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Chiral metal-organic frameworks (CMOFs) with chiral selectivity are one of the high-quality stationary phases for capillary electrochromatography (CEC). However, there is a problem of unsatisfactory enantioseparation performance of capillary columns due to insufficient loading. In this work, a lamellar CMOF (Cu-TC) was grown in situ on the surface of the monolith in a capillary monolithic column to obtain a Cu-TC@monolithic column. The CEC system constructed based on the Cu-TC@monolithic column shows a satisfactory chiral separation performance. Compared with the Cu-TC-based coated column (Cu-TC@coated column), the enantioseparation performance of the CEC system based on the Cu-TC@monolithic column was greatly improved, and the resolutions (Rs) of the model analytes were increased by 80-500%. In addition, the effects of experimental conditions such as the number of cycles of Cu-TC in situ growth, buffer concentration, buffer pH, organic solvent addition and applied voltage on the performance of CEC were also investigated. Finally, the chiral selection mechanism of the stationary phase was explored by selective adsorption experiments. The present work provides a new idea for the development of capillary stationary phases, which has great potential considering the diversity of CMOFs.
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As a common pathological hallmark, protein aggregation into amyloids is a highly complicated phenomenon, attracting extensive research interest for elucidating its structural details and formation mechanisms. Membrane deposition and disulfide-driven protein misfolding play critical roles in amyloid-type aggregation, yet the underlying molecular process remains unclear. Here, we employed sum frequency generation (SFG) vibrational spectroscopy to comprehensively investigate the remodeling process of lysozyme, as the model protein, into amyloid-type aggregates at the cell membrane interface. It was discovered that disulfide reduction concurrently induced the transition of membrane-bound lysozyme from predominantly α-helical to antiparallel ß-sheet structures, under a mode switch of membrane interaction from electrostatic to hydrophobic, and subsequent oligomeric aggregation. These findings shed light on the systematic understanding of dynamic molecular mechanisms underlying membrane-interactive amyloid oligomer formation.
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Amiloide , Disulfuros , Interacciones Hidrofóbicas e Hidrofílicas , Muramidasa , Disulfuros/química , Muramidasa/química , Muramidasa/metabolismo , Amiloide/química , Agregado de Proteínas , Animales , Electricidad EstáticaRESUMEN
Within cell plasma membranes, unsaturated lipids are asymmetrically distributed over the inner and outer leaflets, offering an attractive local structural feature. However, the mechanism to keep lipid transmembrane asymmetry and the closely related transmembrane movement (flip-flop) for unsaturated lipids remain poorly understood. Here, we applied sum frequency generation vibrational spectroscopy to investigate this lipid transmembrane asymmetry upon mimicking the cell membrane homeostatic processes. On the one hand, unsaturated lipids were found to hinder the flip-flop process and preserve lipid transmembrane asymmetry in model cell membranes, owing to the steric hindrance caused by their bent tails. On the other hand, local unsaturated lipids in the mixed unsaturated/saturated lipid bilayer were conducive to the formation of the local asymmetry. Therefore, lipid unsaturation can be recognized as an intrinsic key factor to form and maintain lipid transmembrane asymmetry in cell membranes.
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Membrana Celular , Membrana Dobles de Lípidos , Membrana Dobles de Lípidos/química , Membrana Celular/química , Membrana Celular/metabolismo , Lípidos de la Membrana/químicaRESUMEN
Superchiral fields, supported by chiral plasmonic structures, have shown outstanding performance for chiral molecule sensing via enhanced chiral light-matter interaction. However, this sensing capability cannot fully reveal the chiral origin of the molecules as the chiroptic response of the molecules is intertwined with the chiroptic response of the chiral plasmonic nanostructures, which can potentially be excluded by using a plasmonic racemic mixture. Such a plasmonic racemic mixture is not easily attainable, as it normally requires complex fabrication and expensive instrumentation, whose structural fineness is limited by the fabrication precision. Here, we demonstrate trace-amount chiral molecule detection with plasmonic racemic arrays fabricated by direct laser writing with vector beams, which is facile, cost-effective, and highly controllable. The racemic arrays present no inherent circular differential scattering but a large local superchiral field, which reflects the intrinsic chiral features of the chiral molecules. They are further applied to discriminate enantiomers of phenylalanine with a limit of detection (LOD) of 10.0 ± 2.8 µM, which is an order of magnitude smaller than the LOD of conventional circular dichroism spectroscopy. The strong local superchiral field provided by the plasmonic racemic arrays enlightens the design of a superior sensing platform, which holds promising applications for biomedical detection and enantioselective drug development.
