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To investigate the impact of low temperature on the quality and flavor of ripe red tomatoes, we analyzed transcriptomes and volatile metabolomes of ripe red fruits stored at 0 °C and 20 °C for 8 days. The results showed that 0 °C maintained the sugar content by increasing the expression of sucrose synthetase (SUS) and sucrose transporter (SUT). Low expression of aroma synthesis-related genes, such as alcohol dehydrogenase 1 (ADH1), amino acid decarboxylase 1 A (AADC1A), and branched-chain amino acid aminotransferase 2 (BCAT2), were associated with reduced levels of pentanal, hexanal, 3-methylbutanal, 2-methylbutanal, and 2-phenylethanol. Additionally, the expression of pectinesterase (PE), beta-galactosidase (ß-GAL), and beta-glucosidase (ß-Glu), as well as phytoene synthase1 (PSY1) involved in carotenoid synthesis, was inhibited, thereby maintaining fruits texture and color. Furthermore, storage at 0 °C induced the expression of numerous genes regulating antioxidant and heat shock proteins, which further preserved the postharvest quality of tomatoes.
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Electrogenic biofilms, which have attracted considerable attention in simultaneous wastewater treatment and energy recovery in bioelectrochemical systems, are regulated by chemical communication and potassium channel-mediated electrical signaling. However, how these two communication pathways interact with each other has not been thoroughly investigated. This study first explored the roles of chemical communication, including intracellular bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) and extracellular N-acyl-homoserine lactone (AHL)-mediated quorum sensing, in electrogenic biofilm formation through an integrated analysis of transcriptomics and metabolomics. Electrical signaling disruption inhibited the formation and electroactivity of Geobacter sulfurreducens biofilm, which was mainly ascribed to the reduction in biofilm viability and extracellular protein/polysaccharide ratio. The upregulation of expression levels of genes encoding c-di-GMP and AHL synthesis by transcriptomic analysis, and the increased secretion of N-butanoyl-L-homoserine lactone by metabolomic analysis confirmed the enhancement of chemical communication under electrical signaling disruption, thus indicating a compensatory mechanism among different signaling pathways. Furthermore, protein-protein interaction network showed the convergence of different signaling pathways, with c-di-GMP-related genes acting as central bridges. This study highlights the interaction of different signaling pathways, especially the resilience of c-di-GMP signaling to adverse external stresses, thereby laying the foundation for facilitating electrogenic biofilm formation under adverse conditions in practical applications.
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ETHNOPHARMACOLOGICAL RELEVANCE: Lindera aggregata (Sims) Kosterm is a common traditional herb that has multiple bioactivities. Radix Linderae (LR), the dry roots of Lindera aggregata (Sims) Kosterm, is a traditional Chinese herbal medicine with antioxidant, anti-inflammatory and immunomodulatory properties, first found in Kaibao Era. Norboldine (Nor) is an alkaloid extracted from LR and is one of the primary active ingredients of LR. However, the pharmacological functions and mechanism of Nor in Alzheimer's disease (AD) are still unknown. AIM OF THE STUDY: This study aims to investigate the effect and mechanism of Nor therapy in improving the cognitive impairment and pathological features of 3 × Tg mice. MATERIALS AND METHODS: 3 × Tg mice were treated with two concentrations of Nor for one month and then the memory and cognitive abilities of mice were assessed by novel object recognition experiment and Morris water maze. The impact of Nor on the pathology of ADwere examined in PC12 cells and animal tissues using western blotting and immunofluorescence. Finally, western blotting was used to verify the anti-apoptotic effect of Nor by activating AMPK/GSK3ß/Nrf2 signaling pathway at animal and cellular levels. RESULTS: In this study, we showed that Nor treatment improved the capacity of the learning and memory of 3 × Tg mice and alleviated AD pathology such as Aß deposition. In addition, Nor restored the abnormalities of mitochondrial membrane potential, significantly reduced the production of intracellular ROS and neuronal cell apoptosis. Mechanistically, we combined network pharmacology and experimental verification to show that Nor may exert antioxidant stress and anti-apoptotic through the AMPK/GSK3ß/Nrf2 signaling pathway. CONCLUSION: Our data provide some evidence that Nor exerts a neuroprotective effect through the AMPK/GSK3ß/Nrf2 pathway, thereby improving cognitive impairment in AD model mice. Natural products derived from traditional Chinese medicines are becoming increasingly popular in the process of new drug development and discovery, and our findings provide new perspectives for the discovery of improved treatment strategies for AD.
