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OBJECTIVE: This study aimed to distinguish tuberculous spondylodiscitis (TS) from pyogenic spondylodiscitis (PS) based on laboratory, magnetic resonance imaging (MRI) and computed tomography (CT) findings. Further, a novel diagnostic model for differential diagnosis was developed. METHODS: We obtained MRI, CT and laboratory data from TS and PS patients. Predictive models were built using binary logistic regression analysis. The receiver operating characteristic curve was analyzed. Both internal and external validation was performed. RESULTS: A total of 81 patients with PS (n = 46) or TS (n = 35) were enrolled. All patients had etiological evidence from the focal lesion. Disc signal or height preservation, skip lesion or multi segment (involved segments ≥ 3) involvement, paravertebral calcification, massive sequestra formation, subligamentous bone destruction, bone erosion with osteosclerotic margin, higher White Blood Cell Count (WBC) and positive result of tuberculosis infection T cell spot test (T-SPOT.TB) were more prevalent in the TS group. A diagnostic model was developed and included four predictors: WBC<7.265 * (10^9/L), skip lesion or involved segments ≥ 3, massive sequestra formation and subligamentous bone destruction. The model showed good sensitivity, specificity, and total accuracy (91.4%, 95.7%, and 93.8%, respectively); the area under the receiver operating characteristic curve (AUC) was 0.981, similar to the results of internal validation using bootstrap resampling (1000 replicates) and external validation set, indicating good clinical predictive ability. CONCLUSIONS: This study develop a good diagnostic model based on both CT and MRI, as well as laboratory findings, which may help clinicians distinguish between TS and PS.
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The use of membrane-based guided bone regeneration techniques has great potential for single-stage reconstruction of critical-sized bone defects. Here, a multifunctional bone regeneration membrane combining flexible elasticity, electrical stimulation (ES) and osteoinductive activity is developed by in situ doping of MXene 2D nanomaterials with conductive functionality and ß-TCP particles into a Poly(lactic acid-carbonate (PDT) composite nano-absorbable membrane (P/T/MXene) via electrostatic spinning technique. The composite membrane has good feasibility due to its temperature sensitivity, elastic memory capacity, coordinated degradation profile and easy preparation process. In vitro experiments showed the P/T/MXene membrane effectively promoted the recruitment and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) under ES and enhanced the angiogenic capacity of endothelial cells, which synergistically promoted bone regeneration through neovascularization. In addition, an in vivo rat model of cranial bone defects further confirmed the bone regeneration efficacy of the P/T/MXene membrane. In conclusion, the developed P/T/MXene membrane can effectively promote bone regeneration through their synergistic multifunctional effects, suggesting the membranes have great potential for guiding tissue regeneration and providing guidance for the biomaterials design.
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Background: Acute myeloid leukemia (AML) is the second most frequently occurring type of leukemia in adults. Despite breakthroughs in genetics, the prognosis of AML patients remains dismal. The aim of this study is to find new therapeutic targets and diagnostic markers for AML and to explore their mechanisms of action. Methods: The expression patterns of integrin subunit alpha M (ITGAM) were investigated across different cell types using the Human Protein Atlas (HPA) database. The ITGAM levels across cancer types were analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) database. Prognostic correlations in AML individuals were evaluated using The Cancer Genome Atlas (TGCA) database. ITGAM-associated functions were evaluated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The AML cells were transfected with short-hairpin RNA targeting ITGAM or a control, and subsequently subjected to analysis in order to ascertain the impact of ITGAM on proliferation and apoptosis. Results: The expression of ITGAM was significantly higher in the AML patient samples compared to the control samples. High ITGAM expression was significantly associated with poor overall survival (OS). The knockdown of ITGAM in the AML cells resulted in a decrease in proliferation and an increase in apoptosis. This was accompanied by cell cycle arrest at the G1 phase and a downregulation of protein production for cyclin D1, cyclin E1, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 4 (CDK4). A pathway analysis and a western blot analysis revealed that ITGAM positively regulated mitogen-activated protein kinase (MAPK) signaling by silencing attenuated p38 MAPK (P38), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) phosphorylation, while the total protein levels remained unchanged. Conclusions: ITGAM can serve as a potential prognostic biomarker and therapeutic target for AML. ITGAM production was elevated in AML and indicated poor survival. Silencing ITGAM suppressed AML cell viability and induced apoptosis by blocking cell cycle progression, likely by impeding the activation of the MAPK pathway. Further investigations that directly target the ITGAM-MAPK axis may offer novel strategies for mitigating AML pathogenesis and overcoming chemotherapy resistance.