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Rayos Láser , Estereoisomerismo , Fenilalanina/química , Fenilalanina/análisis , Límite de Detección , Oro/química , Nanoestructuras/química , Resonancia por Plasmón de Superficie/métodosRESUMEN
BACKGROUND: Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear. METHODS: Pyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase-Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitationâquantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient-derived xenograft models were constructed to validate the effects of the drug combinations. RESULTS: As the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)-mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of the BRD4-p-P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5-fluorouracil or regorafenib) in CRC xenograft-bearing animals markedly activated pyroptosis and achieved a significant therapeutic effect. Clinically, HDAC2 is inversely correlated with H3K27ac/p-P65/NLRP3 and is a prognostic factor for CRC patients. CONCLUSION: Collectively, our data revealed a crucial role for HDAC2 in inhibiting NLRP3/GSDMD-mediated pyroptosis in CRC cells and highlighted HDAC2 as a potential therapeutic target for antitumour therapy. HIGHLIGHTS: Silencing of NLRP3 limits the GSDMD-dependent pyroptosis in colorectal cancer. HDAC2-mediated histone deacetylation leads to epigenetic silencing of NLRP3. HDAC2 suppresses the NLRP3 transcription by inhibiting the formation of H3K27ac/BRD4/p-P65 complex. Targeting HDAC2 activates pyroptosis and enhances therapeutic effect.
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Neoplasias Colorrectales , Histona Desacetilasa 2 , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Piroptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Ratones , Animales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Gasderminas , Proteínas de Unión a FosfatoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel human coronavirus, which has triggered a global pandemic of the coronavirus infectious disease 2019 (COVID-19). Outbreaks of emerging infectious diseases continue to challenge human health worldwide. The virus conquers human cells through the angiotensin-converting enzyme 2 receptor-driven pathway by mostly targeting the human respiratory tract. Quercetin is a natural flavonoid widely represented in the plant kingdom. Cumulative evidence has demonstrated that quercetin and its derivatives have various pharmacological properties including anti-cancer, anti-hypertension, anti-hyperlipidemia, anti-hyperglycemia, anti-microbial, antiviral, neuroprotective, and cardio-protective effects, because it is a potential treatment for severe inflammation and acute respiratory distress syndrome. Furthermore, it is the main life-threatening condition in patients with COVID-19. This article provides a comprehensive review of the primary literature on the predictable effectiveness of quercetin and its derivatives docked to multi-target of SARS-CoV-2 and host cells via in silico and some of validation through in vitro, in vivo, and clinically to fight SARS-CoV-2 infections, contribute to the reduction of inflammation, which suggests the preventive and therapeutic latency of quercetin and its derived-products against COVID-19 pandemic, multisystem inflammatory syndromes (MIS), and long-COVID.
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Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer. During the course of this study, we identified that autophagy serves as a cytoprotective mechanism during Nectin-4-MMAE treatment and proposed a strategy to enhance the antitumor effects of Nectin-4-MMAE in bladder cancer. Nectin-4-MMAE rapidly internalized into bladder cancer cells in 30 minutes and released MMAE, inducing the onset of caspase-mediated apoptosis and leading to the inhibition of tumor cell growth. Transcriptomics showed significant alterations in autophagy-associated genes in bladder cancer cells treated with Nectin-4-MMAE, which suggested autophagy was activated by Nectin-4-MMAE. Furthermore, autophagy activation was characterized by ultrastructural analysis of autophagosome accumulation, immunofluorescence of autophagic flux, and immunoblotting autophagy marker proteins SQSTM1 and LC3 I/II. Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells. Additionally, we detected the participation of the AKT/mTOR signaling cascade in the induction of autophagy by Nectin-4-MMAE. The combination of Nectin-4-MMAE and an autophagy inhibitor demonstrated enhanced antitumor effects in the HT1376 xenograft tumor model. After receiving a single dose of Nectin-4-MMAE, the group that received the combination treatment showed a significant decrease in tumor size compared to the group that received only one type of treatment. Notably, one mouse in the combination treatment group achieved complete remission of the tumor. The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.
