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The objective of this study was to analyze the chemical composition and evaluate the biological capabilities of the essential oils (EOs) extracted from leaves and stems of wild Aeschynomene indica L. plants by the hydrodistillation method. By using GC-FID/MS, fifty-six and fifty-five compounds, representing 95.1 and 97.6% of the essential oils in the leaves and stems, respectively, were characterized. The predominant constituents of A. indica EOs were (E)-caryophyllene, linalool, viridiflorol, phytol, hexadecanoic acid, trans-verbenol, and α-guaiene. The antibacterial and synergistic activities of the EOs were assessed by microdilution and checkerboard assays. The results revealed a potent inhibition and bactericidal activity against Staphylococcus aureus and Bacillus subtilis with MICs of 0.312-0.625 mg/mL. When combined with traditional antibiotics, the essential oils of A. indica possessed excellent synergistic effects against all tested bacteria. Additionally, the EOs of A. indica leaves showed higher antioxidant activity (IC50 = 0.11 ± 0.01 µg/mL) compared to the stem oil (IC50 = 0.19 ± 0.01 µg/mL) using the ABTS radical scavenging assay. The in vitro cytotoxicity of EOs against human cancer cell lines HepG2, MCF-7, A-549, and HCT-116 was examined, and MTT assays showed that the EOs possessed a significant cytotoxic potential against MCF-7 breast cancer cells, with IC50 values of 10.04 ± 1.82 and 15.89 ± 1.66 µg/mL, and a moderate cytotoxic activity against other tested cells. In conclusion, the A. indica EOs could be considered a potential source of pharmacologically active compounds.
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Antibacterianos , Antioxidantes , Pruebas de Sensibilidad Microbiana , Aceites Volátiles , Hojas de la Planta , Tallos de la Planta , Aceites Volátiles/farmacología , Aceites Volátiles/química , Antioxidantes/farmacología , Antioxidantes/química , Hojas de la Planta/química , Antibacterianos/farmacología , Antibacterianos/química , Humanos , Tallos de la Planta/química , Bacillus subtilis/efectos de los fármacos , Línea Celular Tumoral , Staphylococcus aureus/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/químicaRESUMEN
BACKGROUND: The incidence of gallstones is high in Qinghai Province. However, the molecular mechanisms underlying the development of gallstones remain unclear. METHODS: In this study, we collected urine samples from 30 patients with gallstones and 30 healthy controls. The urine samples were analysed using multi-omics platforms. Proteomics analysis was conducted using data-independent acquisition, whereas metabolomics analysis was performed using liquid chromatography-mass spectrometry (LC-MS). RESULTS: Among the patients with gallstones, we identified 49 down-regulated and 185 up-regulated differentially expressed proteins as well as 195 up-regulated and 189 down-regulated differentially expressed metabolites. Six pathways were significantly enriched: glycosaminoglycan degradation, arginine and proline metabolism, histidine metabolism, pantothenate and coenzyme A biosynthesis, drug metabolism-other enzymes, and the pentose phosphate pathway. Notably, 10 differentially expressed proteins and metabolites showed excellent predictive performance and were selected as potential biomarkers. CONCLUSION: The findings of our metabolomics and proteomics analyses provide new insights into novel biomarkers for patients with cholelithiasis in high-altitude areas.
