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Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.
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Glicósidos , Oligosacáridos , Ácidos Borónicos/química , Bromuros/química , Catálisis , Glicósidos/química , Glicósidos/síntesis química , Glicosilación , Enlace de Hidrógeno , Oligosacáridos/química , Oligosacáridos/síntesis química , Sulfonas/químicaRESUMEN
Transcription factor ELONGATED HYPOCOTYL5 (HY5) is the central hub for seedling photomorphogenesis. E3 ubiquitin (Ub) ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) inhibits HY5 protein accumulation through ubiquitination. However, the process of HY5 deubiquitination, which antagonizes E3 ligase-mediated ubiquitination to maintain HY5 homeostasis has never been studied. Here, we identified that Arabidopsis thaliana deubiquitinating enzyme, Ub-SPECIFIC PROTEASE 14 (UBP14) physically interacts with HY5 and enhances its protein stability by deubiquitination. The da3-1 mutant lacking UBP14 function exhibited a long hypocotyl phenotype, and UBP14 deficiency led to the failure of rapid accumulation of HY5 during dark to light. In addition, UBP14 preferred to stabilize nonphosphorylated form of HY5 which is more readily bound to downstream target genes. HY5 promoted the expression and protein accumulation of UBP14 for positive feedback to facilitate photomorphogenesis. Our findings thus established a mechanism by which UBP14 stabilizes HY5 protein by deubiquitination to promote photomorphogenesis in A. thaliana.
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Proteínas de Arabidopsis , Arabidopsis , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Regulación de la Expresión Génica de las Plantas , Ubiquitinación , Arabidopsis/metabolismo , Arabidopsis/crecimiento & desarrollo , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/genética , Estabilidad Proteica/efectos de la radiación , Luz , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Hipocótilo/crecimiento & desarrollo , Hipocótilo/metabolismo , Hipocótilo/genéticaRESUMEN
Prostate cancer (PCa) is a malignant disorder of prostate gland being asymptomatic in early stages and high metastatic potential in advanced stages. The chemotherapy and surgical resection have provided favourable prognosis of PCa patients, but advanced and aggressive forms of PCa including CRPC and AVPC lack response to therapy properly, and therefore, prognosis of patients is deteriorated. At the advanced stages, PCa cells do not respond to chemotherapy and radiotherapy in a satisfactory level, and therefore, therapy resistance is emerged. Molecular profile analysis of PCa cells reveals the apoptosis suppression, pro-survival autophagy induction, and EMT induction as factors in escalating malignant of cancer cells and development of therapy resistance. The dysregulation in molecular profile of PCa including upregulation of STAT3 and PI3K/Akt, downregulation of STAT3, and aberrant expression of non-coding RNAs are determining factor for response of cancer cells to chemotherapy. Because of prevalence of drug resistance in PCa, combination therapy including co-utilization of anti-cancer drugs and nanotherapeutic approaches has been suggested in PCa therapy. As a result of increase in DNA damage repair, PCa cells induce radioresistance and RelB overexpression prevents irradiation-mediated cell death. Similar to chemotherapy, nanomaterials are promising for promoting radiosensitivity through delivery of cargo, improving accumulation in PCa cells, and targeting survival-related pathways. In respect to emergence of immunotherapy as a new tool in PCa suppression, tumour cells are able to increase PD-L1 expression and inactivate NK cells in mediating immune evasion. The bioinformatics analysis for evaluation of drug resistance-related genes has been performed.
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Antineoplásicos , Neoplasias de la Próstata , Masculino , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Antineoplásicos/uso terapéutico , Apoptosis , Tolerancia a Radiación , Línea Celular TumoralRESUMEN
DNase I hypersensitive sites (DHSs) are chromatin regions highly sensitive to DNase I enzymes. Studying DHSs is crucial for understanding complex transcriptional regulation mechanisms and localizing cis-regulatory elements (CREs). Numerous studies have indicated that disease-related loci are often enriched in DHSs regions, underscoring the importance of identifying DHSs. Although wet experiments exist for DHSs identification, they are often labor-intensive. Therefore, there is a strong need to develop computational methods for this purpose. In this study, we used experimental data to construct a benchmark dataset. Seven feature extraction methods were employed to capture information about human DHSs. The F-score was applied to filter the features. By comparing the prediction performance of various classification algorithms through five-fold cross-validation, random forest was proposed to perform the final model construction. The model could produce an overall prediction accuracy of 0.859 with an AUC value of 0.837. We hope that this model can assist scholars conducting DNase research in identifying these sites.