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Autofagia , Moléculas de Adhesión Celular , Morfolinas , Nectinas , Neoplasias de la Vejiga Urinaria , Autofagia/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Humanos , Animales , Línea Celular Tumoral , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/genética , Ratones , Morfolinas/farmacología , Morfolinas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Oligopéptidos/farmacología , Apoptosis/efectos de los fármacos , Ratones Desnudos , Cromonas/farmacología , Cloroquina/farmacología , Cloroquina/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Ratones Endogámicos BALB C , Femenino , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Generally, for adhesive joints, the polar water molecules in humid environments can have a critical effect on the interfacial structures and structural evolution adjacent to the solid substrates. Regarding this, it is still a big challenge to detect and understand the interfacial hygrothermal aging process at the molecular level in real time and in situ. In this study, to trace the interfacial hygrothermal aging process of a classical epoxy formula containing diglycidyl ether of biphenyl A (DGEBA) and 2,2'-(ethylenedioxy) diethylamine (EDDA) with sapphire and fused silica in a typical hygrothermal environment (85 °C and 85% RH), sum frequency generation (SFG) vibrational spectroscopy was used to probe the molecular-level interfacial structural change over the time. The structural evolution dynamics at the buried epoxy/sapphire and epoxy/silica interfaces upon hygrothermal aging were revealed directly in situ. The interfacial delamination during hygrothermal aging was also elucidated from the molecular level. Upon hygrothermal aging, the interfacial CH signals, such as the ones from methyl, methylene, and phenyl groups, decreased significantly and the water OH signals increased substantially, indicating the water molecules had diffused into the interfaces and destroyed the original interactions between the epoxy formula and the substrates. Further analysis indicates that when the integrated signals in the CH range declined to their minimum and leveled off, the interfacial delamination happened. The tensile experiment proved the validity of these spectroscopic experimental results. Our study provides first-hand and molecular-level evidence on a direct correlation between the diffusion of the surrounding water molecules into the interface and the evolution/destruction of the interfacial structures during hygrothermal aging. More importantly, it is proved, SFG can be developed into a powerful tool to noninvasively reveal the local interfacial delamination in real time and in situ under extreme hygrothermal conditions, complemented by the mechanic test.
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AIMS: This study aimed to investigate the anti-inflammatory and odontoblastic effects of cerium-containing mesoporous bioactive glass nanoparticles (Ce-MBGNs) on dental pulp cells as novel pulp-capping agents. METHODOLOGY: Ce-MBGNs were synthesized using a post-impregnation strategy based on the antioxidant properties of Ce ions and proposed the first use of Ce-MBGNs for pulp-capping application. The biocompatibility of Ce-MBGNs was analysed using the CCK-8 assay and apoptosis detection. Additionally, the reactive oxygen species (ROS) scavenging ability of Ce-MBGNs was measured using the 2,7-Dichlorofuorescin Diacetate (DCFH-DA) probe. The anti-inflammatory effect of Ce-MBGNs on THP-1 cells was further investigated using flow cytometry and quantitative real-time polymerase chain reaction (RT-qPCR). Moreover, the effect of Ce-MBGNs on the odontoblastic differentiation of the dental pulp cells (DPCs) was assessed by combined scratch assays, RT-qPCR, western blotting, immunocytochemistry, Alizarin Red S staining and tissue-nonspecific alkaline phosphatase staining. Analytically, the secretions of tumour necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were detected with enzyme-linked immunosorbent assay (ELISA). RESULTS: Ce-MBGNs were confirmed to effectively scavenge ROS in THP-1-derived macrophages and DPCs. Flow cytometry and RT-qPCR assays revealed that Ce-MBGNs significantly inhibited the M1 polarization of macrophages (Mφ). Furthermore, the protein levels of TNF-α and IL-1ß were downregulated in THP-1-derived macrophages after stimulation with Ce-MBGNs. With a step-forward virtue of promoting the odontoblastic differentiation of DPCs, we further confirmed that Ce-MBGNs could regulate the formation of a conductive immune microenvironment with respect to tissue repair in DPCs, which was mediated by macrophages. CONCLUSIONS: Ce-MBGNs protected cells from self-produced oxidative damage and exhibited excellent immunomodulatory and odontoblastic differentiation effects on DPCs. As a pulp-capping agent, this novel biomaterial can exert anti-inflammatory effects and promote restorative dentine regeneration in clinical treatment. We believe that this study will stimulate further correlative research on the development of advanced pulp-capping agents.
