High-intensity interval training improves hypothalamic inflammation by suppressing HIF-1α signaling in microglia of male C57BL/6J mice.

Repeated bouts of high-intensity interval training (HIIT) induce an improvement in metabolism via plasticity of melanocortin circuits and attenuated hypothalamic inflammation. HIF-1α, which plays a vital role in hypothalamus-mediated regulation of peripheral metabolism, is enhanced in the hypothalamus by HIIT. This study aimed to investigate the effects of HIIT on hypothalamic HIF-1α expression and peripheral metabolism in obese mice and the underlying molecular mechanisms. By using a high-fat diet (HFD)-induced obesity mouse model, we determined the effect of HIIT on energy balance and the expression of the hypothalamic appetite-regulating neuropeptides, POMC and NPY. Moreover, hypothalamic HIF-1α signaling and its downstream glycolytic enzymes were explored after HIIT intervention. The state of microglia and microglial NF-κB signaling in the hypothalamus were also examined in vivo. In vitro by using an adenovirus carrying shRNA-HIF1ß, we explored the impact of HIF-1 signaling on glycolysis and NF-κB inflammatory signaling in BV2 cells. Food intake was suppressed and whole-body metabolism was improved in exercised DIO mice, accompanied by changes in the expression of POMC and NPY. Moreover, total and microglial HIF-1α signaling were obviously attenuated in the hypothalamus, consistent with the decreased levels of glycolytic enzymes. Both HFD-induced microglial activation and hypothalamic NF-κB signaling were significantly suppressed following HIIT in vivo. In BV2 cells, after HIF-1 complex knockdown, glycolysis and NF-κB inflammatory signaling were significantly attenuated. The data indicate that HIIT improves peripheral metabolism probably via attenuated HFD-induced microglial activation and microglial NF-κB signaling in the hypothalamus, which could be mediated by suppressed microglial HIF-1α signaling.

OsJRL negatively regulates rice cold tolerance via interfering phenylalanine metabolism and flavonoid biosynthesis.

The identification of new genes involved in regulating cold tolerance in rice is urgent because low temperatures repress plant growth and reduce yields. Cold tolerance is controlled by multiple loci and involves a complex regulatory network. Here, we show that rice jacalin-related lectin (OsJRL) modulates cold tolerance in rice. The loss of OsJRL gene functions increased phenylalanine metabolism and flavonoid biosynthesis under cold stress. The OsJRL knock-out (KO) lines had higher phenylalanine ammonia-lyase (PAL) activity and greater flavonoid accumulation than the wild-type rice, Nipponbare (NIP), under cold stress. The leaves had lower levels of reactive oxygen species (ROS) and showed significantly enhanced cold tolerance compared to NIP. In contrast, the OsJRL overexpression (OE) lines had higher levels of ROS accumulation and showed lower cold tolerance than NIP. Additionally, the OsJRL KO lines accumulated more abscisic acid (ABA) and jasmonic acid (JA) under cold stress than NIP. The OsJRL OE lines showed increased sensitivity to ABA compared to NIP. We conclude that OsJRL negatively regulates the cold tolerance of rice via modulation of phenylalanine metabolism and flavonoid biosynthesis.

The anisotropic transport properties of the three-terminal ballistic junction based onα-T3lattice.

The three-terminal ballistic junction (TBJ) has promising applications in nanoelectronics. We investigate the transport properties of aα-T3-based TBJ, where two typical configurations are considered, i.e. the A- and Z-TBJ. It is found that both A- and Z-TBJ exhibit transmission anisotropy, and the transmission of the A-TBJ has stronger anisotropy than that of the Z-TBJ. The amplitude of the rectification coefficient is smaller than that of phosphorene TBJ, but larger than that of graphene TBJ. When the symmetrical input is applied, the output voltage curve exhibits symmetric behavior. While in the case of asymmetric input, the symmetric behavior is broken, and the maximum value of the output voltage can reach a positive value. Interestingly, the voltage output shows a dramatic nonlinear response which may be useful for the voltage diode application with a push-pull input voltage. In addition, the heat fluxes of the asymmetric input are much smaller than those of the symmetric input. The maximum value of the heat flux under the symmetric input exceeds twice of that under the asymmetric input. Our results are useful to design nanoelectronic devices based onα-T3TBJ.

