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The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.
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Diferenciación Celular , Colitis , Células Dendríticas , Células T Auxiliares Foliculares , Animales , Células Dendríticas/inmunología , Colitis/inmunología , Colitis/patología , Células T Auxiliares Foliculares/inmunología , Ratones , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Células TH1/inmunología , Colon/inmunología , Colon/patología , Ratones Noqueados , Centro Germinal/inmunología , Ratones TransgénicosRESUMEN
Ceramide synthases (CerS) catalyze ceramide formation via N-acylation of a sphingoid base with a fatty acyl-CoA and are attractive drug targets for treating numerous metabolic diseases and cancers. Here, we present the cryo-EM structure of a yeast CerS complex, consisting of a catalytic Lac1 subunit and a regulatory Lip1 subunit, in complex with C26-CoA substrate. The CerS holoenzyme exists as a dimer of Lac1-Lip1 heterodimers. Lac1 contains a hydrophilic reaction chamber and a hydrophobic tunnel for binding the CoA moiety and C26-acyl chain of C26-CoA, respectively. Lip1 interacts with both the transmembrane region and the last luminal loop of Lac1 to maintain the proper acyl chain binding tunnel. A lateral opening on Lac1 serves as a potential entrance for the sphingoid base substrate. Our findings provide a template for understanding the working mechanism of eukaryotic ceramide synthases and may facilitate the development of therapeutic CerS modulators.
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Ceramidas , Proteínas de Saccharomyces cerevisiae , Ceramidas/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Oxidorreductasas/metabolismo , Proteínas de la Membrana/metabolismoRESUMEN
To access superconductivity via the electric field effect in a clean, two-dimensional device is a central goal of nanoelectronics. Recently, superconductivity has been realized in graphene moiré heterostructures1-4; however, many of these structures are not mechanically stable, and experiments show signatures of strong disorder. Here we report the observation of superconductivity-manifesting as low or vanishing resistivity at sub-kelvin temperatures-in crystalline rhombohedral trilayer graphene5,6, a structurally metastable carbon allotrope. Superconductivity occurs in two distinct gate-tuned regions (SC1 and SC2), and is deep in the clean limit defined by the ratio of mean free path and superconducting coherence length. Mapping of the normal state Fermi surfaces by quantum oscillations reveals that both superconductors emerge from an annular Fermi sea, and are proximal to an isospin-symmetry-breaking transition where the Fermi surface degeneracy changes7. SC1 emerges from a paramagnetic normal state, whereas SC2 emerges from a spin-polarized, valley-unpolarized half-metal17 and violates the Pauli limit for in-plane magnetic fields by at least one order of magnitude8,9. We discuss our results in view of several mechanisms, including conventional phonon-mediated pairing10,11, pairing due to fluctuations of the proximal isospin order12, and intrinsic instabilities of the annular Fermi liquid13,14. Our observation of superconductivity in a clean and structurally simple two-dimensional metal provides a model system to test competing theoretical models of superconductivity without the complication of modelling disorder, while enabling new classes of field-effect controlled electronic devices based on correlated electron phenomena and ballistic electron transport.
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Ferromagnetism is most common in transition metal compounds where electrons occupy highly localized d orbitals. However, ferromagnetic order may also arise in low-density two-dimensional electron systems1-5. Here we show that gate-tuned van Hove singularities in rhombohedral trilayer graphene6 drive spontaneous ferromagnetic polarization of the electron system into one or more spin and valley flavours. Using capacitance and transport measurements, we observe a cascade of transitions tuned to the density and electronic displacement field between phases in which quantum oscillations have fourfold, twofold or onefold degeneracy, associated with a spin- and valley-degenerate normal metal, spin-polarized 'half-metal', and spin- and valley-polarized 'quarter-metal', respectively. For electron doping, the salient features of the data are well captured by a phenomenological Stoner model7 that includes valley-anisotropic interactions. For hole filling, we observe a richer phase diagram featuring a delicate interplay of broken symmetries and transitions in the Fermi surface topology. Finally, we introduce a moiré superlattice using a rotationally aligned hexagonal boron nitride substrate5,8. Remarkably, we find that the isospin order is only weakly perturbed, with the moiré potential catalysing the formation of topologically nontrivial gapped states whenever itinerant half- or quarter-metal states occur at half- or quarter-superlattice band filling. Our results show that rhombohedral graphene is an ideal platform for well-controlled tests of many-body theory, and reveal magnetism in moiré materials4,5,9,10 to be fundamentally itinerant in nature.