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Background: Osteoarthritis (OA) standing as the most prevalent form of arthritis, closely associates with heightened levels of reactive oxygen species, particularly hypochlorous acid (HOCl). Although there are numerous probes available for detecting HOCl in the OA region, probes with dual functions of diagnostic and therapeutic capabilities are still significantly lacking. While this type of probe can reduce the time gap between diagnosis and treatment, which is clinically needed. Methods: We developed a fluorescent probe (DHU-CBA1) toward HOCl with theranostics functions through the release of methylene blue (MB) and ibuprofen (IBP) in this work. DHU-CBA1 can detect HOCl with high specificity and sensitivity, releasing MB and IBP with an impressive efficiency of ≥ 95% in vitro. Results: DHU-CBA1 exhibits good biosafety, enabling in vivo imaging of endogenous HOCl, along with reducing arthritis scores, improving synovitis and cartilage damage, and maintaining catabolic balance while alleviating senescence in cartilage. Conclusions: This study proposes a novel approach to enhance osteoarthritis therapy by releasing IBP via a smart HOCl-enabled fluorescent probe.
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Corantes Fluorescentes , Ácido Hipocloroso , Ibuprofeno , Azul de Metileno , Osteoartrite , Osteoartrite/tratamento farmacológico , Corantes Fluorescentes/química , Ibuprofeno/administração & dosagem , Animais , Azul de Metileno/química , Camundongos , Humanos , Nanomedicina Teranóstica/métodos , Masculino , Imagem Óptica/métodos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Surgery remains the standard treatment for spinal metastasis. However, uncontrolled intraoperative bleeding poses a significant challenge for adequate surgical resection and compromises surgical outcomes. In this study, we develop a thrombin (Thr)-loaded nanorobot-hydrogel hybrid superstructure by incorporating nanorobots into regenerated silk fibroin nanofibril hydrogels. This superstructure with superior thixotropic properties is injected percutaneously and dispersed into the spinal metastasis of hepatocellular carcinoma (HCC) with easy bleeding characteristics, before spinal surgery in a mouse model. Under near-infrared irradiation, the self-motile nanorobots penetrate into the deep spinal tumor, releasing Thr in a controlled manner. Thr-induced thrombosis effectively blocks the tumor vasculature and reduces bleeding, inhibiting tumor growth and postoperative recurrence with Au nanorod-mediated photothermal therapy. Our minimally invasive treatment platform provides a novel preoperative therapeutic strategy for HCC spinal metastasis effectively controlling intraoperative bleeding and tumor growth, with potentially reduced surgical complications and enhanced operative outcomes.
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BACKGROUND AND AIM: Currently, the relationship between dynamic changes in dietary manganese (Mn) intake and risk of hyperuricemia (HU) is still unclear. This study aimed to identify dietary Mn consumption trajectories in the Chinese adults and assess their relation with the risk of HU. METHODS AND RESULTS: Cohort data from the China Health and Nutrition Survey (CHNS) 1997-2009 were employed in this study. Overall, 6886 adult participants were included. Participants were designated into subgroups based on the trajectories of dietary Mn consumption by sex. Cox proportional hazard models were used to explore the associations between different trajectories and the risk of HU. For men, compared with low stable trajectory group, moderate to high trajectory group was significantly related to reduced risk of HU (HR = 0.61, 95% CI: 0.38 to 0.98) with adjustment for covariates. TC, HDL-C, ApoB, and TG exerted partial regulation function between trajectories and HU. For women, compared with low stable trajectory group, high stable trajectory group was significantly related to reduced risk of HU (HR = 0.76, 95% CI: 0.60 to 0.95) with adjustment for covariates. Similarly, TC, HDL-C, ApoB, and ApoA exerted partial regulation function between trajectories and HU. CONCLUSIONS: Long-term relatively high dietary Mn consumption may have a protective effect against HU in Chinese adults. The differences in HU-related factors among different dietary Mn intake trajectories partially regulated the association between these trajectories and HU.