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Antiinflamatorios , Cerio , Pulpa Dental , Nanopartículas , Pulpa Dental/citología , Pulpa Dental/efectos de los fármacos , Cerio/farmacología , Humanos , Antiinflamatorios/farmacología , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Cerámica/farmacología , Diferenciación Celular/efectos de los fármacos , Vidrio , Odontoblastos/efectos de los fármacos , Regeneración/efectos de los fármacos , Células THP-1 , Materiales de Recubrimiento Pulpar y Pulpectomía/farmacología , Interleucina-1beta/metabolismo , Apoptosis/efectos de los fármacos , Porosidad , Células CultivadasRESUMEN
Glioma is the most common malignant tumour in the central nervous system, accounting for approximately 30 % of the primary tumours of this system. The World Health Organization grades for glioma include: Grade I (pilocytic astrocytoma), Grade II (astrocytoma, oligodastoma, etc.), Grade III (anaplastic astrocytoma, anaplastic oligodastoma, etc.) and Grade IV (glioblastoma). With grade increases, the proliferation, invasion and other malignant biological properties of the glioma are enhanced, and the treatment results are less satisfactory. The overall survival of patients with glioblastoma is less than 15 months. Recent research has focused on the roles of long non-coding RNAs, previously regarded as "transcriptional noise", in diseases, leading to a new understanding of these roles. Therefore, we conducted this review to explore the progress of research regarding the expression and mechanism of long non-coding RNAs in glioma.
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Clinical solutions of bone defects caused by periodontitis involve surgical treatment and subsequent anti-infection treatment using antibiotics. Such a strategy faces a key challenge in that the excessive host immune response results in the damage of periodontal tissues. Consequently, it is of great importance to develop novel periodontitis treatment that allows the regulation of the host immune response and promotes the generation of periodontal tissues. Irisin has a good bone regeneration ability and could reduce the inflammatory reaction by regulating the differentiation of macrophages. In this study, we loaded irisin onto bioactive glass nanoparticles (BGNs) to prepare a composite, irisin-BGNs (IR-BGNs) with anti-inflammatory, bacteriostatic, and tissue regeneration functions, providing a novel idea for the design of ideal materials for repairing oral tissue defects caused by periodontitis. We also verified that the IR-BGNs had better anti-inflammatory properties on RAW264.7 cells compared to irisin and BGNs alone. Strikingly, when hPDLCs were stimulated with IR-BGNs, they exhibited increased expression of markers linked to osteogenesis, ALP activity, and mineralization ability in comparison to the negative control. Furthermore, on the basis of RNA sequencing results, we validated that the p38 pathway can contribute to the osteogenic differentiation of the IR-BGNs. This work may offer new thoughts on the design of ideal materials for repairing oral tissue defects.
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Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 µM for inhibiting sphere formation and 0.5-15 µM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.