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Rearranged during transfection (RET) rearrangement oncoprotein-mediated Ras/MAPK signaling cascade is constitutively activated in cancers. Here, we demonstrate a unique signal niche. The niche is a ternary complex based on the chimeric RET liquid-liquid phase separation. The complex comprises the rearranged kinase (RET fusion); the adaptor (GRB2), and the effector (SHC1). Together, they orchestrate the Ras/MAPK signal cascade, which is dependent on tyrosine kinase. CCDC6-RET fusion undergoes LLPS requiring its kinase domain and its fusion partner. The CCDC6-RET fusion LLPS promotes the autophosphorylation of RET fusion, with enhanced kinase activity, which is necessary for the formation of the signaling niche. Within the signal niche, the interactions among the constituent components are reinforced, and the signal transduction efficiency is amplified. The specific RET fusion-related signal niche elucidates the mechanism of the constitutive activation of the Ras/MAPK signaling pathway. Beyond just focusing on RET fusion itself, exploration of the ternary complex potentially unveils a promising avenue for devising therapeutic strategies aimed at treating RET fusion-driven diseases.
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Proteína Adaptadora GRB2 , Sistema de Señalización de MAP Quinasas , Proteínas de Fusión Oncogénica , Proteínas Proto-Oncogénicas c-ret , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src , Proteínas ras , Humanos , Proteína Adaptadora GRB2/metabolismo , Proteína Adaptadora GRB2/genética , Células HEK293 , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Fusión Oncogénica/genética , Fosforilación , Proteínas Proto-Oncogénicas c-ret/metabolismo , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas ras/metabolismo , Proteínas ras/genética , Transducción de Señal , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/metabolismo , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/genéticaRESUMEN
MuSK is a receptor tyrosine kinase (RTK) that plays essential roles in the formation and maintenance of the neuromuscular junction. Distinct from most members of RTK family, MuSK activation requires not only its cognate ligand agrin but also its coreceptors LRP4. However, how agrin and LRP4 coactivate MuSK remains unclear. Here, we report the cryo-EM structure of the extracellular ternary complex of agrin/LRP4/MuSK in a stoichiometry of 1:1:1. This structure reveals that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, thereby promoting a direct interaction between agrin and MuSK. Our cryo-EM analyses therefore uncover the assembly mechanism of agrin/LRP4/MuSK signaling complex and reveal how MuSK receptor is activated by concurrent binding of agrin and LRP4.
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Agrina , Receptores Colinérgicos , Receptores Colinérgicos/metabolismo , Agrina/química , Agrina/metabolismo , Proteínas Relacionadas con Receptor de LDL/química , Transducción de Señal , Unión Neuromuscular/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Lysine-specific demethylase 6A (KDM6A), also named UTX, is frequently mutated in bladder cancer (BCa). Although known as a tumor suppressor, KDM6A's therapeutic potential in the metastasis of BCa remains elusive. It also remains difficult to fulfill the effective up-regulation of KDM6A levels in bladder tumor tissues in situ to verify its potential in treating BCa metastasis. Here, we report a mucoadhesive messenger RNA (mRNA) nanoparticle (NP) strategy for the intravesical delivery of KDM6A-mRNA in mice bearing orthotopic Kdm6a-null BCa and show evidence of KDM6A's therapeutic potential in inhibiting the metastasis of BCa. Through this mucoadhesive mRNA NP strategy, the exposure of KDM6A-mRNA to the in situ BCa tumors can be greatly prolonged for effective expression, and the penetration can be also enhanced by adhering to the bladder for sustained delivery. This mRNA NP strategy is also demonstrated to be effective for combination cancer therapy with other clinically approved drugs (e.g., elemene), which could further enhance therapeutic outcomes. Our findings not only report intravesical delivery of mRNA via a mucoadhesive mRNA NP strategy but also provide the proof-of-concept for the usefulness of these mRNA NPs as tools in both mechanistic understanding and translational study of bladder-related diseases.