Comparative studies on physicochemical properties of three potato varieties different in RS2 and RS3 contents.

BACKGROUND: At present, increasing importance has been attracted to healthy food enriched in resistant starch (RS), which has great benefits in health-promoting. Raw potato has rich RS2, whereas most RS2 may become digestible after gelatinization, resulting in few RS being left in processed potato. Breeding potatoes with high RS2 or RS3 or both can meet the demand for various healthy potato products. RESULTS: There were apparent discrepancies among three potatoes with contrast RS2 and RS3 content in thermal properties, viscosity and digestibility. ZS-5 had the highest RS2 with 50.17% but the lowest RS3 with 3.31%. Meanwhile, ZS-5 had the largest starch granule, the highest proportion of B3, viscosity and hardness, and the highest digestibility. DN303 with the highest content of RS3 (5.08%) had the lowest hardness and fracturability. MG56-42 with both higher RS2 and RS3 content showed the highest resistance to digestion and moderate hardness and fracturability. CONCLUSION: The present study enriches the potential resources and provides a reliable scientific basis for high RS potatoes breeding. The various features of different potatoes make it possible to screen potatoes according to different demands. © 2023 Society of Chemical Industry.

Nomogram for stratifying patients with lifelong premature ejaculation before using the PHQ-9: An observational study.

OBJECTIVE: A PHQ-9 score ≥ 15, represented as PHQ-9+ , indicates major depressive disorder (MDD). On using PHQ-9, the psychological burden of several patients with lifelong premature ejaculation (LPE) gets aggravated, which may lead to LPE development. We aim to construct a nomogram for predicting the individual risk of PHQ-9+ in patients with LPE and discerning those with low risks, who should avoid the PHQ-9. METHODS: The nomogram was constructed by analysing data of 802 patients from Xijing Hospital and Northwest Women's & Children's Hospital. The LASSO and multivariable logistic regressions were used to identify independent predictors of PHQ-9+ , used for developing the nomogram. The discrimination, calibration and clinical usefulness of the nomogram were assessed in the derivation cohort and an independent validation cohort, which was composed of 505 prospectively enrolled patients from Daxing Hospital and Xijing Hospital. RESULTS: The duration of PE, IELT, a history of PE exacerbation, IIEF-5 score, urinary frequency and physical pain score were identified as independent predictors. The nomogram showed excellent calibration, discrimination and clinical usefulness in the derivation and validation cohorts, with a predictive accuracy of 0.781 and 0.763, respectively. Based on this nomogram, patients were divided into not recommended, recommended and strongly recommended PHQ-9 filling groups, with PHQ-9+ rates of 3.5%, 9.3% and 30.7%, respectively. CONCLUSION: A nomogram to discern LPE patients with low risks of PHQ-9+ was established. This tool can increase the positivity of MDD screening and may improve the therapeutic outcomes of those in the low-risk group.

Selective Encapsulation of Therapeutic mRNA in Engineered Extracellular Vesicles by DNA Aptamer.

Extracellular vesicles (EV)-based delivery of therapeutic mRNAs is challenged by the low loading efficiency. In this study, we designed a DNA aptamer consisting of two parts: the single strand part recognized the AUG region of target mRNA, preventing mRNA from translation and ribosome assembly; and the double strand part containing the elements recognized by the CD9-ZF (zinc finger) motifs, sorting DNA aptamer-mRNA complex into CD9-ZF engineered EVs. In vitro and in vivo studies revealed that the system could efficiently load functional mRNAs to the EVs. Furthermore, adipose specific delivery of loaded Pgc1α mRNA via the strategy could efficiently induce white adipocyte browning. Similarly, delivery of interleukin-10 (Il-10) mRNA via the strategy had potent anti-inflammatory effect in inflammatory bowel disease (IBD) mouse model. Together, our study has proposed an efficient strategy to load therapeutic mRNAs of interest into EVs, which could be used as a promising strategy for gene therapy.

