanced hydrophobic interactions. TEM images showed a core-shell structure with SeNPs as the core and OSAS as the shell. FTIR results indicated hydrogen bonding interactions between OSAS and SeNPs. Due to the negatively charged OSAS shell and hydrogen bonding (OHâ¯Se), OSAS-SeNPs remained non-aggregated for one month at room temperature, demonstrating remarkable stability. This study suggests that using OSAS can address the synthesis and stability issues of SeNPs, making it a potential selenium supplement candidate for further evaluation as an anticancer agent.
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Hydrogel scaffolds have numerous potential applications in the tissue engineering field. However, tough hydrogel scaffolds implanted in vivo are seldom reported because it is difficult to balance biocompatibility and high mechanical properties. Inspired by Chinese ramen, we propose a universal fabricating method (printing-P, training-T, cross-linking-C, PTC & PCT) for tough hydrogel scaffolds to fill this gap. First, 3D printing fabricates a hydrogel scaffold with desired structures (P). Then, the scaffold could have extraordinarily high mechanical properties and functional surface structure by cycle mechanical training with salting-out assistance (T). Finally, the training results are fixed by photo-cross-linking processing (C). The tough gelatin hydrogel scaffolds exhibit excellent tensile strength of 6.66 MPa (622-fold untreated) and have excellent biocompatibility. Furthermore, this scaffold possesses functional surface structures from nanometer to micron to millimeter, which can efficiently induce directional cell growth. Interestingly, this strategy can produce bionic human tissue with mechanical properties of 10 kPa-10 MPa by changing the type of salt, and many hydrogels, such as gelatin and silk, could be improved with PTC or PCT strategies. Animal experiments show that this scaffold can effectively promote the new generation of muscle fibers, blood vessels, and nerves within 4 weeks, prompting the rapid regeneration of large-volume muscle loss injuries.
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Peanut (Arachis hypogaea L.) is a great plant protein source for human diet since it has high protein content in the kernel. Therefore, seed protein content (SPC) is considered a major agronomic and quality trait in peanut breeding. However, few genetic loci underlying SPC have been identified in peanuts, and the underlying regulatory mechanisms remain unknown, limiting the effectiveness of breeding for high-SPC peanut varieties. In this study, a major QTL (qSPCB10.1) controlling peanut SPC was identified within a 2.3 Mb interval in chromosome B10 by QTL-seq using a recombinant inbred line population derived from parental lines with high and low SPCs, respectively. Sequence comparison, transcriptomic analysis, and annotation analysis of the qSPCB10.1 locus were performed. Six differentially expressed genes with sequence variations between two parents were identified as candidate genes underlying qSPCB10.1. Further locus interaction analysis revealed that qSPCB10.1 could not affect the seed oil accumulation unless qOCA08.1XH13 was present, a high seed oil content (SOC) allele for a major QTL underlying SOC. In summary, our study provides a basis for future investigation of the genetic basis of seed protein accumulation and facilitates marker-assisted selection for developing high-SPC peanut genotypes.
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BACKGROUND: Different individuals with renal cell carcinoma (RCC) exhibit substantial heterogeneity in histomorphology, genetic alterations in the proteome, immune cell infiltration patterns, and clinical behavior. OBJECTIVES: This study aims to use single-nucleus sequencing on ten samples (four normal, three clear cell renal cell carcinoma (ccRCC), and three chromophobe renal cell carcinoma (chRCC)) to uncover pathogenic origins and prognostic characteristics in patients with RCC. METHODS: By using two algorithms, inferCNV and k-means, the study explores malignant cells and compares them with the normal group to reveal their origins. Furthermore, we explore the pathogenic factors at the gene level through Summary-data-based Mendelian Randomization and co-localization methods. Based on the relevant malignant markers, a total of 212 machine-learning combinations were compared to develop a prognostic signature with high precision and stability. Finally, the study correlates with clinical data to investigate which cell subtypes may impact patients' prognosis. RESULTS & CONCLUSION: Two main origin tumor cells were identified: Proximal tubule cell B and Intercalated cell type A, which were highly differentiated in epithelial cells, and three gene loci were determined as potential pathogenic genes. The best malignant signature among the 212 prognostic models demonstrated high predictive power in ccRCC: (AUC: 0.920 (1-year), 0.920 (3-year) and 0.930 (5-year) in the training dataset; 0.756 (1-year), 0.828 (3-year), and 0.832 (5-year) in the testing dataset. In addition, we confirmed that LYVE1+ tissue-resident macrophage and TOX+ CD8 significantly impact the prognosis of ccRCC patients, while monocytes play a crucial role in the prognosis of chRCC patients.