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Altitud , Biomarcadores , Cálculos Biliares , Metabolómica , Proteómica , Humanos , Proteómica/métodos , Metabolómica/métodos , Cálculos Biliares/metabolismo , Cálculos Biliares/orina , Femenino , Persona de Mediana Edad , Biomarcadores/orina , Masculino , Cromatografía Liquida/métodos , Adulto , Anciano , Espectrometría de Masas/métodos , Estudios de Casos y ControlesRESUMEN
Background: Acute DeBakey type I aortic dissection is associated with high morbidity and mortality. Little is known regarding the role of leukocyte trajectory in prognosis. Methods: We included adult acute DeBakey type I aortic dissection patients with emergency frozen elephant trunk and total arch replacement in 2 cardiovascular centers (2020-2022). We used latent class mixed model to group patients according to their leukocyte patterns from hospital admission to the first 5 days after surgery. We investigated the association of leukocyte trajectory and 30-day and latest follow-up mortality (October 31, 2023), exploratorily analyzing the effects of ulinastatin treatment on outcome. Results: Of 255 patients included, 3 distinct leukocyte trajectories were identified: 196 in group I (decreasing trajectory), 34 in group II (stable trajectory), and 25 in group III (rising trajectory). Overall, 30-day mortality was 25 (9.8%), ranging from 8.2% (16/196) in group I, 8.8% (3/34) in group II, to 24.0% (6/25) in group III (P for trend = .036). Group III was associated with higher mortality both at 30 days (adjusted hazard ratio, 3.260; 95% CI, 1.071-9.919; P = .037) and at the last follow-up (adjusted hazard ratio, 2.840; 95% CI, 1.098-7.345; P = .031) compared with group I. Conclusions: Distinct and clinically relevant groups can be identified by analyzing leukocyte trajectories, and a rising trajectory was associated with higher short-term and midterm mortality.
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This study aimed to investigate the relationship between hemodialysis duration (HDD) and retinal nerve fiber layer (RNFL) thickness. A total of 60 patients receiving maintenance hemodialysis and 67 healthy controls were analyzed. Spectral domain optical coherence tomography (SD-OCT) was employed to measure annular RNFL thicknesses. The hemodialysis group exhibited reduced temporal and inferior RNFL thicknesses relative to the control group. In hemodialysis patients, the inferior RNFL thickness was negatively correlated with HDD and positively correlated with intraocular pressure (IOP). Moreover, IOP was positively correlated with HDD. Mediation analysis showed that the negative correlation between HDD and inferior RNFL thickness was mediated by IOP. In conclusion, hemodialysis leads to temporal and inferior RNFL thinning, and the thickness reduction is proportional to hemodialysis duration. However, such changes are not induced by an increase in IOP.
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Presión Intraocular , Fibras Nerviosas , Diálisis Renal , Tomografía de Coherencia Óptica , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Fibras Nerviosas/patología , Tomografía de Coherencia Óptica/métodos , Presión Intraocular/fisiología , Anciano , Retina/diagnóstico por imagen , Retina/patología , Adulto , Células Ganglionares de la Retina/patología , Factores de Tiempo , Estudios de Casos y ControlesRESUMEN
Surface ligand chemistry is vital to control the synthesis, diminish surface defects, and improve the electronic coupling of quantum dots (QDs) toward emerging applications in optoelectronic devices. Here, we successfully develop highly homogeneous and dispersed AgBiS2 QDs, focus on the control of interdot spacing, and substitute the long-chain ligands with ammonium iodide in solution. This results in improved electronic coupling of AgBiS2 QDs with excellent surface passivation, which greatly facilitates carrier transport within the QD films. Based on the stable AgBiS2 QD dispersion with the optimal ligand state, a homogeneous and densely packed QD film is prepared by a facile one-step coating process, delivering a champion power conversion efficiency of approximately 8% in the QD solar cells with outstanding shelf life stability. The proposed surface engineering strategy holds the potential to become a universal preprocessing step in the realm of high-performance QD optoelectronic devices.
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Cellular mechanical force plays a crucial role in numerous biological processes, including wound healing, cell development, and metastasis. To enable imaging of intercellular tension, molecular tension probes were designed, which offer a simple and efficient method for preparing Au-DNA intercellular tension probes with universal applicability. The proposed approach utilizes gold nanoparticles linked to DNA hairpins, enabling sensitive visualization of cellular force in vitro. Specifically, the designed Au-DNA intercellular tension probe includes a molecular spring flanked by a fluorophore-quencher pair, which is anchored between cells. As intercellular forces open the hairpin, the fluorophore is de-quenched, allowing for visualization of cellular force. The effectiveness of this approach was demonstrated by imaging the cellular force in living cells using the designed Au-DNA intercellular tension probe.
