Search

Doxorubicin (DOX) is a chemotherapeutic drug for a variety of malignancies, while its application is restricted by the cardiovascular toxic effects characterized by oxidative stress. Ferroptosis is a novel iron-dependent regulated cell death driven by lipid peroxidation. Our study aimed to investigate the role of Elabela (ELA) in DOX-induced oxidative stress and ferroptosis. In cultured rat aortic adventitial fibroblasts (AFs), stimulation with DOX dramatically induced cytotoxicity with reduced cell viability and migration ability, and enhanced lactate dehydrogenase (LDH) activity. Importantly, ELA and ferrostatin-1 (Fer-1) mitigated DOX-mediated augmentation of reactive oxygen species (ROS) in rat aortic AFs, accompanied by upregulated levels of Nrf2, SLC7A11, GPX4, and GSH. In addition, ELA reversed DOX-induced dysregulation of apoptosis- and inflammation-related factors including Bax, Bcl2, interleukin (IL)-1β, IL6, IL-10, and CXCL1. Intriguingly, knockdown of Krüppel-like factor 15 (KLF15) by siRNA abolished ELA-mediated alleviation of ROS production and inflammatory responses. More importanly, KLF15 siRNA impeded the beneficial roles of ELA in DOX-pretreated rat aortic AFs by suppressing the Nrf2/SLC7A11/GPX4 signaling. In conclusion, ELA prevents DOX-triggered promotion of cytotoxicity, and exerts anti-oxidative and anti-ferroptotic effects in rat aortic AFs via activation of the KLF15/GPX4 signaling, indicating a promising therapeutic value of ELA in antagonizing DOX-mediated cardiovascular abnormality and disorders.

Advanced glycation end products (AGEs) have been identified to transduce fibrogenic signals via inducing the activation of their receptor (RAGE)-mediated pathway. Recently, disrupting AGE-RAGE interaction has become a promising therapeutic strategy for chronic heart failure (CHF). Endothelial-to-mesenchymal transition (EndMT) is close to the cardiac fibrosis pathological process. Our previous studies have demonstrated that knockout RAGE suppressed the autophagy-mediated EndMT, and thus alleviated cardiac fibrosis. Plantamajoside (PMS) is the major bioactive compound of Plantago Asiatica, and its activity of anti-fibrosis has been documented in many reports. However, its effect on CHF and the underlying mechanism remains elusive. Thus, we tried to elucidate the protective role of PMS in CHF from the viewpoint of the AGEs/RAGE/autophagy/EndMT axis. Herein, PMS was found to attenuate cardiac fibrosis and dysfunction, suppress EndMT, reduce autophagy levels and serum levels of AGEs, yet did not affect the expression of RAGE in CHF mice. Mechanically, PMS possibly binds to the V-domain of RAGE, which is similar to the interaction between AGEs and RAGE. Importantly, this competitive binding disturbed AGEs-induced the RAGE-autophagy-EndMT pathway in vitro. Collectively, our results indicated that PMS might exert an anti-cardiac fibrosis effect by specifically binding RAGE to suppress the AGEs-activated RAGE/autophagy/EndMT pathway.

