Robust Oxidase-Mimetic Supramolecular Nanocatalyst for Lignin Biodegradation.

Enzymatic catalysis presents an eco-friendly, energy-efficient method for lignin degradation. However, challenges arise due to the inherent incompatibility between enzymes and native lignin. In this work, we introduce a supramolecular catalyst composed of fluorenyl-modified amino acids and Cu2+, designed based on the aromatic stacking of the fluorenyl group, which can operate in ionic liquid environments suitable for the dissolution of native lignin. Amino acids and halide anions of ionic liquids shape the copper site's coordination sphere, showcasing remarkable catechol oxidase-mimetic activity. The catalyst exhibits thermophilic property, and maintains oxidative activity up to 75 °C, which allows the catalyzed degradation of the as-dissolved native lignin with high efficiency even without assistance of the electron mediator. In contrast, at this condition, the native copper-dependent oxidase completely lost its activity. This catalyst with superior stability and activity offer promise for sustainable lignin valorization through biocatalytic routes compatible with ionic liquid pretreatment, addressing limitations in native enzymes for industrially relevant conditions.

Endothelial Intracellular ANG (Angiogenin) Protects Against Atherosclerosis by Decreasing Endoplasmic Reticulum Stress.

BACKGROUND: ANG (angiogenin) is essential for cellular adaptation to endoplasmic reticulum (ER) stress, a process closely associated with cardiovascular diseases, including atherosclerosis. We aimed to investigate the role of ANG in the progression of atherosclerosis and elucidate its underlying molecular mechanisms. METHODS: We constructed adenoassociated virus 9 ANG overexpression vectors and endothelial ANG- and ApoE (apolipoprotein E)-deficient mice to determine the effects of ANG on ER stress and atherosclerotic lesions. RNA sequencing of endothelial ANG- and ApoE-deficient mice identified ANG-dependent downregulation of ST3GAL5 (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) expression, and the direct regulation of ST3GAL5 by ANG was verified by chromatin immunoprecipitation sequencing and luciferase reporter assay results. RESULTS: Reanalysis of expression profiling datasets indicated decreased ANG levels in patients' atherosclerotic lesions, and these data were validated in aortas from ApoE-/- mice. ER stress marker and adhesion molecule levels, aortic root lesions and macrophage deposition were substantially reduced in ApoE-/- mice injected with an adenoassociated virus 9 ANG without signal peptide (ANG-ΔSP) overexpression vector compared with empty and full-length ANG overexpression vectors. Endothelial ANG deficiency significantly elevated ER stress and increased adhesion molecule expression, which aggravated atherosclerotic lesions and enhanced THP-1 monocyte adhesion to endothelial cells in vivo and in vitro, respectively. Furthermore, ANG-ΔSP overexpression significantly attenuated oxidized low-density lipoprotein-induced ER stress and THP-1 monocyte adhesion to endothelial cells, which were reversed by ST3GAL5 inhibition. CONCLUSIONS: These results suggest that endothelial intracellular ANG is a novel therapeutic against atherosclerosis and exerts atheroprotective effects via ST3GAL5-mediated ER stress suppression.

Hepatopancreas immune response during different photoperiods in the Chinese mitten crab, Eriocheir sinensis.