[A new spirocyclic cycloartane triterpenoid from Souliea vaginata].

The 70% ethanol extract of the whole plant of Souliea vaginata was purified by multi-chromatographic methods including macroporous resin,silica gel,Sephadex LH-20,and C18-reversed-phase column chromatography. A new spirocyclic cycloartane triterpenoid was isolated and identified as( 16 R*,20 R*,23 S*,24 R*,25 S*)-16,23: 23,26-diepoxy-15α,24,25-trihydroxy-9,19-cycloart-3ß-O-ß-D-xylopyranoside( 1),and named as soulieoside S. Its planar structure and relative configuration were determined by spectroscopic techniques including 2 D NMR and HRESI-MS. As one of the main components of S. vaginata,compound 1 was evaluated for its anti-inflammatory activity by a lipopolysaccharide( LPS)-stimulated NO production model in RAW264. 7 macrophages,but it didn't show NO production inhibitory effect.

Polysaccharide of sunflower (Helianthus annuus L.) stalk pith inhibits cancer proliferation and metastases via TNF-α pathway.

The decoctions of sunflower (Helianthus annuus L. HAL) stalk pith have been used to treat advanced cancer, and polysaccharide of sunflower stalk pith (HSPP) was key ingredient of the decoctions. To forage specially structured HSPP with anti-tumor effects and to uncover its mechanisms of anticancer activity, syngeneic mouse model of lung carcinoma metastasis was established and the HSPP was found to contain long-chain fatty acid. Encouragingly, the mean survival of the polysaccharide group (47.3 ± 12.8 d) and its sub-fractions group HSPP-4 (50.7 ± 13.0 d) was significantly increased compared with control group (38.7 ± 12.7 d) or positive control group (41.8 ± 13.4 d), (n = 20, P < 0.01 vs. the control group or positive control group). Furthermore, the HSPP exerted inhibitory effects on the tumor cells' metastasis. Eventually, it is postulated that the polysaccharide could inhibit tumor proliferation and metastasis by reduction of TNF-α from the macrophage.

Truncated PD1 Engineered Gas-Producing Extracellular Vesicles for Ultrasound Imaging and Subsequent Degradation of PDL1 in Tumor Cells.

PDL1 blockade therapy holds great promise in cancer immunotherapy. Ultrasound imaging of PDL1 expression in the tumor is of great importance in predicting the therapeutic efficacy. As a proof-of-concept study, a novel ultrasound contrast agent has been innovated here to image and block PDL1 in the tumor tissue. Briefly, extracellular vesicles (EVs) are engineered to display truncated PD1 (tPD1) on the surface to bind PDL1 with high affinity by fusion to EV-abundant transmembrane protein PTGFRN. The engineered EVs are then encapsulated with Ca(HCO3)2 via electroporation and designated as Gp-EVtPD1, which would recognize PDL1 highly expressed cells and produce gas in the endosomes and lysosomes. On the one hand, the echogenic signal intensity correlates well with the PDL1 expression and immune response inhibition in the tumor. On the other hand, during the trajectory of Gp-EVtPD1 in the recipient cells, tPD1 on the EV binds PDL1 and triggers the PDL1 endocytosis and degradation in endosomes/lysosomes in a sequential manner, and thus boosts the anti-tumor immunity of cytotoxic T cells. In summary, Gp-EVtPD1 serves as a novel ultrasound contrast agent and blocker of PDL1, which might be of great advantage in imaging PDL1 expression and conquering immune checkpoint blocker resistance.

Extraction, structural characterization and immunoactivity of glucomannan type polysaccahrides from Lilium brownii var. viridulum Baker.