Hypertension is one of the leading causes of chronic kidney disease characterized with renal fibrosis. This study aimed to investigate roles and mechanisms of sirtuin 7 (SIRT7) in hypertensive renal injury. Mini-pumps were implanted to male C57BL/6 mice to deliver angiotensin (Ang) Ⅱ (1.5 mg/kg/d) or saline for 2 weeks. Ang Ⅱ infusion resulted in marked increases in systolic blood pressure levels, renal ferroptosis and interstitial fibrosis in hypertensive mice, concomitantly with downregulated SIRT7 and Krüppel-like factor 15 (KLF15) levels. Notably, administration of recombinant adeno-associated virus-SIRT7 or ferroptosis inhibitor ferrostatin-1 effectively mitigated Ang Ⅱ-triggered renal ferroptosis, epithelial-mesenchymal transition (EMT), interstitial fibrosis, renal functional and structural injury in hypertensive mice by blunting the KIM-1/NOX4 signaling and enforcing the KLF15/Nrf2 and xCT/GPX4 signaling, respectively. In primary cultured mouse renal tubular epithelial cells (TECs), Ang Ⅱ pretreatment led to repressed SIRT7 expression and augmented ferroptosis as well as partial EMT, which were substantially antagonized by rhSIRT7 or ferrostatin-1 administration. Additionally, both Nrf2 inhibitor ML385 and KLF15 siRNA strikingly abolished the rhSIRT7-mediated beneficial roles in mouse renal TECs in response to Ang Ⅱ with reduced expression of Nrf2, xCT and GPX4. More importantly, ML385 administration remarkably amplified Ang Ⅱ-mediated ROS generation, lipid peroxidation and ferroptosis in renal TECs, which were significantly reversed by ferrostatin-1. In conclusion, SIRT7 alleviates renal ferroptosis, lipid peroxidation, and partial EMT under hypertensive status by facilitating the KLF15/Nrf2 signaling, thereby mitigating renal fibrosis, injury and dysfunction. Targeting SIRT7 signaling serves as a promising strategy for hypertension and hypertensive renal injury.

Circular RNAs (circRNAs) are key regulators in tumor metastasis and drug resistance. This study was designed to investigate circ_0082182 function and mechanism in oxaliplatin (OXA) resistance and cancer progression of colorectal cancer (CRC). The circ_0082182, microRNA-326 (miR-326), and nuclear factor I B (NFIB) levels were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell sensitization was analyzed by Cell Counting Kit-8 assay. The proliferation ability was determined via EdU assay, and apoptosis was measured by flow cytometry. Transwell assay and wound healing assay were performed to assess cell invasion and migration. The protein level was examined through Western blot. The binding interaction was conducted via dual-luciferase reporter assay. Xenograft tumor assay was used to explore the circ_0082182 function in vivo. The circ_0082182 level was upregulated in OXA-resistant CRC samples and cells. Downregulation of circ_0082182 suppressed OXA resistance, proliferation, invasion, and migration but promoted apoptosis of OXA-resistant CRC cells. Circ_0082182 acted as a sponge for miR-326. The regulatory role of circ_0082182 was ascribed to the miR-326 sponging function. MiR-326 directly targeted NFIB to impede OXA resistance and cancer progression in CRC cells. NFIB level was regulated by circ_0082182 via sponging miR-326. Circ_0082182 promoted tumor growth in OXA-resistant xenograft tumor model through mediating the miR-326/NFIB axis. These data suggested that circ_0082182 elevated the NFIB expression to regulate OXA resistance and CRC progression by absorbing miR-326.

In multicellular eukaryotes, autophagy is a conserved process that delivers cellular components to the vacuole or lysosome for recycling during development and stress responses. Induction of autophagy activates AUTOPHAGY-RELATED PROTEIN 1 (ATG1) and ATG13 to form a protein kinase complex that initiates autophagosome formation. However, the detailed molecular mechanism underlying the regulation of this protein complex in plants remains unclear. Here, we determined that in Arabidopsis thaliana, the regulatory proteins 14-3-3λ and 14-3-3κ redundantly modulate autophagy dynamics by facilitating SEVEN IN ABSENTIA OF ARABIDOPSIS THALIANA (SINAT)-mediated proteolysis of ATG13a and ATG13b. 14-3-3λ and 14-3-3κ directly interacted with SINATs and ATG13a/b in vitro and in vivo. Compared to wild-type (WT), the 14-3-3λ 14-3-3κ double mutant showed increased tolerance to nutrient starvation, delayed leaf senescence, and enhanced starvation-induced autophagic vesicles. Moreover, 14-3-3s were required for SINAT1-mediated ubiquitination and degradation of ATG13a. Consistent with their roles in ATG degradation, the 14-3-3λ 14-3-3κ double mutant accumulated higher levels of ATG1a/b/c and ATG13a/b than the WT upon nutrient deprivation. Furthermore, the specific association of 14-3-3s with phosphorylated ATG13a was crucial for ATG13a stability and formation of the ATG1–ATG13 complex. Thus, our findings demonstrate that 14-3-3λ and 14-3-3κ function as molecular adaptors to regulate autophagy by modulating the homeostasis of phosphorylated ATG13.