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Although the cell membrane and cytoskeleton play essential roles in cellular morphogenesis, the interaction between the membrane and cytoskeleton is poorly understood. Cotton fibers are extremely elongated single cells, which makes them an ideal model for studying cell development. Here, we used the sphingolipid biosynthesis inhibitor, fumonisin B1 (FB1), and found that it effectively suppressed the myeloblastosis (MYB) transcription factor GhMYB86, thereby negatively affecting fiber elongation. A direct target of GhMYB86 is GhTUB7, which encodes the tubulin protein, the major component of the microtubule cytoskeleton. Interestingly, both the overexpression of GhMYB86 and GhTUB7 caused an ectopic microtubule arrangement at the fiber tips, and then leading to shortened fibers. Moreover, we found that GhMBE2 interacted with GhMYB86 and that FB1 and reactive oxygen species induced its transport into the nucleus, thereby enhancing the promotion of GhTUB7 by GhMYB86. Overall, we established a GhMBE2-GhMYB86-GhTUB7 regulation module for fiber elongation and revealed that membrane sphingolipids affect fiber elongation by altering microtubule arrangement.
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Single-molecule localization microscopy (SMLM) is a versatile tool for realizing nanoscale imaging with visible light and providing unprecedented opportunities to observe bioprocesses. The integration of machine learning with SMLM enhances data analysis by improving efficiency and accuracy. This tutorial aims to provide a comprehensive overview of the data analysis process and theoretical aspects of SMLM, while also highlighting the typical applications of machine learning in this field. By leveraging advanced analytical techniques, SMLM is becoming a powerful quantitative analysis tool for biological research.
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BACKGROUND: Colorectal cancer is among the most common malignant tumors affecting the gastrointestinal tract. Liver metastases, a complication present in approximately 50% of colorectal cancer patients, are a considerable concern. Recently, studies have revealed the crucial role of miR-455 in tumor pathogenesis. However, the effect of miR-455 on the progression of liver metastases in colorectal cancer remains controversial. As an antagonist of bone morphogenetic protein(BMP), Gremlin 1 (GREM1) may impact organogenesis, body patterning, and tissue differentiation. Nevertheless, the role of miR-455 in regulating GREM1 in colorectal cancer liver metastases and how miR-455/GREM1 axis influences tumour immune microenvironment is unclear. METHODS: Bioinformatics analysis shows that miR-455/GREM1 axis plays crucial role in liver metastasis of intestinal cancer and predicts its possible mechanism. To investigate the impact of miR-455/GREM1 axis on the proliferation, invasion, and migration of colorectal cancer cells, colony formation assay, wound healing and transwell assay were examined in vitro. The Dual-Luciferase reporter gene assay and RNA pull-down assay confirmed a possible regulatory effect between miR-455 and GREM1. In vivo, colorectal cancer liver metastasis(CRLM) model mice was established to inquiry the effect of miR-455/GREM1 axis on tumor growth and macrophage polarization. The marker of macrophage polarization was tested using immunofluorescence(IF) and quantitative real-time polymerase chain reaction(qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), cytokines were detected in culture medium supernatants. RESULTS: We found that miR-455 and BMP6 expression was increased and GREM1 expression was decreased in liver metastase compared with primary tumor. miR-455/GREM1 axis promotes colorectal cancer cells proliferation, migration, invasion via affected PI3K/AKT pathway. Moreover, downregulating GREM1 augmented BMP6 expression in MC38 cell lines, inducing M2 polarization of macrophages, and promoting liver metastasis growth in CRLM model mice. CONCLUSION: These data suggest that miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. These results offer valuable insights and direction for future research and treatment of CRLM.