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Alcaloides , Enfermedad de Alzheimer , Disfunción Cognitiva , Lindera , Extractos Vegetales , Transducción de Señal , Animales , Masculino , Ratones , Ratas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ratones Transgénicos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Células PC12 , Transducción de Señal/efectos de los fármacos , Lindera/química , Extractos Vegetales/administración & dosificación , Alcaloides/administración & dosificaciónRESUMEN
IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1, and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.
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Autoinmunidad , Factor de Transcripción Ikaros , Células Th2 , Ubiquitina-Proteína Ligasas , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/inmunología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología , Autoinmunidad/genética , Células Th2/inmunología , Células Th2/patología , Femenino , Masculino , Enfermedad Relacionada con Inmunoglobulina G4/genética , Enfermedad Relacionada con Inmunoglobulina G4/inmunología , Enfermedad Relacionada con Inmunoglobulina G4/patología , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-fyn/genética , Proteínas Proto-Oncogénicas c-fyn/inmunología , LinajeRESUMEN
The purpose of this study was to investigate the impact of highoxygen-modified atmospheric packaging (HOMAP) on aroma changes in fresh-cut broccoli during storage and to explore its regulatory mechanisms. The results showed that HOMAP reduced the levels of undesirable aroma substances hexanoic acid, isobutyric acid, cyclopentanone and increased glucosinolate accumulation by inhibiting the expression of arogenate/prephenate dehydratase (ADT), bifunctional aspartate aminotransferase and glutamate/aspartate-prephenate aminotransferase (PAT), thiosulfate/3-mercaptopyruvate Transferase (TST) to reduce the odor of fresh-cut broccoli. HOMAP inhibited the expression of respiratory metabolism related genes 6-phosphate fructokinase 1 (PFK), pyruvate kinase (PK), and NADH-ubiquinone oxidoreductase chain 6 (ND6). In HOMAP group, the low expression of phospholipase C (PLC), phospholipase A1 (PLA1), linoleate 9S-lipoxygenase 1 (LOX1) related to lipid metabolism and the high expression of naringenin 3-dioxygenase (F3H), trans-4-Hydroxycinnamate (C4H), glutaredoxin 3 (GRX3), and thioredoxin 1 (TrX1) in the antioxidant system maintained membrane stability while reducing the occurrence of membrane lipid peroxidation.
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Brassica , Embalaje de Alimentos , Oxígeno , Brassica/química , Brassica/metabolismo , Embalaje de Alimentos/instrumentación , Oxígeno/metabolismo , Oxígeno/análisis , Gusto , Odorantes/análisis , Proteínas de Plantas/metabolismo , Aromatizantes/química , Aromatizantes/metabolismo , Almacenamiento de Alimentos , Conservación de Alimentos/métodosRESUMEN
Accurate image segmentation plays a crucial role in computer vision and medical image analysis. In this study, we developed a novel uncertainty guided deep learning strategy (UGLS) to enhance the performance of an existing neural network (i.e., U-Net) in segmenting multiple objects of interest from images with varying modalities. In the developed UGLS, a boundary uncertainty map was introduced for each object based on its coarse segmentation (obtained by the U-Net) and then combined with input images for the fine segmentation of the objects. We validated the developed method by segmenting optic cup (OC) regions from color fundus images and left and right lung regions from Xray images. Experiments on public fundus and Xray image datasets showed that the developed method achieved a average Dice Score (DS) of 0.8791 and a sensitivity (SEN) of 0.8858 for the OC segmentation, and 0.9605, 0.9607, 0.9621, and 0.9668 for the left and right lung segmentation, respectively. Our method significantly improved the segmentation performance of the U-Net, making it comparable or superior to five sophisticated networks (i.e., AU-Net, BiO-Net, AS-Net, Swin-Unet, and TransUNet).