Purpose To retrospectively evaluate breast magnetic resonance imaging (MRI)-based machine learning (ML) model that can preoperatively predict lymphovascular invasion (LVI) status in invasive breast cancer patients with negative axillary lymph nodes (LNs). Methods We retrospectively enrolled 280 patients who underwent pre-operative breast MRI and were confirmed with invasive breast cancer by surgical pathology, with absence of axillary LN metastasis. This cohort included 148 LVI-positive lesions and 141 LVI-negative lesions, randomly divided (7:3) into training and validation cohort. The tumor segmentation from the first postcontrast dynamic contrast-enhanced (DCE)-MRI was semi-automatically implemented using 3D Slicer 5.1.0 software, and radiomics features of each lesion were extracted. Least absolute shrinkage and selection operator (LASSO) regression method was used to select the significant radiomics features, and five different ML algorithms were used to build models. A clinical model was also built and integrated with the radiomics models. The predictive performance of models were evaluated by discrimination and compared using DeLong test. Results A total of 4 clinico‑radiological parameters and 10 selected radiomics features were selected for model construction. The RF model that was built based on the radiomics and clinico‑radiological feature information exhibited the best predictive performance, yielding high AUC (0.97 for train and 0.82 for validation, respectively). The integrated model significantly outperformed the clinical model, whereas showed no significant difference from the radiomics model. Conclusions The RF model integrating radiomics features with clinical information facilitate LVI detection in invasive breast cancer patient with negative axillary LNs preoperatively, which was valuable for clinical decision-making.

With the continuous development of China’s economy, the process of urbanisation and industrialisation has been accelerating, and coupled with the emergence of new energy, China’s urban energy consumption has undergone huge transformation. The urban energy Internet (UEI) is an important part of the country’s ‘carbon peak and carbon neutrality’, and it is also one of the key tasks in the planning, construction and operation of the power grid transformation. The traditional grid-side planning model relies on a single deterministic planning method, and there is less consideration for new influencing factors, which has been difficult to meet the energy demand in the context of the energy Internet. In this paper, research on UEI planning based on the fuzzy synthesis method is proposed. First, the basic architectural model of UEI is constructed. At the same time, the impact of distributed generation, energy storage, demand response, communication and other key technologies on the planning of active distribution networks in the distribution network planning under the UEI is analysed. Then, a fuzzy comprehensive method is proposed to calculate the weight of UEI planning. Finally, the planning and research of UEI prospects from the aspects of equipment form, system planning, operation control, business model and collaborative development are discussed.

Distribution network planning is an important task in the process of power grid construction and development. Scientific and rational planning is the key factor for the economic construction and reliable operation of the power grid. Aiming at the difficulty in quantifying the weight of distribution network planning schemes, a comprehensive evaluation method of distribution network planning schemes based on the interval-valued intuitionistic fuzzy analytic hierarchy process method is proposed. First, a comprehensive evaluation index system is established from the four aspects of power supply, namely reliability, economy, power supply quality and safety of the distribution network. Then, a comprehensive evaluation method of electricity reliability optimised by entropy weight method is adopted by analytic hierarchy process, which considers both subjective situation and objective weighting. At the same time, the comprehensive weight of the aggregation of the criterion layer and the scheme layer is calculated. Finally, the link between the aggregation matrix and the index weights of the criterion layer is used to calculate the weights of the scheme layer so that they can be sorted out. The experimental results show that the effectiveness and feasibility of the planning and analysis indicators and evaluation methods of the method proposed in this paper are verified by a numerical example.

PDF - 1267KB, The established MCL cell lines, JVM-2, JVM-13, MAVER, NCEB-1, and Z-138 were treated with 20 nM CFZ for 0, 6, 12, or 24 hours and apoptosis was detected by Annexin V-binding assays. Representative histograms (left panel) and percentages of apoptotic cells (right panel) are shown.

Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse after treatment with current existing therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the therapeutic effect and mechanism of carfilzomib, a novel long-acting second-generation proteasome inhibitor, in MCL cells. We found that carfilzomib induced growth inhibition and apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition, carfilzomib inhibited the growth and survival signaling pathways NF-κB and STAT3. Interestingly, we discovered that expression of immunoproteasome (i-proteasome) subunits is required for the anti-MCL activity of carfilzomib in MCL cells. In MCL-bearing SCID mice/primary MCL-bearing SCID-hu mice, intravenous administration of 5 mg/kg carfilzomib on days 1 and 2 for 5 weeks slowed/abrogated tumor growth and significantly prolonged survival. Our preclinical data show that carfilzomib is a promising, potentially less toxic treatment for MCL. Furthermore, an intact i-proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-proteasome could serve as a biomarker for identifying patients who will benefit from carfilzomib. Mol Cancer Ther; 12(11); 2494–504. ©2013 AACR.

Background and ObjectivesWhether acupuncture is effective for chronic tension-type headache (CTTH) is inconclusive. We aimed to examine the effectiveness of acupuncture with a follow-up period of 32 weeks.MethodsWe conducted a randomized controlled trial, and 218 participants who were diagnosed with CTTH were recruited from June 2017 to September 2020. The participants in the intervention group received 20 sessions of true acupuncture (TA) over 8 weeks. The acupuncture treatments were standardized across participants, and each acupuncture site was needled to achieve deqi sensation. Each treatment session lasted 30 minutes. The participants in the control group received the same sessions and treatment frequency as those in the superficial acupuncture (SA) group—defined as a type of sham control by avoiding deqi sensation at each acupuncture site. The main outcome was the responder rate at 16 weeks after randomization (week 16) and was followed up at week 32. A responder was defined as a participant who reported at least a 50% reduction in the monthly number of headache days (MHDs).ResultsOur study included 218 participants (mean age: 43.1 years, mean disease duration: 130 months, MHDs: 21.5 days). The responder rate was 68.2% in the TA group (n = 110) vs 48.1% in the SA group (n = 108) at week 16 (OR, 2.65; 95% CI, 1.5 to 4.77; p < 0.001); and it was 68.2% in the TA group vs 50% in the SA group at week 32 (OR, 2.4; 95%CI, 1.36 to 4.3; p < 0.001). The reduction in MHDs was 13.1 ± 9.8 days in the TA group vs 8.8 ± 9.6 days in the SA group at week 16 (mean difference, 4.3 days; 95%CI, 2.0 to 6.5; p < 0.001), and the reduction was 14 ± 10.5 days in the TA group vs 9.5 ± 9.3 days in the SA group at week 32 (mean difference, 4.5 days; 95%CI, 2.1 to 6.8; p < 0.001). Four mild adverse events were reported; 3 in the TA group vs 1in the SA group.DiscussionThe 8-week TA treatment was effective for the prophylaxis of CTTH. Further studies might focus on the cost-effectiveness of the treatment.Trial Registration InformationClinicalTrials.gov: NCT03133884 (clinicaltrials.gov/ct2/show/NCT03133884).Classification of EvidenceThis study provides Class I evidence that acupuncture (achieving deqi sensation) reduces the mean headache days (per month) in patients with CTTH.

BACKGROUND: SQUAMOSA promoter binding protein-like (SPL) proteins are a class of plant-specific transcription factors that play important roles in plant development. However, the majority of SPL genes in strawberry are functionally uncharacterized. OBJECTIVE: To understand the biological functions and elucidate the molecular regulatory mechanisms of SPL genes in strawberry development. METHODS: The FvSPL1 gene from woodland strawberry was cloned and the phylogenetic tree was analyzed using bioinformatics methods. Subcellular localization, transcriptional activity, DNA binding ability and regulatory mechanisms of FvSPL1 were analyzed through biochemical and genetic approaches. RESULTS: Phylogenetic analysis with SPL genes from Arabidopsis, tomato and chrysanthemum indicated that FvSPL1 clustered in the same group as those of the miR156 target site located at the 3′-untranslated region. Further biochemical analysis indicated that FvSPL1 was exclusively localized in the nucleus. Electrophoretic mobility shift assay demonstrated that FvSPL1 could specifically recognize the GTAC motif. Transcriptional activity analysis showed that FvSPL1 is a transcriptional activator that could activate the expression of the FvAP1 gene. Finally, transgenic Arabidopsis overexpressing the FvSPL1 gene exhibited significantly early flowering. Taken together, our study indicated that FvSPL1, similar to its orthologs in Arabidopsis, mainly functions in regulating plant flowering. CONCLUSIONS: These findings provide insight into the mechanism of flowering in strawberry, and contribute to the understanding of strawberry flowering time manipulation which will facilitate the molecular breeding of strawberries.