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Cromatina , Desoxirribonucleasa I , Genoma Humano , Humanos , Desoxirribonucleasa I/metabolismo , Desoxirribonucleasa I/genética , Desoxirribonucleasa I/química , Cromatina/genética , Cromatina/metabolismo , Cromatina/química , Biología Computacional/métodos , Algoritmos , Secuencias Reguladoras de Ácidos Nucleicos/genéticaRESUMEN
Radiotherapy (RT), administered to roughly half of all cancer patients, occupies a crucial role in the landscape of cancer treatment. However, expanding the clinical indications of RT remains challenging. Inspired by the radiation-induced bystander effect (RIBE), we used the mediators of RIBE to mimic RT. Specifically, we discovered that irradiated tumor cell-released microparticles (RT-MPs) mediated the RIBE and had immune activation effects. To further boost the immune activation effect of RT-MPs to achieve cancer remission, even in advanced stages, we engineered RT-MPs with different cytokine and chemokine combinations by modifying their production method. After comparing the therapeutic effect of the engineered RT-MPs in vitro and in vivo, we demonstrated that tIL-15/tCCL19-RT-MPs effectively activated antitumor immune responses, significantly prolonged the survival of mice with malignant pleural effusion (MPE), and even achieved complete cancer remission. When tIL-15/tCCL19-RT-MPs were combined with PD-1 monoclonal antibody (mAb), a cure rate of up to 60% was achieved. This combination therapy relied on the activation of CD8+ T cells and macrophages, resulting in the inhibition of tumor growth and the establishment of immunological memory against tumor cells. Hence, our research may provide an alternative and promising strategy for cancers that are not amenable to conventional RT.
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Micropartículas Derivadas de Células , Derrame Pleural Maligno , Humanos , Animales , Ratones , Linfocitos T CD8-positivos , Terapia Combinada , Citocinas , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial-mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/ß-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3ß that destructs ß-catenin, while ligand-receptor interaction impairs GSK-3ß function to increase ß-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/ß-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance ß-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/ß-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/ß-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression.
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Neoplasias , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Vía de Señalización Wnt , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal/fisiología , Regulación Neoplásica de la Expresión Génica , Neoplasias/genéticaRESUMEN
BACKGROUND: The blood-brain barrier serves as a critical interface between the bloodstream and brain tissue, mainly composed of pericytes, neurons, endothelial cells, and tightly connected basal membranes. It plays a pivotal role in safeguarding brain from harmful substances, thus protecting the integrity of the nervous system and preserving overall brain homeostasis. However, this remarkable selective transmission also poses a formidable challenge in the realm of central nervous system diseases treatment, hindering the delivery of large-molecule drugs into the brain. In response to this challenge, many researchers have devoted themselves to developing drug delivery systems capable of breaching the blood-brain barrier. Among these, blood-brain barrier penetrating peptides have emerged as promising candidates. These peptides had the advantages of high biosafety, ease of synthesis, and exceptional penetration efficiency, making them an effective drug delivery solution. While previous studies have developed a few prediction models for blood-brain barrier penetrating peptides, their performance has often been hampered by issue of limited positive data. RESULTS: In this study, we present Augur, a novel prediction model using borderline-SMOTE-based data augmentation and machine learning. we extract highly interpretable physicochemical properties of blood-brain barrier penetrating peptides while solving the issues of small sample size and imbalance of positive and negative samples. Experimental results demonstrate the superior prediction performance of Augur with an AUC value of 0.932 on the training set and 0.931 on the independent test set. CONCLUSIONS: This newly developed Augur model demonstrates superior performance in predicting blood-brain barrier penetrating peptides, offering valuable insights for drug development targeting neurological disorders. This breakthrough may enhance the efficiency of peptide-based drug discovery and pave the way for innovative treatment strategies for central nervous system diseases.