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Histona Demetilasas/farmacología , Nanopartículas/química , Metástasis de la Neoplasia/prevención & control , ARN Mensajero/farmacología , Adhesividad , Administración Intravesical , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Terapia Genética , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Ratones , Ratones Desnudos , Membrana Mucosa , Neoplasias Experimentales/terapia , ARN Mensajero/administración & dosificación , ARN Mensajero/metabolismo , Neoplasias de la Vejiga UrinariaRESUMEN
Over the past decade, colorectal cancer has reported a higher incidence in younger adults and a lower mortality rate. Recently, the influence of the intestinal flora in the initiation, progression, and treatment of colorectal cancer has been extensively studied, as well as their positive therapeutic impact on inflammation and the cancer microenvironment. Historically, traditional Chinese medicine (TCM) has been widely used in the treatment of colorectal cancer via promoted cancer cell apoptosis, inhibited cancer metastasis, and reduced drug resistance and side effects. The present research is more on the effect of either herbal medicine or intestinal flora on colorectal cancer. The interactions between TCM and intestinal flora are bidirectional and the combined impacts of TCM and gut microbiota in the treatment of colon cancer should not be neglected. Therefore, this review discusses the role of intestinal bacteria in the progression and treatment of colorectal cancer by inhibiting carcinogenesis, participating in therapy, and assisting in healing. Then the complex anticolon cancer effects of different kinds of TCM monomers, TCM drug pairs, and traditional Chinese prescriptions embodied in apoptosis, metastasis, immune suppression, and drug resistance are summarized separately. In addition, the interaction between TCM and intestinal flora and the combined effect on cancer treatment were analyzed. This review provides a mechanistic reference for the application of TCM and intestinal flora in the clinical treatment of colorectal cancer and paves the way for the combined development and application of microbiome and TCM.
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Neoplasias Colorrectales , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Plantas Medicinales , Adulto , Humanos , Medicina Tradicional China , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Microambiente TumoralRESUMEN
IL12B encodes the shared p40 subunit (IL-12p40) of IL-12 and IL-23, which have diverse immune functions and are closely related to the occurrence and development of atherosclerosis (AS). However, the exact role of IL12B in coronary heart disease (CHD) was still unknown. A case-control association analysis was performed between five single nucleotide polymorphisms (SNPs) of IL12B (rs1003199, rs3212219, rs2569254, rs2853694 and rs3212227) and CHD in Chinese Han population (1824 patients with CHD vs. 2784 controls). Logistic regression analyses were used to study the relationships between SNPs and CHD, while multiple linear regression analyses were used to test the association between the SNP and the severity of CHD. In addition, the plasma IL12B concentration of CHD patients were detected by ELISA. We detected a significant association between one of the SNPs, rs2853694-G and CHD (padj = 2.075 × 10-5 , OR, 0.773 [95% CI, 0.686-0.870]). Stratified analysis showed that rs2853694 was associated with CHD in both male and female populations and was significantly associated with both early- and late-onset CHD. In addition, rs2853694 is also related to the different types of CHD including clinical-CHD and anatomical-CHD. Moreover, there are significant differences in serum IL12B concentrations between rs2853694-TT carriers and rs2853694-GT carriers in CHD patients (p = 0.010). A common variant of IL12B was found significantly associated with CHD and its subgroups. As a shared subunit of IL-12 and IL-23, IL-12p40 may play a key role in IL-12/IL-23 axis mediated AS, which is expected to be an effective therapeutic target for CHD.
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Aterosclerosis , Enfermedad Coronaria , Humanos , Masculino , Femenino , Predisposición Genética a la Enfermedad , Subunidad p40 de la Interleucina-12 , Interleucina-12 , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , GenotipoRESUMEN
The designed and ordered co-immobilization of multiple enzymes for vectorial biocatalysis is challenging. Here, a combination of protein phase separation and bioorthogonal linking is used to generate a zeolitic imidazole framework (ZIF-8) containing co-immobilized enzymes. Zn2+ ions induce the clustering of minimal protein modules, such as 6-His tag, proline-rich motif (PRM) and SRC homology 3 (SH3) domains, and allow for phase separation of the coupled aldoketoreductase (AKR) and alcohol dehydrogenase (ADH) at low concentrations. This is achieved by fusing SpyCatcher and PRM-SH3-6His peptide fragments to the C and N termini of AKR, respectively, and the SpyTag to ADH. Addition of 2-methylimidazole results in droplet formation and enables in situ spatial embedding the recombinant AKR and ADH to generate the cascade biocalysis system encapsulated in ZIF-8 (AAE@ZIF). In synthesizing (S)-1-(2-chlorophenyl) ethanol, ater 6 cycles, the yield can still reach 91%, with 99.99% enantiomeric excess (ee) value for each cycle. However, the yield could only reach 72.9% when traditionally encapsulated AKR and ADH in ZIF-8 are used. Thus, this work demonstrates that a combination of protein phase separation and bio-orthogonal linking enables the in situ creation of a stable and spatially organized bi-enzyme system with enhanced channeling effects in ZIF-8.