Photoperiod plays an important role in the growth, development, and metabolism of crustaceans. The growth and reproduction of crabs are closely related to the photoperiod. The hepatopancreas is an important source of innate immune molecules; however, hepatopancreatic patterns of gene expression depending on the photoperiod-which may underlie changes in immune mechanisms-remain unknown. To study the molecular basis of immune regulation in the Chinese mitten crab (Eriocheir sinensis) under different light conditions, a new generation of high-throughput Illumina sequencing technology was used, and functional genes associated with immune function in the hepatopancreas of this crab were explored via assembly of high-quality sequences, gene annotation, and classification. A total of 383,899,798 clean reads from the hepatopancreas of the normal group (12 h/12 h L:D), 387,936,676 clean reads from the continuous light group (24 h/0 h L:D), and 384,872,734 clean reads from the continuous darkness group (0 h/24 h L:D) were obtained. Compared with the normal group, 141, 152, 60, 87, 90, and 101 differentially expressed genes were identified in the groups exposed to continuous light for 2 days, continuous darkness for 2 days, continuous light for 4 days, continuous darkness for 4 days, continuous light for 6 days, and continuous darkness for 6 days, respectively. The results of this study revealed that under continuous light and dark conditions, the crabs were most affected by light on day 2, but the interference gradually decreased with time. We suggest that long-term light or dark treatment makes crabs adaptable to fluctuations in the photoperiod. The expression of genes associated with immune response patterns was found to change during different photoperiods. Prophenoloxidase (proPO) and serine proteinase (kazal-type serine proteinase inhibitor 1 and serine proteinase inhibitor-3) in the proPO-activating system were significantly upregulated in the 2-day continuous light group. Glutathione peroxidase 3 was significantly downregulated under continuous light exposure, while cyclooxygenase was upregulated in the continuous light and dark environments. These results provide insights into the molecular mechanism underlying the effects of the photoperiod on immune regulation and the physiological activity of E. sinensis.

HMGB1 in macrophage nucleus protects against pressure overload induced cardiac remodeling via regulation of macrophage differentiation and inflammatory response.

Pressure overload induced cardiac remodeling is associated with a complex spectrum of pathophysiological mechanisms. As inflammatory cells, macrophages maintain a critical position in mechanical stress-induced myocardial remodeling. HMGB1 is a highly conserved, ubiquitous protein in various types of cells whose biological roles are closely dependent on subcellular sites. However, whether HMGB1 expressed in macrophages performs the protective or pathological responses in cardiac remodeling is unknown. In this study, we generated the myeloid-specific HMGB1 knockout mice and detected the effects of macrophage HMGB1 in response to pathophysiological stress. Our data showed HMGB1 in macrophages played a protective role against the pressure overload induced cardiac pathophysiology. The deletion of HMGB1 in macrophages gains more differentiation of M1-type pro-inflammatory macrophage during the mechanical stress-induced myocardial remodeling, thereby aggravating the inflammatory response in whole heart, resulting in accelerated deterioration of cardiac function. Moreover, in vitro data also validated HMGB1 got involved in the process of macrophage polarization. Macrophages without HMGB1 are more inclined to differentiate into M1 during the stretch process. In summary, the present results indicated that loss of HMGB1 in macrophages can exacerbate heart failure through increased differentiation of pro-inflammatory macrophages and enhanced inflammatory response.

AT1 receptor blocker inhibits HMGB1 expression in pressure overload-induced acute cardiac dysfunction by suppressing the MAPK/NF-κB signaling pathway.

BACKGROUND: High-mobility group box 1 (HMGB1) expression not only peaks during the early phase of pressure overload (PO), but also serves a role in the pathogenesis of PO-induced cardiac remodeling. Meanwhile, angiotensin II type 1 (AT1) receptor blockers reverse PO-induced cardiac remodeling and repress the secretion of inflammatory factors. However, whether AT1 receptor inhibitors decrease HMGB1 expression in the early stages of PO remains unknown. MATERIALS AND METHODS: PO mouse models were established using transverse aortic constriction (TAC), in which losartan was administrated. Transthoracic echocardiography was performed 3 days after the operation, and serum and cardiac HMGB1 expression, as well as the expression levels of related proteins were measured. RESULTS: PO-induced acute cardiac dysfunction was observed 3 days after TAC, and was subsequently slightly, but not significantly relieved by losartan. The expression levels of HMGB1, tumor necrosis factor-α and interleukin-6 in both the serum and myocardium were upregulated in response to TAC, while they were significantly reduced by losartan. Moreover, the phosphorylation of extracellular signal-regulated kinases, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in the myocardium were significantly increased under PO, and this was also prevented by losartan. CONCLUSION: These data suggest that losartan may downregulate the expression of HMGB1 in acute cardiac dysfunction induced by PO by inhibiting the MAPKs/NF-κB signaling pathway, which indicates a novel beneficial role of AT1 receptor antagonists in ameliorating cardiac remodeling under PO.

