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In the present study, eight undescribed compounds, namely caseazins R-Y (1-8) were isolated from the twigs and leaves of Casearia kurzii (Flacourtiaceae). Their structures were elucidated by extensive spectroscopic analysis, nuclear magnetic resonance methods, X-ray diffraction analysis, and ECD calculations. Compound 1 was characterized as a rare 2,3-seco podocarpane carbon skeleton. While compound 8 was a highly oxygenated podocarpane diterpenoid dimer with an oxygen bridge between C-2 and C-11'. In bioassay, the diterpenoid dimer 8 showed potential cytotoxic activity against colorectal cancer cells (SW-620) with IC50 value of 7.29 ± 0.10 µM. Besides, compound 8 exhibited moderate inhibitory activity against colorectal cancer target PI3KαH1047R.
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Antineoplásicos Fitogênicos , Casearia , Diterpenos , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Humanos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Casearia/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Folhas de Planta/química , Relação Dose-Resposta a Droga , Conformação MolecularRESUMO
AIMS: Postmenopausal osteoporosis significantly increases fragility fracture risk. While menopausal estrogen decline coincides with rising follicle-stimulating hormone (FSH), the role of circulating FSH in bone loss remains unclear. This study investigates the direct function of FSH and FSH receptor (FSHR) in bone, focusing on osteocyte-mediated mechanisms. MATERIALS AND METHODS: To probe FSHR function, osteocyte-specific Fshr knockout mice (Dmp1-CreERT; Fshrfl/fl) were generated. Following ovariectomy, Fshr deletion was induced with tamoxifen. We performed RNA-sequencing on femoral cortical bone, validated by digital PCR and ELISA. In vitro assays assessed FSH's effect on PI3K/Akt signaling and osteogenic mineralization. Fracture healing and biomechanics were evaluated using a closed femoral fracture model and three-point bending. KEY FINDINGS: Osteocyte-specific Fshr knockout enhanced bone mineralization, resorption, and formation-resorption coupling, activating the PI3K/Akt pathway. Fshr deletion blocked FSH-mediated PI3K/Akt inhibition and restored osteogenic mineralization in vitro. Knockout mice showed accelerated callus maturation and improved biomechanical healing post-fracture. SIGNIFICANCE: We identify osteocytes as direct FSH target cells. Osteocyte Fshr deletion promotes bone turnover and accelerates fracture repair in ovariectomized mice by enhancing PI3K/Akt signaling. These findings reveal a new pathophysiological mechanism for postmenopausal osteoporosis and suggest a promising therapeutic strategy targeting FSHR.
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Densidade Óssea , Hormônio Foliculoestimulante , Consolidação da Fratura , Osteócitos , Receptores do FSH , Animais , Feminino , Ovariectomia , Camundongos , Receptores do FSH/metabolismo , Receptores do FSH/genética , Camundongos Knockout , Consolidação da Fratura/fisiologia , Hormônio Foliculoestimulante/metabolismo , Hormônio Foliculoestimulante/antagonistas & inibidores , Osteócitos/metabolismo , Osteogênese , Densidade Óssea/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Osteoporose Pós-Menopausa/metabolismo , Transdução de Sinais , Camundongos Endogâmicos C57BLRESUMO
Acetyl-CoA (AcCoA) functions as a pivotal metabolic node that regulates diverse cellular pathways in organisms (e.g., microalgae). Real-time monitoring of intracellular metabolites is essential for elucidating complex biological processes. However, conventional methods for AcCoA detection often suffer from limitations, including cumbersome procedures, substantial matrix interference, dependence on advanced instrumentation, and inadequate sensitivity for trace-level analysis in biological matrices. To address these challenges, this study developed a fluorescent switch biosensor for AcCoA detection based on iron ion (Fe3+)-mediated fluorescence modulation. The sensor utilizes nitrogen-doped carbon dots (N-CDs) synthesized through pyrolysis of sodium alginate and melatonin. The resulting amorphous N-CDs (average diameter: 3.75 nm) exhibit strong blue fluorescence. The biosensor demonstrates high sensitivity and selectivity, achieving a linear detection range of 1-200 µM with a LOD of 0.268 µM. Moreover, owing to the low cytotoxicity and rapid response of the N-CDs, the system enabled real-time monitoring of AcCoA in live microalgal cells, showing a linear fluorescence response in Ochromonas sp. cultures across volumes ranging from 0.8 to 10 mL. This work provides a robust and biocompatible platform with significant potential for advancing AcCoA-related biological research.