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Péptidos de Penetración Celular , Enfermedades del Sistema Nervioso Central , Humanos , Barrera Hematoencefálica/química , Células Endoteliales , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , Péptidos de Penetración Celular/uso terapéutico , Encéfalo , Enfermedades del Sistema Nervioso Central/tratamiento farmacológicoRESUMEN
BACKGROUND: Previous studies implied that local M2 polarization of macrophage promoted mucosal edema and exacerbated TH2 type inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the specific pathogenic role of M2 macrophages and the intrinsic regulators in the development of CRS remains elusive. OBJECTIVE: We sought to investigate the regulatory role of SIRT5 in the polarization of M2 macrophages and its potential contribution to the development of CRSwNP. METHODS: Real-time reverse transcription-quantitative PCR and Western blot analyses were performed to examine the expression levels of SIRT5 and markers of M2 macrophages in sinonasal mucosa samples obtained from both CRS and control groups. Wild-type and Sirt5-knockout mice were used to establish a nasal polyp model with TH2 inflammation and to investigate the effects of SIRT5 in macrophage on disease development. Furthermore, in vitro experiments were conducted to elucidate the regulatory role of SIRT5 in polarization of M2 macrophages. RESULTS: Clinical investigations showed that SIRT5 was highly expressed and positively correlated with M2 macrophage markers in eosinophilic polyps. The expression of SIRT5 in M2 macrophages was found to contribute to the development of the disease, which was impaired in Sirt5-deficient mice. Mechanistically, SIRT5 was shown to enhance the alternative polarization of macrophages by promoting glutaminolysis. CONCLUSIONS: SIRT5 plays a crucial role in promoting the development of CRSwNP by supporting alternative polarization of macrophages, thus providing a potential target for CRSwNP interventions.
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In this study, we investigated the role of the noncanonical pyroptosis pathway in the progression of lethal sepsis. Our findings emphasize the significance of noncanonical pyroptosis in monocytes/macrophages for the survival of septic mice. We observed that inhibiting pyroptosis alone significantly improved the survival rate of septic mice and that the HMGB1 A box effectively suppressed this noncanonical pyroptosis, thereby enhancing the survival of septic mice. Additionally, our cell in vitro experiments unveiled that frHMGB1, originating from lipopolysaccharide-carrying histiocytes, entered macrophages via RAGE, resulting in the direct activation of caspase 11 and the induction of noncanonical pyroptosis. Notably, A box's competitive binding with lipopolysaccharide impeded its entry into the cell cytosol. These findings reveal potential therapeutic strategies for slowing the progression of lethal sepsis by modulating the noncanonical pyroptosis pathway.
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Proteína HMGB1 , Macrófagos , Monocitos , Piroptosis , Sepsis , Animales , Masculino , Ratones , Caspasas Iniciadoras/metabolismo , Caspasas Iniciadoras/genética , Modelos Animales de Enfermedad , Proteína HMGB1/metabolismo , Lipopolisacáridos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Monocitos/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Sepsis/metabolismoRESUMEN
The extracellular matrix (ECM) is a complex assembly of proteins that provide interstitial scaffolding and elastic recoil for human lungs. The pulmonary extracellular matrix is increasingly recognized as an independent bioactive entity, by creating biochemical and mechanical signals that influence disease pathogenesis, making it an attractive therapeutic target. However, the pulmonary ECM proteome ("matrisome") remains challenging to analyze by mass spectrometry due to its inherent biophysical properties and relatively low abundance. Here, we introduce a strategy designed for rapid and efficient characterization of the human pulmonary ECM using the photocleavable surfactant Azo. We coupled this approach with trapped ion mobility MS with diaPASEF to maximize the depth of matrisome coverage. Using this strategy, we identify nearly 400 unique matrisome proteins with excellent reproducibility that are known to be important in lung biology, including key core matrisome proteins.