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BACKGROUND: The quick sequential [sepsis-related] organ failure assessment (qSOFA) acts as a prompt to consider possible sepsis. The contributions of individual qSOFA elements to assessment of severity and for prediction of mortality remain unknown. METHODS: A total of 3974 patients with community-acquired pneumonia were recruited to an observational prospective cohort study. The area under the receiver operating characteristic curve (AUROC), odds ratio, relative risk and Youden's index were employed to assess discrimination. RESULTS: Respiratory rate ≥22/min demonstrated the most superior diagnostic value, indicated by largest odds ratio, relative risk and AUROC, and maximum Youden's index for mortality. However, the indices for altered mentation and systolic blood pressure (SBP) ≤100 mm Hg decreased notably in turn. The predictive validities of respiratory rate ≥22/min, altered mentation and SBP ≤100 mm Hg were good, adequate and poor for mortality, indicated by AUROC (0.837, 0.734 and 0.671, respectively). Respiratory rate ≥22/min showed the strongest associations with SOFA scores, pneumonia severity index, hospital length of stay and costs. However, SBP ≤100 mm Hg was most weakly correlated with the indices. CONCLUSIONS: Respiratory rate ≥22/min made the greatest contribution to parsimonious qSOFA to assess severity and predict mortality. However, the contributions of altered mentation and SBP ≤100 mm Hg decreased strikingly in turn. It is the first known prospective evidence of the contributions of individual qSOFA elements to assessment of severity and for prediction of mortality, which might have implications for more accurate clinical triage decisions.
Respiratory rate ≥22/min demonstrated the most superior diagnostic value.Respiratory rate ≥22/min showed the strongest association with severity.Respiratory rate ≥22/min, altered mentation and SBP ≤100 mm Hg predicted mortality well, adequately and poorly, respectively.
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Escores de Disfunção Orgânica , Curva ROC , Humanos , Masculino , Feminino , Estudos Prospectivos , Idoso , Pessoa de Meia-Idade , Pneumonia/mortalidade , Pneumonia/diagnóstico , Índice de Gravidade de Doença , Infecções Comunitárias Adquiridas/mortalidade , Infecções Comunitárias Adquiridas/diagnóstico , Sepse/mortalidade , Sepse/diagnóstico , Taxa Respiratória , Idoso de 80 Anos ou mais , Pressão Sanguínea , Valor Preditivo dos Testes , PrognósticoRESUMO
Screening approved library is a promising and safe strategy to overcome the limitation of low response rate and drug resistance in immunotherapy. Accumulating evidence showed that the application of antibiotics has been considered to reduce the effectiveness of anti-PD1 immunotherapy in tumor treatment, however, in this study, an antibiotic drug (Eravacycline, ERV) was identified to improve the efficacy of anti-PD1 immunotherapy in melanoma through screening approved library. Administration of ERV significantly attenuated melanoma cells growth as well as directly or indirectly benefited M1 macrophage polarization. Meanwhile, ERV treatment significantly induced cellular autophagy via damage of mitochondria, leading to up-regulation of ROS production, subsequently, raised CCL5 secretion through elevation AP1 binding to CCL5 promoter via p38 or JNK1/2 activation. Knockdown of Ccl5 expression attenuated ERV triggered M1 macrophage polarization in melanoma cells. Clinical analysis revealed a positive association between high expression of CCL5 and improved prognosis as well as a favorable anti-PD1 therapy in melanoma patients. As expected, application of ERV improved the efficacy of anti-PD1. Overall, our results approved that ERV enhances the efficacy of anti-PD1 immunotherapy in melanoma by promoting the polarization of M1 macrophages, which provided novel therapeutic strategy for improving the effectiveness of melanoma anti-PD1 immunotherapy.
