RESUMEN

Organic-inorganic lead halide perovskites (OLHPs) have demonstrated exceptional properties in high-performance photoelectric devices. However, the impact of A-site cations, specifically formamidinium and methylammonium (MA), on the optoelectronic properties of OLHPs, particularly in the context of hot carrier utilization, remains a topic of debate. In this study, we propose a method for characterizing hot carrier transportation by measuring the hot carrier mobility and momentum-dependent transient photocurrent influenced by A-site cations in OLHPs. Our findings reveal that the direction of photon drag current is reversed upon substitution of the MA cation, suggesting the strong localization of hot carriers by the MA cation dipole. Furthermore, the correlation between the hot carrier photoconductivity and the electronic structure in different A-site cation samples indicates that hot carrier mobility in OLHPs can be reduced by >50% due to the influence of A-site cations.

RESUMEN

Nanozymes have been attracting widespread interest for the past decade, especially in the field of cancer therapy, due to their intrinsic catalytic activities, strong stability, and ease of synthesis. However, enhancing their catalytic activity in the tumor microenvironment (TME) remains a major challenge. Herein, we manipulate catalytic activities of Ru nanozymes via modulating lattice spacing in Ru nanocrystals supported on nitrogen-doped carbon support, to achieve improvement in multiple enzyme-like activities that can form cascade catalytic reactions to boost cancer cell killing. In addition, the lattice expansion in Ru nanocrystals improve the responsiveness of the nanozymes to self-powered electric field, achieving maximized cancer therapeutic outcome. Under the electrical stimulation provided by a human self-propelled triboelectric device, the Ru-based nanozyme (Ru1000) with a lattice expansion of 5.99% realizes optimal catalytic performance and cancer therapeutic outcome of breast cancer in female tumor-bearing mice. Through theoretical calculations, we uncover that the lattice expansion and electrical stimulation promote the catalytic reaction, simultaneously, by reducing the electron density and shifting the d-band center of Ru active sites. This work provides opportunities for improving the development of nanozymes.

Asunto(s)

Rutenio , Microambiente Tumoral , Animales , Rutenio/química , Catálisis , Femenino , Ratones , Humanos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Nanopartículas/química , Ratones Endogámicos BALB C , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico

RESUMEN

The effect of Fe3O4 nanoparticles (Fe3O4 NPs) on the electron transfer process in aerobic composting systems remains unexplored. In this study, we compared the electron transfer characteristics of DOM in sludge composting without additives (group CK) and with the addition of 50 mg/kg Fe3O4 NPs additive (group Fe). It was demonstrated that the electron transfer capacity (ETC) and electron donating capacity (EDC) of compost-derived DOM increased by 13%-29% and 40%-47%, respectively, with the addition of Fe3O4 NPs during sludge composting. Analyzing the composition and structure of DOM revealed that Fe3O4 NPs promoted the formation of humic acid-like substances and enhanced the aromatic condensation degree of DOM. Correlation analysis indicated that the increase in EDC of DOM was closely associated with the phenolic group in DOM and influenced by quinone groups and the degree of aromatization of DOM. The higher EDC and the structural evolution of DOM in group Fe reduced the bioaccessibility of Cu, Cr, Ni, Zn. This study contributes to a deeper understanding of the redox evolutionary mechanism of DOM in sludge composting and broadens the application of iron oxides additives.

Asunto(s)

Compostaje , Aguas del Alcantarillado , Aguas del Alcantarillado/química , Sustancias Húmicas/análisis , Electrones , Compuestos Férricos/química

RESUMEN

Fokienia hodginsii (F. hodginsii), belonging to the genus Fokienia of the Cupressaceae. F. hodginsii has significant application value due to its wood properties and great research value in evolutionary studies as a gymnosperm. However, the genome of F. hodginsii remains unknown due to the large size of gymnosperms genome. Pacific Bioscience sequencing, Hi-C mapping, whole-genome Bisulfite Sequencing (BS-Seq), long-read isoform sequencing (Iso-Seq), direct RNA sequencing (DRS), quantitative proteomics, and metabonomics analysis are employed to facilitate genome assembly, gene annotation, and investigation into epigenetic mechanisms. In this study, the 10G F. hodginsii genome is assembled into 11 chromosomes. Furthermore, 50 521 protein-coding genes are annotated and determined that 65% of F. hodginsii genome comprises repetitive sequences. It is discovered that transposable element (TE)-including introns is associated with higher expression. The DNA methylome of F. hodginsii reveals that xylem has a higher DNA methylation level compared to callus. Moreover, DRS reveals the significant alterations in RNA full-length ratio, which potentially associated with poly(A) length (PAL) and alternative polyadenylation (APA). Finally, the morphology measurement and metabonomics analysis revealed the difference of 14 cultivars. In summary, the genomes and epigenetics datasets provide a molecular basis for callus formation in the gymnosperm family.