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Matriz Extracelular , Pulmón , Proteómica , Humanos , Proteómica/métodos , Pulmón/metabolismo , Matriz Extracelular/metabolismo , Compuestos Azo/química , Proteínas de la Matriz Extracelular/metabolismo , Tensoactivos/química , Proteoma/análisis , Espectrometría de Masas/métodosRESUMEN
Temperature is a critical parameter in chemical conversion, significantly affecting the reaction kinetics and thermodynamics. Measuring temperature inside catalyst particles of industrial interest (â¼micrometers to millimeters), which is crucial for understanding the evolution of chemical dynamics at catalytic active sites during reaction and advancing catalyst designs, however, remains a big challenge. Here, we propose an approach combining two-photon confocal microscopy and state-of-the-art upconversion luminescence (UL) imaging to measure the spatiotemporal-resolved temperature within individual catalyst particles in the industrially significant methanol-to-hydrocarbons reaction. Specifically, catalyst particles containing zeolites and functional nanothermometers were fabricated using microfluidic chips. Our experimental results directly demonstrate that the zeolite density and particle size can alter the temperature distribution within a single catalyst particle. Importantly, the observed temperature heterogeneity plays a decisive role in the activation of the reaction intermediate and the utilization of active sites. We expect that this work opens a venue for unveiling the reaction mechanism and kinetics within industrial catalyst particles by considering temperature heterogeneity.
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Tumor-associated macrophages (TAMs) are pivotal in cancer progression, influencing tumor growth, angiogenesis, and immune evasion. This review explores the spatial and temporal heterogeneity of TAMs within the tumor microenvironment (TME), highlighting their diverse subtypes, origins, and functions. Advanced technologies such as single-cell sequencing and spatial multi-omics have elucidated the intricate interactions between TAMs and other TME components, revealing the mechanisms behind their recruitment, polarization, and distribution. Key findings demonstrate that TAMs support tumor vascularization, promote epithelial-mesenchymal transition (EMT), and modulate extracellular matrix (ECM) remodeling, etc., thereby enhancing tumor invasiveness and metastasis. Understanding these complex dynamics offers new therapeutic targets for disrupting TAM-mediated pathways and overcoming drug resistance. This review underscores the potential of targeting TAMs to develop innovative cancer therapies, emphasizing the need for further research into their spatial characteristics and functional roles within the TME.
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Neoplasias , Microambiente Tumoral , Macrófagos Asociados a Tumores , Humanos , Microambiente Tumoral/inmunología , Neoplasias/patología , Neoplasias/inmunología , Neoplasias/metabolismo , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/patología , Animales , Transición Epitelial-Mesenquimal , Neovascularización Patológica/patologíaRESUMEN
BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
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Neoplasias Colorrectales , Predisposición Genética a la Enfermedad , Humanos , Femenino , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/epidemiología , Persona de Mediana Edad , Estudios de Casos y Controles , Factores de Riesgo , Anciano , Terapia de Reemplazo de Hormonas/efectos adversos , Medición de Riesgo , Menopausia , Posmenopausia , Terapia de Reemplazo de Estrógeno/efectos adversosRESUMEN
Pathological cardiac hypertrophy is associated with adverse cardiovascular events and can gradually lead to heart failure, arrhythmia, and even sudden death. However, the current development of treatment strategies has been unsatisfactory. Therefore, it is of great significance to find new and effective drugs for the treatment of myocardial hypertrophy. We found that carnosol can inhibit myocardial hypertrophy induced by PE stimulation, and the effect is very significant at 5 µM. Moreover, we demonstrated that 50 mg/kg of carnosol protect against cardiac hypertrophy and fibrosis induced by TAC surgery in mice. Mechanically, we proved that the inhibitory effect of carnosol on cardiac hypertrophy depends on its regulation on the phosphorylation activation of AMPK. In conclusion, our study suggested that carnosol may be a novel drug component for the treatment of pathological cardiac hypertrophy.
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Proteínas Quinasas Activadas por AMP , Abietanos , Cardiomegalia , Ratones Endogámicos C57BL , Miocitos Cardíacos , Animales , Abietanos/farmacología , Abietanos/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patología , Cardiomegalia/prevención & control , Proteínas Quinasas Activadas por AMP/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Masculino , Ratones , Transducción de Señal/efectos de los fármacos , Fosforilación/efectos de los fármacos , Activación Enzimática/efectos de los fármacosRESUMEN
The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.