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Acetilcoenzima A , Técnicas Biossensoriais , Carbono , Ferro , Microalgas , Nitrogênio , Pontos Quânticos , Microalgas/química , Microalgas/citologia , Microalgas/metabolismo , Carbono/química , Nitrogênio/química , Pontos Quânticos/química , Acetilcoenzima A/análise , Espectrometria de Fluorescência/métodos , Técnicas Biossensoriais/métodos , Limite de Detecção , Ferro/química , FluorescênciaRESUMO
Lymph node metastasis (LNM) is an important cause of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC). However, the mechanism of LNM in ESCC has not been elucidated. Here, we identified interferon-induced proteins with tetratricopeptide repeats 3 (IFIT3) highly expressed in ESCC, especially in LNM tissues. IFIT3 overexpression promoted ESCC cell metastasis in vitro and in vivo. Mechanistically, IFIT3 interacted with LIM and SH3 protein 1 (LASP1) and facilitated the localization of LASP1 to the cell edge, promoting the interaction between LASP1 and Talin1 and the binding of Talin1 to integrin, ultimately activating the FAK-ERK signaling pathway. Clinically, IFIT3 and LASP1 were upregulated in ESCC and LNM tissues and associated with poor prognosis. Moreover, patients with high expression of both IFIT3 and LASP1 have a poorer prognosis. In conclusion, IFIT3 promotes LNM in ESCC through the LASP1/FAK/ERK axis, and IFIT3 is a potential therapeutic target for LNM in ESCC.
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INTRODUCTION: The aim of this work is to predict the implantable Collamer lens (ICL) vault using machine learning (ML) algorithms and a data wrangling approach based on multicenter big data. METHODS: This retrospective cross-sectional study developed ML models using preoperative biometric data and ICL vault from 6715 eyes across five hospitals. Mutual information regression was employed to identify important parameters. A digital vault information system (DVIS) was constructed for data wrangling. ML models integrated with DVIS were used to develop ICL vault prediction and classification models, which were validated in both internal (6552 eyes) and external (163 eyes) validation. RESULTS: The XGBoost model combined with DVIS exhibited statistically superior performance in ICL vault prediction, with lower mean absolute error (MAE) of 39.15 µm (internal validation) and 149.72 µm (external validation) compared to other ML algorithms. The R2 value was 0.86 in the internal validation. For ICL vault classification, the XGBoost algorithm achieved accuracies of 81.4% (internal validation) and 57.27% (external validation), representing accuracy gains of 27.1% and 10.2% respectively, compared to traditional ML algorithms. CONCLUSIONS: The development of DVIS is valuable for ICL vault prediction models, as it provides a data wrangling strategy that improves ML efficiency. Experimental results confirm the applicability of this synergistic method in enhancing existing ML approaches for ICL vault prediction, thereby facilitating more informed clinical decision-making in ICL implantation surgery.
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N,N-dimethylacetamide (DMA) is an organic solvent, used in busulphan, iv-formulation, (Busulfex). DMA is metabolized primarily to N-methylacetamide (MMA) via CYP2E1. In the present study, we investigated the pharmacokinetics and toxicity of DMA and MMA in patients, mice and cell lines. In pediatric patients (6 months to 18 years) undergoing hematopoietic stem cell transplantation, the pharmacokinetics of DMA and MMA were followed during the 4-days Busulfex conditioning (3.2-4 mg/kg, b.i.d). No accumulation of DMA was found; however, a significant increase in clearance and a significant decrease (p < 0.005) in half-lives by the end of treatment were observed which might indicate CYP2E1 autoinduction. Furthermore, continuous increases in plasma concentration of MMA were observed during treatment and a terminal half-life of 15.2 ± 1.7 h was detected. Moreover, ALT was significantly (p = 0.04) increased in > 61% of the patients after conditioning. Additionally, mice were treated with either dimethyl sulfoxide (DMSO), DMA, busulphan in DMSO, Busulfex or saline for 4 days. DMA-treated mice showed elevated ALT and AST values. Interestingly, Busulfex administration did not alter mice liver enzymes. Busulphan in DMA showed higher cytotoxicity compared to busulphan in DMSO in HepG-2, Huh-7 and HL-60 cells. The combination Bu-DMA-MMA exhibited increased cytotoxicity in a concentration-dependent manner. In conclusion, Busulfex administration to pediatric patients resulted in an accumulation of MMA during the 4-days treatment. Busulfex is less toxic compared to Bu dissolved in DMA. MMA addition to Bu in DMA showed higher cytotoxicity. Therefore, MMA with a relatively long half-life may induce hepatotoxicity and/or interaction with subsequently administered drugs; thus further investigations are urgently warranted.