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Zinc (Zn) deficiency not only impairs plant growth and development but also has negative effects on human health. Rice (Oryza Sativa L.) is a staple food for over half of the global population, yet the regulation of Zn deficiency response in rice remains largely unknown. In this study, we provide evidence that two F-group bZIP transcription factors, OsbZIP48/50, play a crucial role in Zn deficiency response. Mutations in OsbZIP48/50 result in impaired growth and reduced Zn/Fe/Cu content under Zn deficiency conditions. The N-terminus of OsbZIP48/OsbZIP50 contains two Zn sensor motifs (ZSMs), deletion or mutation of these ZSMs leads to increased nuclear localization. Both OsbZIP48 and OsbZIP50 exhibit transcriptional activation activity, and the upregulation of 1117 genes involved in metal uptake and other processes by Zn deficiency is diminished in the OsbZIP48/50 double mutant. Both OsbZIP48 and OsbZIP50 bind to the promoter of OsZIP10 and activate the ZDRE cis-element. Amino acid substitution mutation of the ZSM domain of OsbZIP48 in OsbZIP50 mutant background increases the content of Zn/Fe/Cu in brown rice seeds and leaves. Therefore, this study demonstrates that OsbZIP48/50 play a crucial role in regulating metal homoeostasis and identifies their downstream genes involved in the Zn deficiency response in rice.
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Oryza , Zinc , Humanos , Zinc/metabolismo , Oryza/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Metales/metabolismo , Homeostasis , Regulación de la Expresión Génica de las PlantasRESUMEN
PURPOSE: To assess the effectiveness of a deep learning model using contrastenhanced ultrasound (CEUS) images in distinguishing between low-grade (grade I and II) and high-grade (grade III and IV) clear cell renal cell carcinoma (ccRCC). METHODS: A retrospective study was conducted using CEUS images of 177 Fuhrmangraded ccRCCs (93 low-grade and 84 high-grade) from May 2017 to December 2020. A total of 6412 CEUS images were captured from the videos and normalized for subsequent analysis. A deep learning model using the RepVGG architecture was proposed to differentiate between low-grade and high-grade ccRCC. The model's performance was evaluated based on sensitivity, specificity, positive predictive value, negative predictive value and area under the receiver operating characteristic curve (AUC). Class activation mapping (CAM) was used to visualize the specific areas that contribute to the model's predictions. RESULTS: For discriminating high-grade ccRCC from low-grade, the deep learning model achieved a sensitivity of 74.8%, specificity of 79.1%, accuracy of 77.0%, and an AUC of 0.852 in the test set. CONCLUSION: The deep learning model based on CEUS images can accurately differentiate between low-grade and high-grade ccRCC in a non-invasive manner.
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Carcinoma de Células Renales , Aprendizaje Profundo , Neoplasias Renales , Humanos , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/patología , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/patología , Estudios Retrospectivos , Curva ROCRESUMEN
Understanding the mechanisms by which the geomorphic structures affect habitat invasibility by mediating various abiotic and biotic factors is essential for predicting whether these geomorphic structures may provide spatial windows of opportunity to facilitate range-expansion of invasive species in salt marshes. Many studies have linked geomorphic landscape features such as tidal channels to invasion by exotic plants, but the role of tidal channel meanders (i.e., convex and concave sides) in regulating the Spartina alterniflora invasion remains unclear. Here, we examined the combined effects of tidal channel meander-mediated hydrodynamic variables, soil abiotic stresses, and propagule pressure on the colonization of Spartina in the Yellow River Delta, China, by conducting field observations and experiments. The results showed that lower hydrodynamic disturbance, bed shear stress, and higher propagule pressure triggered by eddies due to the convex structure of channel meanders facilitated Spartina seedling establishment and growth, whereas the concave side considerably inhibited the Spartina invasion. Lower soil abiotic stresses also significantly promoted the invasibility of the channel meanders by Spartina. Based on these findings, we propose a conceptual framework to illustrate the effects of the meandering geomorphology of tidal channels on the mechanisms that might allow the landward spread of Spartina and related processes. Our results demonstrate that the meandering geomorphic structures of tidal channels could act as stepping-stones to significantly facilitate the landward invasion of Spartina along tidal channels. This implies that geomorphic characteristics of tidal channels should be integrated into invasive species control and salt marsh management strategies.