To investigate the effect of erythropoietin (EPO) on the differentiation of neural stem cells (NSCs)/neural progenitors (NPs) in the treatment of hypoxic-ischemic injury and its potential mechanisms.Fetal NSCs/NPs were treated with EPO after oxygen and glucose deprivation/reoxygenation (OGD/R). Cell viability, proliferation, and differentiation of NSCs/NPs were detected by CellTiter-Glo, Edu assay, flow cytometry, and quantitative real-time PCR (qPCR). Immunofluorescence staining, co-immunoprecipitation (Co-IP), and western blotting were used to test the existence of EPO receptor/β common receptor (EPOR/βCR) heterodimer on NSCs/NPs and the possible pathway.EPO treatment at different time points increased cell viability without affecting proliferation. EPO treatment immediately after OGD/R promoted oligodendrocyte and astrocyte differentiation, while decreasing neuronal differentiation of NSCs/NPs. EPOR/βCR heterodimer existed on the cell surface of the fetal cortical NSCs/NPs, EPO treatment significantly increased the mRNA expression of βCR and elevated the correlation between EPOR and βCR levels. In addition, mass spectrometry analysis identified Syne-1 as a downstream signaling molecule of the EPOR/βCR heterodimer. Immunofluorescence staining and western blotting indicated that the βCR/Syne-1/H3K9me3 pathway was possibly involved in the differentiation of fetal neural stem cells into the glial cell effect of EPO.EPO treatment immediately after OGD/R could not facilitate fetal NSCs/NPs neurogenesis but promoted the formation of the EPOR/βCR heterodimer on fetal NSCs/NPs, which mediates its function in glial differentiation.

Long-term spaceflight has been proved to cause physical impairments such as motor, cardiovascular and endocrine functions in astronauts. But psychological effects such as mood and social interaction are less well understood. Besides, there are conflicting accounts of their effects on cognitive function. Thus in this study, we exposed mice (18-21 g) to 28-day simulate microgravity and social isolation (SM+SI) and examined its effects on mood, social interaction and cognitive function. We found that four weeks of SM+SI exposure resulted in emotional and specific social barriers, which may be associated with loss of neurons and decreased dendritic spine density in the medial prefrontal cortex. Unexpectedly, SM+SI enhanced the short and long-term cognitive abilities of mice, which may be related to the anti-apoptotic effect of SM+SI regulating the level of apoptotic factors in the hippocampus. These results indicates that SM+SI, as chronic stressor, can induce the body to establish effective coping strategies to enhance individuals' cognitive ability; on the other hand, long-term exposure to SM+SI causes emotional/social barriers. This study further demonstrates SM+SI causes different effects in a brain-region specific manner. Current findings provide a theoretical basis for understanding how SM+SI acts on the brain structure to influence mental health, and may be useful for designing effective prevention for those, including the astronauts, exposed to microgravity.

Many regulators controlling arterial identity are well described; however, transcription factors that promote vein identity and vascular patterning have remained largely unknown. We previously identified the transcription factors Islet2 (Isl2) and Nr2f1b required for specification of the vein and tip cell identity mediated by notch pathway in zebrafish. However, the interaction between Isl2 and Nr2f1b is not known. In this study, we report that Nr2f2 plays minor roles on vein and intersegmental vessels (ISV) growth and dissect the genetic interactions among the three transcription factors Isl2, Nr2f1b, and Nr2f2 using a combinatorial knockdown strategy. The double knockdown of isl2/nr2f1b, isl2/nr2f2, and nr2f1b/nr2f2 showed the enhanced defects in vasculature including less completed ISV, reduced veins, and ISV cells. We further tested the genetic relationship among these three transcription factors. We found isl2 can regulate the expression of nr2f1b and nr2f2, suggesting a model where Isl2 functions upstream of Nr2f1b and Nr2f2. We hypothsized that Isl2 and Nr2f1b can function together through cis-regulatory binding motifs. In-vitro luciferase assay results, we showed that Isl2 and Nr2f1b can cooperatively enhance gene expression. Moreover, co-immunoprecipitation results indicated that Isl2 and Nr2f1b interact physically. Together, we showed that the interaction of the Nr2f1b and Nr2f2 transcription factors in combination with the Islet2 play coordinated roles in the vascular development of zebrafish.