Homogeneous polysaccharide (LBP) was extracted and purified from the bulblets of Lilium brownii var. viridulum Baker with a molecular weight of 312 kDa. The monosaccharides are composed of mannose and glucose, and the corresponding molar ratios are 0.582 and 0.418, respectively. FT-IR, LC-MS, NMR, GC-MS and HPAEC were used to analyze the functional groups, glycosidic linkages and chemical structure of LBP, which was a 1-4-linked glucomannan and contained a dodecasaccharide repeating units of →4)-ß-D-Manp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-α-D-Glcp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Manp-(1 â†’ . In vitro experimental results showed that LBP had noble biocompatibility, and a low dose of 5 µg/mL LBP significantly up-regulated the mRNA expression of TNF-α, iNOS, IL-6, IL-1ß and Toll-like receptors family (TLRs) in RAW 264.7 cells. In conclusion, LBP played an important role in immunomodulation, and further studies on the specific immunomodulatory mechanisms of LBP on RAW 264.7 cells are still needed.

Dual-Functional Nanodroplet for Tumor Vasculature Ultrasound Imaging and Tumor Immunosuppressive Microenvironment Remodeling.

Accurately evaluating tumor neoangiogenesis and conducting precise interventions toward an immune-favorable microenvironment are of significant clinical importance. In this study, a novel nanodroplet termed as the nanodroplet-based ultrasound contrast agent and therapeutic (NDsUCA/Tx) is designed for ultrasound imaging and precise interventions of tumor neoangiogenesis. Briefly, the NDsUCA/Tx shell is constructed from an engineered CMs containing the tumor antigen, vascular endothelial growth factor receptor 1 (VEGFR1) extracellular domain 2-3, and CD93 ligand multimerin 2. The core is composed of perfluorohexane and the immune adjuvant R848. After injection, NDsUCA/Tx is found to be enriched in the tumor vasculature with high expression of CD93. When triggered by ultrasound, the perfluorohexane in NDsUCA/Tx underwent acoustic droplet vaporization and generated an enhanced ultrasound signal. Some microbubbles exploded and the resultant debris (with tumor antigen and R848) together with the adsorbed VEGF are taken up by nearby cells. This cleared the local VEGF for vascular normalization, and also served as a vaccine to activate the immune response. Using a syngeneic mouse model, the satisfactory performance of NDsUCA/Tx in tumor vasculature imaging and immune activation is confirmed. Thus, a multifunctional NDsUCA/Tx is successfully developed for molecular imaging of tumor neoangiogenesis and precise remodeling of the tumor microenvironment.

Electrical detection of pathogenic bacteria via immobilized antimicrobial peptides.

The development of a robust and portable biosensor for the detection of pathogenic bacteria could impact areas ranging from water-quality monitoring to testing of pharmaceutical products for bacterial contamination. Of particular interest are detectors that combine the natural specificity of biological recognition with sensitive, label-free sensors providing electronic readout. Evolution has tailored antimicrobial peptides to exhibit broad-spectrum activity against pathogenic bacteria, while retaining a high degree of robustness. Here, we report selective and sensitive detection of infectious agents via electronic detection based on antimicrobial peptide-functionalized microcapacitive electrode arrays. The semiselective antimicrobial peptide magainin I--which occurs naturally on the skin of African clawed frogs--was immobilized on gold microelectrodes via a C-terminal cysteine residue. Significantly, exposing the sensor to various concentrations of pathogenic Escherichia coli revealed detection limits of approximately 1 bacterium/µL, a clinically useful detection range. The peptide-microcapacitive hybrid device was further able to demonstrate both Gram-selective detection as well as interbacterial strain differentiation, while maintaining recognition capabilities toward pathogenic strains of E. coli and Salmonella. Finally, we report a simulated "water-sampling" chip, consisting of a microfluidic flow cell integrated onto the hybrid sensor, which demonstrates real-time on-chip monitoring of the interaction of E. coli cells with the antimicrobial peptides. The combination of robust, evolutionarily tailored peptides with electronic read-out monitoring electrodes may open exciting avenues in both fundamental studies of the interactions of bacteria with antimicrobial peptides, as well as the practical use of these devices as portable pathogen detectors.