RESUMEN

Solid-state polymer electrolytes (SPEs) are promising for high-performance zinc metal batteries (ZMBs), but they encounter critical challenges of low ionic conductivity, limited Zn2+ transference number (tZn2+), and an unstable electrolyte-electrode interface. Here, we present an effective approach involving a missing-linker metallic organic framework (MOF)-catalyzed poly(ethylene glycol) diacrylate (PEGDA)/polyacrylamide (PAM) copolymer SPE for single Zn2+ conduction and seamless electrolyte-electrode contact. The single-Zn2+ conduction is facilitated by the anchoring of the OTF- anions onto the unsaturated metal sites of missing-linker MOF, while the PEGDA and PAM chains in competitive coordination with Zn2+ ions promote rapid Zn ion transport. Our all-solid-state electrolyte simultaneously achieves a superior ionic conductivity of 1.52 mS cm-1 and a high tZn2+ of 0.83 at room temperature, alongside uniform Zn metal deposition (1000 cycles in symmetric cells) and high Zn plating/striping efficiencies (>99% after 600 cycles in asymmetric cells). Applications of our SPE in Zn//VO2 full cells are further demonstrated with a long lifespan of 2000 cycles and an extremely low-capacity degradation rate of 0.012% per cycle. This work provides an effective strategy for using a missing-linker MOF to catalyze competitively coordinating copolymers for accelerating Zn2+ ion conduction, assisting the future design of all-solid-state ZMBs.

RESUMEN

BACKGROUND: Early detection and treatment are effective methods for the management of oral squamous cell carcinoma (OSCC), which can be facilitated by the detection of tumor-specific OSCC biomarkers. The epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) are important therapeutic targets for OSCC. Multispectral fluorescence molecular imaging (FMI) can facilitate the detection of tumor multitarget expression with high sensitivity and safety. Hence, we developed Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes, in combination with multispectral FMI, to sensitively and noninvasively identify EGFR and PD-L1 expression for the detection and comprehensive treatment of OSCC. METHODS: The expression of EGFR and PD-L1 was analyzed using bioinformatics data sources and specimens. Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes were developed and tested on preclinical OSCC cell line and orthotopic OSCC mouse model, fresh OSCC patients' biopsied samples, and further clinical mouthwash trials were conducted in OSCC patients. RESULTS: EGFR and PD-L1 were specifically expressed in human OSCC cell lines and tumor xenografts. Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes can specifically target to the tumor sites in an in situ human OSCC mouse model with good safety. The detection sensitivity and specificity of Nimotuzumab-ICG in patients were 96.4% and 100%, and 95.2% and 88.9% for Atezolizumab-Cy5.5. CONCLUSIONS: EGFR and PD-L1 are highly expressed in OSCC, the combination of which is important for a precise prognosis of OSCC. EGFR and PD-L1 expression can be sensitively detected using the newly synthesized multispectral fluorescence imaging probes Nimotuzumab-ICG and Atezolizumab-Cy5.5, which can facilitate the sensitive and specific detection of OSCC and improve treatment outcomes. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100045738. Registered 23 April 2021, https://www.chictr.org.cn/bin/project/edit?pid=125220.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , Carcinoma de Células Escamosas , Receptores ErbB , Neoplasias de la Boca , Imagen Óptica , Humanos , Antígeno B7-H1/metabolismo , Animales , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/diagnóstico , Imagen Óptica/métodos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ratones , Femenino , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/diagnóstico , Masculino , Línea Celular Tumoral , Persona de Mediana Edad , Imagen Molecular/métodos , Biomarcadores de Tumor/metabolismo

RESUMEN

Plant glutathione peroxidases (GPXs) are important enzymes for removing reactive oxygen species in plant cells and are closely related to the stress resistance of plants. This study identified the GPX gene family members of pepper (Capsicum annuum L.), "CM333", at the whole-genome level to clarify their expression patterns and enzyme activity changes under abiotic stress and ABA treatment. The results showed that eight CaGPX genes were unevenly distributed across four chromosomes and one scaffold of the pepper genome, and their protein sequences had Cys residues typical of the plant GPX domains. The analysis of collinearity, phylogenetic tree, gene structure, and conserved motifs indicated that the CaGPX gene sequence is conserved, structurally similar, and more closely related to the sequence structure of Arabidopsis. Meanwhile, many cis elements involved in stress, hormones, development, and light response were found in the promoter region of the CaGPX gene. In addition, CaGPX1/4 and CaGPX6 were basically expressed in all tissues, and their expression levels were significantly upregulated under abiotic stress and ABA treatment. Subcellular localization showed that CaGPX1 and CaGPX4 are localized in chloroplasts. Additionally, the variations in glutathione peroxidase activity (GSH-Px) mostly agreed with the variations in gene expression. In summary, the CaGPXs gene may play an important role in the development of peppers and their response to abiotic stress and hormones.