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Acetamidas , Bussulfano , Humanos , Acetamidas/farmacocinética , Acetamidas/toxicidade , Acetamidas/administração & dosagem , Criança , Animais , Adolescente , Pré-Escolar , Camundongos , Masculino , Feminino , Lactente , Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Bussulfano/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Meia-Vida , Dimetil Sulfóxido , Administração IntravenosaRESUMO
Phytochemical studies of the twigs and leaves of Casearia glomerata yielded three previously undescribed phenolic compounds, including two phenylpropanoid derivatives, Casearata A (1) and Casearata B (2), one butyrolactone, Casearata C (3), as well as eleven known compounds 4-14. Their structures were elucidated by nuclear magnetic resonance, infrared, mass spectrometry, and ultraviolet spectroscopy. The absolute configurations of the new compounds were determined by a combination of linear correlation coefficients (R2), DP4+ probability analysis, and electronic circular dichroism calculations. The cytotoxic activity of compounds 1-4 and 6-14 was evaluated. Among these, compound 7 exhibited weak inhibitory effects against MDA-MB-231, HCT-116, HepG2, and A549 tumor cell lines, with IC50 values of 21.70-39.08 µM.
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Acute myeloid leukemia (AML) is a lethal clonal hematopoietic malignancy. Several reports have shown that serum metabolite alterations have been implicated in AML, but the causal relationship and underlying biological mechanisms remain unclear. We performed bidirectional Mendelian randomization (MR) to evaluate the association between 486 serum metabolites and AML. The analytical approaches used to minimize research bias included the inverse variance weighting (IVW), MR-Egger and weighted median (WM) methods. Sensitivity analyses were performed using Cochran's Q Test, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Leave-one-out (LOO) analysis. Metabolic pathway analysis was conducted using the MetaboAnalyst 6.0 platform. We utilized RNA-seq data to explore the potential genes and mechanisms underlying the regulation of AML occurrence by serum metabolites. We identified 23 serum metabolites (13 known and 10 unknown) significantly associated with AML. Sensitivity analyses further validated the robustness of these associations. No evidence of reverse causality was detected by reverse MR analysis. The core pathways were histidine metabolism and fructose/mannose metabolism. Transcriptomic integration revealed 39 overlapping genes (differentially expressed genes vs. metabolite-associated genes) as key mediators, enriched in neuroactive ligand signaling, synaptic vesicle cycle, and GABAergic synapse (KEGG), plus synapse assembly and calmodulin binding and neuron-to-neuron synapse (GO). This study establishes causal links between specific serum metabolites and AML, revealing neuro-related mechanistic pathways. These findings provide novel biomarkers and therapeutic targets for AML precision medicine.
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Leucemia Mieloide Aguda , Análise da Randomização Mendeliana , Metaboloma , Metabolômica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/metabolismo , Humanos , Análise da Randomização Mendeliana/métodos , Metabolômica/métodos , Redes e Vias Metabólicas , Transcriptoma , MultiômicaRESUMO
Chronic graft-versus-host disease (cGVHD) is a major complication for long-term survivors after hematopoietic cell transplantation (HCT). Bronchiolitis obliterans syndrome (BOS) is the crucial manifestation of lung cGVHD. Ruxolitinib has been approved by the Food and Drug Administration (FDA) for cGVHD treatment, but the response for BOS has not been sufficiently evaluated. We conducted a multicenter study involving 125 patients diagnosed with BOS post-HCT who received second-line therapies, including 77 patients treated with ruxolitinib (ruxolitinib group) and 48 patients with non-ruxolitinib therapies (control group). The primary endpoint was progression of BOS. By the third month, 18.2% of patients in the ruxolitinib group progressed, versus 43.8% in the control group (p = 0.001). The 2-year overall survival (OS) was 73.2% (95%CI 63.5%-84.5%) for the ruxolitinib group versus 60.2% (95%CI 47.4%-76.6%) for the control group (p = 0.012). The BOS-progression-free survival (BOS-PFS) was 69.0% (95%CI 59.1%-80.5%) versus 51.2% (95%CI 38.7%-67.7%, p = 0.011). Early switch to second-line therapy for BOS independently favored lower progression incidence (OR = 0.203, [95%CI 0.070-0.585], p = 0.003). Additionally, we observed that ruxolitinib was well-tolerated during the treatment of BOS. In conclusion, our findings indicated that ruxolitinib is an effective and safe second-line option for BOS.