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Glucosa Oxidasa , Liposomas , Sorafenib , Liposomas/química , Humanos , Glucosa Oxidasa/metabolismo , Glucosa Oxidasa/química , Animales , Sorafenib/farmacología , Línea Celular Tumoral , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Metabolismo Energético , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/química , IndolesRESUMEN
Vanadium oxides have aroused attention as cathode materials in aqueous zinc-ion batteries (AZIBs) due to their low cost and high safety. However, low ion diffusion and vanadium dissolution often lead to capacity decay and deteriorating stability during cycling. Herein, vanadium dioxides (VO2) nanobelts are coated with a single-atom cobalt dispersed N-doped carbon (Co-N-C) layer via a facile calcination strategy to form Co-N-C layer coated VO2 nanobelts (VO2@Co-N-C NBs) for cathodes in AZIBs. Various in-/ex situ characterizations demonstrate the interfaces between VO2 layers and Co-N-C layers can protect the VO2 NBs from collapsing, increase ion diffusion, and enhance the Zn2+ storage performance. Additional density functional theory (DFT) simulations demonstrate that CoâOâV bonds between VO2 and Co-N-C layers can enhance interfacial Zn2+ storage. Moreover, the VO2@Co-N-C NBs provided an ultrahigh capacity (418.7 mAh g-1 at 1 A g-1), outstanding long-term stability (over 8000 cycles at 20 A g-1), and superior rate performance.
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Hepatocellular carcinoma (HCC) stands as one of the most malignant tumors characterized by poor prognosis and high mortality rates. Emerging evidence underscores the crucial role of the B7 protein family in various cancers, including HCC. However, the involvement of the human endogenous retrovirus H long-terminal repeat-associated protein 2 (HHLA2, or B7-H5) in HCC remains unclear. Immunohistochemistry was employed to assess the differential expression of HHLA2 between HCC and normal liver tissues. A battery of assays, including CCK8, EdU, tablet clone-forming, Transwell, and wound healing assays, were conducted to elucidate the function and potential mechanisms of HHLA2 in the malignant biological behaviors of HCC. Additionally, a xenograft mouse model was established to evaluate the tumorigenicity of hepatoma cell lines exhibiting different HHLA2 expression levels in vivo. Western blot analysis was used to analyze HHLA2, secretory phosphoprotein 1 (SPP1), and PI3K/AKT/mTOR levels. HHLA2 exhibited elevated expression in HCC tissues, correlating with poor tumor differentiation and shortened overall survival in HCC patients. In vitro experiments demonstrated that HHLA2 overexpression (OE) promoted the proliferation, migration, and invasion of hepatoma cells, while in vivo experiments revealed that HHLA2 OE enhanced HCC tumor growth. Conversely, inhibition of HHLA2 expression yielded the opposite effect. Downregulation of SPP1 inhibited the proliferation, migration, and invasion induced by HHLA2 OE, and this effect was linked to the PI3K/AKT/mTOR signaling pathway. Our findings indicate that HHLA2 promotes the proliferation, migration, and invasion of hepatoma cells via the SPP1/PI3K/AKT signaling pathway, establishing it as a potential therapeutic target for HCC.
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Carcinoma Hepatocelular , Movimiento Celular , Proliferación Celular , Neoplasias Hepáticas , Invasividad Neoplásica , Osteopontina , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Humanos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Masculino , Femenino , Osteopontina/metabolismo , Osteopontina/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Ratones Desnudos , Pronóstico , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , InmunoglobulinasRESUMEN
BACKGROUND: The aim of this multicentre cohort study was to compare the long-term oncological outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for patients with gastric cancer. METHODS: Patients with gastric cancer who underwent radical gastrectomy by robotic or laparoscopic approaches from 1 March 2010 to 31 December 2018 at 10 high-volume centres in China were selected from institutional databases. Patients receiving RG were matched 1 : 1 by propensity score with patients undergoing LG. The primary outcome was 3-year disease-free survival. Secondary outcomes were overall survival and disease recurrence. RESULTS: Some 2055 patients who underwent RG and 4309 patients who had LG were included. The propensity score-matched cohort comprised 2026 RGs and 2026 LGs. Median follow-up was 41 (i.q.r. 39-58) months for the RG group and 39 (38-56) months for the LG group. The 3-year disease-free survival rates were 80.8% in the RG group and 79.5% in the LG group (log rank P = 0.240; HR 0.92, 95% c.i. 0.80 to 1.06; P = 0.242). Three-year OS rates were 83.9 and 81.8% respectively (log rank P = 0.068; HR 0.87, 0.75 to 1.01; P = 0.068) and the cumulative incidence of recurrence over 3 years was 19.3% versus 20.8% (HR 0.95, 0.88 to 1.03; P = 0.219), with no difference between groups. CONCLUSION: RG and LG in patients with gastric cancer are associated with comparable disease-free and overall survival.