Asunto(s)

Ácido Abscísico , Capsicum , Regulación de la Expresión Génica de las Plantas , Glutatión Peroxidasa , Familia de Multigenes , Filogenia , Proteínas de Plantas , Estrés Fisiológico , Capsicum/genética , Capsicum/enzimología , Capsicum/efectos de los fármacos , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Estrés Fisiológico/genética , Ácido Abscísico/farmacología , Ácido Abscísico/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiones Promotoras Genéticas , Secuencia de Aminoácidos

RESUMEN

Metastatic clear cell renal cell carcinoma has heterogenous tumor microenvironment (TME). Among the metastatic lesions, pancreas metastasis is rare and controversy in treatment approaches. Here, extensive primary and metastatic lesion samples were included by single-cell RNA-seq to decipher the distinct metastasis TME. The hypoxic and inflammatory TME of pancreas metastasis was decoded in this study, and the activation of PAX8-myc signaling, and metabolic reprogramming were observed. The active components including endothelial cells, fibroblasts and T cells were profiled. Meanwhile, we also evaluated the effect of anti-angiogenesis treatment in the pancreas metastasis patient. The potential mechanisms of pancreatic tropism, instability of genome, and the response of immunotherapy were also discussed in this work. Taken together, our findings suggest a clue to the heterogeneity in metastasis TME and provide evidence for the treatment of pancreas metastasis in renal cell carcinoma patients.

Asunto(s)

Inhibidores de la Angiogénesis , Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Pancreáticas , RNA-Seq , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/patología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Análisis de la Célula Individual/métodos , Factor de Transcripción PAX8/genética , Factor de Transcripción PAX8/metabolismo , Regulación Neoplásica de la Expresión Génica , Masculino , Femenino , Análisis de Expresión Génica de una Sola Célula

RESUMEN

Despite significant progress achieved in artificial self-sorting in solution, operating self-sorting in the body remains a considerable challenge. Here, we report an in vivo self-sorting peptide system via an in situ assembly evolution for combined cancer therapy. The peptide E3C16-SS-EIY consists of two disulfide-connected segments, E3C16SH and SHEIY, capable of independent assembly into twisted or flat nanoribbons. While E3C16-SS-EIY assembles into nanorods, exposure to glutathione (GSH) leads to the conversion of the peptide into E3C16SH and SHEIY, thus promoting in situ evolution from the nanorods into self-sorted nanoribbons. Furthermore, incorporation of two ligand moieties targeting antiapoptotic protein XIAP and organellar endoplasmic reticulum (ER) into the self-sorted nanoribbons allows for simultaneous inhibition of XIAP and accumulation surrounding ER. This leads to the cytotoxicity toward the cancer cells with elevated GSH levels, through activating caspase-dependent apoptosis and inducing ER dysfunction. In vivo self-sorting of E3C16-SS-EIY decorated with ligand moieties is thoroughly validated by tissue studies. Tumor-bearing mouse experiments confirm the therapeutic efficacy of the self-sorted assemblies for inhibiting tumor growth, with excellent biosafety. Our findings demonstrate an efficient approach to develop in vivo self-sorting systems and thereby facilitating in situ formulation of biomedical agents.

Asunto(s)

Péptidos , Humanos , Animales , Péptidos/química , Péptidos/farmacología , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Glutatión/química , Glutatión/metabolismo , Línea Celular Tumoral , Nanotubos/química