Perfluorocarbon nanoparticle-mediated platelet inhibition promotes intratumoral infiltration of T cells and boosts immunotherapy.

Cancer immunotherapy can stimulate and enhance the ability of the immune system to recognize, arrest, and eliminate tumor cells. Immune checkpoint therapies (e.g., PD-1/PD-L1) have shown an unprecedented and durable clinical response rate in patients among various cancer types. However, a large fraction of patients still does not respond to these checkpoint inhibitors. The main cause of this phenomenon is the limited T-cell infiltration in tumors. Therefore, additional strategies to enhance T-cell trafficking into tumors are urgently needed to improve patients' immune responses. In this study, we screened an array of perfluorocarbon compounds, reporting that albumin-based perfluorotributylamine nanoparticles (PFTBA@Alb) can effectively increase the permeability of tumor blood vessels, and no distinct side effects were found on normal blood vessels. After i.v. administration of PFTBA@Alb, the number of tumor-infiltrating CD8+ and CD4+ T cells showed an obvious rising trend. More important, a striking tumor inhibition rate, reaching nearly 90%, was observed when combining PFTBA@Alb with anti-PD-L1 antibody. These findings suggest that PFTBA@Alb can be regarded as an enhancer for anti-PD-L1 immunotherapy.

Severity and factors of menopausal symptoms in middle-aged women in Gansu Province of China: a cross-sectional study.

OBJECTIVE: To investigate the severity and risk factors of menopausal symptoms in the middle-aged women in Gansu Province of China. METHODS: In this cross-sectional study, a total of 7319 women (aged 40-55 years) attended the health survey in Gansu Province in China were enrolled. Information on demographics, menopausal status, reproductive history, and history of chronic diseases was collected via a structured questionnaire. Severity of menopausal symptom was evaluated by the Modified Kupperman Menopausal Index. Ordinal logistic regression model was applied to explore its risk factors. RESULTS: A total of 7319 participants were included in present study, among them, 3606 (49.27%) had moderate or severe menopausal symptom. Compared with premenopausal women, perimenopausal and postmenopausal women have a higher mKMI score. We observed that older age, higher BMI, non-married status, longer duration of menstruation (≥ 7 days), number of pregnancy (> 3 times), longer duration of breastfeeding (> 12 months), peri- or post-menopausal status, and menopause hormone therapy was positively associated with menopausal symptom score, while higher level of family income, educational and physical activity, and history of gynecological, breast or chronic disease were negatively associated with the score. CONCLUSIONS: Numerous factors were associated with the severity of menopausal symptom among the Chinese women. Because it was gradually increased with aging, more attention is warranted to manage the menopausal symptom.

Molecular Characterization of Carbonic Anhydrase Genes in Lotus japonicus and Their Potential Roles in Symbiotic Nitrogen Fixation.

Carbonic anhydrase (CA) plays a vital role in photosynthetic tissues of higher plants, whereas its non-photosynthetic role in the symbiotic root nodule was rarely characterized. In this study, 13 CA genes were identified in the model legume Lotus japonicus by comparison with Arabidopsis CA genes. Using qPCR and promoter-reporter fusion methods, three previously identified nodule-enhanced CA genes (LjαCA2, LjαCA6, and LjßCA1) have been further characterized, which exhibit different spatiotemporal expression patterns during nodule development. LjαCA2 was expressed in the central infection zone of the mature nodule, including both infected and uninfected cells. LjαCA6 was restricted to the vascular bundle of the root and nodule. As for LjßCA1, it was expressed in most cell types of nodule primordia but only in peripheral cortical cells and uninfected cells of the mature nodule. Using CRISPR/Cas9 technology, the knockout of LjßCA1 or both LjαCA2 and its homolog, LjαCA1, did not result in abnormal symbiotic phenotype compared with the wild-type plants, suggesting that LjßCA1 or LjαCA1/2 are not essential for the nitrogen fixation under normal symbiotic conditions. Nevertheless, the nodule-enhanced expression patterns and the diverse distributions in different types of cells imply their potential functions during root nodule symbiosis, such as CO2 fixation, N assimilation, and pH regulation, which await further investigations.