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Biomarcadores , Hiperuricemia , Manganês , Inquéritos Nutricionais , Fatores de Proteção , Recomendações Nutricionais , Humanos , Hiperuricemia/epidemiologia , Hiperuricemia/diagnóstico , Hiperuricemia/sangue , Hiperuricemia/prevenção & controle , Masculino , Feminino , China/epidemiologia , Manganês/administração & dosagem , Pessoa de Meia-Idade , Fatores de Risco , Adulto , Medição de Risco , Fatores de Tempo , Biomarcadores/sangue , Dieta/efeitos adversos , Fatores Sexuais , Ácido Úrico/sangue , Idoso , Comportamento de Redução do RiscoRESUMO
Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to the imbalance between osteogenesis and osteoclastogenesis, making osteoporotic bone defects healing a significant clinical challenge. Calcium phosphate cement (CPC) is a promising bone substitute material due to its good osteoinductive activity, however, the drawbacks such as fragility, slow degradation rate and incapability to control bone loss restrict its application in osteoporotic bone defects treatment. Currently, we developed the PLGA electrospun nanofiber sheets to carry alendronate (ALN) and magnesium oxide nanoparticle (nMgO) into CPC, therefore, to obtain a high-strength bone cement (C/AM-PL/C). The C/AM-PL/C bone cement had high mechanical strength, anti-washout ability, good injection performance and drug sustained release capacity. More importantly, the C/AM-PL/C cement promoted the osteogenic differentiation of bone marrow mesenchymal stem cells and neovascularization via the release of Mg2+ (from nMgO) and Ca2+ (during the degradation of CPC), and inhibited osteoclastogenesis via the release of ALN in vitro. Moreover, the injection of C/AM-PL/C cement significantly improved bone healing in an OP model with femur condyle defects in vivo. Altogether, the injectable C/AM-PL/C cement could facilitate osteoporotic bone regeneration, demonstrating its capacity as a promising candidate for treatment of osteoporotic bone defects.
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Long-range sequencing grants insight into additional genetic information beyond that which can be accessed by both short reads and modern long-read technology. Several new sequencing technologies are available for long-range datasets such as "Hi-C" and "Linked Reads" with high-throughput and high-resolution genome analysis, and are rapidly advancing the field of genome assembly, genome scaffolding, and more comprehensive variant identification. In this article, we focused on five major long-range sequencing technologies: high-throughput chromosome conformation capture (Hi-C), 10x Genomics Linked Reads, haplotagging, transposase enzyme linked long-read sequencing (TELL-seq), and single tube long fragment read (stLFR). We detailed the mechanisms and data products of the five platforms, introduced several of the most important applications, evaluated the quality of sequencing data from different platforms, and discussed the currently available bioinformatics tools. We hope this work will benefit the selection of appropriate long-range technology for specific biological studies.
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The aim of this study was to evaluate the influence factors of metagenomic next-generation sequencing (mNGS) negative results in the diagnosed patients with spinal infection. mNGS test was applied in a cohort of 114 patients with suspected spinal infection, among which 56 patients had a final diagnosis of spinal infection. mNGS achieved a sensitivity of 75.0% (95% CI, 61.6% to 85.6%) and a specificity of 84.5% (95% CI, 72.6% to 92.7%), using histopathology and culture results as reference. Diagnosed patients with a negative culture result had lower white blood cell account, percentage of neutrophilic granulocyte, C-reactive protein (all P<0.05) and relatively higher rate of prior antimicrobial treatment history (P=0.059). However, diagnosed patients with a negative mNGS result did not have such difference with mNGS-positive patients, suggesting that mNGS was not strictly limited by the above indicators, which presented the advantages of this technique from another point of view.
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Sequenciamento de Nucleotídeos em Larga Escala , Metagenômica , Sensibilidade e Especificidade , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Feminino , Metagenômica/métodos , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Adulto Jovem , Doenças da Coluna Vertebral/microbiologia , Doenças da Coluna Vertebral/diagnósticoRESUMO
We consider how to describe Hamiltonian mechanics in generalized probabilistic theories with the states represented as quasiprobability distributions. We give general operational definitions of energy-related concepts. We define generalized energy eigenstates as the purest stationary states. Planck's constant plays two different roles in the framework: the phase space volume taken up by a pure state and a dynamical factor. The Hamiltonian is a linear combination of generalized energy eigenstates. This allows for a generalized Liouville time-evolution equation that applies to quantum and classical Hamiltonian mechanics and more. The approach enables a unification of quantum and classical energy concepts and a route to discussing energy in a wider set of theories.