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The combination of chemotherapy and ferroptosis therapy can greatly improve the efficiency of tumor treatment. However, ferroptosis-based therapy is limited by the unsatisfactory Fenton activity and insufficient H2O2 supply in tumor cells. In this work, a nano-drug delivery system Cur@DOX@MOF-199 NPs was constructed to combine ferroptosis and apoptosis by loading curcumin (Cur) and doxorubicin (DOX) based on the copper-based organic framework MOF-199. Cur@DOX@MOF-199 NPs decompose quickly by glutathione (GSH), releasing Cu2+, DOX and Cur. Cu2+ can deplete GSH while also being reduced to Cu+; DOX can induce apoptosis and simultaneously boost H2O2 production. Moreover, Cur enhanced the expression of intracellular heme oxygenase-1 (HO-1), for decomposing heme and releasing Fe2+, which further combined with Cu+ to catalyze H2O2 for hydroxyl radical (OH) generation, leading to the accumulation of lipid peroxide and ferroptosis. As a result, Cur@DOX@MOF-199 NPs exhibited significantly enhanced antitumor efficacy in MCF-7 tumor-bearing mouse model, suggesting this nano formulation is an excellent synergetic pathway for apoptosis and ferroptosis.
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PKMYT1, a member of the WEE family, plays a crucial role in the cell cycle by specifically phosphorylating CDK1-CyclinB at Tyr15 and Thr14. Recent investigations have revealed that the amplification of CCNE1 and the inhibition of PKMYT1 kinase collectively result in synthetic lethality, further indicating that PKMYT1 is promising as an effective target for tumor therapy. Existing PKMYT1 inhibitors are mostly derivatives of RP-6306 or pan-inhibitors, limiting their further development. Herein, we conducted virtual screening of a natural product library, and in vitro enzyme experiments demonstrated that EGCG, GCG, and luteolin exhibited potent inhibitory activities with IC50 values of 0.137 µM, 0.159 µM, and 1.5 µM, respectively. Subsequently, analysis of the hit compounds and RP-6306, using different molecular simulation methods, revealed that stable hydrogen bonds with Asp251 and Glu157 in the DFG region were vital for binding to PKMYT1, more so than hydrogen bonds in the hinge and loop regions.
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The repair of critical bone defects caused by various clinical conditions needs to be addressed urgently, and the regeneration of large bone defects depends on early vascularization. Therefore, enhanced vascularization of artificial bone grafts may be a promising strategy for the regeneration of critical-sized bone defects. Taking into account the importance of rapid angiogenesis during bone repair and the potential of piezoelectric stimulation in promoting bone regeneration, novel coaxial electrospun mats coupled with piezoelectric materials and angiogenic drugs were fabricated in this study using coaxial electrospinning technology, with a shell layer loaded with atorvastatin (AVT) and a core layer loaded with zinc oxide (ZnO). AVT was used as an angiogenesis inducer, and piezoelectric stimulation generated by the zinc oxide was used as an osteogenesis enhancer. The multifunctional mats were characterized in terms of morphology, core-shell structure, piezoelectric properties, drug release, and mechanical properties, and their osteogenic and angiogenic capabilities were validated in vivo and ex vivo. The results revealed that the coaxial electrospun mats exhibit a porous surface morphology and nanofibers with a core-shell structure, and the piezoelectricity of the mats improved with increasing ZnO content. Excellent biocompatibility, hydrophilicity and cell adhesion were observed in the multifunctional mats. Early and rapid release of AVT in the fibrous shell layer of the mat promoted angiogenesis in human umbilical vascular endothelial cells (HUVECs), whereas ZnO in the fibrous core layer harvested bioenergy and converted it into electrical energy to enhance osteogenic differentiation of rat bone mesenchymal stem cells (BMSCs), and both modalities synergistically promoted osteogenesis and angiogenesis. Furthermore, optimal bone regeneration was achieved in a model of critical bone defects in the rat mandible. This osteogenesis-promoting effect was induced by electrical stimulation via activation of the calcium signaling pathway. This multifunctional mat coupling piezoelectric stimulation and atorvastatin promotes angiogenesis and bone regeneration, and shows great potential in the treatment of large bone defects.