In recent years, glycyrrhetinic acid (GA) has been popularly used in cosmetics because of its anti-inflammatory and anti-oxidant effects. However, due to the poor water solubility of GA and the barrier effect of human skin, the penetration of GA through the skin may be hindered. Liposomes are a common delivery system for functional compounds in cosmetics. Nonetheless, the stability and transdermal effect of traditional liposomes are limited. The aim of this work was to prepare a new liposome system that contained glycerol and ethanol to enhance the stability of the vesicles and promote the penetration of GA into the skin.The glycethosomes were prepared by ethanol injection and sonication method. The effects of different concentrations of glycerol and ethanol on the particle size, polydispersity (PDI), entrapment efficiency (EE), stability and rheological properties of vesicles were evaluated. Lipophilic and hydrophilic fluorescent probes were used to investigate the microviscosity of vesicles. In vitro permeation tests were performed with pig skin in Franz cells and the concentration of GA in different skin layers was determined by high-performance liquid chromatography (HPLC). The ability of different vesicles to induce lipid extraction and fluidization was analysed by using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR).When glycerol was 50% and ethanol was 25%, the obtained glycethosomes had the smallest particle size and the best stability with a mean particle size of 94.5 nm, PDI 0.216 and 99.8% EE. Fluorescence probe studies indicated that the microviscosity of glycethosomes was the largest when the concentration of glycerol and ethanol was 50% and 25%, which was consistent with the storage stability of glycethosomes. It was found that the glycethosomes had the best transdermal effect and the total skin permeation percentage of GA was 20.67%, while those of ethosomes, glycerosomes, liposomes and dispersion were 10.56%, 9.38%, 7.78% and 5.02%, respectively. And glycethosomes had effectively lipid extraction and fluidization effect on the skin stratum corneum.Compared with other traditional liposomes, glycethosomes can significantly improve the stability of vesicles and the transdermal effect of GA. Glycethosomes is promising vesicles for the delivery of GA.Ces dernières années, l’acide glycyrrhétinique (AG) a souvent été utilisé dans le domaine des cosmétiques en raison de ses effets anti-inflammatoires et anti-oxydants. Cependant, la faible solubilité de l’AG dans l’eau et l’effet barrière de la peau humaine peuvent entraver la pénétration de l’AG à travers la peau. Les liposomes sont fréquemment utilisés comme système d’administration pour les composés fonctionnels dans les cosmétiques, mais la stabilité et l’effet transdermique des liposomes traditionnels demeurent limités. Ce travail a eu pour but de préparer un nouveau système liposomal à base de glycérol et d’éthanol pour améliorer la stabilité des vésicules et favoriser la pénétration de l’AG à travers la peau. MÉTHODES: Les glycéthosomes ont été préparés par injection d’éthanol et suivant une méthode de sonication. Les effets des différentes concentrations de glycérol et d’éthanol sur la taille des particules, la polydispersité (PDI), l’efficacité de capture (entrapment efficiency, EE), la stabilité et les propriétés rhéologiques des vésicules ont été évalués. Des sondes fluorescentes lipophiles et hydrophiles ont été utilisées pour étudier la microviscosité des vésicules. Des tests de perméation in vitro ont été réalisés avec de la peau de porc dans des cellules de Franz, et la concentration d’AG dans différentes couches cutanées a été déterminée par chromatographie en phase liquide à haute performance (CLHP). La capacité des différentes vésicules à induire une extraction lipidique et une fluidisation a été analysée à l’aide d’une spectroscopie infrarouge à réflectance totale atténuée et transformée de Fourier (TR-FTIR). RÉSULTATS: Avec des proportions de 50 % de glycérol et de 25 % d’éthanol, les glycéthosomes obtenus avaient la plus petite taille de particules et la meilleure stabilité avec une taille moyenne de particules de 94,5 nm, une PDI de 0,216 et une efficacité de capture de 99,8 %. Les études par sonde de fluorescence ont indiqué que la microviscosité des glycéthosomes était à son pic lorsque les concentrations de glycérol et d’éthanol s’élevaient respectivement à 50 % et 25 %, soit des proportions cohérentes avec la stabilité de conservation des glycéthosomes. Les glycéthosomes ont présenté le meilleur effet transdermique, et le pourcentage total de perméation cutanée de l’AG était de 20,67 %, tandis que ce pourcentage s’élevait, pour les éthosomes, les glycérosomes, les liposomes et la dispersion, à respectivement 10,56 %, 9,38 %, 7,78 % et 5,02 %. Les glycéthosomes ont aussi eu un effet efficace sur la couche cornée de la peau en ce qui concerne l’extraction des lipides et la fluidisation.Comparés aux liposomes traditionnels, les glycéthosomes peuvent améliorer de façon significative la stabilité des vésicules et l’effet transdermique de l’AG. Les glycéthosomes semblent ainsi constituer des vésicules prometteuses pour l’administration d’AG.