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BACKGROUND: Photon-counting computed tomography (Photon counting CT) utilizes photon-counting detectors to precisely count incident photons and measure their energy. These detectors, compared to traditional energy integration detectors, provide better image contrast and material differentiation. However, Photon counting CT tends to show more noticeable ring artifacts due to limited photon counts and detector response variations, unlike conventional spiral CT. OBJECTIVE: To comprehensively address this issue, we propose a novel feature shared multi-decoder network (FSMDN) that utilizes complementary learning to suppress ring artifacts in Photon counting CT images. METHODS: Specifically, we employ a feature-sharing encoder to extract context and ring artifact features, facilitating effective feature sharing. These shared features are also independently processed by separate decoders dedicated to the context and ring artifact channels, working in parallel. Through complementary learning, this approach achieves superior performance in terms of artifact suppression while preserving tissue details. RESULTS: We conducted numerous experiments on Photon counting CT images with three-intensity ring artifacts. Both qualitative and quantitative results demonstrate that our network model performs exceptionally well in correcting ring artifacts at different levels while exhibiting superior stability and robustness compared to the comparison methods. CONCLUSIONS: In this paper, we have introduced a novel deep learning network designed to mitigate ring artifacts in Photon counting CT images. The results illustrate the viability and efficacy of our proposed network model as a new deep learning-based method for suppressing ring artifacts.
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Artefactos , Fantasmas de Imagen , Fotones , Tomografía Computarizada por Rayos X , Tomografía Computarizada por Rayos X/métodos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Aprendizaje Profundo , AlgoritmosRESUMEN
Bitter melon fruit is susceptible to yellowing, softening, and rotting under room-temperature storage conditions, resulting in reduced commercial value. Nitric oxide (NO) is an important signaling molecule and plays a crucial role in regulating the fruit postharvest quality. In this study, we investigated the effects of NO treatment on changes in sensory and firmness of bitter melon fruit during postharvest storage. Moreover, transcriptomic, metabolomic, and proteomic analyses were performed to elucidate the regulatory mechanisms through which NO treatment delays the ripening and senescence of bitter melon fruit. Our results show that differentially expressed genes (DEGs) were involved in fruit texture (CSLE, ß-Gal, and PME), plant hormone signal transduction (ACS, JAR4, and AUX28), and fruit flavor and aroma (SUS2, LOX, and GDH2). In addition, proteins differentially abundant were associated with fruit texture (PLY, PME, and PGA) and plant hormone signal transduction (PBL15, JAR1, and PYL9). Moreover, NO significantly increased the abundance of key enzymes involved in the phenylpropanoid biosynthetic pathway, thus enhancing the disease resistance and alleviating softening of bitter melon fruit. Finally, differential metabolites mainly included phenolic acids, terpenoids, and flavonoids. These results provide a theoretical basis for further studies on the physiological changes associated with postharvest ripening and senescence of bitter melon fruit. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-023-00110-y.
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Hydrogel is a very promising dressing for hemostasis and wound healing due to its good adhesion and long-term moist environment. However, secondary injury caused by tissue adhesion due to homogeneous hydrogel cannot be ignored. The obvious interface existing in Janus hydrogel will weaken its asymmetric function. Here, a hierarchical adhesive polyacrylic acid-polyurushiol water-oil Janus hydrogel (JPs@PAA-PU) without adhesive layer is fabricated by one-pot method in the stabilization of polystyrene@silica-siliver Janus particles (JPs). The morphological structure, mechanical properties, anisotropic chemical composition, and adhesion performance, in vivo, and in vitro hemostatic properties of Janus hydrogel are investigated. Result shows that the obtained Janus hydrogel possesses obvious compartmentalization in microstructure, functional groups, and chemical elements. Janus hydrogel is provided with asymmetric interfacial toughness with top 52.45 ± 2.29 Kpa and bottom 7.04 ± 0.88 Kpa on porcine liver. The adhesion properties of PAA side to tissue, red blood cells and platelets, promoting effect of PU side on coagulation cascade reaction and its physical battier endow Janus hydrogel with shorter hemostatic time and less blood loss than control group. It also exhibits excellent antibacterial effects against Escherichia coli and Staphylococcus aureus (>90%). Janus hydrogel possesses biosafety, providing safety guarantee for clinical applications in the future.