An Acute Bout of Exercise Suppresses Appetite via Central Lactate Metabolism.

Exercise has been reported to elicit a transient suppression of appetite. Plasma lactate, which is produced by exercising muscle, is believed to have a critical effect on exercise-induced appetite suppression. However, the underlying mechanisms and signaling steps of central lactate metabolism remain unexplored. After central oxamate administration, C57BL/6J male mice performed 10 high-intensity interval running at 90% Vmax for 4 minutes each, which separated by 2 minutes at 12 m/min. Food intake and the expression of hypothalamic appetite-regulating neuropeptides including proopiomelanocortin (POMC) and neuropeptide Y (NPY) were investigated following exercise training. Janus kinase 2 (Jak2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway was also determined by Western blot. In addition, hypoxia-inducible factor-1α (HIF-1α) was investigated to explore the effect of central lactate metabolism following exercise. We found that central oxamate administration reversed exercise-induced suppression of food intake, and as well as changes in the expression of POMC and NPY. Moreover, acute exercise led to an increase in the phosphorylation of Jak2 and STAT3 in the hypothalamus, while central lactate inhibition significantly blunted this effect. In addition, HIF-1α expression increased obviously after exercise, while it was attenuated by central oxamate administration. Collectively, our data reveal that central lactate metabolism mediates exercise-induced suppression of appetite and changes in neuropeptides, possibly through enhanced Jak2-STAT3 signaling.

Synergistic effect of docetaxel and gambogic acid on bone metastasis of lung cancer.

INTRODUCTION: Gambogic acid (GA) as an active compound isolated from Gamboge, have been investigated for many years and proved to be a promising natural anticancer agent for clinical treatment. This study aimed to investigate the inhibitory effect of docetaxel (DTX) combined with gambogic acid on bone metastasis of lung cancer. METHODS: The anti-proliferation effect of the combination of DTX and GA on Lewis lung cancer (LLC) cells was determined by MTT assays. The anticancer effect of the combination of DTX and GA on bone metastasis of lung cancer in vivo was explored. Evaluation of the efficacy of drug therapy was performed by comparing the degree of bone destruction and the pathological section of bone tissue of the treated mice with that of the control mice. RESULTS: In vitro cytotoxicity, cell migration, and osteoclast-induced formation assay showed that GA enhanced the therapeutic effect of DTX in Lewis lung cancer cell with a synergistic effect. In an orthotopic mouse model of bone metastasis, the average survival of the DTX+GA combination group (32.61d±1.06 d) was significantly increased compared with that of the DTX group (25.75 d±0.67 d) or GA group (23.99 d±0.58 d), *P<0.01. CONCLUSION: The combination of DTX and GA has synergistic effect and resulted in more effective inhibition of tumor metastasis, providing a strong preclinical rationale for the clinical development of the DTX+GA combination for treating bone metastasis of lung cancer.

Discrepancies in resistant starch and starch physicochemical properties between rice mutants similar in high amylose content.

The content of resistant starch (RS) was considered positively correlated with the apparent amylose content (AAC). Here, we analyzed two Indica rice mutants, RS111 and Zhedagaozhi 1B, similar in high AAC and found that their RS content differed remarkably. RS111 had higher RS3 content but lower RS2 content than Zhedagaozhi 1B; correspondingly, cooked RS111 showed slower digestibility. RS111 had smaller irregular and oval starch granules when compared with Zhedagaozhi 1B and the wild type. Zhedagaozhi 1B showed a B-type starch pattern, different from RS111 and the wild type, which showed A-type starch. Meantime, RS111 had more fa and fb1 but less fb3 than Zhedagaozhi 1B. Both mutants showed decreased viscosity and swelling power when compared with the parents. RS111 had the lowest viscosity, and Zhedagaozhi 1B had the smallest swelling power. The different fine structures of amylopectin between RS111 and Zhedagaozhi 1B led to different starch types, gelatinization properties, paste viscosity, and digestibility. In addition to enhancing amylose content, modifications on amylopectin structure showed great potent in breeding rice with different RS2 and RS3 content, which could meet the increasing needs for various rice germplasms.