RESUMEN

The pyroptosis of cardiomyocytes has become an essential topic in heart failure research. The abnormal accumulation of these biological factors, including angiotensin II, advanced glycation end products, and various growth factors (such as connective tissue growth factor, vascular endothelial growth factor, transforming growth factor beta, among others), activates the nuclear factor-κB (NF-κB) signaling pathway in cardiovascular diseases, ultimately leading to pyroptosis of cardiomyocytes. Therefore, exploring the underlying molecular biological mechanisms is essential for developing novel drugs and therapeutic strategies. However, our current understanding of the precise regulatory mechanism of this complex signaling pathway in cardiomyocyte pyroptosis is still limited. Given this, this study reviews the milestone discoveries in the field of pyroptosis research since 1986, analyzes in detail the similarities, differences, and interactions between pyroptosis and other cell death modes (such as apoptosis, necroptosis, autophagy, and ferroptosis), and explores the deep connection between pyroptosis and heart failure. At the same time, it depicts in detail the complete pathway of the activation, transmission, and eventual cardiomyocyte pyroptosis of the NF-κB signaling pathway in the process of heart failure. In addition, the study also systematically summarizes various therapeutic approaches that can inhibit NF-κB to reduce cardiomyocyte pyroptosis, including drugs, natural compounds, small molecule inhibitors, gene editing, and other cutting-edge technologies, aiming to provide solid scientific support and new research perspectives for the prevention and treatment of heart failure.

RESUMEN

OBJECTIVE: Coagulation assessment in traumatic brain injury (TBI) typically relies upon laboratory-based standard coagulation tests (SCTs), including the activated partial thromboplastin time (aPTT), INR and platelet count. Rotational thromboelastometry (ROTEM) sigma is an alternative point-of-care assay; however, its role in isolated TBI is under-evaluated. The present study aims to assess the prognostic utility of ROTEM sigma in isolated TBI. METHODS: ROTEM sigma analysis was performed during the initial evaluation of patients presenting to the Royal Adelaide Hospital between February 2022 and 2023 with radiographically demonstrated traumatic intracranial haemorrhage and GCS ≤14. Patients with concomitant severe extracranial injury, or who received blood products or antifibrinolytic therapy prior to sample collection were excluded. RESULTS: Thirty-six patients had blood samples analysed with ROTEM, 25 of these patients were also evaluated with paired SCTs. Twenty-two per cent (8/36) of patients with isolated TBI had a hypocoaguable ROTEM profile, and this was associated with an increased incidence of head injury-related death (50% [4/8] vs 11% [3/28], P = 0.03). Median diagnostic turn-around-times were shorter for ROTEM parameters compared to SCT counterparts: EXTEM clotting time (CT) versus INR (20 vs 63 min, P < 0.01), and INTEM CT versus aPTT (21 vs 63 min, P < 0.01). EXTEM CT, FIBTEM CT and INR values had similar performance in predicting head injury-related death, area under the receiver operator curves were 0.8, 0.8 and 0.7, respectively. CONCLUSIONS: ROTEM sigma expedites the detection of clinically significant coagulopathy in isolated TBI. EXTEM and FIBTEM CT values are more rapidly attainable than INR and comparable in predicting head injury-related death.

RESUMEN

BACKGROUND: Perioperative heparin-free anticoagulation extracorporeal membrane oxygenation (ECMO) for lung transplantation is rarely reported. OBJECTIVE: To evaluate the impact of a heparin-free strategy on bleeding and thrombotic events, blood transfusion, and coagulation function during the early perioperative period and on prognosis, and to observe its effect on different ECMO types. DESIGN: A retrospective cohort study. METHODS: Data were collected from 324 lung transplantation patients undergoing early perioperative heparin-free ECMO between August 2017 and July 2022. Clinical data including perioperative bleeding and thrombotic events, blood product transfusion, coagulation indicators and 1-year survival were analysed. RESULTS: Patients were divided in venovenous (VV; n = 251), venoarterial (VA; n = 40) and venovenous-arterial (VV-A; n = 33) groups. The VV group had the lowest intraoperative bleeding and thoracic drainage within 24 h postoperatively. Vein thrombosis occurred in 30.2% of patients within 10 days postoperatively or 1 week after ECMO withdrawal, and no significant difference was found among the three groups. Double lung transplantation, increased intraoperative bleeding, and increased postoperative drainage were associated with vein thrombosis. Except for acute myocardial infarction in one patient, no other serious thrombotic events occurred. The VV-ECMO group had the lowest demand for blood transfusion. The highest prothrombin time and the lowest fibrinogen levels were observed in the VA group during ECMO run, while the highest platelet counts were found in the VV group. Both intraoperative bleeding and thoracic drainage within 24 h postoperatively were independent predictors for 1-year survival, and no thrombosis-related deaths occurred. CONCLUSION: Short-term heparin-free anticoagulation, particularly VV-ECMO, did not result in serious thrombotic events or thrombosis-related deaths, indicating that it is a safe and feasible strategy for perioperative ECMO in lung transplantation.