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Resinas Acrílicas , Hidrogeles , Animales , Hidrogeles/química , Hidrogeles/farmacología , Resinas Acrílicas/química , Escherichia coli/efectos de los fármacos , Hemostasis/efectos de los fármacos , Porcinos , Hemostáticos/química , Hemostáticos/farmacología , Staphylococcus aureus/efectos de los fármacos , Ratones , Antibacterianos/química , Antibacterianos/farmacologíaRESUMEN
The cultured meat technology has developed rapidly in recent years, but there are still many technical challenges that hinder the large-scale production and commercialization of cultured meat. Firstly, it is necessary to lay the foundation for cultured meat production by obtaining seed cells and maintaining stable cell functions. Next, technologies such as bioreactors are used to expand the scale of cell culture, and three-dimensional culture technologies such as scaffold culture or 3D printing are used to construct the three-dimensional structure of cultured meat. At the same time, it can reduce production costs by developing serum-free medium suitable for cultured meat. Finally, the edible quality of cultured meat is improved by evaluating food safety and sensory flavor, and combining ethical and consumer acceptability issues. Therefore, this review fully demonstrates the current development status and existing technical challenges of the cultured meat production technology with regard to the key points described above, in order to provide research ideas for the industrial production of cultured meat.
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N4-acetylcytidine (ac4C) modification of mRNA has been shown to be present in plant RNAs, but its regulatory function in plant remains largely unexplored. In this study, we investigated the differentially expressed mRNAs, lncRNAs and acetylation modifications of mRNAs in tomato fruits from both genotypes. By comparing wild-type (AC) tomato and the ethylene receptor-mutant (Nr) tomato from mature green (MG) to six days after the breaker (Br6) stage, we identified differences in numerous key genes related to fruit ripening and observed the corresponding lncRNAs positively regulated the target genes expression. At the post-transcriptional level, the acetylation level decreased and increased in AC and Nr tomatoes from MG to Br6 stage, respectively. The integrated analysis of RNA-seq and ac4C-seq data revealed the potential positive role of acetylation modification in regulating gene expression. Furthermore, we found differential acetylation modifications of certain transcripts (ACO, ETR, ERF, PG, CesA, ß-Gal, GAD, AMY, and SUS) in AC and Nr fruits which may explain the differences in ethylene production, fruit texture, and flavor during their ripening processes. The present study provides new insights into the molecular mechanisms by which acetylation modification differentially regulates the ripening process of wild-type and mutant tomato fruits deficient in ethylene signaling.