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Antineoplásicos , Glioma , Humanos , Glioma/tratamiento farmacológico , Glioma/patología , Relación Estructura-Actividad , Apoptosis , Benzamidas/farmacología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular , Proteínas Asociadas a MicrotúbulosRESUMEN
A sandwich-structured composite nanoenzyme (NH2-MIL-101(Fe)@Au@MIP) was prepared using molecularly imprinted polymers, metal-organic frameworks, and gold nanoparticles and a highly selective glutathione (GSH) colorimetric sensor was constructed. The inner part of the composite nanoenzymes is a metal-organic framework loaded with gold nanoparticles (AuNPs), NH2-MIL-101(Fe)@Au, which has superior peroxidase-like activity compared with NH2-MIL-101(Fe). This is due to the surface plasmon resonance effect of AuNPs. GSH can form strong Au-S bonds with AuNPs, which can significantly reduce the enzymatic activity of NH2-MIL-101(Fe)@Au, thereby changing the absorbance at 450 nm of the sensing system. The degree of change in absorbance is correlated with the concentration of GSH. In the outer part, the molecularly imprinted polymer with oxidized glutathione (GSSG) as a dummy template provided specific pores, which significantly improved the selectivity of the sensing system. The sensor showed good GSH sensing performance in the range 1 ~ 50 µM with a lower limit of detection (LOD) of 0.231 µM and good sensing performance in fetal bovine serum, indicating its high potential for clinical diagnostic applications.
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Nanopartículas del Metal , Estructuras Metalorgánicas , Estructuras Metalorgánicas/química , Oro/química , Colorimetría , Nanopartículas del Metal/química , GlutatiónRESUMEN
BACKGROUND: Anembryonic pregnancy affects 12-15 % of clinically recognized pregnancies and a previous anembryonic pregnancy is an independent risk factor for future anembryonic pregnancy. This study aimed to investigate alternations in maternal amino acid profiles and analyze the diagnostic accuracy of amino acid biomarkers for anembryonic pregnancy in the early stage. METHODS: Fasting serum from anembryonic pregnancy patients (n = 103) and healthy pregnancies (n = 97) was collected, and amino acid concentrations were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of each of the amino acid biomarkers and the amino acid profile index for anembryonic pregnancy screening. RESULTS: The concentrations of 15 amino acids were significantly different between anembryonic pregnancy patients and healthy controls, and most of them were significantly higher at 7 weeks' gestational age in anembryonic pregnancy subjects. The area under the curve (AUC) based on an amino acid profile index combined with alanine, citrulline, aspartic acid, threonine, serine and isoleucine was 0.90 (sensitivity 82.76 %, specificity 83.64 %) for distinguishing early anembryonic pregnancy from healthy controls. CONCLUSION: Maternal serum amino acid concentrations were significantly elevated in anembryonic pregnancy patients. The diagnostic potential of amino aicds for anembryonic pregnancy was verified, and the diagnostic efficiency was improved in the use of the amino acid profile index. The amino acid profile is expected to be applied for the risk screening of early-stage of anembryonic pregnancy in the future.
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Aminoácidos , Cromatografía Líquida con Espectrometría de Masas , Embarazo , Femenino , Humanos , Cromatografía Liquida , Espectrometría de Masas en Tándem , Diagnóstico Precoz , Biomarcadores/análisisRESUMEN
BACKGROUND: Multitarget tyrosine kinase inhibitors (mTKIs) such as Regorafenib and Sorafenib have already been approved for the treatment of many solid tumours. However, the efficacy of mTKIs in colorectal cancer (CRC) is limited; the underlined mechanism remains largely elusive. Our study was aimed to find out the resistance mechanism of mTKIs in CRC. METHODS: RNA sequencing was used to identify the expression of Activin A receptor-like type 1 (ACVRL1) under the treatment of mTKIs. Gain/loss-of-function experiments were performed to assess the biological function of ACVRL1 in resistance to mTKIs. The underlying mechanisms of ACVRL1-mediated mTKI resistance were investigated by using liquid chromatography-mass spectrometry assays (LC-MS), co-immunoprecipitation assays (Co-IP), chromatin immunoprecipitation assays, ubiquitination assays, dual luciferase reporter assays, etc. RESULTS: RNA sequencing identified the activation of ACVRL1 under the treatment of mTKIs in CRC cells. ACVRL1 knockdown and overexpression significantly affects the sensitivity of CRC cells to mTKIs both in vitro and vivo. Mechanistically, we found the ß-catenin/TCF-1-KCNQ1OT1/miR-7-5p axis mediated the activation of ACVRL1. Furthermore, LC-MS assays indicated the interaction between ACVRL1 and glutathione peroxidase 2(GPX2) protein. IP assay defined ACVRL1 truncation (282-503aa) could be responsible for interacting with GPX2, and rescue experiments with ACVRL1 truncations confirmed the importance of this interaction in driving mTKI resistance. Co-IP assays confirmed that ACVRL1 associates with ubiquitin-specific peptidase 15(USP15) which directly deubiquinates GPX2 at the K187(K, lysine) site, leading to the accumulation of GPX2 protein. Rescue experiments performed with the lysine mutants in GPX2 CRISPR knockout cell model confirmed the importance of GPX2 K187 mutant. As a result, the increased ROS clearance and decreased cell apoptosis eventually lead to mTKI resistance in CRC. CONCLUSIONS: Our results demonstrate that the Wnt/ß-catenin/KCNQ1OT1/miR-7-5p/ACVRL1/GPX2 biological axis plays a vital role in CRC, targeting which may be an effective approach for overcoming mTKI resistance.