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Atorvastatina , Regeneração Óssea , Osteogênese , Regeneração Óssea/efeitos dos fármacos , Atorvastatina/farmacologia , Atorvastatina/química , Animais , Ratos , Osteogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Humanos , Óxido de Zinco/química , Óxido de Zinco/farmacologia , Masculino , Liberação Controlada de Fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologiaRESUMO
BACKGROUND: In China, community rehabilitation workers are facing a growing challenge related to heavy occupational stress, which is having an impact on employment turnover. Previous studies have explored the effect of the public service motivation of workers in "helping" jobs on occupational stress or turnover intention, but there is a lack of clarification of the impact of altruism on turnover intention in the case of complex pathways involving various factors. METHODS: A stratified sampling method was used, and a total of 82 community rehabilitation workers who assist disabled people from 34 community health centres in Jiangmen city were included in the study from August to October 2022. The turnover intention, occupational stress, burnout, quality of life, altruism, and certain sociodemographic information of community rehabilitation workers were measured using a structured questionnaire. The partial least squares method was employed to construct and test the structural equation model. RESULTS: Although altruism had no direct impact on occupational stress or turnover intention, altruism moderated the effect of occupational stress on burnout (ßMod = -0.208) and quality of life (ßMod = 0.230) and weakened the mediation of burnout and quality of life between occupational stress and turnover intention. CONCLUSIONS: This study proposes to address the dilemma of "strong function" and "weak specialty" in community rehabilitation services and to conduct positive psychological interventions for community rehabilitation workers through the guidance of altruistic values.
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Altruísmo , Esgotamento Profissional , Estresse Ocupacional , Reorganização de Recursos Humanos , Qualidade de Vida , Humanos , China , Masculino , Feminino , Estudos Transversais , Adulto , Reorganização de Recursos Humanos/estatística & dados numéricos , Estresse Ocupacional/psicologia , Esgotamento Profissional/psicologia , Qualidade de Vida/psicologia , Pessoa de Meia-Idade , IntençãoRESUMO
Naphthalocyanine-based agents exhibit huge potential in photodynamic therapy, yet their photodynamic performance is restricted by the penetration depth of the external laser. Herein, we employed 18F-FDG as an internal light source to excite silicon naphthalocyanine nanoparticles to simultaneously circumvent radiative transition and boost 1O2 generation for tumor suppression.
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Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Nanopartículas/química , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Animais , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Camundongos , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Oxigênio Singlete/metabolismo , Oxigênio Singlete/química , Silício/químicaRESUMO
Correction for 'Radiopharmaceutical-activated silicon naphthalocyanine nanoparticles towards tumor photodynamic therapy' by Tingting Wang et al., Chem. Commun., 2024, https://doi.org/10.1039/d4cc03281k.
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Targeting the gut microbiota may be an emerging strategy for the prevention and treatment of Alzheimer's disease (AD). Macro-molecular yeast ß-glucan (BG), derived from the yeast of Saccharomyces cerevisiae, regulates the gut microbiota. This study aimed to investigate the effect and mechanism of long-term BG in high-fat diet (HFD)-induced AD-like pathologies from the perspective of the gut microbiota. Here, we found that 80 weeks of BG treatment ameliorated HFD-induced cognitive dysfunction in rats. In the hippocampus, BG alleviated HFD-induced the activation of astrocytes, microglia, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome pathway, and AD-like pathologies. BG modulated gut dysbiosis through increasing the levels of beneficial bacteria and short-chain fatty acids (SCFAs). BG also attenuated HFD-induced gut barrier impairment. Correlation analysis revealed a close relationship among microbiota, SCFAs, and AD-like pathologies. Furthermore, the fecal microbiota of BG-treated rats and SCFAs treatment mitigated AD-like pathologies via the NLRP3 inflammasome pathway in HFD-fed aged rats. These results suggested that long-term BG promotes the production of SCFAs derived from gut microbiota, which further inhibits NLRP3 inflammasome-mediated neuroinflammation, thereby alleviating HFD-induced AD-like pathologies in rats. BG may become a new strategy for targeting neurodegenerative diseases.