Angiotensin II Increases HMGB1 Expression in the Myocardium Through AT1 and AT2 Receptors When Under Pressure Overload.

High-mobility group box 1 (HMGB1) is increased in the myocardium under pressure overload (PO) and is involved in PO-induced cardiac remodeling. The mechanisms of the upregulation of cardiac HMGB1 expression have not been fully elucidated. In the present study, a mouse transverse aortic constriction (TAC) model was used, and an angiotensin II (Ang II) type 1 (AT1) receptor inhibitor (losartan) or Ang II type 2 (AT2) receptor inhibitor (PD123319) was administrated to mice for 14 days. Cardiac myocytes were cultured and treated with Ang II for 5 minutes to 48 hours conditionally with the blockage of the AT1 or AT2 receptor. TAC-induced cardiac hypertrophy was observed at 14 days after the operation, which was partially reversed by losartan, but not by PD123319. Similarly, the upregulated HMGB1 expression levels observed in both the serum and myocardium induced by TAC were reduced by losartan. Elevated cardiac HMGB1 protein levels, but not mRNA or serum levels, were significantly decreased by PD123319. Furthermore, HMGB1 expression levels in culture media and cardiac myocytes were increased following Ang II treatment in vitro, positively associated with the duration of treatment. Similarly, Ang II-induced upregulation of HMGB1 in vitro was inhibited by both losartan and PD123319. These results suggest that upregulation of HMGB1 in serum and myocardium under PO, which are partially derived from cardiac myocytes, may be induced by Ang II via the AT1 and AT2 receptors. Additionally, amelioration of PO-induced cardiac hypertrophy following losartan treatment may be associated with the reduction of HMGB1 expression through the AT1 receptor.

CRISPR/Cas9 knockout of leghemoglobin genes in Lotus japonicus uncovers their synergistic roles in symbiotic nitrogen fixation.

Legume nodules contain high concentrations of leghemoglobins (Lbs) encoded by several genes. The reason for this multiplicity is unknown. CRISPR/Cas9 technology was used to generate stable mutants of the three Lbs of Lotus japonicus. The phenotypes were characterized at the physiological, biochemical and molecular levels. Nodules of the triple mutants were examined by electron microscopy and subjected to RNA-sequencing (RNA-seq) analysis. Complementation studies revealed that Lbs function synergistically to maintain optimal N2 fixation. The nodules of the triple mutants overproduced superoxide radicals and hydrogen peroxide, which was probably linked to activation of NADPH oxidases and changes in superoxide dismutase isoforms expression. The mutant nodules showed major ultrastructural alterations, including vacuolization, accumulation of poly-ß-hydroxybutyrate and disruption of mitochondria. RNA-seq of c. 20 000 genes revealed significant changes in expression of carbon and nitrogen metabolism genes, transcription factors, and proteinases. Lb-deficient nodules had c. 30-50-fold less heme but similar transcript levels of heme biosynthetic genes, suggesting a post-translational regulatory mechanism of heme synthesis. We conclude that Lbs act additively in nodules and that the lack of Lbs results in early nodule senescence. Our observations also provide insight into the reprogramming of the gene expression network associated with Lb deficiency, probably as a result of uncontrolled intracellular free O2 concentration.

Perfluorocarbon Nanoparticles Mediated Platelet Blocking Disrupt Vascular Barriers to Improve the Efficacy of Oxygen-Sensitive Antitumor Drugs.

