RESUMO
Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.
Assuntos
Neoplasias , Pericitos , Humanos , Pericitos/patologia , Pericitos/fisiologia , Guanilil Ciclase Solúvel , Células Endoteliais/fisiologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neoplasias/genética , Neoplasias/patologia , Guanilato Ciclase , Microambiente TumoralRESUMO
Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.
Assuntos
Síndrome de Rett , Animais , Camundongos , Ácido Glutâmico/metabolismo , Inflamação/genética , Inflamação/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos Knockout , Microglia/metabolismo , Síndrome de Rett/metabolismoRESUMO
In this work, a straightforward approach utilizing distillers' grains (DG) waste and sodium alginate (SA) was developed to prepare functional and bioactive packaging films. Deep eutectic solvents (DESs) were initially synthesized from choline chloride (CO), betaine (BO), glycerol (GO), and oxalic acid. Composite films were then prepared from DES-treated DG slurry and SA at different ratios. Characterization and analysis revealed that adding 75 % CO-treated DG slurry reduced the water vapor permeability (WVP) by over 66 % compared to that of the SA film. Composite films containing CO/BO-treated DG slurry had an ultraviolet light barrier rate exceeding 99 %, while those with 75 % DES-treated DG slurry demonstrated excellent antioxidant activity, with a 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) free radical scavenging rate of 80.14 %-88.35 %, representing a 322.45 %-365.73 % increase compared to that of the pure SA film. These composite films also exhibited favorable mechanical properties (31.58 MPa, 5.53 % EB), thermal stability, and biodegradability, extending the shelf life of grapes by 1.8 times. In conclusion, bioactive composite films derived from DES-treated DG are expected to replace petroleum-based plastics, enhancing sustainable biomass use and environmental responsibility.
Assuntos
Alginatos , Antioxidantes , Solventes Eutéticos Profundos , Permeabilidade , Alginatos/química , Antioxidantes/química , Antioxidantes/farmacologia , Solventes Eutéticos Profundos/química , Vapor , Colina/química , Glicerol/químicaRESUMO
Urban green spaces provide multiple ecosystem services and have great influences on human health. However, the compositions and properties of urban soil are not well understood yet. In this study, soil samples were collected from 45 parks in Ningbo to investigate the relationships among soil physicochemical properties, heavy metals and bacterial communities. The results showed that soil dissolved organic matter (DOM) was of high molecular weight, high aromaticity, and low degree of humification. The contents of heavy metals were all below the China's national standard safety limit (GB 3660-2018). The bioavailability of heavy metals highly correlated with soil pH, the content of DOC, the fluorescent component, the degree of humification and the source of DOM. The most abundant genera were Gemmatimonadaceae_uncultured, Xanthobacteraceae_uncultured, and Acidothermus in all samples, which were related to nitrogen cycle and bioavailability of heavy metals. Soil pH, bioavailability of Zn, Cd, and Pb (CaCl2 extracted) were the main edaphic factors influencing bacterial community composition. It should be noted that there was no significant impact of urbanization on soil physicochemical properties and bacterial composition, but they were determined by the source of soil in urban green spaces. However, with the passage of time, the effect of urbanization on urban green spaces cannot be ignored. Overall, this study provided new insight for understanding the linkage among soil physicochemical properties, heavy metals, and bacterial communities in urban green spaces.
Assuntos
Metais Pesados , Microbiologia do Solo , Poluentes do Solo , Solo , Urbanização , Solo/química , China , Metais Pesados/análise , Poluentes do Solo/análise , Monitoramento Ambiental , BactériasRESUMO
Autophagy is a lysosome-dependent degradation pathway essential for cellular homeostasis, which decreases with age. However, it is unclear how aging induces autophagy decline. Here we show the role of protein S-palmitoylation in autophagy. We identify the palmitoyl acyltransferase DHHC5 as a regulator of autophagy by mediating the palmitoylation of beclin 1, which in turn promotes the formation of ATG14L-containing class III phosphatidylinositol-3-kinase complex I and its lipid kinase activity by promoting the hydrophobic interactions between beclin 1 and adapter proteins ATG14L and VPS15. In aging brains of human and nonhuman primate, the levels of DHHC5 exhibit a marked decrease in expression. We show that DHHC5 deficiency in neurons leads to reduced cellular protein homeostasis in two established murine models of Alzheimer's disease, which exaggerates neurodegeneration in an autophagy-dependent manner. These findings identify reduction of DHHC5-mediated beclin 1 S-palmitoylation as an underlying mechanism by which aging induces autophagy decline.