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The properties of nanopipettes largely rely on the materials introduced onto their inner walls, which allow for a vast extension of their sensing capabilities. The challenge of simultaneously enhancing the sensitivity and selectivity of nanopipettes for pH sensing remains, hindering their practical applications. Herein, we report insulin-modified nanopipettes with excellent pH response performances, which were prepared by introducing insulin onto their inner walls via a two-step reaction involving silanization and amidation. The pH response intensity based on ion current rectification was significantly enhanced by approximately 4.29 times when utilizing insulin-modified nanopipettes compared with bare ones, demonstrating a linear response within the pH range of 2.50 to 7.80. In addition, insulin-modified nanopipettes featured good reversibility and selectivity. The modification processes were monitored using the I-V curves, and the relevant mechanisms were discussed. The effects of solution pH and insulin concentration on the modification results were investigated to achieve optimal insulin introduction. This study showed that the pH response behavior of nanopipettes can be greatly improved by introducing versatile molecules onto the inner walls, thereby contributing to the development and utilization of pH-responsive nanopipettes.
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Insulina , Concentración de Iones de Hidrógeno , Insulina/química , Técnicas Biosensibles/métodos , Iones/químicaRESUMEN
The pancreas is adjacent to critical organs; excessive microwave ablation (MWA) can result in serious complications. The purpose of this paper is to provide the reference data of pancreas MWA for clinicians, analyze the ablation outcomes under different ablation parameters, and determine the critical temperature of pancreatic surface fat liquefaction outflow. Combinations of two power levels (30 W and 55 W), three antenna diameters (1.3 mm, 1.6 mm, and 1.9 mm), and three ablation times (1 min, 1.5 min, and 2 min) were applied to an ex vivo pig pancreas. Temperature measurements were taken at four thermocouple points. The center point is located 5 mm horizontally from the antenna slot, with a temperature measurement point located 5 mm above, below, and to the right of the center point. Main effect analysis and variance analysis were used to quantify the influences of each factor on the ablation outcomes. At 30 W, the antenna diameter contributing the most at 48.5%. At 30 W-1.3 mm-1 min, the spherical index (1.41) is closest to 1. At 55 W, the coagulation zone size was almost only affected by the ablation time, with a contribution rate of 28.7%, the temperature at point C exceeds point B. On the surface of the ex vivo porcine pancreas, the fat outflow temperature was 54ã. Ablation combinations with low power, short duration, and small antenna diameter results in a more nearly spherical coagulation zone. When performing MWA on the pancreas, it is advisable to avoid areas with higher fat content, while keeping the pancreatic surface temperature below 54°C.
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Técnicas de Ablación , Microondas , Páncreas , Temperatura , Animales , Porcinos , Páncreas/cirugía , Tejido Adiposo/cirugíaRESUMEN
Glioblastoma (GBM) presents a daunting challenge due to its resistance to temozolomide (TMZ), a hurdle exacerbated by the proneural-to-mesenchymal transition (PMT) from a proneural (PN) to a mesenchymal (MES) phenotype. TAGLN2 is prominently expressed in GBM, particularly in the MES subtype compared to low-grade glioma (LGG) and the PN subtype. Our research reveals TAGLN2's involvement in PMT and TMZ resistance through a series of in vitro and in vivo experiments. TAGLN2 knockdown can restrain proliferation and invasion, trigger DNA damage and apoptosis, and heighten TMZ sensitivity in GBM cells. Conversely, elevating TAGLN2 levels amplifies resistance to TMZ in cellular and intracranial xenograft mouse models. We demonstrate the interaction relationship between TAGLN2 and ERK1/2 through co-immunoprecipitation (Co-IP) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectrometry analysis. Knockdown of TAGLN2 results in a decrease in the expression of p-ERK1/2, whereas overexpression of TAGLN2 leads to an increase in p-ERK1/2 expression within the nucleus. Subsequently, the regulatory role of TAGLN2 in the expression and control of MGMT has been demonstrated. Finally, the regulation of TAGLN2 by NF-κB has been validated through chromatin immunoprecipitation and ChIP-PCR assays. In conclusion, our results confirm that TAGLN2 exerts its biological functions by interacting with the ERK/MGMT axis and being regulated by NF-κB, thereby facilitating the acquisition of promoting PMT and increased resistance to TMZ therapy in glioblastoma. These results provide valuable insights for the advancement of targeted therapeutic approaches to overcome TMZ resistance in clinical treatments.