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The treatment of osteoporotic bone defect remains a big clinical challenge because osteoporosis (OP) is associated with oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation. Anti-oxidative nanomaterials such as selenium nanoparticles (SeNPs) have positive effect on osteogenesis owing to their pleiotropic pharmacological activity which can exert anti-oxidative stress functions to prevent bone loss and facilitate bone regeneration in OP. In the current study a strategy of one-pot method by introducing Poly (lactic acid-carbonate) (PDT) and ß-Tricalcium Phosphate (ß-TCP) with SeNPs, is developed to prepare an injectable, anti-collapse, shape-adaptive and adhesive bone graft substitute material (PDT-TCP-SE). The PDT-TCP-SE bone graft substitute exhibits sufficient adhesion in biological microenvironments and osteoinductive activity, angiogenic effect and anti-inflammatory as well as anti-oxidative effect in vitro and in vivo. Moreover, the PDT-TCP-SE can protect BMSCs from erastin-induced ferroptosis through the Sirt1/Nrf2/GPX4 antioxidant pathway, which, in together, demonstrated the bone graft substitute material as an emerging biomaterial with potential clinical application for the future treatment of osteoporotic bone defect. STATEMENT OF SIGNIFICANCE: Injectable, anti-collapse, adhesive, plastic and bioactive bone graft substitute was successfully synthesized. Incorporation of SeNPs with PDT into ß-TCP regenerated new bone in-situ by moderating oxidative stress in osteoporotic bone defects area. The PDT-TCP-SE bone graft substitute reduced high ROS levels in osteoporotic bone defect microenvironment. The bone graft substitute could also moderate oxidative stress and inhibit ferroptosis via Sirt1/Nrf2/GPX4 pathway in vitro. Moreover, the PDT-TCP-SE bone graft substitute could alleviate the inflammatory environment and promote bone regeneration in osteoporotic bone defect in vivo. This biomaterial has the advantages of simple synthesis, biocompatibility, anti-collapse, injectable, and regulation of oxidative stress level, which has potential application value in bone tissue engineering.
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Regeneração Óssea , Substitutos Ósseos , Fosfatos de Cálcio , Osteoporose , Estresse Oxidativo , Estresse Oxidativo/efeitos dos fármacos , Animais , Substitutos Ósseos/química , Substitutos Ósseos/farmacologia , Regeneração Óssea/efeitos dos fármacos , Osteoporose/patologia , Osteoporose/terapia , Osteoporose/tratamento farmacológico , Fosfatos de Cálcio/farmacologia , Fosfatos de Cálcio/química , Ratos Sprague-Dawley , Selênio/química , Selênio/farmacologia , Feminino , Osteogênese/efeitos dos fármacos , Poliésteres/química , Poliésteres/farmacologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Ratos , InjeçõesRESUMO
BACKGROUND: Acellular nerve allografts (ANAs) were developed to replace the autologous nerve grafts (ANGs) to fill the peripheral nerve defects. Poor vascularization relative to ANGs has been a limitation of application of ANAs. METHODS: A total of 60 female Sprague-Dawley rats were assigned 3 groups. The rats in A group received ANGs, the rats in B group received ANAs, and the rats in C group were transplanted with ANA carrying endothelial cells (ANA + ECs). In the 1st, 2nd, 4th, and 12th postoperative weeks, 5 rats were selected from each group for evaluating sciatic function index (SFI), electrophysiology, maximum tetanic force recovery rate, tibialis anterior muscle weights recovery rate, and microvessel density. In the 12th postoperative week, the nerves were harvested and stained with toluidine blue and observed under an electron microscope to compare nerve fibers, myelin width, and G-ratio. RESULTS: All the rats survived. In the first and second postoperative weeks, more microvessels were found in the ANA + EC group. In the 12th postoperative week, the nerve fibers were more numerous, and G-ratio was smaller in the C group compared with the B group. The compound muscle action potential and maximum tetanic force recovery rate in the tibialis anterior muscle in the C group were better than those in the B group in the 12th postoperative week. The A group showed better performances in electrophysiology, maximum tetanic force, muscle wet weight, and nerve regeneration. CONCLUSION: ANA + ECs can promote early angiogenesis, promoting nerve regeneration and neurological function recovery.