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Doença de Alzheimer , Eixo Encéfalo-Intestino , Dieta Hiperlipídica , Microbioma Gastrointestinal , Proteína 3 que Contém Domínio de Pirina da Família NLR , Saccharomyces cerevisiae , beta-Glucanas , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , beta-Glucanas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Ratos , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Eixo Encéfalo-Intestino/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Disbiose/tratamento farmacológico , Inflamassomos/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácidos Graxos Voláteis/metabolismo , Ratos Sprague-Dawley , Modelos Animais de DoençasRESUMO
Four new diterpenoid tropolones, salvirrddones A-D (1-4), and four new icetexanes, salvirrddices A-D (9-12), along with thirteen new 11,12-seco-norabietane diterpenoids, salvirrddnor A-M (14-24, 31, 32) and sixteen known compounds (5-8, 13, 25-30, 33-37), were isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Their structures were elucidated by comprehensive spectroscopic analyses, quantum chemical calculations, and X-ray crystallography. Structurally, compounds 1-8 represent a class of rare natural products featuring a unique cyclohepta-2,4,6-trienone moiety with diterpenoid skeletons. Bioassays showed that only diterpenoid tropolones 3, 5, 6, and 7 exhibited significant activity against several human cancer cell lines with IC50 values ranging from 3.01 to 11.63 µM. Additionally, 3 was shown to inhibit Hep3B cell proliferation, block the G0/G1 phase of the cell cycle, induce mitochondrial dysfunction and oxidative stress, promote apoptosis, as well as inhibit migration and invasion in vitro. Meanwhile, 3 demonstrated anti-proliferative, pro-apoptotic, and migration-inhibitory effects in the Hep3B xenograft zebrafish model in vivo. Network pharmacological analysis and molecular docking results suggested that 3 may treat hepatocellular carcinoma (HCC) through the PI3K-Akt signaling pathway, as well as by binding PARP1 and CDK2 targets. Overall, the present results extremely expand the repertoire of diterpenoids from natural products and may provide a novel chemical scaffold for the discovery of new antitumor drugs.
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Antineoplásicos Fitogênicos , Apoptose , Proliferação de Células , Diterpenos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Salvia , Peixe-Zebra , Humanos , Salvia/química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Relação Estrutura-Atividade , Animais , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Drought is one of the most important abiotic stresses, and seriously threatens plant development and productivity. Increasing evidence indicates that chromatin remodelers are pivotal for plant drought response. However, molecular mechanisms of chromatin remodelers-mediated plant drought responses remain obscure. In this study, we found a novel interactor of BRM called BRM-associated protein involved in drought response (BAPID), which interacted with SWI/SNF chromatin remodeler BRM and drought-induced transcription factor Di19. Our findings demonstrated that BAPID acted as a positive drought regulator since drought tolerance was increased in BAPID-overexpressing plants, but decreased in BAPID-deficient plants, and physically bound to PR1, PR2, and PR5 promoters to mediate expression of PR genes to defend against dehydration stress. Genetic approaches demonstrated that BRM acted epistatically to BAPID and Di19 in drought response in Arabidopsis. Furthermore, the BAPID protein-inhibited interaction between BRM and Di19, and suppressed the inhibition of BRM on the Di19-PR module by mediating the H3K27me3 deposition at PR loci, thus changing nucleosome accessibility of Di19 and activating transcription of PR genes in response to drought. Our results shed light on the molecular mechanism whereby the BAPID-BRM-Di19-PRs pathway mediates plant drought responses. We provide data improving our understanding of chromatin remodeler-mediated plant drought regulation network.