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Ecosistema , Humedales , Especies Introducidas , Poaceae , China , Suelo/químicaRESUMEN
Light and thermal detectors based on the laser-induced transverse voltage (LITV) effect have garnered significant interest for their rapid and broad spectral response. In this study, we prepared the La-doped SrTiO3(STO) epitaxial thin films on the 12° inclined single crystal LaAlO3(LAO) (100) substrates using our home-designed metal-organic chemical vapor deposition system. Under the illumination of a 248 nm laser, the LITV signals of LaxSr1-xTiO3films were observed and showed dependence on the La doping level, which can be explained by the changes in the light absorption coefficient, thermal conductivity, and optical penetration depth. The optimized LITV signal was observed with a peak voltage of 23.25 V and a decay time of 106 ns under the laser power density of 1.0 mJ mm-2. The high peak voltage and fast response time of LaxSr1-xTiO3show great potential in the field of light and thermal detection.
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Carbonaceous aerosols (CA) from anthropogenic emissions have been significantly reduced in urban China in recent years. However, the relative contributions of fossil and nonfossil sources to CA in rural and background regions of China remain unclear. In this study, the sources of different carbonaceous fractions in fine aerosols (PM2.5) from five background sites of the China Meteorological Administration Atmosphere Watch Network during the winter of 2019 and 2020 were quantified using radiocarbon (14C) and organic markers. The results showed that nonfossil sources contributed 44-69% to total carbon at these five background sites. Fossil fuel combustion was the predominant source of elemental carbon at all sites (73 ± 12%). Nonfossil sources dominated organic carbon (OC) in these background regions (61 ± 13%), with biomass burning or biogenic-derived secondary organic carbon (SOC) as the most important contributors. However, the relative fossil fuel source to OC in China (39 ± 13%) still exceeds those at other regional/background sites in Asia, Europe, and the USA. SOC dominated the fossil fuel-derived OC, highlighting the impact of regional transport from anthropogenic sources on background aerosol levels. It is therefore imperative to develop and implement aerosol reduction policies and technologies tailored to both the anthropogenic and biogenic emissions to mitigate the environmental and health risks of aerosol pollution across China.
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Contaminantes Atmosféricos , Contaminantes Atmosféricos/análisis , Material Particulado/análisis , Fósiles , Monitoreo del Ambiente/métodos , China , Carbono , Combustibles Fósiles/análisis , Aerosoles/análisis , Estaciones del Año , AtmósferaRESUMEN
Purpose: Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder. Pyroptosis represents a distinctive form of inflammatory cell death that is mediated through the activation of Caspase-1 and inflammasomes. CircRNAs have emerged as a novel class of biomolecules with implications in various human diseases. This study aims to investigate the circRNAs profile of in COPD progression and identify pivotal circRNAs associated with the development of this disease. Methods: he expression profiles of circRNAs in peripheral blood mononuclear cells of COPD patients were assessed by circRNA microarray. Furthermore, flag-labeled vectors were constructed to assess the potential protein-coding capacity of has-circ-0008833. 16HBE cells were stably transfected with lentivirus approach, and cell proliferation and death were assessed to clarify the functional roles of has-circ-0008833 and its encoded protein circ-0008833aa. Additionally, western blot analysis was furthered performed to determine the level of Caspase-1, IL-18, IL-1ß, NLRP3, ASC, and cleaved GSDMD regulated by has-circ-0008833 and circ-0008833-57aa. Results: Initially, we screened the expression profiles of human circRNAs in peripheral blood mononuclear cells of COPD patients, and found that has-circ-0008833 exhibited a significant increase in COPD mononuclear cells. Subsequently, we demonstrated that has-circ-0008833 carried an open reading frame (ORF), which encoded a functional protein, referred to as circ-0008833-57aa. By employing gain-of-function approaches, our results suggested that both circ-0008833 and circ-0008833-57aa inhibited proliferation, but accelerated the rate of 16HBE cell death. Finally, we discovered that circ-0008833 and circ-0008833-57aa promoted the expression of Caspase-1, IL-18, IL-1ß, NLRP3, ASC, and cleaved GSDMD in 16HBE cells. Conclusions: Upregulation of circ-0008833 might promote COPD progression by inducing pyroptosis of bronchial epithelial cells through the encoding of a 57-amino acid peptide.
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MicroARNs , Enfermedad Pulmonar Obstructiva Crónica , Masculino , Humanos , ARN Circular/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis , Interleucina-18/metabolismo , Leucocitos Mononucleares , Células Epiteliales , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Caspasas/metabolismo , MicroARNs/genéticaRESUMEN
The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.