Diversity of arterial cell and phenotypic heterogeneity induced by high-fat and high-cholesterol diet.

Lipid metabolism disorder is the basis of atherosclerotic lesions, in which cholesterol and low-density lipoprotein (LDL) is the main factor involved with the atherosclerotic development. A high-fat and high-cholesterol diet can lead to this disorder in the human body, thus accelerating the process of disease. The development of single-cell RNA sequencing in recent years has opened the possibility to unbiasedly map cellular heterogeneity with high throughput and high resolution; alterations mediated by a high-fat and high-cholesterol diet at the single-cell transcriptomic level can be explored with this mean afterward. We assessed the aortic arch of 16-week old Apoe-/- mice of two control groups (12 weeks of chow diet) and two HFD groups (12 weeks of high fat, high cholesterol diet) to process single-cell suspension and use single-cell RNA sequencing to anatomize the transcripts of 5,416 cells from the control group and 2,739 from the HFD group. Through unsupervised clustering, 14 cell types were divided and defined. Among these cells, the cellular heterogeneity exhibited in endothelial cells and immune cells is the most prominent. Subsequent screening delineated ten endothelial cell subsets with various function based on gene expression profiling. The distribution of endothelial cells and immune cells differs significantly between the control group versus the HFD one. The existence of pathways that inhibit atherosclerosis was found in both dysfunctional endothelial cells and foam cells. Our data provide a comprehensive transcriptional landscape of aortic arch cells and unravel the cellular heterogeneity brought by a high-fat and high-cholesterol diet. All these findings open new perspectives at the transcriptomic level to studying the pathology of atherosclerosis.

A novel tool for improving the accuracy of major depressive disorder screening: A prospective study on andrology with external validation.

Patient Health Questionnaire-9 (PHQ-9) is the most widely used tool for screening for major depressive disorder (MDD). Although its reliability and validity have been proven, missed or misjudged cases during MDD screening are often encountered. A nomogram that considers the weights of depressive symptoms was developed using data from premature ejaculation patients to improve screening accuracy. During a 33-month prospective study, a training cohort comprising 605 participants from Xijing Hospital was used to develop and internally validate the nomogram. A validation cohort comprising 461 patients from Xi'an Daxing Hospital was also used to externally test the nomogram. The nomogram was established by integrating the LASSO regression-based optimal predictors of MDD according to their coefficients in a multivariate logistic regression model. The nomogram was well-calibrated during internal and external validations. Moreover, it showed a better discriminatory capacity and yielded more net benefits in both validations than PHQ-9. With better performance, the nomogram may help reduce the number of missed or misjudged cases during MDD screening. This study is the first to weigh the direct indicators of MDD under the DSM-5 criteria, presenting a fresh concept that can be applied to other populations to enhance screening accuracy.

Exercise Improves Metabolism and Alleviates Atherosclerosis via Muscle-Derived Extracellular Vesicles.

Regular exercise maintains a healthy metabolic profile, while the underlying mechanisms have not been fully elucidated. Extracellular vesicles serve as an important mediator in intercellular communication. In this study, we aimed to explore whether exercise-induced extracellular vesicles (EVs) of skeletal muscle origins contribute to exercise-related protective effects on metabolism. We found that the twelve weeks of swimming training improved glucose tolerance, reduced visceral lipid accumulation, alleviated liver damage, and inhibited atherosclerosis progression in both obese WT mice and ApoE-/- mice, which could be partially blocked by EV biogenesis repression. Injection of skeletal muscle-derived EVs from exercised C57BL/6J mice (twice a week for 12 weeks) had similar protective effects on both obese WT mice and ApoE-/- mice as exercise itself. Mechanistically, these exe-EVs could be endocytosed by major metabolic organs, especially the liver and adipose tissue. With the protein cargos rich in mitochondrial and fatty acid oxidation-related components, exe-EVs remodeled metabolism towards beneficial cardiovascular outcomes. Our study here has shown that exercise remodels metabolism towards beneficial cardiovascular outcomes at least partially via the skeletal muscle secreted EVs. Therapeutic delivery of exe-EVs or the analogues could be promising for prevention of certain cardiovascular and metabolic diseases.