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Bronquiolite Obliterante , Transplante de Células-Tronco Hematopoéticas , Pirazóis , Humanos , Nitrilas , Bronquiolite Obliterante/tratamento farmacológico , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/mortalidade , Pirimidinas , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Adolescente , Adulto Jovem , Idoso , Taxa de Sobrevida , Síndrome de Bronquiolite ObliteranteRESUMO
Cell-laden hydrogel microspheres have gained significant attention in 3D cell culture applications, yet effective cryopreservation methods for these systems remain underexplored. This study developed a microfluidic platform for fabricating monodisperse, cell-laden microspheres and investigated a dimethyl sulfoxide (DMSO)- and fetal bovine serum (FBS)-free cryopreservation approach. The platform enabled rapid production of gelatin methacryloyl (GelMA) and calcium alginate (ALG) microspheres, demonstrating cell viability exceeding 80% for U251 cells in GelMA microspheres and 90% for both U251 cells and induced pluripotent stem cells (iPSCs) in ALG microspheres. A DMSO-/FBS-free cryoprotectant (12% ethylene glycol, 4% trehalose; E/T) was identified that maintained >90% post-thaw viability in GES, U251, HepG2, A549, and 3T6 cells, with iPSCs retaining >80% viability. Crucially, E/T effectively preserved iPSC-laden microspheres while preventing DMSO-induced apoptosis and preserving pluripotency. This work establishes a systematic protocol for cryopreserving cell-laden hydrogel microspheres without DMSO/FBS, providing a clinically translatable strategy to advance 3D cell culture technologies.
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Criopreservação , Crioprotetores , Etilenoglicol , Hidrogéis , Microesferas , Trealose , Trealose/química , Trealose/farmacologia , Criopreservação/métodos , Etilenoglicol/química , Etilenoglicol/farmacologia , Humanos , Sobrevivência Celular/efeitos dos fármacos , Hidrogéis/química , Crioprotetores/química , Crioprotetores/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Alginatos/química , Dimetil Sulfóxido/química , Animais , Microfluídica/métodosRESUMO
Previous studies have found a link between serum metabolite levels and chronic myeloid leukemia (CML), yet their exact causal relationship remains unexplored. Using genome-wide association datasets, we conducted bidirectional Mendelian randomization (MR) analyses to explore the potential causal relationship between 486 serum metabolites and CML. We conducted sensitivity analysis to assess the presence of heterogeneity and pleiotropy. Our Mendelian randomization analysis identified 20 metabolites exerting significant causal effects on CML, including 19 known and 1 unidentified metabolite. Among the 19 identified metabolites, 10 metabolites exhibit a risk effect in CML, whereas 9 manifested a protective effect. Notably, the amino acid metabolite 4-methyl-2-oxopentanoate displayed the strongest positive causal relationship with CML. The CML-associated metabolites were predominantly enriched in the following metabolic pathways: caffeine metabolism, glycerolipid metabolism, glycerophospholipid metabolism, and valine, leucine, and isoleucine biosynthesis. These findings advance our understanding of metabolic interactions in CML, providing critical insights for diagnosis and guiding strategies for prevention and treatment.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Análise da Randomização Mendeliana , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Estudo de Associação Genômica AmplaRESUMO
Repair of skin injuries is often hindered by the challenge of neovascularization, particularly in severely damaged wounds that struggle to self-heal, potentially leading to organ dysfunction or even death. Thus, promoting vascularization is crucial for effective skin repair. This study employed electrostatic spraying to fabricate methacrylated hyaluronic acid (HAMA) hydrogel microspheres for encapsulation of ectodermal mesenchymal stem cells (EMSCs), and optimization of the process parameters to assess their biocompatibility. Under in vitro conditions, EMSCs microspheres were successfully induced to differentiate into structures with vascular networks. Additionally, the optimal modification ratio of dopamine-modified hyaluronic acid (HADA) was determined to enhance the adhesive and mechanical properties of the dressing. Based on these findings, a dressing incorporating cell microspheres and adhesive hydrogels was developed. This dressing demonstrated formation of microvascular structures in vitro. Upon in vivo transplantation, it integrated tightly with surrounding tissues, modulated the inflammatory response, and accelerated wound healing in mouse model. This composite dressing, integrating cell-laden microspheres within a hydrogel's framework, offers a simple and effective approach to promote skin microvascular. STATEMENT OF SIGNIFICANCE: This study describes a hydrogel dressing that uses electrostatically sprayed methacrylated hyaluronic acid (HAMA) microspheres to encapsulate ectodermal mesenchymal stem cells (EMSCs). The hydrogel composition was optimized using dopamine-modified hyaluronic acid (HADA), which improved adhesion, while methacrylated polyvinyl alcohol (PVAMA) enhanced mechanical strength. This highly effective, low-risk hydrogel dressing promoted angiogenesis and accelerated wound healing. The results of this study highlight the potential of hydrogel dressing for clinical applications in tissue engineering and regenerative medicine, thus providing a promising strategy for the treatment of severe skin injuries.