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Proteína Quinasa Activada por ADN , Inhibidores de Proteínas Quinasas , Humanos , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Proteína Quinasa Activada por ADN/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Relación Estructura-Actividad , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Desarrollo de Medicamentos , AnimalesRESUMEN
Natural products represent a paramount source of novel drugs. Numerous plant-derived natural products have demonstrated potent anti-tumor properties, thereby garnering considerable interest in their potential as anti-tumor drugs. This review compiles an overview of 242 recently discovered natural products, spanning the period from 2018 to the present. These natural products, which include 69 terpenoids, 42 alkaloids, 39 flavonoids, 21 steroids, 14 phenylpropanoids, 5 quinolines and 52 other compounds, are characterized by their respective chemical structures, anti-tumor activities, and mechanisms of action. By providing an essential reference and fresh insights, this review aims to support and inspire researchers engaged in the fields of natural products and anti-tumor drug discovery.
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Alcaloides , Antineoplásicos , Productos Biológicos , Productos Biológicos/farmacología , Productos Biológicos/química , Alcaloides/farmacología , Alcaloides/química , Plantas/química , Flavonoides/química , Antineoplásicos/farmacologíaRESUMEN
The Chinese medicinal fungi "Sanghuang" have been long recognized for their significant and valued medicinal properties, as documented in ancient medical literature. However, in traditional folk medicine, various macrofungi sharing similar appearance, habitat, and therapeutic effects with Sanghuang were erroneously used. These Sanghuang-like fungi mainly belong to the Porodaedalea, Phellinus, and Inonotus genera within the Hymenochaetaceae family. Despite the establishment of the Sanghuangporus genus and the identification of multiple species, the emerging taxonomic references based on morphological, ITS, and mycelial structural features have been inadequate to differentiate Sanghuangporus and Sanghuang-like fungi. To address this limitation, this study presents the first comparative and phylogenetic analysis of Sanghuang-related fungi based on mitogenomes. Our results show that Sanghuangporus species show marked convergence in mitochondrial genomic features and form a distinct monophyletic group based on phylogenetic analyses of five datasets. These results not only deepen our understanding of Sanghuang-like fungi but also offer novel insights into their mitochondrial composition and phylogeny, thereby providing new research tools for distinguishing members of the Sanghuangporus genus. KEY POINTS: ⢠Sanghuangporus, Inonotus, and Porodaedalea are monophyly in sanghuang-like species. ⢠Mitogenome-based analysis exhibits high resolution in sanghuang-like genus. ⢠The mitogenomes provide strong evidence for reclassifying Phellinus gilvus S12 as Sanghuangporus vaninii.
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Filogenia , Genoma Mitocondrial , Basidiomycota/genética , Basidiomycota/clasificación , ADN de Hongos/genética , Medicina Tradicional China , Análisis de Secuencia de ADNRESUMEN
The plant microbes are an integral part of the host and play fundamental roles in plant growth and health. There is evidence indicating that plants have the ability to attract beneficial microorganisms through their roots in order to defend against pathogens. However, the mechanisms of plant microbial community assembly from below- to aboveground compartments under pathogen infection remain unclear. In this study, we investigated the bacterial and fungal communities in bulk soil, rhizosphere soil, root, stem, and leaf of both healthy and infected (Potato virus Y disease, PVY) plants. The results indicated that bacterial and fungal communities showed different recruitment strategies in plant organs. The number and abundance of shared bacterial ASVs between bulk and rhizosphere soils decreased with ascending migration from below- to aboveground compartments, while the number and abundance of fungal ASVs showed no obvious changes. Field type, plant compartments, and PVY infection all affected the diversity and structures of microbial community, with stronger effects observed in the bacterial community than the fungal community. Furthermore, PVY infection, rhizosphere soil pH, and water content (WC) contributed more to the assembly of the bacterial community than the fungal community. The analysis of microbial networks revealed that the bacterial communities were more sensitive to PVY infection than the fungal communities, as evidenced by the lower network stability of the bacterial community, which was characterized by a higher proportion of positive edges. PVY infection further increased the bacterial network stability and decreased the fungal network stability. These findings advance our understanding of how microbes respond to pathogen infections and provide a rationale and theoretical basis for biocontrol technology in promoting sustainable agriculture. KEY POINTS: ⢠Different recruitment strategies between plant bacterial and fungal communities. ⢠Bacterial community was more sensitive to PVY infection than fungal community. ⢠pH and WC drove the microbial community assembly under PVY infection.