Currently, limited tumor drug permeation and poor oxygen perfusion are two major bottlenecks that significantly impair the efficacy of existing antitumor drugs, especially oxygen-sensitive antitumor drugs. One vital cause of these major bottlenecks is the abnormal tumor vessel barrier. To the best knowledge of the authors, platelets play a vital role in the maintenance of an abnormal tumor blood barrier through platelet-tumor interaction. Thus, platelet inhibition may present a new way to enhance drug delivery. In this study, it is originally discovered that perfluorotributylamine-based albumin nanoparticles (PFTBA@HSA) possess excellent platelet inhibiting abilities, which then selectively disrupt the tumor vessel barrier, resulting in a remarkably enhanced intratumoral drug accumulation. Interestingly enough, the tumor hypoxia is also obviously relieved by enhanced oxygen carrier red blood cell distribution and PFTBA@HSA infiltration in the tumors. Finally, the efficacy of oxygen-sensitive antitumor drugs is significantly amplified by PFTBA@HSA owing to enhanced drug permeation and relieved tumor hypoxia. Therefore, for the first time, it is demonstrated that PFTBA@HSA could be used as an effective way to improve the efficacy of existing tumor therapies by disrupting tumor vessel barriers through targeted platelet inhibition.

Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta.

Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-ß and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes.

Impact Analysis of Photoperiodic Disorder on the Eyestalk of Chinese Mitten Crab (Eriocheir sinensis) through High-Throughput Sequencing Technology.

Light is an indispensable factor in the healthy growth of living organisms, and alterations in the photoperiod can have consequences for body homeostasis. The eyestalk is a photosensitive organ that secretes various hormones to regulate the Chinese mitten crab (Eriocheir sinensis). However, the photoperiod-dependent eyestalk patterns of gene expression that may underlie changes in body homeostasis are unknown. In this study, we investigated the molecular mechanisms involved in eyestalk transcriptomic responses in E. sinensis under different photoperiod regimes on days 2, 4, and 6. The photoperiods tested were 12, 24, and 0 h light/day. In total, we obtained 110, 958, 348 clean datasets and detected 1809 differentially expressed genes (DEGs). Genes involved in the crustacean hyperglycemic hormone superfamily and juvenile hormones were observed, which play important roles in gonadal development, growth, and immunity in E. sinensis and may also be involved in photoperiod adaptation. In addition, the MAPK signaling pathway was the only signaling pathway identified in the continuous light group but was absent in the continuous darkness group. We suggest that the MAPK pathway is highly responsive to light input during the subjective night and insensitive to light during the middle of the subjective day. These results provide insight into the molecular mechanisms underlying the effects of photoperiod on the immune regulation of E. sinensis.

Monitoring Blood Glucose in Mouse Offspring after Intracytoplasmic sperm injection - Embryo Transfer.

Human lifespan is considerably long, while mouse models can simulate the entire human lifespan in a relatively short period, with one year of mouse life roughly equivalent to 40 human years. Intracytoplasmic sperm injection (ICSI) is a commonly used assisted reproductive technology in clinical practice. However, given its relatively recent emergence about 30 years ago, the long-term effects of this technique on human development remain unclear. In this study, we established the ICSI combined with embryo transfer (ET) method using a mouse model. The results demonstrated that normal mouse sperm, after undergoing in vitro culture and subsequent ICSI, exhibited a fertilization rate of 89.57% and a two-cell rate of 87.38%. Following ET, the birth rate of offspring was approximately 42.50%. Furthermore, as the mice aged, fluctuations in glucose metabolism levels were observed, which may be associated with the application of the ICSI technique. These findings signify that the mouse ICSI-ET technique provides a valuable platform for evaluating the impact of sperm abnormalities on embryo development and their long-term effects on offspring health, particularly concerning glucose metabolism. This study provides important insights for further research on the potential effects of the ICSI technique on human development, emphasizing the necessity for in-depth investigation into the long-term implications of this technology.

Abnormal degree centrality can be a potential imaging biomarker in first-episode, drug-naive bipolar mania.