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BackgroundRAY1216 is an alpha-ketoamide-based peptide inhibitor of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) major protease (Mpro). This study evaluated the absorption, distribution, metabolism and excretion of [14C]-labelled RAY1216 by oral administration.Research design and methodsThis phase Ι study was designed to assess the pharmacokinetics, mass balance and metabolic pathways in 6 healthy Chinese adult men after a single fasting oral administration of 240 mL (containing 400 mg/100 µCi) [14C] RAY1216.ResultsRAY1216 absorbed rapidly in the plasma, with a Cmax of 1796.83 ng/mL, tmax of 1.42 h and t1/2 of 5.97 h. RAY1216 is mainly excreted through feces and a small amount through urine, indicating that the excretion of RAY1216 occurs through the fecal route, within 96 h after administration, the majority (>90%) of the radioactive substances were excreted 104.17% of the metabolites were identified in urine and fecal samples. The radioactive transformation pathways suggest that RAY1216 has multiple metabolic pathways, including Oxidation-dealkylation, Mono-oxidation, Hydrolysis, and Urea binding. There were no reports of death, serious adverse events (SAEs), or withdrawals related to SAEs.ConclusionThe overall recovery rate data of radioactive substances in the excreta of all 6 subjects indicate that favourable mass balance recovery. The overall safety profile is favourable, and it demonstrates promising potential in mitigating both the duration and severity of COVID-19, and the comprehensive clinical safety and therapeutic effect are significantly superior to those of similar COVID-19 treatment drugs. RAY1216 can be referred to and further verified for the Phase II and Phase III clinical trials for the treatment of COVID-19.
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Antivirais , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus , Inibidores de Proteases , SARS-CoV-2 , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Administração Oral , Antivirais/farmacocinética , Antivirais/administração & dosagem , Radioisótopos de Carbono , China , Proteases 3C de Coronavírus/antagonistas & inibidores , COVID-19 , Fezes/química , Voluntários Saudáveis , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , População do Leste AsiáticoRESUMO
In the field of non-small cell lung cancer (NSCLC) treatment, targeted drug delivery to epidermal growth factor receptor (EGFR)-overexpressing tumors remains a significant challenge. This study aims to tackle this issue by engineering extracellular vesicles (EVs) derived from 293 T cells. Through azide-alkyne cycloaddition, EVs were functionalized with GE11 peptides (GE11-EVs), and loaded with doxorubicin to form GE11&DOX@EVs. We conduted Ac4ManNAz metabolic labeling to facilitate the site-specific conjugation of GE11 peptides and fluorescent probes onto the membranes of EVs. Then we comprehensively assessed the targeting efficiency, drug-loading capacity, and therapeutic efficacy of GE11-EVs in A549 NSCLC cells and xenograft models. In vitro experiments demonstrated significantly enhanced uptake of GE11-EVs by EGFR-positive A549 cells compared to unmodified EVs, along with markedly improved cytotoxicity of GE11&DOX@EVs against tumor cells (IC50: 1.6 µg/mL vs. 3.96 µg/mL for free doxorubicin, P < 0.01) and induction of mitochondrial membrane depolarization. Mechanistically, GE11&DOX@EVs upregulated pro-apoptotic proteins (caspase-3/8/9 and Bax) and downregulated anti-apoptotic BCL-2, significantly enhancing apoptosis compared to free DOX. In vivo imaging revealed a two-fold greater tumor accumulation of GE11-EVs than unmodified EVs at 24 h post-injection. GE11&DOX@EVs treatment suppressed tumor growth by 73.7 % in A549 xenografts, significantly outperforming both free doxorubicin (24.9 %) and DOX@EVs (58.6 %) groups (P < 0.05), with minimal systemic toxicity. Future research could further explore the clinical translation potential of this bioorthogonal platform for precision engineering of EVs in NSCLC therapy.