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INTRODUCTION: Apricot (Prunus armeniaca L.) fruits are highly perishable and prone to quality deterioration during storage and transportation. OBJECTIVES: To investigate the effects of LED white light treatment on postharvest ripening of fruits using metabolomics, transcriptomics, and ATAC-Seq analysis. METHODS: Fruits were exposed to 5 µmol m-2 s-1 LED white light for 12 h followed by 12 h of darkness at 20 °C daily for 12 days. The effects of the treatments on the physiological and nutritional quality of the fruits were evaluated. These data were combined with transcriptomic, metabolomic, and ATAC-Seq data from fruits taken on 8 d of treatment to provide insight into the potential mechanism by which LED treatment delays ripening. RESULTS: LED treatment activated pathways involved in ascorbate and aldarate metabolism and flavonoid and phenylpropanoid biosynthesis. Specifically, LED treatment increased the expression of UDP-sugar pyrophosphorylase (USP), L-ascorbate peroxidase (AO), dihydroflavonol 4-reductase (DFR), chalcone synthase (CHS), and caffeoyl-CoA O-methyltransferase (CCOAOMT1), leading to the accumulation of caffeoyl quinic acid, epigallocatechin, and dihydroquercetin and the activation of anthocyanin biosynthesis. LED treatment also affected the expression of genes associated with plant hormone signal transduction, fruit texture and color transformation, and antioxidant activity. The notable genes affected by LED treatment included 1-aminocyclopropane-1-carboxylate synthase (ACS), 1-aminocyclopropane-1-carboxylate oxidase (ACO), hexokinase (HK), lipoxygenase (LOX), malate dehydrogenase (MDH), endoglucanase (CEL), various transcription factors (TCP, MYB, EFR), and peroxidase (POD). ATAC-Seq analysis further revealed that LED treatment primarily regulated phenylpropanoid biosynthesis. CONCLUSION: The results obtained in this study provide insights into the effects of LED light exposure on apricot fruits ripening. LEDs offer a promising approach for extending the shelf life of other fruits and vegetables.
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RATIONALE: Methamphetamine (METH) exposure has toxicity in sperm epigenetic phenotype and increases the risk for developing addiction in their offspring. However, the underlying transgenerational mechanism remains unclear. OBJECTIVES: The current study aims to investigate the profiles of sperm epigenetic modifications in male METH-exposed mice (F0) and medial prefrontal cortex (mPFC) transcriptome in their male first-generation offspring (F1). METHODS: METH-related male F0 and F1 mice model was established to investigate the effects of paternal METH exposure on reproductive functions and sperm DNA methylation in F0 and mPFC transcriptomic profile in F1. During adulthood, F1 was subjected to a conditioned place preference (CPP) test to evaluate sensitivity to METH. The gene levels were verified with qPCR. RESULTS: METH exposure obviously altered F0 sperms DNA methylated profile and male F1 mPFC transcriptomic profile, many of which being related to neuronal system and brain development. In METH-sired male F1, subthreshold dose of METH administration effectively elicited CPP, along with more mPFC activation. After qPCR verification, Sort1 and Shank2 were at higher levels in F0 sperm and F1 mPFC. CONCLUSIONS: Our findings put new insights into paternal METH exposure-altered profiles of F0 sperm DNA methylation and male F1 mPFC transcriptomics. Several genes, such as Sort1 and Shank2, might be used as potential molecules for further research on the transgenerational vulnerability to drug addiction in offspring by paternal drug exposure.
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The small chemical N-1-naphthylphthalamic acid (NPA) has long been used as a polar auxin transport inhibitor. Recent biochemical and structural investigations have revealed that this molecule competes with the auxin IAA (indole-3-acetic acid) inside the PIN-FORMED auxin efflux carriers. However, the existence of any mutations in PIN family proteins capable of uncoupling the docking of IAA from NPA remains unclear. We report that Arabidopsis thaliana seedlings overexpressing SMALL AUXIN UP RNA 41 were hypersensitive to NPA-induced root elongation inhibition. We mutagenized this line to improve the genetic screening efficiency for NPA hyposensitivity mutants. Using bulked segregation analysis and mapping-by-sequencing assessment of these mutants, we identified a core genetic pathway for NPA-induced root elongation inhibition, including genes required for auxin biosynthesis, transportation, and signaling. To evaluate specific changes of auxin