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Laparoscopía , Levamisol/análogos & derivados , Procedimientos Quirúrgicos Robotizados , Neoplasias Gástricas , Humanos , Resultado del Tratamiento , Estudios de Cohortes , Neoplasias Gástricas/cirugía , Gastrectomía , Puntaje de Propensión , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugíaRESUMEN
BACKGROUND: A growing body of evidence indicates a close association between the gut microbiota (GM) and the bone remodeling (BR) process, raising suspicions that the GM may actively participate in BR by modulating the levels of growth factors. However, the precise causal relationship between them remains unclear. Due to many confounding factors, many microorganisms related to BR growth factors have not been identified. We aimed to elucidate the causal relationship between the GM and BR growth factors. METHODS: We evaluated the genome-wide association study (GWAS) summary statistics for GM and five common growth factors associated with BR: namely, bone morphogenetic proteins (BMP), transforming growth factors(TGF), insulin growth factors (IGFs), epidermal growth factors (EGFs), and fibroblast growth factors (FGF). The causal relationship between the GM and BR growth factors was studied by double-sample Mendelian randomized analysis. We used five Mendelian randomization (MR) methods, including inverse variance-weighted (IVW), MR-Egger, simple mode, weighted median, and weighted model methods. RESULTS: Through MR analysis, a total of 56 bacterial genera were co-identified as associated with BMP, TGF, IGF, EGF, and FGF. Among them, eight genera were found to have a causal relationship with multiple growth factors: Marvinbryantia was causally associated with BMP-6 (P = 0.018, OR = 1.355) and TGF-ß2 (P = 0.002, OR = 1.475); Lachnoclostridium, BMP-7 (P = 0.021, OR = 0.73) and IGF-1 (P = 0.046, OR = 0.804); Terrisporobacter, TGF-ß (P = 0.02, OR = 1.726) and FGF-23 levels (P = 0.016, OR = 1.76); Ruminiclostridium5, TGF-ß levels (P = 0.024, OR = 0.525) and FGFR-2 (P = 0.003, OR = 0.681); Erysipelatoclostridium, TGF-ß2 (P = 0.001, OR = 0.739) and EGF and its receptor (EGFR) (P = 0.012, OR = 0.795); Eubacterium_brachy_group, FGFR-2 (P = 0.045, OR = 1.153) and EGF (P = 0.013, OR = 0.7); Prevotella9 with EGFR (P = 0.022, OR = 0.818) and FGFR-2 (P = 0.011, OR = 1.233) and Faecalibacterium with FGF-23 (P = 0.02, OR = 2.053) and IGF-1 (P = 0.005, OR = 0.843). CONCLUSION: We confirmed the causal relationship between the GM and growth factors related to BR, which provides a new perspective for the study of BR, through targeted regulation of specific bacteria to prevent and treat diseases and growth factor-mediated BR disorders.
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Pre-eclampsia (PE) is a dangerous pathological status that occurs during pregnancy and is a leading reason for both maternal and fetal death. Autophagy is necessary for cellular survival in the face of environmental stress as well as cellular homeostasis and energy management. Aberrant microRNA (miRNA) expression is crucial in the pathophysiology of PE. Although studies have shown that miRNA (miR)-190a-3p function is tissue-specific, the precise involvement of miR-190a-3p in PE has yet to be determined. We discovered that miR-190a-3p was significantly lower and death-associated protein kinase 1 (DAPK1) was significantly higher in PE placental tissues compared to normal tissues, which is consistent with the results in cells. The luciferase analyses demonstrated the target-regulatory relationship between miR-190a-3p and DAPK1. The inhibitory effect of miR-190a-3p on autophagy was reversed by co-transfection of si-DAPK1 and miR-190a-3p inhibitors. Thus, our data indicate that the hypoxia-dependent miR-190a-3p/DAPK1 regulatory pathway is implicated in the development and progression of PE by promoting autophagy in trophoblast cells.