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Neoplasias Colorrectales , MicroARNs , Humanos , beta Catenina/genética , beta Catenina/metabolismo , beta Catenina/farmacología , Lisina/genética , Lisina/metabolismo , Lisina/farmacología , MicroARNs/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Receptores de Activinas Tipo II/farmacología , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/farmacologíaRESUMEN
OBJECTIVE: Glioma is one of the leading causes of death in patients with intracranial tumours. RPL34 divergent transcript (RPL34-DT) is a long non-coding ribonucleic acid that is significantly upregulated in glioma tissues. However, the role of RPL34-DT in glioma behavior remains to be elucidated. Therefore, in this study, we focused on the effect of RPL34-DT on the epithelial-mesenchymal transition in gliomas. METHODS: Real-time quantitative reverse transcription polymerase chain reaction was used to detect the levels of RPL34-DT in glioma tissue and cell lines. We further used the LN229 and U251 glioma cell lines to assess the role of RPL34-DT. Wound healing and invasion assays were performed to determine the role of RPL34-DT in migration. Changes in protein levels were assessed by western blotting. RESULTS: We found that RPL34-DT was upregulated in glioma tissues and glioma cell lines. Knockdown of RPL34-AS1 blocked migration of glioma cell. This effect occurred through a decrease of epithelial-mesenchymal transition and ß-catenin. CONCLUSIONS: This study suggests that RPL34-DT affects cell migration in glioma and therefore may serve as a valuable therapeutic target in patients with glioma.
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Glioma , ARN Largo no Codificante , Humanos , Vía de Señalización Wnt , Proliferación Celular , Línea Celular Tumoral , Glioma/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transición Epitelial-Mesenquimal/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica/genéticaRESUMEN
Corals are fundamental organisms in marine and coastal ecosystems. With the advancement of coral protection research in recent years, precise control of the coral culture environment is highly in demand for coral conservation and study. Here, we developed a semi-closed coral culture micro-device system as a multi-functional platform, which can provide accurate and programmable temperature control, a sterile initial environment, long-term stable water quality, an adjustable dissolved oxygen concentration, and a customized light spectrum for corals. Owing to the modular design, the coral culture system can be upgraded or modified by installing desirable new modules or removing existing ones. Currently, under appropriate conditions and with proper system maintenance, the sample corals can survive for at least 30 days in a healthy state. Furthermore, due to the controllable and sterile initial environment, this coral culture system can support research into the symbiotic relationship between corals and associated microorganisms. Therefore, this micro-device system can be applied to monitor and investigate sea corals in a relatively quantitative manner.
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Antozoos , Animales , Ecosistema , Simbiosis , Arrecifes de CoralRESUMEN
Non-small cell lung cancer (NSCLC) is one of the most common types of malignant tumors as well as the leading cause of cancer-related deaths in the world. The application of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has dramatically improved the prognosis of NSCLC patients who harbor EGFR mutations. However, despite an excellent initial response, NSCLC inevitably becomes resistant to EGFR-TKIs, leading to irreversible disease progression. Hence, it is of great significance to shed light on the molecular mechanisms underlying the EGFR-TKI resistance in NSCLC. Long non-coding RNAs (lncRNAs) are critical gene modulators that are able to act as oncogenes or tumor suppressors that modulate tumorigenesis, invasion, and metastasis. Recently, extensive evidence demonstrates that lncRNAs also have a significant function in modulating EGFR-TKI resistance in NSCLC. In this review, we present a comprehensive summary of the lncRNAs involved in EGFR-TKI resistance in NSCLC and focus on their detailed mechanisms of action, including activation of alternative bypass signaling pathways, phenotypic transformation, intercellular communication in the tumor microenvironment, competing endogenous RNAs (ceRNAs) networks, and epigenetic modifications. In addition, we briefly discuss the limitations and the clinical implications of current lncRNAs research in this field.