Brain network abnormalities in emotional response exist in bipolar mania. However, few studies have been published on network degree centrality of first-episode, drug-naive bipolar mania, and healthy controls. This study aimed to assess the utility of neural activity values analyzed via degree centrality methods. Sixty-six first-episode, drug-naive patients with bipolar mania and 60 healthy controls participated in resting-state functional magnetic resonance rescanning and scale estimating. The degree centrality and receiver operating characteristic (ROC) curve methods were used for an analysis of the imaging data. Relative to healthy controls, first-episode bipolar mania patients displayed increased degree centrality values in the left middle occipital gyrus, precentral gyrus, supplementary motor area, Precuneus, and decreased degree centrality values in the left parahippocampal gyrus, right insula and superior frontal gyrus, medial. ROC results exhibited degree centrality values in the left parahippocampal gyrus that could distinguish first-episode bipolar mania patients from healthy controls with 0.8404 for AUC. Support vector machine results showed that reductions in degree centrality values in the left parahippocampal gyrus can be used to effectively differentiate between bipolar disorder patients and healthy controls with respective accuracy, sensitivity, and specificity values of 83.33%, 85.51%, and 88.41%. Increased activity in the left parahippocampal gyrus may be a distinctive neurobiological feature of first-episode, drug-naive bipolar mania. Degree centrality values in the left parahippocampal gyrus might be served as a potential neuroimaging biomarker to discriminate first-episode, drug-naive bipolar mania patients from healthy controls.

Transferrin receptor 1 targeted nanomedicine for brain tumor therapy.

Achieving effective drug delivery to traverse the blood-brain barrier (BBB) and target tumor cells remains the greatest challenge for brain tumor therapy. Importantly, the overexpressed membrane receptors on the brain endothelial cells, especially transferrin receptor 1 (TfR1), which mediate their ligands/antibodies to overcome the BBB by transcytosis, have been emerging as promising targets for brain tumor therapy. By employing ligands (e.g., transferrin, H-ferritin), antibodies or targeting peptides of TfR1 or aptamers, various functional nano-formulations have been developed in the last decade. These agents showed great potential for the treatment of brain diseases due to their ideal size, high loading capacity, controlled drug release and suitable pharmacokinetics. Herein, we summarize the latest advances on TfR1-targeted nanomedicine for brain tumor therapy. Moreover, we also discuss the strategies of improving stability, targeting ability and accumulation of nano-formulations in brain tumors for better outcomes. In this review, we hope to provide inspiration for the rational design of TfR1-targeted nanomedicine against brain tumors.

Deep sequencing of microRNAs reveals circadian-dependent microRNA expression in the eyestalks of the Chinese mitten crab Eriocheir sinensis.

MicroRNAs (miRNAs) are small endogenous non-coding RNAs. In crustaceans, miRNAs might be involved in the regulation of circadian rhythms. Many physiological functions of crustaceans including immunity and hormone secretion exhibit circadian rhythms, but it remains unclear whether specific miRNAs contribute to the alteration of crustacean physiological processes under circadian rhythms. This study investigated the mechanisms of miRNA regulation of circadian rhythms in the Chinese mitten crab (Eriocheir sinensis), one of China's most important aquaculture species. We obtained eyestalks from crab specimens at four time points (6:00; 12:00; 18:00; 24:00) during a 24-h period. We identified 725 mature miRNAs, with 23 known miRNAs differentially expressed depending on the time of day. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that the putative target genes for differentially expressed miRNAs were significantly enriched in the immune response and endocrine-related pathways. Numerous putative target genes are involved in the circadian-related pathways and enriched on circadian-control genes. These results suggest that the expression of miRNAs regulates some specific physiological functions in E. sinensis under circadian cycles. We also profiled various putative target genes enriched under the circadian-related pathway. This study performed miRNA expression in the eyestalks of E. sinensis during a 24-h daily cycle, providing insights into the molecular mechanism underlying crustacean circadian rhythms and suggesting miRNAs' role in studying crustacean physiology should not be overlooked.

Perfluorotributylamine-Loaded Albumin Nanoparticles Downregulate Platelet-Derived TGFß to Inhibit Tumor Metastasis.