BackgroundGastric cancer (GC) is an aggressive malignant tumor with a high degree of heterogeneity, and its immune microenvironment is closely associated with tumor growth, development and drug resistance. Therefore, a classification system of gastric cancer based explicitly on the immune microenvironment context might enrich the strategy for gastric cancer prognosis and therapy.MethodsA total of 668 GC patients were collected from TCGA-STAD (n = 350), GSE15459 (n = 192), GSE57303 (n = 70) and GSE34942 (n = 56) datasets. Three immune-related subtypes (immunity-H, -M, and -L) were identified by hierarchical cluster analysis based on the ssGSEA score of 29 immune microenvironment-related gene sets. The immune microenvironment-related prognosis signature (IMPS) was constructed via univariate Cox regression, Lasso-Cox regression and multivariate Cox regression, and nomogram model combining IMPS and clinical variables was further constructed by the “rms” package. RT-PCR was applied to validate the expression of 7 IMPS genes between two human GC cell lines (AGS and MKN45) and one normal gastric epithelial cell line (GES-1).ResultsThe patients classified as immunity-H subtype exhibited highly expressed immune checkpoint and HLA-related genes, with enriched naïve B cells, M1 macrophages and CD8 T cells. We further constructed and validated a 7-gene (CTLA4, CLDN6, EMB, GPR15, ENTPD2, VWF and AKR1B1) prognosis signature, termed as IMPS. The patients with higher IMPS expression were more likely to be associated with higher pathology grade, more advanced TNM stages, higher T and N stage, and higher ratio of death. In addition, the prediction values of the combined nomogram in predicting 1-year (AUC = 0.750), 3-year (AUC = 0.764) and 5-year (AUC = 0.802) OS was higher than IMPS and individual clinical characteristics.ConclusionsThe IMPS is a novel prognosis signature associated with the immune microenvironment and clinical characteristics. The IMPS and the combined nomogram model provide a relatively reliable predictive index for predicting the survival outcomes of gastric cancer.