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Aloenxertos , Células Endoteliais , Regeneração Nervosa , Ratos Sprague-Dawley , Nervo Isquiático , Animais , Feminino , Ratos , Nervo Isquiático/cirurgia , Nervo Isquiático/lesões , Nervo Isquiático/transplante , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/cirurgia , Recuperação de Função Fisiológica , Distribuição AleatóriaRESUMO
Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra-conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory-polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein-based conduits. Moreover, the NGC can gradually regulate the intra-conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.
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Fibroínas , Regeneração Nervosa , Traumatismos dos Nervos Periféricos , Animais , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Ratos , Traumatismos dos Nervos Periféricos/terapia , Fibroínas/química , Fibroínas/farmacologia , Modelos Animais de Doenças , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Regeneração Tecidual Guiada/métodos , Inflamação , Alicerces Teciduais/química , Nervo Isquiático/lesõesRESUMO
Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single-component dual-functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)-generated HOCl. A representative prodrug (DHU-CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU-CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU-CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase-2 (COX-2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX-2. Downstream prostaglandins E2 and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU-CBA2 promotes infiltration and function of CD8+ T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single-component dual-functional prodrug activated by TME-specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX-2 inhibitor.
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Neoplasias Pulmonares , Fotoquimioterapia , Pró-Fármacos , Neoplasias da Coluna Vertebral , Humanos , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Ciclo-Oxigenase 2 , Linfócitos T CD8-Positivos , Neoplasias da Coluna Vertebral/tratamento farmacológico , Indometacina , Microambiente TumoralRESUMO
Volatile organic compounds (VOCs) play key roles in plant-plant communication, especially in response to pest attack. E-2-hexenal is an important component of VOCs, but it is unclear whether it can induce endogenous plant resistance to insects. Here, we show that E-2-hexenal activates early signaling events in Arabidopsis (Arabidopsis thaliana) mesophyll cells, including an H2O2 burst at the plasma membrane, the directed flow of calcium ions, and an increase in cytosolic calcium concentration. Treatment of wild-type Arabidopsis plants with E-2-hexenal increases their resistance when challenged with the diamondback moth Plutella xylostella L., and this phenomenon is largely lost in the wrky46 mutant. Mechanistically, E-2-hexenal induces the expression of WRKY46 and MYC2, and the physical interaction of their encoded proteins was verified by yeast two-hybrid, firefly luciferase complementation imaging, and in vitro pull-down assays. The WRKY46-MYC2 complex directly binds to the promoter of RBOHD to promote its expression, as demonstrated by luciferase reporter, yeast one-hybrid, chromatin immunoprecipitation, and electrophoretic mobility shift assays. This module also positively regulates the expression of E-2-hexenal-induced naringenin biosynthesis genes (TT4 and CHIL) and the accumulation of total flavonoids, thereby modulating plant tolerance to insects. Together, our results highlight an important role for the WRKY46-MYC2 module in the E-2-hexenal-induced defense response of Arabidopsis, providing new insights into the mechanisms by which VOCs trigger plant defense responses.
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Aldeídos , Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Flavonoides/metabolismo , Saccharomyces cerevisiae/metabolismo , Cálcio/metabolismo , Peróxido de Hidrogênio/metabolismo , Plantas/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismoRESUMO
Intercellular communication between tumor cells and immune cells regulates tumor progression including positive communication with immune activation and negative communication with immune escape. An increasing number of methods are employed to suppress the dominant negative communication in tumors such as PD-L1/PD-1. However, how to effectively improve positive communication is still a challenge. In this study, a nuclear-targeted photodynamic nanostrategy is developed to establish positive spatiotemporal communication, further activating dual antitumor immunity, namely innate and adaptative immunity. The mSiO2 -Ion@Ce6-NLS nanoparticles (NPs) are designed, whose surface is modified by ionic liquid silicon (Ion) and nuclear localization signal peptide (NLS: PKKKRKV), and their pores are loaded with the photosensitizer hydrogen chloride e6 (Ce6). Ion-modified NPs enhance intratumoral enrichment, and NLS-modified NPs exhibit nuclear-targeted characteristics to achieve nuclear-targeted photodynamic therapy (nPDT). mSiO2 -Ion@Ce6-NLS with nPDT facilitate the release of damaged double-stranded DNA from tumor cells to activate macrophages via stimulator of interferon gene signaling and induce the immunogenic cell death of tumor cells to activate dendritic cells via "eat me" signals, ultimately leading to the recruitment of CD8+ T-cells. This therapy effectively strengthens positive communication to reshape the dual antitumor immune microenvironment, further inducing long-term immune memory, and eventually inhibiting tumor growth and recurrence.