signaling activity in mutant roots before and after NPA treatment, the DR5::GFP/DR5::YFP markers were introduced and observed. Most importantly, we discovered a unique mutation in the PIN1 protein, substituting a proline residue with leucine at position 584, leading to a loss of NPA sensitivity while keeping the auxin efflux capacity. Transforming the null mutant pin1-201 with the PIN1::PIN1P584L -GFP fusion construct rescued the PIN1 function and provided NPA hyposensitivity. The proline residue is predicted to be adjacent to a hinge in the middle region of the ninth transmembrane helix of PIN1 and is conserved from moss to higher plants. Our work may bring new insights into the engineering of NPA-resistant PINs for auxin biology studies.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Transporte Biológico , Ácidos Indolacéticos/metabolismo , Mutación/genética , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , Prolina/metabolismoRESUMEN
This paper conducts a systematic statistical analysis of the characteristics of the geographical empirical distributions for the numbers of both cumulative and daily confirmed COVID-19 cases and deaths at county, city, and state levels over a time span from January 2020 to June 2022. The mathematical heavy-tailed distributions can be used for fitting the empirical distributions observed in different temporal stages and geographical scales. The estimations of the shape parameter of the tail distributions using the Generalized Pareto Distribution also support the observations of the heavy-tailed distributions. According to the characteristics of the heavy-tailed distributions, the evolution course of the geographical empirical distributions can be divided into three distinct phases, namely the power-law phase, the lognormal phase I, and the lognormal phase II. These three phases could serve as an indicator of the severity degree of the COVID-19 pandemic within an area. The empirical results suggest important intrinsic dynamics of a human infectious virus spread in the human interconnected physical complex network. The findings extend previous empirical studies and could provide more strict constraints for current mathematical and physical modeling studies, such as the SIR model and its variants based on the theory of complex networks.
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COVID-19 , Humanos , COVID-19/epidemiología , Pandemias , Modelo TransteóricoRESUMEN
We present a new, simulation-based inference method to compute the angular power spectrum of the distribution of foreground gravitational-wave transient events. As a first application of this method, we use the binary black hole mergers observed during the LIGO, Virgo, and KAGRA third observation run to test the spatial distribution of these sources. We find no evidence for anisotropy in their angular distribution. We discuss further applications of this method to investigate other gravitational-wave source populations and their correlations to the cosmological large-scale structure.
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Paternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism remains poorly understood. Male adult mice (F0) were exposed to METH for 30 days, followed by mating with naïve female mice to create the first-generation mice (F1). When growing to adulthood, F1 were subjected to conditioned place preference (CPP) test. Subthreshold dose of METH (sd-METH), insufficient to induce CPP normally, were used in F1. Selective antagonist (betaxolol) for ß1-adrenergic receptor (ADRB1) or its knocking-down virus were administrated into mPFC to regulate ADRB1 function and expression on CaMKII-positive neurons. METH-sired male F1 acquired sd-METH-induced CPP, indicating that paternal METH exposure induce higher sensitivity to METH in male F1. Compared with saline (SAL)-sired male F1, CaMKII-positive neuronal activity was normal without sd-METH, but strongly evoked after sd-METH treatment in METH-sired male F1 during adulthood. METH-sired male F1 had higher ADRB1 levels without sd-METH, which was kept at higher levels after sd-METH treatment in mPFC. Either inhibiting ADRB1 function with betaxolol, or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1CaMKII) with virus transfection efficiently suppressed sd-METH -evoked mPFC activation, and ultimately blocked sd-METH-induced CPP in METH-sired male F1. In the process, the p-ERK1/2 and ΔFosB may be potential subsequent signals of mPFC ADRB1CaMKII. The mPFC ADRB1CaMKII mediates paternal METH exposure-induced higher sensitivity to drug addiction in male offspring, raising a promising pharmacological target for predicting or treating transgenerational addiction.