Asunto(s)

Anticoagulantes , Coagulación Sanguínea , Oxigenación por Membrana Extracorpórea , Trasplante de Pulmón , Trombosis , Humanos , Oxigenación por Membrana Extracorpórea/efectos adversos , Oxigenación por Membrana Extracorpórea/mortalidad , Estudios Retrospectivos , Trasplante de Pulmón/efectos adversos , Trasplante de Pulmón/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Adulto , Trombosis/prevención & control , Trombosis/etiología , Factores de Tiempo , Coagulación Sanguínea/efectos de los fármacos , Resultado del Tratamiento , Factores de Riesgo , Transfusión Sanguínea , Heparina/administración & dosificación , Heparina/efectos adversos , Hemorragia Posoperatoria/prevención & control , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/mortalidad , Pérdida de Sangre Quirúrgica/prevención & control

RESUMEN

BACKGROUND: HPV-16 infection and viral-host integration are the most important risk factors for cervical cancer (CC). The aim of this study is to develop a new molecular strategy integrated both the viral and host genome variations identifying and monitoring CC. METHOD: A total of 312 methylation and 538 RNA-seq datasets were collected from public databases to identify differentially methylated and expressed genes. HPV associated virus integration sites (VISs) were analysed using the ViMIC database. From September 2020 to August 2021, the 70 HPV-16 positive cases retrospectively collected from multi-centre cohorts were subjected to HPV-16 E6 deep sequencing and PCR-based host gene (ASTN1, DLX1, ITGA4, RXFP3, SOX17, ZNF671) methylation detection. RNAseq and expression validation (NNF671) were performed in C-33A cell line harbouring HPV D32E. Lasso and logistic regression algorithm were used to construct the CC diagnostic model. RESULTS: A positive correlation was observed between the average methylation level of CC patients and their pathological features including tumour stage (p = 0.0077) and HPV subtype (p < 0.001). ZNF671 was identified as a CC-specific methylation marker, with an impressive 93% sensitivity. Both HPV-16 D32E mutation and integration of HPV-16 down-regulated the ZNF671 expression. Finally, a CC diagnostic nomogram was developed by integrating ZNF671 methylation level and HPV E6 mutation feature, yielding an exceptional AUC of 0.997 (95% CI: 0.934-1.000). CONCLUSIONS: Our study demonstrated HPV viral mutations are closely related to host gene epigenetic alterations in CC. Integration of the viral and host genetic information might be a new promising strategy for CC screening.

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herb pairs are the most basic and compressed examples of Chinese herbal combinations and can be used to effectively explain the fundamental concepts of traditional Chinese medicine prescriptions. These pairings have gained significant interest due to their subtle therapeutic benefits, minimal side effects, and efficacy in treating complicated chronic conditions. The Banxia-Xiakucao Chinese herb pair (BXHP) consists of Pinellia ternata (Thunb.) Breit. (Banxia) and Prunella vulgaris L. (Xiakucao). This formula was documented in The Medical Classic of the Yellow Emperor approximately 2000 years ago，and clinical research has demonstrated that BXHP effectively treats insomnia. AIM OF THE STUDY: This study aimed to evaluate the efficacy and therapeutic mechanism of the BXHP through a comprehensive strategy involving network pharmacology, molecular docking, transcriptomics, and molecular biology experimental validation. MATERIALS AND METHODS: The composition of BXHP was characterized using the UPLC-Q-TOF-MS. The active compounds were screened to find drug-likeness compounds by analyzing the ADME data. To predict the molecular mechanism of BXHP in sleep deprivation (SD) by network pharmacology and molecular docking. We established a rat model of SD and the in vivo efficacy of BXHP was verified through the pentobarbital sodium righting reflex test, behavioral assays, enzyme-linked immunosorbent assay, transmission electron microscopy, HE staining, and Nissl staining, and the underlying molecular mechanism of BXHP in SD was revealed through transcriptomic and bioinformatic analyses in conjunction with quantitative real-time PCR, Western blot, and immunofluorescence staining. RESULTS: In the present study, we showed for the first time that BXHP reduced sleep latency, prolongs sleep duration, and improves anxiety; lowered serum CORT, IL6, TNF-α and MDA levels; decreased hypothalamic Glu levels; and elevated hypothalamic GABA and 5-HT levels in SD rats. We found 16 active compounds that acted on 583 targets, 145 of which are related to SD. By modularly dissecting the PPI network, we discovered three critical targets, Akt1, CREB1, and PRKACA, all of which play important roles in the effects of BXHP on SD. Molecular docking resulted in the identification of 16 active compounds that strongly bind to key targets. The results of GO and KEGG enrichment analyses of network pharmacology and transcriptomics focused on both the regulation of circadian rhythm and the cAMP signaling pathway, which strongly demonstrated that BXHP affects SD via the cAMP-PKA-CREB-Circadian rhythm pathway. Molecular biology experiments verified this hypothesis. Following BXHP administration, PKA and CREB phosphorylation levels were elevated in SD rats, the cAMP-PKA-CREB signaling pathway was activated, the expression levels of the biological clock genes CLOCK, p-BMAL1/BMAL1, and PER3 were increased, and the rhythmicity of the biological clock was improved. CONCLUSIONS: The active compounds in BXHP can activate the cAMP-PKA-CREB-Circadian rhythm pathway, improve the rhythmicity of the biological clock, promote sleep and ameliorate anxiety, which suggests that BXHP improves SD through a multicomponent, multitarget, multipathway mechanism. This study is important for the development of herbal medicines and clinical therapies for improving sleep deprivation.