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Reductive soil disinfestation (RSD) is an effective bioremediation technique to restructure the soil microbial community and eliminate soilborne phytopathogens. Yet we still lack a comprehensive understanding of the keystone taxa involved and their roles in ecosystem functioning in degraded soils treated by RSD. In this study, the bacteriome network structure in RSD-treated soil and the subsequent cultivation process were explored. As a result, bacterial communities in RSD-treated soil developed more complex topologies and stable co-occurrence patterns. The richness and diversity of keystone taxa were higher in the RSD group (module hub: 0.57%; connector: 23.98%) than in the Control group (module hub: 0.16%; connector: 19.34%). The restoration of keystone taxa in RSD-treated soil was significantly (P < 0.01) correlated with soil pH, total organic carbon, and total nitrogen. Moreover, a strong negative correlation (r = -0.712; P < 0.01) was found between keystone taxa richness and Fusarium abundance. Our results suggest that keystone taxa involved in the RSD network structure are capable of maintaining a flexible generalist mode of metabolism, namely with respect to nitrogen fixation, methylotrophy, and methanotrophy. Furthermore, distinct network modules composed by numerous anti-pathogen agents were formed in RSD-treated soil; i.e., the genera Hydrogenispora, Azotobacter, Sphingomonas, and Clostridium_8 under the soil treatment stage, and the genera Anaerolinea and Pseudarthrobacter under the plant cultivation stage. The study provides novel insights into the association between fungistasis and keystone or sensitive taxa in RSD-treated soil, with significant implications for comprehending the mechanisms of RSD. KEY POINTS: ⢠RSD enhanced bacteriome network stability and restored keystone taxa. ⢠Keystone taxa richness was negatively correlated with Fusarium abundance. ⢠Distinct sensitive OTUs and modules were formed in RSD soil.
Asunto(s)
Fusarium , Microbiota , Suelo/química , Bacterias/metabolismo , Firmicutes , Microbiología del SueloRESUMEN
Multidrug-resistant (MDR) pathogens have been a growing threat to human health over the years. Antimicrobial peptides (AMPs) with broad-spectrum antibiotic activity, as a promising therapeutic candidate, have shown tremendous capability against MDR pathogens. To acquire novel AMPs with better efficacy, we should dig into the antimicrobial mechanism by which AMPs perform their functions. In this study, the interaction processes between three representative AMPs (maculatin 1.1-G15, cupiennin 1a, and aurein 1.2) and the model membrane dDPPG/DPPG bilayer were investigated via sum frequency generation (SFG) vibrational spectroscopy. Two interaction modes for the membrane-bound AMPs were differentiated, i.e., the loosely adsorbed one and the tightly adsorbed one. In the loosely adsorbed mode, AMPs are bound to the bilayer mainly by the electrostatic attraction between the positively charged residues of AMPs and the negatively charged head groups of the lipids. After the charged AMPs and lipids were neutralized by the counter ions, the desorption of AMPs from the membrane lipids happened, as evidenced by the disappearance of the SFG signals from membrane-bound AMPs. While in the tightly adsorbed mode, besides the charged attraction, AMPs are additionally inserted into the membrane lipids via the hydrophobic interaction. Even when the electrostatic attraction was neutralized by the counter ions, the hydrophobic interaction still led to the firm adsorption of AMPs onto the already-neutralized bilayer lipids, as evidenced by the presence of clear SFG signals from membrane-bound AMPs. We thus established a feasible protocol to expand the application of SFG, namely classifying the adsorption modes of AMPs. Such knowledge will surely promote the development and application of AMPs with high efficacy.