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Estimulantes del Sistema Nervioso Central , Metanfetamina , Masculino , Femenino , Ratones , Animales , Metanfetamina/farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Betaxolol , Fosforilación , Estimulantes del Sistema Nervioso Central/farmacologíaRESUMEN
The dendritic cell (DC) vaccine is a promising cancerimmunotherapy strategy, but its efficacy in treating the solid tumor is limited. To overcome this limitation, an oncolytic adenovirus (OAV-IL-12) was developed to enhance antigen targeting ability of adenovirus-assembled DC vaccine (DCs-CD137L/CAIX) for renal carcinoma treatment. Peritumoral administration of OAV-IL-12 increased the number of tumor-infiltrating DCs and their subsets (CD8+DCs and CD103+DCs). Combining OAV-IL-12 with DCs-CD137L/CAIX significantly inhibited the growth of subcutaneous tumors by inducing potent cytotoxic T lymphocyte (CTL) effect and improving the immune infiltration in tumor lesions. Interestingly, this treatment also reduced tumor growth distal to the OAV-IL-12 injecting side via eliciting a systemic CTL response. Furthermore, OAV-IL-12 potentiated DCs-CD137L/CAIX treatment induced dual CTL responses against both CAIX and adenovirus antigens. The therapeutic benefits of this treatment approach mainly relied on multifunctional CD8+T cell immune responses, as indicated by the depletion assay. Moreover, OAV-IL-12 potentiated DCs-CD137L/CAIX treatment generated a long-lasting protective effect against tumors by inducing memory CD8+T cell immune responses. These results suggest that the effective tumor targeting of the adenovirus-based DC vaccine, boosted by OAV-IL-12, is a promising treatment approach for renal carcinoma and other solid tumors.
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Carcinoma de Células Renales , Neoplasias Renales , Vacunas , Humanos , Linfocitos T Citotóxicos , Adenoviridae/genética , Carcinoma de Células Renales/terapia , Antígenos de Neoplasias , Interleucina-12 , Neoplasias Renales/terapia , Células DendríticasRESUMEN
Immune-based checkpoint therapy has made significant progress in cancer treatment, but its therapeutic effect is limited. A replication-defective adenovirus (Ad) vaccine encoding tumor antigen carbonic anhydrase IX (CAIX) combined with Ad-encoding immune checkpoint PD-L1 was developed to treat renal carcinoma. Three tumor models, subcutaneous, lung metastasis and orthotopic tumor were established, and Ad vaccines were used to immunize them and evaluate the vaccine's therapeutic effect. Compared to the single Ad vaccine group, the subcutaneous tumor growth was significantly reduced in Ad-CAIX/Ad-PD-L1 combination group. Co-immunization of Ad-CAIX/Ad-PD-L1 enhanced the induction and maturation of CD11c+ or CD8+CD11c+ DCs in the spleen and tumor and promoted the strong tumor-specific CD8+ T cell immune responses. In vivo CD8 T cell deletion assay showed that the anti-tumor effect of the Ad-CAIX/Ad-PD-L1 vaccine was mainly dependent on functional CD8+ T cell immune responses. Furthermore, the Ad-CAIX/Ad-PD-L1 vaccine effectively inhibited tumor growth and lung metastasis in metastatic or orthotopic models. These results indicate that the combination strategy of the immune checkpoint vaccine shows promising potential as an approach for malignant tumor therapy.
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Evidence is emerging that the process of immune aging is a mechanism leading to autoimmunity. Over lifetime, the immune system adapts to profound changes in hematopoiesis and lymphogenesis, and progressively restructures in face of an ever-expanding exposome. Older adults fail to generate adequate immune responses against microbial infections and tumors, but accumulate aged T cells, B cells and myeloid cells. Age-associated B cells are highly efficient in autoantibody production. T-cell aging promotes the accrual of end-differentiated effector T cells with potent cytotoxic and pro-inflammatory abilities and myeloid cell aging supports a low grade, sterile and chronic inflammatory state (inflammaging). In pre-disposed individuals, immune aging can lead to frank autoimmune disease, manifesting with chronic inflammation and irreversible tissue damage. Emerging data support the concept that autoimmunity results from aging-induced failure of fundamental cellular processes in immune effector cells: genomic instability, loss of mitochondrial fitness, failing proteostasis, dwindling lysosomal degradation and inefficient autophagy. Here, we have reviewed the evidence that malfunctional mitochondria, disabled lysosomes and stressed endoplasmic reticula induce pathogenic T cells and macrophages that drive two autoimmune diseases, rheumatoid arthritis (RA) and giant cell arteritis (GCA). Recognizing immune aging as a risk factor for autoimmunity will open new avenues of immunomodulatory therapy, including the repair of malfunctioning mitochondria and lysosomes.