Asunto(s)

Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Farmacología en Red , Pinellia , Ratas Sprague-Dawley , Privación de Sueño , Transcriptoma , Animales , Privación de Sueño/tratamiento farmacológico , Privación de Sueño/metabolismo , Masculino , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/química , Ratas , Pinellia/química , Transcriptoma/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Sueño/efectos de los fármacos , Pentobarbital/farmacología

RESUMEN

BACKGROUND: Breast cancer mortality varies in urban and rural areas in China. Studies have reported urban-rural difference across time period, however, the evaluation on urban-rural differences in age and birth cohort effects is limited. Our aim was to quantitatively assess urban-rural disparities in age, period and cohort effects in breast cancer mortality in China. METHODS: We collected age-specific breast cancer mortality rates for urban and rural females aged 20-84 years from 1987 to 2021. Hierarchical age-period-cohort (HAPC) models were used to evaluate the effect of area (urban, rural) on breast cancer mortality and investigate urban-rural differences in age, time period and birth cohort effects. RESULTS: We found a significant area (urban, rural) effect on breast cancer mortality in that rural females had a lower mortality risk than urban females [-0.25 (95 % confidence interval (CI): -0.32, -0.17)]. Age trajectories of mortality based on the HAPC model showed nonlinear trends with adjustment for area variable. The urban-rural difference in age effect appeared to be divergent with age, and urban women had higher mortality risk in the senior age group. The urban-rural difference in birth cohort effect indicated a reversal around the birth cohort group of 1962-1966, after which rural females had a higher mortality risk than urban females. CONCLUSION: The area (urban, rural) could affect breast cancer mortality among women, and the effect of urban-rural difference varies with age and birth cohort. To promote the health of urban and rural females, the gap between urban and rural areas should be shorten.

Asunto(s)

Neoplasias de la Mama , Población Rural , Población Urbana , Humanos , Femenino , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/epidemiología , Persona de Mediana Edad , Adulto , Anciano , China/epidemiología , Población Rural/estadística & datos numéricos , Población Urbana/estadística & datos numéricos , Anciano de 80 o más Años , Adulto Joven , Estudios de Cohortes , Factores de Edad , Pueblos del Este de Asia

RESUMEN

BACKGROUND: DNA methylation is an important epigenetic mechanism of gene regulation. The aberrant DNA methylation has been found to play an important role in the initiation and progression of tumors. RESULTS: Transcriptome and DNA methylation data of lung adenocarcinoma (LUAD) patients were co-analyzed and 95 methylation-driven genes (MDGs) was found in relation to LUAD. A prognostic model based on 3 MDGs (GMNN, SPINK2 and VMO1) was constructed by Univariate and Multivariate cox regression analyses. The risk score generated from the prognostic model could be used to classify LUAD patients into high and low risk groups. Furthermore, it was found that the risk score was associated with tumor microenvironment (TME) and clinical characteristics (survival status and T stage) of patients. Interestingly, we identified and validated that the patients in the low-risk group responded better to immunotherapy treatment. Then, a nomogram model based on the risk score and clinical characteristics was established which showed significant prediction value. The down-regulation and hypermethylation levels of vitelline membrane outer layer protein 1 homolog (VMO1) were verified in paired LUAD tumor and non-tumor tissues by pyrosequencing assay and RT-qPCR. Furthermore, MTT, migration and wound healing assays were performed with lentivector-mediated ectopic over-expression and 5-Aza-dC demethylation followed by siRNA rescue experiments to investigate the role of VMO1 in LUAD cells. Our results indicated that VMO1 could inhibit proliferation and migration of A549 and NCI-H1299 cells. CONCLUSIONS: In summary, our experiments constructed a prognostic model with high capacity for risk prediction in LUAD patients. VMO1 had a malignant suppressor role in LUAD cells. The correlation between risk score and TME might elucidate a potential mechanism of oncogenesis and provide an avenue for further therapeutic targets.