Tumor metastasis contributes to the low overall survival of tumor patients, while transforming growth factor-ß (TGFß) has been recognized as a prominently promoting factor in the development of tumor metastasis. Platelets reserve abundant TGFß, which will be secreted to peripheral blood after activation, and they are the dominant source of circulating TGFß. Therefore, downregulation of platelet-derived TGFß is expected to inhibit the metastasis of circulating tumor cells. Here, unfolded human serum albumin (HSA)-coated perfluorotributylamine (PFTBA) nanoparticles were constructed to display a favorable platelet delivery and an antiplatelet effect to downregulate platelet-derived TGFß in vitro and in blood plasma. PFTBA@HSA-mediated TGFß downregulation impaired epithelial-mesenchymal transition of tumor cells as well as their migration and invasion behaviors and enhanced immune surveillance of NK cells. Intravenous injection of PFTBA@HSA effectively reduced tumor metastasis on the lungs or liver to improve the survival rate of mice on multiple metastatic models, including CT26 colon cancer, B16F10 melanoma, and 4T1 breast cancer. Compared with the clinical antiplatelet drug ticagrelor, PFTBA@HSA reduced bleeding risk when displaying a favorable downregulation on platelet-derived TGFß, thereby obtaining a higher therapy benefit. Together, this study confirmed that downregulation of platelet-derived TGFß by PFTBA@HSA will be a potential approach and therapeutic candidate for the prevention of tumor metastasis.

Comparative transcriptome analysis reveals the effects of different feeding times on the hepatopancreas of Chinese mitten crabs.

Feeding rhythms affect a range of physiological functions in crustaceans. To investigate their effect on the physiological functions of Eriocheir sinensis, herein, we analyzed the influence of different feeding times on the hepatopancreas transcriptome via high-throughput sequencing. We harvested the hepatopancreas of crabs at 12:00 on day 11 of the experiment. We weighted the crabs before and after the experiment and found that those in the 06:00 group had the highest weight gain rate. In addition, 512 differentially expressed genes (DEGs) were grouped into nine distinct clusters. Functional enrichment analysis of DEGs showed that E. sinensis metabolic and immune processes were affected by the feeding time. Furthermore, we mapped the DEGs involved in retinol metabolism and the lysosome pathway. To our knowledge, this is the first comparative transcriptomic analysis of the hepatopancreas of E. sinensis based on different feeding times, which provides multi-level information to reveal the mechanism underlying the regulation of feeding rhythms in E. sinensis.

GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation.

The initiation of atherosclerotic plaque is characterized by endothelial cell inflammation. In light of gasdermin E's (GSDME) role in pyroptosis and inflammation, this study elucidates its function in atherosclerosis onset. Employing Gsdme- and apolipoprotein E-deficient (Gsdme-/-/ApoE-/-) and ApoE-/- mice, an atherosclerosis model was created on a Western diet (WD). In vitro examinations with human umbilical vein endothelial cells (HUVECs) included oxidized low-density lipoprotein (ox-LDL) exposure. To explore the downstream mechanisms linked to GSDME, we utilized an agonist targeting the stimulator of the interferon genes (STING) pathway. The results showed significant GSDME activation in ApoE-/- mice arterial tissues, corresponding with atherogenesis. Gsdme-/-/ApoE-/- mice displayed fewer plaques and decreased vascular inflammation. Meanwhile, GSDME's presence was confirmed in endothelial cells. GSDME inhibition reduced the endothelial inflammation induced by ox-LDL. GSDME was linked to mitochondrial damage in endothelial cells, leading to an increase in cytoplasmic double-stranded DNA (dsDNA). Notably, STING activation partially offset the effects of GSDME inhibition in both in vivo and in vitro settings. Our findings underscore the pivotal role of GSDME in endothelial cells during atherogenesis and vascular inflammation, highlighting its influence on mitochondrial damage and the STING pathway, suggesting a potential therapeutic target for vascular pathologies.