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Antineoplásicos Alquilantes , Neoplasias Encefálicas , Resistencia a Antineoplásicos , Glioblastoma , Temozolomida , Animales , Humanos , Ratones , Antineoplásicos Alquilantes/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Metilasas de Modificación del ADN/metabolismo , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/patología , Glioblastoma/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Ratones Desnudos , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Temozolomida/farmacología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Background: Meaning in life is a crucial aspect of psychological well-being, often overlooked despite its clinical significance. This warrants further investigation, especially regarding its relationship with frailty and psychological resilience. Objective: This study aims to assess the status and relevance of frailty, psychological resilience, and meaning in life among older adults in Chinese nursing homes. Additionally, it explores the mediating role of psychological resilience between frailty and meaning in life, providing insights to improve the meaning in life for older adults in nursing homes. Methods: Between August 2022 and November 2022, 302 older adults in Chinese nursing homes were selected using convenience sampling. The study utilized the Socio-demographic Characteristics Questionnaire, Tilburg Frailty Indicator, Connor-Davidson Resilience Scale, and the Source of Meaning Scale for Older Adults. A face-to-face questionnaire survey was conducted, and SPSS 27.0 was employed for analyzing correlations between frailty, psychological resilience, and meaning in life. The mediating effect of psychological resilience was assessed using Model 4 in the Process plug-in. Results: Older adults in nursing homes exhibited a frailty total score of 4.00 (2.00, 5.00), with a prevalence of 28.5%. Psychological resilience scored 66.00 (51.75, 76.00), and meaning in life scored 149.00 (132.00, 158.25). Frailty showed a negative correlation with both meaning in life and psychological resilience, while meaning in life demonstrated a positive correlation with psychological resilience. Psychological resilience exhibited a partial mediating effect, accounting for 51.04% of the total effect between frailty and meaning in life. Conclusion: Frailty incidence is high among older adults in nursing homes, with psychological resilience at a general level and meaning in life in the upper middle level. Psychological resilience plays a crucial role as a partial mediator between frailty and meaning in life. Timely assessment of frailty, targeted interventions, and improvements in psychological resilience are essential for enhancing the meaning in life and promoting successful aging.
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The Omi/HtrA2 inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (Ucf-101) has shown neuroprotective effects in the central nervous system. However, whether Ucf-101 can protect retinal ganglion cells (RGCs) after retinal ischemia/reperfusion (IR) has not been investigated. We aimed to investigate the effects of Ucf-101 on RGCs apoptosis and inflammation after IR-induced retinal injury in mice. We injected Ucf-101 into the mouse vitreous body immediately after IR injury. After 7 days, hematoxylin and eosin staining was conducted to assess retinal tissue damage. Next, retrograde labeling with FluoroGold, counting of RGCs and TUNEL staining were conducted to evaluate apoptosis. Immunohistochemistry, immunofluorescence staining, and western blotting were conducted to analyze protein levels. IR injury-induced retinal tissue damage could be prevented by Ucf-101 treatment. The number of TUNEL-positive RGCs was reduced by Ucf-101 treatment in mice with IR injury. Ucf-101 treatment inhibited the upregulation of Bax, cleaved caspase-3 and cleaved caspase-9 and activated the JNK/ERK/P38 signaling pathway. Furthermore, Ucf-101 treatment inhibited the upregulation of glial fibrillary acidic protein (GFAP), vimentin, Iba1 and CD68 in mice with IR injury. Ucf-101 prevents retinal tissue damage, improves the survival of RGCs, and suppresses microglial overactivation after IR injury. Ucf-101 might be a potential target to prevent RGCs apoptosis and inflammation in neurodegenerative eye diseases.