Asunto(s)

Adenocarcinoma del Pulmón , Metilación de ADN , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Pronóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Masculino , Femenino , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Perfilación de la Expresión Génica , Línea Celular Tumoral , Proliferación Celular/genética , Transcriptoma , Microambiente Tumoral

RESUMEN

Effector proteins secreted by bacteria that infect mammalian and plant cells often subdue eukaryotic host cell defenses by simultaneously affecting multiple targets. However, instances when a bacterial effector injected in the competing bacteria sabotage more than a single target have not been reported. Here, we demonstrate that the effector protein, LtaE, translocated by the type IV secretion system from the soil bacterium Lysobacter enzymogenes into the competing bacterium, Pseudomonas protegens, affects several targets, thus disabling the antibacterial defenses of the competitor. One LtaE target is the transcription factor, LuxR1, that regulates biosynthesis of the antimicrobial compound, orfamide A. Another target is the sigma factor, PvdS, required for biosynthesis of another antimicrobial compound, pyoverdine. Deletion of the genes involved in orfamide A and pyoverdine biosynthesis disabled the antibacterial activity of P. protegens, whereas expression of LtaE in P. protegens resulted in the near-complete loss of the antibacterial activity against L. enzymogenes. Mechanistically, LtaE inhibits the assembly of the RNA polymerase complexes with each of these proteins. The ability of LtaE to bind to LuxR1 and PvdS homologs from several Pseudomonas species suggests that it can sabotage defenses of various competitors present in the soil or on plant matter. Our study thus reveals that the multi-target effectors have evolved to subdue cell defenses not only in eukaryotic hosts but also in bacterial competitors.

Asunto(s)

Proteínas Bacterianas , Lysobacter , Pseudomonas , Sistemas de Secreción Tipo IV , Pseudomonas/genética , Pseudomonas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Lysobacter/genética , Lysobacter/metabolismo , Sistemas de Secreción Tipo IV/genética , Sistemas de Secreción Tipo IV/metabolismo , Regulación Bacteriana de la Expresión Génica , Oligopéptidos/metabolismo , Oligopéptidos/genética , Transactivadores/genética , Transactivadores/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor sigma/genética , Factor sigma/metabolismo

RESUMEN

Neurological injury, as a major pathogenic mechanism in depression, holds significant importance in the research and development of antidepressant drugs. Hemerocallis citrina Baroni (H. citrina), referred to as "Forgetting Sadness Grass," has been confirmed to possess remarkable neuroprotective effects. Studies have identified that the total phenolics in H. citrina Baroni leaves (HLTP) consist of flavonoids and phenolic acids and numerous studies have substantiated the neuroprotective effects of them. Based on this, we propose that HLTP may possess neuroprotective properties. To confirm this hypothesis, we initially employed network pharmacology techniques to predict potential targets for the neuroprotective effects of HLTP based on the Swiss Target Prediction database. GO and KEGG analyses were conducted to predict potential pathways, and a component-target-pathway network was constructed. Molecular docking experiments were then performed to analyze the binding abilities of the selected active components with the main targets. Furthermore, we validated the neuroprotective effects of HLTP and key targets selected through network pharmacology using a corticosterone-induced PC12 neuronal cell damage model. Network pharmacology research has identified that in the HLTP, Quercetin, Rutin, Apigenin, and Isoquercitrin are potential active components that may exert neuroprotective effects by modulating key targets such as AKT1, TNF, TP53, and CASP3 through crucial pathways including PI3K/AKT and apoptosis. Molecular docking revealed that 4-O-Caffeoylquinic acid, 5-O-Caffeoylshikimic acid, 4-p-Coumaroylquinic acid, and 5-O-Feruloylquinic acid exhibit low binding energies with key targets. Particularly, 4-O-Caffeoylquinic acid forms stable binding through hydrogen bonding with residues such as LYS389, GLU49, GLN47, LYS30, ASP44, and GLU40 in AKT1. PC12 cells were stimulated with 200 µmol/L Corticosterone (Cort) for 24 h, and then treated with 50, 100 and 200 µg/mL of HLTP for 24 h. The cell viability of damaged cells were significantly increased in a dose-dependent manner by 9.50%, 10.42% and 21.25%, respectively (P < 0.01). Western blot analysis confirmed that HLTP significantly (P < 0.01) increased the protein expression of PI3K and AKT by 15.24%, 30.44%, 41.03%, and 21.78%, 43.63%, 12.86%, respectively. In addition, through biochemical method, flow cytometry and WB analysis, we found that different concentrations of HLTP can all improve cell damage by reducing ROS, MDA, Ca2+, Cyt-C, Caspase-3, TNF-α and IL-1ß, and increasing SOD, CAT, MMP, Bcl-2/Bax and IL-10. In particular, the HLTP at 200 µg/mL, compared with the Model group, decreased by 140.2%, 54.66%, 51.34%, 65.26%, 40.32%, 63.87%, and 55.38%, and increased by 39.65%, 35.45%, 38.38%, 28.54%, and 39.98%, respectively. Through the above experiments, we verified that HLTP may exert neuroprotective effects by mediating the PI3K/AKT signaling pathway to counteract oxidative stress damage, improve mitochondrial dysfunction, and alleviate inflammatory injury.