Background Stromal interaction molecule 1 (STIM1)-mediated Ca2+ signaling regulates tumor angiogenesis in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related human malignancy. However, the mechanism by which STIM1 modulates the endothelial functional phenotypes contributing to tumor angiogenesis remains elusive. Methods We explored the intercellular communication via exosomal biomolecules released by EBV-infected NPC cells and delivered to endothelial cells (ECs). The NPC cell-derived exosomes were isolated via differential centrifugation and observed with transmission electron microscopy. Exosome particle size was assessed by nanoparticle tracking analysis (NTA). Uptake of exosomes by recipient ECs was detected by fluorescent labeling of the exosomes with PKH26. Tumor angiogenesis-associated profiles were characterized by determining cell proliferation, migration, tubulogenesis, and permeability in human umbilical vein endothelial cells (HUVECs). Activation of the Akt/ERK pathway was elucidated by detecting the phosphorylation level using western blotting. A chick embryo chorioallantoic membrane (CAM) xenograft model was employed to study tumor-associated neovascularization in vivo. Results The NPC cell-derived exosomes harboring EBV-encoded latent membrane protein 1 (LMP1) promoted proliferation, migration, tubulogenesis, and permeability by activating the Akt/ERK pathway in ECs. STIM1 silencing reduced LMP1 enrichment in NPC cell-derived exosomes, thereby reversing its pro-oncogenic effects in an Akt/ERK pathway-dependent manner. Furthermore, STIM1 knockdown in NPC cells blunted tumor-induced vascular network formation and inhibited intra-tumor neovascularization in the chorioallantoic membrane (CAM) xenograft model. Conclusion STIM1 regulates tumor angiogenesis by controlling exosomal EBV-LMP1 delivery to ECs in the NPC tumor microenvironment. Blocking exosome-mediated cell-to-cell horizontal transfer of EBV-associated oncogenic signaling molecules may be an effective therapeutic strategy for NPC.

BACKGROUNDPulmonary edema is a severe complication in patients with acute myocardial infarction which indicates the development of heart failure (HF) and poor prognosis. However, subclinical pulmonary edema after acute ST-segment elevation myocardial infarction (STEMI) without HF has not received enough attention in clinical practice. We aimed to investigate the prognostic value and associated clinical characteristics of subclinical pulmonary edema after acute STEMI without HF detected by chest computed tomography (CT).METHODSA total of 276 patients with acute STEMI without HF who underwent chest CT were included in this study. K-means clustering analysis was performed to classify the patients into different subgroups based on the mean lung density. Clinical characteristics of the different subgroups were compared and used to establish a machine learning model for discriminating between them. Relative risk (RR) for major adverse cardiovascular events (MACEs) during hospitalization was compared between the subgroups.RESULTSThe patients were classified into two subgroups. Subgroup 2 showed higher mean lung density than subgroup 1 (median [IQR], −727 [−747, −704] vs. −806 [−826, −785] HU, P < 0.001), with significantly higher levels of cardiac enzymes and numbers of inflammatory cells and significantly worse left ventricular function than subgroup 1. In the model analysis, the most important clinical characteristics were the levels of cardiac enzymes, numbers of inflammatory cells, and left ventricular function. The risk for MACEs was higher in subgroup 2 than in subgroup 1 (RR, 2.12; P = 0.002).CONCLUSIONSSubclinical pulmonary edema after acute STEMI without HF was mainly associated with elevated levels of cardiac enzymes, followed by increased numbers of inflammatory cells and worse left ventricular function. In addition, subclinical pulmonary edema provided crucial prognostic information for patients during hospitalization.

Studies have shown that spaceflight affects the emotional and social performance of astronauts. Identifying the neural mechanisms underlying the emotional and social effects of spacefaring-specific environments is essential to specify targeted treatment and prevention interventions. Repetitive transcranial magnetic stimulation (rTMS) has been shown to improve the neuronal excitability and is used to treat psychiatric disorders such as depression. To study the changes of excitatory neuron activity in medial prefrontal cortex (mPFC) in simulated space complex environment (SSCE), and to explore the role of rTMS in behavioral disorders caused by SSCE and the neural mechanism. We found that rTMS effectively ameliorated the emotional and social impairments of mice in SSCE, and acute rTMS could instantaneously enhance the excitability of mPFC neurons. During depression-like and social novelty behaviors, chronic rTMS enhanced the mPFC excitatory neuronal activity that was inhibited by SSCE. Above results suggested that rTMS can completely reverse the SSCE-induced mood and social impairment by enhancing the suppressed mPFC excitatory neuronal activity. It was further found that rTMS suppressed the SSCE-induced excessive dopamine D2 receptor expression, which may be the cellular mechanism by which rTMS potentiates the SSCE-evoked hypoactive mPFC excitatory neurons. Our current results raise the possibility of rTMS being applied as a novel neuromodulation for mental health protection in spaceflight.