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Apoptosis , Estrés Oxidativo , Daño por Reperfusión , Células Ganglionares de la Retina , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Ratones , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Masculino , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/efectos de los fármacos , Ratones Endogámicos C57BL , Inflamación/patología , Inflamación/metabolismo , Tiobarbitúricos/metabolismo , Retina/metabolismo , Retina/patología , Furanos/farmacología , Retinitis/etiología , Retinitis/patología , Retinitis/metabolismo , Modelos Animales de Enfermedad , Pirimidinonas , TionasRESUMEN
Graphene-based, high-quality, two-dimensional electronic systems have emerged as a highly tunable platform for studying superconductivity1-21. Specifically, superconductivity has been observed in both electron- and hole-doped twisted graphene moiré systems1-17, whereas in crystalline graphene systems, superconductivity has so far been observed only in hole-doped rhombohedral trilayer graphene (RTG)18 and hole-doped Bernal bilayer graphene (BBG)19-21. Recently, enhanced superconductivity has been demonstrated20,21 in BBG because of the proximity to a monolayer WSe2. Here we report the observation of superconductivity and a series of flavour-symmetry-breaking phases in electron- and hole-doped BBG/WSe2 devices by electrostatic doping. The strength of the observed superconductivity is tunable by applied vertical electric fields. The maximum Berezinskii-Kosterlitz-Thouless transition temperature for the electron- and hole-doped superconductivity is about 210 mK and 400 mK, respectively. Superconductivities emerge only when the applied electric fields drive the BBG electron or hole wavefunctions towards the WSe2 layer, underscoring the importance of the WSe2 layer in the observed superconductivity. The hole-doped superconductivity violates the Pauli paramagnetic limit, consistent with an Ising-like superconductor. By contrast, the electron-doped superconductivity obeys the Pauli limit, although the proximity-induced Ising spin-orbit coupling is also notable in the conduction band. Our findings highlight the rich physics associated with the conduction band in BBG, paving the way for further studies into the superconducting mechanisms of crystalline graphene and the development of superconductor devices based on BBG.
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The utilization of platelet-rich plasma (PRP) has exhibited potential as a therapeutic approach for the management of diabetic foot ulcers (DFUs). However, it is currently not well understood how the diabetic environment may influence PRP-derived exosomes (PRP-Exos) and their potential impact on neutrophil extracellular traps (NETs). This study aims to investigate the effects of the diabetic environment on PRP-Exos, their communication with neutrophils, and the subsequent influence on NETs and wound healing. Through bulk-seq and Western blotting, we confirmed the increased expression of MMP-8 in DFUs. Additionally, we discovered that miRNA-26b-5p plays a significant role in the communication between DFUs and PRP-Exos. In our experiments, we found that PRP-Exos miR-26b-5p effectively improved diabetic wound healing by inhibiting NETs. Further tests validated the inhibitory effect of miR-26b-5p on NETs by targeting MMP-8. Both in vitro and in vivo experiments showed that miRNA-26b-5p from PRP-Exos promoted wound healing by reducing neutrophil infiltration through its targeting of MMP-8. This study establishes the importance of miR-26b-5p in the communication between DFUs and PRP-Exos, disrupting NETs formation in diabetic wounds by targeting MMP-8. These findings provide valuable insights for developing novel therapeutic strategies to enhance wound healing in individuals suffering from DFUs.