RESUMEN

OBJECTIVES: To compare the iatrogenic radial nerve injury (iRNI) rate of different implant (plate vs. intramedullary nail) and surgical approaches during humeral shaft fracture surgery. METHODS: The online PubMed database was used to search for articles describing iRNI after humeral fracture with a publication date from Jan 2000 to October 2023. The following types of articles were selected: (1) case series associating with adult humeral shaft fracture, preoperative radial nerve continuity, non-pathological fracture and non-periprosthetic fracture; (2) involving humeral shaft (OTA/AO 12) fractures. Articles where we were unable to judge surgical approach or fracture pattern (OTA/AO 12) were excluded. The data were analyzed by SPSS 27.0 and Chi-square test was performed to identify incidence of iRNI associated with different implant and surgical approaches. RESULTS: Fifty-four articles with 5063 cases were included, with 3510 cases of the plate, 830 cases of intramedullary nail and 723 cases of uncertain internal fixation. The incidences of iRNI with plate and intramedullary nail were 5.95% (209/3510) and 2.77% (23/830) (p < 0.05). And iRNI incidences of different surgical approaches were 3.7% (3/82) for deltopectoral approach, 5.74% (76/1323) for anterolateral approach, 13.54% (26/192) for lateral approach and 6.68% (50/749) for posterior approach. The iRNI rates were 0.00% (0/33) for anteromedial MIPO, 2.67% (10/374) for anterolateral MIPO and 5.40% (2/37) for posterior MIPO (p > 0.05). The iRNI rates were 2.87% (21/732) for anterograde intramedullary nail and 2.04% (2/98) for retrograde intramedullary nail (p > 0.05). In humeral bone nonunion surgery, the rate of iRNI was 15.00% (9/60) for anterolateral approach, 16.7% (2/12) for lateral approach and 18.2% (6/33) for posterior approach (p > 0.05). CONCLUSION: Intramedullary nailing is the preferred method of internal fixation for humeral shaft fractures that has the lowest rate of iRNI. Compared with anterolateral and posterior approaches, the lateral surgical approach had a higher incidence of iRNI. The rate of iRNI in MIPO was lower than that in open reduction and internal fixation. LEVEL OF EVIDENCE: Level IV.

Asunto(s)

Fijación Intramedular de Fracturas , Fracturas del Húmero , Enfermedad Iatrogénica , Nervio Radial , Humanos , Fracturas del Húmero/cirugía , Nervio Radial/lesiones , Nervio Radial/cirugía , Fijación Intramedular de Fracturas/efectos adversos , Fijación Intramedular de Fracturas/métodos , Placas Óseas/efectos adversos , Fijación Interna de Fracturas/métodos , Fijación Interna de Fracturas/efectos adversos , Clavos Ortopédicos/efectos adversos , Incidencia

RESUMEN

A ratiometric fluorescent and colorimetric detecting assay for NO2- was realized by a hybrid nanosensor (Co2+-CDs@R-CDs) utilizing firstly through the redox reaction of nitrite (NO2-) with Co2+, of which the hybrid nanosensor Co2+-CDs@R-CDs was fabricated by Co2+-doped carbon dots (Co2+-CDs) and a reference of red-emitting carbon dots (R-CDs). The ratiometric fluorescent linear detection range of NO2- was 2.5-45 µM and the limit of detection (LOD) was 0.068 µM with the response time of 120 s. While, the colorimetric linear detection range of NO2- was 2.5-60 µM and the LOD was 0.075 µM. In addition, a portable smartphone system which could measure the R (red), G (green), and B (blue) values of the fluorescence and the visible color of the coated Co2+-CDs@R-CDs paper strip-based sensor had also been developed and successfully applied to detect NO2- in sausage, pickles and tap water samples.