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Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos , Fármacos Fotossensibilizantes/farmacologia , Fotoquimioterapia/métodos , Macrófagos , Imunoterapia/métodos , Microambiente TumoralRESUMO
Innate and adaptive immunity is important for initiating and maintaining immune function. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves as a checkpoint in innate and adaptive immunity, promoting the secretion of pro-inflammatory cytokines and gasdermin D-mediated pyroptosis. As a highly inflammatory form of cell death distinct from apoptosis, pyroptosis can trigger immunogenic cell death and promote systemic immune responses in solid tumors. Previous studies proposed that NLRP3 was activated by translocation to the mitochondria. However, a recent authoritative study has challenged this model and proved that the Golgi apparatus might be a prerequisite for the activation of NLRP3. In this study, we first developed a Golgi apparatus-targeted photodynamic strategy to induce the activation of NLRP3 by precisely locating organelles. We found that Golgi apparatus-targeted photodynamic therapy could significantly upregulate NLRP3 expression to promote the subsequent release of intracellular proinflammatory contents such as IL-1ß or IL-18, creating an inflammatory storm to enhance innate immunity. Moreover, this acute NLRP3 upregulation also activated its downstream classical caspase-1-dependent pyroptosis to enhance tumor immunogenicity, triggering adaptive immunity. Pyroptosis eventually led to immunogenic cell death, promoted the maturation of dendritic cells, and effectively activated antitumor immunity and long-lived immune memory. Overall, this Golgi apparatus-targeted strategy provided molecular insights into the occurrence of immunogenic pyroptosis and offered a platform to remodel the tumor microenvironment.
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Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Inflamassomos/metabolismo , Imunidade Inata , Complexo de Golgi/metabolismo , Interleucina-1beta , Caspase 1/metabolismoRESUMO
Fruit ripening is a crucial stage in quality development, influenced by a diverse array of internal and external factors. Among these factors, epigenetic regulation holds significant importance and has garnered substantial research attention in recent years. Here, this review aims to discuss the breakthrough in epigenetic regulation of tomato (Solanum lycopersicum) fruit ripening, including DNA methylation, N6-Methyladenosine mRNA modification, histone demethylation/deacetylation, and non-coding RNA. Through this brief review, we seek to enhance our understanding of the regulatory mechanisms governing tomato fruit ripening, while providing fresh insights for the precise modulation of these mechanisms.
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As an important member of the plant receptor-like kinases, Catharanthus roseus receptor-like kinase 1-like (CrRLK1L) plays vital roles in plant growth and development, as well as biotic and abiotic stress response. Numerous CrRLK1Ls have been identified and analyzed in various plant species, while our knowledge about eggplant (Solanum melongena L.) CrRLK1Ls is still scarce. Utilizing state-of-the-art genomic data, we conducted the first genome-wide identification and analysis of CrRLK1L proteins in eggplant. In this study, 32 CrRLK1L proteins were identified and analyzed in eggplant. A subsequent gene structure and protein domain analysis showed that the identified eggplant CrRLK1Ls possessed typical features of CrRLK1Ls. A subcellular localization prediction demonstrated that these proteins mostly localized on the plasma membrane. A collinearity analysis showed that some eggplant CrRLK1L genes had predicted intraspecies or interspecies evolutionary duplication events. Promoter analysis suggests that eggplant CrRLK1Ls may be involved in plant hormone signaling, host-pathogen interactions, and environmental responses. Based on transcriptomic gene expression analysis, it is indicated that eggplant CrRLK1Ls may be involved in the resistance response of eggplant to Botrytis cinerea. Together, these results will give us a theoretical foundation and guidance for elaborating the biological functions of CrRLK1Ls in eggplant growth, development, and resistance response.