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Pie Diabético , Exosomas , Trampas Extracelulares , Metaloproteinasa 8 de la Matriz , MicroARNs , Plasma Rico en Plaquetas , Cicatrización de Heridas , Animales , Humanos , Masculino , Ratones , Diabetes Mellitus Experimental/metabolismo , Pie Diabético/terapia , Pie Diabético/metabolismo , Pie Diabético/genética , Exosomas/metabolismo , Trampas Extracelulares/metabolismo , Metaloproteinasa 8 de la Matriz/metabolismo , Metaloproteinasa 8 de la Matriz/genética , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/administración & dosificación , Neutrófilos/metabolismoRESUMEN
BACKGROUND: A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC. METHODS: This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis. RESULTS: A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size. CONCLUSION: Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study. TRIAL REGISTRATION NUMBER: clinicaltrials.gov, NCT04118855.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Axitinib , Carcinoma de Células Renales , Neoplasias Renales , Terapia Neoadyuvante , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Axitinib/uso terapéutico , Axitinib/farmacología , Masculino , Femenino , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Estudios Prospectivos , Nefrectomía/métodosRESUMEN
Characterizing cellular features during seed germination is crucial for understanding the complex biological functions of different embryonic cells in regulating seed vigor and seedling establishment. We performed spatially enhanced resolution omics sequencing (Stereo-seq) and single-cell RNA sequencing (scRNA-seq) to capture spatially resolved single-cell transcriptomes of germinating rice embryos. An automated cell-segmentation model, employing deep learning, was developed to accommodate the analysis requirements. The spatial transcriptomes of 6, 24, 36, and 48 h after imbibition unveiled both known and previously unreported embryo cell types, including two unreported scutellum cell types, corroborated by in situ hybridization and functional exploration of marker genes. Temporal transcriptomic profiling delineated gene expression dynamics in distinct embryonic cell types during seed germination, highlighting key genes involved in nutrient metabolism, biosynthesis, and signaling of phytohormones, reprogrammed in a cell-type-specific manner. Our study provides a detailed spatiotemporal transcriptome of rice embryo and presents a previously undescribed methodology for exploring the roles of different embryonic cells in seed germination.
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Continued interest in the bioactive alkaloids led to the isolation of five undescribed alkaloids (1-5), ophiorglucidines A-E, and seven known analogues (6-12) from the water-soluble fraction of Ophiorrhiza japonica. The structures were elucidated based on spectroscopic data and quantum calculations as well as X-ray crystallographic analysis. The structure of 1 was characterized as a hexacyclic skeleton including a double bridge linking the indole and the monoterpene moieties, which is the first report of a single crystal with this type of structure. Moreover, the inhibitory effect of zwitterionic indole alkaloid glycosides on xanthine oxidase was found for the first time. The alkaloids 2 and 3, both of which have a pentacyclic zwitterionic system, were more active than the reference inhibitor, allopurinol (IC50 = 11.1 µM) with IC50 values of 1.0 µM, and 2.5 µM, respectively. Structure-activity relationships analyses confirmed that the carbonyl group at C-14 was a key functional group responsible for the inhibitory effects of these alkaloids.
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Inhibidores Enzimáticos , Alcaloides Indólicos , Monoterpenos , Rubiaceae , Xantina Oxidasa , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Rubiaceae/química , Relación Estructura-Actividad , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Alcaloides Indólicos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Monoterpenos/química , Monoterpenos/farmacología , Monoterpenos/aislamiento & purificación , Estructura Molecular , Relación Dosis-Respuesta a Droga , Modelos Moleculares , Cristalografía por Rayos XRESUMEN
MAIN CONCLUSION: In this review, we summarize how chlorophyll metabolism in angiosperm is affected by the environmental factors: light, temperature, metal ions, water, oxygen, and altitude. The significance of chlorophyll (Chl) in plant leaf morphogenesis and photosynthesis cannot be overstated. Over time, researchers have made significant advancements in comprehending the biosynthetic pathway of Chl in angiosperms, along with the pivotal enzymes and genes involved in this process, particularly those related to heme synthesis and light-responsive mechanisms. Various environmental factors influence the stability of Chl content in angiosperms by modulating Chl metabolic pathways. Understanding the interplay between plants Chl metabolism and environmental factors has been a prominent research topic. This review mainly focuses on angiosperms, provides an overview of the regulatory mechanisms governing Chl metabolism, and the impact of environmental factors such as light, temperature, metal ions (iron and magnesium), water, oxygen, and altitude on Chl metabolism. Understanding these effects is crucial for comprehending and preserving the homeostasis of Chl metabolism.