Modular Hydrogel Vaccine for Programmable and Coordinate Elicitation of Cancer Immunotherapy.

Immunotherapy holds great promise for the treatment of malignant cancer. However, the lack of sufficient tumor neoantigens and incomplete dendritic cell (DC) maturation compromise the efficacy of immunotherapy. Here, a modular hydrogel-based vaccine capable of eliciting a powerful and sustained immune response is developed. Briefly, CCL21a and ExoGM-CSF+Ce6 (tumor cell-derived exosomes with granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA encapsulated inside and sonosensitizer chlorin e6 (Ce6) incorporated in the surface) are mixed with nanoclay and gelatin methacryloyl, forming the hydrogel designated as CCL21a/ExoGM-CSF+Ce6 @nanoGel. The engineered hydrogel releases CCL21a and GM-CSF with a time gap. The earlier released CCL21a diverts the tumor-draining lymph node (TdLN) metastatic tumor cells to the hydrogel. Consequently, the trapped tumor cells in the hydrogel, in turn, engulf the Ce6-containing exosomes and thus are eradicated by sonodynamic therapy (SDT), serving as the antigen source. Later, together with the remnant CCL21a, GM-CSF produced by cells engulfing ExoGM-CSF+Ce6 continuously recruits and provokes DCs. With the two programmed modules, the engineered modular hydrogel vaccine efficiently inhibits tumor growth and metastasis via diverting TdLN metastatic cancer to hydrogel, killing the trapped tumor cells, and eliciting prolonged and powerful immunotherapy in an orchestrated manner. The strategy would open an avenue for cancer immunotherapy.

An Endogenous Aryl Hydrocarbon Receptor Ligand Induces Preeclampsia-like Phenotypes: Transcriptome, Phosphoproteome, and Cell Functions.

Background: Preeclampsia (PE) is one hypertensive disorder and a leading cause of maternal and fetal mortality and morbidity during human pregnancy. Aryl hydrocarbon receptor (AhR) is a transcription factor, which regulates vascular functions. Exogenous and endogenous AhR ligands can induce hypertension in animals. However, if dysregulation of endogenous AhR ligands contributes to the pathophysiology of PE remains elusive. Methods: We measured AhR activities in human maternal and umbilical vein sera. We also applied physiological, cellular, and molecular approaches to dissect the role of endogenous AhR ligands in vascular functions during pregnancy using pregnant rats and primary human umbilical vein endothelial cells (HUVECs) as models. Results: PE elevated AhR activities in human umbilical vein sera. Exposure of pregnant rats to an endogenous AhR ligand, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) increased blood pressure and proteinuria, while decreased uteroplacental blood flow and reduced fetal and placental weights, all of which are hallmarks of PE. ITE dampened vascular growth and fetal sex-specifically altered immune cell infiltration in rat placentas. ITE also decreased cell proliferation and cell monolayer integrity in HUVECs in vitro . RNA sequencing analysis revealed that ITE dysregulated transcriptome in rat placentas and HUVECs in a fetal sex-specific manner. Bottom-up phosphoproteomics showed that ITE disrupted phosphoproteome in HUVECs. These ITE-dysregulated genes and phosphoproteins were enriched in biological functions and pathways which are highly relevant to diseases of heart, liver, and kidney, vascular functions, inflammation responses, cell death, and kinase inhibition. Conclusions: Dysregulation of endogenous AhR ligands during pregnancy may lead to the development of PE with underlying impaired vascular functions, fetal sex-specific immune cell infiltration and transcriptome, and phosphoproteome. Thus, this study has provided a novel mechanism for the development of PE and potentially other forms of hypertensive pregnancies. These AhR ligand-activated genes and phosphoproteins might represent promising therapeutic and fetal sex-specific targets for PE-impaired vascular functions.