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Aluminum (Al) toxicity is a major limiting factor for plant growth and development in acidic soils. Melatonin, a plant growth regulator and signaling molecule, enhances resistance to multiple stresses. Recent studies show that melatonin alleviates Al toxicity through several complementary mechanisms. Here, we first outline the physiological and molecular impacts of Al stress and the external and internal strategies plants use to cope with it. We then summarize melatonin biosynthesis and its broader roles in stress adaptation. We focus on recent advances in melatonin-mediated mitigation of Al toxicity, highlighting four principal mechanisms: (i) the activation of antioxidant defense systems, (ii) the stimulation of organic acid anion exudation that chelates Al in the rhizosphere, (iii) the modification of cell wall composition to reduce Al binding sites, and (iv) the promotion of intracellular Al sequestration. We also discuss the crosstalk between melatonin and nitric oxide, as well as interactions with phytohormone signaling. Collectively, this review comprehensively synthesizes the current understanding regarding the role of melatonin in alleviating Al toxicity in plants, offering a promising strategy for crop production in acidic environments.
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Background: Acute myeloid leukemia (AML) remains a hematopoietic clonal malignancy that is characterized by a poor prognosis, largely attributable to chemotherapy resistance and a high incidence of post-chemotherapy relapse. Therefore, the identification of novel molecular markers is crucial for optimizing treatment regimens and improving outcomes for this disease. Methods: We first investigated the expression levels of poly(ADP-ribose)polymerase 3(PARP3) mRNA in data from our center and the Gene Expression Omnibus (GEO), then explored the role of PARP3 in AML through cell experiments. Results: Our results demonstrated that the expression levels of PARP3 were significantly elevated in AML samples compared to controls (p < 0.05). Based on the median expression of PARP3, 151 cases of AML from TCGA data were divided into two groups. The results showed that PARP3-high group had markedly shorter overall survival (OS) than the PARP3-low group (OS: median: 1.18 vs. 3.88 years; p < 0.001). The overexpression of PARP3 was correlated with older age and high-risk stratification in the AML from TCGA data (p < 0.05). Finally, we confirmed that specifically down-regulating PARP3 expression impaired AML cell proliferation, disrupted cell cycle process, inhibited migration, accelerated apoptosis, and impaired the PI3K/AKT/mTOR signaling pathway in vitro. Conclusions: PARP3-mediated activation of the PI3K/AKT/mTOR signaling pathway enhances AML cell proliferation and migration, identifying it as a potential therapeutic target for poor-prognosis AML.
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In the contemporary landscape of oncology, immune checkpoint blockade therapy has emerged as a paramount therapeutic modality. However, concomitant with the pervasive deployment of immune checkpoint inhibitors (ICIs), there has been an escalating incidence of adverse drug reactions over the years. Immunological encephalitis, a prevalent form of central nervous system toxicity, poses a significant threat to the lives of affected patients. A 65-year-old male patient, diagnosed with squamous cell carcinoma of the lung, experienced an atypical immune-mediated encephalitis of clinical nature after the administration of a PD-1 inhibitor, specifically Tirelizumab. The present investigation delved into the clinical presentations and suitable therapeutic protocols for immune-mediated encephalitis.
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Introduction: Esophageal cancer (EC) is one of the most aggressive tumor types worldwide, and malnutrition is extremely common among EC patients. By identifying EC biomarkers and conducting risk assessments on patients, more accurate diagnosis and treatment plans can be developed to prolong patients' survival. Methods: This study developed a risk assessment model for post-surgical EC patients using clinical data from patients who underwent esophagectomy. Prognostic factors influencing survival were evaluated using Adaptive Lasso for variable selection, followed by Cox proportional hazards regression and Receiver Operating Characteristic (ROC) curve. Among multiple clinical variables, the International Normalized Ratio (INR) emerged as the most significant predictor of survival. Results: Elevated INR levels were significantly associated with improved 3-year and 5-year survival outcomes compared to the Prognostic Nutritional Index (PNI). Patients with higher INR exhibited notably better postoperative survival rates. Further analysis demonstrated that INR was significantly correlated with the final differentiation degree, final infiltration degree, and final positive/negative status of EC. Discussion: INR serves as a valuable and independent prognostic biomarker for postoperative survival assessment in EC patients. Incorporating INR into clinical risk models can enhance the accuracy of prognosis and assist clinicians in optimizing individualized therapeutic strategies for surgical EC patients.